Rebif
1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 22 micrograms solution for injection in pre-filled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe (0.5 mL) contains 22 micrograms (6 MIU*) of interferon beta-1a**. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 2.5 mg benzyl alcohol per dose of 0.5 mL. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled syringe. 
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/L. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of relapsing multiple sclerosis. In clinical trials, this was 
characterised by two or more acute exacerbations in the previous two years (see section 5.1). 
 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the 
disease. 
 
Rebif is available in three strengths: 8.8 micrograms, 22 micrograms and 44 micrograms. For patients 
initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available in a pack 
that corresponds to the patient needs for the first month of therapy. 
 
Posology 
 
The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneous 
injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection, 
is recommended for patients who cannot tolerate the higher dose in view of the treating specialist. 
 
When first starting treatment with Rebif, the dose should be gradually escalated in order to allow 
tachyphylaxis to develop thus reducing adverse reactions. The Rebif initiation package corresponds to 
the patient needs for the first month of treatment. 
 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records 
in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in 



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children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 
44 micrograms subcutaneous three times per week is similar to that seen in adults. 
 
The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
Rebif is administered by subcutaneous injection. Prior to injection and for an additional 24 hours after 
each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with Rebif 
administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with 
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should 
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and 
a decision for longer term treatment should then be made on an individual basis by the treating 
physician. 
 
4.3 Contraindications 
 
• Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 

section 6.1. 
• Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
General recommendations 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 
Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include 
thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, 
paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased 
platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes 
(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, 
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If 
TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate 
discontinuation of Rebif is recommended. 
 
Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal 
ideation are known to occur in increased frequency in the multiple sclerosis population and in 



4 

association with interferon use. Patients treated with Rebif should be advised to immediately report 
any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting 
depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation 
of therapy with Rebif should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with 
antiepileptics (see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise 
the risk of injection site necrosis patients should be advised to: 
• use an aseptic injection technique, 
• rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred.  
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of 
fluid from the injection site, the patient should be advised to consult with their physician before 
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until 
healing has occurred. Patients with single lesions may continue provided that the necrosis is not too 
extensive. 
 
Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, 
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy 
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times 
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated 
with caution in patients with a history of significant liver disease, clinical evidence of active liver 
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be 
stopped if icterus or other clinical symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six 
months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No 
specific risk factors have been identified. 
 
Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal 
segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative 



5 

glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during 
treatment with interferon-beta products. Events were reported at various time points during treatment 
and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs 
or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in 
patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and 
discontinuation of treatment with Rebif should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those 
laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme 
monitoring and complete and differential blood cell counts and platelet counts are recommended at 
regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically 
thereafter in the absence of clinical symptoms.  
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following 
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be 
performed if clinical findings of thyroid dysfunction appear (see section 4.8). 
 
Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 
Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with 
Rebif 22 micrograms, approximately 24% of patients develop persistent serum antibodies to 
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 
response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance 
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies 
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to 
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the 
benefit/risk ratio of continued Rebif therapy. 
 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity 
limits the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple 
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis 
and should not be used in these patients. 
 
Excipients 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
‘sodium-free’. 
 



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Benzyl alcohol 
 
This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. 
 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, 
which might accumulate over time and cause metabolic acidosis. Use with caution in patients with 
hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might 
accumulate over time and cause metabolic acidosis. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes 
in humans and animals. Caution should be exercised when administering Rebif in combination with 
medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic 
cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been 
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing 
experience indicates no increased risk of major congenital anomalies after pre-conception exposure to 
interferon beta or such exposure during the first trimester of pregnancy. However, the duration of 
exposure during the first trimester is uncertain, because data were collected when interferon beta use 
was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was 
detected and/or confirmed. Experience with exposure during the second and third trimester is very 
limited. 
 
Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The 
risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be 
evaluated based on the currently available data, but the data do not suggest an increased risk so far. 
 
If clinically needed, the use of Rebif may be considered during pregnancy 
 
Breast-feeding 
 
Limited information available on the transfer of interferon beta-1a into breast milk, together with the 
chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a 
excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are 
anticipated.  
Rebif can be used during breast-feeding. 
 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 



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4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like 
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in 
frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to 
experience the typical interferon flu-like syndrome within the first six months after starting treatment. 
Approximately 30% of patients will also experience reactions at the injection site, predominantly mild 
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and 
decreases in white blood cells are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, 
and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of 
Rebif may be temporarily lowered or interrupted, at the discretion of the physician. 
 
List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post-
marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing 
surveillance). The following definitions apply to the frequency terminology used hereafter: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia  
Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic 

purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 

 
Endocrine disorders 
Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or 

hyperthyroidism  
 
Immune system disorders 
Rare:  Anaphylactic reactions*  
 
Hepatobiliary disorders 
Very common: Asymptomatic transaminase increase 
Common: Severe elevations in transaminases 
Uncommon: Hepatitis with or without icterus* 
Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis*  
 
Psychiatric disorders 
Common: Depression, insomnia  
Rare: Suicide attempt* 
 



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Nervous system disorders 
Very common: Headache 
Uncommon: Seizures*  
Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 

paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations*  

 
Eye disorders 
Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 

retinal artery or vein)* 
 
Vascular disorders 
Uncommon: Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: Dyspnoea* 
Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, see 

below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: Diarrhoea, vomiting, nausea 
 
Skin and subcutaneous tissue disorders 
Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: Urticaria* 
Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 

multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: Myalgia, arthralgia 
Rare: Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 
General disorders and administration site conditions 
Very common: Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: Injection site pain, fatigue, rigors, fever 
Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection 

site infections*, increased sweating* 
Rare: Injection site cellulitis* 
Frequency not known: Panniculitis (occurred in the injection site) 
 
Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) 
receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.  
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia.  
An increased formation of auto-antibodies may occur during treatment with interferon beta. 
 



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Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase 
and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to 
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable 
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological 
responses remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are 
induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer 
subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours 
for neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 
 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
 
Relapsing-remitting multiple sclerosis 
 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple 
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously 
three times per week. At licensed posology, Rebif 22 micrograms has been demonstrated to decrease 
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at 
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of 
patients with disability progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms). Over 4 years, the 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


10 

reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated 
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 
Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence 
of clinical progression in the preceding two years and who had not experienced relapses in the 
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was 
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and 
those without relapses in the 2-year period prior to study entry), there was no effect on disability in 
patients without relapses, but in patients with relapses, the proportion with progression in disability at 
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should 
not be used in these patients.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta.  
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple 
dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. An 
increased risk of abortions has been reported in animal studies of other alpha and beta interferons. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 



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6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Poloxamer 188 
L-methionine 
Benzyl alcohol 
Sodium acetate 
Acetic acid for pH adjustment  
Sodium hydroxide for pH adjustment 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original 
package in order to protect from light. 
 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not 
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
6.5 Nature and contents of container 
 
One mL type 1 glass syringe, with a stainless steel needle, containing 0.5 mL solution.  
 
Rebif 22 micrograms is available as a package of 1, 3, 12, or 36 syringes. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled syringe is ready for use. It may also be administered with a 
suitable auto-injector. 
 
For single use only. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 



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8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/001 
EU/1/98/063/002 
EU/1/98/063/003 
EU/1/98/063/020 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


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1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 44 micrograms solution for injection in pre-filled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe (0.5 mL) contains 44 micrograms (12 MIU*) of interferon beta-1a**. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 2.5 mg benzyl alcohol per dose of 0.5 mL. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled syringe. 
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/L. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of  
• patients with a single demyelinating event with an active inflammatory process, if alternative 

diagnoses have been excluded, and if they are determined to be at high risk of developing 
clinically definite multiple sclerosis (see section 5.1) 

• patients with relapsing multiple sclerosis. In clinical trials, this was characterised by two or 
more acute exacerbations in the previous two years (see section 5.1). 

 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the 
disease. 
 
Rebif is available in three strengths: 8.8 micrograms, 22 micrograms and 44 micrograms. For patients 
initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available in a pack 
that corresponds to the patient needs for the first month of therapy. 
 
Posology 
 
When first starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducing 
adverse reactions it is recommended that patients be started at 8.8 micrograms dose subcutaneously 
and the dose be increased over a 4 week period to the targeted dose, according to the following 
schedule: 
 



14 

 Recommended 
Titration 

(% of final dose) 

Titration dose for Rebif 
44 micrograms 

three times per week (tiw) 
Weeks 1-2 20% 8.8 micrograms tiw 
Weeks 3–4 50% 22 micrograms tiw 
Weeks 5+ 100% 44 micrograms tiw 

 
First demyelinating event 
The posology for patients who have experienced a first demyelinating event is 44 micrograms of Rebif 
given three times per week by subcutaneous injection.  
 
Relapsing multiple sclerosis 
The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneous 
injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection, 
is recommended for patients who cannot tolerate the higher dose in view of the treating specialist. 
 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records 
in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in 
children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 
44 micrograms subcutaneous three times per week is similar to that seen in adults. 
 
The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
Rebif is administered by subcutaneous injection. Prior to injection and for an additional 24 hours after 
each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with Rebif 
administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with 
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should 
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and 
a decision for longer term treatment should then be made on an individual basis by the treating 
physician. 
 
4.3 Contraindications 
 
• Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 

section 6.1. 
• Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
General recommendations 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 



15 

to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 
Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include 
thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, 
paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased 
platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes 
(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, 
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If 
TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate 
discontinuation of Rebif is recommended. 
 
Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal 
ideation are known to occur in increased frequency in the multiple sclerosis population and in 
association with interferon use. Patients treated with Rebif should be advised to immediately report 
any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting 
depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation 
of therapy with Rebif should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with 
antiepileptics (see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise 
the risk of injection site necrosis patients should be advised to: 
• use an aseptic injection technique, 
• rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred.  
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of 
fluid from the injection site, the patient should be advised to consult with their physician before 
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until 
healing has occurred. Patients with single lesions may continue provided that the necrosis is not too 
extensive. 
 



16 

Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, 
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy 
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times 
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated 
with caution in patients with a history of significant liver disease, clinical evidence of active liver 
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be 
stopped if icterus or other clinical symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six 
months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No 
specific risk factors have been identified. 
 
Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal 
segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative 
glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during 
treatment with interferon-beta products. Events were reported at various time points during treatment 
and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs 
or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in 
patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and 
discontinuation of treatment with Rebif should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. The overall incidence of these is 
slightly higher with Rebif 44 than Rebif 22 micrograms. Therefore, in addition to those laboratory 
tests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring and 
complete and differential blood cell counts and platelet counts are recommended at regular intervals 
(1, 3 and 6 months) following introduction of Rebif therapy and then periodically thereafter in the 
absence of clinical symptoms. These should be more frequent when initiating Rebif 44 micrograms. 
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following 
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be 
performed if clinical findings of thyroid dysfunction appear (see section 4.8). 
 
Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 
Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with 
Rebif 44 micrograms, approximately 13 to 14% of patients develop persistent serum antibodies to 
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 



17 

response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance 
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies 
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to 
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the 
benefit/risk ratio of continued Rebif therapy. 
 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity 
limits the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple 
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis 
and should not be used in these patients. 
 
Excipients 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
‘sodium-free’. 
 
Benzyl alcohol 
 
This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. 
 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, 
which might accumulate over time and cause metabolic acidosis. Use with caution in patients with 
hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might 
accumulate over time and cause metabolic acidosis. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes 
in humans and animals. Caution should be exercised when administering Rebif in combination with 
medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic 
cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been 
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing 
experience indicates no increased risk of major congenital anomalies after pre-conception exposure to 
interferon beta or such exposure during the first trimester of pregnancy. However, the duration of 
exposure during the first trimester is uncertain, because data were collected when interferon beta use 
was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was 
detected and/or confirmed. Experience with exposure during the second and third trimester is very 
limited. 



18 

 
Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The 
risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be 
evaluated based on the currently available data, but the data do not suggest an increased risk so far. 
 
If clinically needed, the use of Rebif may be considered during pregnancy 
 
Breast-feeding 
 
Limited information available on the transfer of interferon beta-1a into breast milk, together with the 
chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a 
excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are 
anticipated.  
Rebif can be used during breast-feeding. 
 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like 
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in 
frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to 
experience the typical interferon flu-like syndrome within the first six months after starting treatment. 
Approximately 30% of patients will also experience reactions at the injection site, predominantly mild 
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and 
decreases in white blood cells are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, 
and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of 
Rebif may be temporarily lowered or interrupted, at the discretion of the physician. 
 
List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post-
marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing 
surveillance). The following definitions apply to the frequency terminology used hereafter: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia  
Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic 

purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 

 
Endocrine disorders 
Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or 

hyperthyroidism  



19 

 
Immune system disorders 
Rare:  Anaphylactic reactions*  
 
Hepatobiliary disorders 
Very common: Asymptomatic transaminase increase 
Common: Severe elevations in transaminases 
Uncommon: Hepatitis with or without icterus* 
Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis*  
 
Psychiatric disorders 
Common: Depression, insomnia  
Rare: Suicide attempt* 
 
Nervous system disorders 
Very common: Headache 
Uncommon: Seizures*  
Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 

paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations*  

 
Eye disorders 
Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 

retinal artery or vein)* 
 
Vascular disorders 
Uncommon: Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: Dyspnoea* 
Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, see 

below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: Diarrhoea, vomiting, nausea 
 
Skin and subcutaneous tissue disorders 
Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: Urticaria* 
Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 

multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: Myalgia, arthralgia 
Rare: Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 
General disorders and administration site conditions 
Very common: Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: Injection site pain, fatigue, rigors, fever 
Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection 

site infections*, increased sweating* 
Rare: Injection site cellulitis* 
Frequency not known: Panniculitis (occurred in the injection site) 
 



20 

Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) 
receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.  
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia.  
An increased formation of auto-antibodies may occur during treatment with interferon beta. 
 
Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase 
and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to 
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable 
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological 
responses remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are 
induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer 
subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours 
for neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


21 

 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
 
Single clinical event suggestive of multiple sclerosis 
 
One 2-year controlled clinical trial with Rebif was performed in patients with a single clinical event 
suggestive of demyelination due to multiple sclerosis. The patients enrolled into the trial had at least 
two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of 
which is ovoid or periventricular or infratentorial. Any disease other than multiple sclerosis that could 
better explain signs and symptoms of the patient had to be excluded.  
 
Patients were randomised in a double-blind manner to either Rebif 44 micrograms given three times 
per week, Rebif 44 micrograms once weekly, or placebo. If a second clinical demyelinating event 
occurred confirming definite multiple sclerosis, patients switched to the recommended posology of 
Rebif 44 micrograms three times per week in an open label manner, while maintaining blinding as to 
initial randomisation. 
 
Efficacy results of Rebif 44 micrograms given three times per week compared to placebo from this 
study are as follows: 
 

Parameter 
Statistics 

Treatment Treatment Comparison 
Rebif 44 mcg tiw versus Placebo 

Placebo  
(n=171) 

Rebif 44 
mcg tiw 
(n=171) 

Risk 
Reduction 

Cox’s 
Proportional 
Hazard Ratio 

[95% CI] 

Log-Rank 
p-value 

McDonald (2005) Conversion 
Number of events 144 106  

51% 
 

0.49 [0.38;0.64] 
 

<0.001 KM Estimate 85.8% 62.5% 
CDMS Conversion 
Number of events 60 33  

52% 
 

0.48 [0.31;0.73] 
 

<0.001 KM Estimate 37.5% 20.6% 
Mean CUA Lesions per Subject per Scan During the Double Blind Period 
Least Square Means 
(SE) 

 
2.59 (0.30) 

 
0.50 (0.06) 

 
81% 

 
0.19 [0.14;0.26]* 

 
<0.001 

tiw: three times per week, CI: confidence interval, CUA: combined unique active 
* Least Squared Mean Ratio [95% CI] 
 
For the time being there is no well established definition of a high risk patient, although a more 
conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least 
one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the 
initial scan. In any case, treatment should only be considered for patients classified as high risk. 
 
Relapsing-remitting multiple sclerosis 
 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple 
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously 
three times per week. At licensed posology, Rebif 44 micrograms has been demonstrated to decrease 
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at 
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of 
patients with disability progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 27% (Rebif 44 micrograms). Over 4 years, the 
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated 
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 



22 

Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence 
of clinical progression in the preceding two years and who had not experienced relapses in the 
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was 
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and 
those without relapses in the 2-year period prior to study entry), there was no effect on disability in 
patients without relapses, but in patients with relapses, the proportion with progression in disability at 
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should 
not be used in these patients.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta.  
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple 
dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. An 
increased risk of abortions has been reported in animal studies of other alpha and beta interferons. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 



23 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Poloxamer 188 
L-methionine 
Benzyl alcohol 
Sodium acetate 
Acetic acid for pH adjustment  
Sodium hydroxide for pH adjustment 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original 
package in order to protect from light. 
 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not 
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
6.5 Nature and contents of container 
 
One mL type 1 glass syringe, with a stainless steel needle, containing 0.5 mL solution.  
 
Rebif 44 micrograms is available as a package of 1, 3, 12, or 36 syringes. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled syringe is ready for use. It may also be administered with a 
suitable auto-injector. 
 
For single use only. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 



24 

8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/004 
EU/1/98/063/005 
EU/1/98/063/006 
EU/1/98/063/021 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


25 

1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 8.8 micrograms solution for injection in pre-filled syringe 
Rebif 22 micrograms solution for injection in pre-filled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe (0.2 mL) contains 8.8 micrograms (2.4 MIU*) of interferon beta-1a**. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 1.0 mg benzyl alcohol per dose of 0.2 mL. 
For the full list of excipients, see section 6.1. 
 
Each pre-filled syringe (0.5 mL) contains 22 micrograms (6 MIU*) of interferon beta-1a**. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 2.5 mg benzyl alcohol per dose of 0.5 mL.  
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled syringe. 
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/L. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of  
• patients with a single demyelinating event with an active inflammatory process, if alternative 

diagnoses have been excluded, and if they are determined to be at high risk of developing 
clinically definite multiple sclerosis (see section 5.1) 

• patients with relapsing multiple sclerosis. In clinical trials, this was characterised by two or 
more acute exacerbations in the previous two years (see section 5.1). 

 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the 
disease. 
 



26 

Posology 
 
The Rebif initiation package corresponds to the patient needs for the first month of treatment. When 
first starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducing adverse 
reactions, it is recommended that patients be started at 8.8 micrograms dose subcutaneously and the 
dose be increased over a 4 week period to the targeted dose, according to the following schedule: 
 

 Recommended 
Titration 

(% of final dose) 

Titration dose for Rebif 
44 micrograms 

three times per week (tiw) 
Weeks 1-2 20% 8.8 micrograms tiw 
Weeks 3–4 50% 22 micrograms tiw 
Weeks 5+ 100% 44 micrograms tiw 

 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records 
in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in 
children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 
44 micrograms subcutaneous three times per week is similar to that seen in adults. 
 
The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
Rebif is administered by subcutaneous injection. Prior to injection and for an additional 24 hours after 
each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with Rebif 
administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with 
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should 
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and 
a decision for longer term treatment should then be made on an individual basis by the treating 
physician. 
 
4.3 Contraindications 
 
• Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 

section 6.1. 
• Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
General recommendations 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 



27 

Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include 
thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, 
paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased 
platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes 
(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, 
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If 
TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate 
discontinuation of Rebif is recommended. 
 
Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal 
ideation are known to occur in increased frequency in the multiple sclerosis population and in 
association with interferon use. Patients treated with Rebif should be advised to immediately report 
any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting 
depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation 
of therapy with Rebif should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with 
antiepileptics (see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise 
the risk of injection site necrosis patients should be advised to: 
• use an aseptic injection technique, 
• rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred.  
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of 
fluid from the injection site, the patient should be advised to consult with their physician before 
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until 
healing has occurred. Patients with single lesions may continue provided that the necrosis is not too 
extensive. 
 
Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 



28 

transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, 
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy 
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times 
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated 
with caution in patients with a history of significant liver disease, clinical evidence of active liver 
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be 
stopped if icterus or other clinical symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six 
months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No 
specific risk factors have been identified. 
 
Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal 
segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative 
glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during 
treatment with interferon-beta products. Events were reported at various time points during treatment 
and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs 
or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in 
patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and 
discontinuation of treatment with Rebif should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those 
laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme 
monitoring and complete and differential blood cell counts and platelet counts are recommended at 
regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically 
thereafter in the absence of clinical symptoms.  
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following 
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be 
performed if clinical findings of thyroid dysfunction appear (see section 4.8). 
 
Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 
Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with 
Rebif 22 micrograms, approximately 24% of patients develop persistent serum antibodies to 
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 
response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance 
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies 
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to 
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the 
benefit/risk ratio of continued Rebif therapy. 



29 

 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity 
limits the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple 
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis 
and should not be used in these patients. 
 
Excipients 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
‘sodium-free’. 
 
Benzyl alcohol 
 
This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. 
 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, 
which might accumulate over time and cause metabolic acidosis. Use with caution in patients with 
hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might 
accumulate over time and cause metabolic acidosis. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes 
in humans and animals. Caution should be exercised when administering Rebif in combination with 
medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic 
cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been 
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing 
experience indicates no increased risk of major congenital anomalies after pre-conception exposure to 
interferon beta or such exposure during the first trimester of pregnancy. However, the duration of 
exposure during the first trimester is uncertain, because data were collected when interferon beta use 
was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was 
detected and/or confirmed. Experience with exposure during the second and third trimester is very 
limited. 
 
Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The 
risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be 
evaluated based on the currently available data, but the data do not suggest an increased risk so far. 
 



30 

If clinically needed, the use of Rebif may be considered during pregnancy 
 
Breast-feeding 
 
Limited information available on the transfer of interferon beta-1a into breast milk, together with the 
chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a 
excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are 
anticipated.  
Rebif can be used during breast-feeding. 
 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like 
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in 
frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to 
experience the typical interferon flu-like syndrome within the first six months after starting treatment. 
Approximately 30% of patients will also experience reactions at the injection site, predominantly mild 
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and 
decreases in white blood cells are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, 
and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of 
Rebif may be temporarily lowered or interrupted, at the discretion of the physician. 
 
List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post-
marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing 
surveillance). The following definitions apply to the frequency terminology used hereafter: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia  
Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic 

purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 

 
Endocrine disorders 
Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or 

hyperthyroidism  
 
Immune system disorders 
Rare:  Anaphylactic reactions*  
 



31 

Hepatobiliary disorders 
Very common: Asymptomatic transaminase increase 
Common: Severe elevations in transaminases 
Uncommon: Hepatitis with or without icterus* 
Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis*  
 
Psychiatric disorders 
Common: Depression, insomnia  
Rare: Suicide attempt* 
 
Nervous system disorders 
Very common: Headache 
Uncommon: Seizures*  
Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 

paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations*  

 
Eye disorders 
Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 

retinal artery or vein)* 
 
Vascular disorders 
Uncommon: Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: Dyspnoea* 
Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, see 

below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: Diarrhoea, vomiting, nausea 
 
Skin and subcutaneous tissue disorders 
Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: Urticaria* 
Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 

multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: Myalgia, arthralgia 
Rare: Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 
General disorders and administration site conditions 
Very common: Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: Injection site pain, fatigue, rigors, fever 
Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection 

site infections*, increased sweating* 
Rare: Injection site cellulitis* 
Frequency not known: Panniculitis (occurred in the injection site) 
 



32 

Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) 
receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.  
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia.  
An increased formation of auto-antibodies may occur during treatment with interferon beta. 
 
Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase 
and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to 
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable 
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological 
responses remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are 
induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer 
subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours 
for neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


33 

 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
 
Single clinical event suggestive of multiple sclerosis 
 
One 2-year controlled clinical trial with Rebif was performed in patients with a single clinical event 
suggestive of demyelination due to multiple sclerosis. The patients enrolled into the trial had at least 
two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of 
which is ovoid or periventricular or infratentorial. Any disease other than multiple sclerosis that could 
better explain signs and symptoms of the patient had to be excluded.  
 
Patients were randomised in a double-blind manner to either Rebif 44 micrograms given three times 
per week, Rebif 44 micrograms once weekly, or placebo. If a second clinical demyelinating event 
occurred confirming definite multiple sclerosis, patients switched to the recommended posology of 
Rebif 44 micrograms three times per week in an open label manner, while maintaining blinding as to 
initial randomisation. 
 
Efficacy results of Rebif 44 micrograms given three times per week compared to placebo from this 
study are as follows: 
 

Parameter 
Statistics 

Treatment Treatment Comparison 
Rebif 44 mcg tiw versus Placebo 

Placebo  
(n=171) 

Rebif 44 
mcg tiw 
(n=171) 

Risk 
Reduction 

Cox’s 
Proportional 
Hazard Ratio 

[95% CI] 

Log-Rank 
p-value 

McDonald (2005) Conversion 
Number of events 144 106  

51% 
 

0.49 [0.38;0.64] 
 

<0.001 KM Estimate 85.8% 62.5% 
CDMS Conversion 
Number of events 60 33  

52% 
 

0.48 [0.31;0.73] 
 

<0.001 KM Estimate 37.5% 20.6% 
Mean CUA Lesions per Subject per Scan During the Double Blind Period 
Least Square Means 
(SE) 

 
2.59 (0.30) 

 
0.50 (0.06) 

 
81% 

 
0.19 [0.14;0.26]* 

 
<0.001 

tiw: three times per week, CI: confidence interval, CUA: combined unique active 
* Least Squared Mean Ratio [95% CI] 
 
For the time being there is no well established definition of a high risk patient, although a more 
conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least 
one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the 
initial scan. In any case, treatment should only be considered for patients classified as high risk. 
 
Relapsing-remitting multiple sclerosis 
 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple 
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously 
three times per week. At licensed posology, Rebif 22 micrograms has been demonstrated to decrease 
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at 
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of 
patients with disability progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms). Over 4 years, the 
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated 
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 



34 

Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence 
of clinical progression in the preceding two years and who had not experienced relapses in the 
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was 
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and 
those without relapses in the 2-year period prior to study entry), there was no effect on disability in 
patients without relapses, but in patients with relapses, the proportion with progression in disability at 
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should 
not be used in these patients.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta.  
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple 
dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. An 
increased risk of abortions has been reported in animal studies of other alpha and beta interferons. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 



35 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Poloxamer 188 
L-methionine 
Benzyl alcohol 
Sodium acetate 
Acetic acid for pH adjustment  
Sodium hydroxide for pH adjustment 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original 
package in order to protect from light. 
 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not 
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
6.5 Nature and contents of container 
 
For patients starting treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available in 
an initiation pack. The pack contains 6 individual doses of 0.2 mL of Rebif 8.8 micrograms solution for 
injection in a 1 mL type 1 glass syringe with a stainless steel needle and 6 individual doses of 0.5 mL of 
Rebif 22 micrograms solution for injection in a 1 mL type 1 glass syringe with a stainless steel needle.  
 
This pack corresponds to the individual patient needs for the first month of therapy. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled syringe is ready for use. It may also be administered with a 
suitable auto-injector. 
 
For single use only. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 



36 

 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/007 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


37 

1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 22 micrograms/0.5 mL solution for injection in cartridge 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled cartridge contains 66 micrograms (18 MIU*) of interferon beta-1a** in 1.5 mL 
solution, corresponding to 44 micrograms/mL. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 2.5 mg benzyl alcohol per dose of 0.5 mL. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in cartridge. 
Clear to opalescent solution, with pH 3.7 to 4.1 and osmolarity 250 to 450 mOsm/L. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of relapsing multiple sclerosis. In clinical trials, this was 
characterised by two or more acute exacerbations in the previous two years (see section 5.1). 
 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the 
disease. 
 
Posology 
 
The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneous 
injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection, 
is recommended for patients who cannot tolerate the higher dose in view of the treating specialist. 
 
When first starting treatment with Rebif, the dose should be gradually escalated in order to allow 
tachyphylaxis to develop thus reducing adverse reactions. The Rebif initiation package corresponds to 
the patient needs for the first month of treatment. 
 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records 
in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in 
children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 
44 micrograms subcutaneous three times per week is similar to that seen in adults. 
 



38 

The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
Rebif solution for subcutaneous injection in a cartridge is intended for multidose use with the 
RebiSmart electronic injection device following adequate training of the patient and/or carer. 
 
For administration, the instructions provided in the package leaflet and in the instruction manual 
(Instructions for Use) provided with RebiSmart should be followed. 
 
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised 
to decrease flu-like symptoms associated with Rebif administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with 
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should 
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and 
a decision for longer term treatment should then be made on an individual basis by the treating 
physician. 
 
4.3 Contraindications 
 
• Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 

section 6.1. 
• Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
General recommendations 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 
Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include 
thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, 
paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased 
platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes 
(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, 
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If 
TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate 
discontinuation of Rebif is recommended. 
 



39 

Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal 
ideation are known to occur in increased frequency in the multiple sclerosis population and in 
association with interferon use. Patients treated with Rebif should be advised to immediately report 
any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting 
depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation 
of therapy with Rebif should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with 
antiepileptics (see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise 
the risk of injection site necrosis patients should be advised to: 
• use an aseptic injection technique, 
• rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred.  
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of 
fluid from the injection site, the patient should be advised to consult with their physician before 
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until 
healing has occurred. Patients with single lesions may continue provided that the necrosis is not too 
extensive. 
 
Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, 
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy 
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times 
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated 
with caution in patients with a history of significant liver disease, clinical evidence of active liver 
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be 
stopped if icterus or other clinical symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six 
months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No 
specific risk factors have been identified. 
 



40 

Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal 
segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative 
glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during 
treatment with interferon-beta products. Events were reported at various time points during treatment 
and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs 
or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in 
patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and 
discontinuation of treatment with Rebif should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those 
laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme 
monitoring and complete and differential blood cell counts and platelet counts are recommended at 
regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically 
thereafter in the absence of clinical symptoms.  
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following 
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be 
performed if clinical findings of thyroid dysfunction appear (see section 4.8). 
 
Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 
Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with 
Rebif 22 micrograms, approximately 24% of patients develop persistent serum antibodies to 
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 
response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance 
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies 
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to 
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the 
benefit/risk ratio of continued Rebif therapy. 
 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity 
limits the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple 
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis 
and should not be used in these patients. 
 



41 

Excipients 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
‘sodium-free’. 
 
Benzyl alcohol 
 
This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. 
 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, 
which might accumulate over time and cause metabolic acidosis. Use with caution in patients with 
hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might 
accumulate over time and cause metabolic acidosis. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes 
in humans and animals. Caution should be exercised when administering Rebif in combination with 
medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic 
cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been 
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing 
experience indicates no increased risk of major congenital anomalies after pre-conception exposure to 
interferon beta or such exposure during the first trimester of pregnancy. However, the duration of 
exposure during the first trimester is uncertain, because data were collected when interferon beta use 
was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was 
detected and/or confirmed. Experience with exposure during the second and third trimester is very 
limited. 
 
Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The 
risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be 
evaluated based on the currently available data, but the data do not suggest an increased risk so far. 
 
If clinically needed, the use of Rebif may be considered during pregnancy 
 
Breast-feeding 
 
Limited information available on the transfer of interferon beta-1a into breast milk, together with the 
chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a 
excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are 
anticipated.  
 
Rebif can be used during breast-feeding. 



42 

 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like 
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in 
frequency with continued treatment. Approximately 70 % of patients treated with Rebif can expect to 
experience the typical interferon flu-like syndrome within the first six months after starting treatment. 
Approximately 30 % of patients will also experience reactions at the injection site, predominantly mild 
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and 
decreases in white blood cells are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, 
and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of 
Rebif may be temporarily lowered or interrupted, at the discretion of the physician. 
 
List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post-
marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing 
surveillance). The following definitions apply to the frequency terminology used hereafter: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia  
Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic 

purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 

 
Endocrine disorders 
Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or 

hyperthyroidism  
 
Immune system disorders 
Rare:  Anaphylactic reactions*  
 
Hepatobiliary disorders 
Very common: Asymptomatic transaminase increase 
Common: Severe elevations in transaminases 
Uncommon: Hepatitis with or without icterus* 
Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis* 
 
Psychiatric disorders 
Common: Depression, insomnia  
Rare: Suicide attempt* 
 



43 

Nervous system disorders 
Very common: Headache 
Uncommon: Seizures* 
Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 

paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations*  

 
Eye disorders 
Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 

retinal artery or vein)* 
 
Vascular disorders 
Uncommon: Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: Dyspnoea* 
Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, see 

below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: Diarrhoea, vomiting, nausea 
 
Skin and subcutaneous tissue disorders 
Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: Urticaria* 
Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 

multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: Myalgia, arthralgia 
Rare: Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 
General disorders and administration site conditions 
Very common: Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: Injection site pain, fatigue, rigors, fever 
Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection 

site infections*, increased sweating* 
Rare: Injection site cellulitis* 
Frequency not known: Panniculitis (occurred in the injection site) 
 
Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) 
receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.  
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia.  
An increased formation of auto-antibodies may occur during treatment with interferon beta. 
 



44 

Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase 
and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to 
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable 
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological 
responses remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are 
induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer 
subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours 
for neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 
 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
 
Relapsing-remitting multiple sclerosis 
 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple 
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously 
three times per week. At licensed posology, Rebif 22 micrograms has been demonstrated to decrease 
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at 
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of 
patients with disability progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms). Over 4 years, the 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


45 

reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated 
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 
Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence 
of clinical progression in the preceding two years and who had not experienced relapses in the 
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was 
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and 
those without relapses in the 2-year period prior to study entry), there was no effect on disability in 
patients without relapses, but in patients with relapses, the proportion with progression in disability at 
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should 
not be used in these patients.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta.  
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple 
dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. An 
increased risk of abortions has been reported in animal studies of other alpha and beta interferons. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 



46 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Poloxamer 188 
L-methionine 
Benzyl alcohol 
Sodium acetate 
Acetic acid for pH adjustment 
Sodium hydroxide for pH adjustment 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
After first injection use within 28 days. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store the cartridge in 
the original package in order to protect from light.  
 
The device (RebiSmart) containing a pre-filled cartridge of Rebif must be stored in the device storage 
box in a refrigerator (2°C – 8°C). 
 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not 
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
6.5 Nature and contents of container 
 
Cartridges (type 1 glass) with a plunger stopper (rubber) and crimp cap (aluminium and halobutyl rubber) 
containing 1.5 mL solution for injection.  
 
Pack size of 4 or 12 cartridges. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled cartridge is ready for use with the RebiSmart electronic 
injection device. For storage of the device with the cartridge, see section 6.4. 
 
For multidose use. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 



47 

7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/008 
EU/1/98/063/018 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


48 

1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 44 micrograms/0.5 mL solution for injection in cartridge 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled cartridge contains 132 micrograms (36 MIU*) of interferon beta-1a** in 1.5 mL 
solution, corresponding to 88 micrograms/mL. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 2.5 mg benzyl alcohol per dose of 0.5 mL. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in cartridge. 
Clear to opalescent solution, with pH 3.7 to 4.1 and osmolarity 250 to 450 mOsm/L. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of  
• patients with a single demyelinating event with an active inflammatory process, if alternative 

diagnoses have been excluded, and if they are determined to be at high risk of developing 
clinically definite multiple sclerosis (see section 5.1) 

• patients with relapsing multiple sclerosis. In clinical trials, this was characterised by two or 
more acute exacerbations in the previous two years (see section 5.1). 

 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the 
disease. 
 
For patients initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are 
available in a pack that corresponds to the patient needs for the first month of therapy.  
 
Posology 
 
When first starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducing 
adverse reactions it is recommended that patients be started at 8.8 micrograms dose subcutaneously 
and the dose be increased over a 4 week period to the targeted dose, according to the following 
schedule: 
 



49 

 Recommended 
Titration 

(% of final dose) 

Titration dose for Rebif 
44 micrograms 

three times per week (tiw) 
Weeks 1-2 20% 8.8 micrograms tiw 
Weeks 3–4 50% 22 micrograms tiw 
Weeks 5+ 100% 44 micrograms tiw 

 
First demyelinating event 
The posology for patients who have experienced a first demyelinating event is 44 micrograms of Rebif 
given three times per week by subcutaneous injection.  
 
Relapsing multiple sclerosis 
The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneous 
injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection, 
is recommended for patients who cannot tolerate the higher dose in view of the treating specialist.  
 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records 
in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in 
children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 
44 micrograms subcutaneous three times per week is similar to that seen in adults. 
 
The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
Rebif solution for subcutaneous injection in a cartridge is intended for multidose use with the 
RebiSmart electronic injection device following adequate training of the patient and/or carer. 
 
For administration, the instructions provided in the package leaflet and in the instruction manual 
(Instructions for Use) provided with RebiSmart should be followed. 
 
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised 
to decrease flu-like symptoms associated with Rebif administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with 
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should 
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and 
a decision for longer term treatment should then be made on an individual basis by the treating 
physician. 
 
4.3 Contraindications 
 
• Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 

section 6.1. 
• Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 



50 

General recommendations 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 
Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include 
thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, 
paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased 
platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes 
(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, 
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If 
TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate 
discontinuation of Rebif is recommended. 
 
Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal 
ideation are known to occur in increased frequency in the multiple sclerosis population and in 
association with interferon use. Patients treated with Rebif should be advised to immediately report 
any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting 
depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation 
of therapy with Rebif should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with 
antiepileptics (see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise 
the risk of injection site necrosis patients should be advised to: 
• use an aseptic injection technique, 
• rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred.  
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of 
fluid from the injection site, the patient should be advised to consult with their physician before 
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until 



51 

healing has occurred. Patients with single lesions may continue provided that the necrosis is not too 
extensive. 
 
Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, 
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy 
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times 
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated 
with caution in patients with a history of significant liver disease, clinical evidence of active liver 
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be 
stopped if icterus or other clinical symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six 
months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No 
specific risk factors have been identified. 
 
Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal 
segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative 
glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during 
treatment with interferon-beta products. Events were reported at various time points during treatment 
and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs 
or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in 
patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and 
discontinuation of treatment with Rebif should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons.  The overall incidence of these is 
slightly higher with Rebif 44 than Rebif 22 micrograms. Therefore, in addition to those laboratory 
tests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring and 
complete and differential blood cell counts and platelet counts are recommended at regular intervals 
(1, 3 and 6 months) following introduction of Rebif therapy and then periodically thereafter in the 
absence of clinical symptoms. These should be more frequent when initiating Rebif 44 micrograms. 
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following 
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be 
performed if clinical findings of thyroid dysfunction appear (see section 4.8). 
 
Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 



52 

Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with 
Rebif 44 micrograms, approximately 13 to 14% of patients develop persistent serum antibodies to 
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 
response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance 
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies 
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to 
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the 
benefit/risk ratio of continued Rebif therapy. 
 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity 
limits the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple 
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis 
and should not be used in these patients. 
 
Excipients 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
‘sodium-free’. 
 
Benzyl alcohol 
 
This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. 
 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, 
which might accumulate over time and cause metabolic acidosis. Use with caution in patients with 
hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might 
accumulate over time and cause metabolic acidosis. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes 
in humans and animals. Caution should be exercised when administering Rebif in combination with 
medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic 
cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been 
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 



53 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing 
experience indicates no increased risk of major congenital anomalies after pre-conception exposure to 
interferon beta or such exposure during the first trimester of pregnancy. However, the duration of 
exposure during the first trimester is uncertain, because data were collected when interferon beta use 
was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was 
detected and/or confirmed. Experience with exposure during the second and third trimester is very 
limited. 
 
Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The 
risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be 
evaluated based on the currently available data, but the data do not suggest an increased risk so far. 
 
If clinically needed, the use of Rebif may be considered during pregnancy 
 
Breast-feeding 
 
Limited information available on the transfer of interferon beta-1a into breast milk, together with the 
chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a 
excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are 
anticipated.  
 
Rebif can be used during breast-feeding.   
 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like 
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in 
frequency with continued treatment. Approximately 70 % of patients treated with Rebif can expect to 
experience the typical interferon flu-like syndrome within the first six months after starting treatment. 
Approximately 30 % of patients will also experience reactions at the injection site, predominantly mild 
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and 
decreases in white blood cells are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, 
and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of 
Rebif may be temporarily lowered or interrupted, at the discretion of the physician. 
 



54 

List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post-
marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing 
surveillance). The following definitions apply to the frequency terminology used hereafter: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia  
Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic 

purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 

 
Endocrine disorders 
Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or 

hyperthyroidism  
 
Immune system disorders 
Rare:  Anaphylactic reactions*  
 
Hepatobiliary disorders 
Very common: Asymptomatic transaminase increase 
Common: Severe elevations in transaminases 
Uncommon: Hepatitis with or without icterus* 
Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis* 
 
Psychiatric disorders 
Common: Depression, insomnia  
Rare: Suicide attempt* 
 
Nervous system disorders 
Very common: Headache 
Uncommon: Seizures* 
Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 

paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations*  

 
Eye disorders 
Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 

retinal artery or vein)* 
 
Vascular disorders 
Uncommon: Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: Dyspnoea* 
Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, see 

below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: Diarrhoea, vomiting, nausea 
 



55 

Skin and subcutaneous tissue disorders 
Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: Urticaria* 
Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 

multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: Myalgia, arthralgia 
Rare: Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 
General disorders and administration site conditions 
Very common: Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: Injection site pain, fatigue, rigors, fever 
Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection 

site infections*, increased sweating* 
Rare: Injection site cellulitis* 
Frequency not known: Panniculitis (occurred in the injection site) 
 
Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) 
receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.  
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia.  
An increased formation of auto-antibodies may occur during treatment with interferon beta. 
 
Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


56 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase 
and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to 
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable 
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological 
responses remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are 
induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer 
subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours 
for neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 
 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
 
Single clinical event suggestive of multiple sclerosis 
 
One 2-year controlled clinical trial with Rebif was performed in patients with a single clinical event 
suggestive of demyelination due to multiple sclerosis. The patients enrolled into the trial had at least 
two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of 
which is ovoid or periventricular or infratentorial. Any disease other than multiple sclerosis that could 
better explain signs and symptoms of the patient had to be excluded.  
 
Patients were randomised in a double-blind manner to either Rebif 44 micrograms given three times 
per week, Rebif 44 micrograms once weekly, or placebo. If a second clinical demyelinating event 
occurred confirming definite multiple sclerosis, patients switched to the recommended posology of 
Rebif 44 micrograms three times per week in an open label manner, while maintaining blinding as to 
initial randomisation.  
 



57 

Efficacy results of Rebif 44 micrograms given three times per week compared to placebo from this 
study are as follows: 
 

Parameter 
Statistics 

Treatment Treatment Comparison 
Rebif 44 mcg tiw versus Placebo 

Placebo  
(n=171) 

Rebif 44 
mcg tiw 
(n=171) 

Risk 
Reduction 

Cox’s 
Proportional 
Hazard Ratio 

[95% CI] 

Log-Rank 
p-value 

McDonald (2005) Conversion 
Number of events 144 106  

51% 
 

0.49 [0.38;0.64] 
 

<0.001 KM Estimate 85.8% 62.5% 
CDMS Conversion 
Number of events 60 33  

52% 
 

0.48 [0.31;0.73] 
 

<0.001 KM Estimate 37.5% 20.6% 
Mean CUA Lesions per Subject per Scan During the Double Blind Period 
Least Square Means 
(SE) 

 
2.59 (0.30) 

 
0.50 (0.06) 

 
81% 

 
0.19 [0.14;0.26]* 

 
<0.001 

tiw: three times per week, CI: confidence interval, CUA: combined unique active 
* Least Squared Mean Ratio [95% CI] 
 
For the time being there is no well established definition of a high risk patient, although a more 
conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least 
one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the 
initial scan. In any case, treatment should only be considered for patients classified as high risk. 
 
Relapsing-remitting multiple sclerosis 
 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple 
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously 
three times per week. At licensed posology, Rebif 44 micrograms has been demonstrated to decrease 
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at 
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of 
patients with disability progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 27% (Rebif 44 micrograms). Over 4 years, the 
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated 
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 
Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence 
of clinical progression in the preceding two years and who had not experienced relapses in the 
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was 
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and 
those without relapses in the 2-year period prior to study entry), there was no effect on disability in 
patients without relapses, but in patients with relapses, the proportion with progression in disability at 
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should 
not be used in these patients.  
 



58 

5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta.  
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple 
dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. An 
increased risk of abortions has been reported in animal studies of other alpha and beta interferons. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Poloxamer 188 
L-methionine 
Benzyl alcohol 
Sodium acetate 
Acetic acid for pH adjustment 
Sodium hydroxide for pH adjustment 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
After first injection use within 28 days. 
 



59 

6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store the cartridge in 
the original package in order to protect from light.  
 
The device (RebiSmart) containing a pre-filled cartridge of Rebif must be stored in the device storage 
box in a refrigerator (2°C – 8°C). 
 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not 
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
6.5 Nature and contents of container 
 
Cartridges (type 1 glass) with a plunger stopper (rubber) and crimp cap (aluminium and halobutyl rubber) 
containing 1.5 mL solution for injection.  
 
Pack size of 4 or 12 cartridges. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled cartridge is ready for use with the RebiSmart electronic 
injection device. For storage of the device with the cartridge, see section 6.4. 
 
For multidose use. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/009 
EU/1/98/063/019 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


60 

1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 8.8 micrograms/0.1 mL solution for injection in cartridge 
Rebif 22 micrograms/0.25 mL solution for injection in cartridge 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled cartridge contains 132 micrograms (36 MIU*) of interferon beta-1a** in 1.5 mL 
solution, corresponding to 88 micrograms/mL. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 0.5 mg benzyl alcohol per dose of 0.1 mL and 1.25 mg benzyl 
alcohol per dose of 0.25 mL. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in cartridge. 
Clear to opalescent solution, with pH 3.7 to 4.1 and osmolarity 250 to 450 mOsm/L. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of  
• patients with a single demyelinating event with an active inflammatory process, if alternative 

diagnoses have been excluded, and if they are determined to be at high risk of developing 
clinically definite multiple sclerosis (see section 5.1) 

• patients with relapsing multiple sclerosis. In clinical trials, this was characterised by two or 
more acute exacerbations in the previous two years (see section 5.1). 

 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the 
disease. 
 
Posology 
 
The Rebif initiation package corresponds to the patient needs for the first month of treatment. When 
first starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducing adverse 
reactions, it is recommended that patients be started at 8.8 micrograms dose subcutaneously and the 
dose be increased over a 4 week period to the targeted dose, according to the following schedule: 
 



61 

 Recommended 
Titration 

(% of final dose) 

Titration dose for Rebif 
44 micrograms 

three times per week (tiw) 
Weeks 1-2 20% 8.8 micrograms tiw 
Weeks 3-4 50% 22 micrograms tiw 
Weeks 5+ 100% 44 micrograms tiw 

 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records 
in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in 
children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 
44 micrograms subcutaneous three times per week is similar to that seen in adults. 
 
The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
Rebif solution for subcutaneous injection in a cartridge is intended for multidose use with the 
RebiSmart electronic injection device following adequate training of the patient and/or carer. 
 
For administration, the instructions provided in the package leaflet and in the instruction manual 
(Instructions for Use) provided with RebiSmart should be followed. 
 
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised 
to decrease flu-like symptoms associated with Rebif administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with 
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should 
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and 
a decision for longer term treatment should then be made on an individual basis by the treating 
physician. 
 
4.3 Contraindications 
 
• Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 

section 6.1. 
• Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
General recommendations 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 



62 

Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include 
thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, 
paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased 
platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes 
(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, 
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If 
TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate 
discontinuation of Rebif is recommended. 
 
Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal 
ideation are known to occur in increased frequency in the multiple sclerosis population and in 
association with interferon use. Patients treated with Rebif should be advised to immediately report 
any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting 
depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation 
of therapy with Rebif should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with 
antiepileptics (see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise 
the risk of injection site necrosis patients should be advised to: 
• use an aseptic injection technique, 
• rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred.  
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of 
fluid from the injection site, the patient should be advised to consult with their physician before 
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until 
healing has occurred. Patients with single lesions may continue provided that the necrosis is not too 
extensive. 
 
Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 



63 

transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, 
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy 
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times 
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated 
with caution in patients with a history of significant liver disease, clinical evidence of active liver 
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be 
stopped if icterus or other clinical symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six 
months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No 
specific risk factors have been identified. 
 
Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal 
segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative 
glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during 
treatment with interferon-beta products. Events were reported at various time points during treatment 
and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs 
or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in 
patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and 
discontinuation of treatment with Rebif should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those 
laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme 
monitoring and complete and differential blood cell counts and platelet counts are recommended at 
regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically 
thereafter in the absence of clinical symptoms.  
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following 
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be 
performed if clinical findings of thyroid dysfunction appear (see section 4.8). 
 
Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 
Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with 
Rebif 22 micrograms, approximately 24% of patients develop persistent serum antibodies to 
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 
response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance 
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies 
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to 
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the 
benefit/risk ratio of continued Rebif therapy. 



64 

 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity 
limits the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple 
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis 
and should not be used in these patients. 
 
Excipients 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
‘sodium-free’. 
 
Benzyl alcohol 
 
This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. 
 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, 
which might accumulate over time and cause metabolic acidosis. Use with caution in patients with 
hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might 
accumulate over time and cause metabolic acidosis. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes 
in humans and animals. Caution should be exercised when administering Rebif in combination with 
medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic 
cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been 
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing 
experience indicates no increased risk of major congenital anomalies after pre-conception exposure to 
interferon beta or such exposure during the first trimester of pregnancy. However, the duration of 
exposure during the first trimester is uncertain, because data were collected when interferon beta use 
was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was 
detected and/or confirmed. Experience with exposure during the second and third trimester is very 
limited. 
 
Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The 
risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be 
evaluated based on the currently available data, but the data do not suggest an increased risk so far. 
 



65 

If clinically needed, the use of Rebif may be considered during pregnancy 
 
Breast-feeding 
 
Limited information available on the transfer of interferon beta-1a into breast milk, together with the 
chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a 
excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are 
anticipated.  
 
Rebif can be used during breast-feeding.   
 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like 
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in 
frequency with continued treatment. Approximately 70 % of patients treated with Rebif can expect to 
experience the typical interferon flu-like syndrome within the first six months after starting treatment. 
Approximately 30 % of patients will also experience reactions at the injection site, predominantly mild 
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and 
decreases in white blood cells are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, 
and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of 
Rebif may be temporarily lowered or interrupted, at the discretion of the physician. 
 
List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post-
marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing 
surveillance). The following definitions apply to the frequency terminology used hereafter: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia  
Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic 

purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 

 
Endocrine disorders 
Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or 

hyperthyroidism  
 
Immune system disorders 
Rare:  Anaphylactic reactions*  
 



66 

Hepatobiliary disorders 
Very common: Asymptomatic transaminase increase 
Common: Severe elevations in transaminases 
Uncommon: Hepatitis with or without icterus* 
Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis* 
 
Psychiatric disorders 
Common: Depression, insomnia  
Rare: Suicide attempt* 
 
Nervous system disorders 
Very common: Headache 
Uncommon: Seizures* 
Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 

paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations*  

 
Eye disorders 
Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 

retinal artery or vein)* 
 
Vascular disorders 
Uncommon: Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: Dyspnoea* 
Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, see 

below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: Diarrhoea, vomiting, nausea 
 
Skin and subcutaneous tissue disorders 
Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: Urticaria* 
Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 

multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: Myalgia, arthralgia 
Rare: Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 
General disorders and administration site conditions 
Very common: Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: Injection site pain, fatigue, rigors, fever 
Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection 

site infections*, increased sweating* 
Rare: Injection site cellulitis* 
Frequency not known: Panniculitis (occurred in the injection site) 
 



67 

Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) 
receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.  
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia.  
An increased formation of auto-antibodies may occur during treatment with interferon beta. 
 
Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase 
and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to 
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable 
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological 
responses remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are 
induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer 
subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours 
for neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


68 

 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
 
Single clinical event suggestive of multiple sclerosis 
 
One 2-year controlled clinical trial with Rebif was performed in patients with a single clinical event 
suggestive of demyelination due to multiple sclerosis. The patients enrolled into the trial had at least 
two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of 
which is ovoid or periventricular or infratentorial. Any disease other than multiple sclerosis that could 
better explain signs and symptoms of the patient had to be excluded.  
 
Patients were randomised in a double-blind manner to either Rebif 44 micrograms given three times 
per week, Rebif 44 micrograms once weekly, or placebo. If a second clinical demyelinating event 
occurred confirming definite multiple sclerosis, patients switched to the recommended posology of 
Rebif 44 micrograms three times per week in an open label manner, while maintaining blinding as to 
initial randomisation.  
 
Efficacy results of Rebif 44 micrograms given three times per week compared to placebo from this 
study are as follows: 
 

Parameter 
Statistics 

Treatment Treatment Comparison 
Rebif 44 mcg tiw versus Placebo 

Placebo  
(n=171) 

Rebif 44 
mcg tiw 
(n=171) 

Risk 
Reduction 

Cox’s 
Proportional 
Hazard Ratio 

[95% CI] 

Log-Rank 
p-value 

McDonald (2005) Conversion 
Number of events 144 106  

51% 
 

0.49 [0.38;0.64] 
 

<0.001 KM Estimate 85.8% 62.5% 
CDMS Conversion 
Number of events 60 33  

52% 
 

0.48 [0.31;0.73] 
 

<0.001 KM Estimate 37.5% 20.6% 
Mean CUA Lesions per Subject per Scan During the Double Blind Period 
Least Square Means 
(SE) 

 
2.59 (0.30) 

 
0.50 (0.06) 

 
81% 

 
0.19 [0.14;0.26]* 

 
<0.001 

tiw: three times per week, CI: confidence interval, CUA: combined unique active 
* Least Squared Mean Ratio [95% CI] 
 
For the time being there is no well established definition of a high risk patient, although a more 
conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least 
one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the 
initial scan. In any case, treatment should only be considered for patients classified as high risk. 
 
Relapsing-remitting multiple sclerosis 
 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple 
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously 
three times per week. At licensed posology, Rebif 22 micrograms has been demonstrated to decrease 
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at 
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of 
patients with disability progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms). Over 4 years, the 
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated 
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 



69 

Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence 
of clinical progression in the preceding two years and who had not experienced relapses in the 
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was 
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and 
those without relapses in the 2-year period prior to study entry), there was no effect on disability in 
patients without relapses, but in patients with relapses, the proportion with progression in disability at 
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should 
not be used in these patients.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta.  
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple 
dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. An 
increased risk of abortions has been reported in animal studies of other alpha and beta interferons. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 



70 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Poloxamer 188 
L-methionine 
Benzyl alcohol 
Sodium acetate 
Acetic acid for pH adjustment 
Sodium hydroxide for pH adjustment 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
After first injection use within 28 days. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store the cartridge in 
the original package in order to protect from light.  
 
The device (RebiSmart) containing a pre-filled cartridge of Rebif must be stored in the device storage 
box in a refrigerator (2°C – 8°C). 
 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not 
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
6.5 Nature and contents of container 
 
Cartridges (type 1 glass) with a plunger stopper (rubber) and crimp cap (aluminium and halobutyl rubber) 
containing 1.5 mL solution for injection.  
 
Pack size of 2 cartridges. 
This package corresponds to the patient needs for the first month of therapy. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled cartridge is ready for use with the RebiSmart electronic 
injection device. For storage of the device with the cartridge, see section 6.4. 
 
For multidose use. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 



71 

7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/010 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


72 

1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 22 micrograms solution for injection in pre-filled pen 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 22 micrograms (6 MIU*) of interferon beta-1a** in 0.5 mL solution. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 2.5 mg benzyl alcohol per dose of 0.5 mL. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled pen. 
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/L. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of relapsing multiple sclerosis. In clinical trials, this was 
characterised by two or more acute exacerbations in the previous two years (see section 5.1). 
 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the 
disease. 
 
Rebif is available in three strengths: 8.8 micrograms, 22 micrograms and 44 micrograms. For patients 
initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available in a 
package that corresponds to the patient needs for the first month of therapy. 
 
Posology 
 
The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneous 
injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection, 
is recommended for patients who cannot tolerate the higher dose in view of the treating specialist. 
 
When first starting treatment with Rebif, the dose should be gradually escalated in order to allow 
tachyphylaxis to develop thus reducing adverse reactions. The Rebif initiation package corresponds to 
the patient needs for the first month of treatment. 
 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records 
in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in 



73 

children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 
44 micrograms subcutaneous three times per week is similar to that seen in adults. 
 
The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
RebiDose is a ready to use pre-filled pen for subcutaneous injection. It is intended for single use and 
should only be used following adequate training of the patient and/or carer. 
 
For administration of Rebif with RebiDose, the instructions provided in the package leaflet should be 
followed. 
 
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised 
to decrease flu-like symptoms associated with Rebif administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with 
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should 
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and 
a decision for longer term treatment should then be made on an individual basis by the treating 
physician. 
 
4.3 Contraindications 
 
• Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 

section 6.1. 
• Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
General recommendations 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 
Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include 
thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, 
paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased 
platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes 
(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, 
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If 
TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate 
discontinuation of Rebif is recommended. 
 



74 

Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal 
ideation are known to occur in increased frequency in the multiple sclerosis population and in 
association with interferon use. Patients treated with Rebif should be advised to immediately report 
any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting 
depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation 
of therapy with Rebif should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with 
antiepileptics (see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise 
the risk of injection site necrosis patients should be advised to: 
• use an aseptic injection technique, 
• rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred.  
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of 
fluid from the injection site, the patient should be advised to consult with their physician before 
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until 
healing has occurred. Patients with single lesions may continue provided that the necrosis is not too 
extensive. 
 
Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, 
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy 
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times 
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated 
with caution in patients with a history of significant liver disease, clinical evidence of active liver 
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be 
stopped if icterus or other clinical symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six 
months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No 
specific risk factors have been identified. 
 



75 

Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal 
segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative 
glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during 
treatment with interferon-beta products. Events were reported at various time points during treatment 
and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs 
or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in 
patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and 
discontinuation of treatment with Rebif should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those 
laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme 
monitoring and complete and differential blood cell counts and platelet counts are recommended at 
regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically 
thereafter in the absence of clinical symptoms.  
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following 
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be 
performed if clinical findings of thyroid dysfunction appear (see section 4.8). 
 
Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 
Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with 
Rebif 22 micrograms, approximately 24% of patients develop persistent serum antibodies to 
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 
response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance 
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies 
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to 
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the 
benefit/risk ratio of continued Rebif therapy. 
 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity 
limits the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple 
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis 
and should not be used in these patients. 
 



76 

Excipients 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
‘sodium-free’. 
 
Benzyl alcohol 
 
This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. 
 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, 
which might accumulate over time and cause metabolic acidosis. Use with caution in patients with 
hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might 
accumulate over time and cause metabolic acidosis. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes 
in humans and animals. Caution should be exercised when administering Rebif in combination with 
medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic 
cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been 
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing 
experience indicates no increased risk of major congenital anomalies after pre-conception exposure to 
interferon beta or such exposure during the first trimester of pregnancy. However, the duration of 
exposure during the first trimester is uncertain, because data were collected when interferon beta use 
was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was 
detected and/or confirmed. Experience with exposure during the second and third trimester is very 
limited. 
 
Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The 
risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be 
evaluated based on the currently available data, but the data do not suggest an increased risk so far. 
 
If clinically needed, the use of Rebif may be considered during pregnancy 
 
Breast-feeding 
 
Limited information available on the transfer of interferon beta-1a into breast milk, together with the 
chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a 
excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are 
anticipated.  
 
Rebif can be used during breast-feeding.   



77 

 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like 
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in 
frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to 
experience the typical interferon flu-like syndrome within the first six months after starting treatment. 
Approximately 30% of patients will also experience reactions at the injection site, predominantly mild 
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and 
decreases in white blood cells are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, 
and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of 
Rebif may be temporarily lowered or interrupted, at the discretion of the physician. 
 
List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post-
marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing 
surveillance). The following definitions apply to the frequency terminology used hereafter: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia  
Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic 

purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 

 
Endocrine disorders 
Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or 

hyperthyroidism  
 
Immune system disorders 
Rare:  Anaphylactic reactions*  
 
Hepatobiliary disorders 
Very common: Asymptomatic transaminase increase 
Common: Severe elevations in transaminases 
Uncommon: Hepatitis with or without icterus* 
Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis* 
 
Psychiatric disorders 
Common: Depression, insomnia  
Rare: Suicide attempt* 
 



78 

Nervous system disorders 
Very common: Headache 
Uncommon: Seizures* 
Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 

paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations*  

 
Eye disorders 
Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 

retinal artery or vein)* 
 
Vascular disorders 
Uncommon: Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: Dyspnoea* 
Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, see 

below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: Diarrhoea, vomiting, nausea 
 
Skin and subcutaneous tissue disorders 
Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: Urticaria* 
Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 

multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: Myalgia, arthralgia 
Rare: Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 
General disorders and administration site conditions 
Very common: Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: Injection site pain, fatigue, rigors, fever 
Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection 

site infections*, increased sweating* 
Rare: Injection site cellulitis* 
Frequency not known: Panniculitis (occurred in the injection site) 
 
Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) 
receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.  
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia.  
An increased formation of auto-antibodies may occur during treatment with interferon beta. 
 



79 

Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase 
and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to 
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable 
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological 
responses remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are 
induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer 
subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours 
for neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 
 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
 
Relapsing-remitting multiple sclerosis 
 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple 
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously 
three times per week. At licensed posology, Rebif 22 micrograms has been demonstrated to decrease 
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at 
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of 
patients with disability progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms). Over 4 years, the 

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80 

reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated 
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 
Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence 
of clinical progression in the preceding two years and who had not experienced relapses in the 
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was 
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and 
those without relapses in the 2-year period prior to study entry), there was no effect on disability in 
patients without relapses, but in patients with relapses, the proportion with progression in disability at 
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should 
not be used in these patients.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta.  
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple 
dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. An 
increased risk of abortions has been reported in animal studies of other alpha and beta interferons. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 



81 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Poloxamer 188 
L-methionine 
Benzyl alcohol 
Sodium acetate 
Acetic acid for pH adjustment  
Sodium hydroxide for pH adjustment 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original 
package in order to protect from light. 
 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not 
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
6.5 Nature and contents of container 
 
One mL type 1 glass syringe, with a stainless steel needle, containing 0.5 mL solution.  
The syringe is sealed in a disposable pen injector called RebiDose. 
 
Pack sizes of 1, 3 or 12 pre-filled pens. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled pen is ready for use. The carton contains a package leaflet 
with full instructions for use and handling. 
 
For single use only. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 



82 

 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/011 
EU/1/98/063/012 
EU/1/98/063/013 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


83 

1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 44 micrograms solution for injection in pre-filled pen 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 44 micrograms (12 MIU*) of interferon beta-1a** in 0.5 mL solution. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 2.5 mg benzyl alcohol per dose of 0.5 mL. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled pen. 
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/L. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of  
• patients with a single demyelinating event with an active inflammatory process, if alternative 

diagnoses have been excluded, and if they are determined to be at high risk of developing 
clinically definite multiple sclerosis (see section 5.1) 

• patients with relapsing multiple sclerosis. In clinical trials, this was characterised by two or 
more acute exacerbations in the previous two years (see section 5.1). 

 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the 
disease. 
 
Rebif is available in three strengths: 8.8 micrograms, 22 micrograms and 44 micrograms. For patients 
initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available in a 
package that corresponds to the patient needs for the first month of therapy. 
 
Posology 
 
When first starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducing 
adverse reactions it is recommended that patients be started at 8.8 micrograms dose subcutaneously 
and the dose be increased over a 4 week period to the targeted dose, according to the following 
schedule: 
 



84 

 Recommended 
Titration 

(% of final dose) 

Titration dose for Rebif 
44 micrograms 

three times per week (tiw) 
Weeks 1-2 20% 8.8 micrograms tiw 
Weeks 3–4 50% 22 micrograms tiw 
Weeks 5+ 100% 44 micrograms tiw 

 
First demyelinating event 
The posology for patients who have experienced a first demyelinating event is 44 micrograms of Rebif 
given three times per week by subcutaneous injection.  
 
Relapsing multiple sclerosis 
The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneous 
injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection, 
is recommended for patients who cannot tolerate the higher dose in view of the treating specialist.  
 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records 
in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in 
children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 
44 micrograms subcutaneous three times per week is similar to that seen in adults. 
 
The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
RebiDose is a ready to use pre-filled pen for subcutaneous injection. It is intended for single use and 
should only be used following adequate training of the patient and/or carer. 
 
For administration of Rebif with RebiDose, the instructions provided in the package leaflet should be 
followed. 
 
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised 
to decrease flu-like symptoms associated with Rebif administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with 
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should 
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and 
a decision for longer term treatment should then be made on an individual basis by the treating 
physician. 
 
4.3 Contraindications 
 
• Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 

section 6.1. 
• Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 



85 

General recommendations 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 
Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include 
thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, 
paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased 
platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes 
(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, 
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If 
TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate 
discontinuation of Rebif is recommended. 
 
Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal 
ideation are known to occur in increased frequency in the multiple sclerosis population and in 
association with interferon use. Patients treated with Rebif should be advised to immediately report 
any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting 
depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation 
of therapy with Rebif should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with 
antiepileptics (see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise 
the risk of injection site necrosis patients should be advised to: 
• use an aseptic injection technique, 
• rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred.  
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of 
fluid from the injection site, the patient should be advised to consult with their physician before 
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until 



86 

healing has occurred. Patients with single lesions may continue provided that the necrosis is not too 
extensive. 
 
Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, 
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy 
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times 
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated 
with caution in patients with a history of significant liver disease, clinical evidence of active liver 
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be 
stopped if icterus or other clinical symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six 
months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No 
specific risk factors have been identified. 
 
Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal 
segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative 
glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during 
treatment with interferon-beta products. Events were reported at various time points during treatment 
and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs 
or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in 
patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and 
discontinuation of treatment with Rebif should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. The overall incidence of these is 
slightly higher with Rebif 44 than Rebif 22 micrograms. Therefore, in addition to those laboratory 
tests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring and 
complete and differential blood cell counts and platelet counts are recommended at regular intervals 
(1, 3 and 6 months) following introduction of Rebif therapy and then periodically thereafter in the 
absence of clinical symptoms. These should be more frequent when initiating Rebif 44 micrograms. 
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following 
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be 
performed if clinical findings of thyroid dysfunction appear (see section 4.8). 
 
Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 



87 

Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with 
Rebif 44 micrograms, approximately 13 to 14% of patients develop persistent serum antibodies to 
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 
response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance 
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies 
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to 
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the 
benefit/risk ratio of continued Rebif therapy. 
 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity 
limits the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple 
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis 
and should not be used in these patients. 
 
Excipients 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
‘sodium-free’. 
 
Benzyl alcohol 
 
This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. 
 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, 
which might accumulate over time and cause metabolic acidosis. Use with caution in patients with 
hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might 
accumulate over time and cause metabolic acidosis. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes 
in humans and animals. Caution should be exercised when administering Rebif in combination with 
medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic 
cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been 
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 



88 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing 
experience indicates no increased risk of major congenital anomalies after pre-conception exposure to 
interferon beta or such exposure during the first trimester of pregnancy. However, the duration of 
exposure during the first trimester is uncertain, because data were collected when interferon beta use 
was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was 
detected and/or confirmed. Experience with exposure during the second and third trimester is very 
limited. 
 
Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The 
risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be 
evaluated based on the currently available data, but the data do not suggest an increased risk so far. 
 
If clinically needed, the use of Rebif may be considered during pregnancy 
 
Breast-feeding 
 
Limited information available on the transfer of interferon beta-1a into breast milk, together with the 
chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a 
excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are 
anticipated.  
 
Rebif can be used during breast-feeding. 
 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like 
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in 
frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to 
experience the typical interferon flu-like syndrome within the first six months after starting treatment. 
Approximately 30% of patients will also experience reactions at the injection site, predominantly mild 
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and 
decreases in white blood cells are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, 
and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of 
Rebif may be temporarily lowered or interrupted, at the discretion of the physician. 
 



89 

List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post-
marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing 
surveillance). The following definitions apply to the frequency terminology used hereafter: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia  
Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic 

purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 

 
Endocrine disorders 
Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or 

hyperthyroidism  
 
Immune system disorders 
Rare:  Anaphylactic reactions*  
 
Hepatobiliary disorders 
Very common: Asymptomatic transaminase increase 
Common: Severe elevations in transaminases 
Uncommon: Hepatitis with or without icterus* 
Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis* 
 
Psychiatric disorders 
Common: Depression, insomnia  
Rare: Suicide attempt* 
 
Nervous system disorders 
Very common: Headache 
Uncommon: Seizures* 
Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 

paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations*  

 
Eye disorders 
Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 

retinal artery or vein)* 
 
Vascular disorders 
Uncommon: Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: Dyspnoea* 
Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, see 

below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: Diarrhoea, vomiting, nausea 
 



90 

Skin and subcutaneous tissue disorders 
Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: Urticaria* 
Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 

multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: Myalgia, arthralgia 
Rare: Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 
General disorders and administration site conditions 
Very common: Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: Injection site pain, fatigue, rigors, fever 
Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection 

site infections*, increased sweating* 
Rare: Injection site cellulitis* 
Frequency not known: Panniculitis (occurred in the injection site) 
 
Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) 
receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.  
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia.  
An increased formation of auto-antibodies may occur during treatment with interferon beta. 
 
Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 

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91 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase 
and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to 
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable 
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological 
responses remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are 
induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer 
subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours 
for neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 
 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
 
Single clinical event suggestive of multiple sclerosis 
 
One 2-year controlled clinical trial with Rebif was performed in patients with a single clinical event 
suggestive of demyelination due to multiple sclerosis. The patients enrolled into the trial had at least 
two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of 
which is ovoid or periventricular or infratentorial. Any disease other than multiple sclerosis that could 
better explain signs and symptoms of the patient had to be excluded.  
 
Patients were randomised in a double-blind manner to either Rebif 44 micrograms given three times 
per week, Rebif 44 micrograms once weekly, or placebo. If a second clinical demyelinating event 
occurred confirming definite multiple sclerosis, patients switched to the recommended posology of 
Rebif 44 micrograms three times per week in an open label manner, while maintaining blinding as to 
initial randomisation.  
 



92 

Efficacy results of Rebif 44 micrograms given three times per week compared to placebo from this 
study are as follows: 
 

Parameter 
Statistics 

Treatment Treatment Comparison 
Rebif 44 mcg tiw versus Placebo 

Placebo  
(n=171) 

Rebif 44 
mcg tiw 
(n=171) 

Risk 
Reduction 

Cox’s 
Proportional 
Hazard Ratio 

[95% CI] 

Log-Rank 
p-value 

McDonald (2005) Conversion 
Number of events 144 106  

51% 
 

0.49 [0.38;0.64] 
 

<0.001 KM Estimate 85.8% 62.5% 
CDMS Conversion 
Number of events 60 33  

52% 
 

0.48 [0.31;0.73] 
 

<0.001 KM Estimate 37.5% 20.6% 
Mean CUA Lesions per Subject per Scan During the Double Blind Period 
Least Square Means 
(SE) 

 
2.59 (0.30) 

 
0.50 (0.06) 

 
81% 

 
0.19 [0.14;0.26]* 

 
<0.001 

tiw: three times per week, CI: confidence interval, CUA: combined unique active 
* Least Squared Mean Ratio [95% CI] 

 
For the time being there is no well established definition of a high risk patient, although a more 
conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least 
one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the 
initial scan. In any case, treatment should only be considered for patients classified as high risk. 
 
Relapsing-remitting multiple sclerosis 
 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple 
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously 
three times per week. At licensed posology, Rebif 44 micrograms has been demonstrated to decrease 
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at 
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of 
patients with disability progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 27% (Rebif 44 micrograms). Over 4 years, the 
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated 
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 
Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence 
of clinical progression in the preceding two years and who had not experienced relapses in the 
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was 
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and 
those without relapses in the 2-year period prior to study entry), there was no effect on disability in 
patients without relapses, but in patients with relapses, the proportion with progression in disability at 
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should 
not be used in these patients.  
 



93 

5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta.  
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple 
dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. An 
increased risk of abortions has been reported in animal studies of other alpha and beta interferons. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Poloxamer 188 
L-methionine 
Benzyl alcohol 
Sodium acetate 
Acetic acid for pH adjustment  
Sodium hydroxide for pH adjustment 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original 
package in order to protect from light. 



94 

 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not 
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
6.5 Nature and contents of container 
 
One mL type 1 glass syringe, with a stainless steel needle, containing 0.5 mL solution.  
The syringe is sealed in a disposable pen injector called RebiDose. 
 
Pack sizes of 1, 3 or 12 pre-filled pens. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled pen is ready for use. The carton contains a package leaflet 
with full instructions for use and handling. 
 
For single use only. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/014 
EU/1/98/063/015 
EU/1/98/063/016 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


95 

1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 8.8 micrograms solution for injection in pre-filled pen 
Rebif 22 micrograms solution for injection in pre-filled pen 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 8.8 micrograms (2.4 MIU*) of interferon beta-1a** in 0.2 mL solution. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 1.0 mg benzyl alcohol per dose of 0.2 mL. 
For the full list of excipients, see section 6.1. 
 
Each pre-filled pen contains 22 micrograms (6 MIU*) of interferon beta-1a** in 0.5 mL solution. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard 
(GB-23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: Contains 2.5 mg benzyl alcohol per dose of 0.5 mL. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled pen. 
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/L. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of  
• patients with a single demyelinating event with an active inflammatory process, if alternative 

diagnoses have been excluded, and if they are determined to be at high risk of developing 
clinically definite multiple sclerosis (see section 5.1) 

• patients with relapsing multiple sclerosis. In clinical trials, this was characterised by two or 
more acute exacerbations in the previous two years (see section 5.1). 

 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the 
disease. 
 



96 

Posology 
 
The Rebif initiation packs correspond to the patient needs for the first month of treatment. When first 
starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducing adverse 
reactions, it is recommended that patients be started at 8.8 micrograms dose subcutaneously and the 
dose be increased over a 4 week period to the targeted dose, according to the following schedule: 
 

 Recommended 
Titration 

(% of final dose) 

Titration dose for Rebif 
44 micrograms 

three times per week (tiw) 
Weeks 1-2 20% 8.8 micrograms tiw 
Weeks 3–4 50% 22 micrograms tiw 
Weeks 5+ 100% 44 micrograms tiw 

 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records 
in children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in 
children (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 
44 micrograms subcutaneous three times per week is similar to that seen in adults. 
 
The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
RebiDose is a ready to use pre-filled pen for subcutaneous injection. It is intended for single use and 
should only be used following adequate training of the patient and/or carer. 
 
For administration of Rebif with RebiDose, the instructions provided in the package leaflet should be 
followed. 
 
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised 
to decrease flu-like symptoms associated with Rebif administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with 
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should 
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and 
a decision for longer term treatment should then be made on an individual basis by the treating 
physician. 
 
4.3 Contraindications 
 
• Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 

section 6.1. 
• Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 



97 

General recommendations 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 
Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include 
thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, 
paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased 
platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes 
(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, 
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If 
TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate 
discontinuation of Rebif is recommended. 
 
Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal 
ideation are known to occur in increased frequency in the multiple sclerosis population and in 
association with interferon use. Patients treated with Rebif should be advised to immediately report 
any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting 
depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation 
of therapy with Rebif should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with 
antiepileptics (see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise 
the risk of injection site necrosis patients should be advised to: 
• use an aseptic injection technique, 
• rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred.  
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of 
fluid from the injection site, the patient should be advised to consult with their physician before 
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until 



98 

healing has occurred. Patients with single lesions may continue provided that the necrosis is not too 
extensive. 
 
Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, 
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy 
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times 
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated 
with caution in patients with a history of significant liver disease, clinical evidence of active liver 
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be 
stopped if icterus or other clinical symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six 
months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No 
specific risk factors have been identified. 
 
Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal 
segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative 
glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during 
treatment with interferon-beta products. Events were reported at various time points during treatment 
and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs 
or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in 
patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and 
discontinuation of treatment with Rebif should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those 
laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme 
monitoring and complete and differential blood cell counts and platelet counts are recommended at 
regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically 
thereafter in the absence of clinical symptoms.  
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following 
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be 
performed if clinical findings of thyroid dysfunction appear (see section 4.8). 
 
Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 
Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with 



99 

Rebif 22 micrograms, approximately 24% of patients develop persistent serum antibodies to 
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 
response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance 
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies 
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to 
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the 
benefit/risk ratio of continued Rebif therapy. 
 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity 
limits the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple 
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis 
and should not be used in these patients. 
 
Excipients 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
‘sodium-free’. 
 
Benzyl alcohol 
 
This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions. 
 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, 
which might accumulate over time and cause metabolic acidosis. Use with caution in patients with 
hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might 
accumulate over time and cause metabolic acidosis. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes 
in humans and animals. Caution should be exercised when administering Rebif in combination with 
medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic 
cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been 
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing 
experience indicates no increased risk of major congenital anomalies after pre-conception exposure to 
interferon beta or such exposure during the first trimester of pregnancy. However, the duration of 
exposure during the first trimester is uncertain, because data were collected when interferon beta use 
was contraindicated during pregnancy, and treatment likely interrupted when the pregnancy was 



100 

detected and/or confirmed. Experience with exposure during the second and third trimester is very 
limited. 
 
Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The 
risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be 
evaluated based on the currently available data, but the data do not suggest an increased risk so far. 
 
If clinically needed, the use of Rebif may be considered during pregnancy 
 
Breast-feeding 
 
Limited information available on the transfer of interferon beta-1a into breast milk, together with the 
chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a 
excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are 
anticipated.  
 
Rebif can be used during breast-feeding. 
 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like 
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in 
frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to 
experience the typical interferon flu-like syndrome within the first six months after starting treatment. 
Approximately 30% of patients will also experience reactions at the injection site, predominantly mild 
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and 
decreases in white blood cells are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, 
and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of 
Rebif may be temporarily lowered or interrupted, at the discretion of the physician. 
 
List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post-
marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketing 
surveillance). The following definitions apply to the frequency terminology used hereafter: very 
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia  
Rare: Thrombotic microangiopathy including thrombotic thrombocytopenic 

purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 

 



101 

Endocrine disorders 
Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or 

hyperthyroidism  
 
Immune system disorders 
Rare:  Anaphylactic reactions*  
 
Hepatobiliary disorders 
Very common: Asymptomatic transaminase increase 
Common: Severe elevations in transaminases 
Uncommon: Hepatitis with or without icterus* 
Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis* 
 
Psychiatric disorders 
Common: Depression, insomnia  
Rare: Suicide attempt* 
 
Nervous system disorders 
Very common: Headache 
Uncommon: Seizures* 
Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 

paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations*  

 
Eye disorders 
Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 

retinal artery or vein)* 
 
Vascular disorders 
Uncommon: Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: Dyspnoea* 
Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, see 

below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: Diarrhoea, vomiting, nausea 
 
Skin and subcutaneous tissue disorders 
Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: Urticaria* 
Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 

multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: Myalgia, arthralgia 
Rare: Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 



102 

General disorders and administration site conditions 
Very common: Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: Injection site pain, fatigue, rigors, fever 
Uncommon: Injection site necrosis, injection site mass, injection site abscess, injection 

site infections*, increased sweating* 
Rare: Injection site cellulitis* 
Frequency not known: Panniculitis (occurred in the injection site) 
 
Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old) 
receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.  
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia.  
An increased formation of auto-antibodies may occur during treatment with interferon beta. 
 
Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase 
and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to 
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable 

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103 

responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological 
responses remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are 
induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer 
subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours 
for neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 
 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
 
Single clinical event suggestive of multiple sclerosis 
 
One 2-year controlled clinical trial with Rebif was performed in patients with a single clinical event 
suggestive of demyelination due to multiple sclerosis. The patients enrolled into the trial had at least 
two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of 
which is ovoid or periventricular or infratentorial. Any disease other than multiple sclerosis that could 
better explain signs and symptoms of the patient had to be excluded.  
 
Patients were randomised in a double-blind manner to either Rebif 44 micrograms given three times 
per week, Rebif 44 micrograms once weekly, or placebo. If a second clinical demyelinating event 
occurred confirming definite multiple sclerosis, patients switched to the recommended posology of 
Rebif 44 micrograms three times per week in an open label manner, while maintaining blinding as to 
initial randomisation.  
 
Efficacy results of Rebif 44 micrograms given three times per week compared to placebo from this 
study are as follows: 
 

Parameter 
Statistics 

Treatment Treatment Comparison 
Rebif 44 mcg tiw versus Placebo 

Placebo  
(n=171) 

Rebif 44 
mcg tiw 
(n=171) 

Risk 
Reduction 

Cox’s 
Proportional 
Hazard Ratio 

[95% CI] 

Log-Rank 
p-value 

McDonald (2005) Conversion 
Number of events 144 106  

51% 
 

0.49 [0.38;0.64] 
 

<0.001 KM Estimate 85.8% 62.5% 
CDMS Conversion 
Number of events 60 33  

52% 
 

0.48 [0.31;0.73] 
 

<0.001 KM Estimate 37.5% 20.6% 
Mean CUA Lesions per Subject per Scan During the Double Blind Period 
Least Square Means 
(SE) 

 
2.59 (0.30) 

 
0.50 (0.06) 

 
81% 

 
0.19 [0.14;0.26]* 

 
<0.001 

tiw: three times per week, CI: confidence interval, CUA: combined unique active 
* Least Squared Mean Ratio [95% CI] 

 
For the time being there is no well established definition of a high risk patient, although a more 
conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least 
one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the 
initial scan. In any case, treatment should only be considered for patients classified as high risk. 
 
Relapsing-remitting multiple sclerosis 
 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple 
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously 
three times per week. At licensed posology, Rebif 22 micrograms has been demonstrated to decrease 



104 

the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at 
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of 
patients with disability progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms). Over 4 years, the 
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated 
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 
Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence 
of clinical progression in the preceding two years and who had not experienced relapses in the 
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was 
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and 
those without relapses in the 2-year period prior to study entry), there was no effect on disability in 
patients without relapses, but in patients with relapses, the proportion with progression in disability at 
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should 
not be used in these patients.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta.  
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple 
dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. An 
increased risk of abortions has been reported in animal studies of other alpha and beta interferons. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 



105 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Poloxamer 188 
L-methionine 
Benzyl alcohol 
Sodium acetate 
Acetic acid for pH adjustment  
Sodium hydroxide for pH adjustment 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original 
package in order to protect from light. 
 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not 
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
6.5 Nature and contents of container 
 
For patients starting treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available in 
an initiation pack. The pack contains 6 individual doses of 0.2 mL of Rebif 8.8 micrograms solution for 
injection in a 1 mL type 1 glass syringe with a stainless steel needle and 6 individual doses of 0.5 mL of 
Rebif 22 micrograms solution for injection in a 1 mL type 1 glass syringe with a stainless steel needle. 
The syringes are sealed in disposable pen injectors called RebiDose. 
 
This package corresponds to the patient needs for the first month of therapy. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled pen is ready for use. The carton contains a package leaflet 
with full instructions for use and handling. 
 
For single use only. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 



106 

7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/017 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

  

http://www.ema.europa.eu/


107 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



108 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturers of the biological active substance  
 
Merck Serono S.A. – Corsier-sur-Vevey 
Route de Fenil – Z.I.B. 
CH-1804 Corsier-sur-Vevey 
Switzerland 
 
or 
 
Merck Serono S.A. 
Succursale d’Aubonne 
Zone Industrielle de l’Ouriettaz 
CH-1170 Aubonne 
Switzerland 
 
Name and address of the manufacturer responsible for batch release 
 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

  



109 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



110 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



111 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOX OF 1, 3, 12 AND 36 SYRINGES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 22 micrograms solution for injection in pre-filled syringe 
 
interferon beta-1a 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Composition: Each pre-filled syringe (0.5 mL) contains 22 micrograms (6 MIU) of interferon beta-1a. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid and sodium 
hydroxide for pH adjustment and water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
 
1 pre-filled syringe.  
3 pre-filled syringes.  
12 pre-filled syringes. 
36 pre-filled syringes. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
For single dose only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



112 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store the syringe in the original package in order to protect from light. The patient may store Rebif at 
or below 25°C for a single period up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/063/001 1 pre-filled syringe 
EU/1/98/063/002 3 pre-filled syringes 
EU/1/98/063/003 12 pre-filled syringes 
EU/1/98/063/020 36 pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rebif 22 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



113 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



114 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 22 mcg solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
22 micrograms (6 million IU)/0.5 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
  



115 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOX OF 1, 3, 12 AND 36 SYRINGES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 44 micrograms solution for injection in pre-filled syringe 
 
interferon beta-1a 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Composition: Each pre-filled syringe (0.5 mL) contains 44 micrograms (12 MIU) of interferon beta-1a. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid and sodium 
hydroxide for pH adjustment and water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
 
1 pre-filled syringe.  
3 pre-filled syringes.  
12 pre-filled syringes. 
36 pre-filled syringes. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
For single dose only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



116 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store the syringe in the original package in order to protect from light. The patient may store Rebif at 
or below 25°C for a single period up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/063/004 1 pre-filled syringe 
EU/1/98/063/005 3 pre-filled syringes 
EU/1/98/063/006 12 pre-filled syringes 
EU/1/98/063/021 36 pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rebif 44  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



117 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



118 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 44 mcg solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
44 micrograms (12 million IU)/0.5 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 
  



119 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOX OF 6 X 8.8 MICROGRAMS SYRINGES + 6 X 22 MICROGRAMS SYRINGES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 8.8 micrograms solution for injection in pre-filled syringe 
Rebif 22 micrograms solution for injection in pre-filled syringe 
 
interferon beta-1a 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Composition: Each Rebif 8.8 micrograms pre-filled syringe (0.2 mL) contains 8.8 micrograms 
(2.4 Million IU) of interferon beta-1a. 
Each Rebif 22 micrograms pre-filled syringe (0.5 mL) contains 22 micrograms (6 Million IU) of 
interferon beta-1a. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid and sodium 
hydroxide for pH adjustment and water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
 
Initiation pack. 
6 pre-filled syringes of Rebif 8.8 micrograms and 6 pre-filled syringes of Rebif 22 micrograms. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
For single dose only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 



120 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store the syringe in the original package in order to protect from light. The patient may store Rebif at 
or below 25°C for a single period up to 14 days. Rebif must then be returned to the refrigerator and 
used before the expiry date. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/063/007 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rebif 8.8 
rebif 22 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



121 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



122 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 8.8 mcg solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
8.8 micrograms (2.4 million IU)/0.2 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 



123 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 22 mcg solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
22 micrograms (6 million IU)/0.5 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 
  



124 

PARTICULARS TO APPEAR ON THE LAYERS SEPARATORS FOR THE STARTER 
PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
(UPPER FLAP) 
Rebif 8.8 micrograms solution for injection 
interferon beta-1a 
Subcutaneous use 
BRAILLE: rebif 8.8 
 
(LOWER FLAP) 
Rebif 22 micrograms solution for injection 
interferon beta-1a 
Subcutaneous use 
BRAILLE: rebif 22 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
 
4. BATCH NUMBER 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
(UPPER FLAP) 
6 pre-filled syringes of Rebif 8.8 micrograms  
 
(LOWER FLAP) 
6 pre-filled syringes of Rebif 22 micrograms 
  



125 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOX OF 4 OR 12 CARTRIDGES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 22 micrograms/0.5 mL solution for injection in cartridge 
 
interferon beta-1a 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Composition: Each cartridge contains 66 micrograms (18 MIU) of interferon beta-1a in 1.5 mL 
solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid and sodium 
hydroxide for pH adjustment and water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
 
4 cartridges 
12 cartridges 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
For multidose use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
After first injection use within 28 days. 
 
 



126 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store the cartridge in the original package in order to protect from light. 
The device containing a cartridge of Rebif must be stored in the device storage box in a refrigerator 
(2°C – 8°C). The patient may store Rebif at or below 25°C for a single period up to 14 days. Rebif 
must then be returned to the refrigerator and used before the expiry date. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/063/008 4 cartridges 
EU/1/98/063/018 12 cartridges 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rebif 22/0.5 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



127 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



128 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
CARTRIDGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 22 mcg/0.5 mL solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
66 micrograms (18 million IU)/1.5 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 
  



129 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOX OF 4 OR 12 CARTRIDGES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 44 micrograms/0.5 mL solution for injection in cartridge 
 
interferon beta-1a 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Composition: Each cartridge contains 132 micrograms (36 MIU) of interferon beta-1a in 1.5 mL 
solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid and sodium 
hydroxide for pH adjustment and water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
 
4 cartridges 
12 cartridges 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
For multidose use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
After first injection use within 28 days. 
 
 



130 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store the cartridge in the original package in order to protect from light. 
The device containing a cartridge of Rebif must be stored in the device storage box in a refrigerator 
(2°C – 8°C). The patient may store Rebif at or below 25°C for a single period up to 14 days. Rebif 
must then be returned to the refrigerator and used before the expiry date. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/063/009 4 cartridges 
EU/1/98/063/019 12 cartridges 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rebif 44/0.5 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



131 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



132 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
CARTRIDGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 44 mcg/0.5 mL solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
132 micrograms (36 million IU)/1.5 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 
  



133 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOX OF 2 CARTRIDGES  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 8.8 micrograms/0.1 mL solution for injection in cartridge 
Rebif 22 micrograms/0.25 mL solution for injection in cartridge 
 
interferon beta-1a 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Composition: Each cartridge contains 132 micrograms (36 MIU) of interferon beta-1a in 1.5 mL 
solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid and sodium 
hydroxide for pH adjustment and water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
 
Initiation pack. 
2 cartridges  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
For multidose use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
After first injection use within 28 days. 
 



134 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store the cartridge in the original package in order to protect from light. 
The device containing a cartridge of Rebif must be stored in the device storage box in a refrigerator 
(2°C – 8°C). The patient may store Rebif at or below 25°C for a single period up to 14 days. Rebif 
must then be returned to the refrigerator and used before the expiry date. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/063/010  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rebif 8.8/0.1 / 22/0.25 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



135 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



136 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
CARTRIDGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 8.8 mcg/0.1 mL 
Rebif 22 mcg/0.25 mL  
Solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
132 micrograms (36 million IU)/1.5 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 
  



137 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOX OF 1, 3 AND 12 PRE-FILLED PENS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 22 micrograms solution for injection in pre-filled pen 
 
interferon beta-1a 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Composition: Each pre-filled pen contains 22 micrograms (6 MIU) of interferon beta-1a in 0.5 mL 
solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid and sodium 
hydroxide for pH adjustment and water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
 
1 pre-filled pen. RebiDose. 
3 pre-filled pens. RebiDose. 
12 pre-filled pens. RebiDose. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
For single dose only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



138 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store the pre-filled pen in the original package in order to protect from light. The patient may store 
Rebif at or below 25°C for a single period up to 14 days. Rebif must then be returned to the 
refrigerator and used before the expiry date. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/063/011 1 pre-filled pen 
EU/1/98/063/012 3 pre-filled pens 
EU/1/98/063/013 12 pre-filled pens 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rebif 22 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



139 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



140 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
PRE-FILLED PEN 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 22 micrograms solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
22 micrograms (6 million IU)/0.5 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 
  



141 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOX OF 1, 3 AND 12 PRE-FILLED PENS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 44 micrograms solution for injection in pre-filled pen 
 
interferon beta-1a 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Composition: Each pre-filled pen contains 44 micrograms (12 MIU) of interferon beta-1a in 0.5 mL 
solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid and sodium 
hydroxide for pH adjustment and water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
 
1 pre-filled pen. RebiDose. 
3 pre-filled pens. RebiDose. 
12 pre-filled pens. RebiDose. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
For single dose only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



142 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store the pre-filled pen in the original package in order to protect from light. The patient may store 
Rebif at or below 25°C for a single period up to 14 days. Rebif must then be returned to the 
refrigerator and used before the expiry date. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/063/014 1 pre-filled pen 
EU/1/98/063/015 3 pre-filled pens 
EU/1/98/063/016 12 pre-filled pens 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rebif 44  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



143 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



144 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
PRE-FILLED PEN 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 44 micrograms solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
44 micrograms (12 million IU)/0.5 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 
  



145 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOX OF 6 X 8.8 MICROGRAMS PRE-FILLED PENS + 6 X 22 MICROGRAMS PRE-
FILLED PENS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rebif 8.8 micrograms solution for injection in pre-filled pen 
Rebif 22 micrograms solution for injection in pre-filled pen 
 
interferon beta-1a 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Composition: Each Rebif 8.8 micrograms pre-filled pen contains 8.8 micrograms (2.4 Million IU) of 
interferon beta-1a in 0.2 mL solution. 
Each Rebif 22 micrograms pre-filled pen contains 22 micrograms (6 Million IU) of interferon beta-1a 
in 0.5 mL solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid and sodium 
hydroxide for pH adjustment and water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
 
Initiation pack. 
6 pre-filled pens of 8.8 micrograms and 6 pre-filled pens of 22 micrograms. RebiDose. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
For single dose only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 



146 

8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store the pre-filled pen in the original package in order to protect from light. The patient may store 
Rebif at or below 25°C for a single period up to 14 days. Rebif must then be returned to the 
refrigerator and used before the expiry date. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/063/017 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rebif 8.8 
rebif 22 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



147 

 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



148 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
PRE-FILLED PEN 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 8.8 micrograms solution for injection 
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
8.8 micrograms (2.4 million IU)/0.2 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 



149 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
PRE-FILLED PEN 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rebif 22 micrograms solution for injection  
 
interferon beta-1a 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
22 micrograms (6 million IU)/0.5 mL 
 
 
6. OTHER 
 
Merck Europe B.V. 
 
  



150 

PARTICULARS TO APPEAR ON THE LAYERS SEPARATORS FOR THE STARTER 
PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
(UPPER FLAP) 
Rebif 8.8 micrograms solution for injection in pre-filled pen 
interferon beta-1a 
Subcutaneous use 
BRAILLE: rebif 8.8 
 
(LOWER FLAP) 
Rebif 22 micrograms solution for injection in pre-filled pen 
interferon beta-1a 
Subcutaneous use 
BRAILLE: rebif 22 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
 
4. BATCH NUMBER 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
(UPPER FLAP) 
6 pre-filled pens 
RebiDose 
 
(LOWER FLAP) 
6 pre-filled pens 
RebiDose 

  



151 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



152 

Package leaflet: Information for the user 
 

Rebif 22 micrograms solution for injection in pre-filled syringe 
interferon beta-1a 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor, pharmacist or nurse. 
− This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Rebif is and what it is used for 
2. What you need to know before you use Rebif 
3. How to use Rebif 
4. Possible side effects 
5. How to store Rebif 
6. Contents of the pack and other information 
 
 
1. What Rebif is and what it is used for 
 
Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit 
messages between cells. Interferons are produced by the body and play an essential role in the immune 
system. Through mechanisms that are not totally understood, interferons help to limit the damage of 
the central nervous system associated with multiple sclerosis.  
 
Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced 
in the human body. 
 
Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the number and the 
severity of relapses and to slow the progression of disability. 
 
 
2. What you need to know before you use Rebif 
 
Do not use Rebif 
• if you are allergic to natural or recombinant interferon beta or any of the other ingredients of 

this medicine (listed in section 6). 
• if you are severely depressed at present. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Rebif. 
 
• Rebif should only be used under the supervision of your doctor. 
• Before treatment with Rebif, read carefully and follow the advice given under “How to use 

Rebif” in order to minimise the risk of injection site necrosis (skin breakdown and tissue 
destruction) that has been reported in patients treated with Rebif. If you experience troubling 
local reactions, contact your doctor. 

• Talk to your doctor or pharmacist before taking Rebif if you have an allergy (hypersensitivity) 
to any other medicines. 



153 

• Blood clots in the small blood vessels may occur during your treatment. These blood clots could 
affect your kidneys. This might happen several weeks to several years after starting Rebif. Your 
doctor may want to check your blood pressure, blood (platelet count) and the function of your 
kidney. 

 
Inform your doctor if you have a disease of  
• the bone marrow,  
• kidney,  
• liver,  
• heart,  
• thyroid, 
• or if you have experienced depression,  
• or if you have any history of epileptic seizures,  
so that he/she can closely monitor your treatment and any worsening of these conditions. 
 
Other medicines and Rebif 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
In particular you should tell your doctor if you are using antiepileptics or antidepressants. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
No harmful effects on the breastfed newborn/infant are anticipated. Rebif can be used during breast-
feeding. 
 
Driving and using machines 
Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. 
You should discuss this with your doctor if you are concerned. 
 
Rebif contains sodium and benzyl alcohol 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 
‘sodium-free’. 
 
This medicine contains 2.5 mg benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions. 
 
Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called 
“gasping syndrome”) in young children.  
 
Do not use for more than a week in young children (less than 3 years old), unless advised by your 
doctor or pharmacist. 
 
Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver 
or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may 
cause side effects (called “metabolic acidosis”). 
 
 
3. How to use Rebif 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Dose 
The usual dose is 44 micrograms (12 million IU) given three times per week. Your doctor has 
prescribed you a lower dose of 22 micrograms (6 million IU) given three times per week. This lower 
dose is recommended for patients who cannot tolerate the higher dose. 
 



154 

Rebif should be administered three times per week, and if possible: 
• on the same three days every week (at least 48 hours apart, e.g. Monday, Wednesday, Friday) 
• at the same time of day (preferably in the evening). 
 
Use in children and teenagers (2 to 17 years old) 
No formal clinical studies have been conducted in children or teenagers. However there is some 
clinical data available suggesting that the safety profile in children and teenagers receiving Rebif 
22 micrograms or Rebif 44 micrograms three times per week is similar to that seen in adults.   
 
Use in children (below 2 years of age) 
Rebif is not recommended for use in children below 2 years of age. 
 
Method of administration 
Rebif is intended for subcutaneous (under the skin) injection. 
The first injection(s) must be performed under the supervision of an appropriately qualified healthcare 
professional. After receiving adequate training, you, a family member, friend or carer can use Rebif 
syringes to administer the medicine at home. It may also be administered with a suitable auto-injector. 
 
For administration of Rebif, please read the following instructions carefully: 
This medicine is for single use. Only clear to opalescent solution without particles and without visible 
signs of deterioration should be used. 
 
How to inject Rebif 
 

 

• Choose an injection site. Your doctor will advise you on the 
possible injection sites (good sites include the upper thighs 
and the lower abdomen). Hold the syringe like a pencil or 
dart. It is recommended that you keep track of and rotate your 
injection sites, so that one area is not injected too frequently 
in order to minimise the risk of injection site necrosis. 
NOTE: do not use any areas in which you feel lumps, firm 
knots, or pain; talk to your doctor or healthcare professional 
about anything you find. 

 
• Wash your hands thoroughly with soap and water. 
• Remove the Rebif syringe from the blister pack by peeling back the plastic covering. 
• Before the injection, use an alcohol wipe to clean the skin at the injection site. Let the skin dry. 

If a bit of alcohol is left on the skin, you may get a stinging sensation. 
 
 

 

• Gently pinch the skin together around the site (to lift it up a 
bit). 

• Resting your wrist on the skin near the site, stick the needle at 
a right angle straight into the skin with a quick, firm motion. 

 

• Inject the medicine by using a slow, steady push (push the 
plunger all the way in until the syringe is empty). 

• Hold a swab on the injection site. Remove the needle from 
the skin. 

 



155 

• Gently massage the injection site with a dry cotton ball or gauze. 
• Dispose of all used items: once you have finished your injection, immediately discard the 

syringe in an appropriate disposal unit. 
 
If you use more Rebif than you should 
In case of overdose, contact your doctor immediately. 
 
If you forget to use Rebif 
If you miss a dose, continue to inject from the day of the next scheduled dose. Do not use a double 
dose to make up for a forgotten dose. 
 
If you stop using Rebif 
The effects of Rebif may not be noticed immediately. Therefore, you should not stop using Rebif but 
continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please 
consult your doctor.  
 
You should not discontinue the treatment without first contacting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately and stop using Rebif if you experience any of the following serious 
side effects: 
 
• Serious allergic (hypersensitivity) reactions. If, immediately following Rebif administration 

you experience a sudden difficulty breathing, which may appear in association with swelling of 
face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or 
faintness, contact your doctor immediately or seek urgent medical attention. These reactions are 
rare (may affect up to 1 in 1,000 people). 

 
• Inform your doctor immediately if you experience any of the following possible symptoms of a 

liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, 
loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver 
problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and 
confusion. 

 
• Depression is common (may affect up to 1 in 10 people) in treated patients with multiple 

sclerosis. If you feel depressed or develop thoughts of suicide, report it immediately to your 
doctor. 

 
Talk to your doctor if you experience any of the following side effects: 
 
• Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea 

are very common (may affect more than 1 in 10 people). 
These symptoms are usually mild, are more common at the start of the treatment and decrease 
with continued use. 
To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller 
before a dose of Rebif and then for 24 hours after each injection.  

 
• Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin 

breakdown are very common.  
The occurrence of injection site reactions usually decreases over time.  



156 

Tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up to 
1 in 100 people). 
See recommendations in section “Warnings and precautions” to minimise the risk of injection 
site reactions. 
The injection site can become infected (uncommon); the skin may become swollen tender and 
hard and the whole area could be very painful. If you experience any of these symptoms, contact 
your doctor for advice. 
 

• Certain laboratory tests may change. These changes are generally not noticed by the patient 
(no symptoms), are usually reversible and mild, and most often do not require particular 
treatment. 
The number of red blood cells, white blood cells or platelets may decrease either individually 
(very common) or all at one time (rare). Possible symptoms resulting from these changes could 
include tiredness, reduced ability to fight infection, bruising or unexplained bleeding.  
Liver function tests may be disturbed (very common). Inflammation of the liver has also been 
reported (uncommon). If you experience symptoms suggesting a liver disorder, such as loss of 
appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact 
your doctor immediately (see above “Tell your doctor immediately...”). 

 
• Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or 

insufficiently. These changes in the thyroid activity are almost always not felt by the patient as 
symptoms; however your doctor may recommend testing as appropriate. 

 
• MS pseudo-relapse (frequency not known): There is a possibility that at the beginning of your 

treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis 
relapse. For example, your muscles may feel very tense or very weak, preventing you from 
moving as you want. In some cases such symptoms are associated with fever or flu-like 
symptoms described above. If you notice any of these side effects talk to your doctor. 

 
Other possible side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Headache 
 
Common (may affect up to 1 in 10 people): 
• Insomnia (sleeping difficulty) 
• Diarrhoea, nausea, vomiting 
• Itching, rash (skin eruptions) 
• Muscle and joints pain 
• Fatigue, fever, chills 
• Hair loss 
 
Uncommon (may affect up to 1 in 100 people): 
• Hives 
• Epileptic seizures 
• Liver inflammation (hepatitis) 
• Breathing difficulties 
• Blood clots such as deep venous thrombosis 
• Disorders of the retina (back of the eye) such as inflammation or blood clots with consequent 

vision disorders (vision disturbances, loss of vision) 
• Increased sweating 
 
Rare (may affect up to 1 in 1,000 people): 
• Suicide attempt 
• Serious skin reactions - some with mucosal lesions 



157 

• Blood clots in the small blood vessels that can affect your kidneys (thrombotic 
thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased 
bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. Your 
doctor may find changes in your blood and the function of your kidneys. 

• Drug-induced lupus erythematosus: a side-effect of long-term use of Rebif. Symptoms may 
include muscle pain, joint pain and swelling, and rash. You may also experience other signs 
such as fever, weight loss, and fatigue. Usually symptoms disappear within one or two weeks 
after treatment is stopped. 

• Kidney problems including scarring that may reduce your kidney function. 
If you get some or all of these symptoms:  
- foamy urine  
- fatigue  
- swelling, particularly in the ankles and eyelids, and weight gain. 
Tell your doctor as they may be signs of a possible kidney problem. 

 
The following side effects were reported for interferon beta (frequency not known) 
• Dizziness  
• Nervousness 
• Loss of appetite 
• Dilatation of the blood vessels and palpitation  
• Irregularities and/or changes in menstrual flow. 
• Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 

resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. 
Pulmonary arterial hypertension has been seen at various time points during treatment, 
including several years after starting treatment with Rebif. 

• Inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard 
and possibly develop painful red lumps or patches. 

 
You should not stop or alter the medication without your doctor’s advice. 
 
Children and teenagers 
Side effects in children and teenagers are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Rebif 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment). 
 
For the purpose of ambulatory use, you may remove Rebif from the refrigerator and store it not above 
25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and used 
before the expiry date. 
 
Store in the original package in order to protect from light. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


158 

Do not use this medicine if you notice any visible signs of deterioration such as if the solution is no 
longer clear or if it contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Rebif contains  
• The active substance is interferon beta-1a. Each syringe contains 22 micrograms, corresponding 

to 6 million International Units (IU) of interferon beta-1a. 
• The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium 

acetate, acetic acid, sodium hydroxide and water for injections. 
 
What Rebif looks like and contents of the pack 
Rebif is available as a solution for injection in a pre-filled syringe with a fixed needle for 
self-administration. Rebif solution is clear to opalescent. The pre-filled syringe is ready for use and 
contains 0.5 mL of solution. 
Rebif is available in packs of 1, 3, 12 and 36 pre-filled syringes. Not all pack sizes may be marketed.  
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
Manufacturer 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  



159 

Package leaflet: Information for the user 
 

Rebif 44 micrograms solution for injection in pre-filled syringe 
interferon beta-1a 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor, pharmacist or nurse. 
− This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Rebif is and what it is used for 
2. What you need to know before you use Rebif 
3. How to use Rebif 
4. Possible side effects 
5. How to store Rebif 
6. Contents of the pack and other information 
 
 
1. What Rebif is and what it is used for 
 
Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit 
messages between cells. Interferons are produced by the body and play an essential role in the immune 
system. Through mechanisms that are not totally understood, interferons help to limit the damage of 
the central nervous system associated with multiple sclerosis.  
 
Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced 
in the human body. 
 
Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the number and the 
severity of relapses and to slow the progression of disability. It is also approved for use in patients 
who have experienced a single clinical event likely to be a first sign of multiple sclerosis. 
 
 
2. What you need to know before you use Rebif 
 
Do not use Rebif 
• if you are allergic to natural or recombinant interferon beta or any of the other ingredients of 

this medicine (listed in section 6). 
• if you are severely depressed at present. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Rebif. 
 
• Rebif should only be used under the supervision of your doctor. 
• Before treatment with Rebif, read carefully and follow the advice given under “How to use 

Rebif” in order to minimise the risk of injection site necrosis (skin breakdown and tissue 
destruction) that has been reported in patients treated with Rebif. If you experience troubling 
local reactions, contact your doctor. 

• Talk to your doctor or pharmacist before taking Rebif if you have an allergy (hypersensitivity) 
to any other medicines. 



160 

• Blood clots in the small blood vessels may occur during your treatment. These blood clots could 
affect your kidneys. This might happen several weeks to several years after starting Rebif. Your 
doctor may want to check your blood pressure, blood (platelet count) and the function of your 
kidney. 

 
Inform your doctor if you have a disease of  
• the bone marrow,  
• kidney,  
• liver,  
• heart,  
• thyroid, 
• or if you have experienced depression,  
• or if you have any history of epileptic seizures,  
so that he/she can closely monitor your treatment and any worsening of these conditions. 
 
Other medicines and Rebif 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
In particular you should tell your doctor if you are using antiepileptics or antidepressants. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
No harmful effects on the breastfed newborn/infant are anticipated. Rebif can be used during breast-
feeding. 
 
Driving and using machines 
Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. 
You should discuss this with your doctor if you are concerned. 
 
Rebif contains sodium and benzyl alcohol 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 
‘sodium-free’. 
 
This medicine contains 2.5 mg benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions. 
 
Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called 
“gasping syndrome”) in young children.  
 
Do not use for more than a week in young children (less than 3 years old), unless advised by your 
doctor or pharmacist. 
 
Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver 
or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may 
cause side effects (called “metabolic acidosis”). 
 
 
3. How to use Rebif 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Dose 
Patients who have experienced a single clinical event  
The usual dose is 44 micrograms (12 million IU) given three times per week. 
 
Patients with multiple sclerosis 
The usual dose is 44 micrograms (12 million IU) given three times per week.  



161 

 
A lower dose of 22 micrograms (6 million IU) given three times per week is recommended for patients 
who cannot tolerate the higher dose. 
 
Rebif should be administered three times per week, and if possible: 
• on the same three days every week (at least 48 hours apart, e.g. Monday, Wednesday, Friday) 
• at the same time of day (preferably in the evening). 
 
Use in children and teenagers (2 to 17 years old) 
No formal clinical studies have been conducted in children or teenagers. However there is some 
clinical data available suggesting that the safety profile in children and teenagers receiving Rebif 
22 micrograms or Rebif 44 micrograms three times per week is similar to that seen in adults.   
 
Use in children (below 2 years of age) 
Rebif is not recommended for use in children below 2 years of age. 
 
Method of administration 
Rebif is intended for subcutaneous (under the skin) injection. 
The first injection(s) must be performed under the supervision of an appropriately qualified healthcare 
professional. After receiving adequate training, you, a family member, friend or carer can use Rebif 
syringes to administer the medicine at home. It may also be administered with a suitable auto-injector. 
 
For administration of Rebif, please read the following instructions carefully: 
This medicine is for single use. Only clear to opalescent solution without particles and without visible 
signs of deterioration should be used. 
 
How to inject Rebif 
 

 

• Choose an injection site. Your doctor will advise you on the 
possible injection sites (good sites include the upper thighs 
and the lower abdomen). Hold the syringe like a pencil or 
dart. It is recommended that you keep track of and rotate your 
injection sites, so that one area is not injected too frequently 
in order to minimise the risk of injection site necrosis. 
NOTE: do not use any areas in which you feel lumps, firm 
knots, or pain; talk to your doctor or healthcare professional 
about anything you find. 

 
• Wash your hands thoroughly with soap and water. 
• Remove the Rebif syringe from the blister pack by peeling back the plastic covering. 
• Before the injection, use an alcohol wipe to clean the skin at the injection site. Let the skin dry. 

If a bit of alcohol is left on the skin, you may get a stinging sensation. 
 
 

 

• Gently pinch the skin together around the site (to lift it up a 
bit). 

• Resting your wrist on the skin near the site, stick the needle at 
a right angle straight into the skin with a quick, firm motion. 



162 

 

• Inject the medicine by using a slow, steady push (push the 
plunger all the way in until the syringe is empty). 

• Hold a swab on the injection site. Remove the needle from 
the skin. 

 
• Gently massage the injection site with a dry cotton ball or gauze. 
• Dispose of all used items: once you have finished your injection, immediately discard the 

syringe in an appropriate disposal unit. 
 
If you use more Rebif than you should 
In case of overdose, contact your doctor immediately. 
 
If you forget to use Rebif 
If you miss a dose, continue to inject from the day of the next scheduled dose. Do not use a double 
dose to make up for a forgotten dose. 
 
If you stop using Rebif 
The effects of Rebif may not be noticed immediately. Therefore, you should not stop using Rebif but 
continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please 
consult your doctor.  
 
You should not discontinue the treatment without first contacting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately and stop using Rebif if you experience any of the following serious 
side effects: 
 
• Serious allergic (hypersensitivity) reactions. If, immediately following Rebif administration 

you experience a sudden difficulty breathing, which may appear in association with swelling of 
face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or 
faintness, contact your doctor immediately or seek urgent medical attention. These reactions are 
rare (may affect up to 1 in 1,000 people). 

 
• Inform your doctor immediately if you experience any of the following possible symptoms of a 

liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, 
loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver 
problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and 
confusion. 

 
• Depression is common (may affect up to 1 in 10 people) in treated patients with multiple 

sclerosis. If you feel depressed or develop thoughts of suicide, report it immediately to your 
doctor. 

 



163 

Talk to your doctor if you experience any of the following side effects: 
 
• Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea 

are very common (may affect more than 1 in 10 people). 
These symptoms are usually mild, are more common at the start of the treatment and decrease 
with continued use. 
To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller 
before a dose of Rebif and then for 24 hours after each injection.  

 
• Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin 

breakdown are very common.  
The occurrence of injection site reactions usually decreases over time.  
Tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up to 
1 in 100 people). 
See recommendations in section “Warnings and precautions” to minimise the risk of injection 
site reactions. 
The injection site can become infected (uncommon); the skin may become swollen tender and 
hard and the whole area could be very painful. If you experience any of these symptoms, contact 
your doctor for advice. 
 

• Certain laboratory tests may change. These changes are generally not noticed by the patient 
(no symptoms), are usually reversible and mild, and most often do not require particular 
treatment. 
The number of red blood cells, white blood cells or platelets may decrease either individually 
(very common) or all at one time (rare). Possible symptoms resulting from these changes could 
include tiredness, reduced ability to fight infection, bruising or unexplained bleeding.  
Liver function tests may be disturbed (very common). Inflammation of the liver has also been 
reported (uncommon). If you experience symptoms suggesting a liver disorder, such as loss of 
appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact 
your doctor immediately (see above “Tell your doctor immediately...”). 

 
• Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or 

insufficiently. These changes in the thyroid activity are almost always not felt by the patient as 
symptoms; however your doctor may recommend testing as appropriate. 

 
• MS pseudo-relapse (frequency not known): There is a possibility that at the beginning of your 

treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis 
relapse. For example, your muscles may feel very tense or very weak, preventing you from 
moving as you want. In some cases such symptoms are associated with fever or flu-like 
symptoms described above. If you notice any of these side effects talk to your doctor. 

 
Other possible side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Headache 
 
Common (may affect up to 1 in 10 people): 
• Insomnia (sleeping difficulty) 
• Diarrhoea, nausea, vomiting 
• Itching, rash (skin eruptions) 
• Muscle and joints pain 
• Fatigue, fever, chills 
• Hair loss 
 



164 

Uncommon (may affect up to 1 in 100 people): 
• Hives 
• Epileptic seizures 
• Liver inflammation (hepatitis) 
• Breathing difficulties 
• Blood clots such as deep venous thrombosis 
• Disorders of the retina (back of the eye) such as inflammation or blood clots with consequent 

vision disorders (vision disturbances, loss of vision) 
• Increased sweating 
 
Rare (may affect up to 1 in 1,000 people): 
• Suicide attempt 
• Serious skin reactions - some with mucosal lesions 
• Blood clots in the small blood vessels that can affect your kidneys (thrombotic 

thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased 
bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. Your 
doctor may find changes in your blood and the function of your kidneys. 

• Drug-induced lupus erythematosus: a side-effect of long-term use of Rebif. Symptoms may 
include muscle pain, joint pain and swelling, and rash. You may also experience other signs 
such as fever, weight loss, and fatigue. Usually symptoms disappear within one or two weeks 
after treatment is stopped. 

• Kidney problems including scarring that may reduce your kidney function. 
If you get some or all of these symptoms:  
- foamy urine  
- fatigue  
- swelling, particularly in the ankles and eyelids, and weight gain. 
Tell your doctor as they may be signs of a possible kidney problem. 

 
The following side effects were reported for interferon beta (frequency not known) 
• Dizziness  
• Nervousness 
• Loss of appetite 
• Dilatation of the blood vessels and palpitation  
• Irregularities and/or changes in menstrual flow. 
• Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 

resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. 
Pulmonary arterial hypertension has been seen at various time points during treatment, 
including several years after starting treatment with Rebif. 

• Inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard 
and possibly develop painful red lumps or patches. 

 
You should not stop or alter the medication without your doctor’s advice. 
 
Children and teenagers 
Side effects in children and teenagers are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 

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165 

5. How to store Rebif 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment). 
 
For the purpose of ambulatory use, you may remove Rebif from the refrigerator and store it not above 
25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and used 
before the expiry date. 
 
Store in the original package in order to protect from light. 
 
Do not use this medicine if you notice any visible signs of deterioration such as if the solution is no 
longer clear or if it contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Rebif contains 
• The active substance is interferon beta-1a. Each syringe contains 44 micrograms, corresponding 

to 12 million International Units (IU) of interferon beta-1a. 
• The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium 

acetate, acetic acid, sodium hydroxide and water for injections. 
 
What Rebif looks like and contents of the pack 
Rebif is available as a solution for injection in a pre-filled syringe with a fixed needle for 
self-administration. Rebif solution is clear to opalescent. The pre-filled syringe is ready for use and 
contains 0.5 mL of solution. 
Rebif is available in packs of 1, 3, 12 and 36 pre-filled syringes. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
Manufacturer 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  



166 

Package leaflet: Information for the user 
 

Rebif 8.8 micrograms solution for injection in pre-filled syringe 
Rebif 22 micrograms solution for injection in pre-filled syringe 

interferon beta-1a 
Initiation pack 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor, pharmacist or nurse. 
− This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Rebif is and what it is used for 
2. What you need to know before you use Rebif 
3. How to use Rebif 
4. Possible side effects 
5. How to store Rebif 
6. Contents of the pack and other information 
 
 
1. What Rebif is and what it is used for 
 
Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit 
messages between cells. Interferons are produced by the body and play an essential role in the immune 
system. Through mechanisms that are not totally understood, interferons help to limit the damage of 
the central nervous system associated with multiple sclerosis.  
 
Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced 
in the human body. 
 
Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the number and the 
severity of relapses and to slow the progression of disability. It is also approved for use in patients 
who have experienced a single clinical event likely to be a first sign of multiple sclerosis. 
 
 
2. What you need to know before you use Rebif 
 
Do not use Rebif 
• if you are allergic to natural or recombinant interferon beta or any of the other ingredients of 

this medicine (listed in section 6). 
• if you are severely depressed at present. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Rebif. 
 
• Rebif should only be used under the supervision of your doctor. 
• Before treatment with Rebif, read carefully and follow the advice given under “How to use 

Rebif” in order to minimise the risk of injection site necrosis (skin breakdown and tissue 
destruction) that has been reported in patients treated with Rebif. If you experience troubling 
local reactions, contact your doctor. 



167 

• Talk to your doctor or pharmacist before taking Rebif if you have an allergy (hypersensitivity) 
to any other medicines. 

• Blood clots in the small blood vessels may occur during your treatment. These blood clots could 
affect your kidneys. This might happen several weeks to several years after starting Rebif. Your 
doctor may want to check your blood pressure, blood (platelet count) and the function of your 
kidney. 

 
Inform your doctor if you have a disease of  
• the bone marrow,  
• kidney,  
• liver,  
• heart,  
• thyroid, 
• or if you have experienced depression,  
• or if you have any history of epileptic seizures,  
so that he/she can closely monitor your treatment and any worsening of these conditions. 
 
Other medicines and Rebif 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
In particular you should tell your doctor if you are using antiepileptics or antidepressants. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
No harmful effects on the breastfed newborn/infant are anticipated. Rebif can be used during breast-
feeding. 
 
Driving and using machines 
Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. 
You should discuss this with your doctor if you are concerned. 
 
Rebif contains sodium and benzyl alcohol 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 
‘sodium-free’. 
 
This medicine contains 1.0 mg benzyl alcohol per dose of 0.2 mL and 2.5 mg benzyl alcohol per dose 
of 0.5 mL. Benzyl alcohol may cause allergic reactions. 
 
Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called 
“gasping syndrome”) in young children.  
 
Do not use for more than a week in young children (less than 3 years old), unless advised by your 
doctor or pharmacist. 
 
Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver 
or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may 
cause side effects (called “metabolic acidosis”).  
 
 
3. How to use Rebif 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 



168 

Initiating treatment 
Treatment is initiated by gradual increase of the dose (a so-called ‘dose titration’) over a period of 4 
weeks in order to reduce some of the side effects it is recommended that:  
• During weeks one and two, Rebif 8.8 micrograms should be injected three times per week. 
• During weeks three and four, Rebif 22 micrograms should be injected three times per week. 
 
From the fifth week onwards, after you have completed your initiation period, you will follow the 
usual dose regimen prescribed by your doctor. 
 
Dose 
The usual dose is 44 micrograms (12 million IU) given three times per week.  
 
A lower dose of 22 micrograms (6 million IU) given three times per week is recommended for patients 
with multiple sclerosis who cannot tolerate the higher dose 
 
Rebif should be administered three times per week, and if possible: 
• on the same three days every week (at least 48 hours apart, e.g. Monday, Wednesday, Friday) 
• at the same time of day (preferably in the evening). 
 
Use in children and teenagers (2 to 17 years old) 
No formal clinical studies have been conducted in children or teenagers. However there is some 
clinical data available suggesting that the safety profile in children and teenagers receiving Rebif 
22 micrograms or Rebif 44 micrograms three times per week is similar to that seen in adults.   
 
Use in children (below 2 years of age) 
Rebif is not recommended for use in children below 2 years of age. 
 
Method of administration 
Rebif is intended for subcutaneous (under the skin) injection. 
The first injection(s) must be performed under the supervision of an appropriately qualified healthcare 
professional. After receiving adequate training, you, a family member, friend or carer can use Rebif 
syringes to administer the medicine at home. It may also be administered with a suitable auto-injector. 
 
For administration of Rebif, please read the following instructions carefully: 
This medicine is for single use. Only clear to opalescent solution without particles and without visible 
signs of deterioration should be used. 
 
How to inject Rebif 
 

 

• Choose an injection site. Your doctor will advise you on the 
possible injection sites (good sites include the upper thighs 
and the lower abdomen). Hold the syringe like a pencil or 
dart. It is recommended that you keep track of and rotate your 
injection sites, so that one area is not injected too frequently 
in order to minimise the risk of injection site necrosis. 
NOTE: do not use any areas in which you feel lumps, firm 
knots, or pain; talk to your doctor or healthcare professional 
about anything you find. 

 
• Wash your hands thoroughly with soap and water. 
• Remove the Rebif syringe from the blister pack by peeling back the plastic covering. 
• Before the injection, use an alcohol wipe to clean the skin at the injection site. Let the skin dry. 

If a bit of alcohol is left on the skin, you may get a stinging sensation. 
 



169 

 

 

• Gently pinch the skin together around the site (to lift it up a 
bit). 

• Resting your wrist on the skin near the site, stick the needle at 
a right angle straight into the skin with a quick, firm motion. 

 

• Inject the medicine by using a slow, steady push (push the 
plunger all the way in until the syringe is empty). 

• Hold a swab on the injection site. Remove the needle from 
the skin. 

 
• Gently massage the injection site with a dry cotton ball or gauze. 
• Dispose of all used items: once you have finished your injection, immediately discard the 

syringe in an appropriate disposal unit. 
 
If you use more Rebif than you should 
In case of overdose, contact your doctor immediately. 
 
If you forget to use Rebif 
If you miss a dose, continue to inject from the day of the next scheduled dose. Do not use a double 
dose to make up for a forgotten dose. 
 
If you stop using Rebif 
The effects of Rebif may not be noticed immediately. Therefore, you should not stop using Rebif but 
continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please 
consult your doctor.  
 
You should not discontinue the treatment without first contacting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately and stop using Rebif if you experience any of the following serious 
side effects: 
 
• Serious allergic (hypersensitivity) reactions. If, immediately following Rebif administration 

you experience a sudden difficulty breathing, which may appear in association with swelling of 
face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or 
faintness, contact your doctor immediately or seek urgent medical attention. These reactions are 
rare (may affect up to 1 in 1,000 people). 

 
• Inform your doctor immediately if you experience any of the following possible symptoms of a 

liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, 
loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver 
problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and 
confusion. 



170 

 
• Depression is common (may affect up to 1 in 10 people) in treated patients with multiple 

sclerosis. If you feel depressed or develop thoughts of suicide, report it immediately to your 
doctor. 

 
Talk to your doctor if you experience any of the following side effects: 
 
• Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea 

are very common (may affect more than 1 in 10 people). 
These symptoms are usually mild, are more common at the start of the treatment and decrease 
with continued use. 
To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller 
before a dose of Rebif and then for 24 hours after each injection.  

 
• Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin 

breakdown are very common.  
The occurrence of injection site reactions usually decreases over time.  
Tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up to 
1 in 100 people). 
See recommendations in section “Warnings and precautions” to minimise the risk of injection 
site reactions. 
The injection site can become infected (uncommon); the skin may become swollen tender and 
hard and the whole area could be very painful. If you experience any of these symptoms, contact 
your doctor for advice. 
 

• Certain laboratory tests may change. These changes are generally not noticed by the patient 
(no symptoms), are usually reversible and mild, and most often do not require particular 
treatment. 
The number of red blood cells, white blood cells or platelets may decrease either individually 
(very common) or all at one time (rare). Possible symptoms resulting from these changes could 
include tiredness, reduced ability to fight infection, bruising or unexplained bleeding.  
Liver function tests may be disturbed (very common). Inflammation of the liver has also been 
reported (uncommon). If you experience symptoms suggesting a liver disorder, such as loss of 
appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact 
your doctor immediately (see above “Tell your doctor immediately...”). 

 
• Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or 

insufficiently. These changes in the thyroid activity are almost always not felt by the patient as 
symptoms; however your doctor may recommend testing as appropriate. 

 
• MS pseudo-relapse (frequency not known): There is a possibility that at the beginning of your 

treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis 
relapse. For example, your muscles may feel very tense or very weak, preventing you from 
moving as you want. In some cases such symptoms are associated with fever or flu-like 
symptoms described above. If you notice any of these side effects talk to your doctor. 

 
Other possible side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Headache 
 
Common (may affect up to 1 in 10 people): 
• Insomnia (sleeping difficulty) 
• Diarrhoea, nausea, vomiting 
• Itching, rash (skin eruptions) 
• Muscle and joints pain 



171 

• Fatigue, fever, chills 
• Hair loss 
 
Uncommon (may affect up to 1 in 100 people): 
• Hives 
• Epileptic seizures 
• Liver inflammation (hepatitis) 
• Breathing difficulties 
• Blood clots such as deep venous thrombosis 
• Disorders of the retina (back of the eye) such as inflammation or blood clots with consequent 

vision disorders (vision disturbances, loss of vision) 
• Increased sweating 
 
Rare (may affect up to 1 in 1,000 people): 
• Suicide attempt 
• Serious skin reactions - some with mucosal lesions 
• Blood clots in the small blood vessels that can affect your kidneys (thrombotic 

thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased 
bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. Your 
doctor may find changes in your blood and the function of your kidneys. 

• Drug-induced lupus erythematosus: a side-effect of long-term use of Rebif. Symptoms may 
include muscle pain, joint pain and swelling, and rash. You may also experience other signs 
such as fever, weight loss, and fatigue. Usually symptoms disappear within one or two weeks 
after treatment is stopped. 

• Kidney problems including scarring that may reduce your kidney function. 
If you get some or all of these symptoms:  
- foamy urine  
- fatigue  
- swelling, particularly in the ankles and eyelids, and weight gain. 
Tell your doctor as they may be signs of a possible kidney problem. 

 
The following side effects were reported for interferon beta (frequency not known) 
• Dizziness  
• Nervousness 
• Loss of appetite 
• Dilatation of the blood vessels and palpitation  
• Irregularities and/or changes in menstrual flow. 
• Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 

resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. 
Pulmonary arterial hypertension has been seen at various time points during treatment, 
including several years after starting treatment with Rebif. 

• Inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard 
and possibly develop painful red lumps or patches. 

 
You should not stop or alter the medication without your doctor’s advice. 
 
Children and teenagers 
Side effects in children and teenagers are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


172 

5. How to store Rebif 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment). 
 
For the purpose of ambulatory use, you may remove Rebif from the refrigerator and store it not above 
25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and used 
before the expiry date. 
 
Store in the original package in order to protect from light. 
 
Do not use this medicine if you notice any visible signs of deterioration such as if the solution is no 
longer clear or if it contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Rebif contains 
• The active substance is interferon beta-1a.  

− Each 8.8 micrograms syringe contains 8.8 micrograms of interferon beta-1a (2.4 million 
IU).  

− Each 22 micrograms syringe contains 22 micrograms of interferon beta-1a (6 million IU). 
• The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium 

acetate, acetic acid, sodium hydroxide and water for injections. 
 
What Rebif looks like and contents of the pack 
Rebif 8.8 micrograms is a solution for injection in a pre-filled syringe with a fixed needle for 
self-administration. The pre-filled syringe is ready for use and contains 0.2 mL of solution. 
 
Rebif 22 micrograms is a solution for injection in a pre-filled syringe with a fixed needle for 
self-administration. The pre-filled syringe is ready for use and contains 0.5 mL of solution. 
 
Rebif solution is clear to opalescent. 
 
Rebif 8.8 micrograms and Rebif 22 micrograms are supplied in an initiation pack that is intended for 
use during the initial 4 weeks of treatment, during which a gradual increase in Rebif dose is 
recommended. 
 
One-month initiation pack contains six Rebif 8.8 micrograms pre-filled syringes and 
six Rebif 22 micrograms pre-filled syringes. 
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 



173 

Manufacturer 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  



174 

Package leaflet: Information for the user 
 

Rebif 22 micrograms/0.5 mL solution for injection in cartridge 
interferon beta-1a 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor, pharmacist or nurse. 
− This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
 
1. What Rebif is and what it is used for 
2. What you need to know before you use Rebif 
3. How to use Rebif 
4. Possible side effects 
5. How to store Rebif 
6. Contents of the pack and other information 
 
 
1. What Rebif is and what it is used for 
 
Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit 
messages between cells. Interferons are produced by the body and play an essential role in the immune 
system. Through mechanisms that are not totally understood, interferons help to limit the damage of 
the central nervous system associated with multiple sclerosis.  
 
Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced 
in the human body. 
 
Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the number and the 
severity of relapses and to slow the progression of disability. 
 
 
2. What you need to know before you use Rebif 
 
Do not use Rebif 
• if you are allergic to natural or recombinant interferon beta or any of the other ingredients of 

this medicine (listed in section 6). 
• if you are severely depressed at present. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Rebif. 
 
• Rebif should only be used under the supervision of your doctor. 
• Before treatment with Rebif, read carefully and follow the advice given under “How to use 

Rebif” in order to minimise the risk of injection site necrosis (skin breakdown and tissue 
destruction) that has been reported in patients treated with Rebif. If you experience troubling 
local reactions, contact your doctor. 

• Talk to your doctor or pharmacist before taking Rebif if you have an allergy (hypersensitivity) 
to any other medicines. 



175 

• Blood clots in the small blood vessels may occur during your treatment. These blood clots could 
affect your kidneys. This might happen several weeks to several years after starting Rebif. Your 
doctor may want to check your blood pressure, blood (platelet count) and the function of your 
kidney. 

 
Inform your doctor if you have a disease of  
• the bone marrow,  
• kidney,  
• liver,  
• heart,  
• thyroid, 
• or if you have experienced depression,  
• or if you have any history of epileptic seizures,  
so that he/she can closely monitor your treatment and any worsening of these conditions. 
 
Other medicines and Rebif 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
In particular you should tell your doctor if you are using antiepileptics or antidepressants. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
No harmful effects on the breastfed newborn/infant are anticipated. Rebif can be used during breast-
feeding. 
 
Driving and using machines 
Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. 
You should discuss this with your doctor if you are concerned. 
 
Rebif contains sodium and benzyl alcohol 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 
‘sodium-free’. 
 
This medicine contains 2.5 mg benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions. 
 
Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called 
“gasping syndrome”) in young children.  
 
Do not use for more than a week in young children (less than 3 years old), unless advised by your 
doctor or pharmacist. 
 
Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver 
or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may 
cause side effects (called “metabolic acidosis”).  
 
 
3. How to use Rebif 
 
This medicine is for multidose use. 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Dose 
The usual dose is 44 micrograms (12 million IU) given three times per week. Your doctor has 
prescribed you a lower dose of 22 micrograms (6 million IU) given three times per week. This lower 
dose is recommended for patients who cannot tolerate the higher dose 



176 

 
Rebif should be administered three times per week, and if possible: 
• on the same three days every week (at least 48 hours apart, e.g., Monday, Wednesday, Friday)  
• at the same time of day (preferably in the evening). 
 
Use in children and teenagers (2 to 17 years old) 
No formal clinical studies have been conducted in children or teenagers. However there is some 
clinical data available suggesting that the safety profile in children and teenagers receiving Rebif 
22 micrograms or Rebif 44 micrograms three times per week is similar to that seen in adults.   
 
Use in children (below 2 years of age) 
Rebif is not recommended for use in children below 2 years of age. 
 
Method of administration 
• Rebif is intended for subcutaneous (under the skin) injection. 
• The first injection(s) must be performed under the supervision of an appropriately qualified 

healthcare professional. After receiving adequate training, you, a family member, friend or carer 
can use Rebif cartridges with your device to administer the medicine at home. 

• The cartridge is to be used with the RebiSmart electronic injection device. 
• Full instructions for use are provided with your device. Please follow these carefully. 
• Short instructions on how to use Rebif cartridges are given below. 
 
Before you start 
• Wash your hands thoroughly with soap and water. 
• Remove the Rebif cartridge from the blister pack by peeling back the plastic covering. 
• Check (just after removing from the refrigerator) that the cartridge is not accidentally frozen in 

the pack or inside the device. Only clear to opalescent solution without particles and without 
visible signs of deterioration should be used. 

• To place the cartridge in the device and perform the injection follow the instruction manual 
(Instructions for Use) provided with your device. 

 
Where to inject Rebif 
 

 

• Choose an injection site. Your doctor will advise you on the 
possible injection sites (good sites include the upper thighs 
and the lower abdomen). It is recommended that you keep 
track of and rotate your injection sites, so that one area is not 
injected too frequently in order to minimise the risk of 
injection site necrosis. 
NOTE: do not use any areas in which you feel lumps, firm 
knots, or pain; talk to your doctor or healthcare professional 
about anything you find. 

• Before the injection, use an alcohol wipe to clean the skin at 
the injection site. Let the skin dry. If a bit of alcohol is left on 
the skin, you may get a stinging sensation. 

 
How to inject Rebif 
• Your doctor will tell you how to choose the correct dose of 22 micrograms. Please read also the 

instructions in the manual provided with your device (RebiSmart). 
 



177 

RebiSmart • Please ensure that the dose displayed on the screen of the device 
corresponds to the prescribed dose of 22 micrograms before the injection. 

• Place RebiSmart at a right angle (90°) to the skin. 
• Press the injection button. During the injection, the button will flash with 

a green light. 
• Wait until the green light switches off. This tells you that the injection is 

completed.  
• Remove RebiSmart from the injection site. 

 

 
After the injection of Rebif with RebiSmart 
• Remove and discard the needle according to the instruction manual provided with your device. 
• Gently massage the injection site with a dry cotton ball or gauze. 
• Store your device containing a cartridge of Rebif as instructed in section 5 “How to store 

Rebif”. 
 
If you have any further questions, please ask your doctor, nurse or pharmacist. 
 
If you use more Rebif than you should 
In case of overdose, contact your doctor immediately. 
 
If you forget to use Rebif 
If you miss a dose, continue to inject from the day of the next scheduled dose. Do not use a double 
dose to make up for a forgotten dose. 
 
If you stop using Rebif 
The effects of Rebif may not be noticed immediately. Therefore you should not stop using Rebif but 
continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please 
consult your doctor.  
 
You should not discontinue the treatment without first contacting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately and stop using Rebif if you experience any of the following serious 
side effects: 
 
• Serious allergic (hypersensitivity) reactions. If, immediately following Rebif administration 

you experience a sudden difficulty breathing, which may appear in association with swelling of 
face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or 
faintness, contact your doctor immediately or seek urgent medical attention. These reactions are 
rare (may affect up to 1 in 1,000 people). 

 
• Inform your doctor immediately if you experience any of the following possible symptoms of a 

liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, 
loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver 
problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and 
confusion. 

 



178 

• Depression is common (may affect up to 1 in 10 people) in treated patients with multiple 
sclerosis. If you feel depressed or develop thoughts of suicide, report it immediately to your 
doctor. 

 
Talk to your doctor if you experience any of the following side effects: 
 
• Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea 

are very common (may affect more than 1 in 10 people).  
These symptoms are usually mild, are more common at the start of the treatment and decrease 
with continued use.  
To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller 
before a dose of Rebif and then for 24 hours after each injection.  

 
• Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin 

breakdown are very common.  
The occurrence of injection site reactions usually decreases over time.  
Tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up to 
1 in 100 people). 
See recommendations in section “Warnings and precautions” to minimise the risk of injection 
site reactions. 
The injection site can become infected (uncommon); the skin may become swollen tender and 
hard and the whole area could be very painful. If you experience any of these symptoms, contact 
your doctor for advice. 

 
• Certain laboratory tests may change. These changes are generally not noticed by the patient 

(no symptoms), are usually reversible and mild, and most often do not require particular 
treatment. 
The number of red blood cells, white blood cells or platelets may decrease either individually 
(very common) or all at one time (rare). Possible symptoms resulting from these changes could 
include tiredness, reduced ability to fight infection, bruising or unexplained bleeding.  
Liver function tests may be disturbed (very common). Inflammation of the liver has also been 
reported (uncommon). If you experience symptoms suggesting a liver disorder, such as loss of 
appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact 
your doctor immediately (see above “Tell your doctor immediately...”). 

 
• Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or 

insufficiently. These changes in the thyroid activity are almost always not felt by the patient as 
symptoms; however your doctor may recommend testing as appropriate. 

 
• MS pseudo-relapse (frequency not known): There is a possibility that at the beginning of your 

treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis 
relapse. For example, your muscles may feel very tense or very weak, preventing you from 
moving as you want. In some cases such symptoms are associated with fever or flu-like 
symptoms described above. If you notice any of these side effects talk to your doctor. 

 
Other possible side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Headache 
 
Common (may affect up to 1 in 10 people): 
• Insomnia (sleeping difficulty) 
• Diarrhoea, nausea, vomiting 
• Itching, rash (skin eruptions) 
• Muscle and joints pain 
• Fatigue, fever, chills 



179 

• Hair loss 
 
Uncommon (may affect up to 1 in 100 people): 
• Hives 
• Epileptic seizures 
• Liver inflammation (hepatitis) 
• Breathing difficulties 
• Blood clots such as deep venous thrombosis 
• Disorders of the retina (back of the eye) such as inflammation or blood clots with consequent 

vision disorders (vision disturbances, loss of vision) 
• Increased sweating 
 
Rare (may affect up to 1 in 1,000 people): 
• Suicide attempt 
• Serious skin reactions - some with mucosal lesions 
• Blood clots in the small blood vessels that can affect your kidneys (thrombotic 

thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased 
bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. Your 
doctor may find changes in your blood and the function of your kidneys. 

• Drug-induced lupus erythematosus: a side-effect of long-term use of Rebif. Symptoms may 
include muscle pain, joint pain and swelling, and rash. You may also experience other signs 
such as fever, weight loss, and fatigue. Usually symptoms disappear within one or two weeks 
after treatment is stopped. 

• Kidney problems including scarring that may reduce your kidney function. 
If you get some or all of these symptoms:  
- foamy urine  
- fatigue  
- swelling, particularly in the ankles and eyelids, and weight gain. 
Tell your doctor as they may be signs of a possible kidney problem. 

 
The following side effects were reported for interferon beta (frequency not known) 
• Dizziness  
• Nervousness 
• Loss of appetite 
• Dilatation of the blood vessels and palpitation  
• Irregularities and/or changes in menstrual flow 
• Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 

resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. 
Pulmonary arterial hypertension has been seen at various time points during treatment, 
including several years after starting treatment with Rebif. 

• Inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard 
and possibly develop painful red lumps or patches. 

 
You should not stop or alter the medication without your doctor’s advice. 
 
Children and teenagers 
Side effects in children and teenagers are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


180 

5. How to store Rebif 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment). 
 
After first injection use within 28 days. 
 
The device (RebiSmart) containing a pre-filled cartridge of Rebif must be stored in the device storage 
box in a refrigerator (2°C – 8°C). For the purpose of ambulatory use, you may remove Rebif from the 
refrigerator and store it not above 25°C for one single period of up to 14 days. Rebif must then be 
returned to the refrigerator and used before the expiry date. 
 
Store in the original package in order to protect from light. 
 
Do not use this medicine if you notice any visible signs of deterioration such as if the solution is no 
longer clear or if it contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Rebif contains  
• The active substance is interferon beta-1a. Each cartridge contains 66 micrograms 

corresponding to 18 million International Units (IU) of interferon beta-1a. 
• The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium 

acetate, acetic acid, sodium hydroxide and water for injections. 
 
What Rebif looks like and contents of the pack 
Pre-filled cartridge (type 1 glass) with a plunger stopper (rubber) and a crimp cap (aluminium and 
halobutyl rubber), containing 1.5 mL solution for injection. Pack size of 4 or 12 cartridges. Not all pack 
sizes may be marketed. 
 
The cartridge is to be used with the RebiSmart electronic injection device. The device is provided 
separately. 
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
Manufacturer 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
This leaflet was last revised in  
 
 



181 

Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  



182 

Package leaflet: Information for the user 
 

Rebif 44 micrograms/0.5 mL solution for injection in cartridge 
interferon beta-1a 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor, pharmacist or nurse. 
− This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
 
1. What Rebif is and what it is used for 
2. What you need to know before you use Rebif 
3. How to use Rebif 
4. Possible side effects 
5. How to store Rebif 
6. Contents of the pack and other information 
 
 
1. What Rebif is and what it is used for 
 
Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit 
messages between cells. Interferons are produced by the body and play an essential role in the immune 
system. Through mechanisms that are not totally understood, interferons help to limit the damage of 
the central nervous system associated with multiple sclerosis.  
 
Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced 
in the human body. 
 
Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the number and the 
severity of relapses and to slow the progression of disability. It is also approved for use in patients 
who have experienced a single clinical event likely to be a first sign of multiple sclerosis. 
 
 
2. What you need to know before you use Rebif 
 
Do not use Rebif 
• if you are allergic to natural or recombinant interferon beta or any of the other ingredients of 

this medicine (listed in section 6). 
• if you are severely depressed at present. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Rebif. 
 
• Rebif should only be used under the supervision of your doctor. 
• Before treatment with Rebif, read carefully and follow the advice given under “How to use 

Rebif” in order to minimise the risk of injection site necrosis (skin breakdown and tissue 
destruction) that has been reported in patients treated with Rebif. If you experience troubling 
local reactions, contact your doctor. 

• Talk to your doctor or pharmacist before taking Rebif if you have an allergy (hypersensitivity) 
to any other medicines. 



183 

• Blood clots in the small blood vessels may occur during your treatment. These blood clots could 
affect your kidneys. This might happen several weeks to several years after starting Rebif. Your 
doctor may want to check your blood pressure, blood (platelet count) and the function of your 
kidney. 

 
Inform your doctor if you have a disease of  
• the bone marrow,  
• kidney,  
• liver,  
• heart,  
• thyroid, 
• or if you have experienced depression,  
• or if you have any history of epileptic seizures,  
so that he/she can closely monitor your treatment and any worsening of these conditions. 
 
Other medicines and Rebif 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
In particular you should tell your doctor if you are using antiepileptics or antidepressants. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
No harmful effects on the breastfed newborn/infant are anticipated. Rebif can be used during breast-
feeding. 
 
Driving and using machines 
Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. 
You should discuss this with your doctor if you are concerned. 
 
Rebif contains sodium and benzyl alcohol 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 
‘sodium-free’. 
 
This medicine contains 2.5 mg benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions. 
 
Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called 
“gasping syndrome”) in young children.  
 
Do not use for more than a week in young children (less than 3 years old), unless advised by your 
doctor or pharmacist. 
 
Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver 
or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may 
cause side effects (called “metabolic acidosis”). 
 
 
3. How to use Rebif 
 
This medicine is for multidose use. 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Dose 
Patients who have experienced a single clinical event  
The usual dose is 44 micrograms (12 million IU) given three times per week. 
 



184 

Patients with multiple sclerosis 
The usual dose is 44 micrograms (12 million IU) given three times per week.  
 
A lower dose of 22 micrograms (6 million IU) given three times per week is recommended for patients 
who cannot tolerate the higher dose. 
 
Rebif should be administered three times per week, and if possible: 
• on the same three days every week (at least 48 hours apart, e.g., Monday, Wednesday, Friday)  
• at the same time of day (preferably in the evening). 
 
Use in children and teenagers (2 to 17 years old) 
No formal clinical studies have been conducted in children or teenagers. However there is some 
clinical data available suggesting that the safety profile in children and teenagers receiving Rebif 
22 micrograms or Rebif 44 micrograms three times per week is similar to that seen in adults.   
 
Use in children (below 2 years of age) 
Rebif is not recommended for use in children below 2 years of age. 
 
Method of administration 
• Rebif is intended for subcutaneous (under the skin) injection. 
• The first injection(s) must be performed under the supervision of an appropriately qualified 

healthcare professional. After receiving adequate training, you, a family member, friend or carer 
can use Rebif cartridges with your device to administer the medicine at home. 

• The cartridge is to be used with the RebiSmart electronic injection device. 
• Full instructions for use are provided with your device. Please follow these carefully. 
• Short instructions on how to use Rebif cartridges are given below. 
 
Before you start 
• Wash your hands thoroughly with soap and water. 
• Remove the Rebif cartridge from the blister pack by peeling back the plastic covering. 
• Check (just after removing from the refrigerator) that the cartridge is not accidentally frozen in 

the pack or inside the device. Only clear to opalescent solution without particles and without 
visible signs of deterioration should be used. 

• To place the cartridge in the device and perform the injection follow the instruction manual 
(Instructions for Use) provided with your device. 

 
Where to inject Rebif 
 

 

• Choose an injection site. Your doctor will advise you on the 
possible injection sites (good sites include the upper thighs 
and the lower abdomen). It is recommended that you keep 
track of and rotate your injection sites, so that one area is not 
injected too frequently in order to minimise the risk of 
injection site necrosis. 
NOTE: do not use any areas in which you feel lumps, firm 
knots, or pain; talk to your doctor or healthcare professional 
about anything you find. 

• Before the injection, use an alcohol wipe to clean the skin at 
the injection site. Let the skin dry. If a bit of alcohol is left on 
the skin, you may get a stinging sensation. 

 
How to inject Rebif 
• Your doctor will tell you how to choose the correct dose of 44 micrograms. Please read also the 

instructions in the manual provided with your device (RebiSmart). 
 



185 

RebiSmart • Please ensure that the dose displayed on the screen of the device 
corresponds to the prescribed dose of 44 micrograms before the injection. 

• Place RebiSmart at a right angle (90°) to the skin. 
• Press the injection button. During the injection, the button will flash with 

a green light. 
• Wait until the green light switches off. This tells you that the injection is 

completed.  
• Remove RebiSmart from the injection site. 

 

 
After the injection of Rebif with RebiSmart  
• Remove and discard the needle according to the instruction manual provided with your device. 
• Gently massage the injection site with a dry cotton ball or gauze. 
• Store your device containing a cartridge of Rebif as instructed in section 5 “How to store 

Rebif”. 
 
If you have any further questions, please ask your doctor, nurse or pharmacist. 
 
If you use more Rebif than you should 
In case of overdose, contact your doctor immediately. 
 
If you forget to use Rebif 
If you miss a dose, continue to inject from the day of the next scheduled dose. Do not use a double 
dose to make up for a forgotten dose. 
 
If you stop using Rebif 
The effects of Rebif may not be noticed immediately. Therefore you should not stop using Rebif but 
continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please 
consult your doctor.  
 
You should not discontinue the treatment without first contacting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately and stop using Rebif if you experience any of the following serious 
side effects: 
 
• Serious allergic (hypersensitivity) reactions. If, immediately following Rebif administration 

you experience a sudden difficulty breathing, which may appear in association with swelling of 
face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or 
faintness, contact your doctor immediately or seek urgent medical attention. These reactions are 
rare (may affect up to 1 in 1,000 people). 

 
• Inform your doctor immediately if you experience any of the following possible symptoms of a 

liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, 
loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver 
problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and 
confusion. 

 



186 

• Depression is common (may affect up to 1 in 10 people) in treated patients with multiple 
sclerosis. If you feel depressed or develop thoughts of suicide, report it immediately to your 
doctor. 

 
Talk to your doctor if you experience any of the following side effects: 
 
• Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea 

are very common (may affect more than 1 in 10 people).  
These symptoms are usually mild, are more common at the start of the treatment and decrease 
with continued use.  
To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller 
before a dose of Rebif and then for 24 hours after each injection.  

 
• Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin 

breakdown are very common.  
The occurrence of injection site reactions usually decreases over time.  
Tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up to 
1 in 100 people). 
See recommendations in section “Warnings and precautions” to minimise the risk of injection 
site reactions. 
The injection site can become infected (uncommon); the skin may become swollen tender and 
hard and the whole area could be very painful. If you experience any of these symptoms, contact 
your doctor for advice. 

 
• Certain laboratory tests may change. These changes are generally not noticed by the patient 

(no symptoms), are usually reversible and mild, and most often do not require particular 
treatment. 
The number of red blood cells, white blood cells or platelets may decrease either individually 
(very common) or all at one time (rare). Possible symptoms resulting from these changes could 
include tiredness, reduced ability to fight infection, bruising or unexplained bleeding.  
Liver function tests may be disturbed (very common). Inflammation of the liver has also been 
reported (uncommon). If you experience symptoms suggesting a liver disorder, such as loss of 
appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact 
your doctor immediately (see above “Tell your doctor immediately...”). 

 
• Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or 

insufficiently. These changes in the thyroid activity are almost always not felt by the patient as 
symptoms; however your doctor may recommend testing as appropriate. 

 
• MS pseudo-relapse (frequency not known): There is a possibility that at the beginning of your 

treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis 
relapse. For example, your muscles may feel very tense or very weak, preventing you from 
moving as you want. In some cases such symptoms are associated with fever or flu-like 
symptoms described above. If you notice any of these side effects talk to your doctor. 

 
Other possible side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Headache 
 
Common (may affect up to 1 in 10 people): 
• Insomnia (sleeping difficulty) 
• Diarrhoea, nausea, vomiting 
• Itching, rash (skin eruptions) 
• Muscle and joints pain 
• Fatigue, fever, chills 



187 

• Hair loss 
 
Uncommon (may affect up to 1 in 100 people): 
• Hives 
• Epileptic seizures 
• Liver inflammation (hepatitis) 
• Breathing difficulties 
• Blood clots such as deep venous thrombosis 
• Disorders of the retina (back of the eye) such as inflammation or blood clots with consequent 

vision disorders (vision disturbances, loss of vision) 
• Increased sweating 
 
Rare (may affect up to 1 in 1,000 people): 
• Suicide attempt 
• Serious skin reactions - some with mucosal lesions 
• Blood clots in the small blood vessels that can affect your kidneys (thrombotic 

thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased 
bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. Your 
doctor may find changes in your blood and the function of your kidneys. 

• Drug-induced lupus erythematosus: a side-effect of long-term use of Rebif. Symptoms may 
include muscle pain, joint pain and swelling, and rash. You may also experience other signs 
such as fever, weight loss, and fatigue. Usually symptoms disappear within one or two weeks 
after treatment is stopped. 

• Kidney problems including scarring that may reduce your kidney function. 
If you get some or all of these symptoms:  
- foamy urine  
- fatigue  
- swelling, particularly in the ankles and eyelids, and weight gain. 
Tell your doctor as they may be signs of a possible kidney problem. 

 
The following side effects were reported for interferon beta (frequency not known) 
• Dizziness  
• Nervousness 
• Loss of appetite 
• Dilatation of the blood vessels and palpitation  
• Irregularities and/or changes in menstrual flow 
• Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 

resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. 
Pulmonary arterial hypertension has been seen at various time points during treatment, 
including several years after starting treatment with Rebif. 

• Inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard 
and possibly develop painful red lumps or patches. 

 
You should not stop or alter the medication without your doctor’s advice. 
 
Children and teenagers 
Side effects in children and teenagers are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 

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188 

5. How to store Rebif 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment). 
 
After first injection use within 28 days. 
 
The device (RebiSmart) containing a pre-filled cartridge of Rebif must be stored in the device storage 
box in a refrigerator (2°C – 8°C). For the purpose of ambulatory use, you may remove Rebif from the 
refrigerator and store it not above 25°C for one single period of up to 14 days. Rebif must then be 
returned to the refrigerator and used before the expiry date. 
 
Store in the original package in order to protect from light. 
 
Do not use this medicine if you notice any visible signs of deterioration such as if the solution is no 
longer clear or if it contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Rebif contains  
• The active substance is interferon beta-1a. Each cartridge contains 132 micrograms 

corresponding to 36 million International Units (IU) of interferon beta-1a. 
• The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium 

acetate, acetic acid, sodium hydroxide and water for injections. 
 
What Rebif looks like and contents of the pack 
Pre-filled cartridge (type 1 glass) with a plunger stopper (rubber) and a crimp cap (aluminium and 
halobutyl rubber), containing 1.5 mL solution for injection. Pack size of 4 or 12 cartridges. Not all pack 
sizes may be marketed. 
 
The cartridge is to be used with the RebiSmart electronic injection device. The device is provided 
separately. 
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
Manufacturer 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
This leaflet was last revised in  
 
 



189 

Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  



190 

Package leaflet: Information for the user 
 

Rebif 8.8 micrograms/0.1 mL solution for injection in cartridge 
Rebif 22 micrograms/0.25 mL solution for injection in cartridge 

interferon beta-1a 
Initiation pack 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor, pharmacist or nurse. 
− This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
 
1. What Rebif is and what it is used for 
2. What you need to know before you use Rebif 
3. How to use Rebif 
4. Possible side effects 
5. How to store Rebif 
6. Contents of the pack and other information 
 
 
1. What Rebif is and what it is used for 
 
Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit 
messages between cells. Interferons are produced by the body and play an essential role in the immune 
system. Through mechanisms that are not totally understood, interferons help to limit the damage of 
the central nervous system associated with multiple sclerosis.  
 
Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced 
in the human body. 
 
Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the number and the 
severity of relapses and to slow the progression of disability. It is also approved for use in patients 
who have experienced a single clinical event likely to be a first sign of multiple sclerosis. 
 
 
2. What you need to know before you use Rebif 
 
Do not use Rebif 
• if you are allergic to natural or recombinant interferon beta or any of the other ingredients of 

this medicine (listed in section 6). 
• if you are severely depressed at present. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Rebif. 
 
• Rebif should only be used under the supervision of your doctor. 
• Before treatment with Rebif, read carefully and follow the advice given under “How to use 

Rebif” in order to minimise the risk of injection site necrosis (skin breakdown and tissue 
destruction) that has been reported in patients treated with Rebif. If you experience troubling 
local reactions, contact your doctor. 



191 

• Talk to your doctor or pharmacist before taking Rebif if you have an allergy (hypersensitivity) 
to any other medicines. 

• Blood clots in the small blood vessels may occur during your treatment. These blood clots could 
affect your kidneys. This might happen several weeks to several years after starting Rebif. Your 
doctor may want to check your blood pressure, blood (platelet count) and the function of your 
kidney. 

 
Inform your doctor if you have a disease of  
• the bone marrow,  
• kidney,  
• liver,  
• heart,  
• thyroid, 
• or if you have experienced depression,  
• or if you have any history of epileptic seizures,  
so that he/she can closely monitor your treatment and any worsening of these conditions. 
 
Other medicines and Rebif 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
In particular you should tell your doctor if you are using antiepileptics or antidepressants. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
No harmful effects on the breastfed newborn/infant are anticipated. Rebif can be used during breast-
feeding. 
 
Driving and using machines 
Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. 
You should discuss this with your doctor if you are concerned. 
 
Rebif contains sodium and benzyl alcohol 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 
‘sodium-free’. 
 
This medicine contains 0.5 mg benzyl alcohol per dose of 0.1 mL and 1.25 mg benzyl alcohol per dose 
of 0.25 mL. Benzyl alcohol may cause allergic reactions. 
 
Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called 
“gasping syndrome”) in young children.  
 
Do not use for more than a week in young children (less than 3 years old), unless advised by your 
doctor or pharmacist. 
 
Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver 
or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may 
cause side effects (called “metabolic acidosis”). 
 
 
3. How to use Rebif 
 
This medicine is for multidose use. 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 



192 

Initiating treatment 
Treatment is initiated by a gradual increase of the dose (a so-called ‘dose titration’) over a period of 4 
weeks in order to reduce some of the side effects, it is recommended that: 
• During weeks one and two, Rebif 8.8 micrograms should be injected three times per week. 
• During weeks three and four, Rebif 22 micrograms should be injected three times per week. 
 
From the fifth week onwards, after you have completed your initiation period, you will follow the 
usual dose regimen prescribed by your doctor. 
 
Dose 
The usual dose is 44 micrograms (12 million IU) given three times per week. 
 
A lower dose of 22 micrograms (6 million IU) given three times per week is recommended for patients 
with multiple sclerosis who cannot tolerate the higher dose. 
 
Rebif should be administered three times per week, and if possible: 
• on the same three days every week (at least 48 hours apart, e.g., Monday, Wednesday, Friday)  
• at the same time of day (preferably in the evening). 
 
Use in children and teenagers (2 to 17 years old) 
No formal clinical studies have been conducted in children or teenagers. However there is some 
clinical data available suggesting that the safety profile in children and teenagers receiving Rebif 
22 micrograms or Rebif 44 micrograms three times per week is similar to that seen in adults.   
 
Use in children (below 2 years of age) 
Rebif is not recommended for use in children below 2 years of age. 
 
Method of administration 
• Rebif is intended for subcutaneous (under the skin) injection. 
• The first injection(s) must be performed under the supervision of an appropriately qualified 

healthcare professional. After receiving adequate training, you, a family member, friend or carer 
can use Rebif cartridges with your device to administer the medicine at home. 

• The initiation pack contains two identical cartridges of Rebif and you may initiate treatment 
with either cartridge.  

• The cartridge is to be used with the RebiSmart electronic injection device. 
• Full instructions for use are provided with your device. Please follow these carefully. 
• Short instructions on how to use Rebif cartridges  are given below. 
 
Before you start 
• Wash your hands thoroughly with soap and water. 
• Remove the Rebif cartridge from the blister pack by peeling back the plastic covering. 
• Check (just after removing from the refrigerator) that the cartridge is not accidentally frozen in 

the pack or inside the device. Only clear to opalescent solution without particles and without 
visible signs of deterioration should be used. 

• To place the cartridge in the device and perform the injection follow the instruction manual 
(Instructions for Use) provided with your device. 

 



193 

Where to inject Rebif 
 

 

• Choose an injection site. Your doctor will advise you on the 
possible injection sites (good sites include the upper thighs 
and the lower abdomen). It is recommended that you keep 
track of and rotate your injection sites, so that one area is not 
injected too frequently in order to minimise the risk of 
injection site necrosis. 
NOTE: do not use any areas in which you feel lumps, firm 
knots, or pain; talk to your doctor or healthcare professional 
about anything you find. 

• Before the injection, use an alcohol wipe to clean the skin at 
the injection site. Let the skin dry. If a bit of alcohol is left on 
the skin, you may get a stinging sensation. 

 
How to inject Rebif 
• Your doctor will tell you how to choose the correct dose. Please read also the instructions in the 

manual provided with your device (RebiSmart). 
 

RebiSmart • RebiSmart is programmed to guide you through the entire initiation 
process and automatically increases the dose during the initiation period. 
It will also instruct you when you need to change the cartridge.  

• You will need to select the dose prescribed by your doctor via the 
RebiSmart menu to ensure the correct recording of your dose. 

• To activate the “initiation/titration” menu you need to first select 
44 micrograms, then ‘initiation/titration’, press ‘change’, select ‘on’, 
press ‘ok’ and confirm ‘initiation/titration on’ by pressing ‘ok’. 

 
• The device will ensure that:  

− During weeks one and two, Rebif 8.8 micrograms are injected three times per week. 
− During weeks three and four, Rebif 22 micrograms are injected three times per week. 
− From the fifth week onwards, RebiSmart will automatically switch to the usual dose 

regimen. 
• Place RebiSmart at a right angle (90°) to the skin.  
• Press the injection button. During the injection, the button will flash with a green light. 
• Wait until the green light switches off. This tells you that the injection is completed. 
• Remove RebiSmart from the injection site. 

 
After the injection of Rebif with RebiSmart 
• Remove and discard the needle according to the instruction manual provided with your device. 
• Gently massage the injection site with a dry cotton ball or gauze. 
• Store your device containing a cartridge of Rebif as instructed in section 5 “How to store 

Rebif”. 
 
If you have any further questions, please ask your doctor, nurse or pharmacist. 
 
If you use more Rebif than you should 
In case of overdose, contact your doctor immediately. 
 
If you forget to use Rebif 
If you miss a dose, continue to inject from the day of the next scheduled dose. Do not use a double 
dose to make up for a forgotten dose. 
 



194 

If you stop using Rebif 
The effects of Rebif may not be noticed immediately. Therefore you should not stop using Rebif but 
continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please 
consult your doctor.  
 
You should not discontinue the treatment without first contacting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately and stop using Rebif if you experience any of the following serious 
side effects: 
 
• Serious allergic (hypersensitivity) reactions. If, immediately following Rebif administration 

you experience a sudden difficulty breathing, which may appear in association with swelling of 
face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or 
faintness, contact your doctor immediately or seek urgent medical attention. These reactions are 
rare (may affect up to 1 in 1,000 people). 

 
• Inform your doctor immediately if you experience any of the following possible symptoms of a 

liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, 
loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver 
problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and 
confusion. 

 
• Depression is common (may affect up to 1 in 10 people) in treated patients with multiple 

sclerosis. If you feel depressed or develop thoughts of suicide, report it immediately to your 
doctor. 

 
Talk to your doctor if you experience any of the following side effects: 
 
• Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea 

are very common (may affect more than 1 in 10 people).  
These symptoms are usually mild, are more common at the start of the treatment and decrease 
with continued use.  
To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller 
before a dose of Rebif and then for 24 hours after each injection.  

 
• Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin 

breakdown are very common.  
The occurrence of injection site reactions usually decreases over time.  
Tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up to 
1 in 100 people). 
See recommendations in section “Warnings and precautions” to minimise the risk of injection 
site reactions. 
The injection site can become infected (uncommon); the skin may become swollen tender and 
hard and the whole area could be very painful. If you experience any of these symptoms, contact 
your doctor for advice. 

 
• Certain laboratory tests may change. These changes are generally not noticed by the patient 

(no symptoms), are usually reversible and mild, and most often do not require particular 
treatment. 



195 

The number of red blood cells, white blood cells or platelets may decrease either individually 
(very common) or all at one time (rare). Possible symptoms resulting from these changes could 
include tiredness, reduced ability to fight infection, bruising or unexplained bleeding.  
Liver function tests may be disturbed (very common). Inflammation of the liver has also been 
reported (uncommon). If you experience symptoms suggesting a liver disorder, such as loss of 
appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact 
your doctor immediately (see above “Tell your doctor immediately...”). 

 
• Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or 

insufficiently. These changes in the thyroid activity are almost always not felt by the patient as 
symptoms; however your doctor may recommend testing as appropriate. 

 
• MS pseudo-relapse (frequency not known): There is a possibility that at the beginning of your 

treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis 
relapse. For example, your muscles may feel very tense or very weak, preventing you from 
moving as you want. In some cases such symptoms are associated with fever or flu-like 
symptoms described above. If you notice any of these side effects talk to your doctor. 

 
Other possible side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Headache 
 
Common (may affect up to 1 in 10 people): 
• Insomnia (sleeping difficulty) 
• Diarrhoea, nausea, vomiting 
• Itching, rash (skin eruptions) 
• Muscle and joints pain 
• Fatigue, fever, chills 
• Hair loss 
 
Uncommon (may affect up to 1 in 100 people): 
• Hives 
• Epileptic seizures 
• Liver inflammation (hepatitis) 
• Breathing difficulties 
• Blood clots such as deep venous thrombosis 
• Disorders of the retina (back of the eye) such as inflammation or blood clots with consequent 

vision disorders (vision disturbances, loss of vision) 
• Increased sweating 
 
Rare (may affect up to 1 in 1,000 people): 
• Suicide attempt 
• Serious skin reactions - some with mucosal lesions 
• Blood clots in the small blood vessels that can affect your kidneys (thrombotic 

thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased 
bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. Your 
doctor may find changes in your blood and the function of your kidneys. 

• Drug-induced lupus erythematosus: a side-effect of long-term use of Rebif. Symptoms may 
include muscle pain, joint pain and swelling, and rash. You may also experience other signs 
such as fever, weight loss, and fatigue. Usually symptoms disappear within one or two weeks 
after treatment is stopped. 



196 

• Kidney problems including scarring that may reduce your kidney function. 
If you get some or all of these symptoms:  
- foamy urine  
- fatigue  
- swelling, particularly in the ankles and eyelids, and weight gain. 
Tell your doctor as they may be signs of a possible kidney problem. 

 
The following side effects were reported for interferon beta (frequency not known) 
• Dizziness  
• Nervousness 
• Loss of appetite 
• Dilatation of the blood vessels and palpitation  
• Irregularities and/or changes in menstrual flow 
• Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 

resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. 
Pulmonary arterial hypertension has been seen at various time points during treatment, 
including several years after starting treatment with Rebif. 

• Inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard 
and possibly develop painful red lumps or patches. 

 
You should not stop or alter the medication without your doctor’s advice. 
 
Children and teenagers 
Side effects in children and teenagers are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Rebif 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment). 
 
After first injection use within 28 days. 
 
The device (RebiSmart) containing a pre-filled cartridge of Rebif must be stored in the device storage 
box in a refrigerator (2°C – 8°C). For the purpose of ambulatory use, you may remove Rebif from the 
refrigerator and store it not above 25°C for one single period of up to 14 days. Rebif must then be 
returned to the refrigerator and used before the expiry date. 
 
Store in the original package in order to protect from light. 
 
Do not use this medicine if you notice any visible signs of deterioration such as if the solution is no 
longer clear or if it contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 

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197 

 
6. Contents of the pack and other information 
 
What Rebif contains 
• The active substance is interferon beta-1a. Each cartridge contains 132 micrograms 

corresponding to 36 million International Units (IU) of interferon beta-1a.  
• The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium 

acetate, acetic acid, sodium hydroxide and water for injections. 
 
What Rebif looks like and contents of the pack 
Pre-filled cartridge (type 1 glass) with a plunger stopper (rubber) and a crimp cap (aluminium and 
halobutyl rubber), containing 1.5 mL solution for injection. Pack size of 2 cartridges. 
 
The cartridge is to be used with the RebiSmart electronic injection device. The device is provided 
separately. 
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
Manufacturer 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  



198 

Package leaflet: Information for the user 
 

Rebif 22 micrograms solution for injection in pre-filled pen 
interferon beta-1a 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor, pharmacist or nurse. 
− This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
 
1. What Rebif is and what it is used for 
2. What you need to know before you use Rebif 
3. How to use Rebif 
4. Possible side effects 
5. How to store Rebif 
6. Contents of the pack and other information 
 
 
1. What Rebif is and what it is used for 
 
Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit 
messages between cells. Interferons are produced by the body and play an essential role in the immune 
system. Through mechanisms that are not totally understood, interferons help to limit the damage of 
the central nervous system associated with multiple sclerosis.  
 
Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced 
in the human body. 
 
Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the number and the 
severity of relapses and to slow the progression of disability. 
 
 
2. What you need to know before you use Rebif 
 
Do not use Rebif 
• if you are allergic to natural or recombinant interferon beta or any of the other ingredients of 

this medicine (listed in section 6). 
• if you are severely depressed at present. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Rebif. 
 
• Rebif should only be used under the supervision of your doctor. 
• Before treatment with Rebif, read carefully and follow the “RebiDose Instructions for Use” 

provided in a separate booklet, in order to minimise the risk of injection site necrosis (skin 
breakdown and tissue destruction) that has been reported in patients treated with Rebif. If you 
experience troubling local reactions, contact your doctor. 

• Talk to your doctor or pharmacist before taking Rebif if you have an allergy (hypersensitivity) 
to any other medicines. 



199 

• Blood clots in the small blood vessels may occur during your treatment. These blood clots could 
affect your kidneys. This might happen several weeks to several years after starting Rebif. Your 
doctor may want to check your blood pressure, blood (platelet count) and the function of your 
kidney. 

 
Inform your doctor if you have a disease of  
• the bone marrow,  
• kidney,  
• liver,  
• heart,  
• thyroid, 
• or if you have experienced depression,  
• or if you have any history of epileptic seizures,  
so that he/she can closely monitor your treatment and any worsening of these conditions. 
 
Other medicines and Rebif 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
In particular you should tell your doctor if you are using antiepileptics or antidepressants. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
No harmful effects on the breastfed newborn/infant are anticipated. Rebif can be used during breast-
feeding. 
 
Driving and using machines 
Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. 
You should discuss this with your doctor if you are concerned. 
 
Rebif contains sodium and benzyl alcohol 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 
‘sodium-free’. 
 
This medicine contains 2.5 mg benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions. 
 
Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called 
“gasping syndrome”) in young children.  
 
Do not use for more than a week in young children (less than 3 years old), unless advised by your 
doctor or pharmacist. 
 
Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver 
or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may 
cause side effects (called “metabolic acidosis”). 
 
 
3. How to use Rebif 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Dose 
The usual dose is 44 micrograms (12 million IU) given three times per week. Your doctor has 
prescribed you a lower dose of 22 micrograms (6 million IU) given three times per week. This lower 
dose is recommended for patients who cannot tolerate the higher dose. 
 



200 

Rebif should be administered three times per week, and if possible: 
• on the same three days every week (at least 48 hours apart, e.g., Monday, Wednesday, Friday) 
• at the same time of day (preferably in the evening). 
 
Use in children and teenagers (2 to 17 years old) 
No formal clinical studies have been conducted in children or teenagers. However there is some 
clinical data available suggesting that the safety profile in children and teenagers receiving Rebif 
22 micrograms or Rebif 44 micrograms three times per week is similar to that seen in adults.   
 
Use in children (below 2 years of age) 
Rebif is not recommended for use in children below 2 years of age. 
 
Method of administration 
• Rebif is given by injection under the skin (subcutaneously) using a pre-filled pen called 

“RebiDose”. 
• Use each RebiDose only once. 
• The first injection(s) must be performed under the supervision of an appropriately qualified 

healthcare professional. After receiving adequate training, you, a family member, friend or carer 
can use Rebif pre-filled pen to administer the medicine at home. 

• When you do this please read carefully and follow the “RebiDose Instructions for Use” 
provided separately in the booklet. 

 
Only clear to opalescent solution without particles and without visible signs of deterioration should be 
used. 
 
If you use more Rebif than you should 
In case of overdose, contact your doctor immediately. 
 
If you forget to use Rebif 
If you miss a dose, continue to inject from the day of the next scheduled dose. Do not use a double 
dose to make up for a forgotten dose. 
 
If you stop using Rebif 
The effects of Rebif may not be noticed immediately. Therefore, you should not stop using Rebif but 
continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please 
consult your doctor.  
 
You should not discontinue the treatment without first contacting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately and stop using Rebif if you experience any of the following serious 
side effects: 
 
• Serious allergic (hypersensitivity) reactions. If, immediately following Rebif administration 

you experience a sudden difficulty breathing, which may appear in association with swelling of 
face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or 
faintness, contact your doctor immediately or seek urgent medical attention. These reactions are 
rare (may affect up to 1 in 1,000 people). 

 



201 

• Inform your doctor immediately if you experience any of the following possible symptoms of a 
liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, 
loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver 
problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and 
confusion. 

 
• Depression is common (may affect up to 1 in 10 people) in treated patients with multiple 

sclerosis. If you feel depressed or develop thoughts of suicide, report it immediately to your 
doctor. 

 
Talk to your doctor if you experience any of the following side effects: 
 
• Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea 

are very common (may affect more than 1 in 10 people). 
These symptoms are usually mild, are more common at the start of the treatment and decrease 
with continued use. 
To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller 
before a dose of Rebif and then for 24 hours after each injection.  

 
• Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin 

breakdown are very common.  
The occurrence of injection site reactions usually decreases over time.  
Tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up 
to 1 in 100 people). 
See recommendations in section “Warnings and precautions” to minimise the risk of injection 
site reactions. 
The injection site can become infected (uncommon); the skin may become swollen tender and 
hard and the whole area could be very painful. If you experience any of these symptoms, 
contact your doctor for advice. 

 
• Certain laboratory tests may change. These changes are generally not noticed by the patient 

(no symptoms), are usually reversible and mild, and most often do not require particular 
treatment. 
The number of red blood cells, white blood cells or platelets may decrease either individually 
(very common) or all at one time (rare). Possible symptoms resulting from these changes could 
include tiredness, reduced ability to fight infection, bruising or unexplained bleeding.  
Liver function tests may be disturbed (very common). Inflammation of the liver has also been 
reported (uncommon). If you experience symptoms suggesting a liver disorder, such as loss of 
appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact 
your doctor immediately (see above “Tell your doctor immediately...”). 

 
• Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or 

insufficiently. These changes in the thyroid activity are almost always not felt by the patient as 
symptoms; however your doctor may recommend testing as appropriate. 

 
• MS pseudo-relapse (frequency not known): There is a possibility that at the beginning of your 

treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis 
relapse. For example, your muscles may feel very tense or very weak, preventing you from 
moving as you want. In some cases such symptoms are associated with fever or flu-like 
symptoms described above. If you notice any of these side effects talk to your doctor. 

 



202 

Other possible side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Headache 
 
Common (may affect up to 1 in 10 people): 
• Insomnia (sleeping difficulty) 
• Diarrhoea, nausea, vomiting 
• Itching, rash (skin eruptions) 
• Muscle and joints pain 
• Fatigue, fever, chills 
• Hair loss 
 
Uncommon (may affect up to 1 in 100 people): 
• Hives 
• Epileptic seizures 
• Liver inflammation (hepatitis) 
• Breathing difficulties 
• Blood clots such as deep venous thrombosis 
• Disorders of the retina (back of the eye) such as inflammation or blood clots with consequent 

vision disorders (vision disturbances, loss of vision) 
• Increased sweating 
 
Rare (may affect up to 1 in 1,000 people): 
• Suicide attempt 
• Serious skin reactions - some with mucosal lesions 
• Blood clots in the small blood vessels that can affect your kidneys (thrombotic 

thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased 
bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. Your 
doctor may find changes in your blood and the function of your kidneys. 

• Drug-induced lupus erythematosus: a side-effect of long-term use of Rebif. Symptoms may 
include muscle pain, joint pain and swelling, and rash. You may also experience other signs 
such as fever, weight loss, and fatigue. Usually symptoms disappear within one or two weeks 
after treatment is stopped. 

• Kidney problems including scarring that may reduce your kidney function. 
If you get some or all of these symptoms:  
- foamy urine  
- fatigue  
- swelling, particularly in the ankles and eyelids, and weight gain. 
Tell your doctor as they may be signs of a possible kidney problem. 

 
The following side effects were reported for interferon beta (frequency not known) 
• Dizziness  
• Nervousness 
• Loss of appetite 
• Dilatation of the blood vessels and palpitation  
• Irregularities and/or changes in menstrual flow. 
• Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 

resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. 
Pulmonary arterial hypertension has been seen at various time points during treatment, 
including several years after starting treatment with Rebif. 

• Inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard 
and possibly develop painful red lumps or patches. 

 
You should not stop or alter the medication without your doctor’s advice. 



203 

 
Children and teenagers 
Side effects in children and teenagers are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Rebif 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment). 
 
For the purpose of ambulatory use, you may remove Rebif from the refrigerator and store it not above 
25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and used 
before the expiry date. 
 
Store in the original package in order to protect from light. 
 
Do not use this medicine if you notice any visible signs of deterioration such as if the solution is no 
longer clear or if it contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Rebif contains  
• The active substance is interferon beta-1a. Each pre-filled pen contains 22 micrograms, 

corresponding to 6 million International Units (IU) of interferon beta-1a. 
• The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium 

acetate, acetic acid, sodium hydroxide and water for injections. 
 
What Rebif looks like and contents of the pack 
Rebif is available as a solution for injection in a pre-filled pen for self-administration. Rebif solution is 
clear to opalescent. The pre-filled pen is ready for use and contains 0.5 mL of solution. 
Rebif is available in packs of 1, 3 and 12 pre-filled pens (RebiDose). Not all pack sizes may be 
marketed.  
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


204 

Manufacturer 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  



205 

RebiDose Instructions for use 
 

HOW TO USE REBIF PRE-FILLED PEN (RebiDose) 
 
• This section tells you how to use RebiDose.  
• Rebif is given by injection under the skin (subcutaneously). 
• Use each RebiDose only once. 
• The first injection(s) must be performed under the supervision of an appropriately qualified 

healthcare professional. After receiving adequate training, you, a family member, friend or carer 
can use RebiDose to administer the medicine at home. If you have questions about how to inject, 
please ask your doctor, nurse or pharmacist for assistance. 

• Read all the following instructions carefully before using RebiDose. 
 
Equipment 
 
To give yourself an injection you will need: 
• A new RebiDose and 
• Alcohol wipes or similar. 
• a dry cotton ball or gauze 
 
Below is a picture showing what RebiDose looks like. 
 
Before the injection 

 
 

After the injection 

 
 
A. Cap 
B. Transparent window 
C. Plunger 
D. Label 
E. Main body 
F. Button 
G. Safety guard 
H. Needle 

 
 
Before you start 
 
• Wash your hands thoroughly with soap and water. 
• Remove RebiDose from the blister pack by peeling back the plastic covering. 
• Check the appearance of Rebif through the transparent window. It must be clear to opalescent, 

without particles and without any visible signs of deterioration. If there are particles or other 



206 

visible signs of deteriorations, do not use it and contact your doctor, nurse or pharmacist for 
assistance. 

• Check the expiry date on the RebiDose label or on the outer box (as indicated as “EXP”). Do 
not use RebiDose if the expiry date has passed. 

 
Where to inject with RebiDose 
 

 

• Choose an injection site. Your doctor will advise you on 
the possible injection sites (good sites include the upper 
thighs and the lower abdomen.)  

• Keep track of and rotate your injection sites, so that one 
area is not injected too often. This is to minimise the risk 
of skin damage (necrosis). 

• NOTE: do not use any areas in which you feel lumps, 
firm knots, or pain; talk to your doctor or healthcare 
professional about anything you find. 

 
How to inject with RebiDose 
 
• Do not remove the cap until you are ready to administer the injection. 
• Before the injection, use an alcohol wipe to clean the skin at the injection site. Let the skin dry. 

If a bit of alcohol is left on the skin, you may get a stinging sensation. 
 

 

• Hold RebiDose by the main body and use your other hand 
to remove the cap. 

 

• Hold RebiDose at a right angle (90 degrees) to the injection 
site. Push the pen against your skin until you feel resistance. 
This action unlocks the button. 



207 

 

• Keep enough pressure on the skin and press the button with 
your thumb. You will hear a click which indicates the start 
of the injection and the plunger will start moving. Keep 
RebiDose pressed against the skin for at least 10 seconds in 
order to inject all of the medicine. 
It is not necessary to keep the button pressed down with 
your thumb after the injection has begun. 

 

• Remove RebiDose from the injection site. 
The safety guard automatically surrounds the needle and 
locks into place to protect you from the needle. 

 
After the injection 
 

  

• Look through the transparent window to make sure that the 
plunger has moved to the bottom as indicated in the figure. 

• Visually check that there is no liquid left. If there is liquid 
left, not all of the medicine has been injected and you 
should consult your doctor or nurse for assistance. 

 
• Gently massage the injection site with a dry cotton ball or gauze. 
• Do not put the needle cap back on the used RebiDose. This is because the needle is now 

covered by the safety guard. Do not put your fingers in the safety guard. 
• RebiDose is for single use only and should never be reused. 
• Once you have finished your injection, immediately discard RebiDose. Ask your pharmacist 

how to safely dispose of RebiDose. 
 
If you have any further questions, please ask your doctor, nurse or pharmacist. 
 
 
This “Instructions for use” was last revised in 



208 

Package leaflet: Information for the user 
 

Rebif 44 micrograms solution for injection in pre-filled pen 
interferon beta-1a 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor, pharmacist or nurse. 
− This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
 
1. What Rebif is and what it is used for 
2. What you need to know before you use Rebif 
3. How to use Rebif 
4. Possible side effects 
5. How to store Rebif 
6. Contents of the pack and other information 
 
 
1. What Rebif is and what it is used for 
 
Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit 
messages between cells. Interferons are produced by the body and play an essential role in the immune 
system. Through mechanisms that are not totally understood, interferons help to limit the damage of 
the central nervous system associated with multiple sclerosis.  
 
Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced 
in the human body. 
 
Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the number and the 
severity of relapses and to slow the progression of disability. It is also approved for use in patients 
who have experienced a single clinical event likely to be a first sign of multiple sclerosis. 
 
 
2. What you need to know before you use Rebif 
 
Do not use Rebif 
• if you are allergic to natural or recombinant interferon beta or any of the other ingredients of 

this medicine (listed in section 6). 
• if you are severely depressed at present. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Rebif. 
 
• Rebif should only be used under the supervision of your doctor. 
• Before treatment with Rebif, read carefully and follow the “RebiDose Instructions for Use” 

provided in a separate booklet, in order to minimise the risk of injection site necrosis (skin 
breakdown and tissue destruction) that has been reported in patients treated with Rebif. If you 
experience troubling local reactions, contact your doctor. 

• Talk to your doctor or pharmacist before taking Rebif if you have an allergy (hypersensitivity) 
to any other medicines. 



209 

• Blood clots in the small blood vessels may occur during your treatment. These blood clots could 
affect your kidneys. This might happen several weeks to several years after starting Rebif. Your 
doctor may want to check your blood pressure, blood (platelet count) and the function of your 
kidney. 

 
Inform your doctor if you have a disease of  
• the bone marrow,  
• kidney,  
• liver,  
• heart,  
• thyroid, 
• or if you have experienced depression,  
• or if you have any history of epileptic seizures,  
so that he/she can closely monitor your treatment and any worsening of these conditions. 
 
Other medicines and Rebif 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
In particular you should tell your doctor if you are using antiepileptics or antidepressants. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
No harmful effects on the breastfed newborn/infant are anticipated. Rebif can be used during breast-
feeding. 
 
Driving and using machines 
Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. 
You should discuss this with your doctor if you are concerned. 
 
Rebif contains sodium and benzyl alcohol 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 
‘sodium-free’. 
 
This medicine contains 2.5 mg benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions. 
 
Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called 
“gasping syndrome”) in young children.  
 
Do not use for more than a week in young children (less than 3 years old), unless advised by your 
doctor or pharmacist. 
 
Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver 
or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may 
cause side effects (called “metabolic acidosis”). 
 
 
3. How to use Rebif 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Dose 
Patients who have experienced a single clinical event  
The usual dose is 44 micrograms (12 million IU) given three times per week. 
 
Patients with multiple sclerosis 
The usual dose is 44 micrograms (12 million IU) given three times per week.  



210 

 
A lower dose of 22 micrograms (6 million IU) given three times per week is recommended for patients 
who cannot tolerate the higher dose 
 
Rebif should be administered three times per week, and if possible: 
• on the same three days every week (at least 48 hours apart, e.g., Monday, Wednesday, Friday) 
• at the same time of day (preferably in the evening). 
 
Use in children and teenagers (2 to 17 years old) 
No formal clinical studies have been conducted in children or teenagers. However there is some 
clinical data available suggesting that the safety profile in children and teenagers receiving Rebif 
22 micrograms or Rebif 44 micrograms three times per week is similar to that seen in adults.   
 
Use in children (below 2 years of age) 
Rebif is not recommended for use in children below 2 years of age. 
 
Method of administration 
• Rebif is given by injection under the skin (subcutaneously) using a pre-filled pen called 

“RebiDose”. 
• Use each RebiDose only once. 
• The first injection(s) must be performed under the supervision of an appropriately qualified 

healthcare professional. After receiving adequate training, you, a family member, friend or carer 
can use Rebif pre-filled pen to administer the medicine at home. 

• When you do this please read carefully and follow the “RebiDose Instructions for Use” 
provided separately in the booklet. 

 
Only clear to opalescent solution without particles and without visible signs of deterioration should be 
used. 
 
If you use more Rebif than you should 
In case of overdose, contact your doctor immediately. 
 
If you forget to use Rebif 
If you miss a dose, continue to inject from the day of the next scheduled dose. Do not use a double 
dose to make up for a forgotten dose. 
 
If you stop using Rebif 
The effects of Rebif may not be noticed immediately. Therefore, you should not stop using Rebif but 
continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please 
consult your doctor.  
 
You should not discontinue the treatment without first contacting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately and stop using Rebif if you experience any of the following serious 
side effects: 
 
• Serious allergic (hypersensitivity) reactions. If, immediately following Rebif administration 

you experience a sudden difficulty breathing, which may appear in association with swelling of 
face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or 



211 

faintness, contact your doctor immediately or seek urgent medical attention. These reactions are 
rare (may affect up to 1 in 1,000 people). 

 
• Inform your doctor immediately if you experience any of the following possible symptoms of a 

liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, 
loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver 
problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and 
confusion. 

 
• Depression is common (may affect up to 1 in 10 people) in treated patients with multiple 

sclerosis. If you feel depressed or develop thoughts of suicide, report it immediately to your 
doctor. 

 
Talk to your doctor if you experience any of the following side effects: 
 
• Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea 

are very common (may affect more than 1 in 10 people). 
These symptoms are usually mild, are more common at the start of the treatment and decrease 
with continued use. 
To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller 
before a dose of Rebif and then for 24 hours after each injection.  

 
• Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin 

breakdown are very common.  
The occurrence of injection site reactions usually decreases over time.  
Tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up 
to 1 in 100 people). 
See recommendations in section “Warnings and precautions” to minimise the risk of injection 
site reactions. 
The injection site can become infected (uncommon); the skin may become swollen tender and 
hard and the whole area could be very painful. If you experience any of these symptoms, 
contact your doctor for advice. 

 
• Certain laboratory tests may change. These changes are generally not noticed by the patient 

(no symptoms), are usually reversible and mild, and most often do not require particular 
treatment. 
The number of red blood cells, white blood cells or platelets may decrease either individually 
(very common) or all at one time (rare). Possible symptoms resulting from these changes could 
include tiredness, reduced ability to fight infection, bruising or unexplained bleeding.  
Liver function tests may be disturbed (very common). Inflammation of the liver has also been 
reported (uncommon). If you experience symptoms suggesting a liver disorder, such as loss of 
appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact 
your doctor immediately (see above “Tell your doctor immediately...”). 

 
• Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or 

insufficiently. These changes in the thyroid activity are almost always not felt by the patient as 
symptoms; however your doctor may recommend testing as appropriate. 

 
• MS pseudo-relapse (frequency not known): There is a possibility that at the beginning of your 

treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis 
relapse. For example, your muscles may feel very tense or very weak, preventing you from 
moving as you want. In some cases such symptoms are associated with fever or flu-like 
symptoms described above. If you notice any of these side effects talk to your doctor. 

 



212 

Other possible side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Headache 
 
Common (may affect up to 1 in 10 people): 
• Insomnia (sleeping difficulty) 
• Diarrhoea, nausea, vomiting 
• Itching, rash (skin eruptions) 
• Muscle and joints pain 
• Fatigue, fever, chills 
• Hair loss 
 
Uncommon (may affect up to 1 in 100 people): 
• Hives 
• Epileptic seizures 
• Liver inflammation (hepatitis) 
• Breathing difficulties 
• Blood clots such as deep venous thrombosis 
• Disorders of the retina (back of the eye) such as inflammation or blood clots with consequent 

vision disorders (vision disturbances, loss of vision) 
• Increased sweating 
 
Rare (may affect up to 1 in 1,000 people): 
• Suicide attempt 
• Serious skin reactions - some with mucosal lesions 
• Blood clots in the small blood vessels that can affect your kidneys (thrombotic 

thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased 
bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. Your 
doctor may find changes in your blood and the function of your kidneys. 

• Drug-induced lupus erythematosus: a side-effect of long-term use of Rebif. Symptoms may 
include muscle pain, joint pain and swelling, and rash. You may also experience other signs 
such as fever, weight loss, and fatigue. Usually symptoms disappear within one or two weeks 
after treatment is stopped. 

• Kidney problems including scarring that may reduce your kidney function. 
If you get some or all of these symptoms:  
- foamy urine  
- fatigue  
- swelling, particularly in the ankles and eyelids, and weight gain. 
Tell your doctor as they may be signs of a possible kidney problem. 

 
The following side effects were reported for interferon beta (frequency not known) 
• Dizziness  
• Nervousness 
• Loss of appetite 
• Dilatation of the blood vessels and palpitation  
• Irregularities and/or changes in menstrual flow. 
• Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 

resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. 
Pulmonary arterial hypertension has been seen at various time points during treatment, 
including several years after starting treatment with Rebif. 

• Inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard 
and possibly develop painful red lumps or patches. 

 
You should not stop or alter the medication without your doctor’s advice. 



213 

 
Children and teenagers 
Side effects in children and teenagers are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Rebif 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment). 
 
For the purpose of ambulatory use, you may remove Rebif from the refrigerator and store it not above 
25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and used 
before the expiry date. 
 
Store in the original package in order to protect from light. 
 
Do not use this medicine if you notice any visible signs of deterioration such as if the solution is no 
longer clear or if it contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Rebif contains 
• The active substance is interferon beta-1a. Each pre-filled pen contains 44 micrograms, 

corresponding to 12 million International Units (IU) of interferon beta-1a. 
• The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium 

acetate, acetic acid, sodium hydroxide and water for injections. 
 
What Rebif looks like and contents of the pack 
Rebif is available as a solution for injection in a pre-filled pen for self-administration. Rebif solution is 
clear to opalescent. The pre-filled pen is ready for use and contains 0.5 mL of solution. 
Rebif is available in packs of 1, 3 and 12 pre-filled pens (RebiDose). Not all pack sizes may be 
marketed. 
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


214 

Manufacturer 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  



215 

RebiDose Instructions for use 
 

HOW TO USE REBIF PRE-FILLED PEN (RebiDose) 
 
• This section tells you how to use RebiDose.  
• Rebif is given by injection under the skin (subcutaneously). 
• Use each RebiDose only once. 
• The first injection(s) must be performed under the supervision of an appropriately qualified 

healthcare professional. After receiving adequate training, you, a family member, friend or carer 
can use RebiDose to administer the medicine at home. If you have questions about how to inject, 
please ask your doctor, nurse or pharmacist for assistance. 

• Read all the following instructions carefully before using RebiDose. 
 
Equipment 
 
To give yourself an injection you will need: 
• A new RebiDose and 
• Alcohol wipes or similar. 
• a dry cotton ball or gauze 
 
Below is a picture showing what RebiDose looks like. 
 
Before the injection 

 
 

After the injection 

 
 
A. Cap 
B. Transparent window 
C. Plunger 
D. Label 
E. Main body 
F. Button 
G. Safety guard 
H. Needle 

 
 
Before you start 
 
• Wash your hands thoroughly with soap and water. 
• Remove RebiDose from the blister pack by peeling back the plastic covering. 
• Check the appearance of Rebif through the transparent window. It must be clear to opalescent, 

without particles and without any visible signs of deterioration. If there are particles or other 



216 

visible signs of deteriorations, do not use it and contact your doctor, nurse or pharmacist for 
assistance. 

• Check the expiry date on the RebiDose label or on the outer box (as indicated as “EXP”). Do 
not use RebiDose if the expiry date has passed. 

 
Where to inject with RebiDose 
 

 

• Choose an injection site. Your doctor will advise you on 
the possible injection sites (good sites include the upper 
thighs and the lower abdomen.)  

• Keep track of and rotate your injection sites, so that one 
area is not injected too often. This is to minimise the risk 
of skin damage (necrosis). 

• NOTE: do not use any areas in which you feel lumps, 
firm knots, or pain; talk to your doctor or healthcare 
professional about anything you find. 

 
How to inject with RebiDose 
 
• Do not remove the cap until you are ready to administer the injection. 
• Before the injection, use an alcohol wipe to clean the skin at the injection site. Let the skin dry. 

If a bit of alcohol is left on the skin, you may get a stinging sensation. 
 

 

• Hold RebiDose by the main body and use your other hand 
to remove the cap. 

 

• Hold RebiDose at a right angle (90 degrees) to the injection 
site. Push the pen against your skin until you feel resistance. 
This action unlocks the button. 



217 

 

• Keep enough pressure on the skin and press the button with 
your thumb. You will hear a click which indicates the start 
of the injection and the plunger will start moving. Keep 
RebiDose pressed against the skin for at least 10 seconds in 
order to inject all of the medicine. 
It is not necessary to keep the button pressed down with 
your thumb after the injection has begun. 

 

• Remove RebiDose from the injection site. 
The safety guard automatically surrounds the needle and 
locks into place to protect you from the needle. 

 
After the injection 
 

  

• Look through the transparent window to make sure that the 
plunger has moved to the bottom as indicated in the figure. 

• Visually check that there is no liquid left. If there is liquid 
left, not all of the medicine has been injected and you 
should consult your doctor or nurse for assistance. 

 
• Gently massage the injection site with a dry cotton ball or gauze. 
• Do not put the needle cap back on the used RebiDose. This is because the needle is now 

covered by the safety guard. Do not put your fingers in the safety guard. 
• RebiDose is for single use only and should never be reused. 
• Once you have finished your injection, immediately discard RebiDose. Ask your pharmacist 

how to safely dispose of RebiDose. 
 
If you have any further questions, please ask your doctor, nurse or pharmacist. 
 
 
This “Instructions for use” was last revised in 



218 

Package leaflet: Information for the user 
 

Rebif 8.8 micrograms solution for injection in pre-filled pen 
Rebif 22 micrograms solution for injection in pre-filled pen 

interferon beta-1a 
Initiation pack 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor, pharmacist or nurse. 
− This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
 
1. What Rebif is and what it is used for 
2. What you need to know before you use Rebif 
3. How to use Rebif 
4. Possible side effects 
5. How to store Rebif 
6. Contents of the pack and other information 
 
 
1. What Rebif is and what it is used for 
 
Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit 
messages between cells. Interferons are produced by the body and play an essential role in the immune 
system. Through mechanisms that are not totally understood, interferons help to limit the damage of 
the central nervous system associated with multiple sclerosis.  
 
Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced 
in the human body. 
 
Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the number and the 
severity of relapses and to slow the progression of disability. It is also approved for use in patients 
who have experienced a single clinical event likely to be a first sign of multiple sclerosis. 
 
 
2. What you need to know before you use Rebif 
 
Do not use Rebif 
• if you are allergic to natural or recombinant interferon beta or any of the other ingredients of 

this medicine (listed in section 6). 
• if you are severely depressed at present. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before using Rebif. 
 
• Rebif should only be used under the supervision of your doctor. 
• Before treatment with Rebif, read carefully and follow the “RebiDose Instructions for Use” 

provided in a separate booklet, in order to minimise the risk of injection site necrosis (skin 
breakdown and tissue destruction) that has been reported in patients treated with Rebif. If you 
experience troubling local reactions, contact your doctor. 



219 

• Talk to your doctor or pharmacist before taking Rebif if you have an allergy (hypersensitivity) 
to any other medicines. 

• Blood clots in the small blood vessels may occur during your treatment. These blood clots could 
affect your kidneys. This might happen several weeks to several years after starting Rebif. Your 
doctor may want to check your blood pressure, blood (platelet count) and the function of your 
kidney. 

 
Inform your doctor if you have a disease of  
• the bone marrow,  
• kidney,  
• liver,  
• heart,  
• thyroid, 
• or if you have experienced depression,  
• or if you have any history of epileptic seizures,  
so that he/she can closely monitor your treatment and any worsening of these conditions. 
 
Other medicines and Rebif 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
In particular you should tell your doctor if you are using antiepileptics or antidepressants. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
No harmful effects on the breastfed newborn/infant are anticipated. Rebif can be used during breast-
feeding. 
 
Driving and using machines 
Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. 
You should discuss this with your doctor if you are concerned. 
 
Rebif contains sodium and benzyl alcohol 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 
‘sodium-free’. 
 
This medicine contains 1.0 mg benzyl alcohol per dose of 0.2 mL and 2.5 mg benzyl alcohol per dose 
of 0.5 mL. Benzyl alcohol may cause allergic reactions. 
 
Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called 
“gasping syndrome”) in young children.  
 
Do not use for more than a week in young children (less than 3 years old), unless advised by your 
doctor or pharmacist. 
 
Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver 
or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may 
cause side effects (called “metabolic acidosis”).  
 
 
3. How to use Rebif 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 



220 

Initiating treatment 
Treatment is initiated by a gradual increase of the dose (a so-called “dose titration) over a period of 4 
weeks, in order to reduce some of the side effects, it is recommended that: 
• During weeks one and two, Rebif 8.8 micrograms should be injected three times per week. 
• During weeks three and four, Rebif 22 micrograms should be injected three times per week. 
 
From the fifth week onwards, after you have completed your initiation period, you will follow the 
usual dose regimen.  
 
Dose 
The usual dose is 44 micrograms (12 million IU) given three times per week.  
 
A lower dose of 22 micrograms (6 million IU) given three times per week is recommended for patients 
with multiple sclerosis who cannot tolerate the higher dose. 
 
Rebif should be administered three times per week, and if possible: 
• on the same three days every week (at least 48 hours apart, e.g., Monday, Wednesday, Friday) 
• at the same time of day (preferably in the evening). 
 
Use in children and teenagers (2 to 17 years old) 
No formal clinical studies have been conducted in children or teenagers. However there is some 
clinical data available suggesting that the safety profile in children and teenagers receiving Rebif 
22 micrograms or Rebif 44 micrograms three times per week is similar to that seen in adults.   
 
Use in children (below 2 years of age) 
Rebif is not recommended for use in children below 2 years of age. 
 
Method of administration 
• Rebif is given by injection under the skin (subcutaneously) using a pre-filled pen called 

“RebiDose”. 
• Use each RebiDose only once. 
• The first injection(s) must be performed under the supervision of an appropriately qualified 

healthcare professional. After receiving adequate training, you, a family member, friend or carer 
can use Rebif pre-filled pen to administer the medicine at home. 

• When you do this please read carefully and follow the “RebiDose Instructions for Use” 
provided separately in the booklet. 

 
Only clear to opalescent solution without particles and without visible signs of deterioration should be 
used. 
 
If you use more Rebif than you should 
In case of overdose, contact your doctor immediately. 
 
If you forget to use Rebif 
If you miss a dose, continue to inject from the day of the next scheduled dose. Do not use a double 
dose to make up for a forgotten dose. 
 
If you stop using Rebif 
The effects of Rebif may not be noticed immediately. Therefore, you should not stop using Rebif but 
continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please 
consult your doctor.  
 
You should not discontinue the treatment without first contacting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 



221 

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately and stop using Rebif if you experience any of the following serious 
side effects: 
 
• Serious allergic (hypersensitivity) reactions. If, immediately following Rebif administration 

you experience a sudden difficulty breathing, which may appear in association with swelling of 
face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or 
faintness, contact your doctor immediately or seek urgent medical attention. These reactions are 
rare (may affect up to 1 in 1,000 people). 

 
• Inform your doctor immediately if you experience any of the following possible symptoms of a 

liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, 
loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver 
problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and 
confusion. 

 
• Depression is common (may affect up to 1 in 10 people) in treated patients with multiple 

sclerosis. If you feel depressed or develop thoughts of suicide, report it immediately to your 
doctor. 

 
Talk to your doctor if you experience any of the following side effects: 
 
• Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea 

are very common (may affect more than 1 in 10 people). 
These symptoms are usually mild, are more common at the start of the treatment and decrease 
with continued use. 
To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller 
before a dose of Rebif and then for 24 hours after each injection.  

 
• Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin 

breakdown are very common.  
The occurrence of injection site reactions usually decreases over time.  
Tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up 
to 1 in 100 people). 
See recommendations in section “Warnings and precautions” to minimise the risk of injection 
site reactions. 
The injection site can become infected (uncommon); the skin may become swollen tender and 
hard and the whole area could be very painful. If you experience any of these symptoms, 
contact your doctor for advice. 

 
• Certain laboratory tests may change. These changes are generally not noticed by the patient 

(no symptoms), are usually reversible and mild, and most often do not require particular 
treatment. 
The number of red blood cells, white blood cells or platelets may decrease either individually 
(very common) or all at one time (rare). Possible symptoms resulting from these changes could 
include tiredness, reduced ability to fight infection, bruising or unexplained bleeding.  
Liver function tests may be disturbed (very common). Inflammation of the liver has also been 
reported (uncommon). If you experience symptoms suggesting a liver disorder, such as loss of 
appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact 
your doctor immediately (see above “Tell your doctor immediately...”). 

 
• Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or 

insufficiently. These changes in the thyroid activity are almost always not felt by the patient as 
symptoms; however your doctor may recommend testing as appropriate. 



222 

 
• MS pseudo-relapse (frequency not known): There is a possibility that at the beginning of your 

treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis 
relapse. For example, your muscles may feel very tense or very weak, preventing you from 
moving as you want. In some cases such symptoms are associated with fever or flu-like 
symptoms described above. If you notice any of these side effects talk to your doctor. 

 
Other possible side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Headache 
 
Common (may affect up to 1 in 10 people): 
• Insomnia (sleeping difficulty) 
• Diarrhoea, nausea, vomiting 
• Itching, rash (skin eruptions) 
• Muscle and joints pain 
• Fatigue, fever, chills 
• Hair loss 
 
Uncommon (may affect up to 1 in 100 people): 
• Hives 
• Epileptic seizures 
• Liver inflammation (hepatitis) 
• Breathing difficulties 
• Blood clots such as deep venous thrombosis 
• Disorders of the retina (back of the eye) such as inflammation or blood clots with consequent 

vision disorders (vision disturbances, loss of vision) 
• Increased sweating 
 
Rare (may affect up to 1 in 1,000 people): 
• Suicide attempt 
• Serious skin reactions - some with mucosal lesions 
• Blood clots in the small blood vessels that can affect your kidneys (thrombotic 

thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased 
bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. Your 
doctor may find changes in your blood and the function of your kidneys. 

• Drug-induced lupus erythematosus: a side-effect of long-term use of Rebif. Symptoms may 
include muscle pain, joint pain and swelling, and rash. You may also experience other signs 
such as fever, weight loss, and fatigue. Usually symptoms disappear within one or two weeks 
after treatment is stopped. 

• Kidney problems including scarring that may reduce your kidney function. 
If you get some or all of these symptoms:  
- foamy urine  
- fatigue  
- swelling, particularly in the ankles and eyelids, and weight gain. 
Tell your doctor as they may be signs of a possible kidney problem. 

 
The following side effects were reported for interferon beta (frequency not known) 
• Dizziness  
• Nervousness 
• Loss of appetite 
• Dilatation of the blood vessels and palpitation  
• Irregularities and/or changes in menstrual flow. 



223 

• Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 
resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. 
Pulmonary arterial hypertension has been seen at various time points during treatment, 
including several years after starting treatment with Rebif. 

• Inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard 
and possibly develop painful red lumps or patches. 

 
You should not stop or alter the medication without your doctor’s advice. 
 
Children and teenagers 
Side effects in children and teenagers are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Rebif 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment). 
 
For the purpose of ambulatory use, you may remove Rebif from the refrigerator and store it not above 
25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and used 
before the expiry date. 
 
Store in the original package in order to protect from light. 
 
Do not use this medicine if you notice any visible signs of deterioration such as if the solution is no 
longer clear or if it contains particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Rebif contains 
• The active substance is interferon beta-1a.  

− Each 8.8 micrograms pre-filled pen contains 8.8 micrograms of interferon beta-1a 
(2.4 million IU).  

− Each 22 micrograms pre-filled pen contains 22 micrograms of interferon beta-1a (6 million 
IU). 

• The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium 
acetate, acetic acid, sodium hydroxide and water for injections. 

 
What Rebif looks like and contents of the pack 
Rebif 8.8 micrograms is a solution for injection in a pre-filled pen for self-administration. The 
pre-filled pen is ready for use and contains 0.2 mL of solution. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


224 

Rebif 22 micrograms is a solution for injection in a pre-filled pen for self-administration. The 
pre-filled pen is ready for use and contains 0.5 mL of solution. 
 
Rebif solution is clear to opalescent. 
 
Rebif 8.8 micrograms and Rebif 22 micrograms are supplied in an initiation pack that is intended for 
use during the initial 4 weeks of treatment, during which a gradual increase in Rebif dose is 
recommended. 
 
One-month initiation pack contains six Rebif 8.8 micrograms pre-filled pens and 
six Rebif 22 micrograms pre-filled pens. 
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
Manufacturer 
Merck Serono S.p.A. 
Via delle Magnolie 15 
I-70026 Modugno (Bari) 
Italy 
 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  



225 

RebiDose Instructions for use 
 

HOW TO USE REBIF PRE-FILLED PEN (RebiDose) 
 
• This section tells you how to use RebiDose.  
• Rebif is given by injection under the skin (subcutaneously). 
• Use each RebiDose only once. 
• The first injection(s) must be performed under the supervision of an appropriately qualified 

healthcare professional. After receiving adequate training, you, a family member, friend or carer 
can use RebiDose to administer the medicine at home. If you have questions about how to inject, 
please ask your doctor, nurse or pharmacist for assistance. 

• Read all the following instructions carefully before using RebiDose. 
 
Equipment 
 
To give yourself an injection you will need: 
• A new RebiDose and 
• Alcohol wipes or similar. 
• a dry cotton ball or gauze 
 
Below is a picture showing what RebiDose looks like. 
 
Before the injection 

 
 

After the injection 

 
 
A. Cap 
B. Transparent window 
C. Plunger 
D. Label 
E. Main body 
F. Button 
G. Safety guard 
H. Needle 

 
 
Before you start 
 
• Wash your hands thoroughly with soap and water. 
• Remove RebiDose from the blister pack by peeling back the plastic covering. 
• Check the appearance of Rebif through the transparent window. It must be clear to opalescent, 

without particles and without any visible signs of deterioration. If there are particles or other 



226 

visible signs of deteriorations, do not use it and contact your doctor, nurse or pharmacist for 
assistance. 

• Check the expiry date on the RebiDose label or on the outer box (as indicated as “EXP”). Do 
not use RebiDose if the expiry date has passed. 

 
Where to inject with RebiDose 
 

 

• Choose an injection site. Your doctor will advise you on 
the possible injection sites (good sites include the upper 
thighs and the lower abdomen.)  

• Keep track of and rotate your injection sites, so that one 
area is not injected too often. This is to minimise the risk 
of skin damage (necrosis). 

• NOTE: do not use any areas in which you feel lumps, 
firm knots, or pain; talk to your doctor or healthcare 
professional about anything you find. 

 
How to inject with RebiDose 
 
• Do not remove the cap until you are ready to administer the injection. 
• Before the injection, use an alcohol wipe to clean the skin at the injection site. Let the skin dry. 

If a bit of alcohol is left on the skin, you may get a stinging sensation. 
 

 

• Hold RebiDose by the main body and use your other hand 
to remove the cap. 

 

• Hold RebiDose at a right angle (90 degrees) to the injection 
site. Push the pen against your skin until you feel resistance. 
This action unlocks the button. 



227 

 

• Keep enough pressure on the skin and press the button with 
your thumb. You will hear a click which indicates the start 
of the injection and the plunger will start moving. Keep 
RebiDose pressed against the skin for at least 10 seconds in 
order to inject all of the medicine. 
It is not necessary to keep the button pressed down with 
your thumb after the injection has begun. 

 

• Remove RebiDose from the injection site. 
The safety guard automatically surrounds the needle and 
locks into place to protect you from the needle. 

 
After the injection 
 

  

• Look through the transparent window to make sure that the 
plunger has moved to the bottom as indicated in the figure. 

• Visually check that there is no liquid left. If there is liquid 
left, not all of the medicine has been injected and you 
should consult your doctor or nurse for assistance. 

 
• Gently massage the injection site with a dry cotton ball or gauze. 
• Do not put the needle cap back on the used RebiDose. This is because the needle is now 

covered by the safety guard. Do not put your fingers in the safety guard. 
• RebiDose is for single use only and should never be reused. 
• Once you have finished your injection, immediately discard RebiDose. Ask your pharmacist 

how to safely dispose of RebiDose. 
 
If you have any further questions, please ask your doctor, nurse or pharmacist. 
 
 
This “Instructions for use” was last revised in 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  
	A. LABELLING
	B. PACKAGE LEAFLET
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treatment might influence your ability to drive or to use machines. you should discuss this with your doctor if you are concerned. rebif contains sodium and benzyl alcohol this medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially \'sodium-free\'. this medicine contains 2.5 mg benzyl alcohol per dose. benzyl alcohol may cause allergic reactions. benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called "gasping syndrome") in young children. do not use for more than a week in young children (less than 3 years old), unless advised by your doctor or pharmacist. ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver or kidney disease. this is because large amounts of benzyl alcohol can build-up in your body and may cause side effects (called "metabolic acidosis").', 'Entity_Recognition': [{'Text': 'rebif', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 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{'Title': '3. how to use rebif', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. dose the usual dose is 44 micrograms (12 million iu) given three times per week. your doctor has prescribed you a lower dose of 22 micrograms (6 million iu) given three times per week. this lower dose is recommended for patients who cannot tolerate the higher dose. rebif should be administered three times per week, and if possible: on the same three days every week (at least 48 hours apart, e.g. monday, wednesday, friday) at the same time of day (preferably in the evening). use in children and teenagers (2 to 17 years old) no formal clinical studies have been conducted in children or teenagers. however there is some clinical data available suggesting that the safety profile in children and teenagers receiving rebif 22 micrograms or rebif 44 micrograms three times per week is similar to that seen in adults. use in children (below 2 years of age) rebif is not recommended for use in children below 2 years of age. method of administration rebif is intended for subcutaneous (under the skin) injection. the first injection(s) must be performed under the supervision of an appropriately qualified healthcare professional. after receiving adequate training, you, a family member, friend or carer can use rebif syringes to administer the medicine at home. it may also be administered with a suitable auto-injector. for administration of rebif, please read the following instructions carefully: this medicine is for single use. only clear to opalescent solution without particles and without visible signs of deterioration should be used. how to inject rebif choose an injection site. your doctor will advise you on the possible injection sites (good sites include the upper thighs and the lower abdomen). hold the syringe like a pencil or dart. it is recommended that you keep track of and rotate your injection sites, so that one area is not injected too frequently in order to minimise the risk of injection site necrosis. note: do not use any areas in which you feel lumps, firm knots, or pain; talk to your doctor or healthcare professional about anything you find. wash your hands thoroughly with soap and water. remove the rebif syringe from the blister pack by peeling back the plastic covering. before the injection, use an alcohol wipe to clean the skin at the injection site. let the skin dry. if a bit of alcohol is left on the skin, you may get a stinging sensation. gently pinch the skin together around the site (to lift it up a bit). resting your wrist on the skin near the site, stick the needle at a right angle straight into the skin with a quick, firm motion. inject the medicine by using a slow, steady push (push the plunger all the way in until the syringe is empty). hold a swab on the injection site. remove the needle from the skin. gently massage the injection site with a dry cotton ball or gauze. dispose of 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor immediately and stop using rebif if you experience any of the following serious side effects: serious allergic (hypersensitivity) reactions. if, immediately following rebif administration you experience a sudden difficulty breathing, which may appear in association with swelling of face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or faintness, contact your doctor immediately or seek urgent medical attention. these reactions are rare (may affect up to 1 in 1,000 people). inform your doctor immediately if you experience any of the following possible symptoms of a liver problem: jaundice (yellowing of the skin or of the whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. severe liver problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and confusion. depression is common (may affect up to 1 in 10 people) in treated patients with multiple sclerosis. if you feel depressed or develop thoughts of suicide, report it immediately to your doctor. talk to your doctor if you experience any of the following side effects: flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea are very common (may affect more than 1 in 10 people). these symptoms are usually mild, are more common at the start of the treatment and decrease with continued use. to help reduce these symptoms your doctor may advise you to take a fever reducing painkiller before a dose of rebif and then for 24 hours after each injection. injection site reactions including redness, swelling, discoloration, inflammation, pain and skin breakdown are very common. the occurrence of injection site reactions usually decreases over time. tissue destruction (necrosis), abscess and mass at injection site are uncommon (may affect up to 1 in 100 people). see recommendations in section "warnings and precautions" to minimise the risk of injection site reactions. the injection site can become infected (uncommon); the skin may become swollen tender and hard and the whole area could be very painful. if you experience any of these symptoms, contact your doctor for advice. certain laboratory tests may change. these changes are generally not noticed by the patient (no symptoms), are usually reversible and mild, and most often do not require particular treatment. the number of red blood cells, white blood cells or platelets may decrease either individually (very common) or all at one time (rare). possible symptoms resulting from these changes could include tiredness, reduced ability to fight infection, bruising or unexplained bleeding. liver function tests may be disturbed (very common). inflammation of the liver has also been reported (uncommon). if you experience symptoms suggesting a liver disorder, such as loss of appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact your doctor immediately (see above "tell your doctor immediately..."). thyroid dysfunction is uncommon. the thyroid gland may function either excessively, or insufficiently. these changes in the thyroid activity are almost always not felt by the patient as symptoms; however your doctor may recommend testing as appropriate. ms pseudo-relapse (frequency not known): there is a possibility that at the beginning of your treatment with rebif you may experience symptoms that resemble those of a multiple sclerosis relapse. for example, your muscles may feel very tense or very weak, preventing you from moving as you want. in some cases such symptoms are associated with fever or flu-like symptoms described above. if you notice any of these side effects talk to your doctor. other possible side effects include: very common (may affect more than 1 in 10 people): headache common (may affect up to 1 in 10 people): insomnia (sleeping difficulty) diarrhoea, nausea, vomiting itching, rash (skin eruptions) muscle and joints pain fatigue, fever, chills hair loss uncommon (may affect up to 1 in 100 people): hives epileptic seizures liver inflammation (hepatitis) breathing difficulties blood clots such as deep venous thrombosis disorders of the retina (back of the eye) such as inflammation or blood clots with consequent vision disorders (vision disturbances, loss of vision) increased sweating rare (may affect up to 1 in 1,000 people): suicide attempt serious skin reactions - some with mucosal lesions 157 blood clots in the small blood vessels that can affect your kidneys (thrombotic thrombocytopenic purpura or haemolytic uremic syndrome). symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness. your doctor may find changes in your blood and the function of your kidneys. drug-induced lupus erythematosus: a side-effect of long-term use of rebif. symptoms may include muscle pain, joint pain and swelling, and rash. you may also experience other signs such as fever, weight loss, and fatigue. usually symptoms disappear within one or two weeks after treatment is stopped. kidney problems including scarring that may reduce your kidney function. if you get some or all of these symptoms: - foamy urine - fatigue - swelling, particularly in the ankles and eyelids, and weight gain. tell your doctor as they may be signs of a possible kidney problem. the following side effects were reported for interferon beta (frequency not known) dizziness nervousness loss of appetite dilatation of the blood vessels and palpitation irregularities and/or changes in menstrual flow. pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. pulmonary arterial hypertension has been seen at various time points during treatment, including several years after starting treatment with rebif. inflammation of the fatty tissue under the skin (panniculitis), which can make the skin feel hard and possibly develop painful red lumps or patches. you should not stop or alter the medication without your doctor\'s advice. children and teenagers side effects in children and teenagers are similar to those observed in adults. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'rebif', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 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{'Title': '5. how to store rebif', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label after exp. store in a refrigerator (2 8). do not freeze. (to prevent accidental freezing, avoid placing near the freezer compartment). for the purpose of ambulatory use, you may remove rebif from the refrigerator and store it not above 25 for one single period of up to 14 days. rebif must then be returned to the refrigerator and used before the expiry date. store in the original package in order to protect from light. do not use this medicine if you notice any visible signs of deterioration such as if the solution is no longer clear or if it contains particles. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away of medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'rebif', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'accidental freezing', 'Type': 'PROBLEM', 'BeginOffset': 204, 'EndOffset': 223}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 371, 'EndOffset': 373}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 405, 'EndOffset': 407}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 568, 'EndOffset': 581}, {'Text': 'deterioration', 'Type': 'PROBLEM', 'BeginOffset': 617, 'EndOffset': 630}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what rebif contains the active substance is interferon beta-1a. each syringe contains 22 micrograms, corresponding to 6 million international units (iu) of interferon beta-1a. the other ingredients are mannitol, poloxamer 188, l-methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide and water for injections. what rebif looks like and contents of the pack rebif is available as a solution for injection in a pre-filled syringe with a fixed needle for self-administration. rebif solution is clear to opalescent. the pre-filled syringe is ready for use and contains 0.5 ml of solution. rebif is available in packs of 1, 3, 12 and 36 pre-filled syringes. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'rebif', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 10, 'Score': 0.5842503309249878, 'Text': 'rebif', 'Category': 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