Herceptin
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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Herceptin 150 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial contains 150 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced by 
mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion exchange 
chromatography including specific viral inactivation and removal procedures.  
 
The reconstituted Herceptin solution contains 21 mg/mL of trastuzumab. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
White to pale yellow lyophilised powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Breast cancer 
 
Metastatic breast cancer  
 
Herceptin is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer: 
(MBC): 
 
- as monotherapy for the treatment of those patients who have received at least two chemotherapy 

regimens for their metastatic disease. Prior chemotherapy must have included at least an 
anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor 
positive patients must also have failed hormonal therapy, unless patients are unsuitable for these 
treatments. 

 
- in combination with paclitaxel for the treatment of those patients who have not received 

chemotherapy for their metastatic disease and for whom an anthracycline is not suitable. 
 
- in combination with docetaxel for the treatment of those patients who have not received 

chemotherapy for their metastatic disease. 
 
- in combination with an aromatase inhibitor for the treatment of postmenopausal patients with 

hormone-receptor positive MBC, not previously treated with trastuzumab.  
 
Early breast cancer  
 
Herceptin is indicated for the treatment of adult patients with HER2 positive early breast cancer. 
(EBC). 
 
- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see 

section 5.1). 
 



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- following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with 
paclitaxel or docetaxel. 

 
- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.  
 
- in combination with neoadjuvant chemotherapy followed by adjuvant Herceptin therapy, for 

locally advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 
4.4 and 5.1). 

 
Herceptin should only be used in patients with metastatic or early breast cancer whose tumours have 
either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated 
assay (see sections 4.4 and 5.1). 
 
Metastatic gastric cancer 
 
Herceptin in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the 
treatment of adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-
esophageal junction who have not received prior anti-cancer treatment for their metastatic disease. 
 
Herceptin should only be used in patients with metastatic gastric cancer (MGC) whose tumours have 
HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC 3+ 
result. Accurate and validated assay methods should be used (see sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Herceptin treatment 
should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy 
(see section 4.4), and should be administered by a healthcare professional only. 
 
It is important to check the product labels to ensure that the correct formulation (intravenous or 
subcutaneous fixed dose) is being administered to the patient, as prescribed. Herceptin intravenous 
formulation is not intended for subcutaneous administration and should be administered via an 
intravenous infusion only.  
 
Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulations and 
vice versa, using the three-weekly (q3w) dosing regimen, was investigated in study MO22982 (see 
section 4.8). 
 
In order to prevent medication errors it is important to check the vial labels to ensure that the drug 
being prepared and administered is Herceptin (trastuzumab) and not Kadcyla (trastuzumab emtansine). 
 
Posology  
 
Metastatic breast cancer 
 
Three-weekly schedule 
 
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose 
at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose. 
 
Weekly schedule 
 
The recommended initial loading dose of Herceptin is 4 mg/kg body weight. The recommended 
weekly maintenance dose of Herceptin is 2 mg/kg body weight, beginning one week after the loading 
dose. 
 



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Administration in combination with paclitaxel or docetaxel  
 
In the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day following the 
first dose of Herceptin (for dose, see the Summary of Product Characteristics (SmPC) for paclitaxel or 
docetaxel) and immediately after the subsequent doses of Herceptin if the preceding dose of Herceptin 
was well tolerated. 
 
Administration in combination with an aromatase inhibitor 
 
In the pivotal trial (BO16216) Herceptin and anastrozole were administered from day 1. There were no 
restrictions on the relative timing of Herceptin and anastrozole at administration (for dose, see the 
SmPC for anastrozole or other aromatase inhibitors). 
 
Early breast cancer  
 
Three-weekly and weekly schedule 
 
As a three-weekly regimen the recommended initial loading dose of Herceptin is 8 mg/kg body 
weight. The recommended maintenance dose of Herceptin at three-weekly intervals is 6 mg/kg body 
weight, beginning three weeks after the loading dose. 
As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/kg every week) concomitantly 
with paclitaxel following chemotherapy with doxorubicin and cyclophosphamide. 
 
See section 5.1 for chemotherapy combination dosing. 
 
Metastatic gastric cancer 
 
Three-weekly schedule 
 
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose 
at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose. 
 
Breast cancer and gastric cancer  
 
Duration of treatment 
 
Patients with MBC or MGC should be treated with Herceptin until progression of disease.  
Patients with EBC should be treated with Herceptin for 1 year or until disease recurrence, whichever 
occurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).  
 
Dose reduction 
 
No reductions in the dose of Herceptin were made during clinical trials. Patients may continue therapy 
during periods of reversible, chemotherapy-induced myelosuppression but they should be monitored 
carefully for complications of neutropenia during this time. Refer to the SmPC for paclitaxel, 
docetaxel or aromatase inhibitor for information on dose reduction or delays. 
 
If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 points from baseline AND to below 
50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 
3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure 
(CHF) has developed, discontinuation of Herceptin should be strongly considered, unless the benefits 
for the individual patient are deemed to outweigh the risks. All such patients should be referred for 
assessment by a cardiologist and followed up. 
 



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Missed doses 
 
If the patient has missed a dose of Herceptin by one week or less, then the usual maintenance dose 
(weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administered as soon as 
possible. Do not wait until the next planned cycle. Subsequent maintenance doses   should be 
administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.   
 
If the patient has missed a dose of Herceptin by more than one week, a re-loading dose of Herceptin 
should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly 
regimen: 8 mg/kg) as soon as possible. Subsequent Herceptin maintenance doses (weekly regimen: 
2 mg/kg; three-weekly regimen 6 mg/kg respectively) should be administered 7 days or 21 days later 
according to the weekly or three-weekly schedules respectively. 
 
Special populations 
 
Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not 
been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown 
to affect trastuzumab disposition. 
 
Paediatric population 
 
There is no relevant use of Herceptin in the paediatric population. 
 
Method of administration 
 
Herceptin loading dose should be administered as a 90-minute intravenous infusion. Do not administer 
as an intravenous push or bolus. Herceptin intravenous infusion should be administered by a health-
care provider prepared to manage anaphylaxis and an emergency kit should be available. Patients 
should be observed for at least six hours after the start of the first infusion and for two hours after the 
start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms 
(see sections 4.4 and 4.8). Interruption or slowing the rate of the infusion may help control such 
symptoms. The infusion may be resumed when symptoms abate. 
 
If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute 
infusion. 
 
For instructions on reconstitution of Herceptin intravenous formulation before administration, see 
section 6.6. 
 
4.3 Contraindications 
 
∑ Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients listed in section 6.1 
∑ Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary 

oxygen therapy. 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the trade name and the batch 
number of the administered product should be clearly recorded. 
 
HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of 
the testing procedures (see section 5.1). 
 
Currently no data from clinical trials are available on re-treatment of patients with previous exposure 
to Herceptin in the adjuvant setting. 



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Cardiac dysfunction  
 
General considerations 
 
Patients treated with Herceptin are at increased risk for developing CHF (New York Heart Association 
[NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in 
patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly 
following anthracycline (doxorubicin or epirubicin) containing chemotherapy. These may be moderate 
to severe and have been associated with death (see section 4.8). In addition, caution should be 
exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary 
artery disease, CHF, LVEF of <55%, older age. 
 
All candidates for treatment with Herceptin, but especially those with prior anthracycline and 
cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and 
physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition 
(MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop 
cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months 
during treatment and every 6 months following discontinuation of treatment until 24 months from the 
last administration of Herceptin. A careful risk-benefit assessment should be made before deciding to 
treat with Herceptin.  
 
Trastuzumab may persist in the circulation for up to 7 months after stopping Herceptin treatment 
based on population pharmacokinetic analysis of all available data (see section 5.2). Patients who 
receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiac 
dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after 
stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitored 
carefully. 
  
Formal cardiological assessment should be considered in patients in whom there are cardiovascular 
concerns following baseline screening. In all patients cardiac function should be monitored during 
treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac 
dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent 
monitoring (e.g. every 6 - 8 weeks). If patients have a continued decrease in left ventricular function, 
but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of 
Herceptin therapy has been seen.  
 
The safety of continuation or resumption of Herceptin in patients who experience cardiac dysfunction 
has not been prospectively studied. If LVEF percentage drops ≥10 points from baseline AND to below 
50%, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 
weeks. If LVEF has not improved, or declined further, or symptomatic CHF has developed, 
discontinuation of Herceptin should be strongly considered, unless the benefits for the individual 
patient are deemed to outweigh the risks. All such patients should be referred for assessment by a 
cardiologist and followed up. 
 
If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with standard 
medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction 
in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting 
enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of 
patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on 
therapy without additional clinical cardiac events. 
 
Metastatic breast cancer 
 
Herceptin and anthracyclines should not be given concurrently in combination in the MBC setting.  
 



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Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction 
with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and 
anthracyclines. 
 
Early breast cancer  
 
For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 
months during treatment and every 6 months following discontinuation of treatment until 24 months 
from the last administration of Herceptin. In patients who receive anthracycline-containing 
chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last 
administration of Herceptin, or longer if a continuous decrease of LVEF is observed. 
 
Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, 
history of or existing CHF (NYHA Class II –IV), LVEF of < 55%, other cardiomyopathy, cardiac 
arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly 
controlled hypertension (hypertension controlled by standard medical treatment eligible), and 
hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC 
pivotal trials with Herceptin and therefore treatment cannot be recommended in such patients. 
 
Adjuvant treatment 
 
Herceptin and anthracyclines should not be given concurrently in combination in the adjuvant 
treatment setting. 
 
In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events 
was observed when Herceptin was administered after anthracycline-containing chemotherapy 
compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was 
more marked when Herceptin was administered concurrently with taxanes than when administered 
sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred 
within the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of 
5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic 
cardiac or LVEF events was observed in patients who were administered Herceptin concurrently with 
a taxane following anthracycline therapy up to 2.37% compared to approximately 1% in the two 
comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin 
and Herceptin). 
 
Risk factors for a cardiac event identified in four large adjuvant studies included advanced age 
(> 50 years), low LVEF (<55%) at baseline, prior to or following the initiation of paclitaxel treatment, 
decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products. 
In patients receiving Herceptin after completion of adjuvant chemotherapy, the risk of cardiac 
dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of 
Herceptin and a body mass index (BMI) >25 kg/m2. 
 
Neoadjuvant-adjuvant treatment 
 
In patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin should be used 
concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose 
anthracycline regimens i.e. maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin 
360 mg/m2. 
 
If patients have been treated concurrently with a full course of low-dose anthracyclines and Herceptin 
in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. In 
other situations, the decision on the need for additional cytotoxic chemotherapy is determined based 
on individual factors. 
 
Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is 
currently limited to two trials (MO16432 and BO22227).  



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In the pivotal trial MO16432, Herceptin was administered concurrently with neoadjuvant 
chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2 ) .  
 
The incidence of symptomatic cardiac dysfunction was 1.7% in the Herceptin arm .  
 
The pivotal trial BO22227 was designed to demonstrate non-inferiority of treatment with Herceptin 
subcutaneous formulation versus treatment with Herceptin intravenous formulation based on co-
primary PK and efficacy endpoints (trastuzumab Ctrough at pre-dose Cycle 8, and pCR rate at definitive 
surgery, respectively) (See Section 5.1. of Herceptin subcutaneous formulation SmPC).  In the pivotal 
trial BO22227, Herceptin was administered concurrently with neoadjuvant chemotherapy that 
contained four cycles of epirubicin (cumulative dose 300 mg/m2); at a median follow-up exceeding 70 
months, the incidence of cardiac failure/congestive cardiac failure was 0.3% in the Herceptin 
intravenous arm. 
 
Clinical experience is limited in patients above 65 years of age. 
 
Infusion-related reactions (IRRs) and hypersensitivity 
 
Serious IRRs to Herceptin infusion including dyspnoea, hypotension, wheezing, hypertension, 
bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory 
distress, urticaria and angioedema have been reported (see section 4.8). Pre-medication may be used to 
reduce risk of occurrence of these events. The majority of these events occur during or within 2.5 
hours of the start of the first infusion.  Should an infusion reaction occur the infusion should be 
discontinued or the rate of infusion slowed and the patient should be monitored until resolution of all 
observed symptoms (see section 4.2). These symptoms can be treated with an analgesic/antipyretic 
such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. The majority of 
patients experienced resolution of symptoms and subsequently received further infusions of Herceptin. 
Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-
agonists, and corticosteroids. In rare cases, these reactions are associated with a clinical course 
culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of 
advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction. 
Therefore, these patients should not be treated with Herceptin (see section 4.3). 
 
Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical 
deterioration have also been reported. Fatalities have occurred within hours and up to one week 
following infusion. On very rare occasions, patients have experienced the onset of infusion symptoms 
and pulmonary symptoms more than six hours after the start of the Herceptin infusion. Patients should 
be warned of the possibility of such a late onset and should be instructed to contact their physician if 
these symptoms occur. 
 
Pulmonary events 
 
Severe pulmonary events have been reported with the use of Herceptin in the post-marketing setting 
(see section 4.8). These events have occasionally been fatal. In addition, cases of interstitial lung 
disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, 
pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been 
reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy 
with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, 
vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or 
with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced 
malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients 
should not be treated with Herceptin (see section 4.3).  Caution should be exercised for pneumonitis, 
especially in patients being treated concomitantly with taxanes.  
 



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4.5 Interaction with other medicinal products and other forms of interaction 
 
No formal drug interaction studies have been performed. Clinically significant interactions between 
Herceptin and the concomitant medicinal products used in clinical trials have not been observed.  
 
Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents 
 
Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC 
suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-
paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 
4 mg/kg IV loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w IV, respectively). 
However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 
dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this 
metabolite was unclear.   
 
Data from study JP16003, a single-arm study of Herceptin (4 mg/kg IV loading dose and 2 mg/kg IV 
weekly) and docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggested that 
concomitant administration of Herceptin had no effect on the single dose pharmacokinetics of 
docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female 
Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and 
cisplatin when used with or without Herceptin. The results of this substudy suggested that the 
exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of 
cisplatin or by concurrent use of cisplatin plus Herceptin. However, capecitabine itself showed higher 
concentrations and a longer half-life when combined with Herceptin. The data also suggested that the 
pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use 
of capecitabine plus Herceptin. 
 
Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advanced 
inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.  
 
Effect of antineoplastic agents on trastuzumab pharmacokinetics 
 
By comparison of simulated serum trastuzumab concentrations after Herceptin monotherapy (4 mg/kg 
loading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with HER2- positive 
MBC (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on the 
pharmacokinetics of trastuzumab was found. 
 
Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study 
(H0648g) in which patients were treated concomitantly with Herceptin and paclitaxel and two Phase II 
studies in which Herceptin was administered as monotherapy (W016229 and MO16982),  in women 
with HER2-positive MBC indicates that individual and mean trastuzumab trough serum 
concentrations varied within and across studies but there was no clear effect of the concomitant 
administration of paclitaxel on the pharmacokinetics of trastuzumab. Comparison of trastuzumab PK 
data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with 
Herceptin, paclitaxel and doxorubicin to trastuzumab PK data in studies where Herceptin was 
administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide 
or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the 
pharmacokinetics of trastuzumab.  
 
Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the 
PK of trastuzumab. 
 
The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of 
trastuzumab. 
 



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4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential  
 
Women of childbearing potential should be advised to use effective contraception during treatment 
with Herceptin and for 7 months after treatment has concluded (see section 5.2). 
 
Pregnancy 
 
Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the 
weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation and have revealed no 
evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early 
(days 20–50 of gestation) and late (days 120–150 of gestation) foetal development period was 
observed. It is not known whether Herceptin can affect reproductive capacity. As animal reproduction 
studies are not always predictive of human response, Herceptin should be avoided during pregnancy 
unless the potential benefit for the mother outweighs the potential risk to the foetus.  
 
In the post-marketing setting, cases of foetal renal growth and/or function impairment in association 
with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been 
reported in pregnant women receiving Herceptin. Women who become pregnant should be advised of 
the possibility of harm to the foetus. If a pregnant woman is treated with Herceptin, or if a patient 
becomes pregnant while receiving Herceptin or within 7 months following the last dose of Herceptin, 
close monitoring by a multidisciplinary team is desirable. 
 
Breast-feeding 
 
A study conducted in lactating Cynomolgus monkeys at doses 25 times that of the weekly human 
maintenance dose of 2 mg/kg Herceptin intravenous formulation demonstrated that trastuzumab is 
secreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated 
with any adverse effects on their growth or development from birth to 1 month of age. It is not known 
whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the 
potential for harm to the infant is unknown, women should not breast-feed during Herceptin therapy 
and for 7 months after the last dose. 
 
Fertility  
 
There is no fertility data available.   
 
4.7 Effects on ability to drive and use machines 
 
Herceptin has a minor influence on the ability to drive or use machines (see section 4.8). Dizziness 
and somnolence may occur during treatment with Herceptin (see section 4.8). Patients experiencing 
infusion-related symptoms (see section 4.4) should be advised not to drive and use machines until 
symptoms abate. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Amongst the most serious and/or common adverse reactions reported in Herceptin usage (intravenous 
and subcutaneous formulations) to date are cardiac dysfunction, infusion-related reactions, 
haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions. 
 
Tabulated list of adverse reactions 
 
In this section, the following categories of frequency have been used: very common (≥1/10), common 
(≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare 



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(<1/10,000), not known (cannot be estimated from the available data). Within each frequency 
grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Presented in Table 1 are adverse reactions that have been reported in association with the use of 
intravenous Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the 
post-marketing setting.  
 
All the terms included are based on the highest percentage seen in pivotal clinical trials.  In addition, 
terms reported in the post marketing setting are included in Table 1.  
 
Table 1 Undesirable Effects Reported with Intravenous Herceptin Monotherapy or in Combination 
with Chemotherapy in Pivotal Clinical Trials (N = 8386) and in Post-Marketing 
 
System organ class Adverse reaction Frequency  
Infections and infestations Infection Very common 

Nasopharyngitis Very common 
Neutropenic sepsis Common 
Cystitis Common 
  
Influenza Common 
Sinusitis Common 
Skin infection Common 
Rhinitis Common 
Upper respiratory tract infection Common 
Urinary tract infection Common 
  
  
Pharyngitis Common 
  

Neoplasms benign, 
malignant and unspecified 
(incl. Cysts and polyps) 

Malignant neoplasm progression Not known 
Neoplasm progression Not known 

Blood and lymphatic 
system disorders 

Febrile neutropenia Very common  
Anaemia Very common 
Neutropenia Very common 
White blood cell count 
decreased/leukopenia  

Very common 

Thrombocytopenia Very common 
Hypoprothrombinaemia Not known 
Immune thrombocytopenia Not known 

Immune system disorders Hypersensitivity Common 
+Anaphylactic reaction Rare 
+Anaphylactic shock Rare 

Metabolism and nutrition 
disorders 

Weight decreased/Weight loss Very common 
Anorexia Very common 
Tumour lysis syndrome Not known 
Hyperkalaemia Not known 

Psychiatric disorders Insomnia Very common 
Anxiety Common 
Depression Common 
  

Nervous system disorders 1Tremor Very common 
Dizziness Very common  
Headache Very common  
Paraesthesia Very common 



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System organ class Adverse reaction Frequency  
Dysgeusia Very common 
Peripheral neuropathy Common 
Hypertonia Common 
Somnolence Common 
  
  
  

Eye disorders Conjunctivitis Very common 
Lacrimation increased Very common 
Dry eye Common 
Papilloedema Not known 
Retinal haemorrhage Not known 

Ear and labyrinth disorders Deafness Uncommon 
Cardiac disorders 1 Blood pressure decreased Very common 

1 Blood pressure increased Very common 
1 Heart beat irregular Very common 

  
1Cardiac flutter Very common 
Ejection fraction decreased* Very common 
+Cardiac failure (congestive) Common  
+1Supraventricular tachyarrhythmia Common 
Cardiomyopathy Common 
1Palpitation Common 
Pericardial effusion Uncommon 
Cardiogenic shock Not known 
  
  
Gallop rhythm present Not known 

Vascular disorders Hot flush Very common 
+1 Hypotension Common 
Vasodilatation Common 

Respiratory, thoracic and 
mediastinal disorders 

  
+Dyspnoea Very common  
Cough Very common 
Epistaxis Very common 
Rhinorrhoea Very common 
+Pneumonia Common 
Asthma Common 
Lung disorder Common 
+Pleural effusion Common 
+1Wheezing Uncommon 
Pneumonitis Uncommon 
+Pulmonary fibrosis Not known 
+Respiratory distress Not known 
+Respiratory failure Not known 
+Lung infiltration Not known 
+Acute pulmonary oedema Not known 
+Acute respiratory distress syndrome Not known 
+Bronchospasm Not known 
+Hypoxia Not known 
+Oxygen saturation decreased Not known 
Laryngeal oedema Not known 
Orthopnoea Not known 



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System organ class Adverse reaction Frequency  
Pulmonary oedema Not known 
Interstitial lung disease Not known 

Gastrointestinal disorders Diarrhoea  Very common  
Vomiting  Very common  
Nausea Very common  
1 Lip swelling Very common 

Abdominal pain Very common  

Dyspepsia Very common 

Constipation Very common 
Stomatitis Very common 
Haemorrhoids Common 
Dry mouth Common 

Hepatobiliary disorders Hepatocellular injury Common 
Hepatitis Common 
Liver tenderness Common 
Jaundice Rare 
  

Skin and subcutaneous 
tissue disorders  

Erythema Very common 
Rash Very common 
1 Swelling face Very common 
Alopecia Very common 
Nail disorder Very common 
Palmar-plantar erythrodysaesthesia 
syndrome 

Very common 

Acne Common 
Dry skin Common 
Ecchymosis Common 
Hyperhydrosis Common 
Maculopapular rash Common 
Pruritus Common 
Onychoclasis Common 
Dermatitis Common 
Urticaria Uncommon 
Angioedema Not known 

Musculoskeletal and 
connective tissue disorders 

Arthralgia Very common 
1Muscle tightness Very common 
Myalgia Very common 
Arthritis Common 
Back pain Common 
Bone pain Common 
Muscle spasms Common 
Neck Pain Common 
Pain in extremity Common 

Renal and urinary disorders Renal disorder Common 
Glomerulonephritis membranous Not known 
Glomerulonephropathy Not known 
Renal failure Not known 

Pregnancy, puerperium and 
perinatal conditions 

Oligohydramnios Not known 
Renal hypoplasia Not known 
Pulmonary hypoplasia Not known 

Reproductive system and Breast inflammation/mastitis Common 



14 

System organ class Adverse reaction Frequency  
breast disorders 
General disorders and 
administration site 
conditions 

Asthenia Very common 
Chest pain Very common 
Chills Very common 
Fatigue Very common 
Influenza-like symptoms Very common 
Infusion related reaction Very common 
Pain Very common 
Pyrexia Very common 
Mucosal inflammation Very common 
Peripheral oedema Very common 
Malaise Common 
Oedema Common 

Injury, poisoning and 
procedural complications 

Contusion Common 

+ Denotes adverse reactions that have been reported in association with a fatal outcome. 
1 Denotes adverse reactions that are reported largely in association with Infusion-related reactions. Specific 
percentages for these are not available. 
* Observed with combination therapy following anthracyclines and combined with taxanes 
 
Description of selected adverse reactions 
 
Cardiac dysfunction 
 
Congestive heart failure (NYHA Class II – IV) is a common adverse reaction associated with the use 
of Herceptin and has been associated with a fatal outcome (see section 4.4). Signs and symptoms of 
cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or 
reduced ventricular ejection fraction, have been observed in patients treated with Herceptin (see 
section 4.4). 
 
In 3 pivotal clinical trials of adjuvant Herceptin given in combination with chemotherapy, the 
incidence of grade 3/4 cardiac dysfunction (specifically symptomatic Congestive Heart Failure) was 
similar in patients who were administered chemotherapy alone (ie did not receive Herceptin) and in 
patients who were administered Herceptin sequentially after a taxane (0.3-0.4 %). The rate was highest 
in patients who were administered Herceptin concurrently with a taxane (2.0 %). In the neoadjuvant 
setting, the experience of concurrent administration of Herceptin and low dose anthracycline regimen 
is limited (see section 4.4). 
 
When Herceptin was administered after completion of adjuvant chemotherapy NYHA Class III-IV 
heart failure was observed in 0.6 % of patients in the one-year arm after a median follow-up of 12 
months.  In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA 
Class III & IV) in the Herceptin 1 year treatment arm was 0.8 %, and the rate of mild symptomatic and 
asymptomatic left ventricular dysfunction was 4.6 %. 
 
Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥50 % 
after the event) was evident for 71.4 % of Herceptin-treated patients. Reversibility of mild 
symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5 % of patients. 
Approximately 17 % of cardiac dysfunction related events occurred after completion of Herceptin. 
 
In the pivotal metastatic trials of intravenous Herceptin, the incidence of cardiac dysfunction varied 
between 9 % and 12 % when it was combined with paclitaxel compared with 1 % – 4 % for paclitaxel 
alone. For monotherapy, the rate was 6 % – 9 %. The highest rate of cardiac dysfunction was seen in 
patients receiving Herceptin concurrently with anthracycline/cyclophosphamide (27 %), and was 
significantly higher than for anthracycline/cyclophosphamide alone (7 % – 10 %). In a subsequent trial 
with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2 % in 
patients receiving Herceptin and docetaxel, compared with 0 % in patients receiving docetaxel alone. 



15 

Most of the patients (79 %) who developed cardiac dysfunction in these trials experienced an 
improvement after receiving standard treatment for CHF. 
  
Infusion reactions, allergic-like reactions and hypersensitivity 
 
It is estimated that approximately 40 % of patients who are treated with Herceptin will experience 
some form of infusion-related reaction. However, the majority of infusion-related reactions are mild to 
moderate in intensity (NCI-CTC grading system) and tend to occur earlier in treatment, i.e. during 
infusions one, two and three and lessen in frequency in subsequent infusions. Reactions include chills, 
fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, 
respiratory distress, rash, nausea, vomiting and headache (see section 4.4). The rate of infusion-related 
reactions of all grades varied between studies depending on the indication, the data collection 
methodology, and whether trastuzumab was given concurrently with chemotherapy or as 
monotherapy. 
 
Severe anaphylactic reactions requiring immediate additional intervention can occur usually during 
either the first or second infusion of Herceptin (see section 4.4) and have been associated with a fatal 
outcome.  
 
Anaphylactoid reactions have been observed in isolated cases. 
 
Haematotoxicity 
 
Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred very 
commonly. The frequency of occurrence of hypoprothrombinemia is not known. The risk of 
neutropenia may be slightly increased when trastuzumab is administered with docetaxel following 
anthracycline therapy. 
 
Pulmonary events 
 
Severe pulmonary adverse reactions occur in association with the use of Herceptin and have been 
associated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acute 
respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute 
pulmonary oedema and respiratory insufficiency (see section 4.4). 
 
Details of risk minimisation measures that are consistent with the EU Risk Management Plan are 
presented in (section 4.4) Warnings and Precautions. 
 
Immunogenicity 
 
In the neoadjuvant-adjuvant EBC study (BO22227), at a median follow-up exceeding 70 months, 
10.1 % (30/296) of patients treated with Herceptin intravenous developed antibodies against 
trastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 
30 patients in the Herceptin intravenous arm.  
 
The clinical relevance of these antibodies is not known. The presence of anti-trastuzumab antibodies 
had no impact on pharmacokinetics, efficacy (determined by pathological Complete Response [pCR] 
and event free survival [EFS]) and safety determined by occurrence of administration related reactions 
(ARRs) of Herceptin intravenous. 
 
There are no immunogenicity data available for Herceptin in gastric cancer. 
 
Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulation and vice 
versa 
 
Study MO22982 investigated switching between the Herceptin intravenous and Herceptin 
subcutaneous formulation with a primary objective to evaluate patient preference for either 



16 

intravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one using 
subcutaneous formulation in vial and one using subcutaneous formulation in administration system) 
were investigated using a 2-arm, cross-over design with 488 patients being randomized to one of two 
different three-weekly Herceptin treatment sequences (IV [Cycles 1-4]→ SC [Cycles 5-8], or SC 
[Cycles 1-4]→ IV [Cycles 5-8]). Patients were either naïve to Herceptin IV treatment (20.3%) or pre-
exposed to Herceptin IV (79.7%). For the sequence IV→SC (SC vial and SC formulation in 
administration system cohorts combined), adverse event rates (all grades) were described pre-
switching (Cycles 1-4) and post-switching (Cycles 5-8) as 53.8% vs. 56.4%, respectively; for the 
sequence SC→IV (SC vial and SC formulation in administration system cohorts combined), adverse 
event rates (all grades) were described pre- and post-switching as 65.4% vs. 48.7%, respectively. 
Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatment 
discontinuations due to adverse events were low (<5%) and similar to post-switching rates (Cycles 5-
8). No grade 4 or grade 5 adverse events were reported. 
 
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 
 
There is no experience with overdose in human clinical trials. Single doses of Herceptin alone greater 
than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of 10 mg/kg q3w 
following a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic gastric cancer 
patients. Doses up to this level were well tolerated. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03 
 
Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal 
growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20 %-30 % of primary 
breast cancers. Studies of HER2-positivity rates in gastric cancer (GC) using immunohistochemistry 
(IHC) and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) have 
shown that there is a broad variation of HER2-positivity ranging from 6.8 % to 34.0 % for IHC and 
7.1 % to 42.6 % for FISH. Studies indicate that breast cancer patients whose tumours overexpress 
HER2 have a shortened disease-free survival compared to patients whose tumours do not overexpress 
HER2. The extracellular domain of the receptor (ECD, p105) can be shed into the blood stream and 
measured in serum samples. 
 
Mechanism of action 
 
Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of 
HER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 
signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism 
of HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit 
the proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent 
mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated 
ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared 
with cancer cells that do not overexpress HER2. 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


17 

Detection of HER2 overexpression or HER2 gene amplification 
 
Detection of HER2 overexpression or HER2 gene amplification in breast cancer 
Herceptin should only be used in patients whose tumours have HER2 overexpression or HER2 gene 
amplification as determined by an accurate and validated assay. HER2 overexpression should be 
detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see section 
4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or 
chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Herceptin 
treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive 
FISH or CISH result.  
 
To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, 
which can ensure validation of the testing procedures. 
 
The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2: 
 
Table 2 Recommended Scoring System to Evaluate the IHC Staining Patterns in Breast Cancer 
 
Score  Staining pattern HER2 overexpression 

assessment 
0 No staining is observed or membrane staining is 

observed in < 10 % of the tumour cells  
Negative 

1+  A faint/barely perceptible membrane staining is 
detected in > 10 % of the tumour cells. The cells are 
only stained in part of their membrane. 

Negative 

2+ A weak to moderate complete membrane staining is 
detected in > 10 % of the tumour cells. 

Equivocal 

3+  Strong complete membrane staining is detected in 
> 10 % of the tumour cells. 

Positive 

 
In general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to 
the chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the 
HER2 gene per tumour cell if no chromosome 17 control is used. 
 
In general, CISH is considered positive if there are more than 5 copies of the HER2 gene per nucleus 
in greater than 50 % of tumour cells. 
 
For full instructions on assay performance and interpretation please refer to the package inserts of 
validated FISH and CISH assays.  Official recommendations on HER2 testing may also apply. 
 
For any other method that may be used for the assessment of HER2 protein or gene expression, the 
analyses should only be performed by laboratories that provide adequate state-of-the-art performance 
of validated methods.  Such methods must clearly be precise and accurate enough to demonstrate 
overexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) and 
strong (congruent with 3+) overexpression of HER2. 
 
Detection of HER2 over expression or HER2 gene amplification in gastric cancer 
 
Only an accurate and validated assay should be used to detect HER2 over expression or HER2 gene 
amplification. IHC is recommended as the first testing modality and in cases where HER2 gene 
amplification status is also required, either a silver-enhanced in situ hybridization (SISH) or a FISH 
technique must be applied. SISH technology is however, recommended to allow for the parallel 
evaluation of tumor histology and morphology. To ensure validation of testing procedures and the 
generation of accurate and reproducible results, HER2 testing must be performed in a laboratory 
staffed by trained personnel. Full instructions on assay performance and results interpretation should 
be taken from the product information leaflet provided with the HER2 testing assays used. 
   



18 

In the ToGA (BO18255) trial, patients whose tumours were either IHC3+ or FISH positive were 
defined as HER2 positive and thus included in the trial. Based on the clinical trial results, the 
beneficial effects were limited to patients with the highest level of HER2 protein overexpression, 
defined by a 3+ score by IHC, or a 2+ score by IHC and a positive FISH result.  
 
In a method comparison study (study D008548) a high degree of concordance (>95 %) was observed 
for SISH and FISH techniques for the detection of HER2 gene amplification in gastric cancer patients. 
 
HER2 over expression should be detected using an immunohistochemistry (IHC)-based assessment of 
fixed tumour blocks; HER2 gene amplification should be detected using in situ hybridisation using 
either SISH or FISH on fixed tumour blocks.  
 
The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3: 
 
Table 3 Recommended Scoring System to Evaluate the IHC Staining Patterns in Gastric Cancer 
 
Score Surgical specimen - staining 

pattern 
Biopsy  specimen –  
staining pattern 

HER2 
overexpression 
assessment 

0 
No reactivity or membranous 
reactivity in < 10 % of tumour 
cells 

No reactivity or membranous 
reactivity in any tumour cell Negative 

1+ 

Faint ⁄ barely perceptible 
membranous reactivity in  ≥ 
10 % of tumour cells; cells are 
reactive only in part of their 
membrane 

Tumour cell cluster with a faint ⁄ 
barely perceptible membranous 
reactivity irrespective of 
percentage of tumour cells 
stained 

Negative 

2+ 

Weak to moderate complete, 
basolateral or lateral 
membranous reactivity in 
≥ 10 % of tumour cells 

Tumour cell cluster with a weak 
to moderate complete, 
basolateral or lateral 
membranous reactivity 
irrespective of percentage of 
tumour cells stained 

Equivocal 

3+ 

Strong complete, basolateral 
or lateral membranous 
reactivity in ≥ 10 % of tumour 
cells 

Tumour cell cluster with a 
strong complete, basolateral or 
lateral membranous reactivity 
irrespective of percentage of 
tumour cells stained 

Positive 

 
In general, SISH or FISH is considered positive if the ratio of the HER2 gene copy number per tumour 
cell to the chromosome 17 copy number is greater than or equal to 2.  
 
Clinical efficacy and safety 
 
Metastatic breast cancer 
 
Herceptin has been used in clinical trials as monotherapy for patients with MBC who have tumours 
that overexpress HER2 and who have failed one or more chemotherapy regimens for their metastatic 
disease (Herceptin alone). 
 
Herceptin has also been used in combination with paclitaxel or docetaxel for the treatment of patients 
who have not received chemotherapy for their metastatic disease. Patients who had previously 
received anthracycline-based adjuvant chemotherapy were treated with paclitaxel (175 mg/m2 infused 
over 3 hours) with or without Herceptin. In the pivotal trial of docetaxel (100 mg/m2 infused over 
1 hour) with or without Herceptin, 60 % of the patients had received prior anthracycline-based 
adjuvant chemotherapy. Patients were treated with Herceptin until progression of disease. 
 



19 

The efficacy of Herceptin in combination with paclitaxel in patients who did not receive prior adjuvant 
anthracyclines has not been studied. However, Herceptin plus docetaxel was efficacious in patients 
whether or not they had received prior adjuvant anthracyclines. 
 
The test method for HER2 overexpression used to determine eligibility of patients in the pivotal 
Herceptin monotherapy and Herceptin plus paclitaxel clinical trials employed immunohistochemical 
staining for HER2 of fixed material from breast tumours using the murine monoclonal antibodies 
CB11 and 4D5. These tissues were fixed in formalin or Bouin’s fixative. This investigative clinical 
trial assay performed in a central laboratory utilised a 0 to 3+ scale. Patients classified as staining 2+ 
or 3+ were included, while those staining 0 or 1+ were excluded. Greater than 70 % of patients 
enrolled exhibited 3+ overexpression. The data suggest that beneficial effects were greater among 
those patients with higher levels of overexpression of HER2 (3+). 
 
The main test method used to determine HER2 positivity in the pivotal trial of docetaxel, with or 
without Herceptin, was immunohistochemistry. A minority of patients was tested using fluorescence 
in-situ hybridisation (FISH). In this trial, 87 % of patients entered had disease that was IHC3+, and 
95 % of patients entered had disease that was IHC3+ and/or FISH-positive. 
 
Weekly dosing in metastatic breast cancer 
 
The efficacy results from the monotherapy and combination therapy studies are summarised in 
Table 4: 
 
Table 4 Efficacy Results from the Monotherapy and Combination Therapy Studies 
 
Parameter Monotherapy Combination Therapy 

 Herceptin1 
 
 

N=172 

Herceptin 
plus 

paclitaxel2 
N=68 

Paclitaxel2 
 
 

N=77 

Herceptin 
plus 

docetaxel3 
N=92 

Docetaxel3 
 
 

N=94 
Response rate 
(95 %CI) 

18 % 
(13 - 25) 

49 % 
(36 - 61) 

17 % 
(9 - 27) 

61 % 
(50-71) 

34 % 
(25-45) 

Median duration of 
response (months) 
(95 %CI) 

9.1 
(5.6-10.3) 

8.3 
(7.3-8.8) 

4.6 
(3.7-7.4) 

11.7 
(9.3 – 15.0) 

5.7 
(4.6-7.6) 

Median TTP 
(months) (95 %CI) 

3.2 
(2.6-3.5) 

7.1 
(6.2-12.0) 

3.0 
(2.0-4.4) 

11.7 
(9.2-13.5) 

6.1 
(5.4-7.2) 

Median Survival 
(months) (95 %CI) 

16.4 
(12.3-ne) 

24.8 
(18.6-33.7) 

17.9 
(11.2-23.8) 

31.2 
(27.3-40.8) 

22.74 
(19.1-30.8) 

TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached. 
1. Study H0649g: IHC3+ patient subset 
2. Study H0648g: IHC3+ patient subset 
3. Study M77001: Full analysis set (intent-to-treat), 24 months results 
 
Combination treatment with Herceptin and anastrozole 
Herceptin has been studied in combination with anastrozole for first line treatment of MBC in HER2 
overexpressing, hormone-receptor (i.e. estrogen-receptor (ER) and/or progesterone-receptor (PR)) 
positive postmenopausal patients. Progression free survival was doubled in the Herceptin plus 
anastrozole arm compared to anastrozole (4.8 months versus 2.4 months). For the other parameters the 
improvements seen for the combination were for overall response (16.5 % versus 6.7 %); clinical 
benefit rate (42.7 % versus 27.9 %); time to progression (4.8 months versus 2.4 months). For time to 
response and duration of response no difference could be recorded between the arms. The median 
overall survival was extended by 4.6 months for patients in the combination arm. The difference was 



20 

not statistically significant, however more than half of the patients in the anastrozole alone arm 
crossed over to a Herceptin containing regimen after progression of disease. 
 
Three -weekly dosing in metastatic breast cancer  
 
The efficacy results from the non-comparative monotherapy and combination therapy studies are 
summarised in Table 5: 
 
Table 5 Efficacy Results from the Non-Comparative Monotherapy and Combination Therapy Studies 
 
Parameter Monotherapy Combination Therapy 

 Herceptin1 
 

N=105 

Herceptin2 
 

N=72 

Herceptin plus 
paclitaxel3 

N=32 

Herceptin plus  
docetaxel4 

N=110 
Response rate 
(95 %CI) 

24 % 
(15 - 35) 

27 % 
(14 - 43) 

59 % 
(41-76) 

73 % 
(63-81) 

Median duration of 
response (months) 
(range) 

10.1 
(2.8-35.6) 

7.9 
(2.1-18.8) 

10.5 
(1.8-21) 

13.4 
(2.1-55.1) 

Median TTP 
(months) (95 %CI) 

3.4 
(2.8-4.1) 

7.7 
(4.2-8.3) 

12.2 
(6.2-ne) 

13.6 
(11-16) 

Median Survival 
(months) (95 %CI) 

ne ne ne 
 

47.3 
(32-ne) 

TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached. 
1. Study WO16229: loading dose 8 mg/kg, followed by 6 mg/kg 3 weekly schedule 
2. Study MO16982: loading dose 6 mg/kg weekly x 3; followed by 6 mg/kg 3-weekly schedule 
3. Study BO15935 
4. Study MO16419 
 
Sites of progression 
The frequency of progression in the liver was significantly reduced in patients treated with the 
combination of Herceptin and paclitaxel, compared to paclitaxel alone (21.8 % versus 45.7 %; 
p=0.004). More patients treated with Herceptin and paclitaxel progressed in the central nervous system 
than those treated with paclitaxel alone (12.6 % versus 6.5 %; p=0.377). 
 
Early breast cancer (adjuvant setting) 
 
Early breast cancer is defined as non-metastatic primary invasive carcinoma of the breast. 
In the adjuvant treatment setting, Herceptin was investigated in 4 large multicentre, randomised, trials.
  
- Study BO16348 was designed to compare one and two years of three-weekly Herceptin 

treatment versus observation in patients with HER2 positive EBC following surgery, established 
chemotherapy and radiotherapy (if applicable). In addition, comparison of two years of 
Herceptin treatment versus one year of Herceptin treatment was performed. Patients assigned to 
receive Herceptin were given an initial loading dose of 8 mg/kg, followed by 6 mg/kg every 
three weeks for either one or two years. 

- The NSABP B-31 and NCCTG N9831 studies that comprise the joint analysis were designed to 
investigate the clinical utility of combining Herceptin treatment with paclitaxel following AC 
chemotherapy, additionally the NCCTG N9831 study also investigated adding Herceptin 
sequentially to AC→P chemotherapy in patients with HER2 positive EBC following surgery. 

- The BCIRG 006 study was designed to investigate combining Herceptin treatment with 
docetaxel either following AC chemotherapy or in combination with docetaxel and carboplatin 
in patients with HER2 positive EBC following surgery. 

 



21 

Early breast cancer in the HERA trial was limited to operable, primary, invasive adenocarcinoma of 
the breast, with axillary nodes positive or axillary nodes negative if tumors at least 1 cm in diameter.  
 
In the joint analysis of the NSABP B-31 and NCCTG N9831 studies, EBC was limited to women with 
operable breast cancer at high risk, defined as HER2-positive and axillary lymph node positive or 
HER2 positive and lymph node negative with high risk features (tumor size > 1 cm and ER negative or 
tumor size > 2 cm, regardless of hormonal status). 
 
In the BCIRG 006 study HER2 positive, EBC was defined as either lymph node positive or high risk 
node negative patients with no (pN0) lymph node involvement, and at least 1 of the following factors: 
tumour size greater than 2 cm, estrogen receptor and progesterone receptor negative, histological 
and/or nuclear grade 2-3, or age < 35 years). 
 
The efficacy results from the BO16348 trial following 12 months* and 8 years** median follow-up 
are summarized in Table 6: 
 
Table 6 Efficacy Results from Study BO16348 
 
 Median follow-up 

12 months* 
Median follow-up 

8 years** 
Parameter Observation 

N=1693 
Herceptin 

1 Year 
N = 1693 

Observation 
N= 1697*** 

Herceptin 
1 Year 

N = 1702*** 
Disease-free survival     
- No. patients with event 219 (12.9 %) 127 (7.5 %) 570 (33.6 %) 471 (27.7 %) 
- No. patients without event 1474 (87.1 %) 1566 (92.5 %) 1127 (66.4 %) 1231 (72.3 %) 
P-value versus Observation < 0.0001 < 0.0001 
Hazard Ratio versus Observation 0.54 0.76 
Recurrence-free survival     
- No. patients with event 208 (12.3 %) 113 (6.7 %) 506 (29.8 %) 399 (23.4 %) 
- No. patients without event 1485 (87.7 %) 1580 (93.3 %) 1191 (70.2 %) 1303 (76.6 %) 
P-value versus Observation < 0.0001 < 0.0001 
Hazard Ratio versus Observation 0.51 0.73 
Distant disease-free survival     
- No. patients with event 184 (10.9 %) 99 (5.8 %) 488 (28.8 %) 399 (23.4 %) 
- No. patients without event 1508 (89.1 %) 1594 (94.6 %) 1209 (71.2 %) 1303 (76.6 %) 
P-value versus Observation < 0.0001 < 0.0001 
Hazard Ratio versus Observation 0.50 0.76 
Overall survival (death)     
- No. patients with event 40 (2.4 %) 31 (1.8 %) 350 (20.6 %) 278 (16.3 %) 
- No. patients without event 1653 (97.6 %) 1662 (98.2 %) 1347 (79.4 %) 1424 (83.7 %) 
P-value versus Observation 0.24 0.0005 
Hazard Ratio versus Observation 0.75 0.76 
*Co-primary endpoint of DFS of 1 year versus observation met the pre-defined statistical boundary 
**Final analysis (including crossover of 52 % of patients from the observation arm to Herceptin) 
*** There is a discrepancy in the overall sample size due to a small number of patients who were randomized 
after the cut-off date for the 12-month median follow-up analysis 
 
The efficacy results from the interim efficacy analysis crossed the protocol pre-specified statistical 
boundary for the comparison of 1-year of Herceptin versus observation. After a median follow-up of 
12 months, the hazard ratio (HR) for disease free survival (DFS) was 0.54 (95 % CI 0.44, 0.67) which 
translates into an absolute benefit, in terms of a 2-year disease-free survival rate, of 7.6 percentage 
points (85.8 % versus 78.2 %) in favour of the Herceptin arm. 
 



22 

A final analysis was performed after a median follow-up of 8 years, which showed that 1 year 
Herceptin treatment is associated with a 24 % risk reduction compared to observation only (HR=0.76, 
95 % CI 0.67, 0.86). This translates into an absolute benefit in terms of an 8 year disease free survival 
rate of 6.4 percentage points in favour of 1 year Herceptin treatment.  
 
In this final analysis, extending Herceptin treatment for a duration of two years did not show 
additional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 years 
versus 1 year=0.99 (95 % CI: 0.87, 1.13), p-value=0.90 and OS HR=0.98 (0.83, 1.15); p-value= 0.78]. 
The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm (8.1 % versus 
4.6 % in the 1-year treatment arm). More patients experienced at least one grade 3 or 4 adverse event 
in the 2-year treatment arm (20.4 %) compared with the 1-year treatment arm (16.3 %). 
 
In the NSABP B-31 and NCCTG N9831 studies Herceptin was administered in combination with 
paclitaxel, following AC chemotherapy.  
 

Doxorubicin and cyclophosphamide were administered concurrently as follows: 
 
- intravenous push doxorubicin, at 60 mg/ m2, given every 3 weeks for 4 cycles. 
 

 - intravenous cyclophosphamide, at 600 mg/ m2 over 30 minutes, given every 3 weeks for 4 
  cycles. 

 
Paclitaxel, in combination with Herceptin, was administered as follows: 

 
- intravenous paclitaxel - 80 mg/m2 as a continuous intravenous infusion, given every week 

for 12 weeks.  
or  

- intravenous paclitaxel - 175 mg/m2 as a continuous intravenous infusion, given every 3 
weeks for 4 cycles (day 1 of each cycle). 

 
The efficacy results from the joint analysis of the NSABP B-31 and NCCTG 9831 trials at the time of 
the definitive analysis of DFS* are summarized in Table 7. The median duration of follow up was 1.8 
years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm.   
 
Table 7 Summary of Efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831 
trials at the time of the definitive DFS analysis* 
 

Parameter 
 

AC→P 
(n=1679) 

AC→PH 
(n=1672) 

Hazard Ratio vs 
AC→P 

(95% CI) 
p-value 

Disease-free survival 
No. patients with event (%) 

 
261 (15.5) 

 
133 (8.0) 

 
0.48 (0.39, 0.59) 

p<0.0001 
Distant Recurrence 
No. patients with event 

 
193 (11.5) 

 
96 (5.7) 

 
0.47 (0.37, 0.60) 

p<0.0001 
Death (OS event): 
No. patients with event  

 
92 (5.5) 

 
62 (3.7) 

 
0.67 (0.48, 0.92) 

p=0.014** 
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab 
* At median duration of follow up of 1.8 years for the patients in the AC→P arm and 2.0 years for 
patients in the AC→PH arm 
** p value for OS did not cross the pre-specified statistical boundary for comparison of AC→PH vs. 
AC→P 
 



23 

For the primary endpoint, DFS, the addition of Herceptin to paclitaxel chemotherapy resulted in a 
52 % decrease in the risk of disease recurrence. The hazard ratio translates into an absolute benefit, in 
terms of 3-year disease-free survival rate estimates of 11.8 percentage points (87.2 % versus 75.4 %) 
in favour of the AC→PH (Herceptin) arm. 
 
At the time of a safety update after a median of 3.5-3.8 years follow up, an analysis of DFS reconfirms 
the magnitude of the benefit shown in the definitive analysis of DFS. Despite the cross-over to 
Herceptin in the control arm, the addition of Herceptin to paclitaxel chemotherapy resulted in a 52 % 
decrease in the risk of disease recurrence. The addition of Herceptin to paclitaxel chemotherapy also 
resulted in a 37 % decrease in the risk of death. 
 
The pre-planned final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG 
N9831 was performed when 707 deaths had occurred (median follow-up 8.3 years in the AC→P H 
group). Treatment with AC→PH resulted in a statistically significant improvement in OS compared 
with AC→P (stratified HR=0.64; 95% CI [0.55, 0.74]; log-rank p-value < 0.0001).  At 8 years, the 
survival rate was estimated to be 86.9% in the AC→PH arm and 79.4% in the AC→P arm, an absolute 
benefit of 7.4% (95% CI 4.9%, 10.0%). 
The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are 
summarized in Table 8 below: 
 
Table 8 Final Overall Survival Analysis from the joint analysis of trials NSABP  
B-31 and NCCTG N9831  
 
Parameter 
 

AC→P 
(N=2032) 

AC→PH 
(N=2031) 

p-value versus 
AC→P 

 

Hazard Ratio 
versus 
AC→P 

(95% CI) 
Death (OS event): 
No. patients with event (%) 

 
418 (20.6%) 

 
289 (14.2%) 

 
< 0.0001 

 
0.64 

(0.55, 0.74) 
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab 

DFS analysis was also performed at the final analysis of OS from the joint analysis of studies 
NSABP B-31 and NCCTG N9831. The updated DFS analysis results (stratified HR = 0.61; 95% CI 
[0.54, 0.69]) showed a similar DFS benefit compared to the definitive primary DFS analysis, despite 
24.8% patients in the AC→P arm who crossed over to receive Herceptin. At 8 years, the disease-free 
survival rate was estimated to be 77.2% (95% CI: 75.4, 79.1) in the AC→PH arm, an absolute benefit 
of 11.8% compared with the AC→P arm. 
 
In the BCIRG 006 study Herceptin was administered either in combination with docetaxel, following 
AC chemotherapy (AC→DH) or in combination with docetaxel and carboplatin (DCarbH).  
 
Docetaxel was administered as follows: 

- intravenous docetaxel - 100 mg/m2 as an intravenous infusion over 1 hour, given every 3 
weeks for 4 cycles (day 2 of first docetaxel cycle, then day 1 of each subsequent cycle)  

or  
- intravenous docetaxel - 75 mg/m2 as an intravenous infusion over 1 hour, given every 3 

weeks for 6 cycles (day 2 of cycle 1, then day 1 of each subsequent cycle)  
which was followed by: 

- carboplatin – at target AUC = 6 mg/mL/min administered by intravenous infusion over 30-
60 minutes repeated every 3 weeks for a  total of six cycles 

 
Herceptin was administered weekly with chemotherapy and 3 weekly thereafter for a total of 52 
weeks. 
 
The efficacy results from the BCIRG 006 are summarized in Tables 9 and 10. The median duration of 
follow up was 2.9 years in the AC→D arm and 3.0 years in each of the AC→DH and DCarbH arms. 



24 

 
Table 9 Overview of Efficacy Analyses BCIRG 006  AC→D versus AC→DH 
 

Parameter 
 

AC→D 
(n=1073) 

AC→DH 
(n=1074) 

Hazard Ratio vs 
AC→D 

(95 % CI) 
p-value 

Disease-free survival    
No. patients with event 195 134 0.61 (0.49, 0.77) 

p<0.0001 
Distant recurrence    
No. patients with event 144 95 0.59 (0.46, 0.77) 

p<0.0001 
Death (OS event)    
No. patients with event 80 49 0.58 (0.40, 0.83) 

p=0.0024 

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; AC→DH = doxorubicin plus 
cyclophosphamide, followed by docetaxel plus trastuzumab; CI = confidence interval 

 
Table 10 Overview of Efficacy Analyses BCIRG 006  AC→D versus DCarbH  
 

Parameter 
 

AC→D 
(n=1073) 

DCarbH 
(n=1074) 

Hazard Ratio vs 
AC→D 

(95 % CI) 
Disease-free survival    
No. patients with event 195 145 0.67 (0.54, 0.83) 

p=0.0003 
Distant recurrence    
No. patients with event 144 103 0.65 (0.50, 0.84) 

p=0.0008 
Death (OS event)    
No. patients with event 80 56 0.66 (0.47, 0.93) 

p=0.0182 

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; DCarbH = docetaxel, carboplatin and 
trastuzumab; CI = confidence interval 
 
In the BCIRG 006 study for the primary endpoint, DFS, the hazard ratio translates into an absolute 
benefit, in terms of 3-year disease-free survival rate estimates of 5.8 percentage points (86.7  % versus 
80.9 %) in favour of the AC→DH (Herceptin) arm and 4.6 percentage points (85.5 % versus 80.9  %) 
in favour of the DCarbH (Herceptin) arm compared to AC→D. 
 
In study BCIRG 006, 213/1075 patients in the DCarbH (TCH) arm, 221/1074 patients in the ACÆDH 
(ACÆTH) arm, and 217/1073 in the AC→D (ACÆT) arm had a Karnofsky performance status ≤90 
(either 80 or 90). No disease-free survival (DFS) benefit was noticed in this subgroup of patients 
(hazard ratio = 1.16, 95 % CI [0.73, 1.83] for DCarbH (TCH) versus ACÆD (ACÆT); hazard ratio 
0.97, 95 % CI [0.60, 1.55] for ACÆDH (ACÆTH) versus ACÆD). 
 



25 

In addition a post-hoc exploratory analysis was performed on the data sets from the joint analysis (JA) 
NSABP B-31/NCCTG N9831* and BCIRG006 clinical studies combining DFS events and 
symptomatic cardiac events and summarised in Table 11:  
 
Table 11 Post-Hoc Exploratory Analysis Results from the Joint Analysis NSABP B-31/NCCTG 
N9831* and BCIRG006 Clinical Studies Combining DFS Events and Symptomatic Cardiac Events 
 

 ACÆPH  
(vs. ACÆP) 

(NSABP B-31 and 
NCCTG N9831)* 

 

ACÆDH  
(vs. ACÆD) 
(BCIRG 006) 

DCarbH  
(vs. ACÆD) 
(BCIRG 006) 

Primary efficacy analysis 
DFS Hazard ratios 

(95 % CI) 
p-value 

 
0.48 

(0.39, 0.59)  
p<0.0001 

 
0.61 

(0.49, 0.77) 
p< 0.0001 

 
0.67 

(0.54, 0.83) 
p=0.0003 

Long term follow-up efficacy 
analysis** 

DFS Hazard ratios 
(95 % CI) 

p-value 

 
 

0.61 
(0.54, 0.69) 
p<0.0001 

 
 

0.72 
(0.61, 0.85) 
p<0.0001 

 
 

0.77 
(0.65, 0.90) 
p=0.0011 

Post-hoc exploratory analysis 
with DFS and symptomatic 

cardiac events 
Long term follow-up** 

Hazard ratios 
(95 % CI) 

 
 
 

0.67 
(0.60, 0.75) 

 
 
 

0.77 
(0.66, 0.90) 

 
 
 

0.77 
(0.66, 0.90) 

 
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel; Carb: carboplatin; H: trastuzumab 
CI = confidence interval 
* At the time of the definitive analysis of DFS. Median duration of follow up was 1.8 years in the AC→P arm 
and 2.0 years in the AC→PH arm 
** Median duration of long term follow-up for the Joint Analysis clinical studies was 8.3 years (range: 0.1 to 
12.1) for the AC→PH arm and 7.9 years (range: 0.0 to 12.2) for the AC→P arm;  Median duration of long term 
follow-up for the BCIRG 006 study was 10.3 years in both the AC→D arm (range: 0.0 to 12.6) arm and the 
DCarbH arm (range: 0.0 to 13.1), and was 10.4 years (range: 0.0 to 12.7) in the AC→DH  arm 
 
Early breast cancer (neoadjuvant-adjuvant setting) 
 
So far, no results are available which compare the efficacy of Herceptin administered with 
chemotherapy in the adjuvant setting with that obtained in the neo-adjuvant/adjuvant setting. 
 
In the neoadjuvant-adjuvant treatment setting, study MO16432, a multicentre randomised trial, was 
designed to investigate the clinical efficacy of concurrent administration of Herceptin with 
neoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant 
Herceptin, up to a total treatment duration of 1 year. The study recruited patients with newly 
diagnosed locally advanced (Stage III) or inflammatory EBC. Patients with HER2+ tumours were 
randomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant 
Herceptin, or neoadjuvant chemotherapy alone. 
 



26 

In study MO16432, Herceptin (8 mg/kg loading dose, followed by 6 mg/kg maintenance every 3 
weeks) was administered concurrently with 10 cycles of neoadjuvant chemotherapy 
 
as follows: 
 

∑ Doxorubicin 60mg/m2 and paclitaxel 150 mg/m2, administered 3-weekly for 3 cycles, 
 

which was followed by 
∑ Paclitaxel 175 mg/m2 administered 3-weekly for 4 cycles, 

 
which was followed by 

∑ CMF on day 1 and 8 every 4 weeks for 3 cycles 
 

which was followed after surgery by 
∑ additional cycles of adjuvant Herceptin (to complete 1 year of treatment) 

 
The efficacy results from Study MO16432 are summarized in Table 12. The median duration of 
follow-up in the Herceptin arm was 3.8 years. 
 
Table 12 Efficacy Results from MO16432 
 

Parameter 
 

Chemo + 
Herceptin 
(n=115) 

Chemo only 
(n=116) 

 

Event-free survival   Hazard Ratio 
(95% CI) 

No. patients with event 46 59 0.65 (0.44, 0.96) 
p=0.0275 

Total pathological complete 
response* (95 % CI) 

40 % 
(31.0, 49.6) 

20.7 % 
(13.7, 29.2) 

P=0.0014 

Overall survival   Hazard Ratio 
(95 % CI) 

No. patients with event 22 33 0.59 (0.35, 1.02) 
p=0.0555 

* defined as absence of any invasive cancer both in the breast and axillary nodes 
 
An absolute benefit of 13 percentage points in favour of the Herceptin arm was estimated in terms of 
3-year event-free survival rate (65 % versus 52 %). 
 
Metastatic gastric cancer 
 
Herceptin has been investigated in one randomised, open-label phase III trial ToGA (BO18255) in 
combination with chemotherapy versus chemotherapy alone.  
 
Chemotherapy was administered as follows: 
 

- capecitabine - 1000 mg/m2 orally twice daily for 14 days every 3 weeks for 6 cycles 
(evening of day 1 to morning of day 15 of each cycle)  

or  
- intravenous 5-fluorouracil - 800 mg/m2/day as a continuous intravenous infusion over 5 

days, given every 3 weeks for 6 cycles (days 1 to 5 of each cycle)  
 
Either of which was administered with: 
 

- cisplatin - 80 mg/m2 every 3 weeks for 6 cycles on day 1 of each cycle. 
 



27 

The efficacy results from study BO18225 are summarized in Table 13:  
 
Table 13 Efficacy Results from BO18225 
 

Parameter FP 
N = 290 

FP +H 
N = 294 

HR (95 % CI) p-value 

Overall Survival, Median months 11.1 13.8 0.74 (0.60-0.91) 0.0046 
Progression-Free Survival, 
Median months 

5.5 6.7 0.71 (0.59-0.85) 0.0002 

Time to Disease Progression, 
Median months 

5.6 7.1 0.70 (0.58-0.85) 0.0003 

Overall Response Rate, % 34.5 % 47.3 % 1.70a (1.22, 2.38) 0.0017 
Duration of Response, Median 
months 

4.8 6.9 0.54 (0.40-0.73) < 0.0001 

FP + H: Fluoropyrimidine/cisplatin  + Herceptin  
FP: Fluoropyrimidine/cisplatin  
a Odds ratio 
 
Patients were recruited to the trial who were previously untreated for HER2-positive inoperable 
locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal 
junction not amenable to curative therapy. The primary endpoint was overall survival which was 
defined as the time from the date of randomization to the date of death from any cause. At the time of 
the analysis a total of 349 randomized patients had died: 182 patients (62.8 %) in the control arm and 
167 patients (56.8 %) in the treatment arm. The majority of the deaths were due to events related to the 
underlying cancer. 
 
Post-hoc subgroup analyses indicate that positive treatment effects are limited to targeting tumours 
with higher levels of HER2 protein (IHC 2+/FISH+ or IHC 3+). The median overall survival for the 
high HER2 expressing group was 11.8 months versus 16 months, HR 0.65 (95 % CI 0.51-0.83) and 
the median progression free survival was 5.5 months versus 7.6 months, HR 0.64 (95 % CI 0.51-0.79) 
for FP versus FP + H, respectively. For overall survival, the HR was 0.75 (95 % CI 0.51-1.11) in the 
IHC 2+/FISH+ group and the HR was 0.58 (95 % CI 0.41-0.81) in the IHC 3+/FISH+ group. 
 
In an exploratory subgroup analysis performed in the TOGA (BO18255) trial there was no apparent 
benefit on overall survival with the addition of Herceptin in patients with ECOG PS 2 at baseline [HR 
0.96 (95 % CI 0.51-1.79)], non measurable [HR 1.78 (95 % CI 0.87-3.66)] and locally advanced 
disease [HR 1.20 (95 % CI 0.29-4.97)].  
 
Paediatric population  
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Herceptin in all subsets of the paediatric population for breast and gastric cancer (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis 
using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or 
other tumor types, and healthy volunteers, in 18 Phase I, II and III trials receiving Herceptin IV. A 
two-compartment model with parallel linear and non-linear elimination from the central compartment 
described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance 
increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can 
be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval (see Table 16). 
MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central compartment 
volume (Vc)) and population-predicted steady-state exposures (Cmin, Cmax and AUC). Linear clearance 
was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC.  The non-linear 
elimination parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 



28 

µg/mL for the Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The central 
compartment volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC.  
In the final population PK model, in addition to primary tumor type, body-weight, serum aspartate 
aminotransferase and albumin were identified as a statistically significant covariates affecting the 
exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab 
exposure suggests that these covariates are unlikely to have a clinically meaningful effect on 
trastuzumab concentrations. 
 
The population predicted PK exposure values (median with 5th - 95th Percentiles) and PK parameter 
values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treated 
with the approved q1w and q3w dosing regimens are shown in Table 14 (Cycle 1), Table 15 (steady-
state), and Table 16 (PK parameters). 
 
Table 14 Population Predicted Cycle 1 PK Exposure Values (median with 5th - 95th Percentiles) for 
Herceptin IV Dosing Regimens in MBC, EBC and AGC Patients 
 

Regimen Primary tumor type N 
Cmin 

(µg/mL) 
Cmax 

(µg/mL) 
AUC0-21days 

(µg.day/mL) 

8mg/kg + 
6mg/kg q3w 

MBC 805 28.7  (2.9 - 46.3) 
182  

(134 - 280) 
1376 

(728 - 1998) 

EBC 390 30.9  (18.7 - 45.5) 
176  

(127 - 227) 
1390 

(1039 - 1895) 

AGC 274 23.1 (6.1 - 50.3) 
132 

(84.2 – 225) 
1109 

(588 – 1938) 

4mg/kg + 
2mg/kg qw 

MBC 805 37.4  (8.7 - 58.9) 
76.5  

(49.4 - 114) 
1073  

(597 – 1584) 

EBC 390 38.9  (25.3 - 58.8) 
76.0 

(54.7 - 104) 
1074  

(783 - 1502) 
 
Table 15 Population Predicted Steady State PK Exposure Values (median with 5th - 95th Percentiles) 
for Herceptin IV Dosing Regimens in MBC, EBC and AGC Patients 
 

Regimen Primary tumor type N 
Cmin,ss* 

(µg/mL) 
Cmax,ss** 
(µg/mL) 

AUCss, 0-21days 
(µg.day/mL) 

Time to 
steady-
state*** 
(week) 

8mg/kg + 
6mg/kg q3w 

MBC 805 44.2  (1.8 - 85.4) 
179  

(123 - 266) 
1736  

(618 - 2756) 12 

EBC 390 53.8  (28.7 - 85.8) 
184  

(134 - 247) 
1927  

(1332 -2771) 15 

AGC 274 32.9  (6.1 – 88.9) 
131  

(72.5 -251) 
1338  

(557 - 2875) 9 

4mg/kg + 
2mg/kg qw 

MBC 805 63.1  (11.7 - 107) 
107  

(54.2 - 164) 
1710  

(581 - 2715) 12 

EBC 390 72.6  (46 - 109) 
115  

(82.6 - 160) 
1893  

(1309 -2734) 14 

*Cmin,ss – Cmin at steady state  
**Cmax,ss = Cmax at steady state 
*** time to 90% of steady-state 
 



29 

Table 16 Population Predicted PK Parameter Values at Steady State for Herceptin IV Dosing 
Regimens in MBC, EBC and AGC Patients 
 

Regimen Primary tumor type N 

Total CL range 
from Cmax,ss to 

Cmin,ss 
(L/day) 

t1/2 range from Cmax,ss to 
Cmin,ss 
(day)  

8mg/kg + 
6mg/kg q3w 

MBC 805 0.183 - 0.302  15.1 - 23.3 

EBC 390 0.158 - 0.253 17.5 – 26.6 

AGC 274 0.189 - 0.337 12.6 - 20.6 

4mg/kg + 
2mg/kg qw 

MBC 805 0.213 - 0.259 17.2 - 20.4 

EBC 390 0.184 - 0.221 19.7 - 23.2 
 
Trastuzumab washout 
 
Trastuzumab washout period was assessed following q1w or q3w intravenous administration using the 
population PK model. The results of these simulations indicate that at least 95% of patients will reach 
concentrations that are <1 μg/mL (approximately 3% of the population predicted Cmin,ss, or about 97% 
washout) by 7 months. 
 
Circulating shed HER2 ECD 
 
The exploratory analyses of covariates with information in only a subset of patients suggested that 
patients with greater shed HER2-ECD  level had faster nonlinear clearance (lower Km) (P < 0.001). 
There was a correlation between shed antigen and SGOT/AST levels; part of the impact of shed 
antigen on clearance may have been explained by SGOT/AST levels.  
 
Baseline levels of the shed HER2-ECD observed in MGC patients were comparable to those in MBC 
and EBC patients and no apparent impact on trastuzumab clearance was observed.  
 
5.3 Preclinical safety data 
 
There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, or 
reproductive toxicity in teratology, female fertility or late gestational toxicity/placental transfer 
studies. Herceptin is not genotoxic. A study of trehalose, a major formulation excipient did not reveal 
any toxicities. 
 
No long-term animal studies have been performed to establish the carcinogenic potential of Herceptin, 
or to determine its effects on fertility in males. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
L-histidine hydrochloride monohydrate 
L-histidine 
a,a-trehalose dihydrate 
polysorbate 20 
 



30 

6.2 Incompatibilities 
 
This medicinal product must not be mixed or diluted with other medicinal products except those 
mentioned under section 6.6. 
 
Do not dilute with glucose solutions since these cause aggregation of the protein. 
 
6.3 Shelf life 
 
Unopened vial 
 
4 years 
 
Aseptic reconstitution and dilution: 
 
After aseptic reconstitution with sterile water for injection, chemical and physical stability of the 
reconstituted solution has been demonstrated for 48 hours at 2°C – 8°C. 
 
After aseptic dilution in polyvinylchloride, polyethylene or polypropylene bags containing sodium 
chloride 9 mg/mL (0.9 %) solution for injection, chemical and physical stability of Herceptin has been 
demonstrated for up to 30 days at 2 oC – 8oC, and 24 hours at temperatures not exceeding 30°C. 
 
From a microbiological point of view, the reconstituted solution and Herceptin infusion solution 
should be used immediately. If not used immediately, in-use storage times and conditions prior to use 
are the responsibility of the user, and would not normally be longer than 24 hours at 2°C to 8°C, 
unless reconstitution and dilution have taken place under controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2∞C – 8∞C). 
 
Do not freeze the reconstituted solution. 
 
For storage conditions of the opened medicinal product, see section 6.3 and 6.6. 
 
6.5 Nature and contents of container 
 
Herceptin vial: 
 
One 15 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film 
containing 150 mg of trastuzumab. 
 
Each carton contains one vial. 
 
6.6 Special precautions for disposal and other handling 
 
Herceptin IV is provided in sterile, preservative-free, non-pyrogenic, single use vials.  
 
Appropriate aseptic technique should be used for reconstitution and dilution procedures. Care must be 
taken to ensure the sterility of prepared solutions. Since the medicinal product does not contain any 
anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed.  
 
Aseptic preparation, handling and storage:  
 
Aseptic handling must be ensured when preparing the infusion. Preparation should be:  
∑ performed under aseptic conditions by trained personnel in accordance with good practice rules 

especially with respect to the aseptic preparation of parenteral products.  



31 

∑ prepared in a laminar flow hood or biological safety cabinet using standard precautions for the 
safe handling of intravenous agents. 

∑ followed by adequate storage of the prepared solution for intravenous infusion to ensure 
maintenance of the aseptic conditions 

 
Each vial of Herceptin is reconstituted with 7.2 mL of sterile water for injection (not supplied). Use of 
other reconstitution solvents should be avoided.  
 
This yields a 7.4 mL solution for single-dose use, containing approximately 21 mg/mL trastuzumab, at 
a pH of approximately 6.0. A volume overage of 4 % ensures that the labelled dose of 150 mg can be 
withdrawn from each vial. 
 
Herceptin should be carefully handled during reconstitution. Causing excessive foaming during 
reconstitution or shaking the reconstituted solution may result in problems with the amount of 
Herceptin that can be withdrawn from the vial. 
 
The reconstituted solution should not be frozen. 
 
Instructions for aseptic reconstitution: 
 
1) Using a sterile syringe, slowly inject 7.2 mL of sterile water for injection in the vial containing the 
lyophilised Herceptin, directing the stream into the lyophilised cake. 
2) Swirl the vial gently to aid reconstitution. DO NOT SHAKE! 
 
Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed 
for approximately 5 minutes. The reconstituted Herceptin results in a colourless to pale yellow 
transparent solution and should be essentially free of visible particulates. 
 
Instructions for aseptic dilution of the reconstituted solution 
 
Determine the volume of the solution required: 

∑ based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose 
of 2 mg trastuzumab/kg body weight: 

 
Volume (mL) = Body weight (kg) x dose (4 mg/kg for loading or 2 mg/kg for maintenance)  
   21 (mg/mL, concentration of reconstituted solution)  
 

∑ based on a loading dose of 8 mg trastuzumab/kg body weight, or a subsequent 3-weekly dose 
of 6 mg trastuzumab/kg body weight: 

 
Volume (mL) = Body weight (kg) x dose (8 mg/kg for loading or 6 mg/kg for maintenance)  
   21 (mg/mL, concentration of reconstituted solution)  
 
The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag 
containing 250 mL of 0.9 % sodium chloride solution. Do not use with glucose-containing solutions 
(see section 6.2). The bag should be gently inverted to mix the solution in order to avoid foaming.  
 
Parenteral medicinal products should be inspected visually for particulate matter and discoloration 
prior to administration. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 
No incompatibilities between Herceptin and polyvinylchloride, polyethylene or polypropylene bags 
have been observed. 
 
 



32 

7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/145/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 28 August 2000 
Date of latest renewal: 28 August 2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

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


33 

1. NAME OF THE MEDICINAL PRODUCT 
 
Herceptin 600 mg solution for injection in vial 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial of 5 mL contains 600 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced 
by mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion 
exchange chromatography including specific viral inactivation and removal procedures. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection 
 
Clear to opalescent solution, colourless to yellowish. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Breast cancer 
 
Metastatic breast cancer 
 
Herceptin is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer 
(MBC): 
 
- as monotherapy for the treatment of those patients who have received at least two chemotherapy 

regimens for their metastatic disease. Prior chemotherapy must have included at least an 
anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor 
positive patients must also have failed hormonal therapy, unless patients are unsuitable for these 
treatments. 

 
- in combination with paclitaxel for the treatment of those patients who have not received 

chemotherapy for their metastatic disease and for whom an anthracycline is not suitable. 
 
- in combination with docetaxel for the treatment of those patients who have not received 

chemotherapy for their metastatic disease. 
 
- in combination with an aromatase inhibitor for the treatment of postmenopausal patients with 
 hormone-receptor positive MBC, not previously treated with trastuzumab. 
 
Early breast cancer 
 
Herceptin is indicated for the treatment of adult patients with HER2 positive early breast cancer 
(EBC). 
 
- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see 

section 5.1). 
 
- following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with 

paclitaxel or docetaxel. 



34 

 
- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin. 
- in combination with neoadjuvant chemotherapy followed by adjuvant Herceptin therapy, for 

locally advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 
4.4 and 5.1). 

 
Herceptin should only be used in patients with metastatic or early breast cancer whose tumours have 
either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated 
assay (see sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Herceptin treatment 
should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy 
(see section 4.4), and should be administered by a healthcare professional only. 
 
It is important to check the product labels to ensure that the correct formulation (intravenous or 
subcutaneous fixed dose) is being administered to the patient, as prescribed. Herceptin subcutaneous 
formulation is not intended for intravenous administration and should be administered via a 
subcutaneous injection only.  
 
Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulations and 
vice versa, using the three-weekly (q3w) dosing regimen, was investigated in study MO22982 (see 
section 4.8). 
 
In order to prevent medication errors it is important to check the vial labels to ensure that the drug 
being prepared and administered is Herceptin (trastuzumab) and not Kadcyla (trastuzumab emtansine). 
 
Posology 
 
The recommended dose for Herceptin subcutaneous formulation is 600 mg irrespective of the patient’s 
body weight. No loading dose is required. This dose should be administered subcutaneously over 2-5 
minutes every three weeks. 
 
In the pivotal trial (BO22227) Herceptin subcutaneous formulation was administered in the 
neoadjuvant/adjuvant setting in patients with early breast cancer. The preoperative chemotherapy 
regimen consisted of docetaxel (75 mg/m²) followed by FEC (5FU, epirubicin and cyclophosphamide) 
at a standard dose. 
 
See section 5.1 for chemotherapy combination dosing. 
 
Duration of treatment 
 
Patients with MBC should be treated with Herceptin until progression of disease. Patients with EBC 
should be treated with Herceptin for 1 year or until disease recurrence, whichever occurs first; 
extending treatment in EBC beyond one year is not recommended (see section 5.1). 
 
Dose reduction 
 
No reductions in the dose of Herceptin were made during clinical trials. Patients may continue therapy 
during periods of reversible, chemotherapy-induced myelosuppression butthey should be monitored 
carefully for complications of neutropenia during this time. Refer to the Summary of Product 
Characteristics (SmPC) for paclitaxel, docetaxel or aromatase inhibitor for information on dose 
reduction or delays. 
 
If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 points from baseline AND to below 
50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 



35 

3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure 
(CHF) has developed, discontinuation of Herceptin should be strongly considered, unless the benefits 
for the individual patient are deemed to outweigh the risks. All such patients should be referred for 
assessment by a cardiologist and followed up. 
 
Missed doses 
 
If the patient misses a dose of Herceptin subcutaneous formulation, it is recommended to administer 
the next 600 mg dose (i.e. the missed dose) as soon as possible. The interval between consecutive 
Herceptin subcutaneous formulation administrations should not be less than three weeks. 
 
Special populations 
 
Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not 
been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown 
to affect trastuzumab disposition. 
 
Paediatric population 
 
There is no relevant use of Herceptin in the paediatric population. 
 
Method of administration 
 
The 600 mg dose should be administered as a subcutaneous injection only over 2-5 minutes every 
three weeks. The injection site should be alternated between the left and right thigh. New injections 
should be given at least 2.5 cm from the old site and never into areas where the skin is red, bruised, 
tender, or hard. During the treatment course with Herceptin subcutaneous formulation other medicinal 
products for subcutaneous administration should preferably be injected at different sites. Patients 
should be observed for six hours after the first injection and for two hours after subsequent injections 
for signs or symptoms of administration-related reactions (see sections 4.4 and 4.8).  
 
For instructions on use and handling of Herceptin subcutaneous formulation refer to section 6.6. 
 
4.3 Contraindications 
 
∑ Hypersensitivity to trastuzumab, murine proteins, hyaluronidase or to any of the other 

excipients listed in section 6.1. 
∑ Severe dyspnoea at rest due to complications of advanced malignancy or requiring 

supplementary oxygen therapy. 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the trade name and the batch 
number of the administered product should be clearly recorded. 
 
HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of 
the testing procedures (see section 5.1). 
 
Currently no data from clinical trials are available on re-treatment of patients with previous exposure 
to Herceptin in the adjuvant setting. 
 



36 

Cardiac dysfunction 
 
General considerations 
 
Patients treated with Herceptin are at increased risk for developing CHF (New York Heart Association 
[NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in 
patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly 
following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. These may be 
moderate to severe and have been associated with death (see section 4.8). In addition, caution should 
be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary 
artery disease, CHF, LVEF of <55%, older age. 
 
All candidates for treatment with Herceptin, but especially those with prior anthracycline and 
cyclophosphamide exposure, should undergo baseline cardiac assessment including history and 
physical examination and electrocardiogram (ECG), echocardiogram, and/or multigated acquisition 
(MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop 
cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months 
during treatment and every 6 months following discontinuation of treatment until 24 months from the 
last administration of Herceptin. A careful risk-benefit assessment should be made before deciding to 
treat with Herceptin. 
 
Trastuzumab may persist in the circulation for up to 7 months after stopping Herceptin treatment 
based on population pharmacokinetic analysis of all available data (see section 5.2). Patients who 
receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiac 
dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after 
stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitored 
carefully. 
 
Formal cardiological assessment should be considered in patients in whom there are cardiovascular 
concerns following baseline screening. In all patients cardiac function should be monitored during 
treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac 
dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent 
monitoring (e.g. every 6-8 weeks). If patients have a continued decrease in left ventricular function, 
but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of 
Herceptin therapy has been seen. 
 
The safety of continuation or resumption of Herceptin in patients who experience cardiac dysfunction 
has not been prospectively studied. If LVEF percentage drops ≥ 10 points from baseline AND to 
below 50%, treatment should be suspended and a repeat LVEF assessment performed within 
approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF has 
developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the 
individual patient are deemed to outweigh the risks. All such patients should be referred for 
assessment by a cardiologist and followed up. 
 
If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with standard 
medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction 
in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting 
enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of 
patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on 
therapy without additional clinical cardiac events. 
 
Metastatic breast cancer 
 
Herceptin and anthracyclines should not be given concurrently in combination in the MBC setting. 
 



37 

Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction 
with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and 
anthracyclines. 
 
Early breast cancer 
 
For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 
months during treatment and every 6 months following discontinuation of treatment until 24 months 
from the last administration of Herceptin. In patients who receive anthracycline-containing 
chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last 
administration of Herceptin, or longer if a continuous decrease of LVEF is observed. 
 
Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, 
history of or existing CHF (NYHA Class II –IV), LVEF of < 55%, other cardiomyopathy, cardiac 
arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly 
controlled hypertension (hypertension controlled by standard medical treatment eligible), and 
hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC 
pivotal trials with Herceptin and therefore treatment cannot be recommended in such patients. 
 
Adjuvant treatment 
 
Herceptin and anthracyclines should not be given concurrently in the adjuvant treatment setting. 
 
In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events 
was observed when Herceptin (intravenous formulation) was administered after anthracycline-
containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel 
and carboplatin and was more marked when Herceptin (intravenous formulation) was administered 
concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen 
used, most symptomatic cardiac events occurred within the first 18 months. In one of the 3 pivotal 
studies conducted in which a median follow-up of 5.5 years was available (BCIRG006) a continuous 
increase in the cumulative rate of symptomatic cardiac or LVEF events was observed (up to 2.37 %) in 
patients who were administered Herceptin concurrently with a taxane following anthracycline therapy, 
compared to approximately 1 % in the two comparator arms (anthracycline plus cyclophosphamide 
followed by taxane and taxane, carboplatin and Herceptin). 
 
Risk factors for a cardiac event identified in four large adjuvant studies included advanced age 
(> 50 years), low LVEF (<55%) at baseline, prior to or following the initiation of paclitaxel treatment, 
decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products. 
In patients receiving Herceptin after completion of adjuvant chemotherapy, the risk of cardiac 
dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of 
Herceptin and a body mass index (BMI) >25 kg/m2. 
 
Neoadjuvant-adjuvant treatment 
 
In patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin should be used 
concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose 
anthracycline regimens, i.e., with maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin 
360 mg/m2. 
 
If patients have been treated concurrently with a full course of low-dose anthracyclines and Herceptin 
in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. In 
other situations, the decision on the need for additional cytotoxic chemotherapy is determined based 
on individual factors. 
 
Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is 
currently limited to two trials (MO16432 and BO22227).  
 



38 

In the pivotal trial MO16432, Herceptin was administered concurrently with neoadjuvant 
chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2) . The incidence of 
symptomatic cardiac dysfunction was 1.7% in the Herceptin arm . 
 
In the pivotal trial BO22227, Herceptin was administered concurrently with neoadjuvant 
chemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m2); at a median 
follow-up exceeding 70 months, the incidence of cardiac failure/congestive cardiac failure was 0.3% 
in the Herceptin intravenous arm and 0.7% in the Herceptin subcutaneous arm.  In patients with lower 
body weights (<59 kg, the lowest body weight quartile) the fixed dose used in the Herceptin 
subcutaneous arm was not associated with an increased risk of cardiac events or significant drop in 
LVEF. 
 
Clinical experience is limited in patients above 65 years of age. 
 
Administration-related reactions 
 
Administration-related reactions (ARRs) are known to occur with Herceptin subcutaneous 
formulation. Pre-medication may be used to reduce risk of occurrence of ARRs. 
 
Although serious ARRs, including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, 
reduced oxygen saturation and respiratory distress, were not reported in the clinical trial with the 
Herceptin subcutaneous formulation, caution should be exercised as these have been associated with 
the intravenous formulation. Patients should be observed for ARRs for six hours after the first 
injection and for two hours after subsequent injections. They can be treated with an 
analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as 
diphenhydramine. Serious reactions to intravenous Herceptin have been treated successfully with 
supportive therapy such as oxygen, beta-agonists, and corticosteroids. In rare cases, these reactions 
were associated with a clinical course culminating in a fatal outcome. Patients experiencing dyspnoea 
at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a 
fatal ARR. Therefore, these patients should not be treated with Herceptin (see section 4.3). 
 
Pulmonary events 
 
Caution is recommended with Herceptin subcutaneous formulation as severe pulmonary events have 
been reported with the use of the intravenous formulation in the post-marketing setting (see section 
4.8). These events have occasionally been fatal and may occur as part of an infusion-related reaction 
or with delayed onset. In addition, cases of interstitial lung disease including lung infiltrates, acute 
respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute 
pulmonary oedema and respiratory insufficiency have been reported. Risk factors associated with 
interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies 
known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. 
Patients experiencing dyspnoea at rest due to complications of advanced malignancy and 
comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be 
treated with Herceptin (see section 4.3). Caution should be exercised for pneumonitis, especially in 
patients being treated concomitantly with taxanes. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No formal drug interaction studies have been performed. Clinically significant interactions between 
Herceptin and the concomitant medicinal products used in clinical trials have not been observed.  
 
Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents 
 
Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC 
suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-
paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 
4 mg/kg IV loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w IV, respectively). 



39 

However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 
dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this 
metabolite was unclear.   
 
Data from study JP16003, a single-arm study of Herceptin (4 mg/kg IV loading dose and 2 mg/kg IV 
weekly) and docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggested that 
concomitant administration of Herceptin had no effect on the single dose pharmacokinetics of 
docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female 
Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and 
cisplatin when used with or without Herceptin. The results of this substudy suggested that the 
exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of 
cisplatin or by concurrent use of cisplatin plus Herceptin. However, capecitabine itself showed higher 
concentrations and a longer half-life when combined with Herceptin. The data also suggested that the 
pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use 
of capecitabine plus Herceptin. 
 
Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advanced 
inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.  
 
Effect of antineoplastic agents on trastuzumab pharmacokinetics 
 
By comparison of simulated serum trastuzumab concentrations after Herceptin monotherapy (4 mg/kg 
loading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with HER2- positive 
MBC (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on the 
pharmacokinetics of trastuzumab was found. 
 
Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study 
(H0648g) in which patients were treated concomitantly with Herceptin and paclitaxel and two Phase II 
studies in which Herceptin was administered as monotherapy (W016229 and MO16982), in women 
with HER2-positive MBC indicates that individual and mean trastuzumab trough serum 
concentrations varied within and across studies but there was no clear effect of the concomitant 
administration of paclitaxel on the pharmacokinetics of trastuzumab. Comparison of trastuzumab PK 
data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with 
Herceptin, paclitaxel and doxorubicin to trastuzumab PK data in studies where Herceptin was 
administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide 
or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the 
pharmacokinetics of trastuzumab.  
 
Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the 
PK of trastuzumab. 
 
The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of 
trastuzumab. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception 
 
Women of childbearing potential should be advised to use effective contraception during treatment 
with Herceptin and for 7 months after treatment has concluded (see section 5.2). 
 
Pregnancy 
 
Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the 
weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation and have revealed no 
evidence of impaired fertility or harm to the fetus. Placental transfer of trastuzumab during the early 
(days 20-50 of gestation) and late (days 120-150 of gestation) fetal development period was observed. 



40 

It is not known whether Herceptin can affect reproductive capacity. As animal reproduction studies are 
not always predictive of human response, Herceptin should be avoided during pregnancy unless the 
potential benefit for the mother outweighs the potential risk to the fetus. 
 
In the post-marketing setting, cases of fetal renal growth and/or function impairment in association 
with oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus, have been 
reported in pregnant women receiving Herceptin. Women who become pregnant should be advised of 
the possibility of harm to the fetus. If a pregnant woman is treated with Herceptin, or if a patient 
becomes pregnant while receiving Herceptin or within 7 months following last dose of Herceptin, 
close monitoring by a multidisciplinary team is desirable. 
 
Breast-feeding 
 
A study conducted in lactating Cynomolgus monkeys at doses 25 times that of the weekly human 
maintenance dose of 2 mg/kg Herceptin intravenous formulation demonstrated that trastuzumab is 
secreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated 
with any adverse effects on their growth or development from birth to 1 month of age. It is not known 
whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the 
potential for harm to the infant is unknown, women should not breast-feed during Herceptin therapy 
and for 7 months after the last dose. 
 
Fertility 
 
There is no fertility data available.  
 
4.7 Effects on ability to drive and use machines 
 
Herceptin has a minor influence on the ability to drive or use machines (see section 4.8). Dizziness 
and somnolence may occur during treatment with Herceptin (see section 4.8). Patients experiencing 
administration-related symptoms (see section 4.4) should be advised not to drive and use machines 
until symptoms abate. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Amongst the most serious and/or common adverse reactions reported in Herceptin usage (intravenous 
and subcutaneous formulations) to date are cardiac dysfunction, administration-related reactions, 
haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions. 
 
The safety profile of Herceptin subcutaneous formulation (evaluated in 298 and 297 patients treated 
with the intravenous and subcutaneous formulations respectively) from the pivotal trial in EBC was 
overall similar to the known safety profile of the intravenous formulation.  
 
Severe adverse events (defined according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE grade ≥3) version 3.0) were equally distributed between both 
Herceptin formulations (52.3 % versus 53.5 % in the intravenous formulation versus subcutaneous 
formulation respectively).  
 
Some adverse events / reactions were reported with a higher frequency for the subcutaneous 
formulation: 

∑ Serious adverse events (most of which were identified because of in-patient hospitalisation or 
prolongation of existing hospitalisation): 14.1 % for the intravenous formulation versus 
21.5 % for the subcutaneous formulation. The difference in serious adverse event rates 
between formulations was mainly due to infections with or without neutropenia (4.4 % versus 
8.1 %) and cardiac disorders (0.7 % versus 1.7 %); 



41 

∑ Post-operative wound infections (severe and/or serious): 1.7  % versus 3.0  % for the 
intravenous formulation versus subcutaneous formulation, respectively; 

∑ Administration-related reactions: 37.2 % versus 47.8 % for the intravenous formulation versus 
subcutaneous formulation, respectively during the treatment phase; 

∑ Hypertension: 4.7 % versus 9.8 % for the intravenous formulation versus subcutaneous 
formulation respectively.   

 
Tabulated list of adverse reactions with the intravenous formulation 
 
In this section, the following categories of frequency have been used: very common (≥1/10), common 
(≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare 
(<1/10,000), not known (cannot be estimated from the available data). Within each frequency 
grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Presented in Table 1 are adverse reactions that have been reported in association with the use of 
intravenous Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the 
post-marketing setting. 
 
All the terms included are based on the highest percentage seen in pivotal clinical trials. In addition, 
terms reported in the post marketing setting are included in Table 1. 
 
Table 1: Undesirable effects reported with intravenous Herceptin monotherapy or in combination with 
chemotherapy in pivotal clinical trials (N = 8386) and in post-marketing 
 
System organ class Adverse reaction Frequency  
Infections and infestations Infection Very common 

Nasopharyngitis Very common 
Neutropenic sepsis Common 
Cystitis Common 
  
Influenza Common 
Sinusitis Common 
Skin infection Common 
Rhinitis Common 
Upper respiratory tract infection Common 
Urinary tract infection Common 
  
  
Pharyngitis Common 
  

Neoplasms benign, 
malignant and unspecified 
(incl. Cysts and polyps) 

Malignant neoplasm progression Not known 
Neoplasm progression Not known 

Blood and lymphatic 
system disorders 

Febrile neutropenia Very common  
Anaemia Very common 
Neutropenia Very common 
White blood cell count 
decreased/leukopenia 

Very common 

Thrombocytopenia Very common 
Hypoprothrombinaemia Not known 
Immune thrombocytopenia Not known 

Immune system disorders Hypersensitivity Common 
+Anaphylactic reaction Rare 
+Anaphylactic shock Rare 

Metabolism and nutrition Weight decreased/Weight loss Very common 



42 

System organ class Adverse reaction Frequency  
disorders Anorexia Very common 

Tumour lysis syndrome Not known 
Hyperkalaemia Not known 

Psychiatric disorders Insomnia Very common 
Anxiety Common 
Depression Common 
  

Nervous system disorders 1Tremor Very common 
Dizziness Very common  
Headache Very common  
Paraesthesia  Very common 
Dysgeusia Very common 
Peripheral neuropathy Common 
Hypertonia Common 
Somnolence Common 
  
  
  

Eye disorders Conjunctivitis Very common 
Lacrimation increased Very common 
Dry eye Common 
Papilloedema Not known 
Retinal haemorrhage Not known 

Ear and labyrinth disorders Deafness Uncommon 
Cardiac disorders 1 Blood pressure decreased Very common 

1 Blood pressure increased Very common 
1 Heart beat irregular Very common 

  
1Cardiac flutter Very common 
Ejection fraction decreased* Very common 
+Cardiac failure (congestive) Common 
+1Supraventricular tachyarrhythmia Common 
Cardiomyopathy Common 
1Palpitation Common 

 Pericardial effusion Uncommon 
Cardiogenic shock Not known 
  
  
Gallop rhythm present Not known 

Vascular disorders Hot flush Very common 
+1 Hypotension Common 
Vasodilatation Common 

Respiratory, thoracic and 
mediastinal disorders 

  
+Dyspnoea Very common 
Cough Very common 
Epistaxis Very common 
Rhinorrhoea Very common 
+Pneumonia Common 
Asthma Common 
Lung disorder Common 
+Pleural effusion Common 
+1Wheezing Uncommon 
Pneumonitis Uncommon 



43 

System organ class Adverse reaction Frequency  
+Pulmonary fibrosis Not known 
+Respiratory distress Not known 
+Respiratory failure Not known 
+Lung infiltration Not known 
+Acute pulmonary oedema Not known 
+Acute respiratory distress syndrome Not known 
+Bronchospasm Not known 
+Hypoxia Not known 
+Oxygen saturation decreased Not known 
Laryngeal oedema Not known 
Orthopnoea Not known 
Pulmonary oedema Not known 
Interstitial lung disease Not known 

Gastrointestinal disorders Diarrhoea  Very common 
Vomiting  Very common 
Nausea Very common 
1 Lip swelling Very common 

Abdominal pain Very common 

Dyspepsia Very common 
Constipation Very common 
Stomatitis  Very common 
Haemorrhoids Common 

 Dry mouth Common 
Hepatobiliary disorders Hepatocellular Injury Common 

Hepatitis Common 
Liver Tenderness Common 
Jaundice Rare 
  

Skin and subcutaneous 
tissue disorders  

Erythema Very common 
Rash Very common 
1 Swelling face Very common 
Alopecia Very common 
Nail disorder Very common 
Palmar-plantar erythrodysaesthesia 
syndrome 

Very common 

Acne Common 
Dry skin Common 
Ecchymosis Common 
Hyperhydrosis Common 
Maculopapular rash Common 
Pruritus Common 
Onychoclasis Common 
Dermatitis Common 
Urticaria Uncommon 
Angioedema Not known 

Musculoskeletal and 
connective tissue disorders 

Arthralgia Very common 
1Muscle tightness Very common 
Myalgia Very common 
Arthritis Common 
Back pain Common 
Bone pain Common 
Muscle spasms Common 



44 

System organ class Adverse reaction Frequency  
Neck pain Common 
Pain in extremity Common 

Renal and urinary disorders Renal disorder Common 
Glomerulonephritis membranous Not known 
Glomerulonephropathy Not known 
Renal failure Not known 

Pregnancy, puerperium and 
perinatal conditions 

Oligohydramnios Not known 
Renal hypoplasia Not known 
Pulmonary hypoplasia Not known  

Reproductive system and 
breast disorders 

Breast inflammation/mastitis Common 

General disorders and 
administration site 
conditions 

Asthenia Very common 
Chest pain Very common 
Chills Very common 
Fatigue Very common 
Influenza-like symptoms Very common 
Infusion related reaction Very common 
Pain Very common 
Pyrexia Very common 
Mucosal inflammation Very common 
Peripheral oedema Very common 
Malaise Common 

 Oedema Common 
Injury, poisoning and 
procedural complications 

Contusion Common 

+ Denotes adverse reactions that have been reported in association with a fatal outcome. 
1 Denotes adverse reactions that are reported largely in association with administration-related reactions. 
Specific percentages for these are not available. 
* Observed with combination therapy following anthracyclines and combined with taxanes 
 
Description of selected adverse reactions 
 
Cardiac dysfunction 
 
Congestive heart failure (NYHA Class II-IV) is a common adverse reaction to Herceptin. It has been 
associated with a fatal outcome. Signs and symptoms of cardiac dysfunction such as dyspnoea, 
orthopnoea, increased cough, pulmonary oedema, S3 gallop, or reduced ventricular ejection fraction, 
have been observed in patients treated with Herceptin (see section 4.4). 
 
In 3 pivotal EBC clinical trials of adjuvant intravenous Herceptin given in combination with 
chemotherapy, the incidence of grade 3/4 cardiac dysfunction (specifically symptomatic congestive 
heart failure) was similar in patients who were administered chemotherapy alone (ie did not receive 
Herceptin) and in patients who were administered Herceptin sequentially after a taxane (0.3-0.4 %). 
The rate was highest in patients who were administered Herceptin concurrently with a taxane (2.0 %). 
In the neoadjuvant setting, the experience of concurrent administration of Herceptin and low dose 
anthracycline regimen is limited (see section 4.4). 
 
When Herceptin was administered after completion of adjuvant chemotherapy NYHA Class III-IV 
heart failure was observed in 0.6 % of patients in the one-year arm after a median follow-up of 12 
months. In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA 
Class III & IV) in the Herceptin 1 year treatment arm was 0.8 %, and the rate of mild symptomatic and 
asymptomatic left ventricular dysfunction was 4.6 %. 
Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥50 % 
after the event) was evident for 71.4 % of Herceptin-treated patients. Reversibility of mild 



45 

symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5 % of patients. 
Approximately 17 % of cardiac dysfunction related events occurred after completion of Herceptin. 
 
In the pivotal metastatic trials of intravenous Herceptin, the incidence of cardiac dysfunction varied 
between 9 % and 12 % when it was combined with paclitaxel compared with 1 % – 4 % for paclitaxel 
alone. For monotherapy, the rate was 6 % – 9 %. The highest rate of cardiac dysfunction was seen in 
patients receiving Herceptin concurrently with anthracycline/cyclophosphamide (27 %), and was 
significantly higher than for anthracycline/cyclophosphamide alone (7 % – 10 %). In a subsequent trial 
with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2 % in 
patients receiving Herceptin and docetaxel, compared with 0 % in patients receiving docetaxel alone. 
Most of the patients (79 %) who developed cardiac dysfunction in these trials experienced an 
improvement after receiving standard treatment for CHF. 
 
Administration-related reactions/hypersensitivity 
 
Administration-related reactions (ARRs)/hypersensitivity reactions such as chills and/or fever, 
dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory 
distress, rash, nausea, vomiting and headache were seen in Herceptin clinical trials (see section 4.4). 
The rate of ARRs of all grades varied between studies depending on the indication, the data collection 
methodology, and whether trastuzumab was given concurrently with chemotherapy or as 
monotherapy. 
 
Anaphylactoid reactions have been observed in isolated cases. 
 
Haematotoxicity 
 
Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred very 
commonly. The frequency of occurrence of hypoprothrombinemia is not known. The risk of 
neutropenia may be slightly increased when trastuzumab is administered with docetaxel following 
anthracycline therapy. 
 
Pulmonary events 
 
Severe pulmonary adverse reactions occur in association with the use of Herceptin and have been 
associated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acute 
respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute 
pulmonary oedema and respiratory insufficiency (see section 4.4). 
 
Description of selected adverse reactions with the subcutaneous formulation 
 
Administration-related reactions 
 
In the pivotal trial, the rate of all grade ARRs was 37.2 % with the Herceptin intravenous formulation 
and 47.8 % with the Herceptin subcutaneous formulation; severe grade 3 reactions were reported in 
2.0 % and 1.7 % of the patients, respectively during the treatment phase; no severe grade 4 or 5 
reactions were observed. All of the severe ARRs with the Herceptin subcutaneous formulation 
occurred during concurrent administration with chemotherapy. The most frequent severe reaction was 
drug hypersensitivity. 
 
The systemic reactions included hypersensitivity, hypotension, tachycardia, cough, and dyspnoea. The 
local reactions included erythema, pruritus, oedema, rash and pain at the site of the injection. 
 
Infections 
 
The rate of severe infections (NCI CTCAE grade ≥3) was 5.0 % versus 7.1 %, in the Herceptin 
intravenous formulation arm and the Herceptin subcutaneous formulation arm respectively. 
 



46 

The rate of serious infections (most of which were identified because of in-patient hospitalisation or 
prolongation of existing hospitalisation) was 4.4 % in the Herceptin intravenous formulation arm and 
8.1 % in the Herceptin subcutaneous formulation arm. The difference between formulations was 
mainly observed during the adjuvant treatment phase (monotherapy) and was mainly due to 
postoperative wound infections, but also to various other infections such as respiratory tract infections, 
acute pyelonephritis and sepsis. They resolved within a mean of 13 days in the Herceptin intravenous 
treatment arm and a mean of 17 days in the Herceptin subcutaneous treatment arm. 
 
Hypertensive events 
 
In the pivotal trial BO22227, there were more than twice as many patients reporting all grade 
hypertension with the Herceptin subcutaneous  formulation (4.7 % versus 9.8 % in the intravenous and 
subcutaneous formulations respectively), with a greater proportion of patients with severe events (NCI 
CTCAE grade ≥3) <1 % versus 2.0 % the intravenous and subcutaneous formulations respectively. All 
but one patient who reported severe hypertension had a history of hypertension before they entered the 
study. Some of the severe events occurred on the day of the injection. 
 
Immunogenicity 
 
In the neoadjuvant-adjuvant EBC study  (BO22227), at a median follow-up exceeding 70 months, 
10.1% (30/296) of patients treated with Herceptin intravenous and 15.9 % (47/295) of patients 
receiving Herceptin subcutaneous vial developed antibodies against trastuzumab. Neutralizing anti-
trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in the Herceptin 
intravenous arm and 3 of 47 in the Herceptin subcutaneous arm. 21.0 % of patients treated with 
Herceptin subcutaneous formulation developed antibodies against the excipient hyaluronidase 
(rHuPH20).  
 
The clinical relevance of these antibodies is not known.The presence of anti-trastuzumab antibodies 
had no impact on pharmacokinetics, efficacy (determined by pathological Complete Response [pCR] 
and event free survival [EFS]) and safety determined by occurrence of administration related reactions 
(ARRs) of Herceptin intravenous and Herceptin subcutaneous. 
 
Details of risk minimisation measures that are consistent with the EU Risk Management Plan are 
presented in Section 4.4. 
 
Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulation and vice 
versa 
 
Study MO22982 investigated switching between the Herceptin intravenous and Herceptin 
subcutaneous formulation with a primary objective to evaluate patient preference for either the 
intravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one using 
subcutaneous formulation in vial and one using subcutaneous formulation in administration system) 
were investigated using a 2-arm, cross-over design with 488 patients being randomized to one of two 
different three-weekly Herceptin treatment sequences (IV [Cycles 1-4]→ SC [Cycles 5-8], or SC 
[Cycles 1-4]→ IV [Cycles 5-8]). Patients were either naïve to Herceptin IV treatment (20.3%) or pre-
exposed to Herceptin IV (79.7%). For the sequence IV→SC (SC vial and SC formulation in 
administration system cohorts combined), adverse event rates (all grades) were described pre-
switching (Cycles 1-4) and post-switching (Cycles 5-8) as 53.8% vs. 56.4%, respectively; for the 
sequence SC→IV (SC vial and SC formulation in administration system cohorts combined), adverse 
event rates (all grades) were described pre- and post-switching as 65.4% vs. 48.7%, respectively. 
Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatment 
discontinuations due to adverse events were low (<5%) and similar to post-switching rates (Cycles 5-
8). No grade 4 or grade 5 adverse events were reported. 
 



47 

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 
 
Single doses of up to 960 mg of Herceptin subcutaneous formulation have been administered with no 
reported untoward effects. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03 
 
Herceptin subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an 
enzyme used to increase the dispersion and absorption of co-administered drugs when administered 
subcutaneously. 
 
Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal 
growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20% - 30% of primary 
breast cancers. Studies indicate that breast cancer patients whose tumours overexpress HER2 have a 
shortened disease-free survival compared to patients whose tumours do not overexpress HER2. The 
extracellular domain of the receptor (ECD, p105) can be shed into the blood stream and measured in 
serum samples. 
 
Mechanism of action 
 
Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of 
HER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 
signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism 
of HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit 
the proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent 
mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated 
ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared 
with cancer cells that do not overexpress HER2. 
 
Detection of HER2 overexpression or HER2 gene amplification 
 
Detection of HER2 overexpression or HER2 gene amplification in breast cancer 
 
Herceptin should only be used in patients whose tumours have HER2 overexpression or HER2 gene 
amplification as determined by an accurate and validated assay. HER2 overexpression should be 
detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see section 
4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or 
chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Herceptin 
treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive 
FISH or CISH result. 
 
To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, 
which can ensure validation of the testing procedures. 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


48 

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2: 
 
Table 2: Recommended scoring system to evaluate the IHC staining patterns 
 
Score  Staining pattern HER2 overexpression 

assessment 
0 No staining is observed or membrane staining is 

observed in < 10 % of the tumour cells  
Negative 

1+  A faint/barely perceptible membrane staining is 
detected in > 10 % of the tumour cells. The cells are 
only stained in part of their membrane. 

Negative 

2+ A weak to moderate complete membrane staining is 
detected in > 10 % of the tumour cells. 

Equivocal 

3+  Strong complete membrane staining is detected in 
> 10 % of the tumour cells. 

Positive 

 
In general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to 
the chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the 
HER2 gene per tumour cell if no chromosome 17 control is used. 
 
In general, CISH is considered positive if there are more than 5 copies of the HER2 gene per nucleus 
in greater than 50 % of tumour cells. 
 
For full instructions on assay performance and interpretation please refer to the package inserts of 
validated FISH and CISH assays. Official recommendations on HER2 testing may also apply. 
 
For any other method that may be used for the assessment of HER2 protein or gene expression, the 
analyses should only be performed by laboratories that provide adequate state-of-the-art performance 
of validated methods. Such methods must clearly be precise and accurate enough to demonstrate 
overexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) and 
strong (congruent with 3+) overexpression of HER2. 
 
Clinical efficacy and safety 
 
Metastatic breast cancer 
 
Intravenous formulation 
 
Herceptin has been used in clinical trials as monotherapy for patients with MBC who have tumours 
that overexpress HER2 and who have failed one or more chemotherapy regimens for their metastatic 
disease (Herceptin alone). 
 
Herceptin has also been used in combination with paclitaxel or docetaxel for the treatment of patients 
who have not received chemotherapy for their metastatic disease. Patients who had previously 
received anthracycline-based adjuvant chemotherapy were treated with paclitaxel (175 mg/m2 infused 
over 3 hours) with or without Herceptin. In the pivotal trial of docetaxel (100 mg/m2 infused over 
1 hour) with or without Herceptin, 60 % of the patients had received prior anthracycline-based 
adjuvant chemotherapy. Patients were treated with Herceptin until progression of disease. 
 
The efficacy of Herceptin in combination with paclitaxel in patients who did not receive prior adjuvant 
anthracyclines has not been studied. However, Herceptin plus docetaxel was efficacious in patients 
whether or not they had received prior adjuvant anthracyclines. 
 
The test method for HER2 overexpression used to determine eligibility of patients in the pivotal 
Herceptin monotherapy and Herceptin plus paclitaxel clinical trials employed immunohistochemical 
staining for HER2 of fixed material from breast tumours using the murine monoclonal antibodies 
CB11 and 4D5. These tissues were fixed in formalin or Bouin’s fixative. This investigative clinical 



49 

trial assay performed in a central laboratory utilised a 0 to 3+ scale. Patients classified as staining 2+ 
or 3+ were included, while those staining 0 or 1+ were excluded. Greater than 70 % of patients 
enrolled exhibited 3+ overexpression. The data suggest that beneficial effects were greater among 
those patients with higher levels of overexpression of HER2 (3+). 
 
The main test method used to determine HER2 positivity in the pivotal trial of docetaxel, with or 
without Herceptin, was immunohistochemistry. A minority of patients was tested using fluorescence 
in-situ hybridisation (FISH). In this trial, 87 % of patients entered had disease that was IHC3+, and 
95 % of patients entered had disease that was IHC3+ and/or FISH-positive. 
 
Weekly dosing in metatstatic breast cancer 
 
The efficacy results from the monotherapy and combination therapy studies are summarised in Table 
3: 
 
Table 3: Efficacy results from the monotherapy and combination therapy studies 
 
Parameter Monotherapy Combination Therapy 

 Herceptin1 
 
 

N=172 

Herceptin 
plus 

paclitaxel2 
N=68 

Paclitaxel2 
 
 

N=77 

Herceptin 
plus 

docetaxel3 
N=92 

Docetaxel3 
 
 

N=94 
Response rate 
(95 %CI) 

18 % 
(13-25) 

49 % 
(36- 61) 

17 % 
(9-27) 

61 % 
(50-71) 

34 % 
(25-45) 

Median duration of 
response (months) 
(95 %CI) 

9.1 
(5.6-10.3) 

8.3 
(7.3-8.8) 

4.6 
(3.7-7.4) 

11.7 
(9.3–15.0) 

5.7 
(4.6-7.6) 

Median TTP 
(months) (95 %CI) 

3.2 
(2.6-3.5) 

7.1 
(6.2-12.0) 

3.0 
(2.0-4.4) 

11.7 
(9.2-13.5) 

6.1 
(5.4-7.2) 

Median Survival 
(months) (95 %CI) 

16.4 
(12.3-ne) 

24.8 
(18.6-33.7) 

17.9 
(11.2-23.8) 

31.2 
(27.3-40.8) 

22.74 
(19.1-30.8) 

TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached. 
1. Study H0649g: IHC3+ patient subset 
2. Study H0648g: IHC3+ patient subset 
3. Study M77001: Full analysis set (intent-to-treat), 24 months results 
 
Combination treatment with Herceptin and anastrozole 
Herceptin has been studied in combination with anastrozole for first line treatment of MBC in HER2 
overexpressing, hormone-receptor (i.e. estrogen-receptor (ER) and/or progesterone-receptor (PR)) 
positive postmenopausal patients. Progression free survival was doubled in the Herceptin plus 
anastrozole arm compared to anastrozole (4.8 months versus 2.4 months). For the other parameters the 
improvements seen for the combination were for overall response (16.5 % versus 6.7 %); clinical 
benefit rate (42.7 % versus 27.9 %); time to progression (4.8 months versus 2.4 months). For time to 
response and duration of response no difference could be recorded between the arms. The median 
overall survival was extended by 4.6 months for patients in the combination arm. The difference was 
not statistically significant, however more than half of the patients in the anastrozole alone arm 
crossed over to a Herceptin containing regimen after progression of disease. 
 



50 

Three -weekly dosing in metastatic breast cancer 
 
The efficacy results from the non-comparative monotherapy and combination therapy studies are 
summarised in Table 4: 
 
Table 4: Efficacy results from the non-comparative monotherapy and combination therapy studies 
 
Parameter Monotherapy Combination Therapy 

 Herceptin1 
 

N=105 

Herceptin2 
 

N=72 

Herceptin plus 
paclitaxel3 

N=32 

Herceptin plus  
docetaxel4 

N=110 
Response rate 
(95 %CI) 

24 % 
(15-35) 

27 % 
(14-43) 

59 % 
(41-76) 

73 % 
(63-81) 

Median duration of 
response (months) 
(range) 

10.1 
(2.8-35.6) 

7.9 
(2.1-18.8) 

10.5 
(1.8-21) 

13.4 
(2.1-55.1) 

Median TTP 
(months) (95 %CI) 

3.4 
(2.8-4.1) 

7.7 
(4.2-8.3) 

12.2 
(6.2-ne) 

13.6 
(11-16) 

Median Survival 
(months) (95 %CI) 

ne ne ne 
 

47.3 
(32-ne) 

TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached. 
1. Study WO16229: loading dose 8 mg/kg, followed by 6 mg/kg 3 weekly schedule 
2. Study MO16982: loading dose 6 mg/kg weekly x 3; followed by 6 mg/kg 3-weekly schedule 
3. Study BO15935 
4. Study MO16419 
 
Sites of progression 
 
The frequency of progression in the liver was significantly reduced in patients treated with the 
combination of Herceptin and paclitaxel, compared to paclitaxel alone (21.8 % versus 45.7 %; 
p=0.004). More patients treated with Herceptin and paclitaxel progressed in the central nervous system 
than those treated with paclitaxel alone (12.6 % versus 6.5 %; p=0.377). 
 
Early breast cancer (adjuvant setting) 
 
Intravenous formulation 
 
Early breast cancer is defined as non-metastatic primary invasive carcinoma of the breast. 
In the adjuvant treatment setting, Herceptin was investigated in 4 large multicentre, randomised, trials. 
- Study BO16348 was designed to compare one and two years of three-weekly Herceptin 

treatment versus observation in patients with HER2 positive EBC following surgery, established 
chemotherapy and radiotherapy (if applicable). In addition, comparison of two years of 
Herceptin treatment versus one year of Herceptin treatment was performed. Patients assigned to 
receive Herceptin were given an initial loading dose of 8 mg/kg, followed by 6 mg/kg every 
three weeks for either one or two years. 

- Studies NSABP B-31 and NCCTG N9831 that comprise the joint analysis were designed to 
investigate the clinical utility of combining Herceptin treatment with paclitaxel following AC 
chemotherapy, additionally the NCCTG N9831 study also investigated adding Herceptin 
sequentially to AC→P chemotherapy in patients with HER2 positive EBC following surgery. 

- Study BCIRG 006 study was designed to investigate combining Herceptin treatment with 
docetaxel either following AC chemotherapy or in combination with docetaxel and carboplatin 
in patients with HER2 positive EBC following surgery. 

 



51 

Early breast cancer in the BO16348 Study was limited to operable, primary, invasive adenocarcinoma 
of the breast, with axillary nodes positive or axillary nodes negative if tumors at least 1 cm in 
diameter. 
 
In the joint analysis of the NSABP B-31 and NCCTG N9831 studies, EBC was limited to women with 
operable breast cancer at high risk, defined as HER2-positive and axillary lymph node positive or 
HER2 positive and lymph node negative with high risk features (tumor size > 1 cm and ER negative or 
tumor size > 2 cm, regardless of hormonal status). 
 
In the BCIRG 006 study HER2 positive, EBC was defined as either lymph node positive or high risk 
node negative patients with no (pN0) lymph node involvement, and at least 1 of the following factors: 
tumour size greater than 2 cm, estrogen receptor and progesterone receptor negative, histological 
and/or nuclear grade 2-3, or age < 35 years. 
 
The efficacy results from study BO16348 following 12 months* and 8 years** median follow-up are 
summarized in the Table 5: 
 
Table 5: Efficacy results from study BO16348 
 
 Median follow-up 

12 months* 
Median follow-up 

8 years** 
Parameter Observation 

N=1693 
Herceptin 

1 Year 
N = 1693 

Observation 
N= 1697*** 

Herceptin 
1 Year 

N = 1702*** 
Disease-free survival     
- No. patients with event 219 (12.9 %) 127 (7.5 %) 570 (33.6 %) 471 (27.7 %) 
- No. patients without event 1474 (87.1 %) 1566 (92.5 %) 1127 (66.4 %) 1231 (72.3 %) 
P-value versus Observation < 0.0001 < 0.0001 
Hazard Ratio versus Observation 0.54 0.76 
Recurrence-free survival     
- No. patients with event 208 (12.3 %) 113 (6.7 %) 506 (29.8 %) 399 (23.4 %) 
- No. patients without event 1485 (87.7 %) 1580 (93.3 %) 1191 (70.2 %) 1303 (76.6 %) 
P-value versus Observation < 0.0001 < 0.0001 
Hazard Ratio versus Observation 0.51 0.73 
Distant disease-free survival     
- No. patients with event 184 (10.9 %) 99 (5.8 %) 488 (28.8 %) 399 (23.4 %) 
- No. patients without event 1508 (89.1 %) 1594 (94.6 %) 1209 (71.2 %) 1303 (76.6 %) 
P-value versus Observation < 0.0001 < 0.0001 
Hazard Ratio versus Observation 0.50 0.76 
Overall survival (death)     
- No. patients with event 40 (2.4 %) 31 (1.8 %) 350 (20.6 %) 278 (16.3 %) 
- No. patients without event 1653 (97.6 %) 1662 (98.2 %) 1347 (79.4 %) 1424 (83.7 %) 
P-value versus Observation 0.24 0.0005 
Hazard Ratio versus Observation 0.75 0.76 
*Co-primary endpoint of DFS of 1 year versus observation met the pre-defined statistical boundary 
**Final analysis (including crossover of 52 % of patients from the observation arm to Herceptin) 
*** There is a discrepancy in the overall sample size due to a small number of patients who were randomized 
after the cut-off date for the 12-month median follow-up analysis 
 
The efficacy results from the interim efficacy analysis crossed the protocol pre-specified statistical 
boundary for the comparison of 1-year of Herceptin versus observation. After a median follow-up of 
12 months, the hazard ratio (HR) for disease free survival (DFS) was 0.54 (95 % CI 0.44, 0.67) which 
translates into an absolute benefit, in terms of a 2-year disease-free survival rate, of 7.6 percentage 
points (85.8 % versus 78.2 %) in favour of the Herceptin arm. 
 



52 

A final analysis was performed after a median follow-up of 8 years, which showed that 1 year 
Herceptin treatment is associated with a 24 % risk reduction compared to observation only (HR=0.76, 
95 % CI 0.67, 0.86). This translates into an absolute benefit in terms of an 8 year disease free survival 
rate of 6.4 percentage points in favour of 1 year Herceptin treatment.  
 
In this final analysis, extending Herceptin treatment for a duration of two years did not show 
additional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 years 
versus 1 year=0.99 (95 % CI: 0.87, 1.13), p-value=0.90 and OS HR=0.98 (0.83, 1.15); p-value= 0.78]. 
The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm (8.1 % versus 
4.6 % in the 1-year treatment arm). More patients experienced at least one grade 3 or 4 adverse event 
in the 2-year treatment arm (20.4 %) compared with the 1-year treatment arm (16.3 %). 
 
In the NSABP B-31 and NCCTG N9831 studies Herceptin was administered in combination with 
paclitaxel, following AC chemotherapy. 
 

Doxorubicin and cyclophosphamide were administered concurrently as follows: 
 
- intravenous push doxorubicin, at 60 mg/ m2, given every 3 weeks for 4 cycles. 
 

 - intravenous cyclophosphamide, at 600 mg/ m2 over 30 minutes, given every 3 weeks for 4 
  cycles. 

 
Paclitaxel, in combination with Herceptin, was administered as follows: 

 
- intravenous paclitaxel - 80 mg/m2 as a continuous intravenous infusion, given every week 

for 12 weeks. 
or 

- intravenous paclitaxel - 175 mg/m2 as a continuous intravenous infusion, given every 3 
weeks for 4 cycles (day 1 of each cycle). 

 
The efficacy results from the joint analysis of the NSABP B-31 and NCCTG 9831 trials at the time of 
the definitive analysis of DFS* are summarized in Table 6. The median duration of follow up was 1.8 
years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm. 
 
Table 6: Summary of Efficacy results from the joint analysis studies NSABP B-31 and 
NCCTG N9831 at the time of the definitive DFS analysis* 

Parameter 
 

AC→P 
(n=1679) 

AC→PH 
(n=1672) 

Hazard Ratio vs 
AC→P 

(95 % CI) 
p-value 

Disease-free survival 
No. patients with event (%) 

 
261 (15.5) 

 
133 (8.0) 

 
0.48 (0.39, 0.59) 

p<0.0001 
Distant Recurrence 
No. patients with event 

 
193 (11.5) 

 
96 (5.7) 

 
0.47 (0.37, 0.60) 

p<0.0001 
Death (OS event): 
No. patients with event  

 
92 (5.5) 

 
62 (3.7) 

 
0.67 (0.48, 0.92) 

p=0.014** 
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab 
* at median duration of follow up of 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the 
AC→PH arm 
** p value for OS did not cross the pre-specified statistical boundary for comparison of AC→PH vs. AC→P 
 
For the primary endpoint, DFS, the addition of Herceptin to paclitaxel chemotherapy resulted in a 
52 % decrease in the risk of disease recurrence. The hazard ratio translates into an absolute benefit, in 



53 

terms of 3-year disease-free survival rate estimates of 11.8 percentage points (87.2 % versus 75.4 %) 
in favour of the AC→PH (Herceptin) arm. 
At the time of a safety update after a median of 3.5-3.8 years follow up, an analysis of DFS reconfirms 
the magnitude of the benefit shown in the definitive analysis of DFS. Despite the cross-over to 
Herceptin in the control arm, the addition of Herceptin to paclitaxel chemotherapy resulted in a 52 % 
decrease in the risk of disease recurrence. The addition of Herceptin to paclitaxel chemotherapy also 
resulted in a 37 % decrease in the risk of death. 
 
The pre-planned final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG 
N9831 was performed when 707 deaths had occurred (median follow-up 8.3 years in the AC→PH 
group). Treatment with AC→PH resulted in a statistically significant improvement in OS compared 
with ACÆP (stratified HR=0.64; 95% CI [0.55, 0.74]; log-rank p-value < 0.0001).  At 8 years, the 
survival rate was estimated to be 86.9% in the ACÆPH arm and 79.4% in the ACÆP arm, an absolute 
benefit of 7.4% (95% CI 4.9%, 10.0%). 

The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are 
summarized in Table 7: 

Table 7: Final Overall Survival Analysis from the joint analysis of trials NSABP  
B-31 and NCCTG N9831  
 
Parameter 
 

AC→P 
(N=2032) 

AC→PH 
(N=2031) 

p-value versus 
AC→P 

 

Hazard Ratio 
versus 
AC→P 

(95% CI) 
Death (OS event): 
No. patients with event (%) 

 
418 (20.6%) 

 
289 (14.2%) 

 
< 0.0001 

 
0.64 

(0.55, 0.74) 
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab 

DFS analysis was also performed at the final analysis of OS from the joint analysis of studies 
NSABP B-31 and NCCTG N9831. The updated DFS analysis results (stratified HR = 0.61; 95% CI 
[0.54, 0.69]) showed a similar DFS benefit compared to the definitive primary DFS analysis, despite 
24.8% patients in the AC→P arm who crossed over to receive Herceptin. At 8 years, the disease-free 
survival rate was estimated to be 77.2% (95% CI: 75.4, 79.1) in the AC→PH arm, an absolute benefit 
of 11.8% compared with the AC→P arm. 
 
In the BCIRG 006 study Herceptin was administered either in combination with docetaxel, following 
AC chemotherapy (AC→DH) or in combination with docetaxel and carboplatin (DCarbH). 
 
Docetaxel was administered as follows: 

- intravenous docetaxel - 100 mg/m2 as an intravenous infusion over 1 hour, given every 3 
weeks for 4 cycles (day 2 of first docetaxel cycle, then day 1 of each subsequent cycle) 

or  
- intravenous docetaxel - 75 mg/m2 as an intravenous infusion over 1 hour, given every 3 

weeks for 6 cycles (day 2 of cycle 1, then day 1 of each subsequent cycle) 
which was followed by: 

- carboplatin – at target AUC = 6 mg/mL/min administered by intravenous infusion over 30-
60 minutes repeated every 3 weeks for a total of six cycles 

 
Herceptin was administered weekly with chemotherapy and 3 weekly thereafter for a total of 52 
weeks. 
 
The efficacy results from the BCIRG 006 are summarized in Tables 8 and 9. The median duration of 
follow up was 2.9 years in the AC→D arm and 3.0 years in each of the AC→DH and DCarbH arms. 
 



54 

Table 8: Overview of efficacy analyses BCIRG 006 AC→D versus AC→DH 
 

Parameter 
 

AC→D 
(n=1073) 

AC→DH 
(n=1074) 

Hazard Ratio vs 
AC→D 

(95 % CI) 
p-value 

Disease-free survival    
No. patients with event 195 134 0.61 (0.49, 0.77) 

p<0.0001 
Distant recurrence    
No. patients with event 144 95 0.59 (0.46, 0.77) 

p<0.0001 
Death (OS event)    
No. patients with event 80 49 0.58 (0.40, 0.83) 

p=0.0024 

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; AC→DH = doxorubicin plus 
cyclophosphamide, followed by docetaxel plus trastuzumab; CI = confidence interval 
 

Table 9: Overview of efficacy analyses BCIRG 006 AC→D versus DCarbH 
 

Parameter 
 

AC→D 
(n=1073) 

DCarbH 
(n=1074) 

Hazard Ratio vs 
AC→D 

(95 % CI) 
Disease-free survival    
No. patients with event 195 145 0.67 (0.54, 0.83) 

p=0.0003 
Distant recurrence    
No. patients with event 144 103 0.65 (0.50, 0.84) 

p=0.0008 
Death (OS event)    
No. patients with event 80 56 0.66 (0.47, 0.93) 

p=0.0182 

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; DCarbH = docetaxel, 
carboplatin and trastuzumab; CI = confidence interval 
 
In the BCIRG 006 study for the primary endpoint, DFS, the hazard ratio translates into an absolute 
benefit, in terms of 3-year disease-free survival rate estimates of 5.8 percentage points (86.7 % versus 
80.9 %) in favour of the AC→DH (Herceptin) arm and 4.6 percentage points (85.5 % versus 80.9 %) 
in favour of the DCarbH (Herceptin) arm compared to AC→D. 
 
In study BCIRG 006, 213/1075 patients in the DCarbH (TCH) arm, 221/1074 patients in the ACÆDH 
(ACÆTH) arm, and 217/1073 in the AC→D (ACÆT) arm had a Karnofsky performance status ≤90 
(either 80 or 90). No disease-free survival (DFS) benefit was noticed in this subgroup of patients 
(hazard ratio = 1.16, 95 % CI [0.73, 1.83] for DCarbH (TCH) versus ACÆD (ACÆT); hazard ratio 
0.97, 95 % CI [0.60, 1.55] for ACÆDH (ACÆTH) versus ACÆD). 
 



55 

In addition a post-hoc exploratory analysis was performed on the data sets from the joint analysis (JA) 
NSABP B-31/NCCTG N9831* and BCIRG006 clinical studies combining DFS events and 
symptomatic cardiac events and summarised in Table 10: 
 
Table 10: Post-hoc exploratory analysis results from the joint analysis NSABP B-31/NCCTG N9831* 
and BCIRG006 clinical studies combining DFS events and symptomatic cardiac events 
 

 ACÆPH 
(vs. ACÆP) 

(NSABP B-31 and 
NCCTG N9831)* 

 

ACÆDH 
(vs. ACÆD) 
(BCIRG 006) 

DCarbH 
(vs. ACÆD) 
(BCIRG 006) 

Primary efficacy analysis 
DFS Hazard ratios 

(95 % CI) 
p-value 

 
0.48 

(0.39, 0.59) 
p<0.0001 

 
0.61 

(0.49, 0.77) 
p< 0.0001 

 
0.67 

(0.54, 0.83) 
p=0.0003 

Long term follow-up efficacy 
analysis** 

DFS Hazard ratios 
(95 % CI) 

p-value 

 
 

0.61 
(0.54, 0.69) 
p<0.0001 

 
 

0.72 
(0.61, 0.85) 
p<0.0001 

 
 

0.77 
(0.65, 0.90) 
p=0.0011 

Post-hoc exploratory analysis 
with DFS and symptomatic 

cardiac events 
Long term follow-up** 

Hazard ratios 
(95 % CI) 

 
 
 

0.67 
(0.60, 0.75) 

 
 
 

0.77 
(0.66, 0.90) 

 
 
 

0.77 
(0.66, 0.90) 

 
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel; Carb: carboplatin; H: trastuzumab 
CI = confidence interval 
* At the time of the definitive analysis of DFS. Median duration of follow up was 1.8 years in the AC→P arm 
and 2.0 years in the AC→PH arm 
** Median duration of long term follow-up for the Joint Analysis clinical studies was 8.3 years (range: 0.1 to 
12.1) for the AC→PH arm and 7.9 years (range: 0.0 to 12.2) for the AC→P arm;  Median duration of long term 
follow-up for the BCIRG 006 study was 10.3 years in both the AC→D arm (range: 0.0 to 12.6) and the DCarbH 
arm (range: 0.0 to 13.1), and was 10.4 years (range: 0.0 to 12.7) in the AC→DH arm 
 
Early breast cancer – (neoadjuvant-adjuvant setting) 
 
Intravenous formulation 
 
So far, no results are available which compare the efficacy of Herceptin administered with 
chemotherapy in the adjuvant setting with that obtained in the neo-adjuvant/adjuvant setting. 
 
In the neoadjuvant-adjuvant treatment setting, study MO16432, a multicentre randomised trial, was 
designed to investigate the clinical efficacy of concurrent administration of Herceptin with 
neoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant 
Herceptin, up to a total treatment duration of 1 year. The study recruited patients with newly 
diagnosed locally advanced (Stage III) or inflammatory EBC. Patients with HER2+ tumours were 
randomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant 
Herceptin, or neoadjuvant chemotherapy alone. 
 



56 

In study MO16432, Herceptin (8 mg/kg loading dose, followed by 6 mg/kg maintenance every 3 
weeks) was administered concurrently with 10 cycles of neoadjuvant chemotherapy 
 
as follows: 
 

- Doxorubicin 60mg/m2 and paclitaxel 150 mg/m2, administered 3-weekly for 3 cycles, 
 

which was followed by 
- Paclitaxel 175 mg/m2 administered 3-weekly for 4 cycles, 

 
which was followed by 

- CMF on day 1 and 8 every 4 weeks for 3 cycles 
 

which was followed after surgery by 
- additional cycles of adjuvant Herceptin (to complete 1 year of treatment) 

 
The efficacy results from Study MO16432 are summarized in Table 11. The median duration of 
follow-up in the Herceptin arm was 3.8 years. 
 
Table 11: Efficacy results from MO16432 
 

Parameter 
 

Chemo + 
Herceptin 
(n=115) 

Chemo only 
(n=116) 

 

Event-free survival   Hazard Ratio 
(95 % CI) 

No. patients with event 46 59 0.65 (0.44, 0.96) 
p=0.0275 

Total pathological complete 
response* (95 % CI) 

40 % 
(31.0, 49.6) 

20.7 % 
(13.7, 29.2) 

P=0.0014 

Overall survival   Hazard Ratio 
(95 % CI) 

No. patients with event 22 33 0.59 (0.35, 1.02) 
p=0.0555 

* defined as absence of any invasive cancer both in the breast and axillary nodes 
 
An absolute benefit of 13 percentage points in favour of the Herceptin arm was estimated in terms of 
3-year event-free survival rate (65 % versus. 52 %). 
 
Subcutaneous formulation 
 
Study BO22227 was designed to demonstrate non-inferiority of treatment with Herceptin 
subcutaneous formulation versus Herceptin intravenous formulation based on co-primary PK and 
efficacy endpoints (trastuzumab Ctrough at pre-dose Cycle 8, and pCR rate at definitive surgery, 
respectively). A total of 595 patients with HER2-positive, operable or locally advanced breast cancer 
(LABC) including inflammatory breast cancer received eight cycles of either Herceptin intravenous 
formulation or Herceptin subcutaneous formulation concurrently with chemotherapy (4 cycles of 
docetaxel, 75 mg/m2 intravenous infusion, followed by 4 cycles of FEC ([5-Fluorouracil, 500 mg/m2; 
epirubicin, 75 mg/m2; cyclophosphamide, 500 mg/m2 each intravenous bolus or infusion]), followed 
by surgery, and continued therapy with Herceptin intravenous formulation or Herceptin subcutaneous 
formulation as originally randomized for 10 additional cycles, for a total of one year of treatment. 
 
The analysis of the efficacy co-primary endpoint, pCR, defined as absence of invasive neoplastic cells 
in the breast, resulted in rates of 40.7 % (95 % CI: 34.7, 46.9) in the Herceptin intravenous arm and 
45.4 % (95 % CI: 39.2 %, 51.7 %) in the Herceptin subcutaneous arm, a difference of 4.7 percentage 
points in favour of the Herceptin subcutaneous arm. The lower boundary of the one-sided 97.5 % 



57 

confidence interval for the difference in pCR rates was -4.0, establishing the non-inferiority of 
Herceptin subcutaneous for the co-primary endpoint  
 
Table 12: Summary of pathological Complete Response (pCR)  

 Herceptin IV    
 (N = 263) 

Herceptin SC 
(N=260) 

pCR (absence ofinvasive neoplastic cells in breast 107 (40.7%) 118 (45.4%) 
     Non-responders 156 (59.3%) 142 (54.6%) 

Exact 95% CI for pCR Rate*   (34.7; 46.9) (39.2; 51.7) 
Difference in pCR (SC minus IV arm) 4.70 
Lower bound one-sided 97.5% CI for the 
difference in pCR** 

-4.0 

*Confidence interval for one sample binomial using Pearson-Clopper method 
**Continuity correction of Anderson and Hauck (1986) has been used in this calculation 
 
Analyses with longer term follow-up of a median duration exceeding 40 months supported the non-
inferior efficacy of Herceptin subcutaneous compared to Herceptin intravenous with comparable 
results of both EFS and OS (3-year EFS rates of 73% in the Herceptin intravenous arm and 76% in the 
Herceptin subcutaneous arm, and 3-year OS rates of 90% in the Herceptin intravenous arm and 92% in 
the Herceptin subcutaneous arm).  
 
For non-inferiority of the PK co-primary endpoint, steady-state trastuzumab Ctrough value at the end of 
treatment Cycle 7, refer to section 5.2. Pharmacokinetic Properties. For the comparative safety profile 
see section 4.8. 
 
The final analysis at a median follow-up exceeding 70 months showed similar EFS and OS between 
patients who received Herceptin IV and those who received Herceptin SC. The 6-year EFS rate was 
65% in both arms (ITT population: HR=0.98 [95% CI: 0.74;1.29]) and the OS rate, 84% in both arms 
(ITT population: HR=0.94 [95% CI: 0.61;1.45]). 

 
Study MO28048 investigating the safety and tolerability of Herceptin subcutaneous formulation as 
adjuvant therapy in HER2 positive EBC patients who were enrolled in either a Herceptin subcutaneous 
vial cohort (N=1868 patients, including 20 patients receiving neoadjuvant therapy) or a Herceptin 
subcutaneous administration system cohort (N=710 patients, including 21 patients receiving 
neoadjuvant therapy) resulted in no new safety signals. Results were consistent with the known safety 
profile for Herceptin intravenous and Herceptin subcutaneous formulations. In addition, treatment of 
lower body weight patients with Herceptin subcutaneous fixed dose in adjuvant EBC was not 
associated with increased safety risk, adverse events and serious adverse events, compared to the 
higher body weight patients. The final results of study BO22227 at a median follow-up exceeding 70 
months were also consistent with the known safety profile for Herceptin IV and Herceptin SC, and no 
new safety signals were observed. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Herceptin in all subsets of the paediatric population for breast cancer (see section 4.2 for information 
on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of trastuzumab at a dose of 600 mg administered three-weekly by the 
subcutaneous route was compared to the intravenous route (8 mg/kg loading dose, 6 mg/kg 
maintenance every three weeks) in the phase III study BO22227. The pharmacokinetic results for the 
co primary endpoint, Ctrough pre dose Cycle 8, showed non-inferiority of the Herceptin subcutaneous 
compared to the Herceptin intravenous dose adjusted by body weight.  



58 

 
The mean Ctrough during the neoadjuvant treatment phase, at the pre dose Cycle 8 time point, was 
higher in the Herceptin subcutaneous arm (78.7 µg/mL) than the Herceptin intravenous arm 
(57.8 µg/mL) of the study. During the adjuvant phase of treatment, at the pre-dose Cycle 13 time 
point, the mean Ctrough values were 90.4 µg/mL and 62.1 µg/mL, respectively. Based on the observed 
data in study BO22227, steady state with the intravenous formulation was reached at cycle 8. With 
Herceptin subcutaneous formulation, concentrations were approximately at steady-state following 
Cycle 7 dose (pre-dose Cycle 8) with small increase in concentration (<15%) up to cycle 13. The mean 
Ctrough at the subcutaneous pre- dose cycle 18 was 90.7 µg/mL and is similar to that of cycle 13, 
suggesting no further increase after cycle 13. 
 
The median Tmax following subcutaneous administration was approximately 3 days, with high 
interindividual variability (range 1-14 days). The mean Cmax was expectedly lower in the Herceptin 
subcutaneous formulation (149 μg/mL) than in the intravenous arm (end of infusion value: 221 
μg/mL). 
 
The mean AUC0-21 days following the Cycle 7 dose was approximately 10 % higher with the Herceptin 
subcutaneous formulation as compared to the Herceptin intravenous formulation, with mean AUC 
values of 2268 µg/mL•day and 2056 µg/mL•day, respectively. The AUC0-21 days following Cycle 12 
dose was approximately 20 % higher with the Herceptin subcutaneous formulation than the Herceptin 
intravenous dose, with mean AUC values of 2610 µg/mL•day and 2179 µg/mL•day, respectively. Due 
to the significant impact of body weight on trastuzumab clearance and the use of a fixed dose for the 
subcutaneous administration the difference in exposure between subcutaneous and intravenous 
administration was dependent on body weight: in patients with a body weight < 51 kg, mean steady 
state AUC of trastuzumab was about 80% higher after subcutaneous than after intravenous treatment 
whereas in the highest BW group (> 90 kg) AUC was 20% lower after subcutaneous than after 
intravenous treatment. 
 
A population PK model with parallel linear and nonlinear elimination from the central compartment 
was constructed using pooled Herceptin SC and Herceptin IV PK data from the phase III study 
BO22227 to describe the observed PK concentrations following Herceptin IV and Herceptin SC 
administration in EBC patients. Bioavailability of trastuzumab given as the subcutaneous formulation 
was estimated to be 77.1%, and the first order absorption rate constant was estimated to be 0.4 day-1. 
Linear clearance was 0.111 L/day and the central compartment volume (Vc) was 2.91 L. The 
Michaelis-Menten parameter values were 11.9 mg/day and 33.9 µg/mL for Vmax and Km, respectively. 
Body weight and serum alanine aminotransferase (SGPT/ALT) showed a statistically significant 
influence on PK, however, simulations demonstrated that no dose adjustments are required in EBC 
patients. The population predicted PK exposure parameter values (median with 5th - 95th Percentiles) 
for Herceptin SC dosing regimens in EBC patients are shown in Table 13 below. 
 
Table 13 Population Predicted PK Exposure Values (median with 5th - 95th Percentiles) for the 
Herceptin SC 600 mg Q3W Dosing Regimen in EBC patients 
 

Primary tumor 
type and 
Regimen 

Cycle N 
Cmin 

(µg/mL) 
Cmax 

(µg/mL) 
AUC0-21days 

(µg.day/mL) 

EBC 600 mg 
Herceptin SC q3w 

Cycle 1 297 
28.2 

(14.8 - 40.9) 
79.3 

(56.1 - 109) 
1065 

(718 - 1504) 

Cycle 7 
(steady 
state) 

297 
75.0 

(35.1 - 123) 
149 

(86.1 - 214) 
2337 

(1258 - 3478) 

 



59 

Trastuzumab washout 
 
Trastuzumab washout period was assessed following subcutaneous administration using the 
population PK model. The results of these simulations indicate that at least 95% of patients will reach 
concentrations that are <1 μg/mL (approximately 3% of the population predicted Cmin,ss, or about 97% 
washout) by 7 months. 
 
5.3 Preclinical safety data 
 
Herceptin Intravenous  
 
There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, or 
reproductive toxicity in teratology, female fertility or late gestational toxicity/placental transfer 
studies. Herceptin is not genotoxic. A study of trehalose, a major formulation excipient did not reveal 
any toxicities. 
 
No long-term animal studies have been performed to establish the carcinogenic potential of Herceptin, 
or to determine its effects on fertility in males. 
 
Herceptin Subcutaneous  
 
A single dose study in rabbits and a 13-week repeat dose toxicity study in Cynomolgus monkeys were 
conducted. The rabbit study was performed to specifically examine local tolerance aspects. The 13-
week study was performed to confirm that the change in route of administration and the use of the 
novel excipient recombinant human hyaluronidase (rHuPH20) did not have an effect on the Herceptin 
safety characteristics. Herceptin subcutaneous formulation was locally and systemically well tolerated. 
 
Hyaluronidase is found in most tissues of the human body. Non-clinical data for recombinant human 
hyaluronidase reveal no special hazard for humans based on conventional studies of repeated dose 
toxicity including safety pharmacology endpoints.  Reproductive toxicology studies with rHuPH20 
revealed embryofetal toxicity in mice at high systemic exposure, but did not show teratogenic 
potential. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Recombinant human hyaluronidase (rHuPH20) 
L-histidine 
L-histidine hydrochloride monohydrate 
α,α-trehalose dihydrate 
L-methionine 
Polysorbate 20 
Water for injections 
 
6.2 Incompatibilities 
 
Herceptin subcutaneous formulation is a ready to use solution which should not be mixed or diluted 
with other products. 
 
No incompatibilities between Herceptin subcutaneous formulation and polypropylene or 
polycarbonate syringe material or stainless steel transfer and injection needles and polyethylene Luer 
cone stoppers have been observed. 

 



60 

6.3 Shelf life 
 
21 months. 
 
Once transferred from the vial to the syringe the medicinal product is physically and chemically stable 
for 28 days at 2°C – 8°C and for 6 hours (cumulative time in the vial and the syringe) at ambient 
temperature (max. 30°C) in diffused daylight. 
As Herceptin does not contain any antimicrobial-preservative, from a microbiological point of view, 
the medicine should be used immediately.  
 
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. 
Once removed from the refrigerator Herceptin subcutaneous formulation must be administered within 
6 hours and should not be kept above 30°C.  
 
For storage conditions of the opened medicinal product, see section 6.3 and 6.6. 
 
6.5 Nature and contents of container 
 
One 6 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film 
containing 5 mL of solution (600 mg of trastuzumab). 
 
Each carton contains one vial. 
 
6.6 Special precautions for disposal and other handling 
 
Herceptin should be inspected visually to ensure there is no particulate matter or discolouration prior 
to administration. 
 
Herceptin is for single-use only. 
 
As Herceptin does not contain any antimicrobial-preservative, from a microbiological point of view, 
the medicine should be used immediately. If not used immediately, preparation should take place in 
controlled and validated aseptic conditions. After transfer of the solution to the syringe, it is 
recommended to replace the transfer needle by a syringe closing cap to avoid drying of the solution in 
the needle and not compromise the quality of the medicinal product. The hypodermic injection needle 
must be attached to the syringe immediately prior to administration followed by volume adjustment to 
5 mL.  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 



61 

8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/145/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 28 August 2000 
Date of latest renewal: 28 August 2010 
 
 
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. 
 
  



62 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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   

 



63 

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) 
 
Roche Diagnostics GmbH 
Pharma Biotech Penzberg 
Nonnenwald 2 
D-82377 Penzberg 
Germany 
 
Genentech Inc. 
1000 New Horizons Way 
Vacaville, CA 95688 
USA 
 
Roche Singapore Technical Operations Pte. Ltd. 
10 Tuas Bay Link 
637394 Singapore 
Singapore 
 
Lonza Biologics Tuas Pte Ltd 
35 Tuas South Ave. 6 
637377 Singapore  
Singapore 
 
Lonza Portsmouth 
101 International Dr. 
Portsmouth, NH 03801 
USA 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
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 
 
The requirements for submission of periodic safety update reports 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. 
 
 



64 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT   

 
∑ Risk Management Plan (RMP) 
 
The MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as 
agreed in the 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. 

  



65 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
  



66 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



67 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON  

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Herceptin 150 mg powder for concentrate for solution for infusion 
 
Trastuzumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
The vial contains 150 mg trastuzumab. After reconstitution 1 ml concentrate contains 21 mg of 
trastuzumab 
 
 
3. LIST OF EXCIPIENTS 
 
L-histidine hydrochloride monohydrate, L-histidine, polysorbate 20, a,a-trehalose dihydrate. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use only after reconstitution and dilution 
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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2ºC – 8ºC). 
 
 



68 

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 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1//00/145/001 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
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  
 
  



69 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Herceptin 150 mg powder for concentrate 
Trastuzumab 
For intravenous use only 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 

  



70 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Herceptin 600 mg solution for injection in vial 
Trastuzumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 600 mg/5 mL trastuzumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Recombinant human hyaluronidase (rHuPH20) 
L-histidine 
L-histidine hydrochloride monohydrate 
α,α-trehalose dihydrate 
L-methionine 
Polysorbate 20 
Water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use only. 
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 
 
 



71 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2ºC – 8ºC). 
Keep the vial in the outer carton in order to protect from light. 
Do not freeze. 
 
 
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 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/145/002 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
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  
.  



72 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Herceptin 600 mg solution for injection 
Trastuzumab 
For subcutaneous use only 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
600 mg/5 ml 
 
 
6. OTHER 
 
  



73 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



74 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Herceptin 150 mg powder for concentrate for solution for infusion 
Trastuzumab 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
∑ Keep this leaflet. You may need to read it again. 
∑ If you have any further questions, ask your doctor or pharmacist. 
∑ If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.  
 
In this leaflet:  
1. What Herceptin is and what it is used for 
2. What you need to know before you are given Herceptin 
3. How Herceptin is given 
4. Possible side effects 
5. How to store Herceptin 
6. Contents of the pack and other information 
 
 
1. What Herceptin is and what it is used for  
 
Herceptin contains the active substance trastuzumab, which is a monoclonal antibody. Monoclonal 
antibodies attach to specific proteins or antigens. Trastuzumab is designed to bind selectively to an 
antigen called human epidermal growth factor receptor 2 (HER2).  HER2 is found in large amounts on 
the surface of some cancer cells where it stimulates their growth.  When Herceptin binds to HER2 it 
stops the growth of such cells and causes them to die.  
 
Your doctor may prescribe Herceptin for the treatment of breast and gastric cancer when: 
∑ You have early breast cancer, with high levels of a protein called HER2. 
∑ You have metastatic breast cancer (breast cancer that has spread beyond the original tumour) 

with high levels of HER2. Herceptin may be prescribed in combination with the chemotherapy 
medicine paclitaxel or docetaxel as first treatment for metastatic breast cancer or it may be 
prescribed alone if other treatments have proved unsuccessful. It is also used in combination 
with medicines called aromatase inhibitors with patients with high levels of HER2 and hormone 
receptor-positive metastatic breast cancer (cancer that is sensitive to the presence of female sex 
hormones). 

∑ You have metastatic gastric cancer with high levels of HER2, when it is in combination with 
the other cancer medicines capecitabine or 5-flououracil and cisplatin. 

 
 
2. What you need to know before you are given Herceptin  
 
Do not use Herceptin if: 
∑ you are allergic to trastuzumab, to murine (mouse) proteins, or to any of the other ingredients of 

this medicine (listed in section 6). 
∑ you have severe breathing problems at rest due to your cancer or if you need oxygen treatment. 
 
Warnings and precautions 
 
Your doctor will closely supervise your therapy.  
 



75 

Heart checks 
Treatment with Herceptin alone or with a taxane may affect the heart, especially if you have ever used 
an anthracycline (taxanes and anthracyclines are two other kinds of medicine used to treat cancer).  
The effects may be moderate to severe and could cause death. Therefore, your heart function will be 
checked before, during (every three months) and after (up to two to five years) treatment with 
Herceptin. If you develop any signs of heart failure (inadequate pumping of blood by the heart), your 
heart function may be checked more frequently (every six to eight weeks), you may receive treatment 
for heart failure or you may have to stop Herceptin treatment. 
 
Talk to your doctor, pharmacist or nurse before you are given Herceptin if: 
 
∑ you have had heart failure, coronary artery disease, heart valve disease (heart murmurs), high 

blood pressure, taken any high blood pressure medicine or are currently taking any high blood 
pressure medicine.  

 
∑ you have ever had or are currently using a medicine called doxorubicin or epirubicin (medicines 
 used to treat cancer).  These medicines (or any other anthracyclines) can damage heart muscle 
 and increase the risk of heart problems with Herceptin. 
 
∑ you suffer from breathlessness., especially if you are currently using a taxane. Herceptin can 

cause breathing difficulties, especially when it is first given. This could be more serious if you 
are already breathless. Very rarely, patients with severe breathing difficulties before treatment 
have died when they were given Herceptin. 

 
∑ you have ever had any other treatment for cancer. 
 
If you receive Herceptin with any other medicine to treat cancer, such as paclitaxel, docetaxel, an 
aromatase inhibitor, capecitabine, 5-fluorouracil, or cisplatin you should also read the patient 
information leaflets for these products.  
 
Children and adolescents 
Herceptin is not recommended for anyone under the age of 18 years. 
 
Other medicines and Herceptin 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or may take any other 
medicines. 
 
It may take up to 7 months for Herceptin to be removed from the body. Therefore you should tell your 
doctor, pharmacist or nurse that you have had Herceptin if you start any new medicine in the 7 months 
after stopping treatment. 
 
Pregnancy  

∑ If you are pregnant, think you may be pregnant or are planning to have a baby, ask your 
doctor, pharmacist or nurse for advice before taking this medicine.  

∑ You should use effective contraception during treatment with Herceptin and for at least 
7 months after treatment has ended.   

∑ Your doctor will advise you of the risks and benefits of taking Herceptin during pregnancy. In 
rare cases, a reduction in the amount of (amniotic) fluid that surrounds the developing baby 
within the womb has been observed in pregnant women receiving Herceptin. This condition 
may be harmful to your baby in the womb and has been associated with the lungs not 
developing fully resulting in foetal death.  

 
Breast-feeding 
Do not breast-feed your baby during Herceptin therapy and for 7 months after the last dose of 
Herceptin as Herceptin may pass to your baby through your breast milk. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 



76 

 
Driving and using machines 
Herceptin may affect your ability to drive a car or operate machines.If during treatment you experience 
symptoms, such as dizziness, sleepiness, chills or fever, you should not drive or use machines until 
these symptoms disappear. 
 
Sodium  
Herceptin contains less than 1 mmol of sodium per dose, i.e. it is essentially sodium-free. 
 
 
3. How Herceptin is given 
 
Before starting the treatment your doctor will determine the amount of HER2 in your tumour. Only 
patients with a large amount of HER2 will be treated with Herceptin. Herceptin should only be given 
by a doctor or nurse. Your doctor will prescribe a dose and treatment regimen that is right for you. The 
dose of Herceptin depends on your body weight.  
 
Two different types (formulations) of Herceptin exist: 
• one is given as an infusion into a vein (intravenous infusion) 
• the other is given as an injection under the skin (subcutaneous injection).  
It is important to check the product labels to ensure that the correct formulation is being given as 
prescribed. Herceptin intravenous formulation is not for subcutaneous use and should be given as an 
intravenous infusion only. 
Your doctor may consider switching your Herceptin intravenous treatment to Herceptin subcutaneous 
treatment (and vice versa) if considered appropriate for you. 
 
Herceptin intravenous formulation is given as an intravenous infusion (“drip”) directly into your veins. 
The first dose of your treatment is given over 90 minutes and you will be observed by a health 
professional while it is being given in case you have any side effects. If the first dose is well tolerated 
the next doses may be given over 30 minutes (see section 2 under “Warnings and precautions”). The 
number of infusions you receive will depend on how you respond to the treatment. Your doctor will 
discuss this with you. 
 
In order to prevent medication errors it is important to check the vial labels to ensure that the medicine 
being prepared and given is Herceptin (trastuzumab) and not trastuzumab emtansine. 
 
For early breast cancer, metastatic breast cancer and metastatic gastric cancer, Herceptin is given 
every 3 weeks. Herceptin may also be given once a week for metastatic breast cancer.  
 
If you stop using Herceptin 
Do not stop using this medicine without talking to your doctor first. All doses should be taken at the 
right time every week or every three weeks (depending on your dosing schedule). This helps your 
medicine work as well as it can. 
 
It may take up to 7 months for Herceptin to be removed from your body. Therefore your doctor may 
decide to continue to check your heart functions, even after you finish treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, Herceptin can cause side effects, although not everybody gets them. Some of these 
side effects may be serious and may lead to hospitalisation. 
 
During a Herceptin infusion, chills, fever and other flu like symptoms may occur. These are very 
common (may affect more than 1 in 10 people). Other infusion-related symptoms are: feeling sick 



77 

(nausea), vomiting, pain, increased muscle tension and shaking, headache, dizziness, breathing 
difficulties, high or low blood pressure, heart rhythm disturbances (palpitations, heart fluttering or 
irregular heart beat), swelling of the face and lips, rash and feeling tired. Some of these symptoms can 
be serious and some patients have died (see section 2 under “Warnings and precautions”). 
 
These effects mainly occur with the first intravenous infusion (“drip” into your vein) and during the 
first few hours after the start of the infusion. They are usually temporary. You will be observed by a 
health care professional during the infusion and for at least six hours after the start of the first infusion 
and for two hours after the start of other infusions. If you develop a reaction, they will slow down or 
stop the infusion and may give you treatment to counteract the side effects. The infusion may be 
continued after the symptoms improve. 
 
Occasionally, symptoms start later than six hours after the infusion begins. If this happens to you, 
contact your doctor immediately. Sometimes, symptoms may improve and then get worse later. 
 
Serious side effects 
Other side effects can occur at any time during treatment with Herceptin, not just related to an 
infusion. Tell a doctor or nurse straight away, if you notice any of the following side effects:  
 
∑ Heart problems can sometimes occur during treatment and occasionally after treatment has 

stopped and can be serious. They include weakening of the heart muscle possibly leading to heart 
failure, inflammation of the lining around the heart and heart rhythm disturbances. This can lead to 
symptoms such as breathlessness (including breathlessness at night), cough, fluid retention 
(swelling) in the legs or arms, palpitations (heart fluttering or irregular heart beat) (see section 2. 
Heart checks).  
 
Your doctor will monitor your heart regularly during and after treatment but you should tell your 
doctor immediately if you notice any of the above symptoms. 
 

∑ Tumour lysis syndrome (a group of metabolic complications occurring after cancer treatment 
characterized by high blood levels of potassium and phosphate, and low blood levels of calcium). 
Symptoms may include kidney problems (weakness, shortness of breath, fatigue and confusion), 
heart problems (fluttering of the heart or a faster or slower heartbeat), seizures, vomiting or 
diarrhoea and tingling in the mouth, hands or feet 

 
If you experience any of the above symptoms when your treatment with Herceptin has finished, you 
should see your doctor and tell them that you have previously been treated with Herceptin. 
 
Very common side effects of Herceptin: may affect more than 1 in 10 people 
 
∑ infections  
∑ diarrhoea  
∑ constipation 
∑ heartburn (dyspepsia) 
∑ fatigue 
∑ skin rashes  
∑ chest pain  
∑ abdominal pain 
∑ joint pain 
∑ low counts of red blood cells and white blood cells (which help fight infection) sometimes with 

fever  
∑ muscle pain 
∑ conjunctivitis 
∑ watery eyes 
∑ nose bleeds 
∑ runny nose 



78 

∑ hair loss 
∑ tremor 
∑ hot flush 
∑ dizziness 
∑ nail disorders 
∑ weight loss  
∑ loss of appetite 
∑ inability to sleep (insomnia) 
∑ altered taste 
∑ low platelet count 
∑  bruising 
∑ numbness or tingling of the fingers and toes  
∑ redness, swelling or sores in your mouth and/or throat 
∑ pain, swelling, redness or tingling of hands and/or feet 
∑ breathlessness 
∑ headache 
∑ cough 
∑ vomiting 
∑ nausea 
 
Common side effects of Herceptin: may affect up to 1 in 10 people 
 
∑ allergic reactions ∑ dry mouth and skin 
∑ throat infections ∑ dry eyes 
∑ bladder and skin infections ∑ sweating 
∑  ∑ feeling weak and unwell 
∑ inflammation of the breast ∑ anxiety 
∑ inflammation of the liver ∑ depression 
∑ kidney disorders  
∑ increased muscle tone or tension 

(hypertonia) 
∑ asthma 
∑ infection of lungs 

∑ pain in the arms and/or legs ∑ lung disorders 
∑ itchy rash ∑ back pain 
∑ sleepiness (somnolence) ∑ neck pain 
∑ haemorrhoids ∑ bone pain 
∑ itchiness ∑ acne 

∑ leg cramps 
  

  
Uncommon side effects of Herceptin: may affect up to 1 in 100 people:  
 
∑ deafness 
∑ bumpy rash∑ wheezing 
∑  inflammation or scarring of the lungs 
 
 
Rare side effects of Herceptin: may affect up to 1 in 1000 people 
 
 
∑ jaundice 
 
∑  anaphylactic reactions 
 



79 

Other side effects that have been reported with Herceptin use:  frequency cannot be estimated 
from the available data 
 
∑ abnormal or impaired blood clotting 
 
∑ high potassium levels 
∑ swelling or bleeding at the back of the eyes 
∑ shock  
∑ abnormal heart rhythm 
∑ respiratory distress 
∑ respiratory failure 
∑ acute accumulation of fluid in the lungs 
∑ acute narrowing of the airways 
∑ abnormally low oxygen levels in the blood 
∑ difficulty in breathing when lying flat 
∑ liver damage 
∑ swelling of the face, lips and throat 
∑ kidney failure 
∑ abnormally low levels of fluid around baby in womb 
∑ failure of the lungs of the baby to develop in the womb  
∑ abnormal development of the kidneys of the baby in the womb  
 
Some of the side-effects you experience may be due to your underlying cancer. If you receive 
Herceptin in combination with chemotherapy, some of them may also be due to the chemotherapy.  
 
If you get any side effects, talk to your doctor, pharmacist or nurse.  
 
Reporting of side effects  
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Herceptin 
 
Herceptin will be stored by the health professionals at the hospital or clinic. 
 

∑ Keep this medicine out of the sight and reach of children. 
∑ Do not use this medicine after the expiry date which is stated on the outer carton and on the 

vial label after EXP. The expiry date refers to the last day of that month. 
∑ The unopened vial should be stored in a refrigerator (2°C – 8°C).  
∑ Do not freeze the reconstituted solution. 
∑ Infusion solutions should be used immediately after dilution. If not used immediately, in-use 

storage times and conditions prior to use are the responsibility of the user, and would not 
normally be longer than 24 hours at 2°C – 8°C. 

∑ Do not use Herceptin if you notice any particulate matter or discoloration prior to 
administration. 

∑ Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist 
how to dispose of medicines no longer required. These measures will help to protect the 
environment. 

 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


80 

6. Contents of the pack and other information 
 
What Herceptin contains 
 
∑ The active substance is trastuzumab. Each vial contains 150 mg trastuzumab that has to be 

dissolved in 7.2 mL of water for injection. The resulting solution contains approximately 
21 mg/mL trastuzumab. 

 
∑ The other ingredient(s) are L-histidine hydrochloride monohydrate, L-histidine, α,α-trehalose 

dihydrate, polysorbate 20.  
 
What Herceptin looks like and contents of the pack 
 
Herceptin is a powder for concentrate for solution for intravenous infusion, which is supplied in 
a glass vial with a rubber stopper containing 150 mg of trastuzumab. The powder is a white to pale 
yellow pellet. Each carton contains 1 vial of powder. 
 
Marketing Authorisation Holder 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
Roche Pharma AG 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen  
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Danmark 
Roche a/s 
Tlf: +45 - 36 39 99 99 
 

Malta 
(See United Kingdom) 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 



81 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

France 
Roche 
Tél: +33 (0)1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o. 
Tel: + 385 1 47 22 333 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 

Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 67 039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



82 

This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 
The following information is intended for medical or healthcare professionals only 
 
Herceptin IV is provided in sterile, preservative-free, non-pyrogenic, single use vials. 
 
Always keep this medicine in the closed original pack at a temperature of 2ºC – 8 ºC in a refrigerator.  
 
Appropriate aseptic technique should be used for reconstitution and dilution procedures. Care must be 
taken to ensure the sterility of prepared solutions. Since the medicinal product does not contain any 
anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed.  
 
A vial of Herceptin aseptically reconstituted with sterile water for injections (not supplied) is 
chemically and physically stable for 48 hours at 2ºC – 8 ºC after reconstitution and must not be frozen.  
 
After aseptic dilution in polyvinylchloride, polyethylene or polypropylene bags containing sodium 
chloride 9 mg/mL (0.9 %) solution for injection, chemical and physical stability of Herceptin has been 
demonstrated for up to 30 days at 2 oC – 8oC, and 24 hours at temperatures not exceeding 30°C. 
 
From a microbiological point of view, the reconstituted solution and Herceptin infusion solution 
should be used immediately. If not used immediately, in-use storage times and conditions prior to use 
are the responsibility of the user, and would not normally be longer than 24 hours at 2°C to 8°C, 
unless reconstitution and dilution have taken place under controlled and validated aseptic conditions. 
 
Aseptic preparation, handling and storage:  
 
Aseptic handling must be ensured when preparing the infusion. Preparation should be:  

∑ performed under aseptic conditions by trained personnel in accordance with good practice 
rules especially with respect to the aseptic preparation of parenteral products.  

∑ prepared in a laminar flow hood or biological safety cabinet using standard precautions for the 
safe handling of intravenous agents. 

∑ followed by adequate storage of the prepared solution for intravenous infusion to ensure 
maintenance of the aseptic conditions 

 
Each vial of Herceptin is reconstituted with 7.2 mL of water for injections (not supplied). Use of other 
reconstitution solvents should be avoided. This yields a 7.4 mL solution for single-dose use, 
containing approximately 21 mg/mL trastuzumab. A volume overage of 4 % ensures that the labelled 
dose of 150 mg can be withdrawn from each vial.  
 
Herceptin should be carefully handled during reconstitution. Causing excessive foaming during 
reconstitution or shaking the reconstituted Herceptin may result in problems with the amount of 
Herceptin that can be withdrawn from the vial.  
 
Instructions for aseptic reconstitution: 
 
1) Using a sterile syringe, slowly inject 7.2 mL of water for injections in the vial containing the 
lyophilised Herceptin, directing the stream into the lyophilised cake. 
2) Swirl vial gently to aid reconstitution. DO NOT SHAKE! 
 
Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed 
for approximately 5 minutes. The reconstituted Herceptin results in a colourless to pale yellow 
transparent solution and should be essentially free of visible particulates.  
 



83 

Instructions for aseptic dilution of the reconstituted solution 
 
Determine the volume of the solution required: 

∑ based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose 
of 2 mg trastuzumab/kg body weight: 

 
Volume (mL) = Body weight (kg) x dose (4 mg/kg for loading or 2 mg/kg for maintenance)  
   21 (mg/mL, concentration of reconstituted solution)  
 

∑ based on a loading dose of 8 mg trastuzumab/kg body weight, or a subsequent 3-weekly dose 
of 6 mg trastuzumab/kg body weight: 

 
Volume (mL) = Body weight (kg) x dose (8 mg/kg for loading or 6 mg/kg for maintenance)  
   21 (mg/mL, concentration of reconstituted solution)  
 
The appropriate amount of solution should be withdrawn from the vial and added to a 
polyvinylchloride, polyethylene or polypropylene infusion bag containing 250 mL of 0.9 % sodium 
chloride solution. Do not use with glucose-containing solutions. The bag should be gently inverted to 
mix the solution in order to avoid foaming. Parenteral solutions should be inspected visually for 
particulates and discoloration prior to administration.  



84 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Herceptin 600 mg solution for injection in vial 
Trastuzumab 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
∑ Keep this leaflet. You may need to read it again. 
∑ If you have any further questions, ask your doctor, pharmacist or nurse. 
∑ If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.  
 
What is in this leaflet: 
1. What Herceptin is and what it is used for 
2. What you need to know before you are given Herceptin 
3. How Herceptin is given 
4. Possible side effects 
5. How to store Herceptin 
6. Contents of the pack and other information 
 
 
1. What Herceptin is and what it is used for 
 
Herceptin contains the active substance trastuzumab, which is a monoclonal antibody. Monoclonal 
antibodies attach to specific proteins or antigens. Trastuzumab is designed to bind selectively to an 
antigen called human epidermal growth factor receptor 2 (HER2). HER2 is found in large amounts on 
the surface of some cancer cells where it stimulates their growth. When Herceptin binds to HER2 it 
stops the growth of such cells and causes them to die. 
 
Your doctor may prescribe Herceptin for the treatment of breast cancer when: 
∑ You have early breast cancer, with high levels of a protein called HER2. 
∑ You have metastatic breast cancer (breast cancer that has spread beyond the original tumour) 

with high levels of HER2. Herceptin may be prescribed in combination with the chemotherapy 
medicines paclitaxel or docetaxel as first treatment for metastatic breast cancer or it may be 
prescribed alone if other treatments have proved unsuccessful. It is also used in combination 
with medicines called aromatase inhibitors with patients with high levels of HER2 and hormone 
receptor-positive metastatic breast cancer (cancer that is sensitive to the presence of female sex 
hormones). 

 
 
2. What you need to know before you are given Herceptin 
 
Do not use Herceptin if: 
∑ you are allergic to trastuzumab (the active substance of Herceptin), murine (mouse) proteins, or 

any of the other ingredients of this medicine (listed in section 6). 
∑ you have severe breathing problems at rest due to your cancer or if you need oxygen treatment. 
 
Warnings and precautions 
Your doctor will closely supervise your therapy. 
 
Heart checks 
Treatment with Herceptin alone or with a taxane may affect the heart, especially if you have ever used 
an anthracycline (taxanes and anthracyclines are two other kinds of medicine used to treat cancer). The 
effects may be moderate to severe and could cause death. Therefore, your heart function will be 
checked before, during (every three months) and after (up to two to five years) treatment with 
Herceptin. If you develop any signs of heart failure (i.e. inadequate pumping of blood by the heart), 



85 

your heart function may be checked more frequently (every six to eight weeks), you may receive 
treatment for heart failure or you may have to stop Herceptin treatment. 
 
Talk to your doctor, pharmacist or nurse before you are given Herceptin if: 
∑ you have had heart failure, coronary artery disease, heart valve disease (heart murmurs), high 

blood pressure, taken any high blood pressure medicine or are currently taking any high blood 
pressure medicine. 

∑ you have ever had or are currently using a medicine called doxorubicin or epirubicin (medicines 
used to treat cancer). These medicines (or any other anthracyclines) can damage heart muscle 
and increase the risk of heart problems with Herceptin. 

∑ you suffer from breathlessness, especially if you are currently using a taxane. Herceptin can 
cause breathing difficulties, especially when it is first given. This could be more serious if you 
are already breathless. Very rarely, patients with severe breathing difficulties before treatment 
have died when they were given Herceptin. 

∑ you have ever had any other treatment for cancer. 
 
If you receive Herceptin with any other medicine to treat cancer, such as paclitaxel, docetaxel, an 
aromatase inhibitor, carboplatin or cisplatin you should also read the patient information leaflets for 
these products. 
 
Children and adolescents 
Herceptin is not recommended for anyone under the age of 18 years. 
 
Other medicines and Herceptin 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 
 
It may take up to 7 months for Herceptin to be removed from the body. Therefore you should tell your 
doctor, pharmacist or nurse that you have had Herceptin if you start any new medicine in the 7 months 
after stopping treatment. 
 
Pregnancy  
∑ If you are pregnant, think you may be pregnant or are planning to have a baby, you must tell 

your doctor, pharmacist or nurse before taking this medicine.  
∑ You should use effective contraception during treatment with Herceptin and for at least 

7 months after treatment has ended.  
 

Your doctor will advise you of the risks and benefits of taking Herceptin during pregnancy. In rare 
cases, a reduction in the amount of (amniotic) fluid that surrounds the developing baby within the 
womb has been observed in pregnant women receiving Herceptin. This condition may be harmful to 
your baby in the womb and has been associated with the lungs not developing fully resulting in foetal 
death.  
 
Breast-feeding 
Do not breast-feed your baby during Herceptin therapy and for 7 months after the last dose of 
Herceptin as Herceptin may pass to your baby through your breast milk. 
 
Ask your doctor, pharmacist or nurse for advice before taking any medicine. 
 
Driving and using machines 
Herceptin may affect your ability to drive a car or operate machines. If during treatment, you 
experience symptoms, such as dizziness, sleepiness, chills or fever, you should not drive or use 
machines until these symptoms disappear. 
 
Sodium  
Herceptin contains less than 1 mmol of sodium per dose, i.e. it is essentially sodium-free. 
 



86 

3. How Herceptin is given 
 
Before starting the treatment your doctor will determine the amount of HER2 in your tumour. Only 
patients with a large amount of HER2 will be treated with Herceptin. Herceptin should only be given 
by a doctor or nurse.  
 
 Two different types (formulations) of Herceptin exist: 
∑ one is given as an infusion into a vein (intravenous infusion) 
∑ the other is given as an injection under the skin (subcutaneous injection).  
It is important to check the product labels to ensure that the correct formulation is being given as 
prescribed. Herceptin subcutaneous fixed dose formulation is not for intravenous use and should be 
given as a subcutaneous injection only. 

Your doctor may consider switching your Herceptin intravenous treatment to Herceptin subcutaneous 
treatment (and vice versa) if considered appropriate for you. 
 
In order to prevent medication errors it is also important to check the vial labels to ensure that the 
medicine being prepared and given is Herceptin (trastuzumab) and not trastuzumab emtansine. 
The recommended dose is 600 mg. Herceptin is given as a subcutaneous injection (under the skin) 
over 2 to 5 minutes every three weeks. 
 
The injection site should be alternated between the left and right thigh. New injections should be given 
at least 2.5 cm away from an old site. No injection should be given into areas where the skin is red, 
bruised, tender or hard. 
If other medicines for subcutaneous use are used during the treatment course with Herceptin, a 
different injection site should be used. 
 
Herceptin should not be mixed or diluted with other products. 
 
If you stop using Herceptin 
Do not stop using this medicine without talking to your doctor first. All doses should be taken at the 
right time every three weeks. This helps your medicine work as well as it can. 
 
It may take up to 7 months for Herceptin to be removed from your body. Therefore your doctor may 
decide to continue to check your heart functions, even after you finish treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of 
these side effects may be serious and may lead to hospitalisation. 
 
During treatment with Herceptin, chills, fever and other flu like symptoms may occur. These are very 
common (may affect more than 1 in 10 people). Other symptoms are: feeling sick (nausea), vomiting, 
pain, increased muscle tension and shaking, headache, dizziness, breathing difficulties, high or low 
blood pressure, heart rhythm disturbances (palpitations, heart fluttering or irregular heart beat), 
swelling of the face and lips, rash and feeling tired. Some of these symptoms can be serious and some 
patients have died (see the section “Warnings and precautions”). 
 
You will be observed by a healthcare professional during the administration and for six hours after the 
start of the first administration and for two hours after the start of other administrations.  
 



87 

Serious side effects 
Other side effects can occur at any time during treatment with Herceptin. Tell a doctor or nurse 
straight away, if you notice any of the following side effects:  
 
∑ Heart problems can sometimes occur during treatment and occasionally after treatment has 

stopped and can be serious. They include weakening of the heart muscle possibly leading to heart 
failure, inflammation of the lining around the heart and heart rhythm disturbances. This can lead to 
symptoms such as breathlessness (including breathlessness at night), cough, fluid retention 
(swelling) in the legs or arms, palpitations (heart fluttering or irregular heart beat) (see section 2. 
Heart checks).  

 
Your doctor will monitor your heart regularly during and after treatment but you should tell your 
doctor immediately if you notice any of the above symptoms. 

 
∑ Tumour lysis syndrome (a group of metabolic complications occurring after cancer treatment 

characterized by high blood levels of potassium and phosphate, and low blood levels of calcium). 
Symptoms may include kidney problems (weakness, shortness of breath, fatigue and confusion), 
heart problems (fluttering of the heart or a faster or slower heartbeat), seizures, vomiting or 
diarrhoea and tingling in the mouth, hands or feet 

 
If you experience any of the above symptoms when your treatment with Herceptin has finished, you 
should see your doctor and tell them that you have previously been treated with Herceptin. 
 
Two different types (formulations) of Herceptin exist:  

∑ one is given as an infusion into a vein over 30 to 90 minutes 
∑  the other is given as a subcutaneous injection over 2 to 5 minutes.  

In the clinical study comparing these two formulations, infections and cardiac events leading to 
hospitalisation were more frequent with the subcutaneous formulation. There were also more local 
reactions at the site of injection and more increases in blood pressure. Other side effects were similar.  
 
Very common side effects of Herceptin: may affect more than 1 in 10 people 
 
∑ infections 
∑ diarrhoea 
∑ constipation 
∑ heartburn (dyspepsia) 
∑ fatigue 
∑ skin rashes 
∑ chest pain 
∑ abdominal pain 
∑ joint pain 
∑ low counts of red blood cells and white blood cells (which help fight infection) sometimes with 

fever 
∑ muscle pain 
∑ conjunctivitis 
∑ watery eyes 
∑ nose bleeds 
∑ runny nose 
∑ hair loss 
∑ tremor 
∑ hot flush 
∑ dizziness 
∑ nail disorders 
∑ weight loss  
∑ loss of appetite 



88 

∑ inability to sleep (insomnia) 
∑ altered taste 
∑ low platelet count 
∑ bruising 
∑ numbness or tingling of the fingers and toes  
∑ redness, swelling or sores in your mouth and/or throat 
∑ pain, swelling, redness or tingling of hands and/or feet 
∑ breathlessness 
∑ headache 
∑ cough 
∑ vomiting 
∑ nausea 
 
Common side effects of Herceptin: may affect up to 1 in 10 people 
 
∑ allergic reactions ∑ dry mouth and skin 
∑ throat infections ∑ dry eyes 
∑ bladder and skin infections ∑ sweating 
 ∑ feeling weak and unwell 
∑ inflammation of the breast ∑ anxiety 
∑ inflammation of the liver ∑ depression 
∑ kidney disorders  
∑ increased muscle tone or tension 

(hypertonia) 
∑ asthma 
∑ infection of lungs 

∑ pain in the arms and/or legs ∑ lung disorders 
∑ itchy rash ∑ back pain 
∑ sleepiness (somnolence) ∑ neck pain 
∑ haemorrhoids ∑ bone pain 
∑ itchiness 
 

∑ acne 
∑ leg cramps 

  
  

Uncommon side effects of Herceptin: may affect up to 1 in 100 people 
 
∑ deafness 
∑ bumpy rash 
∑ wheezing 
∑ inflammation or scarring of the lungs 
 
Rare side effects of Herceptin: may affect up to 1 in 1,000 people 
 
∑ jaundice 
 
∑  anaphylactic reactions 
 
Other side effects that have been reported with Herceptin use: frequency cannot be estimated from 
the available data 
 
∑ abnormal or impaired blood clotting 
∑ high potassium levels 
∑ swelling or bleeding at the back of the eyes 
∑ shock 
∑ abnormal heart rhythm 
∑ respiratory distress 



89 

∑ respiratory failure 
∑ acute accumulation of fluid in the lungs 
∑ acute narrowing of the airways 
∑ abnormally low oxygen levels in the blood 
∑ difficulty in breathing when lying flat 
∑ liver damage 
∑ swelling of the face, lips and throat 
∑ kidney failure 
∑ abnormally low levels of fluid around baby in womb 
∑ failure of the lungs of the baby to develop in the womb  
∑ abnormal development of the kidneys of the baby in the womb  
 
Some of the side effects you experience may be due to your underlying breast cancer. If you receive 
Herceptin in combination with chemotherapy, some of them may also be due to the chemotherapy. 
 
If you get any side effects, talk to your doctor, pharmacist or nurse.  
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Herceptin 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton and on the vial label 
after EXP. The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C). 
 
Keep the vial in the outer carton to protect from light. 
 
Do not freeze. 
 
Upon opening of the vial, the solution should be used immediately. 
 
Do not use this medicine if you notice any particulate matter or discoloration prior to administration. 
 
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Herceptin contains 
 
∑ The active substance is trastuzumab. One vial of 5 mL contains 600 mg of trastuzumab. 
 
∑ The other ingredients are recombinant human hyaluronidase (rHuPH20), L-histidine, L-histidine 

hydrochloride monohydrate, α,α-trehalose dihydrate, L-methionine, polysorbate 20, water for 
injections. 

 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


90 

What Herceptin looks like and contents of the pack 
Herceptin is a solution for injection that is supplied in a glass vial with a butyl rubber stopper 
containing 5 mL (600 mg) of trastuzumab. The solution is clear to opalescent and colourless to 
yellowish. 
 
Each carton contains one vial. 
 
Marketing Authorisation Holder 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Danmark 
Roche a/s 
Tlf: +45 - 36 39 99 99 
 

Malta 
(See United Kingdom) 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E. 
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 



91 

France 
Roche 
Tél: +33 (0)1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o. 
Tel: + 385 1 47 22 333 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 

Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland 
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika 
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy 
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος 
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 67 039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 


	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
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treatments have proved unsuccessful. it is also used in combination with medicines called aromatase inhibitors with patients with high levels of her2 and hormone receptor-positive metastatic breast cancer (cancer that is sensitive to the presence of female sex hormones). ∑ you have metastatic gastric cancer with high levels of her2, when it is in combination with the other cancer medicines capecitabine or 5-flououracil and cisplatin.', 'Entity_Recognition': [{'Text': 'herceptin', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 6, 'BeginOffset': 0, 'EndOffset': 9, 'Score': 0.997175931930542, 'Text': 'herceptin', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'the active substance trastuzumab', 'Type': 'TREATMENT', 'BeginOffset': 19, 'EndOffset': 51}, {'Text': 'a monoclonal antibody', 'Type': 'PROBLEM', 'BeginOffset': 62, 'EndOffset': 83}, {'Id': 30, 'BeginOffset': 85, 'EndOffset': 106, 'Score': 0.8935645818710327, 'Text': 'monoclonal 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{'Title': '2. what you need to know before you are given herceptin', 'Section_Content': 'do not use herceptin if: ∑ you are allergic to trastuzumab, to murine (mouse) proteins, or to any of the other ingredients of this medicine (listed in section 6). ∑ you have severe breathing problems at rest due to your cancer or if you need oxygen treatment. warnings and precautions your doctor will closely supervise your therapy. heart checks treatment with herceptin alone or with a taxane may affect the heart, especially if you have ever used an anthracycline (taxanes and anthracyclines are two other kinds of medicine used to treat cancer). the effects may be moderate to severe and could cause death. therefore, your heart function will be checked before, during (every three months) and after (up to two to five years) treatment with herceptin. if you develop any signs of heart failure (inadequate pumping of blood by the heart), your heart function may be checked more frequently (every six to eight weeks), you may receive treatment for heart failure or you may have to stop herceptin treatment. talk to your doctor, pharmacist or nurse before you are given herceptin if: ∑ you have had heart failure, coronary artery disease, heart valve disease (heart murmurs), high blood pressure, taken any high blood pressure medicine or are currently taking any high blood pressure medicine. ∑ you have ever had or are currently using a medicine called doxorubicin or epirubicin (medicines used to treat cancer). these medicines (or any other anthracyclines) can damage heart muscle and increase the risk of heart problems with herceptin. ∑ you suffer from breathlessness., especially if you are currently using a taxane. herceptin can cause breathing difficulties, especially when it is first given. this could be more serious if you are already breathless. very rarely, patients with severe breathing difficulties before treatment have died when they were given herceptin. ∑ you have ever had any other treatment for cancer. if you receive herceptin with any other medicine to treat cancer, such as paclitaxel, docetaxel, an aromatase inhibitor, capecitabine, 5-fluorouracil, or cisplatin you should also read the patient information leaflets for these products. children and adolescents herceptin is not recommended for anyone under the age of 18 years. other medicines and herceptin tell your doctor, pharmacist or nurse if you are taking, have recently taken or may take any other medicines. it may take up to 7 months for herceptin to be removed from the body. therefore you should tell your doctor, pharmacist or nurse that you have had herceptin if you start any new medicine in the 7 months after stopping treatment. pregnancy ∑ if you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor, pharmacist or nurse for advice before taking this medicine. ∑ you should use effective contraception during treatment with herceptin and for at least 7 months after treatment has ended. ∑ your doctor will advise you of the risks and benefits of taking herceptin during pregnancy. in rare cases, a reduction in the amount of (amniotic) fluid that surrounds the developing baby within the womb has been observed in pregnant women receiving herceptin. this condition may be harmful to your baby in the womb and has been associated with the lungs not developing fully resulting in foetal death. breast-feeding do not breast-feed your baby during herceptin therapy and for 7 months after the last dose of herceptin as herceptin may pass to your baby through your breast milk. ask your doctor or pharmacist for advice before taking any medicine. driving and using machines herceptin may affect your ability to drive a car or operate machines.if during treatment you experience symptoms, such as dizziness, sleepiness, chills or fever, you should not drive or use machines until these symptoms disappear. sodium herceptin contains less than 1 mmol of sodium per dose, i.e. 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{'Title': '3. how herceptin is given', 'Section_Content': 'before starting the treatment your doctor will determine the amount of her2 in your tumour. only patients with a large amount of her2 will be treated with herceptin. herceptin should only be given by a doctor or nurse. your doctor will prescribe a dose and treatment regimen that is right for you. the dose of herceptin depends on your body weight. two different types (formulations) of herceptin exist: one is given as an infusion into a vein (intravenous infusion) the other is given as an injection under the skin (subcutaneous injection). it is important to check the product labels to ensure that the correct formulation is being given as prescribed. herceptin intravenous formulation is not for subcutaneous use and should be given as an intravenous infusion only. your doctor may consider switching your herceptin intravenous treatment to herceptin subcutaneous treatment (and vice versa) if considered appropriate for you. herceptin intravenous formulation is given as an intravenous infusion ("drip") directly into your veins. the first dose of your treatment is given over 90 minutes and you will be observed by a health professional while it is being given in case you have any side effects. if the first dose is well tolerated the next doses may be given over 30 minutes (see section 2 under "warnings and precautions"). the number of infusions you receive will depend on how you respond to the treatment. your doctor will discuss this with you. in order to prevent medication errors it is important to check the vial labels to ensure that the medicine being prepared and given is herceptin (trastuzumab) and not trastuzumab emtansine. for early breast cancer, metastatic breast cancer and metastatic gastric cancer, herceptin is given every 3 weeks. herceptin may also be given once a week for metastatic breast cancer. if you stop using herceptin do not stop using this medicine without talking to your doctor first. all doses should be taken at the right time every week or every three weeks (depending on your dosing schedule). this helps your medicine work as well as it can. it may take up to 7 months for herceptin to be removed from your body. therefore your doctor may decide to continue to check your heart functions, even after you finish treatment. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'herceptin', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 16, 'EndOffset': 29}, {'Id': 30, 'BeginOffset': 84, 'EndOffset': 90, 'Score': 0.6018834710121155, 'Text': 'tumour', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.715739905834198}]}, {'Id': 6, 'BeginOffset': 155, 'EndOffset': 164, 'Score': 0.9987819790840149, 'Text': 'herceptin', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, herceptin can cause side effects, although not everybody gets them. some of these side effects may be serious and may lead to hospitalisation. during a herceptin infusion, chills, fever and other flu like symptoms may occur. these are very common (may affect more than 1 in 10 people). other infusion-related symptoms are: feeling sick 77 (nausea), vomiting, pain, increased muscle tension and shaking, headache, dizziness, breathing difficulties, high or low blood pressure, heart rhythm disturbances (palpitations, heart fluttering or irregular heart beat), swelling of the face and lips, rash and feeling tired. some of these symptoms can be serious and some patients have died (see section 2 under "warnings and precautions"). these effects mainly occur with the first intravenous infusion ("drip" into your vein) and during the first few hours after the start of the infusion. they are usually temporary. you will be observed by a health care professional during the infusion and for at least six hours after the start of the first infusion and for two hours after the start of other infusions. if you develop a reaction, they will slow down or stop the infusion and may give you treatment to counteract the side effects. the infusion may be continued after the symptoms improve. occasionally, symptoms start later than six hours after the infusion begins. if this happens to you, contact your doctor immediately. sometimes, symptoms may improve and then get worse later. serious side effects other side effects can occur at any time during treatment with herceptin, not just related to an infusion. tell a doctor or nurse straight away, if you notice any of the following side effects: ∑ heart problems can sometimes occur during treatment and occasionally after treatment has stopped and can be serious. they include weakening of the heart muscle possibly leading to heart failure, inflammation of the lining around the heart and heart rhythm disturbances. this can lead to symptoms such as breathlessness (including breathlessness at night), cough, fluid retention (swelling) in the legs or arms, palpitations (heart fluttering or irregular heart beat) (see section 2. heart checks). your doctor will monitor your heart regularly during and after treatment but you should tell your doctor immediately if you notice any of the above symptoms. ∑ tumour lysis syndrome (a group of metabolic complications occurring after cancer treatment characterized by high blood levels of potassium and phosphate, and low blood levels of calcium). symptoms may include kidney problems (weakness, shortness of breath, fatigue and confusion), heart problems (fluttering of the heart or a faster or slower heartbeat), seizures, vomiting or diarrhoea and tingling in the mouth, hands or feet if you experience any of the above symptoms when your treatment with herceptin has finished, you should see your doctor and tell them that you have previously been treated with herceptin. very common side effects of herceptin: may affect more than 1 in 10 people ∑ infections ∑ diarrhoea ∑ constipation ∑ heartburn (dyspepsia) ∑ fatigue ∑ skin rashes ∑ chest pain ∑ abdominal pain ∑ joint pain ∑ low counts of red blood cells and white blood cells (which help fight infection) sometimes with fever ∑ muscle pain ∑ conjunctivitis ∑ watery eyes ∑ nose bleeds ∑ runny nose 78 ∑ hair loss ∑ tremor ∑ hot flush ∑ dizziness ∑ nail disorders ∑ weight loss ∑ loss of appetite ∑ inability to sleep (insomnia) ∑ altered taste ∑ low platelet count ∑ bruising ∑ numbness or tingling of the fingers and toes ∑ redness, swelling or sores in your mouth and/or throat ∑ pain, swelling, redness or tingling of hands and/or feet ∑ breathlessness ∑ headache ∑ cough ∑ vomiting ∑ nausea common side effects of herceptin: may affect up to 1 in 10 people ∑ allergic reactions ∑ dry mouth and skin ∑ throat infections ∑ dry eyes ∑ bladder and skin infections ∑ sweating ∑ ∑ feeling weak and unwell ∑ inflammation of the breast ∑ anxiety ∑ inflammation of the liver ∑ depression ∑ kidney disorders ∑ increased muscle tone or tension (hypertonia) ∑ asthma ∑ infection of lungs ∑ pain in the arms and/or legs ∑ lung disorders ∑ itchy rash ∑ back pain ∑ sleepiness (somnolence) ∑ neck pain ∑ haemorrhoids ∑ bone pain ∑ itchiness ∑ acne ∑ leg cramps uncommon side effects of herceptin: may affect up to 1 in 100 people: ∑ deafness ∑ bumpy rash∑ wheezing ∑ inflammation or scarring of the lungs rare side effects of herceptin: may affect up to 1 in 1000 people ∑ jaundice ∑ anaphylactic reactions 79 other side effects that have been reported with herceptin use: frequency cannot be estimated from the available data ∑ abnormal or impaired blood clotting ∑ high potassium levels ∑ swelling or bleeding at the back of the eyes ∑ shock ∑ abnormal heart rhythm ∑ respiratory distress ∑ respiratory failure ∑ acute accumulation of fluid in the lungs ∑ acute narrowing of the airways ∑ abnormally low oxygen levels in the blood ∑ difficulty in breathing when lying flat ∑ liver damage ∑ swelling of the face, lips and throat ∑ kidney failure ∑ abnormally low levels of fluid around baby in womb ∑ failure of the lungs of the baby to develop in the womb ∑ abnormal development of the kidneys of the baby in the womb some of the side-effects you experience may be due to your underlying cancer. if you receive herceptin in combination with chemotherapy, some of them may also be due to the chemotherapy. if you get any side effects, talk to your doctor, pharmacist or nurse. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 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'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.73276686668396}]}, {'Id': 270, 'BeginOffset': 5580, 'EndOffset': 5592, 'Score': 0.9224215745925903, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7483913898468018}]}, {'Id': 271, 'BeginOffset': 5663, 'EndOffset': 5675, 'Score': 0.9544892311096191, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6426902413368225}]}, {'Id': 272, 'BeginOffset': 5724, 'EndOffset': 5736, 'Score': 0.8664984703063965, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7057369947433472}]}, {'Id': 273, 'BeginOffset': 5790, 'EndOffset': 5801, 'Score': 0.38983914256095886, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6171137690544128}]}, {'Id': 274, 'BeginOffset': 5815, 'EndOffset': 5827, 'Score': 0.8619772791862488, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7417212724685669}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 5883, 'EndOffset': 5896}]}
{'Title': '5. how to store herceptin', 'Section_Content': 'herceptin will be stored by the health professionals at the hospital or clinic. ∑ keep this medicine out of the sight and reach of children. ∑ do not use this medicine after the expiry date which is stated on the outer carton and on the vial label after exp. the expiry date refers to the last day of that month. ∑ the unopened vial should be stored in a refrigerator (2 8). ∑ do not freeze the reconstituted solution. ∑ infusion solutions should be used immediately after dilution. if not used immediately, in-use storage times and conditions prior to use are the responsibility of the user, and would not normally be longer than 24 hours at 2 8. ∑ do not use herceptin if you notice any particulate matter or discoloration prior to administration. ∑ medicines should not be disposed of via wastewater or household waste. ask your pharmacist how to dispose of medicines no longer required. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'herceptin', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 0, 'EndOffset': 9, 'Score': 0.99784255027771, 'Text': 'herceptin', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 154, 'EndOffset': 167}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 369, 'EndOffset': 370}, {'Text': '8.', 'Type': 'NUMBER', 'BeginOffset': 371, 'EndOffset': 373}, {'Text': 'infusion solutions', 'Type': 'TREATMENT', 'BeginOffset': 421, 'EndOffset': 439}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 631, 'EndOffset': 633}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 643, 'EndOffset': 644}, {'Text': '8.', 'Type': 'NUMBER', 'BeginOffset': 645, 'EndOffset': 647}, {'Id': 1, 'BeginOffset': 661, 'EndOffset': 670, 'Score': 0.9991216063499451, 'Text': 'herceptin', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.7697950005531311}]}, {'Text': 'any particulate matter', 'Type': 'PROBLEM', 'BeginOffset': 685, 'EndOffset': 707}, {'Text': 'discoloration', 'Type': 'PROBLEM', 'BeginOffset': 711, 'EndOffset': 724}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 752, 'EndOffset': 761}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 861, 'EndOffset': 870}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 891, 'EndOffset': 905}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what herceptin contains ∑ the active substance is trastuzumab. each vial contains 150 mg trastuzumab that has to be dissolved in 7.2 ml of water for injection. the resulting solution contains approximately 21 mg/ml trastuzumab. ∑ the other ingredient(s) are l-histidine hydrochloride monohydrate, l-histidine, α,α-trehalose dihydrate, polysorbate 20. what herceptin looks like and contents of the pack herceptin is a powder for concentrate for solution for intravenous infusion, which is supplied in a glass vial with a rubber stopper containing 150 mg of trastuzumab. the powder is a white to pale yellow pellet. each carton contains 1 vial of powder.', 'Entity_Recognition': [{'Text': 'herceptin', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 14, 'Score': 0.9975027441978455, 'Text': 'herceptin', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 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