Tysabri
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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TYSABRI 300 mg concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of concentrate contains 20 mg of natalizumab. 
 
When diluted (see section 6.6), the solution for infusion contains approximately 2.6 mg/ml of 
natalizumab. 
 
Natalizumab is a recombinant humanised anti-α4-integrin antibody produced in a murine cell line by 
recombinant DNA technology. 
 
 
Excipient with known effect 
 
Each vial contains 2.3 mmol (or 52 mg) sodium. When diluted in 100 ml sodium chloride 9 mg/ml 
(0.9%) the medicinal product contains 17.7 mmol (or 406 mg) sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
 
Colourless, clear to slightly opalescent solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
TYSABRI is indicated as single disease modifying therapy in adults with highly active relapsing 
remitting multiple sclerosis for the following patient groups: 
 
• Patients with highly active disease despite a full and adequate course of treatment with at least 

one disease modifying therapy (DMT) (for exceptions and information about washout periods 
see sections 4.4 and 5.1)  
 

or 
 
• Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more 

disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI 
or a significant increase in T2 lesion load as compared to a previous recent MRI. 

 



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4.2 Posology and method of administration 
 
TYSABRI therapy is to be initiated and continuously supervised by specialised physicians 
experienced in the diagnosis and treatment of neurological conditions, in centres with timely access to 
MRI.  
 
Patients treated with TYSABRI must be given the patient alert card and be informed about the risks of 
the medicinal product (see also package leaflet). After 2 years of treatment, patients should be re-
informed about the risks of TYSABRI, especially the increased risk of Progressive Multifocal 
Leukoencephalopathy (PML), and should be instructed together with their caregivers on early signs 
and symptoms of PML. 
 
Resources for the management of hypersensitivity reactions and access to MRI should be available. 
 
Some patients may have been exposed to immunosuppressive medicinal products (e.g. mitoxantrone, 
cyclophosphamide, azathioprine). These medicinal products have the potential to cause prolonged 
immunosuppression, even after dosing is discontinued. Therefore the physician must confirm that such 
patients are not immunocompromised before starting treatment with TYSABRI (see also section 4.4). 
 
Posology 
 
TYSABRI 300 mg is administered by intravenous infusion once every 4 weeks. 
 
Continued therapy must be carefully reconsidered in patients who show no evidence of therapeutic 
benefit beyond 6 months  
 
Data on the safety and efficacy of natalizumab at 2 years were generated from controlled, double–
blind studies. After 2 years continued therapy should be considered only following a reassessment of 
the potential for benefit and risk. Patients should be re-informed about the risk factors for PML, like 
duration of treatment, immunosuppressant use prior to receiving TYSABRI and the presence of anti-
John Cunningham virus (JCV) antibodies (see section 4.4.). 
 
Readministration 
 
The efficacy of re-administration has not been established, for safety see section 4.4. 
 
Special populations  
 
Elderly 
 
TYSABRI is not recommended for use in patients aged over 65 due to a lack of data in this 
population. 
 
Renal and hepatic impairment 
 
Studies have not been conducted to examine the effects of renal or hepatic impairment. 
 
The mechanism for elimination and results from population pharmacokinetics suggest that dose 
adjustment would not be necessary in patients with renal or hepatic impairment. 
 
Paediatric population 
 
The safety and efficacy of TYSABRI in children and adolescents up to 18 years have not been 
established. No recommendation on a posology can be made. Currently available data are described in 
sections 4.8 and 5.1  
 
Method of administration 



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TYSABRI is for intravenous use. 
 
For instructions on dilution of the medicinal product before administration, see section 6.6. 
 
After dilution (see section 6.6), the infusion is to be administered over approximately 1 hour and 
patients are to be observed during the infusion and for 1 hour after the completion of the infusion for 
signs and symptoms of hypersensitivity reactions. 
 
TYSABRI must not be administered as a bolus injection. 
 
4.3 Contraindications 
 
Hypersensitivity to natalizumab or to any of the excipients listed in section 6.1. 
 
Progressive multifocal leukoencephalopathy (PML). 
 
Patients with increased risk for opportunistic infections, including immunocompromised patients 
(including those currently receiving immunosuppressive therapies or those immunocompromised by 
prior therapies (see sections 4.4 and 4.8). 
 
Combination with other DMTs. 
 
Known active malignancies, except for patients with cutaneous basal cell carcinoma. 
 
 
4.4 Special warnings and precautions for use 
 
Traceability  

In order to improve the traceability of biological medicinal products, the name and batch number of 
the administered product should be clearly recorded. 
 
Progressive Multifocal Leukoencephalopathy (PML) 
 
Use of TYSABRI has been associated with an increased risk of PML, an opportunistic infection 
caused by JC virus, which may be fatal or result in severe disability. Due to this increased risk of 
developing PML, the benefits and risks of TYSABRI treatment should be individually reconsidered by 
the specialist physician and the patient; patients must be monitored at regular intervals throughout and 
should be instructed together with their caregivers on early signs and symptoms of PML. JC virus also 
causes JCV granule cell neuronopathy (GCN) which has been reported in patients treated with 
TYSABRI. Symptoms of JCV GCN are similar to symptoms of PML (i.e. cerebellar syndrome). 
 
The following risk factors are associated with an increased risk of PML. 
 
• The presence of anti-JCV antibodies. 

 
• Treatment duration, especially beyond 2 years. After 2 years all patients should be re-informed 

about the risk of PML with TYSABRI.  
 

• Immunosuppressant use prior to receiving TYSABRI. 
 

Patients who are anti-JCV antibody positive are at an increased risk of developing PML compared to 
patients who are anti-JCV antibody negative. Patients who have all three risk factors for PML (i.e., are 
anti-JCV antibody positive and have received more than 2 years of TYSABRI therapy, and have 
received prior immunosuppressant therapy) have a significantly higher risk of PML.  



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In anti-JCV antibody positive TYSABRI treated patients who have not used prior 
immunosuppressants the level of anti-JCV antibody response (index) is associated with the level of 
risk for PML.  
 
In anti-JCV antibody positive patients, extended interval dosing of TYSABRI (average dosing interval 
of approximately 6 weeks) is suggested to be associated with a lower PML risk compared to approved 
dosing. If utilising extended interval dosing, caution is required because the efficacy of extended 
interval dosing has not been established and the associated benefit risk balance is currently unknown 
(see section 5.1). For further information, refer to the Physician Information and Management 
Guidelines. 
 
In patients considered at high risk treatment with TYSABRI should only be continued if the benefits 
outweigh the risks. For the estimation of PML risk in the different patient subgroups, please refer to 
the Physician Information and Management Guidelines. 
 
Anti-JCV antibody testing 
 
Anti-JCV antibody testing provides supportive information for risk stratification of TYSABRI 
treatment. Testing for serum anti-JCV antibody prior to initiating TYSABRI therapy or in patients 
receiving the medicinal product with an unknown antibody status is recommended. Anti-JCV antibody 
negative patients may still be at risk of PML for reasons such as a new JCV infection, fluctuating 
antibody status or a false negative test result. Re-testing of anti-JCV antibody negative patients every 6 
months is recommended. Retesting low index patients who have no history of prior 
immunosuppressant use every 6 months once they reach the 2 year treatment point is recommended.  
 
The anti-JCV antibody assay (ELISA) should not be used to diagnose PML. Use of 
plasmapheresis/plasma exchange (PLEX) or intravenous immunoglobulin (IVIg) can affect 
meaningful interpretation of serum anti-JCV antibody testing.  Patients should not be tested for anti-
JCV antibodies within 2 weeks of PLEX due to removal of antibodies from the serum, or within 6 
months of IVIg (i.e. 6 months = 5x half-life for immunoglobulins).    
 
For further information on anti-JCV antibody testing please see Physician Information and 
Management Guidelines. 
  
MRI screening for PML 
  
Before initiation of treatment with TYSABRI, a recent (usually within 3 months) MRI should be 
available as a reference, and be repeated at least on a yearly basis. More frequent MRIs (e.g. on a 3 to 
6 monthly basis) using an abbreviated protocol should be considered for patients at higher risk of 
PML. This includes: 

• Patients who have all three risk factors for PML (i.e., are anti-JCV antibody positive 
and have received more than 2 years of TYSABRI therapy, and have received prior 
immunosuppressant therapy),  

or 

• Patients with a high anti-JCV antibody index who have received more than 2 years of 
TYSABRI therapy and without prior history of immunosuppressant therapy.  

Current evidence suggests that the risk of PML is low at an index equal to or below 0.9 and increases 
substantially above 1.5 for patients who have been on treatment with TYSABRI for longer than 2 
years (see the Physician Information and Management Guidelines for further information). 
 
No studies have been performed to evaluate the efficacy and safety of TYSABRI when switching 
patients from DMTs with an immunosuppressant effect. It is unknown if patients switching from these 
therapies to TYSABRI have an increased risk of PML, therefore these patients should be monitored 
more frequently (i.e. similarly to patients switching from immunosuppressants to TYSABRI). 



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PML should be considered as a differential diagnosis in any MS patient taking TYSABRI presenting 
with neurological symptoms and/or new brain lesions in MRI. Cases of asymptomatic PML based on 
MRI and positive JCV DNA in the cerebrospinal fluid have been reported.  
 
Physicians should refer to the Physician Information and Management Guidelines for further 
information on managing the risk of PML in TYSABRI-treated patients.    
 
If PML or JCV GCN is suspected, further dosing must be suspended until PML has been 
excluded.  
 
The clinician should evaluate the patient to determine if the symptoms are indicative of neurological 
dysfunction and, if so, whether these symptoms are typical of MS or possibly suggestive of PML or 
JCV GCN. If any doubt exists, further evaluation, including MRI scan preferably with contrast 
(compared with pre-treatment baseline MRI), CSF testing for JC Viral DNA and repeat neurological 
assessments, should be considered as described in the Physician Information and Management 
Guidelines (see educational guidance). Once the clinician has excluded PML and/or JCV GCN (if 
necessary, by repeating clinical, imaging and/or laboratory investigations if clinical suspicion 
remains), dosing of TYSABRI may resume. 
 
The physician should be particularly alert to symptoms suggestive of PML or JCV GCN that the 
patient may not notice (e.g. cognitive, psychiatric symptoms or cerebellar syndrome). Patients should 
also be advised to inform their partner or caregivers about their treatment, since they may notice 
symptoms that the patient is not aware of. 
 
PML has been reported following discontinuation of TYSABRI in patients who did not have findings 
suggestive of PML at the time of discontinuation. Patients and physicians should continue to follow 
the same monitoring protocol and be alert for any new signs or symptoms that may be suggestive of 
PML for approximately 6 months following discontinuation of TYSABRI. 
 
If a patient develops PML the dosing of TYSABRI must be permanently discontinued. 
 
Following reconstitution of the immune system in immunocompromised patients with PML improved 
outcome has been seen.  
 
Based on a retrospective analysis of natalizumab-treated patients since its approval, no difference was 
observed on 2-year survival after PML diagnosis between patients who received PLEX and those who 
did not. For other considerations on the management of PML, see the Physician Informaion and 
Management Guidelines. 
 
PML and IRIS (Immune Reconstitution Inflammatory Syndrome) 
 
IRIS occurs in almost all TYSABRI PML patients after withdrawal or removal of the medicinal 
product. IRIS is thought to result from the restoration of immune function in patients with PML, which 
can lead to serious neurological complications and may be fatal. Monitoring for development of IRIS 
and appropriate treatment of the associated inflammation during recovery from PML should be 
undertaken (see the Physician Information and Management Guidelines for further information). 
 
Infections including other opportunistic infections 
 
Other opportunistic infections have been reported with use of TYSABRI, primarily in patients with 
Crohn’s disease who were immunocompromised or where significant co-morbidity existed, however 
increased risk of other opportunistic infections with use of the medicinal product in patients without 
these co-morbidities cannot currently be excluded. Opportunistic infections were also detected in MS 
patients treated with TYSABRI as a monotherapy (see section 4.8). 
 



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TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and 
varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the 
postmarketing setting in multiple sclerosis patients receiving TYSABRI (see section 4.8).  If herpes 
encephalitis or meningitis occurs, the medicinal product should be discontinued, and appropriate 
treatment for herpes encephalitis or meningitis should be administered. 
 
Acute retinal necrosis (ARN) is a rare fulminant viral infection of the retina caused by the family of 
herpes viruses (e.g. varicella zoster). ARN has been observed in patients being administered 
TYSABRI and can be potentially blinding. Patients presenting with eye symptoms such as decreased 
visual acuity, redness and painful eye should be referred for retinal screening for ARN. Following 
clinical diagnosis of ARN, discontinuation of TYSABRI should be considered in these patients. 
 
Prescribers should be aware of the possibility that other opportunistic infections may occur during 
TYSABRI therapy and should include them in the differential diagnosis of infections that occur in 
TYSABRI-treated patients. If an opportunistic infection is suspected, dosing with TYSABRI is to be 
suspended until such infections can be excluded through further evaluations. 
 
If a patient receiving TYSABRI develops an opportunistic infection, dosing of the medicinal product 
must be permanently discontinued. 
 
Educational guidance 
 
All physicians who intend to prescribe TYSABRI must ensure they are familiar with the Physician 
Information and Management Guidelines. 
 
Physicians must discuss the benefits and risks of TYSABRI therapy with the patient and provide them 
with a Patient Alert Card. Patients should be instructed that if they develop any infection then they 
should inform their physician that they are being treated with TYSABRI. 
 
Physicians should counsel patients on the importance of uninterrupted dosing, particularly in the early 
months of treatment (see hypersensitivity). 
 
Hypersensitivity 
 
Hypersensitivity reactions have been associated with TYSABRI, including serious systemic reactions 
(see section 4.8). These reactions usually occurred during the infusion or up to 1 hour after completion 
of the infusion. The risk for hypersensitivity was greatest with early infusions and in patients re-
exposed to TYSABRI following an initial short exposure (one or two infusions) and extended period 
(three months or more) without treatment. However, the risk of hypersensitivity reactions should be 
considered for every infusion administered. 
 
Patients are to be observed during the infusion and for 1 hour after the completion of the infusion (see 
section 4.8). Resources for the management of hypersensitivity reactions should be available. 
 
Discontinue administration of TYSABRI and initiate appropriate therapy at the first symptoms or 
signs of hypersensitivity. 
 
Patients who have experienced a hypersensitivity reaction must be permanently discontinued from 
treatment with TYSABRI. 
 
Concurrent treatment with immunosuppressants 
 
The safety and efficacy of TYSABRI in combination with other immunosuppressive and 
antineoplastic therapies have not been fully established. Concurrent use of these agents with 
TYSABRI may increase the risk of infections, including opportunistic infections, and is 
contraindicated (see section 4.3). 
 



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In Phase 3 MS clinical trials, concomitant treatment of relapses with a short course of corticosteroids 
was not associated with an increased rate of infection. Short courses of corticosteroids can be used in 
combination with TYSABRI. 
 
Prior treatment with immunosuppressive or immunomodulatory therapies  
 
Patients with a treatment history of immunosuppressant medications are at increased risk for PML. 
No studies have been performed to evaluate the efficacy and safety of TYSABRI when switching 
patients from DMTs with an immunosuppressant effect. It is unknown if patients switching from these 
therapies to TYSABRI have an increased risk of PML, therefore these patients should be monitored 
more frequently (i.e. similarly to patients switching from immunosuppressants to TYSABRI, see MRI 
screening for PML). 
 
Care should be taken with patients who have previously received immunosuppressants to allow 
sufficient time for immune function recovery to occur. Physicians must evaluate each individual case 
to determine whether there is evidence of an immunocompromised state prior to commencing 
treatment with TYSABRI (see section 4.3). 
When switching patients from another DMT to TYSABRI, the half-life and mode of action of the 
other therapy must be considered in order to avoid an additive immune effect whilst at the same time 
minimising the risk of disease reactivation. A Complete Blood Count (CBC, including lymphocytes) is 
recommended prior to initiating TYSABRI to ensure that immune effects of the previous therapy (i.e. 
cytopenia) have resolved.  
 
Patients can switch directly from beta interferon or glatiramer acetate to TYSABRI providing there are 
no signs of relevant treatment-related abnormalities e.g. neutropenia and, lymphopenia.  
 
When switching from dimethyl fumarate, the washout period should be sufficient for lymphocyte 
count to recover before treatment with TYSABRI is started. 
 
Following discontinuation of fingolimod, lymphocyte count progressively returns to normal range 
within 1 to 2 months after stopping therapy. The washout period should be sufficient for lymphocyte 
count to recover before treatment with TYSABRI is started. 
 
Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, 
clearance of teriflunomide from plasma can take from several months up to 2 years. An accelerated 
elimination procedure as defined in the teriflunomide Summary of Product Characteristics is 
recommended or alternatively washout period should not be shorter than 3.5 months. Caution 
regarding potential concomitant immune effects is required when switching patients from 
teriflunomide to TYSABRI. 
 
Alemtuzumab has profound prolonged immunosuppressive effects. As the actual duration of these 
effects is unknown, initiating treatment with TYSABRI after alemtuzumab is not recommended unless 
the benefits clearly outweigh the risks for the individual patient. 
 
Immunogenicity 
 
Disease exacerbations or infusion related events may indicate the development of antibodies against 
natalizumab. In these cases the presence of antibodies should be evaluated and if these remain positive 
in a confirmatory test after at least 6 weeks, treatment should be discontinued, as persistent antibodies 
are associated with a substantial decrease in efficacy of TYSABRI and an increased incidence of 
hypersensitivity reactions (see section 4.8). 
 
Since patients who have received an initial short exposure to TYSABRI and then had an extended 
period without treatment are at a higher risk of developing anti-natalizumab antibodies and/or 
hypersensitivity upon redosing, the presence of antibodies should be evaluated and if these remain 
positive in a confirmatory test after at least 6 weeks, the patient should not receive further treatment 
with TYSABRI. 



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Hepatic events 
 
Spontaneous serious adverse reactions of liver injury have been reported during the post marketing 
phase. These liver injuries may occur at any time during treatment, even after the first dose. In some 
instances, the reaction reoccurred when TYSABRI was reintroduced. Some patients with a past 
medical history of an abnormal liver test have experienced an exacerbation of abnormal liver test 
while on TYSABRI. Patients should be monitored as appropriate for impaired liver function, and be 
instructed to contact their physician in case signs and symptoms suggestive of liver injury occur, such 
as jaundice and vomiting. In cases of significant liver injury TYSABRI should be discontinued. 
 
Stopping TYSABRI therapy 
 
If a decision is made to stop treatment with natalizumab, the physician needs to be aware that 
natalizumab remains in the blood, and has pharmacodynamic effects (e.g increased lymphocyte 
counts) for approximately 12 weeks following the last dose. Starting other therapies during this 
interval will result in a concomitant exposure to natalizumab. For medicinal products such as 
interferon and glatiramer acetate, concomitant exposure of this duration was not associated with safety 
risks in clinical trials. No data are available in MS patients regarding concomitant exposure with 
immunosuppressant medication. Use of these medicinal products soon after the discontinuation of 
natalizumab may lead to an additive immunosuppressive effect. This should be carefully considered 
on a case-by-case basis, and a wash-out period of natalizumab might be appropriate. Short courses of 
steroids used to treat relapses were not associated with increased infections in clinical trials. 
 
Sodium content in TYSABRI 
 
TYSABRI contains 2.3 mmol (or 52 mg) sodium per vial of medicinal product. When diluted in 
100 ml sodium chloride 9 mg/ml (0.9%) this medicinal product contains 17.7 mmol (or 406 mg) 
sodium per dose. To be taken into consideration by patients on a controlled sodium diet. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
TYSABRI is contraindicated in combination with other DMTs (see section 4.3). 
 
Immunisations 
 
In a randomised, open label study of 60 patients with relapsing MS there was no significant difference 
in the humoral immune response to a recall antigen (tetanus toxoid) and only slightly slower and 
reduced humoral immune response to a neoantigen (keyhole limpet haemocyanin) was observed in 
patients who were treated with TYSABRI for 6 months compared to an untreated control group. Live 
vaccines have not been studied. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
Studies in animals have shown reproductive toxicity (see section 5.3).  
 
Data from clinical trials, a prospective pregnancy registry, post-marketing cases and available 
literature do not suggest an effect of TYSABRI exposure on pregnancy outcomes. 
 
The completed prospective TYSABRI pregnancy registry contained 355 pregnancies with available 
outcomes. There were 316 live births, 29 of which were reported to have birth defects. Sixteen of the 
29 were classified as major defects. The rate of defects corresponds to the defect rates reported in 
other pregnancy registries involving MS patients. There is no evidence of a specific pattern of birth 
defects with TYSABRI. 
 



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Cases from published literature reported transient mild to moderate thrombocytopenia and anaemia 
observed in infants born to women exposed to TYSABRI in their third trimester of pregnancy. 
Therefore, it is recommended that newborns of women exposed to the medicinal product during the 
third trimester of pregnancy are monitored for potential haematological abnormalities. 
 
If a woman becomes pregnant while taking TYSABRI, discontinuation of the medicinal product 
should be considered. A benefit-risk evaluation of the use of TYSABRI during pregnancy should take 
into account the patient’s clinical condition and the possible return of disease activity after stopping 
the medicinal product. 
 
Breast-feeding 
 
Natalizumab is excreted in human milk. The effect of natalizumab on newborn/infants is unknown. 
Breast-feeding should be discontinued during treatment with TYSABRI. 
 
Fertility 
 
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human 
dose; natalizumab did not affect male fertility.  
It is considered unlikely that natalizumab will affect fertility performance in humans following the 
maximum recommended dose.  
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed with 
TYSABRI. However, given that dizziness has been very commonly reported, patients who experience 
this adverse reaction should be advised not to drive or use machines until it has resolved. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
In placebo-controlled trials in 1,617 MS patients treated with natalizumab for up to 2 years (placebo: 
1,135), adverse events leading to discontinuation of therapy occurred in 5.8% of patients treated with 
natalizumab (placebo: 4.8%). Over the 2-year duration of the studies, 43.5% of patients treated with 
natalizumab reported adverse reactions (placebo: 39.6%).  
 
The highest incidence of adverse reactions identified from placebo-controlled trials in multiple 
sclerosis patients with natalizumab given at the recommended dose, are reported as dizziness, nausea, 
urticaria and rigors associated with infusions.  
 
Tabulated list of adverse reactions 
 
Adverse reactions reported with natalizumab with an incidence of 0.5% greater than reported with 
placebo are shown below.  
 
The reactions are reported as MedDRA preferred terms under the MedDRA primary system organ 
class. Frequencies were defined as follows: 
 
Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100). 
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 



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MedDRA System Organ Class Adverse reaction Frequency category 
Infections and infestations Urinary tract infection Very common 

Nasopharyngitis Very common 
Immune system disorders Urticaria Common 

Hypersensitivity Uncommon 
Nervous system disorders Headache Very common 

Dizziness Very common 
Progressive Multifocal 
Leukoencephalopathy (PML) 
 

Uncommon 

Gastrointestinal disorders Vomiting Common 
Nausea Very common 

Musculoskeletal and connective 
tissue disorders 

Arthralgia 
 

Very common 

General disorders and 
administration site conditions 

Rigors 
 

Common 

Pyrexia Common 
Fatigue Very common 

 
 
Description of selected adverse reactions 
 
Infusion reactions 
 
In 2-year controlled clinical trials in MS patients, an infusion-related event was defined as an adverse 
event occurring during the infusion or within 1 hour of the completion of the infusion. These occurred 
in 23.1% of MS patients treated with natalizumab (placebo: 18.7%). Events reported more commonly 
with natalizumab than with placebo included dizziness, nausea, urticaria and rigors.  
 
Hypersensitivity reactions 
 
In 2-year controlled clinical trials in MS patients, hypersensitivity reactions occurred in up to 4% of 
patients. Anaphylactic/anaphylactoid reactions occurred in less than 1% of patients receiving 
TYSABRI. Hypersensitivity reactions usually occurred during the infusion or within the 1-hour period 
after the completion of the infusion (See section 4.4). In post-marketing experience, there have been 
reports of hypersensitivity reactions which have occurred with one or more of the following associated 
symptoms: hypotension, hypertension, chest pain, chest discomfort, dyspnoea, angioedema, in 
addition to more usual symptoms such as rash and urticaria. 
  
Immunogenicity 
 
In 10% of patients antibodies against natalizumab were detected in 2-year controlled clinical trials in 
MS patients. Persistent anti-natalizumab antibodies (one positive test reproducible on retesting at least 
6 weeks later) developed in approximately 6% of patients. Antibodies were detected on only one 
occasion in an additional 4% of patients. Persistent antibodies were associated with a substantial 
decrease in the effectiveness of TYSABRI and an increased incidence of hypersensitivity reactions. 
Additional infusion-related reactions associated with persistent antibodies included rigors, nausea, 
vomiting and flushing (see section 4.4). 
 
If, after approximately 6 months of therapy, persistent antibodies are suspected, either due to reduced 
efficacy or due to occurrence of infusion-related events, they may be detected and confirmed with a 
subsequent test 6 weeks after the first positive test. Given that efficacy may be reduced or the 
incidence of hypersensitivity or infusion-related reactions may be increased in a patient with persistent 
antibodies, treatment should be discontinued in patients who develop persistent antibodies. 
 



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Infections, including PML and opportunistic infections 
 
In 2-year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per 
patient-year in both natalizumab- and placebo-treated patients. The nature of the infections was 
generally similar in natalizumab- and placebo-treated patients. A case of cryptosporidium diarrhoea 
was reported in MS clinical trials. In other clinical trials, cases of additional opportunistic infections 
have been reported, some of which were fatal. The majority of patients did not interrupt natalizumab 
therapy during infections and recovery occurred with appropriate treatment. 
 
In clinical trials, herpes infections (Varicella-Zoster virus, Herpes-simplex virus) occurred slightly 
more frequently in natalizumab-treated patients than in placebo-treated patients. In post marketing 
experience, serious, life-threatening, and sometimes fatal cases of encephalitis and meningitis caused 
by herpes simplex or varicella zoster have been reported in multiple sclerosis patients receiving 
TYSABRI.  The duration of treatment with TYSABRI prior to onset ranged from a few months to 
several years (see section 4.4). 
 
In postmarketing experience, rare cases of ARN have been observed in patients receiving TYSABRI. 
Some cases have occurred in patients with central nervous system (CNS) herpes infections (e.g. herpes 
meningitis and encephalitis). Serious cases of ARN, either affecting one or both eyes, led to blindness 
in some patients. The treatment reported in these cases included anti-viral therapy and in some cases, 
surgery (see section 4.4). 
 
Cases of PML have been reported from clinical trials, post-marketing observational studies and post-
marketing passive surveillance. PML usually leads to severe disability or death (see section 4.4).  
Cases of JCV GCN have also been reported during postmarketing use of TYSABRI. Symptoms of 
JCV GCN are similar to PML. 
 
Hepatic events 
 
Spontaneous cases of serious liver injuries, increased liver enzymes, hyperbilirubinaemia have been 
reported during the post marketing phase (see section 4.4). 
 
Anaemia and haemolytic anaemia 
 
Rare, serious cases of anaemia and haemolytic anaemia have been reported in patients treated with 
TYSABRI in post-marketing observational studies. 
 
Malignancies 
 
No differences in incidence rates or the nature of malignancies between natalizumab- and 
placebo-treated patients were observed over 2 years of treatment. However, observation over longer 
treatment periods is required before any effect of natalizumab on malignancies can be excluded. See 
section 4.3. 
 
Effects on laboratory tests 
 
In 2-year controlled clinical trials in MS patients TYSABRI treatment was associated with increases in 
circulating lymphocytes, monocytes, eosinophils, basophils and nucleated red blood cells. Elevations 
in neutrophils were not seen. Increases from baseline for lymphocytes, monocytes, eosinophils and 
basophils ranged from 35% to 140% for individual cell types but mean cell counts remained within 
normal ranges. During treatment with TYSABRI, small reductions in haemoglobin (mean decrease 
0.6 g/dl), haematocrit (mean decrease 2%) and red blood cell counts (mean decrease 0.1 x 106/l) were 
seen. All changes in haematological variables returned to pre-treatment values, usually within 
16 weeks of last dose of the medicinal product and the changes were not associated with clinical 
symptoms. In post-marketing experience, there have also been reports of eosinophilia (eosinophil 
count >1,500/mm3) without clinical symptoms. In such cases where TYSABRI therapy was 
discontinued the elevated eosinophil levels resolved. 



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Paediatric population 
 
Serious adverse events were evaluated in 621 MS paediatric patients included in a meta-analysis (see 
also Section 5.1). Within the limitations of these data, there were no new safety signals identified in 
this patient population. 1 case of  herpes meningitis was reported in the meta-analysis. No cases of 
PML were identified in the meta-analysis, however, PML has been reported in natalizumab treated 
paediatric patients in the post-marketing setting. 
 
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 
 
No case of overdose has been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Selective immunosuppressive agents, ATC code: L04AA23 
 
Pharmacodynamic effects 
 
Natalizumab is a selective adhesion-molecule inhibitor and binds to the α4-subunit of human integrins, 
which is highly expressed on the surface of all leukocytes, with the exception of neutrophils. 
Specifically, natalizumab binds to the α4β1 integrin, blocking the interaction with its cognate receptor, 
vascular cell adhesion molecule-1 (VCAM-1), and ligands osteopontin, and an alternatively spliced 
domain of fibronectin, connecting segment-1 (CS-1). Natalizumab blocks the interaction of α4β7 
integrin with the mucosal addressin cell adhesion molecule-1 (MadCAM-1). Disruption of these 
molecular interactions prevents transmigration of mononuclear leukocytes across the endothelium into 
inflamed parenchymal tissue. A further mechanism of action of natalizumab may be to suppress 
ongoing inflammatory reactions in diseased tissues by inhibiting the interaction of α4-expressing 
leukocytes with their ligands in the extracellular matrix and on parenchymal cells. As such, 
natalizumab may act to suppress inflammatory activity present at the disease site, and inhibit further 
recruitment of immune cells into inflamed tissues. 
 
In MS, lesions are believed to occur when activated T-lymphocytes cross the blood-brain barrier 
(BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on 
inflammatory cells and endothelial cells of the vessel wall. The interaction between α4β1 and its 
targets is an important component of pathological inflammation in the brain and disruption of these 
interactions leads to reduced inflammation. Under normal conditions, VCAM-1 is not expressed in the 
brain parenchyma. However, in the presence of pro-inflammatory cytokines, VCAM-1 is upregulated 
on endothelial cells and possibly on glial cells near the sites of inflammation. In the setting of central 
nervous system (CNS) inflammation in MS, it is the interaction of α4β1 with VCAM-1, CS-1 and 
osteopontin that mediates the firm adhesion and transmigration of leukocytes into the brain 
parenchyma and may perpetuate the inflammatory cascade in CNS tissue. Blockade of the molecular 
interactions of α4β1 with its targets reduces inflammatory activity present in the brain in MS and 
inhibits further recruitment of immune cells into inflamed tissue, thus reducing the formation or 
enlargement of MS lesions. 
 

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


14 
 

Clinical efficacy 
 
Efficacy as monotherapy has been evaluated in one randomised, double-blind, placebo-controlled 
study lasting 2 years (AFFIRM study) in relapsing-remitting MS patients who had experienced at least 
1 clinical relapse during the year prior to entry and had a Kurtzke Expanded Disability Status Scale 
(EDSS) score between 0 and 5. Median age was 37 years, with a median disease duration of 5 years. 
The patients were randomised with a 2:1 ratio to receive TYSABRI 300 mg (n = 627) or placebo 
(n = 315) every 4 weeks for up to 30 infusions. Neurological evaluations were performed every 
12 weeks and at times of suspected relapse. MRI evaluations for T1-weighted gadolinium 
(Gd)-enhancing lesions and T2-hyperintense lesions were performed annually. 
 
Study features and results are presented in the table below. 
 



15 
 

AFFIRM study: Main features and results  

Design  Monotherapy; randomised double-blind placebo-controlled parallel-group trial for 120 weeks 
Subjects  RRMS (McDonald criteria) 
Treatment Placebo / Natalizumab 300 mg i.v. every 4 weeks 
One year endpoint Relapse rate 
Two year endpoint Progression on EDSS 

Secondary endpoints  Relapse rate derived variables / MRI-derived variables 
Subjects  Placebo Natalizumab 
Randomised  315 627 
Completing 1 years   296 609 
Completing 2 years   285 589 
   
Age yrs, median (range) 37 (19-50) 36 (18-50) 
MS-history yrs, median (range) 6.0 (0-33) 5.0 (0-34) 
Time since diagnosis, yrs median 
(range) 2.0 (0-23) 2.0 (0-24) 

Relapses in previous 12 months, 
median (range) 

 
1.0 (0-5) 

 
1.0 (0-12) 

EDSS-baseline, median (range) 2 (0-6.0) 2 (0-6.0) 
   
RESULTS    
Annual relapse rate    

After one year (primary endpoint)   0.805 0.261 
After two years 0.733 0.235 

One year   Rate ratio 0.33 CI95% 0.26 ; 0.41 
Two years  Rate ratio 0.32 CI95% 0.26 ; 0.40 

Relapse free    
After one year   53% 76% 

After two years 41% 67% 
   
Disability    

Proportion progressed1(12-week 
confirmation; primary outcome) 29% 17% 

 Hazard ratio 0.58, CI95% 0.43; 0.73, p<0.001 
Proportion progressed1(24-week 

confirmation) 23% 11% 

 Hazard ratio 0.46, CI95% 0.33; 0.64, p<0.001 
MRI (0-2 years)   

Median % change in T2-
hyperintense lesion volume +8.8% 

-9.4% 
(p<0.001) 

Mean number of new or newly-
enlarging T2-hyperintense lesions 11.0 

1.9 
(p<0.001) 

Mean number of T1-hypointense 
lesions 4.6 

1.1 
(p<0.001) 

Mean number of Gd-enhancing 
lesions 1.2 

0.1 
(p<0.001) 

 

1 Progression of disability was defined as at least a 1.0 point increase on the EDSS from a baseline 
EDSS >=1.0 sustained for 12 or 24 weeks or at least a 1.5 point increase on the EDSS from a baseline 
EDSS =0 sustained for 12 or 24 weeks. 
 
In the sub-group of patients indicated for treatment of rapidly evolving relapsing remitting MS 
(patients with 2 or more relapses and 1 or more Gd+ lesion), the annualised relapse rate was 0.282 in 



16 
 

the TYSABRI treated group (n = 148) and 1.455 in the placebo group (n = 61) (p <0.001). Hazard 
ratio for disability progression was 0.36 (95% CI: 0.17, 0.76) p = 0.008. These results were obtained 
from a post hoc analysis and should be interpreted cautiously. No information on the severity of the 
relapses before inclusion of patients in the study is available. 
 
Interim analysis of results (as of May 2015) from the ongoing TYSABRI Observational Program 
(TOP), a phase 4, multicentre, single-arm study (n=5770) demonstrated that patients switching from 
beta interferon (n= 3255) or glatiramer acetate (n= 1384) to TYSABRI showed a sustained, significant 
decrease in annualised relapse rate (p< 0.0001). Mean EDSS scores remained stable over 5 years. 
Consistent with efficacy results observed for patients switching from beta interferon or glatiramer 
acetate to TYSABRI, for patients switching from fingolimod (n=147) to TYSABRI, a significant 
decrease in annualised relapse rate (ARR) was observed, which remained stable over 2 years, and 
mean EDSS scores remained similar from baseline to Year 2. The limited sample size and shorter 
duration of TYSABRI exposure for this subgroup of patients should be considered when interpreting 
these data. 
A post-marketing meta-analysis was conducted using data from 621 paediatric MS patients treated 
with TYSABRI (median age 17 years, range was 7-18 years, 91% aged ≥14 years). Within this 
analysis, a limited subset of patients with data available prior to treatment (158 of the 621 patients) 
demonstrated a reduction in ARR from 1.466 (95% CI 1.337, 1.604) prior to treatment to 0.110 (95% 
CI 0.094, 0.128). 
 
In a pre-specified, retrospective analysis of US anti-JCV antibody positive TYSABRI patients 
(TOUCH registry), the risk of PML was compared between patients treated with the approved dosing 
interval and patients treated with extended interval dosing as identified in the last 18 months of 
exposure (EID, average dosing intervals of approximately 6 weeks). The majority (85%) of patients 
dosed with EID had received the approved dosing for ≥1 year prior to switching to EID. The interim 
analysis showed a lower risk of PML in patients treated with EID (hazard ratio = 0.06 95% CI of 
hazard ratio = 0.01- 0.22). The efficacy of TYSABRI when administered with EID has not been 
established, and therefore the benefit/risk balance of EID is unknown (see section 4.4). 
 
Efficacy has been modelled for patients who switch to longer dosing after ≥1 year of approved 
TYSABRI dosing and who did not experience a relapse in the year prior to switching. Current 
pharmacokinetic/pharmacodynamic statistical modelling and simulation indicate that the risk of MS 
disease activity for patients switching to longer dosing intervals may be higher for patients with body 
weight >80kg or those with dosing intervals ≥7 weeks. No prospective clinical studies have been 
completed to validate these findings.  
 
5.2 Pharmacokinetic properties 
 
Following the repeat intravenous administration of a 300 mg dose of natalizumab to MS patients, the 
mean maximum observed serum concentration was 110 ± 52 μg/ml. Mean average steady-state trough 
natalizumab concentrations over the dosing period ranged from 23 μg/ml to 29 μg/ml. The predicted 
time to steady-state was approximately 36 weeks. 
 
A population pharmacokinetics analysis was conducted on samples from over 1,100 MS patients 
receiving doses ranging from 3 to 6 mg/kg natalizumab. Of these, 581 patients received a fixed 
300 mg dose as monotherapy. The mean ± SD steady-state clearance was 13.1 ± 5.0 ml/h, with a mean 
± SD half-life of 16 ± 4 days. The analysis explored the effects of selected covariates including body 
weight, age, gender, hepatic and renal function, and presence of anti-natalizumab antibodies upon 
pharmacokinetics. Only body weight and the presence of anti-natalizumab antibodies were found to 
influence natalizumab disposition. Body weight was found to influence clearance in a less-than-
proportional manner, such that a 43% change in body weight resulted in a 31% to 34% change in 
clearance. The change in clearance was not clinically significant. The presence of persistent anti-
natalizumab antibodies increased natalizumab clearance approximately 3-fold, consistent with reduced 
serum natalizumab concentrations observed in persistently antibody-positive patients, (see section 
4.8). 



17 
 

 
The pharmacokinetics of natalizumab in paediatric MS patients has not been established. The 
pharmacokinetics of natalizumab in patients with renal or hepatic insufficiency has not been studied. 
 
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. 
 
Consistent with the pharmacological activity of natalizumab, altered trafficking of lymphocytes was 
seen as white blood cell increases as well as increased spleen weights in most in vivo studies. These 
changes were reversible and did not appear to have any adverse toxicological consequences. 
 
In studies conducted in mice, growth and metastasis of melanoma and lymphoblastic leukaemia 
tumour cells was not increased by the administration of natalizumab. 
 
No clastogenic or mutagenic effects of natalizumab were observed in the Ames or human 
chromosomal aberration assays. Natalizumab showed no effects on in vitro assays of 
α4-integrin-positive tumour line proliferation or cytotoxicity. 
 
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human 
dose; natalizumab did not affect male fertility. 
 
The effect of natalizumab on reproduction was evaluated in 5 studies, 3 in guinea pigs and 2 in 
cynomolgus monkeys. These studies showed no evidence of teratogenic effects or effects on growth of 
offspring. In one study in guinea pigs, a small reduction in pup survival was noted. In a study in 
monkeys, the number of abortions was doubled in the natalizumab 30 mg/kg treatment groups versus 
matching control groups. This was the result of a high incidence of abortions in treated groups in the 
first cohort that was not observed in the second cohort. No effects on abortion rates were noted in any 
other study. A study in pregnant cynomolgus monkeys demonstrated natalizumab-related changes in 
the foetus that included mild anaemia, reduced platelet counts, increased spleen weights and reduced 
liver and thymus weights. These changes were associated with increased splenic extramedullary 
haematopoiesis, thymic atrophy and decreased hepatic haematopoiesis. Platelet counts were also 
reduced in offspring born to mothers treated with natalizumab until parturition, however there was no 
evidence of anaemia in these offspring. All changes were observed at doses in excess of the human 
dose and were reversed upon clearance of natalizumab. 
 
In cynomolgus monkeys treated with natalizumab until parturition, low levels of natalizumab were 
detected in the breast milk of some animals. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate, monobasic, monohydrate 
Sodium phosphate, dibasic, heptahydrate 
Sodium chloride 
Polysorbate 80 (E433) 
Water for injections 
 
6.2 Incompatibilities 
 
TYSABRI must not be mixed with other medicinal products except those mentioned in section 6.6. 
 



18 
 

6.3 Shelf life 
 
Unopened vial 
4 years 
 
Diluted solution 
 
After dilution with sodium chloride 9 mg/ml (0.9%) solution for injection, immediate use is 
recommended. If not used immediately, the diluted solution must be stored at 2˚C - 8˚C and infused 
within 8 hours of dilution. In-use storage times and conditions prior to use are the responsibility of the 
user. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2˚C - 8˚C). 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product see section 6.3. 
 
6.5 Nature and contents of container 
 
15 ml concentrate in a vial (type I glass) with a stopper (chlorobutyl rubber) and a seal (aluminium) 
with a flip-off cap.  
Pack size of one vial per carton. 
 
6.6 Special precautions for disposal and other handling 
 
Instructions for use: 
• Inspect the TYSABRI vial for particles prior to dilution and administration. If particles are 

observed and/or the liquid in the vial is not colourless, clear to slightly opalescent, the vial must 
not be used. 

 
• Use aseptic technique when preparing TYSABRI solution for intravenous (IV) infusion. 

Remove flip-off cap from the vial. Insert the syringe needle into the vial through the centre of 
the rubber stopper and remove 15 ml concentrate for solution for infusion. 

 
• Add the 15 ml concentrate for solution for infusion to 100 ml sodium chloride 9 mg/ml (0.9%) 

solution for injection. Gently invert the TYSABRI solution to mix completely. Do not shake. 
 
• TYSABRI must not be mixed with other medicinal products or diluents. 
 
• Visually inspect the diluted medicinal product for particles or discolouration prior to 

administration. Do not use if it is discoloured or if foreign particles are seen. 
 
• The diluted medicinal product is to be used as soon as possible and within 8 hours of dilution. If 

the diluted medicinal product is stored at 2˚C - 8˚C (do not freeze), allow the solution to warm 
to room temperature prior to infusion. 

 
• The diluted solution is to be infused intravenously over 1 hour at a rate of approximately 

2 ml/minute. 
 
• After the infusion is complete, flush the intravenous line with sodium chloride 9 mg/ml (0.9%) 

solution for injection. 
 
• Each vial is for single–use only. 
 



19 
 

• Any unused medicinal product or waste material must be disposed of in accordance with local 
requirements. 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Biogen Netherlands B.V. 
Prins Mauritslaan 13 
1171 LP Badhoevedorp 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/346/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27th June 2006 
Date of latest renewal: 18th April 2016 
 
 
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. 



20 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) 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 



21 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s) 
 
Biogen Inc 
5000 Davis Drive 
Research Triangle Park 
NC 27709-4627 
USA 
 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
DK-3400 Hillerød 
Denmark 
 
 
Name and address of the manufacturers responsible for batch release 
 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
DK-3400 Hillerød 
Denmark 
 
 
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.  



22 
 

 
 
• Additional risk minimisation measures  
 
Based on how patients treated with TYSABRI are currently monitored at national level, the Marketing 
Authorisation Holder (MAH) shall discuss and agree with the National Competent Authorities 
measures to enhance further this monitoring (e.g. registries, post-marketing surveillance studies) as 
appropriate. The MAH shall implement agreed measures for monitoring within a time frame agreed 
with the National Competent Authorities. 
 
The Marketing Authorisation Holder must, following discussions and agreement with the National 
Competent Authorities in each Member State where TYSABRI is marketed, ensure that all physicians 
who intend to prescribe TYSABRI are provided with a physician pack containing the following 
elements: 

• Summary of Product Characteristics and Package Leaflet 
• Physician information about TYSABRI 
• Patient alert card  
• Treatment initiation and treatment continuation forms 
• Treatment discontinuation form 
 
The physician information about TYSABRI shall contain the following key elements: 

• That TYSABRI therapy is to be initiated and continuously supervised by specialised physicians 
experienced in the diagnosis and treatment of neurological conditions, in centres with timely 
access to MRI. 

• Information that atypical/opportunistic infections, in particular PML, may occur with TYSABRI 
and include: 
o Opportunistic infections (other than PML): 

o TYSABRI increases the risk of developing encephalitis, meningitis and acute retinal 
necrosis (ARN) caused by herpes simplex and varicella zoster viruses 

o Guidance on screening for ARN. 

o That the risk of PML increases with increasing duration of treatment and that treatment 
beyond 24 months carries additional risk and other factors associated with an increased 
risk for the development of PML 

 Presence of anti-JC virus antibodies 
 Level of the antibody response (index) for patients without a history of 

immunosuppressant treatment 
 Immunosuppressant treatment prior to the use of TYSABRI 

o A stratification of the risk of developing PML based on the identified risk factors and 
presentation of the PML risk in a given time interval of treatment as well as the 
cumulative PML risk 

o PML risk estimates algorithm summarizes PML risk by anti- John Cunningham virus 
(JCV) antibody status, prior IS use and duration of treatment (by year of treatment) and 
stratifies this risk by index value when applicable. 

o The recommendation that patients should have MRI scans at the following times: 

 Within 3 months prior to starting TYSABRI 
 Annually during treatment with TYSABRI 
 More frequent MRIs (e.g. on a 3 to 6 monthly basis) for patients at high risk for 

PML. 



23 
 

 At the first sign of any symptoms indicative of the possibility of PML. 

o  Description of MRI protocols for baseline, routine screening and in case of PML 
suspicion 

o  Anti-JCV antibody testing, frequency of testing, interpretation of qualitative and 
quantitative results, seroprevalence of JCV-antibodies and seroconversion rate over time 

o  Diagnosis and prognosis of symptomatic and asymptomatic PML  

− differentiation between PML and MS 

− early recognition and intervention may improve outcome 

Discussion of PML in TYSABRI Treated Patients 

During extended pre-registration trials, two cases of PML were reported in MS patients and a full 
safety evaluation revealed one further case in a clinical trial patient with Crohn’s Disease.  In the post-
marketing setting, the risk of PML has been well characterized over the first 6 years of treatment with 
the identification of different levels of PML risk in different patient subgroups.   

Patients who have all three risk factors for PML (i.e., are anti-JCV antibody positive and have 
received more than 2 years of TYSABRI therapy, and have received prior immunosuppressant 
therapy) have a higher risk of PML. In anti-JCV antibody positive TYSABRI treated patients who 
have not used prior immunosuppressants the level of anti-JCV antibody response (index) is associated 
with the level of risk for PML (i.e. the risk is greater in those with a high antibody index compared to 
those with a low index). Currently available evidence suggests that the risk of PML is low at an index 
equal to or below 0.9 and increases substantially above 1.5 for patients who have been on treatment 
with TYSABRI for longer than 2 years.  

Irrespective of the presence or absence of PML risk factors, heightened clinical vigilance for PML 
should be maintained in all patients treated with TYSABRI and for 6 months following 
discontinuation of therapy. 

o Description of PML and incidence. Analysis of STRATIFY JCV showed the prevalence 
of anti-JCV antibodies to be approximately 55%.  Anti-JCV antibody prevalence in the 
EU was reported as ranging from 48.8% to 69.5% in the EU in a cross sectional study of 
MS patients irrespective of treatment. In the MS population, anti-JCV antibody prevalence 
increased with age and was lower in women than in men in all cohorts tested.  In general, 
anti-JCV antibody prevalence did not appear to be affected by prior immunosuppressant 
use, prior exposure to TYSABRI, or duration of TYSABRI exposure. 

o Patients, their partners and care givers are advised of symptoms that may be indicative of 
early PML and the need for counseling on the need to be vigilant for these symptoms 
while on TYSABRI treatment, and also for approximately 6 months after the last dose of 
TYSABRI (PML has also been reported up to 6 months following the last dose of  
TYSABRI in patients who did not have findings suggestive of PML at the time of 
discontinuation).  

o Information provided regarding - In all cases where further investigation of change in 
neurological status or change in brain MRI is indicated, TYSABRI must be suspended and 
not restarted until non MS pathology has been confidently excluded. Suspension of 
TYSABRI therapy, for short duration (days or weeks), is not expected to compromise 
therapeutic efficacy based on the pharmacodynamics of the drug. 



24 
 

The decision to suspend TYSABRI at any stage may be based on the initial clinical presentation, MRI 
findings, the evolution of symptoms or signs and/or the response to corticosteroid treatment. 

o Confirmation that TYSABRI should be permanently discontinued if PML is confirmed. 

o Management of PML 

o Monitoring strategy after discontinuation of TYSABRI treatment 

o The need to inform patients about the benefits and risk of TYSABRI and provide them 
with: 

− A copy of the treatment initiation form 

− A patient alert card including a core text agreed by the CHMP 

o If treatment is to be continued for longer than 24 months, the need to inform 
patients about the increased risk of PML and provide them with a copy of the 
treatment continuation form 

o Description of Immune Reconstitution Inflammatory Syndrome (IRIS) is provided 

Clinical neurologic deterioration in patients with PML and/or JCV GCN may be caused by JCV-
mediated destruction of CNS tissue, or upon restoration of immune function, by an intracerebral 
immune inflammatory reaction known as immune reconstitution inflammatory syndrome (IRIS).  IRIS 
is generally suspected when patients with PML exhibit signs of clinical worsening usually, but not 
always, accompanied by gadolinium enhancement of PML lesions with or without mass effect on 
brain MRI.   The clinical worsening is a result of local inflammatory reaction, including oedema, and 
manifests as a worsening of neurological symptoms including hemiparesis, ataxia, speech 
abnormalities, visual disturbance, cognitive/behavioural changes and seizure (dependent on the site of 
IRIS).  Severe sequelae can occur including coma and death. Although JC viral load in the CSF might 
be expected to decline in the setting of IRIS, it is also possible that due to the breakdown of the blood 
brain barrier (BBB) and release of JCV from cells lysed during IRIS, it can be increased. 

In patients treated with TYSABRI, IRIS has occurred within days to several weeks after TYSABRI 
removal by plasma exchange (PLEX) or immunoabsorption (IA).  Although the inflammatory reaction 
following immune reconstitution may be a necessary step to remove JCV-infected cells, it may 
become necessary to treat the active immune reaction to prevent potential damage caused by IRIS 
(Talan 2009; Elston and Thacker 2009) and can be life-threatening and may therefore require 
management in an intensive care unit.  Therefore, following PLEX or IA, periodic clinical monitoring 
of patients, including MRI monitoring, may be useful for the early detection of IRIS. The diagnosis 
and management of IRIS is a controversial issue and there is no consensus concerning its treatment. 
However, it has recently been suggested that corticosteroids may be useful to treat IRIS, particularly in 
patients with severe to life-threatening IRIS (Tan et al., 2009, Clifford et al., 2010).  The following 
steroid regimens have been reported for the treatment of IRIS in the literature: 

1) Oral prednisone 1.5 mg/kg/d x 2 wks with taper over 2 months 

2)  Intravenous methylprednisolone (1 g/d for 3 or 5 d) with oral taper over 2 months 

If further deterioration occurs during steroid taper and this is judged to be due to continuing or new 
inflammatory reactions a further course of higher dose steroids may be necessary. 



25 
 

Prophylactic steroid treatment is currently not recommended.  As scientific and medical knowledge, 
including both diagnostic criteria and management of IRIS is rapidly eveolving, please contact 
Medical affairs in your country for the most up to date information on treatment recommendations.   

• Possibility of other opportunistic infections  
• The need to inform the National Competent Authority about any cases of PML 
• Information about any registry or other monitoring system set up in the Member State and how 

to enter patients 
 
Information about extended interval dosing (EID)  

• Reminder of the approved dosing; cross reference to EU SmPC  

• Present the results of the TOUCH analysis which showed clinically and statistically 
significant reduction in PML risk in patients who are treated with EID (dosing interval 6 
weeks) compared to Standard interval dosing (dosing interval 4 weeks).  

• Switching usually occurred after 1 year (median of 25 standard interval doses) in the 
secondary definition 

• Inform about an ongoing study assessing the efficacy, tolerability and safety of switching 
to EID after at least 12 months on approved dosing. 

• Present data from PK/PD/efficacy modelling from clinical trial data that suggests efficacy 
of 6 week dosing more similar to 4 weeks if occurs >1 year of 4 weekly treatment 

• Present data from PK/PD/efficacy modelling from the RESTORE study which indicates 
that risk of return of MS disease activity more likely with increased body weight (>80kg) 
or longer dosing intervals (>7 weeks). Monitoring for potential signs of return of MS 
disease activity in patients switching dosing intervals.  

 
The treatment initiation form should contain the following elements: 

• That the aim of the treatment initiation form is to provide patients with information on PML and 
IRIS  

• Information on PML and IRIS including the risk of developing PML during TYSABRI 
treatment stratified by prior treatment with immunosuppressants and JCV infection.  

• Confirmation that the doctor has discussed the risks of PML and the risk of IRIS if treatment is 
discontinued following suspicion of PML  

• Confirmation of patient understanding of the risks of PML and that they have received a copy of 
the form and a patient alert card  

• Patient details, signature and date  
• Prescriber name, signature and date 
 
The treatment continuation form should contain the elements of the treatment initiation form and, in 
addition, a statement that the risks of PML increase with duration of treatment and that treatment 
beyond 24 months carries additional risk. 
 

The treatment discontinuation form  

• Inform patient that PML has been reported up to 6 months after stopping Tysabri  

• Reminder of PML symptoms 

• When MRI imaging may be warranted 



26 
 

• Keep alert card with the them after discontinuation 

• Reporting of side effects 

 

Patient alert card  

• Reminder to show the card to any doctor involved with their treatment  

• Reminder to read the package leaflet carefully before starting Tysabri 

• Reminder to keep the card with them for 6 months after the last dose of Tysabri  

• Reminder to show the card to patients and caregivers and provides a list of symptoms 
that may be associated with the development of PML 

• Reminder not to start Tysabri if there is a serious problem with their immune system 

• Reminder no to take any other long-term medicines for MS while receiving Tysabri 

• A description of PML, potential symptoms and management of PML 

• A reminder regarding serious infections and the need to speak to their doctor if they 
have severe persistent infection  

• A reminder of where to report side effects 

• Details of the patient, treating doctor and date Tysabri was started 
 



27 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



28 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



29 
 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TYSABRI 300 mg concentrate for solution for infusion 
natalizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 15 ml vial of concentrate contains 300 mg natalizumab (20 mg/ml). When diluted the solution 
for infusion contains approximately 2.6 mg/ml of natalizumab. 
 
 
3. LIST OF EXCIPIENTS 
 
sodium phosphate, monobasic, monohydrate; sodium phosphate, dibasic, heptahydrate; sodium 
chloride; polysorbate 80 (E433) and water for injections. 
 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
concentrate for solution for infusion 
1 x 15 ml vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use.  
Dilute before infusion. 
After dilution, do not shake.  
 
Read the package leaflet before use. 
 
 
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 
 
 



30 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2˚C - 8˚C). Do not freeze. Keep the vial in the outer carton in order to protect 
from light. 
 
 
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 
 
Biogen Netherlands B.V. 
Prins Mauritslaan 13 
1171 LP Badhoevedorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/346/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



31 
 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
TYSABRI 300 mg concentrate for solution for infusion 
natalizumab 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Dilute before infusion. After dilution, do not shake.  
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
15 ml 
 
 
6. OTHER 
 



32 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



33 
 

Package leaflet: Information for the patient 
 

TYSABRI 300 mg concentrate for solution for infusion 
natalizumab 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 
In addition to this leaflet you will be given a Patient Alert Card, which contains important safety 
information that you need to know before you are given TYSABRI (pronounced tie-SA-bree) and 
during treatment with TYSABRI. 
 
- Keep this leaflet and the Patient Alert Card. You may need to read them again. Keep the leaflet 

and Alert Card with you during treatment and for six months after the last dose of TYSABRI, 
since side effects may occur even after you have stopped treatment. 

- If you have any further questions, ask your doctor.  
- If you get any side effects talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What TYSABRI is and what it is used for 
2. What you need to know before you use TYSABRI 
3. How to use TYSABRI 
4. Possible side effects 
5. How to store TYSABRI 
6. Contents of the pack and other information 
 
 
1. What TYSABRI is and what it is used for 
 
TYSABRI contains the active substance (natalizumab). This active ingredient is called a monoclonal 
antibody. These antibodies work by binding to proteins in the body so that the harmful effect of that 
protein is removed.  
 
TYSABRI is used to treat multiple sclerosis (MS). MS causes inflammation in the brain that damages 
the nerve cells. TYSABRI stops the cells that cause inflammation from going into your brain. This 
reduces nerve damage caused by MS. 
 
 
What are the symptoms of multiple sclerosis? 
The symptoms of MS vary from patient to patient, and you may experience some or none of them.  
 
Symptoms can include; walking problems, numbness in the face, arms or legs, problems seeing 
things, tiredness, feeling off-balance or light headed, bladder and bowel problems, difficulty in 
thinking and concentrating, depression, acute or chronic pain, sexual problems, and stiffness and 
muscle spasms. When the symptoms flare up, it is called a relapse (also known as an exacerbation or 
an attack). When a relapse occurs, you may notice the symptoms suddenly, within a few hours, or 
slowly progressing over several days. Your symptoms will then usually improve gradually (this is 
called a remission). 
 
In clinical trials, TYSABRI approximately halved the progression of the disabling effects of MS and 
also decreased the number of MS attacks by about two-thirds. When you receive TYSABRI you might 
not notice any improvement, but TYSABRI may still be working to prevent your MS becoming worse. 



34 
 

 
 
2. What you need to know before you use TYSABRI 
 
Before you start treatment with TYSABRI, it is important that you and your doctor have discussed the 
benefits you would expect to receive from this treatment and the risks that are associated with it. 
 
Do not use TYSABRI 
• If you are allergic to natalizumab or any of the other ingredients of this medicine (listed in 

section 6). 
 
• If your doctor has told you that you have PML (progressive multifocal leukoencephalopathy). 

PML is a rare infection of the brain. 
 
• If your doctor tells you that you have a serious problem with your immune system (due to 

disease for example, HIV or due to a medicine you are taking or have previously taken 
 
• If you are taking medicines that suppress or modulate the immune system including other 

medicines used to treat MS disease. These medicines cannot be used with TYSABRI (see Using 
other medicines, below). 

 
• If you have an active cancer (unless it is a type of skin cancer called basal cell carcinoma). 
 
 
Warnings and precautions 
Talk to your doctor before using TYSABRI. 
 
Infections 
 
Tell your doctor immediately if you have, or think you have, any sort of infection (see side effects). 
Some infections other than PML may also be serious and can be due to viruses, bacteria, or other 
causes. 
 
There have been cases of a rare brain infection called PML (progressive multifocal 
leukoencephalopathy) that have occurred in patients who have been given TYSABRI. PML may lead 
to severe disability or death.  
 
• The symptoms of PML may be similar to an MS relapse (e.g. weakness or visual changes). 

Therefore, if you believe your MS is getting worse or if you notice any new symptoms while 
you are on TYSABRI treatment or for up to 6 months after stopping TYSABRI treatment, it is 
very important that you speak to your doctor as soon as possible. 
 

• Speak with your partner or caregivers and inform them about your treatment. Symptoms might 
arise that you might not become aware of by yourself, such as changes in mood or behaviour, 
memory lapses, speech and communication difficulties, which your doctor may need to 
investigate further to rule out PML. You should remain aware for symptoms that might arise for 
up to 6 months after stopping TYSABRI treatment.  
 

• You will also find this information in the Patient Alert Card you have been given by your 
doctor. It is important that you keep this Alert Card and show it to your partner or caregivers. 

 

PML is associated with an uncontrolled increase of the JC virus in the brain, although the reason for 
this increase in some patients treated with TYSABRI is unknown. A condition called JCV GCN (JC 
virus granule cell neuronopathy) is also caused by JC virus and has occurred in some patients who 
have been given TYSABRI. The symptoms of JCV GCN are similar to PML. JC virus is a common 
virus which infects many people but does not normally cause noticeable illness.  



35 
 

Your doctor may test your blood to check if you have antibodies to the JC virus before you start 
treatment with TYSABRI. These antibodies are a sign that you have been infected by JC virus. Your 
doctor may repeat this blood test while you are on TYSABRI treatment to check if anything has 
changed.   
 
The risk of PML with TYSABRI is higher:  
• If you have antibodies to the JC virus in your blood. 
• The longer that you are on treatment especially if you have been on treatment for more than two 

years.  
• If you have previously taken a medicine called an immunosuppressant. These medicines reduce 

the activity of your body’s immune system.  
 
If you have all three risks described above your chance of getting PML is higher.  
 
If you have previously not been treated with immunosuppressants and have received TYSABRI for 2 
years or longer, the level of your anti-JCV antibody response may be associated with the risk of 
getting PML. 
 
For those with a lower risk of PML, your doctor may repeat the test regularly to check if anything has 
changed if: 

• If you do not have antibodies to the JC virus in your blood OR 
• If you have been treated for more than 2 years and you have a lower level of JCV antibodies in 

your blood. 
You should discuss with your doctor if TYSABRI is the most suitable treatment for you before 
you start taking TYSABRI and when you have been taking TYSABRI for more than two years.  
 
In patients with PML a reaction known as IRIS (Immune Reconstitution Inflammatory Syndrome) is 
likely to occur after treatment for PML, as TYSABRI is removed from your body. IRIS may lead to 
your condition getting worse, including worsening of brain function. 
 
Allergic reactions 
A few patients have had an allergic reaction to TYSABRI. Your doctor will check for allergic 
reactions during the infusion and for 1 hour afterwards. 
 
Will TYSABRI always work? 
In a few patients who use TYSABRI, over time the body’s natural defence may stop TYSABRI from 
working properly (the body develops antibodies to TYSABRI). Your doctor can decide whether 
TYSABRI is not working properly for you by testing your blood and will stop TYSABRI, if 
necessary. 
 
Other medicines and TYSABRI 
Tell your doctor if you are taking or have recently taken or might take any other medicines.  
 
• You must not use TYSABRI if you are being treated with other medicines to treat your MS 

disease 
 

• You may not be able to use TYSABRI if you are currently receiving or have previously 
received medicines that affect your immune system  

 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine 
 
• Do not use TYSABRI if you are pregnant unless you have discussed this with your doctor. Be 

sure to tell your doctor immediately if you are pregnant, think you may be pregnant, or if you 
are planning to become pregnant. 



36 
 

 
• Do not breast-feed whilst using TYSABRI. You should discuss with your doctor whether you 

choose to breast-feed or to use TYSABRI. 
 
Driving and using machines 
There are no studies on the effects of TYSABRI on the ability to drive and use machines. However, if 
you experience dizziness, a very common side effect, then you should not drive or use machines. 
 
TYSABRI contains sodium 
 
Each vial of TYSABRI contains 2.3 mmol (or 52 mg) of sodium. After dilution for use, this medicinal 
product contains 17.7 mmol (or 406 mg) sodium per dose. This should be considered if you are on a 
controlled sodium diet. 
 
 
3. How to use TYSABRI 
 
TYSABRI will be given to you by a doctor experienced in the treatment of MS. Your doctor may 
switch you directly from another medicine for MS to TYSABRI if there are no signs of abnormalities 
caused by your previous treatment. Your doctor should do a blood test in order to test for 
abnormalities and whether you have antibodies to the JC virus. To switch from some MS medicines, 
your doctor may advise you to wait for a certain time to ensure that most of the previous medicine has 
left your body. Initiating treatment with TYSABRI after alemtuzumab is generally not recommended. 
If you have been treated with alemtuzumab, a thorough evaluation and discussion with your doctor is 
required to decide if a switch to TYSABRI is appropriate for you. 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
• The recommended dose for adults is 300 mg given once every 4 weeks. 
 
• TYSABRI must be diluted before it is given to you. It is given as a drip into a vein (by 

intravenous infusion), usually in your arm. This takes about 1 hour. 
 
• Information for medical or healthcare professionals on how to prepare and administer 

TYSABRI is provided at the end of this leaflet. 
 
• It is important to continue with your medicine for as long as you and your doctor decide that it 

is helping you. Continuous dosing with TYSABRI is important, especially during the first few 
months of treatment. This is because patients who received one or two doses of TYSABRI and 
then had a gap in treatment of three months or more, were more likely to have an allergic 
reaction when resuming treatment. 

 
If you miss your dose of TYSABRI 
If you miss your usual dose of TYSABRI, arrange with your doctor to receive it as soon as you can. 
You can then continue to receive your dose of TYSABRI every 4 weeks. 
 
Always use this medicine exactly as described in this leaflet or as your doctor has told you. Check 
with your doctor if you are not sure.  
 
If you have any further questions on TYSABRI, ask your doctor.  
 
 



37 
 

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Speak to your doctor or nurse immediately if you notice any of the following 
 
Symptoms of serious infections including: 
− An unexplained fever 
− Severe diarrhoea 
− Shortness of breath 
− Prolonged dizziness 
− Headache 
− Weight loss 
− Listlessness 
− Impaired vision 
− Pain or redness of the eye(s) 
 
A group of symptoms caused by a serious infection of the brain including: 
– Changes in personality and behaviour such as confusion, delirium or loss of consciousness, 

seizures (fits), headache, nausea / vomiting, stiff neck, extreme sensitivity to bright light, fever, 
rash (anywhere on the body). 

 
These symptoms may be caused by an infection of the brain (encephalitis) or its covering layer 
(meningitis). 
 
 
Signs of allergy to TYSABRI, during or shortly after your infusion: 
• Itchy rash (hives) 
• Swelling of your face, lips or tongue 
• Difficulty breathing 
• Chest pain or discomfort 
• Increase or decrease in your blood pressure (your doctor or nurse will notice this if they are 

monitoring your blood pressure). 
 
Signs of a possible liver problem: 
• Yellowing of your skin or the whites of your eyes 
• Unusual darkening of the urine. 
 
TYSABRI can also have other side effects. 
 
Side effects are listed below by how commonly they have been reported in clinical trials: 
 
Very common side effects that may affect more than 1 in 10 people: 
• Urinary tract infection 
• Sore throat and runny or blocked up nose 
• Headache 
• Dizziness 
• Feeling sick (nausea) 
• Joint pain 
• Tiredness 
 
Common side effects that may affect up to 1 in 10 people: 
• Shivering 
• Itchy rash (hives) 
• Being sick (vomiting) 



38 
 

• Fever 
 
Uncommon side effects that may affect up to 1 in 100 people: 
• Severe allergy (hypersensitivity) 
• Progressive multifocal leukoencephalopathy (PML) 
 
Rare side effects that may affect up to 1 in 1,000 people: 
• Unusual infections (so-called “Opportunistic infections”) 
• Severe anaemia (decrease in your red blood cells which can make your skin pale and can make 

you feel breathless or lacking energy) 
 
Speak to your doctor as soon as possible if you think you have an infection. 
Show the Alert Card and this package leaflet to any doctor involved with your treatment, not only to 
your neurologist. 
 
You will also find this information in the Patient Alert Card you have been given by your doctor. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. 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 TYSABRI 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date stated on the label and carton. The expiry date refers to 
the last day of that month. 
 
Unopened vial: 
Store in a refrigerator (2°C to 8°C). 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
Diluted solution: 
After dilution, immediate use is recommended. If not used immediately, the diluted solution must be 
stored at 2˚C - 8˚C and infused within 8 hours of dilution. 
 
Do not use this medicine if you notice particles in the liquid and/or the liquid in the vial is discoloured. 
 
 
6. Contents of the pack and other information 
 
What TYSABRI contains 
The active substance is natalizumab. Each 15 ml vial of concentrate contains 300 mg natalizumab 
(20 mg/ml). When diluted, the solution for infusion contains approximately 2.6 mg/ml of natalizumab. 
 
The other ingredients are: 
Sodium phosphate, monobasic, monohydrate, 
Sodium phosphate, dibasic, heptahydrate, 
Sodium chloride (see section 2 ‘TYSABRI contains sodium’), 
Polysorbate 80 (E433) 
Water for injections 
 
What TYSABRI looks like and contents of the pack 
TYSABRI is a clear, colourless to slightly cloudy liquid.  

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


39 
 

Each carton contains one glass vial. 
 
Marketing Authorisation Holder 
Biogen Netherlands B.V. 
Prins Mauritslaan 13 
1171 LP Badhoevedorp 
The Netherlands 
 
Manufacturer 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
DK-3400 Hillerød 
Denmark  
 
For any further information about this medicine, please contact the local representative of the 
Marketing Authorisation Holder.  
 
België/Belgique/Belgien 
Biogen Belgium N.V./S.A. 
Tél/Tel: +32 2 219 12 18 
 

Lietuva 
UAB "JOHNSON & JOHNSON" 
Tel: +370 5 278 68 88 
 

България 
ТП ЕВОФАРМА 
Teл.: +359 2 962 12 00 
 

Luxembourg/Luxemburg 
Biogen Belgium N.V./S.A. 
Tél/Tel: +32 2 219 12 18 
 

Česká republika 
Biogen (Czech Republic) s.r.o. 
Tel: +420 255 706 200 
 

Magyarország 
Biogen Hungary Kft. 
Tel.: +36 (1) 899 9883 

Danmark 
Biogen (Denmark) A/S 
Tlf: +45 77 41 57 57 
 

Malta 
Pharma MT limited 
Tel: +356 213 37008/9 
 

Deutschland 
Biogen GmbH 
Tel: +49 (0) 89 99 6170 
 

Nederland 
Biogen Netherlands B.V. 
Tel: +31 20 542 2000 

Eesti 
UAB "JOHNSON & JOHNSON" Eesti filiaal 
Tel: +372 617 7410 
 

Norge 
Biogen Norway AS 
Tlf: +47 23 40 01 00  

Ελλάδα 
Genesis Pharma SA  
Τηλ: +30 210 8771500 
 

Österreich 
Biogen Austria GmbH 
Tel: +43 1 484 46 13 

España 
Biogen Spain SL 
Tel: +34 91 310 7110 
 

Polska 
Biogen Poland Sp. z o.o. 
Tel.: +48 22 351 51 00 
 

France 
Biogen France SAS 
Tél: +33 (0)1 41 37 95 95 
 

Portugal 
Biogen Portugal Sociedade Farmacêutica 
Unipessoal, Lda 
Tel: +351 21 318 8450 
 



40 
 

Hrvatska 
Medis Adria d.o.o. 
Tel: +385 (0) 1 230 34 46 
 

România 
Johnson & Johnson Romania S.R.L. 
Tel: +40 21 207 18 00 
 

Ireland 
Biogen Idec (Ireland) Ltd. 
Tel: +353 (0)1 463 7799 
 

Slovenija 
Biogen Pharma d.o.o. 
Tel: +386 1 511 02 90 
 

Ísland 
Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika 
Biogen Slovakia s.r.o. 
Tel: +421 2 323 340 08 

Italia 
Biogen Italia s.r.l. 
Tel: +39 02 584 9901 
 

Suomi/Finland 
Biogen Finland Oy 
Puh/Tel: +358 207 401 200 
 

Κύπρος 
Genesis Pharma (Cyprus) Ltd 
Τηλ: +357 22 76 57 40 
 

Sverige 
Biogen Sweden AB 
Tel: +46 8 594 113 60 
 

Latvija 
UAB "JOHNSON & JOHNSON" filiāle Latvijā 
Tel: +371 678 93561 
 

United Kingdom 
Biogen Idec Limited 
Tel: +44 (0) 1628 50 1000 
 

 
This leaflet was last revised in {MM/YYYY}.  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
--------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only: 
 
1. Inspect the TYSABRI vial for particles prior to dilution and administration. If particles are 

observed and/or the liquid in the vial is not colourless, clear to slightly opalescent, the vial must 
not be used. 

 
2. Use aseptic technique when preparing TYSABRI solution for intravenous infusion. Remove 

flip-top from the vial. Insert the syringe needle into the vial through the centre of the rubber 
stopper and remove 15 ml concentrate for solution for infusion. 

 
3. Add the 15 ml concentrate for solution for infusion to 100 ml sodium chloride 9 mg/ml (0.9%) 

solution for injection. Gently invert the TYSABRI solution to mix completely. Do not shake. 
 
4. TYSABRI must not be mixed with other medicinal products or diluents. 
 
5. Visually inspect the diluted medicinal product for particles or discolouration prior to 

administration. Do not use if it is discoloured or if foreign particles are seen. 
 
6. The diluted medicinal product is to be used as soon as possible and within 8 hours of dilution. If 

the diluted medicinal product is stored at 2°C - 8°C (do not freeze), allow the solution to warm 
to room temperature prior to infusion. 

 



41 
 

7. The diluted solution is to be infused intravenously over 1 hour at a rate of approximately 
2 ml/minute. 

 
8. After the infusion is complete, flush the intravenous line with sodium chloride 9 mg/ml (0.9%) 

solution for injection. 
 
9. Each vial is for single–use only. 
 
10. In order to improve traceability of biological medicinal products, the product name (Tysabri) 

and batch number of the administered product should be clearly recorded. 
 
11. Any unused medicinal product or waste material must be disposed of in accordance with local 

requirements. 
 



42 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 

 



43 
 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for natalizumab, the scientific 
conclusions of CHMP are as follows: 
 
The MAH conducted a retrospective analysis on the impact of plasma exchange/plasmapheresis 
(PLEX) on the outcome (2-year survival post-PML) of natalizumab-associated progressive multifocal 
leukoencephalopathy (PML). This analysis suggested that PLEX is not associated with a statistically 
significant effect on survival and appears to have no impact on improving post-PML outcomes. As 
PLEX is frequently used in clinical practise for treatment of PML, PRAC agreed that physicians 
should be informed about the new data on PLEX via an update of the sections 4.4 and 5.2 of the 
SmPC. 
 
Further, the MAH proposed updating the adverse drug reaction (ADR) frequencies of some adverse 
events (from “common” to “very common”) in the section 4.8 of SmPC and Package Leaflet. The 
changes in ADR frequencies are to correct typographical errors and are considered acceptable. 
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
Grounds for the variation to the terms of the marketing authorisation(s) 
 
On the basis of the scientific conclusions for natalizumab the CHMP is of the opinion that the benefit-
risk balance of the medicinal product(s) containing natalizumab is unchanged subject to the proposed 
changes to the product information 
 
The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) 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
	ANNEX IV
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it is called a relapse (also known as an exacerbation or an attack). when a relapse occurs, you may notice the symptoms suddenly, within a few hours, or slowly progressing over several days. your symptoms will then usually improve gradually (this is called a remission). in clinical trials, tysabri approximately halved the progression of the disabling effects of ms and also decreased the number of ms attacks by about two-thirds. when you receive tysabri you might not notice any improvement, but tysabri may still be working to prevent your ms becoming worse.', 'Entity_Recognition': [{'Text': 'tysabri', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 10, 'BeginOffset': 0, 'EndOffset': 7, 'Score': 0.9616933465003967, 'Text': 'tysabri', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 39, 'EndOffset': 50, 'Score': 0.9846965074539185, 'Text': 'natalizumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a 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{'Title': '2. what you need to know before you use tysabri', 'Section_Content': "before you start treatment with tysabri, it is important that you and your doctor have discussed the benefits you would expect to receive from this treatment and the risks that are associated with it. do not use tysabri if you are allergic to natalizumab or any of the other ingredients of this medicine (listed in section 6). if your doctor has told you that you have pml (progressive multifocal leukoencephalopathy). pml is a rare infection of the brain. if your doctor tells you that you have a serious problem with your immune system (due to disease for example, hiv or due to a medicine you are taking or have previously taken if you are taking medicines that suppress or modulate the immune system including other medicines used to treat ms disease. these medicines cannot be used with tysabri (see using other medicines, below). if you have an active cancer (unless it is a type of skin cancer called basal cell carcinoma). warnings and precautions talk to your doctor before using tysabri. infections tell your doctor immediately if you have, or think you have, any sort of infection (see side effects). some infections other than pml may also be serious and can be due to viruses, bacteria, or other causes. there have been cases of a rare brain infection called pml (progressive multifocal leukoencephalopathy) that have occurred in patients who have been given tysabri. pml may lead to severe disability or death. the symptoms of pml may be similar to an ms relapse (e.g. weakness or visual changes). therefore, if you believe your ms is getting worse or if you notice any new symptoms while you are on tysabri treatment or for up to 6 months after stopping tysabri treatment, it is very important that you speak to your doctor as soon as possible. speak with your partner or caregivers and inform them about your treatment. symptoms might arise that you might not become aware of by yourself, such as changes in mood or behaviour, memory lapses, speech and communication difficulties, which your doctor may need to investigate further to rule out pml. you should remain aware for symptoms that might arise for up to 6 months after stopping tysabri treatment. you will also find this information in the patient alert card you have been given by your doctor. it is important that you keep this alert card and show it to your partner or caregivers. pml is associated with an uncontrolled increase of the jc virus in the brain, although the reason for this increase in some patients treated with tysabri is unknown. a condition called jcv gcn (jc virus granule cell neuronopathy) is also caused by jc virus and has occurred in some patients who have been given tysabri. the symptoms of jcv gcn are similar to pml. jc virus is a common virus which infects many people but does not normally cause noticeable illness. your doctor may test your blood to check if you have antibodies to the jc virus before you start treatment with tysabri. these antibodies are a sign that you have been infected by jc virus. your doctor may repeat this blood test while you are on tysabri treatment to check if anything has changed. the risk of pml with tysabri is higher: if you have antibodies to the jc virus in your blood. the longer that you are on treatment especially if you have been on treatment for more than two years. if you have previously taken a medicine called an immunosuppressant. these medicines reduce the activity of your body's immune system. if you have all three risks described above your chance of getting pml is higher. if you have previously not been treated with immunosuppressants and have received tysabri for 2 years or longer, the level of your anti-jcv antibody response may be associated with the risk of getting pml. for those with a lower risk of pml, your doctor may repeat the test regularly to check if anything has changed if: if you do not have antibodies to the jc virus in your blood or if you have been treated for more than 2 years and you have a lower level of jcv antibodies in your blood. you should discuss with your doctor if tysabri is the most suitable treatment for you before you start taking tysabri and when you have been taking tysabri for more than two years. in patients with pml a reaction known as iris (immune reconstitution inflammatory syndrome) is likely to occur after treatment for pml, as tysabri is removed from your body. iris may lead to your condition getting worse, including worsening of brain function. allergic reactions a few patients have had an allergic reaction to tysabri. your doctor will check for allergic reactions during the infusion and for 1 hour afterwards. will tysabri always work? in a few patients who use tysabri, over time the body's natural defence may stop tysabri from working properly (the body develops antibodies to tysabri). your doctor can decide whether tysabri is not working properly for you by testing your blood and will stop tysabri, if necessary. other medicines and tysabri tell your doctor if you are taking or have recently taken or might take any other medicines. you must not use tysabri if you are being treated with other medicines to treat your ms disease you may not be able to use tysabri if you are currently receiving or have previously received medicines that affect your immune system pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine do not use tysabri if you are pregnant unless you have discussed this with your doctor. be sure to tell your doctor immediately if you are pregnant, think you may be pregnant, or if you are planning to become pregnant. do not breast-feed whilst using tysabri. you should discuss with your doctor whether you choose to breast-feed or to use tysabri. driving and using machines there are no studies on the effects of tysabri on the 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before it is given to you. it is given as a drip into a vein (by intravenous infusion), usually in your arm. this takes about 1 hour. information for medical or healthcare professionals on how to prepare and administer tysabri is provided at the end of this leaflet. it is important to continue with your medicine for as long as you and your doctor decide that it is helping you. continuous dosing with tysabri is important, especially during the first few months of treatment. this is because patients who received one or two doses of tysabri and then had a gap in treatment of three months or more, were more likely to have an allergic reaction when resuming treatment. if you miss your dose of tysabri if you miss your usual dose of tysabri, arrange with your doctor to receive it as soon as you can. you can then continue to receive your dose of tysabri every 4 weeks. always use this medicine exactly as described in this leaflet or as your doctor has told you. check with your doctor if you are 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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. speak to your doctor or nurse immediately if you notice any of the following symptoms of serious infections including: − an unexplained fever − severe diarrhoea − shortness of breath − prolonged dizziness − headache − weight loss − listlessness − impaired vision − pain or redness of the eye(s) a group of symptoms caused by a serious infection of the brain including: changes in personality and behaviour such as confusion, delirium or loss of consciousness, seizures (fits), headache, nausea / vomiting, stiff neck, extreme sensitivity to bright light, fever, rash (anywhere on the body). these symptoms may be caused by an infection of the brain (encephalitis) or its covering layer (meningitis). signs of allergy to tysabri, during or shortly after your infusion: itchy rash (hives) swelling of your face, lips or tongue difficulty breathing chest pain or discomfort increase or decrease in your blood pressure (your doctor or nurse will notice this if they are monitoring your blood pressure). signs of a possible liver problem: yellowing of your skin or the whites of your eyes unusual darkening of the urine. tysabri can also have other side effects. side effects are listed below by how commonly they have been reported in clinical trials: very common side effects that may affect more than 1 in 10 people: urinary tract infection sore throat and runny or blocked up nose headache dizziness feeling sick (nausea) joint pain tiredness common side effects that may affect up to 1 in 10 people: shivering itchy rash (hives) being sick (vomiting) 38 fever uncommon side effects that may affect up to 1 in 100 people: severe allergy (hypersensitivity) progressive multifocal leukoencephalopathy (pml) rare side effects that may affect up to 1 in 1,000 people: unusual infections (so-called "opportunistic infections") severe anaemia (decrease in your red blood cells which can make your skin pale and can make you feel breathless or lacking energy) speak to your doctor as soon as possible if you think you have an infection. show the alert card and this package leaflet to any doctor involved with your treatment, not only to your neurologist. you will also find this information in the patient alert card you have been given by your doctor. reporting of side effects if you get any side effects, talk to your doctor. 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': 'tysabri', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 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{'Title': '5. how to store tysabri', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date stated on the label and carton. the expiry date refers to the last day of that month. unopened vial: store in a refrigerator (2 to 8). do not freeze. keep the vial in the outer carton in order to protect from light. diluted solution: after dilution, immediate use is recommended. if not used immediately, the diluted solution must be stored at 2˚c - 8˚c and infused within 8 hours of dilution. do not use this medicine if you notice particles in the liquid and/or the liquid in the vial is discoloured.', 'Entity_Recognition': [{'Text': 'tysabri', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 237, 'EndOffset': 238}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 273, 'EndOffset': 289}, {'Text': 'the diluted solution', 'Type': 'TREATMENT', 'BeginOffset': 411, 'EndOffset': 431}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 456, 'EndOffset': 457}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 479, 'EndOffset': 480}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 511, 'EndOffset': 524}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': "what tysabri contains the active substance is natalizumab. each 15 ml vial of concentrate contains 300 mg natalizumab (20 mg/ml). when diluted, the solution for infusion contains approximately 2.6 mg/ml of natalizumab. the other ingredients are: sodium phosphate, monobasic, monohydrate, sodium phosphate, dibasic, heptahydrate, sodium chloride (see section 2 'tysabri contains sodium'), polysorbate 80 (e433) water for injections what tysabri looks like and contents of the pack tysabri is a clear, colourless to slightly cloudy liquid. each carton contains one glass vial.", 'Entity_Recognition': [{'Text': 'tysabri', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 12, 'Score': 0.9462994933128357, 'Text': 'tysabri', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 46, 'EndOffset': 57, 'Score': 0.9899501800537109, 'Text': 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