ONTRUZANT 150mg powder for concentrate infusion solution medication leaflet

Ontruzant 150 mg powder for concentrate for solution for infusion

Ontruzant 420 mg powder for concentrate for solution for infusion

Ontruzant 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 several chromatographysteps including specific viral inactivation and removal procedures.

Ontruzant 420 mg powder for concentrate for solution for infusion

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

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

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to pale yellow lyophilised powder.

Breast cancer

Metastatic breast cancer

Ontruzant is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer(MBC):

- as monotherapy for the treatment of those patients who have received at least twochemotherapy regimens for their metastatic disease. Prior chemotherapy must have included at leastan anthracycline 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 notreceived chemotherapy for their metastatic disease and for whom an anthracycline is notsuitable.

- in combination with docetaxel for the treatment of those patients who have notreceived chemotherapy for their metastatic disease.

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

Early breast cancer

Ontruzant is indicated for the treatment of adult patients with HER2 positive early breast cancer(EBC).

- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable)(see section 5.1).

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

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

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

Ontruzant 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 andvalidated assay (see sections 4.4 and 5.1).

Metastatic gastric cancer

Ontruzant in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for thetreatment of adult patients with HER2 positive metastatic adenocarcinoma of the stomach orgastro-oesophageal junction who have not received prior anti-cancer treatment for their metastaticdisease.

Ontruzant should only be used in patients with metastatic gastric cancer (MGC) whose tumours have

HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC3+result. Accurate and validated assay methods should be used (see sections 4.4 and 5.1).

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Ontruzanttreatment should only be initiated by a physician experienced in the administration of cytotoxicchemotherapy (see section 4.4), and should be administered by a healthcare professional only.

Ontruzant 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 Ontruzant (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 maintenancedose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.

Weekly schedule

The recommended initial loading dose of Ontruzant is 4 mg/kg body weight. The recommendedweekly maintenance dose of Ontruzant is 2 mg/kg body weight, beginning one week after theloading dose.

Administration in combination with paclitaxel or docetaxel

In the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day followingthe first dose of trastuzumab (for dose, see the Summary of Product Characteristics (SmPC) forpaclitaxel or docetaxel) and immediately after the subsequent doses of trastuzumab if the precedingdose 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 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 Ontruzant is 8 mg/kg bodyweight. The recommended maintenance dose of Ontruzant at three-weekly intervals is 6 mg/kgbody 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 maintenancedose at 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 Ontruzant until progression of disease. Patients with

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

No reductions in the dose of trastuzumab were made during clinical trials. Patients may continuetherapy during periods of reversible, chemotherapy-induced myelosuppression but they should bemonitored carefully for complications of neutropenia during this time. Refer to the SmPC forpaclitaxel, 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 Ontruzant 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 Ontruzant by one week or less, then the usual maintenance dose(weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administered as soon as possible.

Do not wait until the next planned cycle. Subsequent maintenance doses should be administered7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

If the patient has missed a dose of Ontruzant by more than one week, a re-loading dose of

Ontruzant should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg;three-weekly regimen: 8 mg/kg) as soon as possible. Subsequent Ontruzant maintenance doses(weekly regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should be administered7 days or 21 days later according 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 Ontruzant in the paediatric population.

Ontruzant is for intravenous use. The loading dose should be administered as a 90-minute intravenousinfusion. Administration as an intravenous push or bolus is prohibited. Ontruzant intravenous infusionshould be administered by a healthcare provider prepared to manage anaphylaxis and an emergency kitshould be available. Patients should be observed for at least six hours after the start of the firstinfusion and for two hours after the start of the subsequent infusions for symptoms like fever andchills or other infusion-related symptoms (see sections 4.4 and 4.8). Interruption or slowing the rate ofthe 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-minuteinfusion.

For instructions on reconstitution of Ontruzant 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 the traceability of biological medicinal products, the 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 previousexposure 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 beenobserved in patients receiving trastuzumab therapy alone or in combination with paclitaxel ordocetaxel, 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 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 every3 months during treatment and every 6 months following discontinuation of treatment until24 months from the last administration of trastuzumab. A careful risk-benefit assessment should bemade before deciding to treat with trastuzumab.

Trastuzumab may persist in the circulation for up to 7 months after stopping trastuzumab treatmentbased on population pharmacokinetic analysis of all available data (see section 5.2). Patients whoreceive anthracyclines after stopping trastuzumab may possibly be at increased risk of cardiacdysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 monthsafter stopping trastuzumab. If anthracyclines are used, the patient’s cardiac function should bemonitored 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 morefrequent monitoring (e.g. every 6-8 weeks). If patients have a continued decrease in left ventricularfunction, but remain asymptomatic, the physician should consider discontinuing therapy if no clinicalbenefit of trastuzumab therapy has been seen.

The safety of continuation or resumption of trastuzumab in patients who experience cardiacdysfunction 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 withinapproximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF hasdeveloped, discontinuation of trastuzumab 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 trastuzumab therapy, it should be treated withstandard medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiacdysfunction in pivotal trials improved with standard CHF treatment consisting of anangiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and abeta-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit oftrastuzumab 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 cardiacdysfunction with trastuzumab treatment, although the risk is lower than with concurrent use oftrastuzumab and anthracyclines.

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 trastuzumab. In patients who receive anthracycline-containingchemotherapy further monitoring is recommended, and should occur yearly up to 5 years from thelast 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, cardiacarrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorlycontrolled hypertension (hypertension controlled by standard medical treatment eligible), andhaemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBCpivotal 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 theadjuvant treatment 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 whenadministered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiacevents occurred within the first 18 months. In one of the 3 pivotal studies conducted in which amedian follow-up of 5.5 years was available (BCIRG006) a continuous increase in the cumulativerate of symptomatic cardiac or LVEF events was observed in patients who were administeredtrastuzumab concurrently with a taxane following anthracycline therapy up to 2.37% compared toapproximately 1% in the two comparator arms (anthracycline plus cyclophosphamide followed bytaxane and taxane, carboplatin and trastuzumab).

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

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

Neoadjuvant-adjuvant treatment

In patients with EBC eligible for neoadjuvant-adjuvant treatment, trastuzumab 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/m orepirubicin 360 mg/m .

If patients have been treated concurrently with a full course of low-dose anthracyclines andtrastuzumab in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given aftersurgery. In other situations, the decision on the need for additional cytotoxic chemotherapy isdetermined based on individual factors.

Experience of concurrent administration of trastuzumab with low-dose anthracycline regimensis currently limited to the trial MO16432.

In the pivotal trial MO16432, trastuzumab was administered concurrently withneoadjuvant chemotherapy containing three cycles of doxorubicin (cumulative dose180 mg/m ).

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, respiratorydistress, urticaria and angioedema have been reported (see section 4.8). Pre-medication may be usedto reduce 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 trastuzumab (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-marketingsetting (see section 4.8). These events have occasionally been fatal. In addition, cases of interstitiallung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia,pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratoryinsufficiency have been reported. Risk factors associated with interstitial lung disease include prioror concomitant therapy with other anti-neoplastic therapies known to be associated with it such astaxanes, gemcitabine, vinorelbine and radiation therapy. These events may occur as part of aninfusion-related reaction or with a delayed onset. Patients experiencing dyspnoea at rest due tocomplications of advanced malignancy and comorbidities may be at increased risk of pulmonaryevents. Therefore, these patients should not be treated with trastuzumab (see section 4.3). Cautionshould be exercised for pneumonitis, especially in patients being treated concomitantly withtaxanes.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

No formal drug interaction studies have been performed. Clinically significant interactions betweentrastuzumab 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 metabolites6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence oftrastuzumab (8 mg/kg or 4 mg/kg loading dose as an intravenous infusion followed by 6 mg/kg q3wor 2 mg/kg q1w infusion, 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 ofthis metabolite was unclear.

Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg loading dose as anintravenous infusion and 2 mg/kg infusion weekly) and docetaxel (60 mg/m intravenous infusion)in Japanese women with HER2-positive MBC, suggested that concomitant administration oftrastuzumab had no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was asubstudy of BO18255 (ToGA) performed in male and female Japanese patients with advancedgastric cancer to study the pharmacokinetics of capecitabine and cisplatin when used with or withouttrastuzumab. The results of this substudy suggested that the exposure to the bioactive metabolites(e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use ofcisplatin plus trastuzumab. However, capecitabine itself showed higher concentrations and a longerhalf-life when combined with trastuzumab. The data also suggested that the pharmacokinetics ofcisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabineplus 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 intravenous infusion) and observed serum concentrations in Japanesewomen with HER2-positive MBC (study JP16003) no evidence of a PK effect of concurrentadministration 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 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 (H0648g), suggested no effect of doxorubicin and paclitaxel on the pharmacokinetics oftrastuzumab.

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 duringtreatment with trastuzumab 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 ofthe weekly human maintenance dose of 2 mg/kg trastuzumab intravenous formulation and haverevealed no evidence of impaired fertility or harm to the fetus. Placental transfer of trastuzumabduring the early (days 20-50 of gestation) and late (days 120-150 of gestation) foetal developmentperiod was observed. It is not known whether trastuzumab can affect reproductive capacity. Asanimal reproduction studies are not always predictive of human response, trastuzumab should beavoided during pregnancy unless the potential benefit for the mother outweighs the potential risk tothe fetus.

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 fetus, have beenreported in pregnant women receiving trastuzumab. Women who become pregnant should be advisedof the possibility of harm to the fetus. If a pregnant woman is treated with trastuzumab, or if a patientbecomes pregnant while receiving trastuzumab or within 7 months following the last dose oftrastuzumab, close monitoring by a multidisciplinary team is desirable.

A study conducted in Cynomolgus monkeys at doses 25 times that of the weekly humanmaintenance dose of 2 mg/kg trastuzumab intravenous formulation from days 120 to 150 ofpregnancy demonstrated that trastuzumab is secreted in the milk postpartum. The exposure totrastuzumab in utero and the presence of trastuzumab in the serum of infant monkeys was notassociated with any adverse effects on their growth or development from birth to 1 month of age.

It is not known whether trastuzumab is secreted in human milk. As human IgG1 is secreted intohuman milk, and the potential for harm to the infant is unknown, women should not breast-feedduring trastuzumab therapy and for 7 months after the last dose.

There is no fertility data available.

Ontruzant has a minor influence on the ability to drive or use machines (see section 4.8). Dizzinessand somnolence may occur during treatment with Ontruzant (see section 4.8). Patients experiencinginfusion-related symptoms (see section 4.4) should be advised not to drive and use machines untilsymptoms abate.

Amongst the most serious and/or common adverse reactions reported in Ontruzant 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 inthe 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 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 neoplasm progression Not knownmalignant and unspecified Neoplasm progression Not known(incl. Cysts and polyps)

Blood and lymphatic system Febrile neutropenia Very commondisorders Anaemia Very common

Neutropenia Very common

White blood cell count Very commondecreased/leukopenia

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

Tumour lysis syndrome Not known

Hyperkalaemia Not known

Psychiatric disorders Insomnia Very common

Anxiety Common

Depression Common

Nervous system disorders Tremor Very common

Dizziness Very common

Headache Very common

Paraesthesia Very common

Dysgeusia Very common

Peripheral neuropathy Common

System organ class Adverse reaction Frequency

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 Blood pressure decreased Very common

Blood pressure increased Very common

Heart beat irregular Very common

Cardiac flutter Very common

Ejection fraction decreased* Very common+

Cardiac failure (congestive) Common

Supraventricular tachyarrhythmia Common

Cardiomyopathy Common

Palpitation Common

Pericardial effusion Uncommon

Cardiogenic shock Not known

Gallop rhythm present Not known

Vascular disorders Hot flush Very common

Hypotension 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

Wheezing Uncommon

Pneumonitis Uncommon+

Pulmonary fibrosis Not known+

Respiratory distress Not known+

Respiratory failure Not known+

Lung infiltration Not known+

Acute pulmonary oedema Not known+

Acute respiratory distress syndrome Not known+

Bronchospasm Not known+

Hypoxia Not known+

Oxygen saturation decreased Not known

Laryngeal oedema Not known

Orthopnoea Not known

Pulmonary oedema Not known

Interstitial lung disease Not known

Gastrointestinal disorders Diarrhoea Very common

Vomiting Very common

Nausea Very common

Lip swelling Very common

Abdominal pain Very common

Dyspepsia Very common

Constipation Very common

Stomatitis Very common

System organ class Adverse reaction Frequency

Haemorrhoids Common

Dry mouth Common

Hepatobiliary disorders Hepatocellular injury Common

Hepatitis Common

Liver tenderness Common

Jaundice Rare

Skin and subcutaneous Erythema Very commontissue disorders Rash Very common

Swelling 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 Muscle 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

General disorders and Asthenia Very commonadministration site Chest pain Very commonconditions 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

System organ class Adverse reaction Frequency

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-related reactions. Specificpercentages 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 use oftrastuzumab 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 mildto moderate 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 ofinfusion-related reactions of all grades varied between studies depending on the indication, the datacollection methodology, 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 docetaxelfollowing anthracycline therapy.

Pulmonary events

Severe pulmonary adverse reactions occur in association with the use of trastuzumab and havebeen 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 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 intravenous trastuzumab 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-trastuzumabantibodies had no impact on pharmacokinetics, efficacy (determined by pathological Complete

Response [pCR] and event free survival [EFS]) and safety determined by occurrence ofadministration 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 trastuzumab alonegreater than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of10 mg/kg q3w following a loading dose of 8 mg/kg has been studied in a clinical trial with metastaticgastric cancer patients. Doses up to this level were well tolerated.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, ATC code: L01FD01

Ontruzant is a biosimilar medicinal product. Detailed information is available on the website of the

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

Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermalgrowth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20%-30% of primarybreast 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 IHCand 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 notoverexpress HER2. The extracellular domain of the receptor (ECD, p105) can be shed into the bloodstream and measured in serum 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 activationmechanism of HER2. As a result, trastuzumab has been shown, in both in vitro assays and inanimals, 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 HER2overexpressing 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 HER2gene amplification as determined by an accurate and validated assay. HER2 overexpression shouldbe detected 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 fortrastuzumab treatment if they show strong HER2 overexpression as described by a 3+ score by IHCor a positive FISH or CISH result.

To ensure accurate and reproducible results, the testing must be performed in a specialisedlaboratory, 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

HER2 overexpression

Score Staining patternassessment

No staining is observed or membrane staining is0 Negativeobserved in <10% of the tumour cells

A faint/barely perceptible membrane staining is1+ detected in >10% of the tumour cells. The cells are only Negativestained in part of their membrane.

A weak to moderate complete membrane staining is2+ Equivocaldetected in >10% of the tumour cells.

Strong complete membrane staining is detected in >10%3+ Positiveof 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 overexpression or HER2 gene amplification in gastric cancer

Only an accurate and validated assay should be used to detect HER2 overexpression 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 tumor 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 interpretationshould 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 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

HER2

Surgical specimen - staining Biopsy specimen - staining

Score overexpressionpattern patternassessment

No reactivity or membranous

No reactivity or membranous0 reactivity in <10% of tumour Negativereactivity in any tumour cellcells

Faint ⁄ barely perceptible Tumour cell cluster with amembranous reactivity in faint⁄barely perceptible1+ ≥10% of tumour cells; cells membranous reactivity Negativeare reactive only in part of irrespective of percentage oftheir membrane tumour cells stained

Tumour cell cluster with a weak

Weak to moderate complete, to moderate complete,basolateral or lateral basolateral or lateral2+ Equivocalmembranous reactivity in membranous reactivity≥10% of tumour cells irrespective of percentage oftumour cells stained

Tumour cell cluster with a strong

Strong complete, basolateralcomplete, basolateral or lateralor lateral membranous3+ membranous reactivity Positivereactivity in ≥10% of tumourirrespective of percentage ofcellstumour 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 havetumours that overexpress HER2 and who have failed one or more chemotherapy regimens for theirmetastatic disease (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 hadpreviously received anthracycline-based adjuvant chemotherapy were treated with paclitaxel(175 mg/m infused over 3 hours) with or without trastuzumab. In the pivotal trial of docetaxel(100 mg/m infused over 1 hour) with or without trastuzumab, 60% of the patients had received prioranthracycline-based adjuvant chemotherapy. Patients were treated with trastuzumab until progressionof 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.

This investigative clinical trial assay performed in a central laboratory utilised a 0 to 3+ scale.

Patients classified as staining 2+ or 3+ were included, while those staining 0 or 1+ were excluded.

Greater than 70% of patients enrolled exhibited 3+ overexpression. The data suggest that beneficialeffects 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 orwithout trastuzumab, was immunohistochemistry. A minority of patients was tested usingfluorescence 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

Trastuzumab Trastuzumab

Trastuzumab1 plus Paclitaxel2 plus Docetaxel3

N=172 paclitaxel2 N=77 docetaxel3 N=94

N=68 N=92

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

Median duration of9.1 8.3 4.6 11.7 5.7response (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 3.2 7.1 3.0 11.7 6.1(months) (95%CI) (2.6-3.5) (6.2-12.0) (2.0-4.4) (9.2-13.5) (5.4-7.2)

Median survival 16.4 24.8 17.9 31.2 22.74(months) (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. estrogen-receptor (ER) and/or progesterone-receptor(PR)) positive postmenopausal patients. Progression free survival was doubled in the trastuzumabplus anastrozole arm compared to anastrozole (4.8 months versus 2.4 months). For the otherparameters the improvements seen for the combination were for overall response (16.5% versus6.7%); clinical benefit rate (42.7% versus 27.9%); time to progression (4.8 months versus2.4 months). For time to response and duration of response no difference could be recorded betweenthe arms. The median overall survival was extended by 4.6 months for patients in the combinationarm. The difference was not statistically significant, however more than half of the patients in theanastrozole alone arm crossed over to a trastuzumab containing regimen after progression of disease.

Three-weekly dosing in metastatic breast cancer

The efficacy results from the non-comparative monotherapy and combination therapystudies are summarised in Table 5:

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

Parameter Monotherapy Combination therapy1 2

Trastuzumab Trastuzumab Trastuzumab Trastuzumab3 4

N=105 N=72 plus paclitaxel plus docetaxel

N=32 N=110

Response rate24% (15-35) 27% (14-43) 59% (41-76) 73% (63-81)(95%CI)

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

Median TTP3.4 (2.8-4.1) 7.7 (4.2-8.3) 12.2 (6.2-ne) 13.6 (11-16)(months) (95%CI)

Median Survivalne ne ne 47.3 (32-ne)(months) (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,established chemotherapy and radiotherapy (if applicable). In addition, comparison of twoyears 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 weredesigned to investigate the clinical utility of combining trastuzumab treatment withpaclitaxel following AC chemotherapy, additionally the NCCTG N9831 study alsoinvestigated 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 treatmentwith docetaxel either following AC chemotherapy or in combination with docetaxel andcarboplatin in patients with HER2 positive EBC following surgery.

Early breast cancer in the HERA trial was limited to operable, primary, invasive adenocarcinomaof the breast, with axillary nodes positive or axillary nodes negative if tumours at least 1 cm indiameter.

In the joint analysis of the NSABP B-31 and NCCTG N9831 studies, EBC was limited to womenwith operable breast cancer at high risk, defined as HER2-positive and axillary lymph nodepositive 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 orhigh-risk node negative patients with no (pN0) lymph node involvement, and at least 1 of thefollowing factors: tumour size greater than 2 cm, estrogen receptor and progesterone receptornegative, histological and/or nuclear grade 2-3, or age <35 years).

The efficacy results from the BO16348 trial following 12 months* and 8 years** medianfollow-up are summarized in Table 6:

Table 6 Efficacy results from Study BO16348

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

Trastuzumab Trastuzumab

Observation Observation

Parameter 1 Year 1 Year

N=1693 N=1697***

N=1693 N=1702***

Disease-free survival

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

Trastuzumab Trastuzumab

Observation Observation

Parameter 1 Year 1 Year

N=1693 N=1697***

N=1693 N=1702***

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

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

P-value versus observation <0.0001 < 0.0001

Hazard ratio versus observation 0.54 0.76

Recurrence-free survival

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

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

P-value versus observation <0.0001 <0.0001

Hazard ratio versus 0.51 0.73observation

Distant disease-free survival

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

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

P-value versus observation <0.0001 <0.0001

Hazard ratio versus observation 0.50 0.76

Overall survival (death)

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

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

P-value versus observation 0.24 0.0005

Hazard ratio versus observation 0.75 0.76

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

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

*** There is a discrepancy in the overall sample size due to a small number of patients who 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-specifiedstatistical boundary for the comparison of 1-year of trastuzumab versus observation. After amedian follow-up of 12 months, the hazard ratio (HR) for disease free survival (DFS) was 0.54(95% CI 0.44, 0.67) which translates into an absolute benefit, in terms of a 2-year disease-freesurvival 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-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 adversereactions 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 combinationwith paclitaxel, following AC chemotherapy.

Doxorubicin and cyclophosphamide were administered concurrently as follows:

- intravenous push doxorubicin, at 60 mg/m , given every 3 weeks for 4 cycles.

- intravenous cyclophosphamide, at 600 mg/m over 30 minutes, given every 3 weeks for4 cycles.

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

- intravenous paclitaxel - 80 mg/m as a continuous intravenous infusion, given every week for12 weeks.

or

- intravenous paclitaxel - 175 mg/m as a continuous intravenous infusion, given every 3 weeksfor 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*

Hazard ratio vs

AC→P AC→PH

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

Disease-free survival261 (15.5) 133 (8.0) 0.48 (0.39, 0.59)

No. patients with event (%)p<0.0001

Distant recurrence193 (11.5) 96 (5.7) 0.47 (0.37, 0.60)

No. patients with eventp<0.0001

Death (OS event):

92 (5.5) 62 (3.7) 0.67 (0.48, 0.92)

No. patients with eventp=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%)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 DFSreconfirms the magnitude of the benefit shown in the definitive analysis of DFS. Despite thecross-over to trastuzumab in the control arm, the addition of trastuzumab to paclitaxel chemotherapyresulted in a 52% 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→PHgroup). 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, anabsolute 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 N9831are summarized in Table 8 below:

Table 8 Final overall survival analysis from the joint analysis of trials NSABP B-31 and NCCTG

N9831

Hazard ratio

AC→P AC→PH p-value versus versus

Parameter(N=2032) (N=2031) AC→P AC→P (95%

CI)

Death (OS event):

No. patients with event (%) 418 (20.6%) 289 (14.2%) <0.0001 0.64(0.55, 0.74)

A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab

DFS analysis was also performed at the final analysis of OS from the joint analysis of studies

NSABP B-31 and NCCTG N9831. The updated DFS analysis results (stratified HR = 0.61; 95%

CI [0.54, 0.69]) showed a similar DFS benefit compared to the definitive primary DFS analysis,despite the 24.8% patients in the AC→P arm who crossed over to receive trastuzumab. At 8 years,the disease-free survival rate was estimated to be 77.2% (95% CI: 75.4, 79.1) in the AC→PH arm,an absolute benefit of 11.8% compared with the AC→P arm.

In the BCIRG 006 study trastuzumab was administered either in combination with docetaxel, following

AC chemotherapy (AC→DH) or in combination with docetaxel and carboplatin (DCarbH).

Docetaxel was administered as follows:

- intravenous docetaxel - 100 mg/m as an intravenous infusion over 1 hour, given every3 weeks for 4 cycles (day 2 of first docetaxel cycle, then day 1 of each subsequent cycle)or

- intravenous docetaxel - 75 mg/m 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 totalof 52 weeks.

The efficacy results from the BCIRG 006 are summarized in Tables 9 and 10. The median durationof follow up was 2.9 years in the AC→D arm and 3.0 years in each of the AC→DH and DCarbHarms.

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

Hazard ratio vs

AC→D AC→DH

Parameter AC→D (95% CI)(n=1073) (n=1074)p-value

Disease-free survival195 134 0.61 (0.49, 0.77)

No. patients with eventp<0.0001

Distant recurrence144 95 0.59 (0.46, 0.77)

No. patients with eventp<0.0001

Death (OS event)80 49 0.58 (0.40, 0.83)

No. patients with eventp=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

AC→D DCarbH Hazard ratio vs

Parameter(n=1073) (n=1074) AC→D (95% CI)

Disease-free survival195 145 0.67 (0.54, 0.83)

No. patients with eventp=0.0003

Distant recurrence144 103 0.65 (0.50, 0.84)

No. patients with eventp=0.0008

Death (OS event)0.66 (0.47, 0.93)

No. patients with event80 56 p=0.0182

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; DCarbH = docetaxel, carboplatin andtrastuzumab; 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** 0.67 0.77 0.77hazard ratios (0.60, 0.75) (0.66, 0.90) (0.66, 0.90)(95% CI)

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→Parm 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 to12.1) for the AC→PH arm and 7.9 years (range: 0.0 to 12.2) for the AC→P arm; Median duration of long termfollow-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 administeredwith chemotherapy in the adjuvant setting with that obtained in the neo-adjuvant/adjuvantsetting.

In the neoadjuvant-adjuvant treatment setting, study MO16432, a multicentre randomised trial,was designed 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:

2 2

* Doxorubicin 60 mg/m and paclitaxel 150 mg/m , administered 3-weekly for3 cycles, which was followed by

* Paclitaxel 175 mg/m 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

Chemo +

Chemo only

Parameter trastuzumab(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 complete 40% 20.7%p=0.0014response* (95% CI) (31.0, 49.6) (13.7, 29.2)

Overall survival Hazard ratio(95% CI)

No. patients with event 0.59 (0.35, 1.02)22 33p=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 of3-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/m orally twice daily for 14 days every 3 weeks for 6 cycles (eveningof day 1 to morning of day 15 of each cycle)or

- intravenous 5-fluorouracil - 800 mg/m /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/m 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

FP FP +H

Parameter 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) 0.0002median months

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

Overall response rate,% 34.5% 47.3% 1.70 (1.22, 2.38) 0.0017

Duration of response, median4.8 6.9 0.54 (0.40-0.73) <0.0001months

FP + H: fluoropyrimidine/cisplatin + trastuzumab

FP: fluoropyrimidine/cisplatina Odds ratio

Patients who were previously untreated for HER2-positive inoperable locally advanced or recurrentand/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction not amenable tocurative therapy were recruited to the trial. 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 tothe underlying cancer.

Post-hoc subgroup analyses indicate that positive treatment effects are limited to targetingtumours with higher levels of HER2 protein (IHC2+/FISH+ or IHC3+). The median overallsurvival for the high HER2-expressing group was 11.8 months versus 16 months, HR 0.65 (95%

CI 0.51-0.83) and the median progression free survival was 5.5 months versus 7.6 months, HR 0.64(95% CI 0.51-0.79) for FP versus FP + H, respectively. For overall survival, the HR was 0.75 (95%

CI 0.51-1.11) in the IHC2+/FISH+ group and the HR was 0.58 (95% CI 0.41-0.81) in the

IHC3+/FISH+ group.

In an exploratory subgroup analysis performed in the TOGA (BO18255) trial there was no 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 modelanalysis 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 receivingtrastuzumab via an intravenous infusion. A two-compartment model with parallel linear andnon-linear elimination from the central compartment described the trastuzumab concentration-timeprofile. 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 withdecreasing concentrations within a dosing interval (see Table 16). MBC and EBC patients hadsimilar PK parameters (e.g. clearance (CL), the central compartment volume (Vc)) andpopulation-predicted steady-state exposures (Cmin, Cmax and AUC). Linear clearance was 0.136 L/dayfor MBC, 0.112 L/day for EBC and 0.176 L/day for AGC. The non-linear elimination parametervalues were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 µg/mL for the

Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The central compartmentvolume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC. In the finalpopulation PK model, in addition to primary tumour type, body-weight, serum aspartateaminotransferase and albumin were identified as statistically significant covariates affecting theexposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumabexposure suggests that these covariates are unlikely to have a clinically meaningful effect ontrastuzumab concentrations.

The population predicted PK exposure values (median with 5th-95th Percentiles) and PKparameter values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGCpatients 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 infusion dosing regimens in MBC, EBC and AGC patients

Primary Cmin Cmax AUC

Regimen N 0-21daystumour type (µg/mL) (µg/mL) (µg.day/mL)28.7

MBC 805 182 (134-280) 1376 (728-1998)(2.9-46.3)8mg/kg + 30.9

EBC 390 176 (127-227) 1390 (1039-1895)6mg/kg q3w (18.7-45.5)23.1

AGC 274 132 (84.2-225) 1109 (588-1938)(6.1-50.3)37.4

MBC 805 76.5 (49.4-114) 1073 (597-1584)4mg/kg + (8.7-58.9)2mg/kg qw 38.9

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

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

Time to

Primary Cmin,ss* Cmax,ss** AUCss, 0-21 days steady-state

Regimen Ntumour type (µg/mL) (µg/mL) (µg.day/mL) ***(week)44.2 179 1736

MBC 805 12(1.8-85.4) (123-266) (618-2756)8mg/kg + 53.8 184 1927

EBC 390 156mg/kg q3w (28.7-85.8) (134-247) (1332-2771)32.9 131 1338

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

Time to

Primary Cmin,ss* Cmax,ss** AUC

Regimen N ss, 0-21 days steady-statetumour type (µg/mL) (µg/mL) (µg.day/mL) ***(week)63.1 107 1710

MBC 805 124mg/kg + (11.7-107) (54.2-164) (581-2715)2mg/kg qw 72.6 115 1893

EBC 390 14(46-109) (82.6-160) (1309-2734)

*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 intravenousinfusion dosing regimens in MBC, EBC and AGC patients

Total CL range t1/2 range from Cmax,ss to

Primary

Regimen N from Cmax,ss to Cmin,ss Cmin,sstumour type(L/day) (day)

MBC 805 0.183-0.302 15.1-23.38mg/kg +

EBC 390 0.158-0.253 17.5-26.66mg/kg q3w

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 µg/mL (approximately 3% of the population predicted Cmin,ss, or about 97%washout) by 7 months.

Circulating shed HER2 ECD

The exploratory analyses of covariates with information in only a subset of patients suggested 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. Trastuzumab is not genotoxic. A study of trehalose, a major formulation excipient, did notreveal any toxicities.

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

L-histidine hydrochloride monohydrate

L-histidineα,α-trehalose dihydratepolysorbate 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 vials4 years.

After aseptic reconstitution with sterile water for injections, chemical and physical stability ofthe reconstituted solution has been demonstrated for 7 days at 2°C-8°C.

After aseptic dilution in polyvinylchloride, polyethylene or polypropylene bags containing sodiumchloride 9 mg/mL (0.9%) solution for injection, chemical and physical stability of Ontruzant has beendemonstrated for up to 30 days at 2ºC - 8ºC, and 24 hours at temperatures not exceeding 30°C.

From a microbiological point of view, the reconstituted solution and Ontruzant infusion solutionshould be used immediately. If not used immediately, in-use storage times and conditions prior to useare the responsibility of the user, and would not normally be longer than 24 hours at 2°C to 8°C,unless reconstitution and dilution have taken place under controlled and validated aseptic conditions.

Store in a refrigerator (2°C-8°C).

Do not freeze the reconstituted solution.

For storage conditions of the reconstituted and diluted medicinal product, see section 6.3 and 6.6.

Ontruzant 150 mg powder for concentrate for solution for infusion

One 15 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin filmcontaining 150 mg of trastuzumab

Each carton contains one vial.

Ontruzant 420 mg powder for concentrate for solution for infusion

One 40 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin filmcontaining 420 mg of trastuzumab

Each carton contains one vial.

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

Appropriate aseptic technique should be used for reconstitution and dilution procedures. Caremust be taken to ensure the sterility of prepared solutions. Since the medicinal product doesnot contain any anti-microbial preservative or bacteriostatic agents, aseptic technique mustbe observed.

Aseptic preparation, handling and storage

Aseptic handling must be ensured when preparing the infusion. Preparation should be:

* performed under aseptic conditions by trained personnel in accordance with good practice rulesespecially with respect to the 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

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

Ontruzant that can be withdrawn from the vial.

The reconstituted solution should not be frozen.

Ontruzant 150 mg powder for concentrate for solution for infusion

Each 150 mg vial of Ontruzant is reconstituted with 7.2 mL of sterile water for injection (notsupplied). 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 canbe withdrawn from each vial.

Ontruzant 420 mg powder for concentrate for solution for infusion

Each 420 mg vial of Ontruzant is reconstituted with 20 mL of sterile water for injection (notsupplied). Use of other reconstitution solvents should be avoided.

This yields a 21 mL solution for single-dose use, containing approximately 21 mg/mL trastuzumab,at a pH of approximately 6.0. A volume overage of 5% ensures that the labelled dose of 420 mg canbe withdrawn from each vial.

Ontruzant vial Volume of sterile water for Final concentrationinjections150 mg vial + 7.2 mL = 21 mg/mL420 mg vial + 20 mL = 21 mg/mL

Instructions for aseptic reconstitution

* Using a sterile syringe, slowly inject the appropriate volume (as noted above) of sterile water forinjection in the vial containing the lyophilised Ontruzant, directing the stream into the lyophilisedcake.

* 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 Ontruzant results in a colourless to pale yellowtransparent solution and should be essentially free of visible particulates.

Instructions for aseptic dilution of the reconstituted solution

Determine the volume of the solution required:

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

Body weight (kg) x dose (4 mg/kg for loading or 2 mg/kg for maintenance)

Volume (mL) =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 mgtrastuzumab/kg body weight:

Body weight (kg) x dose (8 mg/kg for loading or 6 mg/kg for maintenance)

Volume (mL) =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 0.9% sodium chloride solution. Do notuse with glucose-containing solutions (see section 6.2). The bag should be gently inverted to mixthe solution in order to avoid foaming.

Parenteral medicinal products should be inspected visually for particulate matter anddiscoloration prior to administration.

No incompatibilities between Ontruzant and polyvinylchloride, polyethylene or polypropylene bagshave been observed.

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

Samsung Bioepis NL B.V.

Olof Palmestraat 102616 LR Delft

The Netherlands

EU/1/17/1241/001

EU/1/17/1241/002

Date of first authorisation: 15 November 2017

Date of latest renewal: 19 July 2022

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

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