Ontruzant

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ontruzant 150 mg powder for concentrate for solution for infusion 
Ontruzant 420 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Ontruzant 150 mg powder for concentrate for solution for infusion 
 
One vial contains 150 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced by 
mammalian (Chinese hamster ovary) cell suspension culture and purified by several chromatography 
steps including specific viral inactivation and removal procedures. 
 
Ontruzant 420 mg powder for concentrate for solution for infusion 
 
One vial contains 420 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced by 
mammalian (Chinese hamster ovary) cell suspension culture and purified by several chromatography 
steps including specific viral inactivation and removal procedures. 
 
The reconstituted Ontruzant 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 
 
Ontruzant 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. 



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- 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 
 
Ontruzant 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. 
 
- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin. 
 
- in combination with neoadjuvant chemotherapy followed by adjuvant Ontruzant therapy, for 
locally advanced (including inflammatory) disease or tumours >2 cm in diameter (see sections 4.4 
and 5.1). 
 
Ontruzant 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 
 
Ontruzant 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-oesophageal junction who have not received prior anti-cancer treatment for their metastatic 
disease. 
 
Ontruzant 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 IHC3+ 
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). Ontruzant 
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. 
 
Ontruzant intravenous formulation is not intended for subcutaneous administration and should be 
administered via an intravenous infusion only. 
 
In order to prevent medication errors it is important to check the vial labels to ensure that the medicinal 
product being prepared and administered is Ontruzant (trastuzumab) and not trastuzumab emtansine. 
 



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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 Ontruzant is 4 mg/kg body weight. The recommended 
weekly maintenance dose of Ontruzant is 2 mg/kg body weight, beginning one week after the 
loading dose. 
 
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 trastuzumab (for dose, see the Summary of Product Characteristics (SmPC) for 
paclitaxel or docetaxel) and immediately after the subsequent doses of trastuzumab if the preceding 
dose of trastuzumab was well tolerated. 
 
Administration in combination with an aromatase inhibitor 
In the pivotal trial (BO16216) trastuzumab and anastrozole were administered from day 1. There were 
no restrictions on the relative timing of trastuzumab 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 Ontruzant is 8 mg/kg body 
weight. The recommended maintenance dose of Ontruzant 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 Ontruzant until progression of disease. Patients with 
EBC should be treated with Ontruzant 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 trastuzumab 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 



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3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure 
(CHF) has developed, discontinuation of Ontruzant 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 has missed a dose of Ontruzant 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 Ontruzant by more than one week, a re-loading dose of 
Ontruzant should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; 
three-weekly regimen: 8 mg/kg) as soon as possible. Subsequent Ontruzant 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 Ontruzant in the paediatric population. 
 
Method of administration  
 
Ontruzant is for intravenous use. The loading dose should be administered as a 90-minute intravenous 
infusion. Administration as an intravenous push or bolus is prohibited. Ontruzant 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 Ontruzant 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 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). 
 



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Currently no data from clinical trials are available on re-treatment of patients with previous 
exposure to trastuzumab in the adjuvant setting. 
 
Cardiac dysfunction 
 
General considerations 
 
Patients treated with trastuzumab 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 trastuzumab 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 trastuzumab, 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 trastuzumab. A careful risk-benefit assessment should be 
made before deciding to treat with trastuzumab. 
 
Trastuzumab may persist in the circulation for up to 7 months after stopping trastuzumab treatment 
based on population pharmacokinetic analysis of all available data (see section 5.2). Patients who 
receive anthracyclines after stopping trastuzumab may possibly be at increased risk of cardiac 
dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months 
after stopping trastuzumab. 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 trastuzumab therapy has been seen. 
 
The safety of continuation or resumption of trastuzumab 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 trastuzumab 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 trastuzumab 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 
trastuzumab treatment continued on therapy without additional clinical cardiac events. 
 
Metastatic breast cancer 
 
Trastuzumab 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 trastuzumab treatment, although the risk is lower than with concurrent use of 
trastuzumab 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 trastuzumab. In patients who receive anthracycline-containing 
chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the 
last administration of trastuzumab, 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 
haemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC 
pivotal trials with trastuzumab and therefore treatment cannot be recommended in such patients. 
 
Adjuvant treatment 
 
Trastuzumab 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 trastuzumab was administered after anthracycline-containing chemotherapy 
compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was 
more marked when trastuzumab 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 
trastuzumab 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 trastuzumab). 
 
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 trastuzumab after completion of adjuvant chemotherapy, the risk of cardiac 
dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of 
trastuzumab and a body mass index (BMI) >25 kg/m2. 
 
Neoadjuvant-adjuvant treatment 
 
In patients with EBC eligible for neoadjuvant-adjuvant treatment, trastuzumab 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 
trastuzumab 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. 
 



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Experience of concurrent administration of trastuzumab with low-dose anthracycline regimens 
is currently limited to the trial MO16432. 
 
In the pivotal trial MO16432, trastuzumab 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 trastuzumab arm. 
 
Clinical experience is limited in patients above 65 years of age. 
 
Infusion-related reactions (IRRs) and hypersensitivity 
 
Serious IRRs to trastuzumab 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 
trastuzumab. 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 trastuzumab (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 trastuzumab 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 trastuzumab 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 trastuzumab (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 
trastuzumab and the concomitant medicinal products used in clinical trials have not been observed. 
 



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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 loading dose as an intravenous infusion followed by 6 mg/kg q3w 
or 2 mg/kg q1w infusion, 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 trastuzumab (4 mg/kg loading dose as an 
intravenous infusion and 2 mg/kg infusion weekly) and docetaxel (60 mg/m2 intravenous infusion) 
in Japanese women with HER2-positive MBC, suggested that concomitant administration of 
trastuzumab 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 
trastuzumab. 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 trastuzumab. However, capecitabine itself showed higher concentrations and a longer 
half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of 
cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine 
plus trastuzumab. 
 
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 trastuzumab monotherapy 
(4 mg/kg loading/2 mg/kg q1w intravenous infusion) 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 trastuzumab and paclitaxel and two 
Phase II studies in which trastuzumab 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 
trastuzumab, paclitaxel and doxorubicin to trastuzumab PK data in studies where trastuzumab was 
administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide 
or paclitaxel (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 trastuzumab 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 trastuzumab 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. It is not known whether trastuzumab can affect reproductive capacity. As 
animal reproduction studies are not always predictive of human response, trastuzumab 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 trastuzumab. Women who become pregnant should be advised 
of the possibility of harm to the fetus. If a pregnant woman is treated with trastuzumab, or if a patient 
becomes pregnant while receiving trastuzumab or within 7 months following the last dose of 
trastuzumab, 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 trastuzumab 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 trastuzumab 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 
 
Ontruzant may have a minor influence on the ability to drive or use machines (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 Ontruzant usage 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 
(<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. 
 



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Presented in Table 1 are adverse reactions that have been reported in association with the use of 
intravenous trastuzumab 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 trastuzumab 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 
Herpes zoster Common 
Influenza Common 
Sinusitis Common 
Skin infection Common 
Rhinitis Common 
Upper respiratory tract infection Common 
Urinary tract infection Common 
Erysipelas Common 
Cellulitis Common 
Pharyngitis Common 
Sepsis Uncommon 

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 Not known 
+Anaphylactic shock Not known 

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 
Thinking abnormal Common 

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



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System organ class Adverse reaction Frequency 
Somnolence Common 
Ataxia Common 
Paresis Rare 
Brain oedema Not known 

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 1Blood pressure decreased Very common 

1Blood pressure increased Very common 
1Heart beat irregular Very common 
1Palpitation Very common 
1Cardiac flutter Very common 
Ejection fraction decreased* Very common 
+Cardiac failure (congestive) Common 
+1Supraventricular tachyarrhythmia Common 
Cardiomyopathy Common 
Pericardial effusion Uncommon 
Cardiogenic shock Not known 
Pericarditis Not known 
Bradycardia Not known 
Gallop rhythm present Not known 

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

Respiratory, thoracic and 
mediastinal disorders 

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



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System organ class Adverse reaction Frequency 
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 
Hepatic failure Not known 

Skin and subcutaneous 
tissue disorders 

Erythema Very common 
Rash Very common 
1Swelling 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 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 



14 

System organ class Adverse reaction Frequency 
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 
trastuzumab 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 trastuzumab (see 
section 4.4). 
 
In 3 pivotal clinical trials of adjuvant trastuzumab 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 (i.e. did not receive trastuzumab) and 
in patients who were administered trastuzumab sequentially after a taxane (0.3-0.4%). The rate was 
highest in patients who were administered trastuzumab concurrently with a taxane (2.0%). In the 
neoadjuvant setting, the experience of concurrent administration of trastuzumab and low-dose 
anthracycline regimen is limited (see section 4.4). 
 
When trastuzumab 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 trastuzumab 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 trastuzumab-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 trastuzumab. 
 
In the pivotal metastatic trials of intravenous trastuzumab, 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 trastuzumab 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 trastuzumab 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. 
 
Infusion reactions, allergic-like reactions and hypersensitivity 
It is estimated that approximately 40% of patients who are treated with trastuzumab 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, 



15 

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 trastuzumab (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 hypoprothrombinaemia 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 trastuzumab 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 intravenous trastuzumab developed antibodies against 
trastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 
30 patients in the trastuzumab 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 trastuzumab intravenous. 
 
There are no immunogenicity data available for trastuzumab in gastric cancer. 
 
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 trastuzumab 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. 
 
 



16 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03 
 
Ontruzant is a biosimilar medicinal product. Detailed information is available on the website of the 
European Medicines Agency http://www.ema.europa.eu. 
 
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. 
 
Detection of HER2 overexpression or HER2 gene amplification 
 
Detection of HER2 overexpression or HER2 gene amplification in breast cancer 
Trastuzumab 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 
trastuzumab 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 



17 

Score Staining pattern HER2 overexpression 
assessment 

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 overexpression or HER2 gene amplification in gastric cancer 
Only an accurate and validated assay should be used to detect HER2 overexpression 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. 
 
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: 
 



18 

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 
 
Trastuzumab 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 (trastuzumab alone). 
 
Trastuzumab 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 trastuzumab. In the pivotal trial of docetaxel 
(100 mg/m2 infused over 1 hour) with or without trastuzumab, 60% of the patients had received prior 
anthracycline-based adjuvant chemotherapy. Patients were treated with trastuzumab until progression 
of disease. 
 
The efficacy of trastuzumab in combination with paclitaxel in patients who did not receive prior 
adjuvant anthracyclines has not been studied. However, trastuzumab 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 
trastuzumab monotherapy and trastuzumab 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+). 
 



19 

The main test method used to determine HER2 positivity in the pivotal trial of docetaxel, with or 
without trastuzumab, 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 

 Trastuzumab1 
N=172 

Trastuzumab 
plus 

paclitaxel2 

N=68 

Paclitaxel2 

N=77 

Trastuzumab 
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 trastuzumab and anastrozole 
Trastuzumab 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 trastuzumab 
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 trastuzumab 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 
 Trastuzumab1 

N=105 
Trastuzumab2 

N=72 
Trastuzumab 

plus paclitaxel3 

N=32 

Trastuzumab 
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) 



20 

Parameter Monotherapy Combination therapy 
 Trastuzumab1 

N=105 
Trastuzumab2 

N=72 
Trastuzumab 

plus paclitaxel3 

N=32 

Trastuzumab 
plus docetaxel4 

N=110 
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 trastuzumab and paclitaxel, compared to paclitaxel alone (21.8% versus 45.7%; 
p=0.004). More patients treated with trastuzumab 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, trastuzumab was investigated in 4 large multicentre, randomised, 
trials. 
 
- Study BO16348 was designed to compare one and two years of three-weekly trastuzumab 

treatment versus observation in patients with HER2 positive EBC following surgery, 
established chemotherapy and radiotherapy (if applicable). In addition, comparison of two 
years of trastuzumab treatment versus one year of trastuzumab treatment was performed. 
Patients assigned to receive trastuzumab 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 trastuzumab treatment with 
paclitaxel following AC chemotherapy, additionally the NCCTG N9831 study also 
investigated adding trastuzumab sequentially to AC→P chemotherapy in patients with 
HER2 positive EBC following surgery. 

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

 
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 tumours 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 (tumour size >1 cm and 
ER negative or tumour 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: 
 



21 

Table 6 Efficacy results from Study BO16348 

 Median follow-up 
12 months* 

Median follow-up 
8 years** 

Parameter Observation 
N=1693 

Trastuzumab 
1 Year 
N=1693 

Observation 
N=1697*** 

Trastuzumab 
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 trastuzumab) 
*** 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 trastuzumab 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 trastuzumab arm. 
 
A final analysis was performed after a median follow-up of 8 years, which showed that 1-year 
trastuzumab 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 trastuzumab treatment. 
 
In this final analysis, extending trastuzumab 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 trastuzumab 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. 
 



22 

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

 
Paclitaxel, in combination with trastuzumab, 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 
 
For the primary endpoint, DFS, the addition of trastuzumab 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 (trastuzumab) 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 trastuzumab in the control arm, the addition of trastuzumab to paclitaxel chemotherapy 
resulted in a 52% decrease in the risk of disease recurrence. The addition of trastuzumab 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 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: 
 



23 

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 the 24.8% patients in the AC→P arm who crossed over to receive trastuzumab. 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 trastuzumab 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 

 
Trastuzumab 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. 
 
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 
 



24 

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 (trastuzumab) arm and 4.6 percentage points (85.5% versus 80.9% ) 
in favour of the DCarbH (trastuzumab) arm compared to AC→D. 
 
In study BCIRG 006, 213/1075 patients in the DCarbH (TCH) arm, 221/1074 patients in the AC→DH 
(AC→TH) arm, and 217/1073 in the AC→D (AC→T) 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 AC→D (AC→T); hazard ratio 
0.97, 95% CI [0.60, 1.55] for AC→DH (AC→TH) versus AC→D). 
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 
 AC→PH  

(vs. AC→P) 
(NSABP B-31 and 
NCCTG N9831)* 

AC→DH 
(vs. AC→D) 

(BCIRG 006) 

DCarbH 
(vs. AC→D) 
(BCIRG 006) 

Primary efficacy analysis    
DFS hazard ratios 0.48 0.61 0.67 

(95% CI) (0.39, 0.59) (0.49, 0.77) (0.54, 0.83) 
p-value p<0.0001 p<0.0001 p=0.0003 

Long term follow-up efficacy 
analysis** 

   

DFS hazard ratios 0.61 0.72 0.77 
(95% CI) (0.54, 0.69) (0.61, 0.85) (0.65, 0.90) 
p-value p<0.0001 p<0.0001 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 



25 

 
Early breast cancer (neoadjuvant-adjuvant setting) 
 
So far, no results are available which compare the efficacy of trastuzumab 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 trastuzumab with 
neoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant 
trastuzumab, 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 
trastuzumab, or neoadjuvant chemotherapy alone. 
In study MO16432, trastuzumab (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 60 mg/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 trastuzumab (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 trastuzumab arm was 3.8 years. 
 
Table 12 Efficacy results from MO16432 

Parameter 
Chemo + 

trastuzumab 
(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 trastuzumab arm was estimated in terms of 
3-year event-free survival rate (65% versus 52%). 
 
Metastatic gastric cancer 
 
Trastuzumab has been investigated in one randomised, open-label phase III trial ToGA (BO18255) 
in combination with chemotherapy versus chemotherapy alone. 
 



26 

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. 
 
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 + trastuzumab 
FP: fluoropyrimidine/cisplatin  
a Odds ratio 
 
Patients 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 were recruited to the trial. 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 (IHC2+/FISH+ or IHC3+). 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 IHC2+/FISH+ group and the HR was 0.58 (95% CI 0.41-0.81) in the 
IHC3+/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 trastuzumab 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 
trastuzumab in all subsets of the paediatric population for breast and gastric cancer (see section 4.2 for 
information on paediatric use). 
 



27 

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 tumour types, and healthy volunteers, in 18 Phase I, II and III trials receiving 
trastuzumab via an intravenous infusion. 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 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 tumour type, body-weight, serum aspartate 
aminotransferase and albumin were identified as 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 
trastuzumab intravenous infusion dosing regimens in MBC, EBC and AGC patients 

Regimen Primary 
tumour 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 
trastuzumab intravenous infusion dosing regimens in MBC, EBC and AGC patients 

Regimen Primary 
tumour type N Cmin,ss* 

(µg/mL) 
Cmax,ss** 
(µg/mL) 

AUCss, 0-21 days 
(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 



28 

Regimen Primary 
tumour type N Cmin,ss* 

(µg/mL) 
Cmax,ss** 
(µg/mL) 

AUCss, 0-21 days 
(µg.day/mL) 

Time to 
steady-state

*** 
(week) 

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 
 
Table 16 Population predicted PK parameter values at steady state for trastuzumab intravenous 
infusion dosing regimens in MBC, EBC and AGC patients 

Regimen Primary 
tumour 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. Trastuzumab 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 
trastuzumab, or to determine its effects on fertility in males. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
L-histidine hydrochloride monohydrate 
L-histidine 
α,α-trehalose dihydrate 
polysorbate 20 



29 

 
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 vials: 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 7 days 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 Ontruzant has been 
demonstrated for up to 30 days at 2ºC - 8ºC, and 24 hours at temperatures not exceeding 30°C. 
 
From a microbiological point of view, the reconstituted solution and Ontruzant 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 
 
Ontruzant 150 mg powder for concentrate for solution for infusion 
 
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. 
 
Ontruzant 420 mg powder for concentrate for solution for infusion 
 
One 40 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film 
containing 420 mg of trastuzumab 
 
Each carton contains one vial. 
 
6.6 Special precautions for disposal and other handling 
 
Ontruzant 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 



30 

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. 
• 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 
 
Ontruzant should be carefully handled during reconstitution. Causing excessive foaming during 
reconstitution or shaking the reconstituted solution may result in problems with the amount of 
Ontruzant that can be withdrawn from the vial. 
 
The reconstituted solution should not be frozen. 
 
Ontruzant 150 mg powder for concentrate for solution for infusion 
 
Each 150 mg vial of Ontruzant 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. 
 
Ontruzant 420 mg powder for concentrate for solution for infusion 
 
Each 420 mg vial of Ontruzant is reconstituted with 20 mL of sterile water for injection (not 
supplied). Use of other reconstitution solvents should be avoided. 
This yields a 21 mL solution for single-dose use, containing approximately 21 mg/mL trastuzumab, 
at a pH of approximately 6.0. A volume overage of 5% ensures that the labelled dose of 420 mg can 
be withdrawn from each vial. 
 

Ontruzant vial  Volume of sterile water for 
injections 

 Final concentration 

150 mg vial + 7.2 mL = 21 mg/mL 
420 mg vial + 20 mL = 21 mg/mL 

  
Instructions for aseptic reconstitution 
1) Using a sterile syringe, slowly inject the appropriate volume (as noted above) of sterile water for 
injection in the vial containing the lyophilised Ontruzant, 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 Ontruzant 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) 

 



31 

• 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. 
 
No incompatibilities between Ontruzant and polyvinylchloride, polyethylene or polypropylene bags 
have been observed. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1241/001 
EU/1/17/1241/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 November 2017 
 
 
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. 



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 

 



33 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
 MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) of the biological active substance(s)  
 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
Hillerød, DK-3400 
Denmark 
 
Name and address of the manufacturer(s) responsible for batch release 

 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
Hillerød, DK-3400 
Denmark 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 

 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 
any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 



34 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 



35 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



37 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ontruzant 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 
 
Excipients: 
L-histidine hydrochloride monohydrate, L-histidine, α,α-trehalose dihydrate, polysorbate 20. 
 
 
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. 
 
 



38 

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 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10, 2616 LR Delft 
The Netherlands  
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1241/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



39 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ontruzant 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 
 
 



40 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ontruzant 420 mg powder for concentrate for solution for infusion  
trastuzumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
The vial contains 420 mg trastuzumab. After reconstitution 1 mL concentrate contains 21 mg of 
trastuzumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: 
L-histidine hydrochloride monohydrate, L-histidine, α,α-trehalose dihydrate, polysorbate 20. 
 
 
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. 
 
 



41 

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 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10, 2616 LR Delft 
The Netherlands  
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1241/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



42 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ontruzant 420 mg powder for concentrate for solution for infusion 
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 
 
 



43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



44 

Package leaflet: Information for the user 
 

Ontruzant 150 mg powder for concentrate for solution for infusion 
Ontruzant 420 mg powder for concentrate for solution for infusion 

trastuzumab 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.  
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- 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, or pharmacist or nurse. This includes any 

possible side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Ontruzant is and what it is used for 
2. What you need to know before you are given Ontruzant 
3. How Ontruzant is given 
4. Possible side effects 
5. How to store Ontruzant 
6. Contents of the pack and other information 
 
 
1. What Ontruzant is and what it is used for 
 
Ontruzant 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 Ontruzant binds to HER2 it 
stops the growth of such cells and causes them to die. 
 
Your doctor may prescribe Ontruzant 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. Ontruzant 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 Ontruzant 
 
Do not use Ontruzant 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. 
 



45 

Warnings and precautions 
 
Your doctor will closely supervise your therapy. 
 
Heart checks 
Treatment with Ontruzant (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 
Ontruzant. 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 Ontruzant treatment. 
 
Talk to your doctor, pharmacist or nurse before you are given Ontruzant 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 Ontruzant. 

 
• you suffer from breathlessness., especially if you are currently using a taxane. Ontruzant 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 Ontruzant. 

 
• you have ever had any other treatment for cancer. 
 
If you receive Ontruzant 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 
Ontruzant is not recommended for anyone under the age of 18 years. 
 
Other medicines and Ontruzant 
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 Ontruzant to be removed from the body. Therefore you should tell your 
doctor, pharmacist or nurse that you have had Ontruzant 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 Ontruzant and for at least 7 months 

after treatment has ended. 
• Your doctor will advise you of the risks and benefits of taking Ontruzant 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 Ontruzant. This condition may be 
harmful to your baby in the womb and has been associated with the lungs not developing fully 
resulting in fetal death. 

 



46 

Breast-feeding 
Do not breast-feed your baby during Ontruzant therapy and for 7 months after the last dose of 
Ontruzant as Ontruzant may pass to your baby through your breast milk. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
Ontruzant may affect your ability to drive a car or operate machines. If during treatment you 
experience symptoms, such as chills or fever, you should not drive or use machines until these 
symptoms disappear. 
 
 
3. How Ontruzant 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 Ontruzant. Ontruzant 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 Ontruzant depends on your body weight. 
 
Ontruzant is given as an infusion into a vein (intravenous infusion, “drip”). This intravenous 
formulation is not for subcutaneous use and should be given as an intravenous infusion only. 
 
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 (see section 2 under “Warnings 
and precautions”). If the first dose is well tolerated the next doses may be given over 30 minutes. 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 Ontruzant (trastuzumab) and not trastuzumab emtansine. 
 
Ontruzant is given every 3 weeks for early breast cancer, metastatic breast cancer and metastatic 
gastric cancer. Ontruzant may also be given once a week for metastatic breast cancer. 
 
If you stop using Ontruzant 
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 Ontruzant 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, Ontruzant can cause side effects, although not everybody gets them. Some of these 
side effects may be serious and may lead to hospitalisation. 
 



47 

During an Ontruzant 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 
(nausea), vomiting, pain, increased muscle tension and shaking, headache, dizziness, breathing 
difficulties, wheezing, 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 Ontruzant, 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 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 Ontruzant has finished, you 
should see your doctor and tell them that you have previously been treated with Ontruzant. 
 
The following list of side effects can occur at any time during treatment with Ontruzant, not just 
related to an infusion. 
 
Very common side effects of Ontruzant (may affect more than 1 in 10 people): 
• infections 
• diarrhoea 
• constipation 
• dyspepsia (heartburn) 
• 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 



48 

• muscle pain 
• conjunctivitis 
• watery eyes 
• nose bleeds 
• runny nose 
• hair loss 
• tremor 
• hot flush 
• dizziness 
• nail disorders 
• weight loss 
• loss of appetite 
• insomnia (inability to sleep) 
• 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 Ontruzant (may affect up to 1 in 10 people): 
 
• allergic reactions 
• throat infections 
• bladder and skin infections 
• shingles 
• inflammation of the breast 
• inflammation of the liver 
• kidney disorders 
• hypertonia 
 (increased muscle tone or tension) 
• pain in the arms and/or legs 
• itchy rash 
• somnolence (sleepiness) 
• haemorrhoids 
• itchiness 
• leg cramps 

• dry mouth and skin 
• dry eyes 
• sweating 
• feeling weak and unwell 
• anxiety 
• depression 
• abnormal thinking 
• asthma 
• infection of lungs 
• lung disorders 
• back pain 
• neck pain 
• bone pain 
• acne 
 

 
Uncommon side effects of Ontruzant (may affect up to 1 in 100 people): 
 
• deafness 
• bumpy rash 
• blood infection 
 
Rare side effects of Ontruzant (may affect up to 1 in 1000 people): 
 
• muscle weakness 
• jaundice (yellowish discoloration of the skin or eyes) 
• inflammation or scarring of the lungs 
 



49 

Other side effects that have been reported with Ontruzant use (frequency cannot be estimated 
from the available data): 
 
• abnormal or impaired blood clotting 
• anaphylactic reactions (serious allergic reaction) 
• high potassium levels 
• swelling of the brain 
• swelling or bleeding at the back of the eyes 
• shock 
• swelling of the lining of the heart 
• slow heart rate 
• 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/failure 
• swelling of the face, lips and throat 
• kidney failure 
During pregnancy: 
• 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 
Ontruzant 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 Ontruzant 
 
Ontruzant 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 2°C - 8°C. 

• Do not use Ontruzant 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. 

 
 



50 

6. Contents of the pack and other information 
 
What Ontruzant contains  
 
• The active substance is trastuzumab. Each vial contains either: 

- 150 mg trastuzumab that has to be dissolved in 7.2 mL of water for injection, or 
- 420 mg trastuzumab that has to be dissolved in 20 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 Ontruzant looks like and contents of the pack 
 
Ontruzant is a powder for concentrate for solution for intravenous infusion, which is supplied in a glass 
vial with a rubber stopper containing either 150 mg or 420 mg of trastuzumab. The powder is a white 
to pale yellow pellet. Each carton contains 1 vial of powder. 
 
 
Marketing Authorisation Holder 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
Manufacturer 
 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
Hillerød, DK-3400 
Denmark 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10, 
2616 LR Delft 
The Netherlands 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
MSD Belgium BVBA/SPRL 
Tél/Tel: +32(0)27766211 
dpoc_belux@merck.com 
 

Lietuva 
UAB Merck Sharp & Dohme 
Tel. + 370 5 278 02 47 
msd_lietuva@merck.com 
 

България 
Мерк Шарп и Доум България ЕООД 
Тел.: +359 2 819 3737 
info-msdbg@merck.com 
 

Luxembourg/Luxemburg 
MSD Belgium BVBA/SPRL 
Tél/Tel: +32(0)27766211 
dpoc_belux@merck.com 
 

Česká republika 
Merck Sharp & Dohme s.r.o. 
Tel: +420 233 010 111 
dpoc_czechslovak@merck.com 
 

Magyarország 
MSD Pharma Hungary Kft. 
Tel.: +36 1 888 5300 
hungary_msd@merck.com 
 



51 

Danmark 
Organon Danmark ApS  
Tlf: + 45 44 84 68 00 
info.denmark@organon.com 

Malta 
Merck Sharp & Dohme Cyprus Limited 
Tel: 8007 4433 (+356 99917558) 
malta_info@merck.com 
 

Deutschland 
MSD SHARP & DOHME GMBH 
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612) 
e-mail@msd.de 
 

Nederland 
Merck Sharp & Dohme B.V. 
Tel.: 0800 9999000 
(+31 23 5153153) 
medicalinfo.nl@merck.com 
 

Eesti 
Merck Sharp & Dohme OÜ 
Tel.: +372 6144 200 
msdeesti@merck.com 
 

Norge 
MSD (Norge) AS 
Tlf: +47 32 20 73 00 
msdnorge@msd.no 
 

Ελλάδα 
MSD Α.Φ.Β.Ε.Ε. 
Τηλ: +30 210 98 97 300 
dpoc_greece@merck.com 
 

Österreich 
Merck Sharp & Dohme Ges.m.b.H. 
Tel: +43 (0) 1 26 044 
msd-medizin@merck.com 
 

España 
Organon Salud, S.L. 
Tel: +34 91 591 12 79 

Polska 
MSD Polska Sp. z o.o. 
Tel: +48 22 549 51 00 
msdpolska@merck.com 
 

France 
MSD France 
Tél: + 33 (0) 1 80 46 40 40 
 

Portugal 
Merck Sharp & Dohme, Lda 
Tel: +351 21 4465700 
inform_pt@merck.com  
 

Hrvatska 
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333 
croatia_info@merck.com 
 
Ireland 
Merck Sharp & Dohme Ireland (Human Health) 
Limited 
Tel: +353 (0)1 2998700 
medinfo_ireland@merck.com 
 

România 
Merck Sharp & Dohme Romania S.R.L. 
Tel: +40 21 529 29 00 
msdromania@merck.com 
 
Slovenija 
Merck Sharp & Dohme, inovativna zdravila d.o.o. 
Tel: +386 1 5204 201 
msd.slovenia@merck.com 
 

Ísland 
Vistor hf. 
Sími: + 354 535 7000  

Slovenská republika 
Merck Sharp & Dohme, s. r. o. 
Tel: +421 2 58282010 
dpoc_czechslovak@merck.com 
 

Italia 
MSD Italia S.r.l. 
Tel: +39 06 361911 
medicalinformation.it@merck.com 
 

Suomi/Finland 
Organon Finland Oy 
Puh/Tel: +358 (0) 29 170 3520 
info.finland@organon.com 
  

Κύπρος 
Merck Sharp & Dohme Cyprus Limited 
Τηλ.: 800 00 673 (+357 22866700) 
cyprus_info@merck.com 
 

Sverige 
Merck Sharp & Dohme (Sweden) AB 
Tel: +46 77 5700488 
medicinskinfo@merck.com 
 



52 

Latvija 
SIA Merck Sharp & Dohme Latvija 
Tel: + 371 67364224 
msd_lv@merck.com 
 

United Kingdom 
Merck Sharp & Dohme Limited 
Tel: +44 (0) 1992 467272 
medicalinformationuk@merck.com  
 

 
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. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 



53 

The following information is intended for healthcare professionals only 
 
Ontruzant 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 - 8ºC 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 Ontruzant aseptically reconstituted with sterile water for injections (not supplied) is 
chemically and physically stable for 7 days at 2ºC - 8ºC 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 Ontruzant has 
been demonstrated for up to  30 days at 2ºC - 8ºC, and subsequently for 24 hours at temperatures not 
exceeding 30°C. 
 
From a microbiological point of view, the reconstituted solution and Ontruzant 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 
 
Ontruzant 150 mg powder for concentrate for solution for infusion 
Each 150 mg vial of Ontruzant 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. 
 
Ontruzant 420 mg powder for concentrate for solution for infusion 
Each 420 mg vial of Ontruzant is reconstituted with 20 mL of water for injections (not supplied). Use 
of other reconstitution solvents should be avoided. This yields a 21 mL solution for single-dose use, 
containing approximately 21 mg/mL trastuzumab. A volume overage of 5% ensures that the labelled 
dose of 420 mg can be withdrawn from each vial. 
 

Ontruzant vial  Volume of sterile water for 
injections 

 Final concentration 

150 mg vial + 7.2 mL = 21 mg/mL 
420 mg vial + 20 mL = 21 mg/mL 

 
Instructions for aseptic reconstitution: 
 
Ontruzant should be carefully handled during reconstitution. Causing excessive foaming during 
reconstitution or shaking the reconstituted Ontruzant may result in problems with the amount of 
Ontruzant that can be withdrawn from the vial. 
 



54 

 
1) Using a sterile syringe, slowly inject the appropriate volume (as noted above) of water for injections 
in the vial containing the lyophilised Ontruzant, 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 Ontruzant 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 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. 
 


	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