Ogivri

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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 
 
Ogivri 150 mg powder for concentrate for solution for infusion 
Ogivri 420 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Ogivri 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 affinity and ion exchange 
chromatography including specific viral inactivation and removal procedures. 
 
Ogivri 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 affinity and ion exchange 
chromatography including specific viral inactivation and removal procedures. 
 
The reconstituted Ogivri solution contains 21 mg/mL of trastuzumab. 
 
Excipient with known effect 
 
Each 150 mg vial contains 115.2 mg sorbitol (E420).  
Each 420 mg vial contains 322.6 mg sorbitol (E420).  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion (powder for concentrate). 
 
White to pale yellow lyophilised powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Breast cancer 
 
Metastatic breast cancer 

 
Ogivri 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 



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anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor 
positive patients must also have failed hormonal therapy, unless patients are unsuitable for these 
treatments 

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

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

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

hormone-receptor positive MBC, not previously treated with trastuzumab. 
 

Early breast cancer 

 
Ogivri 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 Ogivri therapy, for locally 

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

 
Ogivri should only be used in patients with metastatic or EBC 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 
 
Ogivri 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 gastroesophageal 
junction who have not received prior anti-cancer treatment for their metastatic disease. 
 
Ogivri should only be used in patients with metastatic gastric cancer (MGC) whose tumours have 
HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC 3+ 
result. Accurate and validated assay methods should be used (see sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Trastuzumab 
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. 
 
Ogivri intravenous formulation is not intended for subcutaneous administration and should be 
administered via an intravenous infusion only. 
 
If an alternate route of administration is required, other trastuzumab products offering such an option 
should be used. 
 



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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 trastuzumab and not trastuzumab emtansine. 
 
Posology 
 
Metastatic breast cancer 

 

Three-weekly schedule 

The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose 
at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose. 
 

Weekly schedule 

The recommended initial loading dose of trastuzumab is 4 mg/kg body weight. The recommended 
weekly maintenance dose of trastuzumab 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 trastuzumab is 8 mg/kg body 
weight. The recommended maintenance dose of trastuzumab 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 trastuzumab until progression of disease. 
Patients with EBC should be treated with trastuzumab 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 



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monitored carefully for complications of neutropenia during this time. Refer to the SmPC for 
paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays. 
 
If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 points from baseline AND to below 
50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 
3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure 
(CHF) has developed, discontinuation of 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. 
 

Missed doses 

If the patient has missed a dose of trastuzumab 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 trastuzumab by more than one week, a re-loading dose of 
trastuzumab should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-
weekly regimen: 8 mg/kg) as soon as possible. Subsequent trastuzumab 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 trastuzumab in the paediatric population. 
 
Method of administration 
 
Trastuzumab loading dose should be administered as a 90-minute intravenous infusion. Do not 
administer as an intravenous push or bolus. Trastuzumab intravenous infusion should be administered 
by a healthcare 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 the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
• Hypersensitivity to the active substance, 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. 
 



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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). 
 
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 Ogivri 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 



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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. 
 
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 
hemodynamic 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 



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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. 
 
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. 
 



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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. 
 
Sorbitol content 
 
Ogivri 150 mg contains 115.2 mg sorbitol in each vial.  
Ogivri 420 mg contains 322.6 mg sorbitol in each vial. 
Patients with hereditary fructose intolerance (HFI) must not be given this medicine unless strictly 
necessary. 
A detailed history with regards to HFI symptoms has to be taken of each patient prior to being given 
this medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. Clinically significant interactions between trastuzumab 
and the concomitant medicinal products used in clinical trials have not been observed. 
 
Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents 
 

Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC 
suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-
paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 
4 mg/kg intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous, 
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 were unclear. 
 
Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg intravenous loading dose and 
2 mg/kg intravenous weekly) and docetaxel (60 mg/m2 intravenous) 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 sub study of BO18255 (ToGA) performed 
in male and female Japanese patients with advanced gastric cancer (AGC) to study the 
pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. The results of 
this sub study 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. 
 



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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) 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 (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the 
pharmacokinetics of trastuzumab. 
 
Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the 
PK of trastuzumab. 
 
The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of 
trastuzumab. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
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 foetus. Placental transfer of trastuzumab during the 
early (days 20–50 of gestation) and late (days 120–150 of gestation) foetal development period was 
observed. It is not known whether 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 foetus. 
 
In the post-marketing setting, cases of foetal renal growth and/or function impairment in association 
with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been 
reported in pregnant women receiving trastuzumab. Women who become pregnant should be advised 
of the possibility of harm to the foetus. 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 



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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 
 
Ogivri may have a minor influence on the ability to drive and 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 trastuzumab usage 
(intravenous and subcutaneous formulations) to date are cardiac dysfunction, infusion-related 
reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions. 
 
Tabulated list of adverse reactions 
 
In this section, the following categories of frequency have been used: very common (≥ 1/10), common 
(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare 
(< 1/10,000), not known (cannot be estimated from the available data). Within each frequency 
grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Presented in Table 1 are adverse reactions that have been reported in association with the use of 
intravenous 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 



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System organ class Adverse reaction Frequency 
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 
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 1 Blood pressure decreased Very common 

1 Blood pressure increased Very common 
1 Heart 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 



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System organ class Adverse reaction Frequency 
Pericarditis Not known 
Bradycardia Not known 
Gallop rhythm present Not known 

Vascular disorders Hot flush Very common 
+1 Hypotension 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 
1 Lip swelling Very common 
Abdominal pain Very common 
Dyspepsia Very common 
Constipation Very common 
Stomatitis Very common 
Haemorrhoids Common 
Dry mouth Common 

Hepatobiliary disorders Hepatocellular injury Common 
Hepatitis Common 
Liver tenderness Common 
Jaundice Rare 
Hepatic failure Not known 

Skin and subcutaneous 
tissue disorders 

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

Very common 



14 

System organ class Adverse reaction Frequency 
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 
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 

 



15 

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, 
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. 
 



16 

Haematotoxicity 

Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred very 
commonly. The frequency of occurrence of hypoprothrombinemia is not known. The risk of 
neutropenia may be slightly increased when trastuzumab is administered with docetaxel following 
anthracycline therapy. 
 

Pulmonary events 

Severe pulmonary adverse reactions occur in association with the use of 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 trastuzumab intravenous 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. 
 
Switching treatment between trastuzumab intravenous and trastuzumab subcutaneous formulation and 
vice versa. 
 
Study MO22982 investigated switching between the trastuzumab intravenous and trastuzumab 
subcutaneous formulation with a primary objective to evaluate patient preference for either 
intravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one using 
subcutaneous formulation in vial and one using subcutaneous formulation in administration system) 
were investigated using a 2-arm, cross-over design with 488 patients being randomized to one of two 
different three-weekly Trastuzumab treatment sequences (intravenous [Cycles 1-4]→ subcutaneous 
[Cycles 5-8], or subcutaneous [Cycles 1-4]→ intravenous [Cycles 5-8]). Patients were either naïve to 
trastuzumab intravenous treatment (20.3 %) or pre-exposed to trastuzumab intravenous (79.7 %). For 
the sequence intravenous → subcutaneous (subcutaneous vial and subcutaneous formulation in 
administration system cohorts combined), adverse event rates (all grades) were described pre-
switching (Cycles 1-4) and post-switching (Cycles 5-8) as 53.8 % vs. 56.4 %, respectively; for the 
sequence subcutaneous → intravenous (subcutaneous vial and subcutaneous formulation in 
administration system cohorts combined), adverse event rates (all grades) were described pre- and 
post-switching as 65.4 % vs. 48.7 %, respectively. 
Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatment 
discontinuations due to adverse events were low (< 5 %) and similar to post-switching rates (Cycles 5-
8). No grade 4 or grade 5 adverse events were reported. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 



17 

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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03 
 
Ogivri 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 
Ogivri 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. 
 

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


18 

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

assessment 
0 No staining is observed or membrane staining is 

observed in < 10 % of the tumour cells 
Negative 

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

Negative 

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

Equivocal 

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

Positive 

 
In general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to 
the chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the 
HER2 gene per tumour cell if no chromosome 17 control is used. 
 
In general, CISH is considered positive if there are more than 5 copies of the HER2 gene per nucleus 
in greater than 50 % of tumour cells. 
 
For full instructions on assay performance and interpretation please refer to the package inserts of 
validated FISH and CISH assays. Official recommendations on HER2 testing may also apply. 
 
For any other method that may be used for the assessment of HER2 protein or gene expression, the 
analyses should only be performed by laboratories that provide adequate state-of-the-art performance 
of validated methods. Such methods must clearly be precise and accurate enough to demonstrate 
overexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) and 
strong (congruent with 3+) overexpression of HER2. 
 

Detection of HER2 over expression or HER2 gene amplification in gastric cancer 

Only an accurate and validated assay should be used to detect HER2 over expression or HER2 gene 
amplification. IHC is recommended as the first testing modality and in cases where HER2 gene 
amplification status is also required, either a silver-enhanced in situ hybridization (SISH) or a FISH 
technique must be applied. SISH technology is however, recommended to allow for the parallel 
evaluation of tumour 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. 
 



19 

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3: 
 
Table 3 Recommended scoring system to evaluate the IHC staining patterns in gastric cancer 
 
Score Surgical specimen - staining 

pattern 
Biopsy specimen – 
staining pattern 

HER2 
overexpression 
assessment 

 
0 

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

No reactivity or membranous 
reactivity in any tumour cell 

 
Negative 

 
1+ 

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

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

 
Negative 

 
2+ 

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

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

 
Equivocal 

 
3+ 

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

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

 
Positive 

 
In general, SISH or FISH is considered positive if the ratio of the HER2 gene copy number per tumour 
cell to the chromosome 17 copy number is greater than or equal to 2. 
 
Clinical efficacy and safety 
 

Metastatic breast cancer 

 

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 



20 

classified as staining 2+ or 3+ were included, while those staining 0 or 1+ were excluded. Greater than 
70 % of patients enrolled exhibited 3+ overexpression. The data suggest that beneficial effects were 
greater among those patients with higher levels of overexpression of HER2 (3+). 
 
The main test method used to determine HER2 positivity in the pivotal trial of docetaxel, with or 
without 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. 
 



21 

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) 

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) 
 
EBC 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. 

 



22 

EBC 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: 
 
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 
- No. patients without event  
P-value versus Observation  
Hazard Ratio versus Observation 

 
219 (12.9 %)        127 (7.5 %) 

1474 (87.1 %)     1566 (92.5 %) 
< 0.0001 

0.54 

 
570 (33.6 %)       471 (27.7 %) 
1127 (66.4 %)     1231 (72.3 %) 

< 0.0001 
0.76 

Recurrence-free survival 
- No. patients with event 
- No. patients without event  
P-value versus Observation  
Hazard Ratio versus Observation 

 
208 (12.3 %)        113 (6.7 %) 

1485 (87.7 %)     1580 (93.3 %) 
< 0.0001 

0.51 

 
506 (29.8 %)       399 (23.4 %) 
1191 (70.2 %)     1303 (76.6 %) 

< 0.0001 
0.73 

Distant disease-free survival 
- No. patients with event 
- No. patients without event  
P-value versus Observation  
Hazard Ratio versus Observation 

 
184 (10.9 %)         99 (5.8 %) 

1508 (89.1 %)     1594 (94.6 %) 
< 0.0001 

0.50 

 
488 (28.8 %)       399 (23.4 %) 
1209 (71.2 %)     1303 (76.6 %) 

< 0.0001 
0.76 

Overall survival (death) 
- No. patients with event 
- No. patients without event  
P-value versus Observation  
Hazard Ratio versus Observation 

 
40 (2.4 %)           31 (1.8 %) 

1653 (97.6 %)     1662 (98.2 %) 
0.24 
0.75 

 
350 (20.6 %)       278 (16.3 %) 
1347 (79.4 %)     1424 (83.7 %) 

0.0005 
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 randomised 
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 



23 

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 yea r= 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. 
- 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 N9831 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 (%) 
 
Distant Recurrence 
No. patients with event 
 
Death (OS event): 
No. patients with event 

 
261 (15.5) 

 
 

193 (11.5) 
 
 

92 (5.5) 

 
133 (8.0) 

 
 

96 (5.7) 
 
 

62 (3.7) 

 
0.48 (0.39, 0.59) 

p < 0.0001 
 

0.47 (0.37, 0.60) 
p < 0.0001 

 
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 
 



24 

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→P H 
group). Treatment with AC→PH resulted in a statistically significant improvement in OS compared 
with AC→P (stratified HR = 0.64; 95% CI [0.55, 0.74]; log-rank p-value < 0.0001). At 8 years, the 
survival rate was estimated to be 86.9 % in the AC→PH arm and 79.4 % in the AC→P arm, an 
absolute benefit of 7.4 % (95 % CI 4.9 %, 10.0 %). 
 
The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are 
summarized in Table 8 below: 
 
Table 8 Final overall survival analysis from the joint analysis of trials NSABP B-31 and NCCTG 
N9831 
 
Parameter AC→P 

(N = 2032) 
AC→PH 

(N = 2031) 
p-value versus 

AC→P 
Hazard Ratio 
versus AC→P 

(95 % CI) 

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

 
418 (20.6 %) 

 
289 (14.2 %) 

 
< 0.0001 

 
0.64  

(0.55, 0.74) 
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab 
 
DFS analysis was also performed at the final analysis of OS from the joint analysis of studies NSABP 
B-31 and NCCTG N9831. The updated DFS analysis results (stratified HR = 0.61; 95% CI [0.54, 
0.69]) showed a similar DFS benefit compared to the definitive primary DFS analysis, despite 24.8 % 
patients in the AC→P arm who crossed over to receive 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. 



25 

 
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 
 
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) 
p-value 

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: 
 



26 

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 
(95 % CI) 
p-value 

 
0.48  

(0.39, 0.59) 
 p < 0.0001 

 
0.61 

(0.49, 0.77) 
 p < 0.0001 

 
0.67  

(0.54, 0.83)  
p = 0.0003 

Long term follow-up efficacy 
analysis** 
DFS Hazard ratios 
(95 % CI) 
p-value 

 
 

0.61 
(0.54, 0.69) 
p < 0.0001 

 
 

0.72 
(0.61, 0.85) 
p < 0.0001 

 
 

0.77 
(0.65, 0.90) 
p = 0.0011 

Post-hoc exploratory analysis 
with DFS and symptomatic 
cardiac events  
Long term follow-up** 
Hazard ratios 
(95 % CI) 

 
 
 

0.67  
(0.60, 0.75) 

 
 
 

0.77 
(0.66, 0.90) 

 
 
 

0.77  
(0.66, 0.90) 

A: doxorubicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel; Carb: carboplatin; H: trastuzumab 
CI = confidence interval 
* At the time of the definitive analysis of DFS. Median duration of follow up was 1.8 years in the 
AC→P arm and 2.0 years in the AC→PH arm 
** Median duration of long term follow-up for the Joint Analysis clinical studies was 8.3 years (range: 
0.1 to 12.1) for the AC→PH arm and 7.9 years (range: 0.0 to 12.2) for the AC→P arm; Median 
duration of long term follow-up for the BCIRG 006 study was 10.3 years in both the AC→D arm 
(range: 0.0 to 12.6) arm and the DCarbH arm (range: 0.0 to 13.1), and was 10.4 years (range: 0.0 to 
12.7) in the AC→DH arm 
 
Early breast cancer (neoadjuvant-adjuvant setting) 
 
So far, no results are available which compare the efficacy of 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 



27 

- 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 
 
No. patients with event 

 
 

46 

 
 

59 

Hazard Ratio 
(95 % CI) 

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 
 
No. patients with event 

 
 

22 

 
 

33 

Hazard Ratio 
(95 % CI) 

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. 
 
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. 
 



28 

The efficacy results from study BO18225 are summarised 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 were recruited to the trial who were previously untreated for HER2-positive inoperable locally 
advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal 
junction not amenable to curative therapy. The primary endpoint was overall survival which was 
defined as the time from the date of randomisation to the date of death from any cause. At the time of 
the analysis a total of 349 randomised patients had died: 182 patients (62.8 %) in the control arm and 
167 patients (56.8 %) in the treatment arm. The majority of the deaths were due to events related to the 
underlying cancer. 
 
Post-hoc subgroup analyses indicate that positive treatment effects are limited to targeting tumours 
with higher levels of HER2 protein (IHC 2+/FISH+ or IHC 3+). The median overall survival for the 
high HER2 expressing group was 11.8 months versus 16 months, HR 0.65 (95 % CI 0.51-0.83) and 
the median progression free survival was 5.5 months versus 7.6 months, HR 0.64 (95 % CI 0.51-0.79) 
for FP versus FP + H, respectively. For overall survival, the HR was 0.75 (95 % CI 0.51-1.11) in the 
IHC 2+/FISH+ group and the HR was 0.58 (95 % CI 0.41-0.81) in the IHC 3+/FISH+ group. 
 
In an exploratory subgroup analysis performed in the TOGA (BO18255) trial there was no apparent 
benefit on overall survival with the addition of 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 the 
reference medicinal product containing trastuzumab in all subsets of the paediatric population for 
breast and gastric cancer (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis 
using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or 
other tumour types, and healthy volunteers, in 18 Phase I, II and III trials receiving trastuzumab IV. A 
two-compartment model with parallel linear and non-linear elimination from the central compartment 
described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance 
increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can 
be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval (see Table 16). 
MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central compartment 
volume (Vc)) and population-predicted steady-state exposures (Cmin, Cmax and AUC). Linear clearance 
was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC. The non-linear elimination 



29 

parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 mcg/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 a statistically significant covariates affecting the 
exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab 
exposure suggests that these covariates are unlikely to have a clinically meaningful effect on 
trastuzumab concentrations. 
 
The population predicted PK exposure values (median with 5th - 95th Percentiles) and PK parameter 
values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treated 
with the approved q1w and q3w dosing regimens are shown in Table 14 (cycle 1), Table 15 (steady- 
state), and Table 16 (PK parameters). 
 
Table 14 Population predicted cycle 1 PK exposure values (median with 5th - 95th percentiles) 
fortrastuzumab intravenous dosing regimens in MBC, EBC and AGC patients 
 

Regimen Primary tumour type N 
Cmin 

(mcg/mL) 
Cmax 

(mcg/mL) 
AUC0-21days 

(mcg.day/mL) 
 

8 mg/kg + 
6 mg/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) 

 
4 mg/kg + 

2 mg/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) 

 



30 

Table 15 Population predicted steady state PK exposure values (median with 5th - 95th percentiles)for 
trastuzumab intravenous dosing regimens in MBC, EBC and AGC patients 
 
 
Regimen 

 
Primary 

tumour type 

 
N 

 
Cmin,ss* 

(mcg/mL) 

 
Cmax,ss** 

(mcg/mL) 

 
AUCss, 0-21days 

(mcg.day/mL) 

Time to 
steady- 
state*** 
(week) 

 
8 mg/kg + 

6 mg/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 

 
4 mg/kg + 

2 mg/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 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) 

8 mg/kg + 
6 mg/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 

4 mg/kg + 
2 mg/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 mcg/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. 
 



31 

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.  
 
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 
L-histidine 
Sorbitol (E420) 
Macrogol 3350 
Hydrochloric acid (for pH adjustment) 
Sodium hydroxide (for pH adjustment) 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed or diluted with other medicinal products except those 
mentioned in section 6.6. 
 
Glucose solutions must not be used for dilution since these cause aggregation of the protein. 
 
6.3 Shelf life 
 
4 years. 
 
After reconstitution with sterile water for injections, the reconstituted solution is physically and 
chemically stable for 48 hours at 2°C – 8°C. Any remaining reconstituted solution should be 
discarded. 
 
Solutions of Ogivri for intravenous infusion are physically and chemically stable in polyvinylchloride, 
polyethylene or polypropylene bags containing sodium chloride 9 mg/mL (0.9 %) solution for 
injection for 24 hours at temperatures not exceeding 30°C. 
 
From a microbiological point of view, the reconstituted solution and Ogivri infusion solution should 
be used immediately. The product is not intended to be stored after reconstitution and dilution unless 
this has taken place under controlled and validated aseptic conditions. If not used immediately, in-use 
storage times and conditions are the responsibility of the user. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C). 
 
For storage conditions after reconstitution of the medicinal product, see sections 6.3 and 6.6. 
 



32 

6.5 Nature and contents of container  
 
Ogivri 150 mg powder for concentrate for solution for infusion 
 
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. 
 
Ogivri 420 mg powder for concentrate for solution for infusion 
 
50 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 
 
Ogivri should be carefully handled during reconstitution. Causing excessive foaming during 
reconstitution or shaking the reconstituted solution may result in problems with the amount of Ogivri 
that can be withdrawn from the vial. 
 
The reconstituted solution should not be frozen.  
 
Ogivri 150 mg powder for concentrate for solution for infusion 
 
Appropriate aseptic technique should be used. Each 150 mg vial of Ogivri is reconstituted with 7.2 mL 
of sterile 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, 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. 
 
Ogivri 420 mg powder for concentrate for solution for infusion 
 
Each 420 mg vial of Ogivri is reconstituted with 20 mL of sterile 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, at a pH of approximately 6.0. A volume 
overage of 4.8 % ensures that the labelled dose of 420 mg can be withdrawn from each vial. 
 

Ogivri 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 reconstitution 
 
1) Using a sterile syringe, slowly inject the appropriate volume (as noted above) of sterile water for 
injections in the vial containing the lyophilised Ogivri, 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 Ogivri results in a colourless to pale yellow transparent 
solution and should be essentially free of visible particulates. 
 



33 

Determine the volume of the solution required: 
 
•    based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose of 2 mg 
trastuzumab/kg body weight: 
 

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

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

Volume (mL) = Body weight (kg) x dose (8 mg/kg for loading or 6 mg/kg for maintenance) 
21 (mg/mL, concentration of reconstituted solution) 

 
The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag 
containing 250 mL of sodium chloride 9 mg/mL (0.9 %) solution for injection. 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. Once the infusion is prepared it should be administered immediately. If diluted 
aseptically, it may be stored for 24 hours (do not store above 30°C). 
 
Parenteral medicinal products should be inspected visually for particulate matter and discoloration 
prior to administration. 
 
Ogivri is for single-use only, as the product contains no preservatives.  
 
No incompatibilities between Ogivri 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 
 
Mylan S.A.S. 
117 allée des Parcs 
69800 Saint-Priest 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1341/001 
EU/1/18/1341/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 12 December 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 



34 

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

  

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


35 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 

 



36 

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)  

Biocon Biologics India Limited 
Block No. B1, B2, Q13 of Q1 and W20 &  
Unit S18, 1st Floor, Block B4 
Special Economic Zone Plot Nos. 2, 3, 4 & 5 
Phase-IV-Bommasandra-Jigani Link Road-Bommasandra Post 
560 099 Bengaluru 
INDIA 
 
Name and address of the manufacturer(s) responsible for batch release 

McDermott Laboratories Limited T/A Mylan Dublin Biologics 
Newenham Court 
Northern Cross 
Malahide Road 
Dublin 17 
Ireland 
 
Mylan Germany GmbH 
Zweigniederlassung Bad Homburg v. d. Hoehe, Benzstrasse 1 
Bad Homburg v. d. Hoehe 
Hessen, 61352,  
Germany 

 
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 



37 

and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

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

  



38 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



39 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



40 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ogivri 150 mg powder for concentrate for solution for infusion 
trastuzumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
The vial contains 150 mg trastuzumab.  
After reconstitution, 1 mL concentrate contains 21 mg of trastuzumab. 
 
 
3. LIST OF EXCIPIENTS 
 
L-histidine hydrochloride, L-histidine, sorbitol (E420), macrogol 3350, hydrochloric acid and sodium 
hydroxide.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use only after reconstitution and dilution 
 
 
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 
 
  



41 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
 
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 
 
Mylan S.A.S. 
117 allée des Parcs 
69800 Saint-Priest 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1341/001 
 
 
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 
  



42 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ogivri 150 mg powder for concentrate 
trastuzumab 
For IV 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 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ogivri 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 
 
L-histidine hydrochloride, L-histidine, sorbitol (E420), macrogol 3350, hydrochloric acid and sodium 
hydroxide.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use only after reconstitution and dilution 
 
 
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 
 
  



44 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
 
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 
 
Mylan S.A.S. 
117 allée des Parcs 
69800 Saint-Priest 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1341/002 
 
 
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  



45 

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



46 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



47 

Package leaflet: Information for the user 
 

Ogivri 150 mg powder for concentrate for solution for infusion 
Ogivri 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, pharmacist or nurse. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

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

 
 
2. What you need to know before you are given Ogivri  
 

Do not use Ogivri: 
• if you are allergic to trastuzumab, murine (mouse) proteins, or any of the other ingredients 

of this medicine (listed in section 6). 



48 

• if you have severe breathing problems at rest due to your cancer or if you need oxygen 
treatment. 

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

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

 
• you have ever had any other treatment for cancer. 
 
If you receive Ogivri 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 
Ogivri is not recommended for anyone under the age of 18 years. 
 
Other medicines and Ogivri 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any 
other medicines. 
 
It may take up to 7 months for Ogivri to be removed from the body. Therefore, you should tell your 
doctor, pharmacist or nurse that you have had Ogivri if you start any new medicine in the 7 months after 
stopping treatment. 
 
Pregnancy and breast-feeding  
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, 
ask your doctor, pharmacist or nurse for advice before taking this medicine. 
 



49 

Pregnancy 
 
• You should use effective contraception during treatment with Ogivri and for at least 7 

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

 
Breast-feeding 
 
Do not breast-feed your baby during Ogivri therapy and for 7 months after the last dose of Ogivri as 
this medicine may pass to your baby through your breast milk. Ask your doctor or pharmacist for 
advice before taking any medicine. 
 
Driving and using machines 
Ogivri 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. 
 
Ogivri contains sorbitol (E420) 
Ogivri 150 mg powder for concentrate for solution for infusion. 
This medicine contains 115.2 mg sorbitol in each vial.  
 
Ogivri 420 mg powder for concentrate for solution for infusion. 
This medicine contains 322.6 mg sorbitol in each vial.  
 
Sorbitol is a source of fructose. If you have hereditary fructose intolerance (HFI), a rare genetic 
disorder, you must not receive this medicine. Patients with HFI cannot break down fructose, which 
may cause serious side effects.  
You must tell your doctor before receiving this medicine if you have HFI or if you can no longer take 
sweet foods or drinks because you feel sick, vomit or get unpleasant effects such as bloating, stomach 
cramps or diarrhoea. 
 
 
3. How Ogivri 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 Ogivri. Ogivri 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 Ogivri depends on your body weight. 
 
The first dose of your treatment is given over 90 minutes and you will be observed by a health 
professional while it is being given in case you have any side effects. If the first dose is well tolerated 
the next doses may be given over 30 minutes (see section 2 under “Warnings and precautions”). The 
number of infusions you receive will depend on how you respond to the treatment. Your doctor will 
discuss this with you. 
  
Ogivri 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. 
 
For early breast cancer, metastatic breast cancer and metastatic gastric cancer, Ogivri is given every 3 
weeks. Ogivri may also be given once a week for metastatic breast cancer. 
 



50 

In order to prevent medication errors it is important to check the vial labels to ensure that the medicine 
being prepared and given is Ogivri (trastuzumab) and not trastuzumab emtansine. 
 
If you stop using Ogivri 
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 Ogivri to be removed from your body. Therefore, your doctor may 
decide to continue to check your heart functions, even after you finish treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Some of these side effects may be serious and may lead to hospitalisation. 
 
During an Ogivri 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 Ogivri, 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 

characterised 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 



51 

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

fever 
• muscle pain 
• conjunctivitis (discharge with itching of the eyes and crusty eyelids) 
• watery eyes 
• nose bleeds 
• runny nose 
• hair loss 
• tremor 
• hot flush 
• dizziness 
• nail disorders 
• weight loss 
• loss of appetite 
• inability to sleep (insomnia) 
• altered taste 
• low platelet count 
• bruising 
• numbness or tingling of the fingers and toes 
• redness, swelling or sores in your mouth and/or throat 
• pain, swelling, redness or tingling of hands and/or feet 
• breathlessness 
• headache 
• cough 
• vomiting 
• nausea (feeling sick) 
 
Common side effects: may affect up to 1 in 10 people 
• allergic reactions  
• dry mouth and skin 
• throat infections  
• dry eyes 
• bladder and skin infections  
• sweating 
• shingles  
• feeling weak and unwell 



52 

• inflammation of the breast  
• anxiety 
• inflammation of the liver  
• depression 
• kidney disorders  
• abnormal thinking 
• increased muscle tone or tension (hypertonia)  
• asthma 
• infection of lungs 
• pain in the arms and/or legs  
• lung disorders 
• itchy rash  
• back pain 
• sleepiness (somnolence)  
• neck pain 
• haemorrhoids (swelling of blood vessels around the back passage)  
• bone pain 
• itchiness  
• acne 
• leg cramps 
 
Uncommon side effects: may affect up to 1 in 100 people 
• deafness 
• bumpy rash 
• blood infection 
 
Rare side effects: may affect up to 1 in 1000 people 
• muscle weakness 
• jaundice (yellowing of the skin and the whites of the eyes) 
• inflammation or scarring of the lungs 
 
Side effects of not known frequency: frequency cannot be estimated from the available data 
• abnormal or impaired blood clotting 
• anaphylactic reactions (serious sudden allergic reaction with symptoms such as rash, itchy skin, 

difficulty breathing or feeling dizzy or faint) 
• high potassium levels 
• swelling of the brain 
• swelling or bleeding at the back of the eyes 
• shock (a dangerous decrease of blood pressure causing symptoms like rapid, shallow breathing, 

cold, clammy skin, a rapid, weak pulse, dizziness, weakness and fainting) 
• 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 



53 

• abnormally low levels of fluid around baby in womb 
• failure of lungs to develop in the womb 
• abnormal kidney development in the womb 
 
Some of the side effects you experience may be due to your underlying breast cancer. If you receive 
Ogivri in combination with chemotherapy, some of them may also be due to the chemotherapy.  
 
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 Ogivri 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton and on the vial label 
after EXP. The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C). 
 
Infusion solutions should be used immediately after dilution. Do not use Ogivri if you notice any 
particulate matter or discoloration prior to administration. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Ogivri contains  
 
- The active substance is trastuzumab. Each vial contains either; 

o 150 mg trastuzumab that has to be dissolved in 7.2 mL of water for injections, or 
o 420 mg trastuzumab that has to be dissolved in 20 mL of water for injections.  

- The resulting solution contains approximately 21 mg/mL trastuzumab. 
- The other ingredient(s) are L-histidine hydrochloride, L-histidine, sorbitol (E420 (see section 2 

“Ogivri contains sorbitol”)), macrogol 3350, hydrochloric acid and sodium hydroxide (for pH 
adjustment). 

 
What Ogivri looks like and contents of the pack 
 
Ogivri 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  
Mylan S.A.S. 
117 allée des Parcs 
69800 Saint-Priest 
France 
 

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


54 

Manufacturer 
McDermott Laboratories Limited T/A Mylan Dublin Biologics 
Newenham Court 
Northern Cross 
Malahide Road 
Dublin 17 
Ireland 
 
Mylan Germany GmbH 
Zweigniederlassung Bad Homburg v. d. Hoehe, Benzstrasse 1 
Bad Homburg v. d. Hoehe 
Hessen, 61352,  
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

België/Belgique/Belgien 
Mylan EPD bvba/sprl 
Tél/Tel: + 32 (0)2 658 61 00 
 

Lietuva 
Mylan Healthcare UAB 
Tel: +370 5 205 1288 
 

България 
Майлан ЕООД 
Teл.: +359 2 44 55 400 
 

Luxembourg/Luxemburg 
Mylan EPD bvba/sprl 
Tel: + 32 (0)2 658 61 00 
(Belgique/Belgien) 
 

Česká republika 
Mylan Healthcare CZ s.r.o. 
Tel: +420 222 004 400 
 

Magyarország 
Mylan EPD Kft 
Tel: + 36 1 465 2100  

Denmark 
Mylan Denmark ApS 
Tlf: +45 28116932 
 

Malta 
V.J. Salomone Pharma Ltd 
Tel: + 356 21 22 01 74 
 

Deutschland 
Mylan Healthcare GmbH  
Tel: +49 800 0700 800 
 

Nederland 
Mylan Healthcare B.V. 
Tel: +31 (0)20 426 3300 

Eesti 
BGP Products Switzerland GmbH Eesti 
filiaal 
Tel: + 372 6363 052 
 

Norge 
Mylan Healthcare Norge AS 
Tel: + 47 66 75 33 00 
 

Ελλάδα  
BGP ΠΡΟΪΟΝΤΑ Μ.Ε.Π.Ε.  
Τηλ:  +30 210 9891 777 
 

Österreich 
Mylan Österreich GmbH 
Tel: +43 1 86390 
 



55 

España 
Mylan Pharmaceuticals, S.L. 
Tel: +34 900 102 712 
 

Polska 
Mylan Healthcare Sp. z o.o. 
Tel: + 48 22 546 64 00 
 

France 
Mylan Medical SAS 
Tel: +33 1 56 64 10 70 
 

Portugal 
Mylan, Lda. 
Tel: + 351 21 412 72 56 
 

Hrvatska 
Mylan Hrvatska d.o.o.   
Tel: +385 1 23 50 599 

România 
BGP Products SRL 
Tel: + 40 372 579 000 
 

Ireland 
Mylan Ireland Limited 
Tel: +353 (0) 87 1694982  

Slovenija 
Mylan Healthcare d.o.o. 
Tel: + 386 1 236 31 80 
 

Ísland 
Icepharma hf 
Tel: +354 540 8000 
 

Slovenská republika 
Mylan s.r.o. 
Tel: +421 2 32 199 100 

Italia 
Mylan Italia SRL 
Tel: + 39 02 612 46921 
 

Suomi/Finland 
Mylan Finland OY 
Puh/Tel: + 358 20 720 9555 

Κύπρος 
Varnavas Hadjipanayis Ltd. 
Τηλ: + 357 2220 7723 
 

Sverige 
Mylan AB  
Tel: + 46 855 522 750 
 

Latvija 
Mylan Healthcare SIA  
Tel: +371 676 055 80 

United Kingdom 
Generics [UK] Ltd 
Tel: +44 1707 853000 

 
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. 
 
 
---------------------------------------------------------------------------------------------------------------------------  
 



56 

The following information is intended for healthcare professionals only 
 
Always keep this medicine in the closed original pack at a temperature of 2ºC – 8 ºC in a refrigerator. 
A vial of Ogivri reconstituted with water for injections (not supplied) is stable for 48 hours at 
2ºC – 8ºC after reconstitution and must not be frozen. 
 
Ogivri should be carefully handled during reconstitution. Causing excessive foaming during 
reconstitution or shaking the reconstituted Ogivri may result in problems with the amount of 
Ogivri that can be withdrawn from the vial. 
 
Ogivri 150 mg powder for concentrate for solution for infusion 
Appropriate aseptic technique should be used. Each 150 mg vial of Ogivri is reconstituted with 
7.2 mL of sterile 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. 
 
Ogivri 420 mg powder for concentrate for solution for infusion 
Appropriate aseptic technique should be used. Each 420 mg vial of Ogivri is reconstituted with 20 mL 
of sterile 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 4.8 % ensures that the labelled dose of 420 mg can be withdrawn from each vial. 
 

Ogivri 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 reconstitution 
 
1) Using a sterile syringe, slowly inject the appropriate volume (as noted above) of water for 
injections in the vial containing the lyophilised Ogivri, 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 Ogivri results in a colourless to pale yellow 
transparent solution and should be essentially free of visible particulates. 
 
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) 
 



57 

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 sodium 
chloride 9 mg/mL (0.9%) solution for injection. 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. Once the 
infusion is prepared it should be administered immediately. If diluted aseptically, it may be stored 
for 24 hours (do not store above 30°C). 
 


	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