ZERCEPAC 60mg powder for concentrate infusion solution medication leaflet

Zercepac 60 mg powder for concentrate for solution for infusion

Zercepac 150 mg powder for concentrate for solution for infusion

Zercepac 420 mg powder for concentrate for solution for infusion

Zercepac 60 mg powder for concentrate for solution for infusion

One vial contains 60 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced bymammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion exchangechromatography including specific viral inactivation and removal procedures.

Zercepac 150 mg powder for concentrate for solution for infusion

One vial contains 150 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced bymammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion exchangechromatography including specific viral inactivation and removal procedures.

Zercepac 420 mg powder for concentrate for solution for infusion

One vial contains 420 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced bymammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion exchangechromatography including specific viral inactivation and removal procedures.

The reconstituted Zercepac solution contains 21 mg/mL of trastuzumab.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to pale yellow lyophilised powder.

Breast cancer

Metastatic breast cancer

Zercepac 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 chemotherapyregimens for their metastatic disease. Prior chemotherapy must have included at least ananthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptorpositive patients must also have failed hormonal therapy, unless patients are unsuitable for thesetreatments.

- in combination with paclitaxel for the treatment of those patients who have not receivedchemotherapy 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 receivedchemotherapy for their metastatic disease.

- in combination with an aromatase inhibitor for the treatment of postmenopausal patients withhormone-receptor positive MBC, not previously treated with trastuzumab.

Early breast cancer

Zercepac 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) (seesection 5.1).

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

- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

- in combination with neoadjuvant chemotherapy followed by adjuvant Zercepac therapy, forlocally advanced (including inflammatory) disease or tumours > 2 cm in diameter (seesections 4.4 and 5.1).

Zercepac should only be used in patients with metastatic or early breast cancer whose tumours haveeither HER2 overexpression or HER2 gene amplification as determined by an accurate and validatedassay (see sections 4.4 and 5.1).

Metastatic gastric cancer

Zercepac in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatmentof adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-oesophagealjunction who have not received prior anti-cancer treatment for their metastatic disease.

Zercepac 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).

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Zercepac treatmentshould 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.

Zercepac intravenous formulation is not intended for subcutaneous administration and should beadministered via an intravenous infusion only.

In order to prevent medication errors, it is important to check the vial labels to ensure that themedicinal product being prepared and administered is Zercepac (trastuzumab) and not anothertrastuzumab-containing product (e.g. trastuzumab emtansine or trastuzumab deruxtecan).

Metastatic breast cancer

Three-weekly schedule

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

Weekly schedule

The recommended initial loading dose of Zercepac is 4 mg/kg body weight. The recommended weeklymaintenance dose of Zercepac 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 thefirst dose of trastuzumab (for dose, see the Summary of Product Characteristics (SmPC) for paclitaxelor docetaxel) and immediately after the subsequent doses of trastuzumab if the preceding dose oftrastuzumab was well tolerated.

Administration in combination with an aromatase inhibitor

In the pivotal trial (BO16216) trastuzumab and anastrozole were administered from day 1. There wereno restrictions on the relative timing of trastuzumab and anastrozole at administration (for dose, seethe 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 Zercepac is 8 mg/kg body weight.

The recommended maintenance dose of Zercepac 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) concomitantlywith 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 doseat three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.

Breast cancer and gastric cancer

Patients with MBC or MGC should be treated with Zercepac until progression of disease.

Patients with EBC should be treated with Zercepac for 1 year or until disease recurrence, whicheveroccurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).

No reductions in the dose of Zercepac were made during clinical trials. Patients may continue therapyduring periods of reversible, chemotherapy-induced myelosuppression but they should be monitoredcarefully 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 below50%, treatment should be suspended and a repeat LVEF assessment performed within approximately3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure(CHF) has developed, discontinuation of Zercepac should be strongly considered, unless the benefitsfor the individual patient are deemed to outweigh the risks. All such patients should be referred forassessment by a cardiologist and followed up.

If the patient has missed a dose of Zercepac 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 aspossible. Do not wait until the next planned cycle. Subsequent maintenance doses should beadministered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

If the patient has missed a dose of Zercepac by more than one week, a re-loading dose of Zercepacshould be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weeklyregimen: 8 mg/kg) as soon as possible. Subsequent Zercepac maintenance doses (weekly regimen:2 mg/kg; three-weekly regimen 6 mg/kg respectively) should be administered 7 days or 21 days lateraccording to the weekly or three-weekly schedules respectively.

Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have notbeen carried out. In a population pharmacokinetic analysis, age and renal impairment were not shownto affect trastuzumab disposition.

There is no relevant use of Zercepac in the paediatric population.

Zercepac is for intravenous use only. The loading dose should be administered as a 90-minuteintravenous infusion. Do not administer as an intravenous push or bolus. Zercepac intravenousinfusion should be administered by a healthcare provider prepared to manage anaphylaxis and anemergency kit should be available. Patients should be observed for at least six hours after the start ofthe first infusion and for two hours after the start of the subsequent infusions for symptoms like feverand chills or other infusion-related symptoms (see sections 4.4 and 4.8). Interruption or slowing therate of the infusion may help control such symptoms. The infusion may be resumed when symptomsabate.

If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minuteinfusion.

For instructions on reconstitution of Zercepac intravenous formulation before administration, seesection 6.6.

* Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients listed in section 6.1

* Severe dyspnoea at rest due to complications of advanced malignancy or requiringsupplementary oxygen therapy.

In order to improve traceability of biological medicinal products, the trade name and the batch numberof the administered product should be clearly recorded.

HER2 testing must be performed in a specialised laboratory which can ensure adequate validation ofthe testing procedures (see section 5.1).

Currently no data from clinical trials are available on re-treatment of patients with previous exposureto Zercepac in the adjuvant setting.

Cardiac dysfunction

General considerations

Patients treated with Zercepac are at increased risk for developing CHF (New York Heart Association[NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed inpatients receiving trastuzumab therapy alone or in combination with paclitaxel or docetaxel,particularly following anthracycline (doxorubicin or epirubicin) containing chemotherapy. These maybe moderate to severe and have been associated with death (see section 4.8). In addition, cautionshould be exercised in treating patients with increased cardiac risk, e.g. hypertension, documentedcoronary artery disease, CHF, LVEF of <55%, older age.

All candidates for treatment with Zercepac, but especially those with prior anthracycline andcyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history andphysical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition(MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who developcardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 monthsduring treatment and every 6 months following discontinuation of treatment until 24 months from thelast administration of Zercepac. A careful risk-benefit assessment should be made before deciding totreat with Zercepac.

Trastuzumab may persist in the circulation for up to 7 months after stopping Zercepac treatment basedon population pharmacokinetic analysis of all available data (see section 5.2). Patients who receiveanthracyclines after stopping Zercepac may possibly be at increased risk of cardiac dysfunction. Ifpossible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping

Zercepac. 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 cardiovascularconcerns following baseline screening. In all patients cardiac function should be monitored duringtreatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiacdysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequentmonitoring (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

Zercepac therapy has been seen.

The safety of continuation or resumption of Zercepac in patients who experience cardiac dysfunctionhas not been prospectively studied. If LVEF percentage drops ≥10 points from baseline AND tobelow 50%, treatment should be suspended and a repeat LVEF assessment performed withinapproximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF hasdeveloped, discontinuation of Zercepac should be strongly considered, unless the benefits for theindividual patient are deemed to outweigh the risks. All such patients should be referred forassessment by a cardiologist and followed up.

If symptomatic cardiac failure develops during Zercepac therapy, it should be treated with standardmedicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunctionin pivotal trials improved with standard CHF treatment consisting of an angiotensin-convertingenzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority ofpatients with cardiac symptoms and evidence of a clinical benefit of trastuzumab treatment continuedon therapy without additional clinical cardiac events.

Metastatic breast cancer

Zercepac 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 dysfunctionwith Zercepac treatment, although the risk is lower than with concurrent use of Zercepac andanthracyclines.

Early breast cancer

For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every3 months during treatment and every 6 months following discontinuation of treatment until 24 monthsfrom the last administration of Zercepac. In patients who receive anthracycline-containingchemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the lastadministration of Zercepac, 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, cardiacarrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorlycontrolled hypertension (hypertension controlled by standard medical treatment eligible), andhemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBCpivotal trials with trastuzumab and therefore treatment cannot be recommended in such patients.

Adjuvant treatment

Zercepac and anthracyclines should not be given concurrently in combination in the adjuvanttreatment setting.

In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac eventswas observed when trastuzumab was administered after anthracycline-containing chemotherapycompared to administration with a non-anthracycline regimen of docetaxel and carboplatin and wasmore marked when trastuzumab was administered concurrently with taxanes than when administeredsequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurredwithin the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomaticcardiac or LVEF events was observed in patients who were administered trastuzumab concurrentlywith a taxane following anthracycline therapy up to 2.37% compared to approximately 1% in the twocomparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatinand trastuzumab).

Risk factors for a cardiac event identified in four large adjuvant studies included advanced age(>50 years), low LVEF (<55%) at baseline, prior to or following the initiation of paclitaxel treatment,decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products.

In patients receiving trastuzumab after completion of adjuvant chemotherapy, the risk of cardiacdysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation oftrastuzumab and a body mass index (BMI) >25 kg/m2.

Neoadjuvant-adjuvant treatment

In patients with EBC eligible for neoadjuvant-adjuvant treatment, Zercepac should be usedconcurrently with anthracyclines only in chemotherapy-naive patients and only with low-doseanthracycline regimens i.e. maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin360 mg/m2.

If patients have been treated concurrently with a full course of low-dose anthracyclines and Zercepacin the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. Inother situations, the decision on the need for additional cytotoxic chemotherapy is determined basedon individual factors.

Experience of concurrent administration of trastuzumab with low dose anthracycline regimens iscurrently limited to two trials (MO16432 and BO22227).

In the pivotal trial MO16432, trastuzumab was administered concurrently with neoadjuvantchemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2).

The incidence of symptomatic cardiac dysfunction was 1.7% in the trastuzumab arm.

In the pivotal trial BO22227, trastuzumab was administered concurrently with neoadjuvantchemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m2); at a medianfollow-up exceeding 70 months, the incidence of congestive cardiac failure was 0.3% in thetrastuzumab intravenous 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, respiratorydistress, urticaria and angioedema have been reported (see section 4.8). Pre-medication may be used toreduce risk of occurrence of these events. The majority of these events occur during or within2.5 hours of the start of the first infusion. Should an infusion reaction occur the infusion should bediscontinued or the rate of infusion slowed and the patient should be monitored until resolution of allobserved symptoms (see section 4.2). These symptoms can be treated with an analgesic/antipyreticsuch as meperidine or paracetamol, or an antihistamine such as diphenhydramine. The majority ofpatients experienced resolution of symptoms and subsequently received further infusions oftrastuzumab. 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 courseculminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications ofadvanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction.

Therefore, these patients should not be treated with Zercepac (see section 4.3).

Initial improvement followed by clinical deterioration and delayed reactions with rapid clinicaldeterioration have also been reported. Fatalities have occurred within hours and up to one weekfollowing infusion. On very rare occasions, patients have experienced the onset of infusion symptomsand pulmonary symptoms more than six hours after the start of the trastuzumab infusion. Patientsshould be warned of the possibility of such a late onset and should be instructed to contact theirphysician if these symptoms occur.

Pulmonary events

Severe pulmonary events have been reported with the use of trastuzumab in the post-marketing setting(see section 4.8). These events have occasionally been fatal. In addition, cases of interstitial lungdisease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis,pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have beenreported. Risk factors associated with interstitial lung disease include prior or concomitant therapywith 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 orwith a delayed onset. Patients experiencing dyspnoea at rest due to complications of advancedmalignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patientsshould not be treated with Zercepac (see section 4.3). Caution should be exercised for pneumonitis,especially in patients being treated concomitantly with taxanes.

No formal drug interaction studies have been performed. Clinically significant interactions between

Zercepac 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 MBCsuggested 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 or4 mg/kg IV loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w IV, respectively).

However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of thismetabolite was unclear.

Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg IV loading dose and 2 mg/kg

IV weekly) and docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggestedthat concomitant administration of trastuzumab had no effect on the single dose pharmacokinetics ofdocetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female

Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine andcisplatin when used with or without trastuzumab. The results of this substudy suggested that theexposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use ofcisplatin or by concurrent use of cisplatin plus trastuzumab. However, capecitabine itself showedhigher concentrations and a longer half-life when combined with trastuzumab. The data also suggestedthat the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or byconcurrent use of capecitabine plus trastuzumab.

Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advancedinoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.

Effect of antineoplastic agents on trastuzumab pharmacokinetics

By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy(4 mg/kg loading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with

HER2- positive MBC (study JP16003) no evidence of a PK effect of concurrent administration ofdocetaxel 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), inwomen with HER2-positive MBC indicates that individual and mean trastuzumab trough serumconcentrations varied within and across studies but there was no clear effect of the concomitantadministration of paclitaxel on the pharmacokinetics of trastuzumab. Comparison of trastuzumab PKdata from Study M77004 in which women with HER2-positive MBC were treated concomitantly withtrastuzumab, paclitaxel and doxorubicin to trastuzumab PK data in studies where trastuzumab wasadministered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamideor paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on thepharmacokinetics 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 oftrastuzumab.

Women of childbearing potential should be advised to use effective contraception during treatmentwith Zercepac and for 7 months after treatment has concluded (see section 5.2).

Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of theweekly human maintenance dose of 2 mg/kg trastuzumab intravenous formulation and have revealedno evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during theearly (days 20-50 of gestation) and late (days 120-150 of gestation) foetal development period wasobserved. It is not known whether trastuzumab can affect reproductive capacity. As animalreproduction studies are not always predictive of human response, trastuzumab should be avoidedduring 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 associationwith oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have beenreported in pregnant women receiving trastuzumab. Women who become pregnant should be advisedof the possibility of harm to the foetus. If a pregnant woman is treated with Zercepac, or if a patientbecomes pregnant while receiving Zercepac or within 7 months following the last dose of Zercepac,close monitoring by a multidisciplinary team is desirable.

A study conducted in Cynomolgus monkeys at doses 25 times that of the weekly human maintenancedose of 2 mg/kg trastuzumab intravenous formulation from days 120 to 150 of pregnancydemonstrated that trastuzumab is secreted in the milk postpartum. The exposure to trastuzumab inutero and the presence of trastuzumab in the serum of infant monkeys was not associated with anyadverse effects on their growth or development from birth to 1 month of age. It is not known whethertrastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the potentialfor harm to the infant is unknown, women should not breast-feed during Zercepac therapy and for7 months after the last dose.

There is no fertility data available.

Zercepac has minor influence on the ability to drive or use machines (see section 4.8).

Dizziness and somnolence may occur during treatment with Zercepac (see section 4.8).

Patients experiencing infusion-related symptoms (see section 4.4) should be advised not to drive anduse machines until symptoms abate.

Amongst the most serious and/or common adverse reactions reported in trastuzumab usage to date arecardiac dysfunction, infusion-related reactions, haematotoxicity (in particular neutropenia), infectionsand pulmonary 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 frequencygrouping, 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 ofintravenous trastuzumab alone or in combination with chemotherapy in pivotal clinical trials and in thepost-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 combinationwith chemotherapy in pivotal clinical trials (N = 8386) and in post-marketing

System organ class Adverse reaction Frequency

Infections and infestations Infection Very common

Nasopharyngitis Very common

Neutropenic sepsis Common

Cystitis Common

Influenza Common

Sinusitis Common

Skin infection Common

Rhinitis Common

Upper respiratory tract infection Common

Urinary tract infection Common

Pharyngitis Common

Neoplasms benign, malignant Malignant neoplasm progression Not knownand unspecified (incl. Cystsand polyps) Neoplasm progression Not known

Blood and lymphatic system Febrile neutropenia Very commondisorders Anaemia Very common

Neutropenia Very common

White blood cell count decreased/leukopenia Very common

Thrombocytopenia Very common

Hypoprothrombinaemia Not known

Immune thrombocytopenia Not known

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

Metabolism and nutrition Weight decreased/Weight loss Very commondisorders Anorexia Very common

System organ class Adverse reaction Frequency

Tumour lysis syndrome Not known

Hyperkalaemia Not known

Psychiatric disorders Insomnia Very common

Anxiety Common

Depression Common

Nervous system disorders 1Tremor Very common

Dizziness Very common

Headache Very common

Paraesthesia Very common

Dysgeusia Very common

Peripheral neuropathy Common

Hypertonia Common

Somnolence Common

Eye disorders Conjunctivitis Very common

Lacrimation increased Very common

Dry eye Common

Papilloedema Not known

Retinal haemorrhage Not known

Ear and labyrinth disorders Deafness Uncommon

Cardiac disorders 1Blood pressure decreased Very common1 Blood pressure increased Very common1 Heart beat irregular Very common1Cardiac flutter Very common

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

Cardiomyopathy Common1Palpitation Common

Pericardial effusion Uncommon

Cardiogenic shock Not known

Gallop rhythm present Not known

Vascular disorders Hot flush Very common+1Hypotension Common

Vasodilatation Common

Respiratory, thoracic and +Dyspnoea Very commonmediastinal disorders Cough Very common

Epistaxis Very common

Rhinorrhoea Very common+Pneumonia Common

Asthma Common

Lung disorder Common+Pleural effusion Common+1Wheezing Uncommon

Pneumonitis Uncommon+Pulmonary fibrosis Not known+Respiratory distress Not known+Respiratory failure Not known+Lung infiltration Not known+Acute pulmonary oedema Not known+Acute respiratory distress syndrome Not known+Bronchospasm Not known+Hypoxia Not known+Oxygen saturation decreased Not known

System organ class Adverse reaction Frequency

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 common1 Lip swelling Very common

Abdominal pain Very common

Dyspepsia Very common

Constipation Very common

Stomatitis Very common

Haemorrhoids Common

Dry mouth Common

Hepatobiliary disorders Hepatocellular injury Common

Hepatitis Common

Liver tenderness Common

Jaundice Rare

Skin and subcutaneous tissue Erythema Very commondisorders Rash Very common1Swelling face Very common

Alopecia Very common

Nail disorder Very common

Palmar-plantar erythrodysaesthesia Very commonsyndrome

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 Arthralgia Very commonconnective tissue disorders 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 Oligohydramnios Not knownperinatal conditions Renal hypoplasia Not known

Pulmonary hypoplasia Not known

Reproductive system and Breast inflammation/mastitis Commonbreast disorders

System organ class Adverse reaction Frequency

General disorders and Asthenia Very commonadministration site conditions 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 Contusion Commonprocedural complications+ 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-relatedreactions. Specific percentages for these are not available.

* Observed with combination therapy following anthracyclines and combined with taxanes

Cardiac dysfunction

Congestive heart failure (NYHA Class II - IV) is a common adverse reaction associated with the useof trastuzumab and has been associated with a fatal outcome (see section 4.4). Signs and symptoms ofcardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, orreduced ventricular ejection fraction, have been observed in patients treated with trastuzumab (seesection 4.4).

In 3 pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy, theincidence of grade 3/4 cardiac dysfunction (specifically symptomatic Congestive Heart Failure) wassimilar in patients who were administered chemotherapy alone (i.e. did not receive trastuzumab) andin patients who were administered trastuzumab sequentially after a taxane (0.3-0.4%). The rate washighest in patients who were administered trastuzumab concurrently with a taxane (2.0%). In theneoadjuvant setting, the experience of concurrent administration of trastuzumab and low doseanthracycline regimen is limited (see section 4.4).

When trastuzumab was administered after completion of adjuvant chemotherapy NYHA Class III-IVheart failure was observed in 0.6% of patients in the one-year arm after a median follow-up of12 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 mildsymptomatic 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 mildsymptomatic 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 variedbetween 9% and 12% when it was combined with paclitaxel compared with 1%-4% for paclitaxelalone. For monotherapy, the rate was 6% - 9%. The highest rate of cardiac dysfunction was seen inpatients receiving trastuzumab concurrently with anthracycline/cyclophosphamide (27%), and wassignificantly higher than for anthracycline/cyclophosphamide alone (7%-10%). In a subsequent trialwith prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2% inpatients 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 animprovement 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 experiencesome form of infusion-related reaction. However, the majority of infusion-related reactions are mild tomoderate in intensity (NCI-CTC grading system) and tend to occur earlier in treatment, i.e. duringinfusions 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-relatedreactions of all grades varied between studies depending on the indication, the data collectionmethodology, and whether trastuzumab was given concurrently with chemotherapy or asmonotherapy.

Severe anaphylactic reactions requiring immediate additional intervention can occur usually duringeither the first or second infusion of trastuzumab (see section 4.4) and have been associated with afatal outcome.

Anaphylactoid reactions have been observed in isolated cases.

Haematotoxicity

Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred verycommonly. The frequency of occurrence of hypoprothrombinaemia is not known. The risk ofneutropenia may be slightly increased when trastuzumab is administered with docetaxel followinganthracycline therapy.

Pulmonary events

Severe pulmonary adverse reactions occur in association with the use of trastuzumab and have beenassociated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acuterespiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acutepulmonary oedema and respiratory insufficiency (see section 4.4).

Details of risk minimisation measures that are consistent with the EU Risk Management Plan arepresented in (section 4.4) Warnings and Precautions.

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 againsttrastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of30 patients in the trastuzumab intravenous arm.

The clinical relevance of these antibodies is not known. The presence of anti-trastuzumab antibodieshad no impact on pharmacokinetics, efficacy (determined by pathological Complete Response [pCR]and event free survival [EFS]) and safety determined by occurrence of administration related reactions(ARRs) of trastuzumab intravenous.

There are no immunogenicity data available for trastuzumab in gastric cancer.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience with overdose in human clinical trials. Single doses of Zercepac alone greaterthan 10 mg/kg have not been administered in the clinical trials; a maintenance dose of 10 mg/kg q3wfollowing a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic gastric cancerpatients. Doses up to this level were well tolerated.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FD01

Zercepac 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 epidermalgrowth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20%-30% of primary breastcancers. 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 shownthat there is a broad variation of HER2-positivity ranging from 6.8% to 34.0% for IHC and 7.1% to42.6% for FISH. Studies indicate that breast cancer patients whose tumours overexpress HER2 have ashortened disease-free survival compared to patients whose tumours do not overexpress HER2. Theextracellular domain of the receptor (ECD, p105) can be shed into the blood stream and measured inserum samples.

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 HER2signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanismof HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibitthe proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potentmediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated

ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells comparedwith 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

Zercepac should only be used in patients whose tumours have HER2 overexpression or HER2 geneamplification as determined by an accurate and validated assay. HER2 overexpression should bedetected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (seesection 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

Zercepac treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or apositive FISH or CISH result.

To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory,which can ensure validation of the testing procedures.

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:

Table 2 Recommended scoring system to evaluate the IHC staining patterns in breast cancer

Score Staining pattern HER2 overexpressionassessment0 No staining is observed or membrane staining is Negativeobserved in <10% of the tumour cells

A faint/barely perceptible membrane staining is Negative1+ detected in >10% of the tumour cells. The cells areonly stained in part of their membrane.

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

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

In general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell tothe 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 nucleusin greater than 50% of tumour cells.

For full instructions on assay performance and interpretation please refer to the package inserts ofvalidated 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, theanalyses should only be performed by laboratories that provide adequate state-of-the-art performanceof validated methods. Such methods must clearly be precise and accurate enough to demonstrateoverexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) andstrong (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 geneamplification. IHC is recommended as the first testing modality and in cases where HER2 geneamplification status is also required, either a silver-enhanced in situ hybridization (SISH) or a FISHtechnique must be applied. SISH technology is however, recommended to allow for the parallelevaluation of tumour histology and morphology. To ensure validation of testing procedures and thegeneration of accurate and reproducible results, HER2 testing must be performed in a laboratorystaffed by trained personnel. Full instructions on assay performance and results interpretation shouldbe 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 weredefined as HER2 positive and thus included in the trial. Based on the clinical trial results, thebeneficial 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 observedfor 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 offixed tumour blocks; HER2 gene amplification should be detected using in situ hybridisation usingeither SISH or FISH on fixed tumour blocks.

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3:

Table 3 Recommended scoring system to evaluate the IHC staining patterns in gastric cancer

Score Surgical specimen - staining Biopsy specimen - staining HER2pattern pattern overexpressionassessment

No reactivity or membranous No reactivity or membranous0 reactivity in <10% of tumour reactivity in any tumour cell Negativecells

Faint ⁄ barely perceptible Tumour cell cluster with a faint ⁄membranous reactivity in barely perceptible membranous1+ ≥10% of tumour cells; cells are reactivity irrespective of Negativereactive only in part of their percentage of tumour cellsmembrane stained

Weak to moderate complete, Tumour cell cluster with a weakbasolateral or lateral to moderate complete, basolateral2+ membranous reactivity in or lateral membranous reactivity Equivocal≥10% of tumour cells irrespective of percentage oftumour cells stained

Strong complete, basolateral or Tumour cell cluster with a stronglateral membranous reactivity complete, basolateral or lateral3+ in ≥10% of tumour cells membranous reactivity Positiveirrespective of percentage oftumour cells stained

In general, SISH or FISH is considered positive if the ratio of the HER2 gene copy number per tumourcell to the chromosome 17 copy number is greater than or equal to 2.

Metastatic breast cancer

Trastuzumab has been used in clinical trials as monotherapy for patients with MBC who have tumoursthat overexpress HER2 and who have failed one or more chemotherapy regimens for their metastaticdisease (trastuzumab alone).

Trastuzumab has also been used in combination with paclitaxel or docetaxel for the treatment ofpatients who have not received chemotherapy for their metastatic disease. Patients who had previouslyreceived anthracycline-based adjuvant chemotherapy were treated with paclitaxel (175 mg/m2 infusedover 3 hours) with or without trastuzumab. In the pivotal trial of docetaxel (100 mg/m2 infused over1 hour) with or without trastuzumab, 60% of the patients had received prior anthracycline-basedadjuvant chemotherapy. Patients were treated with trastuzumab until progression of disease.

The efficacy of trastuzumab in combination with paclitaxel in patients who did not receive prioradjuvant anthracyclines has not been studied. However, trastuzumab plus docetaxel was efficacious inpatients whether or not they had received prior adjuvant anthracyclines.

The test method for HER2 overexpression used to determine eligibility of patients in the pivotaltrastuzumab monotherapy and trastuzumab plus paclitaxel clinical trials employedimmunohistochemical staining for HER2 of fixed material from breast tumours using the murinemonoclonal antibodies CB11 and 4D5. These tissues were fixed in formalin or Bouin’s fixative. Thisinvestigative clinical trial assay performed in a central laboratory utilised a 0 to 3+ scale. Patientsclassified as staining 2+ or 3+ were included, while those staining 0 or 1+ were excluded. Greater than70% of patients enrolled exhibited 3+ overexpression. The data suggest that beneficial effects weregreater 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 orwithout trastuzumab, was immunohistochemistry. A minority of patients was tested using fluorescencein-situ hybridisation (FISH). In this trial, 87% of patients entered had disease that was IHC3+, and95% 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 Trastuzumab Paclitaxel2 Trastuzumab Docetaxel3plus paclitaxel2 plus docetaxel3

N=172 N=68 N=77 N=92 N=94

Response rate 18% 49% 17% 61% 34%(95%CI) (13 - 25) (36 - 61) (9 - 27) (50-71) (25-45)

Median durationof response 9.1 8.3 4.6 11.7 5.7(months) (5.6-10.3) (7.3-8.8) (3.7-7.4) (9.3 - 15.0) (4.6-7.6)(95%CI)

Median TTP(months) 3.2 7.1 3.0 11.7 6.1(95%CI) (2.6-3.5) (6.2-12.0) (2.0-4.4) (9.2-13.5) (5.4-7.2)

Median Survival 22.74(months) 16.4 24.8 17.9 31.2(95%CI) (12.3-ne) (18.6-33.7) (11.2-23.8) (27.3-40.8) (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 subset2. Study H0648g: IHC3+ patient subset3. 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. oestrogen-receptor (ER) and/or progesterone-receptor(PR)) positive postmenopausal patients. Progression free survival was doubled in the trastuzumab plusanastrozole arm compared to anastrozole (4.8 months versus 2.4 months). For the other parameters theimprovements seen for the combination were for overall response (16.5% versus 6.7%); clinicalbenefit rate (42.7% versus 27.9%); time to progression (4.8 months versus 2.4 months). For time toresponse and duration of response no difference could be recorded between the arms. The medianoverall survival was extended by 4.6 months for patients in the combination arm. The difference wasnot statistically significant, however more than half of the patients in the anastrozole alone armcrossed over to a trastuzumab containing regimen after progression of disease.

Three -weekly dosing in metastatic breast cancer

The efficacy results from the non-comparative monotherapy and combination therapy studies aresummarised in Table 5:

Table 5 Efficacy results from the non-comparative monotherapy and combination therapy studies

Parameter Monotherapy Combination therapy

Trastuzumab1 Trastuzumab2 Trastuzumab plus Trastuzumab pluspaclitaxel3 docetaxel4

N=105 N=72 N=32 N=110

Response rate 24% 27% 59% 73%(95%CI) (15 - 35) (14 - 43) (41-76) (63-81)

Median duration 10.1 7.9 10.5 13.4of response (2.8-35.6) (2.1-18.8) (1.8-21) (2.1-55.1)(months) (range)

Median TTP 3.4 7.7 12.2 13.6(months) (2.8-4.1) (4.2-8.3) (6.2-ne) (11-16)(95%CI)

Median Survival ne ne ne 47.3(months) (32-ne)(95%CI)

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 schedule2. Study MO16982: loading dose 6 mg/kg weekly x 3; followed by 6 mg/kg 3-weekly schedule3. Study BO159354. Study MO16419

Sites of progression

The frequency of progression in the liver was significantly reduced in patients treated with thecombination 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 nervoussystem than those treated with paclitaxel alone (12.6% versus 6.5%; p=0.377).

Early breast cancer (adjuvant setting)

Early breast cancer is defined as non-metastatic primary invasive carcinoma of the breast.

In the adjuvant treatment setting, trastuzumab was investigated in 4 large multicentre, randomised,trials.

- Study BO16348 was designed to compare one and two years of three-weekly trastuzumabtreatment versus observation in patients with HER2 positive EBC following surgery, establishedchemotherapy and radiotherapy (if applicable). In addition, comparison of two years oftrastuzumab treatment versus one year of trastuzumab treatment was performed. Patientsassigned to receive trastuzumab were given an initial loading dose of 8 mg/kg, followed by6 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 toinvestigate the clinical utility of combining trastuzumab treatment with paclitaxel following ACchemotherapy, additionally the NCCTG N9831 study also investigated adding trastuzumabsequentially to AC→P chemotherapy in patients with HER2 positive EBC following surgery.

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

Early breast cancer in the HERA trial was limited to operable, primary, invasive adenocarcinoma ofthe 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 withoperable 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 negativeor 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 risknode negative patients with no (pN0) lymph node involvement, and at least 1 of the following factors:tumour size greater than 2 cm, oestrogen receptor and progesterone receptor negative, histologicaland/or nuclear grade 2-3, or age <35 years.

The efficacy results from the BO16348 trial following 12 months* and 8 years** median follow-upare summarized in Table 6:

Table 6 Efficacy results from study BO16348

Median follow-up Median follow-up12 months* 8 years**

Parameter Observation Trastuzumab Observation Trastuzumab

N=1693 1 Year N= 1697*** 1 Year

N = 1693 N = 1702***

Disease-free survival

- No. patients with event 219 (12.9%) 127 (7.5%) 570 (33.6%) 471 (27.7%)

- No. patients without event 1474 (87.1%) 1566 (92.5%) 1127 (66.4%) 1231 (72.3%)

P-value versus Observation < 0.0001 < 0.0001

Hazard Ratio versus Observation 0.5 4 0.7 6

Recurrence-free survival

- No. patients with event 208 (12.3%) 113 (6.7%) 506 (29.8%) 399 (23.4%)

- No. patients without event 1485 (87.7%) 1580 (93.3%) 1191 (70.2%) 1303 (76.6%)

P-value versus Observation < 0.0001 < 0.0001

Hazard Ratio versus Observation 0.5 1 0.7 3

Distant disease-free survival

- No. patients with event 184 (10.9%) 99 (5.8%) 488 (28.8%) 399 (23.4%)

- No. patients without event 1508 (89.1%) 1594 (94.6%) 1209 (71.2%) 1303 (76.6%)

P-value versus Observation < 0.0001 < 0.0001

Hazard Ratio versus Observation 0.5 0 0.7 6

Overall survival (death)

- No. patients with event 40 (2.4%) 31 (1.8%) 350 (20.6%) 278 (16.3%)

- No. patients without event 1653 (97.6%) 1662 (98.2%) 1347 (79.4%) 1424 (83.7%)

P-value versus Observation 0.24 0.0005

Hazard Ratio versus Observation 0.75 0.76

*Co-primary endpoint of DFS of 1 year versus observation met the pre-defined statistical boundary

**Final analysis (including crossover of 52% of patients from the observation arm to trastuzumab)

*** There is a discrepancy in the overall sample size due to a small number of patients who wererandomized 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 statisticalboundary for the comparison of 1-year of trastuzumab versus observation. After a median follow-up of12 months, the hazard ratio (HR) for disease free survival (DFS) was 0.54 (95% CI 0.44, 0.67) whichtranslates into an absolute benefit, in terms of a 2-year disease-free survival rate, of 7.6 percentagepoints (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 yeartrastuzumab 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 diseasefree 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 showadditional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 yearsversus 1 year=0.99 (95% CI: 0.87, 1.13), p-value=0.90 and OS HR=0.98 (0.83, 1.15); p-value=0.78].

The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm (8.1% versus4.6% in the 1-year treatment arm). More patients experienced at least one grade 3 or 4 adverse event inthe 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 withpaclitaxel, 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 for4 cycles.

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

- intravenous paclitaxel - 80 mg/m2 as a continuous intravenous infusion, given everyweek for 12 weeks.

or

- intravenous paclitaxel - 175 mg/m2 as a continuous intravenous infusion, given every3 weeks for 4 cycles (day 1 of each cycle).

The efficacy results from the joint analysis of the NSABP B-31 and NCCTG 9831 trials at the time ofthe definitive analysis of DFS* are summarized in Table 7. The median duration of follow up was1.8 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 N9831trials at the time of the definitive DFS analysis*

Parameter AC→P AC→PH Hazard ratio vs AC→P(n=1679) (n=1672) (95% CI)p-value

Disease-free survival

No. patients with event (%) 261 (15.5) 133 (8.0) 0.48 (0.39, 0.59)p<0.0001

Distant recurrence

No. patients with event 193 (11.5) 96 (5.7) 0.47 (0.37, 0.60)p<0.0001

Death (OS event): 0.67 (0.48, 0.92)

No. patients with event 92 (5.5) 62 (3.7) 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 forpatients in the AC→PH arm

** p value for OS did not cross the pre-specified statistical boundary for comparison of AC→PH vs.

AC→P

For the primary endpoint, DFS, the addition of trastuzumab to paclitaxel chemotherapy resulted in a52% decrease in the risk of disease recurrence. The hazard ratio translates into an absolute benefit, interms of 3-year disease-free survival rate estimates of 11.8 percentage points (87.2% versus 75.4%) infavour 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 reconfirmsthe magnitude of the benefit shown in the definitive analysis of DFS. Despite the cross-over totrastuzumab in the control arm, the addition of trastuzumab to paclitaxel chemotherapy resulted in a52% decrease in the risk of disease recurrence. The addition of trastuzumab to paclitaxelchemotherapy 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 Hgroup). Treatment with AC→PH resulted in a statistically significant improvement in OS comparedwith AC→P (stratified HR=0.64; 95% CI [0.55, 0.74]; log-rank p-value <0.0001). At 8 years, thesurvival rate was estimated to be 86.9% in the AC→PH arm and 79.4% in the AC→P arm, an absolutebenefit 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 aresummarized 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 AC→PH p-value versus Hazard Ratio(N=2032) (N=2031) AC→P versus AC→P (95%

Death (OS event): 0.64

No. patients with event 418 (20.6%) 289 (14.2%) < 0.0001 (0.55, 0.74)

A: d oxorubicin; 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-freesurvival rate was estimated to be 77.2% (95% CI: 75.4, 79.1) in the AC→PH arm, an absolute benefitof 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 every3 weeks for 4 cycles (day 2 of first docetaxel cycle, then day1 of each subsequent cycle)or

- intravenous docetaxel - 75 mg/m2 as an intravenous infusion over 1 hour, given every3 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 over30-60 minutes repeated every 3 weeks for a total of six cycles

Trastuzumab was administered weekly with chemotherapy and 3 weekly thereafter for a total of52 weeks.

The efficacy results from the BCIRG 006 are summarized in Tables 9 and 10. The median duration offollow 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 AC→DH Hazard ratio vs(n=1073) (n=1074) 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 pluscyclophosphamide, followed by docetaxel plus trastuzumab; CI = confidence interval

Table 10 Overview of efficacy analyses BCIRG 006 AC→D versus DCarbH

Parameter AC→D DCarbH Hazard ratio vs(n=1073) (n=1074) AC→D(95% CI)

Disease-free survival

No. patients with event 195 145 0.67 (0.54, 0.83)p=0.0003

Distant recurrence

No. patients with event 144 103 0.65 (0.50, 0.84)p=0.0008

Death (OS event)

No. patients with event 80 56 0.66 (0.47, 0.93)p=0.0182

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

In the BCIRG 006 study for the primary endpoint, DFS, the hazard ratio translates into an absolutebenefit, in terms of 3-year disease-free survival rate estimates of 5.8 percentage points (86.7% versus80.9%) 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 ratio0.97, 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 andsymptomatic cardiac events and summarised in Table 11:

Table 11 Post-hoc exploratory analysis results from the joint analysis NSABP B-31/NCCTG N9831*and BCIRG006 clinical studies combining DFS events and symptomatic cardiac events

AC→PH AC→DH DCarbH(vs. AC→P) (vs. AC→D) (vs. AC→D)(NSABP B-31 and (BCIRG 006) (BCIRG 006)

NCCTG N9831)*

Primary efficacy analysis

DFS hazard ratios 0.48 0.61 0.67(95% CI) (0.39, 0.59) (0.49, 0.77) (0.54, 0.83)p-value p<0.0001 p< 0.0001 p=0.0003

Long term follow-up efficacyanalysis**

DFS hazard ratios 0.61 0.72 0.77(95% CI) (0.54, 0.69) (0.61, 0.85) (0.65, 0.90)p-value p<0.0001 p<0.0001 p=0.0011

Post-hoc exploratory analysiswith DFS and symptomaticcardiac events

Long term follow-up** hazard 0.67 0.77 0.77ratios (95% CI) (0.60, 0.75) (0.66, 0.90) (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; Medianduration 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 to12.7) in the AC→DH arm

Early breast cancer (neoadjuvant-adjuvant setting)

So far, no results are available which compare the efficacy of trastuzumab administered withchemotherapy 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, wasdesigned to investigate the clinical efficacy of concurrent administration of trastuzumab withneoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvanttrastuzumab, up to a total treatment duration of 1 year. The study recruited patients with newlydiagnosed locally advanced (Stage III) or inflammatory EBC. Patients with HER2+ tumours wererandomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvanttrastuzumab, or neoadjuvant chemotherapy alone.

In study MO16432, trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance every3 weeks) was administered concurrently with 10 cycles of neoadjuvant chemotherapyas follows:

* Doxorubicin 60 mg/m2 and paclitaxel 150 mg/m2, administered 3-weekly for 3 cycles,which was followed by

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

* CMF on day 1 and 8 every 4 weeks for 3 cycleswhich 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 offollow-up in the trastuzumab arm was 3.8 years.

Table 12 Efficacy results from MO16432

Parameter Chemo + trastuzumab Chemo only (n=116)(n=115)

Event-free survival Hazard Ratio (95% CI)

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

Total pathological 40% 20.7% (13.7, 29.2) P=0.0014complete response* (95% (31.0, 49.6)

CI)

Overall survival Hazard Ratio (95% CI)

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

* defined as absence of any invasive cancer both in the breast and axillary nodes

An absolute benefit of 13 percentage points in favour of the trastuzumab arm was estimated in termsof 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) incombination 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 over5 days, given every 3 weeks for 6 cycles (days 1 to 5 of each cycle)

Either of which was administered with:

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

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

Table 13 Efficacy results from BO18225

Parameter FP FP +H HR (95% CI) p-value

N = 290 N = 294

Overall survival, Median months 11.1 13.8 0.74 (0.60-0.91) 0.0046

Progression-free survival, 5.5 6.7 0.71 (0.59-0.85) 0.0002

Median months

Time to disease progression, 5.6 7.1 0.70 (0.58-0.85) 0.0003

Median months

Overall response rate, % 34.5% 47.3% 1.70a (1.22, 0.0017

Duration of response, 4.8 6.9 0.54 (0.40- 0.73) < 0.0001

Median months

FP + H: Fluoropyrimidine/cisplatin + trastuzumab

FP: Fluoropyrimidine/cisplatina Odds ratio

Patients were recruited to the trial who were previously untreated for HER2-positive inoperablelocally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophagealjunction not amenable to curative therapy. The primary endpoint was overall survival which wasdefined as the time from the date of randomization to the date of death from any cause. At the time ofthe analysis a total of 349 randomized patients had died: 182 patients (62.8%) in the control arm and167 patients (56.8%) in the treatment arm. The majority of the deaths were due to events related to theunderlying cancer.

Post-hoc subgroup analyses indicate that positive treatment effects are limited to targeting tumourswith higher levels of HER2 protein (IHC 2+/FISH+ or IHC 3+). The median overall survival for thehigh HER2 expressing group was 11.8 months versus 16 months, HR 0.65 (95% CI 0.51-0.83) and themedian 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 apparentbenefit 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 advanceddisease [HR 1.20 (95% CI 0.29-4.97)].

The European Medicines Agency has waived the obligation to submit the results of studies withtrastuzumab in all subsets of the paediatric population for breast and gastric cancer (see section 4.2 forinformation on paediatric use).

The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysisusing pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC orother tumour types, and healthy volunteers, in 18 Phase I, II and III trials receiving trastuzumabintravenous. A two-compartment model with parallel linear and non-linear elimination from thecentral compartment described the trastuzumab concentration-time profile. Due to non-linearelimination, total clearance increased with decreasing concentration. Therefore, no constant value forhalf-life of trastuzumab can be deduced. The t1/2 decreases with decreasing concentrations within adosing interval (see Table 16). MBC and EBC patients had similar PK parameters (e.g. clearance(CL), the central compartment volume (Vc)) and population-predicted steady-state exposures (Cmin,

Cmax and AUC). Linear clearance was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for

AGC. The non-linear elimination parameter values were 8.81 mg/day for the maximum eliminationrate (Vmax) and 8.92 mcg/mL for the Michaelis-Menten constant (Km) for the MBC, EBC, and AGCpatients. The central compartment volume was 2.62 L for patients with MBC and EBC and 3.63 L forpatients 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 statisticallysignificant covariates affecting the exposure of trastuzumab. However, the magnitude of effect ofthese covariates on trastuzumab exposure suggests that these covariates are unlikely to have aclinically meaningful effect on trastuzumab concentrations.

The population predicted PK exposure values (median with 5th - 95th percentiles) and PK parametervalues at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treatedwith 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 Cmax AUC0-21days(mcg/mL) (mcg/mL) (mcg.day/mL)

MBC 805 28.7 182 1376(2.9 - 46.3) (134 - 280) (728 - 1998)8mg/kg +6mg/kg EBC 390 30.9 176 1390q3w (18.7 - 45.5) (127 - 227) (1039 - 1895)

AGC 274 23.1 132 1109(6.1 - 50.3) (84.2 - 225) (588 - 1938)

MBC 805 37.4 76.5 10734mg/kg + (8.7 - 58.9) (49.4 - 114) (597 - 1584)2mg/kg qw

EBC 390 38.9 76.0 1074(25.3 - 58.8) (54.7 - 104) (783 - 1502)

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

Primary C C AUC Time to

Regimen min,ss* max,ss** ss, 0-21daystumourtype N (mcg/mL) (mcg/mL) (mcg.day/mL) steady-state***

MBC 805 44.2 179 1736(1.8 - 85.4) (123 - 266) (618 - 2756) 128 mg/kg + EBC 390 53.8 184 19276 mg/kg q3w (28.7 - 85.8) (134 - 247) (1332 -2771) 15

AGC 274 32.9 131 1338(6.1 - 88.9) (72.5 -251) (557 - 2875) 9

MBC 805 63.1 107 17104 mg/kg + (11.7 - 107) (54.2 - 164) (581 - 2715) 122 mg/kg qw

EBC 390 72.6 115 1893(46 - 109) (82.6 - 160) (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 dosingregimens in MBC, EBC and AGC patients

Regimen Primary N Total CL range from t1/2 range fromtumour type Cmax,ss to Cmin,ss (L/day) Cmax,ss to Cmin,ss (day)

MBC 805 0.183 - 0.302 15.1 - 23.38mg/kg +6mg/kg q3w EBC 390 0.158 - 0.253 17.5 - 26.6

AGC 274 0.189 - 0.337 12.6 - 20.64mg/kg + MBC 805 0.213 - 0.259 17.2 - 20.42mg/kg qw EBC 390 0.184 - 0.221 19.7 - 23.2

Trastuzumab washout

Trastuzumab washout period was assessed following q1w or q3w intravenous administration using thepopulation PK model. The results of these simulations indicate that at least 95% of patients will reachconcentrations that are <1 mcg/mL (approximately 3% of the population predicted Cmin,ss, or about97% washout) by 7 months.

Circulating shed HER2 ECD

The exploratory analyses of covariates with information in only a subset of patients suggested thatpatients 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 shedantigen on clearance may have been explained by SGOT/AST levels.

Baseline levels of the shed HER2-ECD observed in MGC patients were comparable to those in MBCand EBC patients and no apparent impact on trastuzumab clearance was observed.

There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, orreproductive toxicity in teratology, female fertility or late gestational toxicity/placental transferstudies. Zercepac is not genotoxic. A study of trehalose, a major formulation excipient did not revealany toxicities.

No long-term animal studies have been performed to establish the carcinogenic potential of Zercepac,or to determine its effects on fertility in males.

L-histidine hydrochloride monohydrate

L-histidineα, α-trehalose dihydrate

Polysorbate 20

This medicinal product must not be mixed or diluted with other medicinal products except thosementioned under section 6.6.

Do not dilute with glucose solutions since these cause aggregation of the protein.

Unopened vial4 years.

After aseptic reconstitution with sterile water for injection, chemical and physical stability of thereconstituted solution has been demonstrated for 48 hours at 2°C - 8°C.

After aseptic dilution in polyethylene or polypropylene bags containing sodium chloride 9 mg/mL(0.9%) solution for injection, chemical and physical stability of Zercepac has been demonstrated forup to 84 days at 2°C - 8°C, 7 days at 23°C - 27°C and 24 hours at 30°C.

From a microbiological point of view, the reconstituted solution and Zercepac infusion solution shouldbe used immediately. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user, unless reconstitution have taken place under controlled and validated asepticconditions.

Do not freeze the reconstituted solution.

Store in a refrigerator (2°C - 8°C).

For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.

Zercepac 60 mg powder for concentrate for solution for infusion

One 10 mL clear glass type I vial with bromobutyl rubber stopper containing 60 mg of trastuzumab.

Each carton contains one vial.

Zercepac 150 mg powder for concentrate for solution for infusion

One 20 mL clear glass type I vial with bromobutyl rubber stopper containing 150 mg of trastuzumab.

Each carton contains one vial.

Zercepac 420 mg powder for concentrate for solution for infusion

One 50 mL clear glass type I vial with bromobutyl rubber stopper containing 420 mg of trastuzumab.

Each carton contains one vial.

Zercepac is provided in sterile, preservative-free, non-pyrogenic, single use vials.

Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents,appropriate aseptic technique should be used for reconstitution and dilution procedures. Care must betaken to ensure the sterility of prepared solutions.

Aseptic preparation, handling and storage:

The infusion preparation should be:

* performed by trained personnel in accordance with good practice rules especially with respect tothe aseptic preparation of parenteral products.

* prepared in a laminar flow hood or biological safety cabinet using standard precautions for thesafe handling of intravenous agents.

* followed by adequate storage of the prepared solution for intravenous infusion to ensuremaintenance of the aseptic conditions.

Instructions for aseptic reconstitution:

1) Using a sterile syringe, slowly inject the appropriate volume (as noted below) of sterile waterfor injection (not supplied) in the vial containing the lyophilised Zercepac, directing the streaminto the lyophilised cake. Use of other reconstitution solvents should be avoided.

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 undisturbedfor approximately 5 minutes. The reconstituted Zercepac results in a colourless to pale yellowtransparent solution and should be essentially free of visible particulates.

Zercepac 60 mg powder for concentrate for solution for infusion

Reconstitution of the 60 mg vial with 3.0 mL of sterile water for injection yields a 3.1 mL solution forsingle-dose use, containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. Avolume overage of 8% ensures that the labelled dose of 60 mg can be withdrawn from each vial.

Zercepac 150 mg powder for concentrate for solution for infusion

Reconstitution of the 150 mg vial with 7.2 mL of sterile water for injection yields a 7.5 mL solutionfor single-dose use containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. Avolume overage of 5% ensures that the labelled dose of 150 mg can be withdrawn from each vial.

Zercepac 420 mg powder for concentrate for solution for infusion

Reconstitution of the 420 mg vial with 20.0 mL of sterile water for injection yields a 20.6 mL solutionfor single-dose use, containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. Avolume overage of 3% ensures that the labelled dose of 420 mg can be withdrawn from each vial.

Zercepac should be carefully handled during reconstitution. Causing excessive foaming duringreconstitution or shaking the reconstituted solution may result in problems with the amount of

Zercepac that can be withdrawn from the vial.

The reconstituted solution should not be frozen.

Instructions for aseptic dilution of the reconstituted solution

Determine the volume of the solution required:

* based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose of2 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 of6 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 using a sterile needle andsyringe and added to an infusion bag containing 250 mL of 9 mg/ml (0.9%) sodium chloride solution.

Do not use with glucose-containing solutions (see section 6.2). The bag should be gently inverted tomix the solution in order to avoid foaming.

Parenteral medicinal products should be inspected visually for particulate matter and discolorationprior to administration.

No incompatibilities between Zercepac and polyethylene or polypropylene bags have been observed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center,

Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona, Spain

Zercepac 60 mg powder for concentrate for solution for infusion

EU/1/20/1456/002

Zercepac 150 mg powder for concentrate for solution for infusion

EU/1/20/1456/001

Zercepac 420 mg powder for concentrate for solution for infusion

EU/1/20/1456/003

Date of first authorisation: 27th July 2020

Detailed information on this medicinal product is available on the website of the European Medicines

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