HERCEPTIN 600mg / 5ml injectible solution medication leaflet

Herceptin 600 mg solution for injection in vial

One vial of 5 mL contains 600 mg of trastuzumab, a humanised IgG1 monoclonal antibody producedby mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ionexchange chromatography including specific viral inactivation and removal procedures.

For the full list of excipients, see section 6.1.

Solution for injection

Clear to opalescent solution, colourless to yellowish.

Breast cancer

Metastatic breast cancer

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

- as monotherapy for the treatment of those patients who have received at least two 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

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

- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (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 Herceptin therapy, forlocally advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections4.4 and 5.1).

Herceptin 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).

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

It is important to check the product labels to ensure that the correct formulation (intravenous orsubcutaneous fixed dose) is being administered to the patient, as prescribed. Herceptin subcutaneousformulation is not intended for intravenous administration and should be administered via asubcutaneous injection only.

Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulations andvice versa, using the three-weekly (q3w) dosing regimen, was investigated in study MO22982 (seesection 4.8).

In order to prevent medication errors it is important to check the vial labels to ensure that the drugbeing prepared and administered is Herceptin (trastuzumab) and not another trastuzumab-containingproduct (e.g. trastuzumab emtansine or trastuzumab deruxtecan).

The recommended dose for Herceptin subcutaneous formulation is 600 mg irrespective of the patient’sbody weight. No loading dose is required. This dose should be administered subcutaneously over 2-5minutes every three weeks.

In the pivotal trial (BO22227) Herceptin subcutaneous formulation was administered in theneoadjuvant/adjuvant setting in patients with early breast cancer. The preoperative chemotherapyregimen consisted of docetaxel (75 mg/m²) followed by FEC (5FU, epirubicin and cyclophosphamide)at a standard dose.

See section 5.1 for chemotherapy combination dosing.

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

No reductions in the dose of Herceptin were made during clinical trials. Patients may continue therapyduring periods of reversible, chemotherapy-induced myelosuppression butthey should be monitoredcarefully for complications of neutropenia during this time. Refer to the Summary of Product

Characteristics (SmPC) for paclitaxel, docetaxel or aromatase inhibitor for information on dosereduction 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 Herceptin 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 misses a dose of Herceptin subcutaneous formulation, it is recommended to administerthe next 600 mg dose (i.e. the missed dose) as soon as possible. The interval between consecutive

Herceptin subcutaneous formulation administrations should not be less than three weeks.

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 Herceptin in the paediatric population.

The 600 mg dose should be administered as a subcutaneous injection only over 2-5 minutes everythree weeks. The injection site should be alternated between the left and right thigh. New injectionsshould be given at least 2.5 cm from the old site and never into areas where the skin is red, bruised,tender, or hard. During the treatment course with Herceptin subcutaneous formulation other medicinalproducts for subcutaneous administration should preferably be injected at different sites. Patientsshould be observed for 30 minutes after the first injection and for 15 minutes after subsequentinjections for signs or symptoms of administration-related reactions (see sections 4.4 and 4.8).

For instructions on use and handling of Herceptin subcutaneous formulation refer to section 6.6.

* Hypersensitivity to trastuzumab, murine proteins, hyaluronidase or to any of the otherexcipients 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 trade name and the batchnumber of 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 Herceptin in the adjuvant setting.

Cardiac dysfunction

General considerations

Patients treated with Herceptin are at increased risk for developing CHF (New York Heart Association[NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed inpatients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularlyfollowing anthracycline (doxorubicin or epirubicin)-containing chemotherapy. These may bemoderate to severe and have been associated with death (see section 4.8). In addition, caution shouldbe exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronaryartery disease, CHF, LVEF of <55%, older age.

All candidates for treatment with Herceptin, but especially those with prior anthracycline andcyclophosphamide exposure, should undergo baseline cardiac assessment including history andphysical examination and 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 Herceptin. A careful risk-benefit assessment should be made before deciding totreat with Herceptin.

Trastuzumab may persist in the circulation for up to 7 months after stopping Herceptin treatmentbased on population pharmacokinetic analysis of all available data (see section 5.2). Patients whoreceive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiacdysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months afterstopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitoredcarefully.

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

Herceptin therapy has been seen.

The safety of continuation or resumption of Herceptin 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 Herceptin 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 Herceptin 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 Herceptin treatment continued ontherapy without additional clinical cardiac events.

Metastatic breast cancer

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

Early breast cancer

For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3months during treatment and every 6 months following discontinuation of treatment until 24 monthsfrom the last administration of Herceptin. In patients who receive anthracycline-containingchemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the lastadministration of Herceptin, or longer if a continuous decrease of LVEF is observed.

Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment,history of or existing CHF (NYHA Class II -IV), LVEF of < 55%, other cardiomyopathy, 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 Herceptin and therefore treatment cannot be recommended in such patients.

Adjuvant treatment

Herceptin and anthracyclines should not be given concurrently in the adjuvant treatment setting.

In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac eventswas observed when Herceptin (intravenous formulation) was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxeland carboplatin and was more marked when Herceptin (intravenous formulation) was administeredconcurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimenused, most symptomatic cardiac events occurred within the first 18 months. In one of the 3 pivotalstudies conducted in which a median follow-up of 5.5 years was available (BCIRG006) a continuousincrease in the cumulative rate of symptomatic cardiac or LVEF events was observed (up to 2.37 %) inpatients who were administered Herceptin concurrently with a taxane following anthracycline therapy,compared to approximately 1 % in the two comparator arms (anthracycline plus cyclophosphamidefollowed by taxane and taxane, carboplatin and Herceptin).

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

In patients receiving Herceptin after completion of adjuvant chemotherapy, the risk of cardiacdysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of

Herceptin and a body mass index (BMI) >25 kg/m2.

Neoadjuvant-adjuvant treatment

In patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin should be usedconcurrently with anthracyclines only in chemotherapy-naive patients and only with low-doseanthracycline regimens, i.e., with 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 Herceptinin 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, Herceptin was administered concurrently with neoadjuvantchemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2) . The incidence ofsymptomatic cardiac dysfunction was 1.7% in the Herceptin arm .

In the pivotal trial BO22227, Herceptin 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 cardiac failure/congestive cardiac failure was 0.3%in the Herceptin intravenous arm and 0.7% in the Herceptin subcutaneous arm. In patients with lowerbody weights (<59 kg, the lowest body weight quartile) the fixed dose used in the Herceptinsubcutaneous arm was not associated with an increased risk of cardiac events or significant drop in

LVEF.

Clinical experience is limited in patients above 65 years of age.

Administration-related reactions

Administration-related reactions (ARRs) are known to occur with Herceptin subcutaneousformulation. Pre-medication may be used to reduce risk of occurrence of ARRs.

Although serious ARRs, including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia,reduced oxygen saturation and respiratory distress, were not reported in the clinical trial with the

Herceptin subcutaneous formulation, caution should be exercised as these have been associated withthe intravenous formulation. Patients should be observed for ARRs for 30 minutes after the firstinjection and for 15 minutes after subsequent injections. ARRs considered mild in severity can betreated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such asdiphenhydramine. Serious reactions to intravenous Herceptin have been treated successfully withsupportive therapy such as oxygen, beta-agonists, and corticosteroids. In rare cases, these reactionswere associated with a clinical course culminating in a fatal outcome. Patients experiencing dyspnoeaat rest due to complications of advanced malignancy and comorbidities may be at increased risk of afatal ARR. Therefore, these patients should not be treated with Herceptin (see section 4.3).

Pulmonary events

Caution is recommended with Herceptin subcutaneous formulation as severe pulmonary events havebeen reported with the use of the intravenous formulation in the post-marketing setting (see section4.8). These events have occasionally been fatal and may occur as part of an infusion-related reactionor with delayed onset. In addition, cases of interstitial lung disease including lung infiltrates, acuterespiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acutepulmonary oedema and respiratory insufficiency have been reported. Risk factors associated withinterstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapiesknown to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy.

Patients experiencing dyspnoea at rest due to complications of advanced malignancy andcomorbidities may be at increased risk of pulmonary events. Therefore, these patients should not betreated with Herceptin (see section 4.3). Caution should be exercised for pneumonitis, especially inpatients being treated concomitantly with taxanes.

Herceptin 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 between

Herceptin and the concomitant medicinal products used in clinical trials have not been observed.

Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents

Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive 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 Herceptin (4 mg/kg IV loading dose and 2 mg/kg IVweekly) and docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggested thatconcomitant administration of Herceptin 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 Herceptin. 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 Herceptin. However, capecitabine itself showed higherconcentrations and a longer half-life when combined with Herceptin. The data also suggested that thepharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent useof capecitabine plus Herceptin.

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 Herceptin monotherapy (4 mg/kgloading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with HER2- positive

MBC (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on thepharmacokinetics of trastuzumab was found.

Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study(H0648g) in which patients were treated concomitantly with Herceptin and paclitaxel and two Phase IIstudies in which Herceptin was administered as monotherapy (W016229 and MO16982), in womenwith 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 with

Herceptin, paclitaxel and doxorubicin to trastuzumab PK data in studies where Herceptin 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 Herceptin 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 Herceptin intravenous formulation and have revealed noevidence of impaired fertility or harm to the fetus. Placental transfer of trastuzumab during the early(days 20-50 of gestation) and late (days 120-150 of gestation) fetal development period was observed.

It is not known whether Herceptin can affect reproductive capacity. As animal reproduction studies arenot always predictive of human response, Herceptin should be avoided during pregnancy unless thepotential benefit for the mother outweighs the potential risk to the fetus.

In the post-marketing setting, cases of fetal renal growth and/or function impairment in associationwith oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus, have beenreported in pregnant women receiving Herceptin. Women who become pregnant should be advised ofthe possibility of harm to the fetus. If a pregnant woman is treated with Herceptin, or if a patientbecomes pregnant while receiving Herceptin or within 7 months following last dose of Herceptin,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 Herceptin intravenous formulation from days 120 to 150 of pregnancy demonstratedthat trastuzumab is secreted in the milk postpartum. The exposure to trastuzumab in utero and thepresence of trastuzumab in the serum of infant monkeys was not associated with any adverse effectson their growth or development from birth to 1 month of age. It is not known whether trastuzumab issecreted in human milk. As human IgG1 is secreted into human milk, and the potential for harm to theinfant is unknown, women should not breast-feed during Herceptin therapy and for 7 months after thelast dose.

There is no fertility data available.

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

Amongst the most serious and/or common adverse reactions reported in Herceptin usage (intravenousand subcutaneous formulations) to date are cardiac dysfunction, administration-related reactions,haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions.

The safety profile of Herceptin subcutaneous formulation (evaluated in 298 and 297 patients treatedwith the intravenous and subcutaneous formulations respectively) from the pivotal trial in EBC wasoverall similar to the known safety profile of the intravenous formulation.

Severe adverse events (defined according to National Cancer Institute Common Terminology Criteriafor Adverse Events (NCI CTCAE grade ≥3) version 3.0) were equally distributed between both

Herceptin formulations (52.3 % versus 53.5 % in the intravenous formulation versus subcutaneousformulation respectively).

Some adverse events/reactions were reported with a higher frequency for the subcutaneousformulation:

* Serious adverse events (most of which were identified because of in-patient hospitalisation orprolongation of existing hospitalisation): 14.1 % for the intravenous formulation versus21.5 % for the subcutaneous formulation. The difference in serious adverse event ratesbetween formulations was mainly due to infections with or without neutropenia (4.4 % versus8.1 %) and cardiac disorders (0.7 % versus 1.7 %);

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

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

* Hypertension: 4.7 % versus 9.8 % for the intravenous formulation versus subcutaneousformulation respectively.

Tabulated list of adverse reactions with the intravenous formulation

In this section, the following categories of frequency have been used: very common (≥1/10), common(≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare(<1/10,000), not known (cannot be estimated from the available data). Within each 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 Herceptin 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 Herceptin monotherapy or in combination withchemotherapy 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 Febrile neutropenia Very commonsystem disorders Anaemia Very common

Neutropenia Very common

System organ class Adverse reaction Frequency

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 1Tremor Very common

Dizziness Very common

Headache Very common

Paraesthesia Very common

Dysgeusia Very common

Peripheral neuropathy Common

Hypertonia Common

Somnolence Common

Eye disorders Conjunctivitis Very common

Lacrimation increased Very common

Dry eye Common

Papilloedema Not known

Retinal haemorrhage Not known

Ear and labyrinth disorders Deafness Uncommon

Cardiac disorders 1 Blood pressure decreased Very 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+1 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+1Wheezing Uncommon

System organ class Adverse reaction Frequency

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 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 Erythema Very commontissue disorders Rash Very common1 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 1Muscle tightness Very common

Myalgia Very common

Arthritis Common

Back pain Common

Bone pain Common

Muscle spasms Common

System organ class Adverse reaction Frequency

Neck pain Common

Pain in extremity Common

Renal and urinary disorders Renal disorder Common

Glomerulonephritis membranous Not known

Glomerulonephropathy Not known

Renal failure Not known

Pregnancy, puerperium and 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

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 administration-related reactions.

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 to Herceptin. It has beenassociated with a fatal outcome. Signs and symptoms of cardiac dysfunction such as dyspnoea,orthopnoea, increased cough, pulmonary oedema, S3 gallop, or reduced ventricular ejection fraction,have been observed in patients treated with Herceptin (see section 4.4).

In 3 pivotal EBC clinical trials of adjuvant intravenous Herceptin given in combination withchemotherapy, the incidence of grade 3/4 cardiac dysfunction (specifically symptomatic congestiveheart failure) was similar in patients who were administered chemotherapy alone (ie did not receive

Herceptin) and in patients who were administered Herceptin sequentially after a taxane (0.3-0.4 %).

The rate was highest in patients who were administered Herceptin concurrently with a taxane (2.0 %).

In the neoadjuvant setting, the experience of concurrent administration of Herceptin and low doseanthracycline regimen is limited (see section 4.4).

When Herceptin 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 of 12months. In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA

Class III & IV) in the Herceptin 1 year treatment arm was 0.8 %, and the rate of mild symptomatic andasymptomatic left ventricular dysfunction was 4.6 %.

Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥50 %after the event) was evident for 71.4 % of Herceptin-treated patients. Reversibility of mildsymptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5 % of patients.

Approximately 17 % of cardiac dysfunction related events occurred after completion of Herceptin.

In the pivotal metastatic trials of intravenous Herceptin, the incidence of cardiac dysfunction 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 Herceptin 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 Herceptin 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.

Administration-related reactions/hypersensitivity

Administration-related reactions (ARRs)/hypersensitivity reactions such as chills and/or fever,dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratorydistress, rash, nausea, vomiting and headache were seen in Herceptin clinical trials (see section 4.4).

The rate of ARRs of all grades varied between studies depending on the indication, the data collectionmethodology, and whether trastuzumab was given concurrently with chemotherapy or asmonotherapy.

Anaphylactoid reactions have been observed in isolated cases.

Haematotoxicity

Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred verycommonly. The frequency of occurrence of hypoprothrombinemia 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 Herceptin 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).

Description of selected adverse reactions with the subcutaneous formulation

Administration-related reactions

In the pivotal trial, the rate of all grade ARRs was 37.2 % with the Herceptin intravenous formulationand 47.8 % with the Herceptin subcutaneous formulation; severe grade 3 reactions were reported in2.0 % and 1.7 % of the patients, respectively during the treatment phase; no severe grade 4 or 5reactions were observed. All of the severe ARRs with the Herceptin subcutaneous formulationoccurred during concurrent administration with chemotherapy. The most frequent severe reaction wasdrug hypersensitivity.

The systemic reactions included hypersensitivity, hypotension, tachycardia, cough, and dyspnoea. Thelocal reactions included erythema, pruritus, oedema, rash and pain at the site of the injection.

The rate of severe infections (NCI CTCAE grade ≥3) was 5.0 % versus 7.1 %, in the Herceptinintravenous formulation arm and the Herceptin subcutaneous formulation arm respectively.

The rate of serious infections (most of which were identified because of in-patient hospitalisation orprolongation of existing hospitalisation) was 4.4 % in the Herceptin intravenous formulation arm and8.1 % in the Herceptin subcutaneous formulation arm. The difference between formulations wasmainly observed during the adjuvant treatment phase (monotherapy) and was mainly due topostoperative wound infections, but also to various other infections such as respiratory tract infections,acute pyelonephritis and sepsis. They resolved within a mean of 13 days in the Herceptin intravenoustreatment arm and a mean of 17 days in the Herceptin subcutaneous treatment arm.

Hypertensive events

In the pivotal trial BO22227, there were more than twice as many patients reporting all gradehypertension with the Herceptin subcutaneous formulation (4.7 % versus 9.8 % in the intravenous andsubcutaneous formulations respectively), with a greater proportion of patients with severe events (NCI

CTCAE grade ≥3) <1 % versus 2.0 % the intravenous and subcutaneous formulations respectively. Allbut one patient who reported severe hypertension had a history of hypertension before they entered thestudy. Some of the severe events occurred on the day of the injection.

In the neoadjuvant-adjuvant EBC study (BO22227), at a median follow-up exceeding 70 months,10.1% (30/296) of patients treated with Herceptin intravenous and 15.9 % (47/295) of patientsreceiving Herceptin subcutaneous vial developed antibodies against trastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in the Herceptinintravenous arm and 3 of 47 in the Herceptin subcutaneous arm. 21.0 % of patients treated with

Herceptin subcutaneous formulation developed antibodies against the excipient hyaluronidase(rHuPH20).

The clinical relevance of these antibodies is not known.The presence of anti-trastuzumab 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 Herceptin intravenous and Herceptin subcutaneous.

Details of risk minimisation measures that are consistent with the EU Risk Management Plan arepresented in Section 4.4.

Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulation and viceversa

Study MO22982 investigated switching between the Herceptin intravenous and Herceptinsubcutaneous formulation with a primary objective to evaluate patient preference for either theintravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one usingsubcutaneous formulation in vial and one using subcutaneous formulation in administration system)were investigated using a 2-arm, cross-over design with 488 patients being randomized to one of twodifferent three-weekly Herceptin treatment sequences (IV [Cycles 1-4]→ SC [Cycles 5-8], or SC[Cycles 1-4]→ IV [Cycles 5-8]). Patients were either naïve to Herceptin IV treatment (20.3%) or pre-exposed to Herceptin IV (79.7%). For the sequence IV→SC (SC vial and SC formulation inadministration system cohorts combined), adverse event rates (all grades) were described pre-switching (Cycles 1-4) and post-switching (Cycles 5-8) as 53.8% vs. 56.4%, respectively; for thesequence SC→IV (SC vial and SC formulation in administration system cohorts combined), adverseevent rates (all grades) were described pre- and post-switching as 65.4% vs. 48.7%, respectively.

Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatmentdiscontinuations due to adverse events were low (<5%) and similar to post-switching rates (Cycles 5-8). No grade 4 or grade 5 adverse events were reported.

Reporting 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.

Single doses of up to 960 mg of Herceptin subcutaneous formulation have been administered with noreported untoward effects.

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

Herceptin subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), anenzyme used to increase the dispersion and absorption of co-administered drugs when administeredsubcutaneously.

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 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

Herceptin 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 (see section4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) orchromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Herceptintreatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive

FISH or CISH result.

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

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

Table 2: Recommended scoring system to evaluate the IHC staining patterns

Score Staining pattern HER2 overexpressionassessment0 No staining is observed or membrane staining is Negativeobserved in < 10 % of the tumour cells1+ A faint/barely perceptible membrane staining is Negativedetected 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.

Metastatic breast cancer

Intravenous formulation

Herceptin 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 (Herceptin alone).

Herceptin has also been used in combination with paclitaxel or docetaxel for the treatment of patientswho 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 Herceptin. In the pivotal trial of docetaxel (100 mg/m2 infused over1 hour) with or without Herceptin, 60 % of the patients had received prior anthracycline-basedadjuvant chemotherapy. Patients were treated with Herceptin until progression of disease.

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

The test method for HER2 overexpression used to determine eligibility of patients in the pivotal

Herceptin monotherapy and Herceptin plus paclitaxel clinical trials employed immunohistochemicalstaining for HER2 of fixed material from breast tumours using the murine monoclonal antibodies

CB11 and 4D5. These tissues were fixed in formalin or Bouin’s fixative. This investigative clinicaltrial 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 patientsenrolled exhibited 3+ overexpression. The data suggest that beneficial effects were greater amongthose 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 Herceptin, 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 metatstatic breast cancer

The efficacy results from the monotherapy and combination therapy studies are summarised in Table3:

Table 3: Efficacy results from the monotherapy and combination therapy studies

Parameter Monotherapy Combination Therapy

Herceptin1 Hercepti Paclitaxe Hercepti Docetaxen plus l2 n plus l3paclitaxe docetaxel

N=172 l2 3

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

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

Median Survival 16.4 24.8 17.9 31.2 22.74(months) (12.3-ne) (18.6- (11.2- (27.3- (19.1-(95 %CI) 33.7) 23.8) 40.8) 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 Herceptin and anastrozole

Herceptin has been studied in combination with anastrozole for first line treatment of MBC in HER2overexpressing, hormone-receptor (i.e. estrogen-receptor (ER) and/or progesterone-receptor (PR))positive postmenopausal patients. Progression free survival was doubled in the Herceptin 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 Herceptin containing regimen after progression of disease.

Three -weekly dosing in metastatic breast cancer

The efficacy results from the non-comparative monotherapy and combination therapy studies aresummarised in Table 4:

Table 4: Efficacy results from the non-comparative monotherapy and combination therapy studies

Parameter Monotherapy Combination Therapy

Herceptin1 Herceptin2 Herceptin plus Herceptin 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 Herceptin and paclitaxel, compared to paclitaxel alone (21.8 % versus 45.7 %;p=0.004). More patients treated with Herceptin and paclitaxel progressed in the central nervous systemthan those treated with paclitaxel alone (12.6 % versus 6.5 %; p=0.377).

Early breast cancer (adjuvant setting)

Intravenous formulation

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

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

- Study BO16348 was designed to compare one and two years of three-weekly Herceptintreatment versus observation in patients with HER2 positive EBC following surgery, establishedchemotherapy and radiotherapy (if applicable). In addition, comparison of two years of

Herceptin treatment versus one year of Herceptin treatment was performed. Patients assigned toreceive Herceptin were given an initial loading dose of 8 mg/kg, followed by 6 mg/kg everythree weeks for either one or two years.

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

- Study BCIRG 006 study was designed to investigate combining Herceptin 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 BO16348 Study was limited to operable, primary, invasive adenocarcinomaof the breast, with axillary nodes positive or axillary nodes negative if tumors at least 1 cm indiameter.

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 (tumor size > 1 cm and ER negative ortumor 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, estrogen receptor and progesterone receptor negative, histologicaland/or nuclear grade 2-3, or age < 35 years.

The efficacy results from study BO16348 following 12 months* and 8 years** median follow-up aresummarized in the Table 5:

Table 5: Efficacy results from study BO16348

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

Parameter Observation Herceptin Observation Herceptin

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 0.54 0.76

Recurrence-free survival

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

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

P-value versus Observation < 0.0001 < 0.0001

Hazard Ratio versus Observation 0.51 0.73

Distant disease-free survival

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

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

P-value versus Observation < 0.0001 < 0.0001

Hazard Ratio versus Observation 0.50 0.76

Overall survival (death)

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

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

P-value versus Observation 0.24 0.0005

Hazard Ratio versus Observation 0.75 0.76

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

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

*** There is a discrepancy in the overall sample size due to a small number of patients who were randomizedafter 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 Herceptin 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 Herceptin arm.

A final analysis was performed after a median follow-up of 8 years, which showed that 1 year

Herceptin treatment is associated with a 24 % risk reduction compared to observation only (HR=0.76,95 % CI 0.67, 0.86). This translates into an absolute benefit in terms of an 8 year disease free survivalrate of 6.4 percentage points in favour of 1 year Herceptin treatment.

In this final analysis, extending Herceptin treatment for a duration of two years did not 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 eventin the 2-year treatment arm (20.4 %) compared with the 1-year treatment arm (16.3 %).

In the NSABP B-31 and NCCTG N9831 studies Herceptin was administered in combination 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 for 4cycles.

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

- intravenous paclitaxel - 80 mg/m2 as a continuous intravenous infusion, given every weekfor 12 weeks.or

- intravenous paclitaxel - 175 mg/m2 as a continuous intravenous infusion, given every 3weeks 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 6. The median duration of follow up was 1.8years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm.

Table 6: Summary of Efficacy results from the joint analysis studies NSABP B-31 and

NCCTG N9831 at the time of the definitive DFS analysis*

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

Disease-free survival

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

Distant Recurrence

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

Death (OS event):

No. patients with event 92 (5.5) 62 (3.7) 0.67 (0.48, 0.92)p=0.014**

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

* at median duration of follow up of 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the

AC→PH arm

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

For the primary endpoint, DFS, the addition of Herceptin to paclitaxel chemotherapy resulted in 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 (Herceptin) 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 to

Herceptin in the control arm, the addition of Herceptin to paclitaxel chemotherapy resulted in a 52 %decrease in the risk of disease recurrence. The addition of Herceptin to paclitaxel chemotherapy alsoresulted 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 N9831was performed when 707 deaths had occurred (median follow-up 8.3 years in the AC→PH group).

Treatment with AC→PH resulted in a statistically significant improvement in OS compared with

AC→P (stratified HR=0.64; 95% CI [0.55, 0.74]; log-rank p-value < 0.0001). At 8 years, the survivalrate was estimated to be 86.9% in the AC→PH arm and 79.4% in the AC→P arm, an absolute benefitof 7.4% (95% CI 4.9%, 10.0%).

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

Table 7: 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% 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, despite24.8% patients in the AC→P arm who crossed over to receive Herceptin. 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 Herceptin was administered either in combination with docetaxel, following

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

Docetaxel was administered as follows:

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

- intravenous docetaxel - 75 mg/m2 as an intravenous infusion over 1 hour, given every 3weeks for 6 cycles (day 2 of cycle 1, then day 1 of each subsequent cycle)which was followed by:

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

Herceptin was administered weekly with chemotherapy and 3 weekly thereafter for a total of 52weeks.

The efficacy results from the BCIRG 006 are summarized in Tables 8 and 9. 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 8: 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 9: 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 (Herceptin) arm and 4.6 percentage points (85.5 % versus 80.9 %)in favour of the DCarbH (Herceptin) arm compared to AC→D.

In study BCIRG 006, 213/1075 patients in the DCarbH (TCH) arm, 221/1074 patients in the 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 10:

Table 10: Post-hoc exploratory analysis results from the joint analysis NSABP B-31/NCCTG N9831*and BCIRG006 clinical studies combining DFS events and symptomatic cardiac events

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 0.77

Hazard 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→P armand 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) and the DCarbHarm (range: 0.0 to 13.1), and was 10.4 years (range: 0.0 to 12.7) in the AC→DH arm

Early breast cancer - (neoadjuvant-adjuvant setting)

Intravenous formulation

So far, no results are available which compare the efficacy of Herceptin administered 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 Herceptin withneoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant

Herceptin, up to a total treatment duration of 1 year. The study recruited patients with newlydiagnosed locally advanced (Stage III) or inflammatory EBC. Patients with HER2+ tumours wererandomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant

Herceptin, or neoadjuvant chemotherapy alone.

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

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

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

- CMF on day 1 and 8 every 4 weeks for 3 cycleswhich was followed after surgery by

- additional cycles of adjuvant Herceptin (to complete 1 year of treatment)

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

Table 11: Efficacy results from MO16432

Parameter Chemo + Chemo only

Herceptin (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 22 33 0.59 (0.35, 1.02)p=0.0555

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

An absolute benefit of 13 percentage points in favour of the Herceptin arm was estimated in terms of3-year event-free survival rate (65 % versus. 52 %).

Subcutaneous formulation

Study BO22227 was designed to demonstrate non-inferiority of treatment with Herceptinsubcutaneous formulation versus Herceptin intravenous formulation based on co-primary PK andefficacy endpoints (trastuzumab Ctrough at pre-dose Cycle 8, and pCR rate at definitive surgery,respectively). A total of 595 patients with HER2-positive, operable or locally advanced breast cancer(LABC) including inflammatory breast cancer received eight cycles of either Herceptin intravenousformulation or Herceptin subcutaneous formulation concurrently with chemotherapy (4 cycles ofdocetaxel, 75 mg/m2 intravenous infusion, followed by 4 cycles of FEC ([5-Fluorouracil, 500 mg/m2;epirubicin, 75 mg/m2; cyclophosphamide, 500 mg/m2 each intravenous bolus or infusion]), followedby surgery, and continued therapy with Herceptin intravenous formulation or Herceptin subcutaneousformulation as originally randomized for 10 additional cycles, for a total of one year of treatment.

The analysis of the efficacy co-primary endpoint, pCR, defined as absence of invasive neoplastic cellsin the breast, resulted in rates of 40.7 % (95 % CI: 34.7, 46.9) in the Herceptin intravenous arm and45.4 % (95 % CI: 39.2 %, 51.7 %) in the Herceptin subcutaneous arm, a difference of 4.7 percentagepoints in favour of the Herceptin subcutaneous arm. The lower boundary of the one-sided 97.5 %confidence interval for the difference in pCR rates was -4.0, establishing the non-inferiority of

Herceptin subcutaneous for the co-primary endpoint

Table 12: Summary of pathological Complete Response (pCR)

Herceptin IV Herceptin SC(N = 263) (N=260)pCR (absence ofinvasive neoplastic cells in breast 107 (40.7%) 118 (45.4%)

Non-responders 156 (59.3%) 142 (54.6%)

Exact 95% CI for pCR Rate* (34.7; 46.9) (39.2; 51.7)

Difference in pCR (SC minus IV arm) 4.70

Lower bound one-sided 97.5% CI for the -4.0difference in pCR**

*Confidence interval for one sample binomial using Pearson-Clopper method

**Continuity correction of Anderson and Hauck (1986) has been used in this calculation

Analyses with longer term follow-up of a median duration exceeding 40 months supported the non-inferior efficacy of Herceptin subcutaneous compared to Herceptin intravenous with comparableresults of both EFS and OS (3-year EFS rates of 73% in the Herceptin intravenous arm and 76% in the

Herceptin subcutaneous arm, and 3-year OS rates of 90% in the Herceptin intravenous arm and 92% inthe Herceptin subcutaneous arm).

For non-inferiority of the PK co-primary endpoint, steady-state trastuzumab Ctrough value at the end oftreatment Cycle 7, refer to section 5.2. Pharmacokinetic Properties. For the comparative safety profilesee section 4.8.

The final analysis at a median follow-up exceeding 70 months showed similar EFS and OS betweenpatients who received Herceptin IV and those who received Herceptin SC. The 6-year EFS rate was65% in both arms (ITT population: HR=0.98 [95% CI: 0.74;1.29]) and the OS rate, 84% in both arms(ITT population: HR=0.94 [95% CI: 0.61;1.45]).

Study MO28048 investigating the safety and tolerability of Herceptin subcutaneous formulation asadjuvant therapy in HER2 positive EBC patients who were enrolled in either a Herceptin subcutaneousvial cohort (N=1868 patients, including 20 patients receiving neoadjuvant therapy) or a Herceptinsubcutaneous administration system cohort (N=710 patients, including 21 patients receivingneoadjuvant therapy) resulted in no new safety signals. Results were consistent with the known safetyprofile for Herceptin intravenous and Herceptin subcutaneous formulations. In addition, treatment oflower body weight patients with Herceptin subcutaneous fixed dose in adjuvant EBC was notassociated with increased safety risk, adverse events and serious adverse events, compared to thehigher body weight patients. The final results of study BO22227 at a median follow-up exceeding 70months were also consistent with the known safety profile for Herceptin IV and Herceptin SC, and nonew safety signals were observed.

The European Medicines Agency has waived the obligation to submit the results of studies with

Herceptin in all subsets of the paediatric population for breast cancer (see section 4.2 for informationon paediatric use).

The pharmacokinetics of trastuzumab at a dose of 600 mg administered three-weekly by thesubcutaneous route was compared to the intravenous route (8 mg/kg loading dose, 6 mg/kgmaintenance every three weeks) in the phase III study BO22227. The pharmacokinetic results for theco primary endpoint, Ctrough pre dose Cycle 8, showed non-inferiority of the Herceptin subcutaneouscompared to the Herceptin intravenous dose adjusted by body weight.

The mean Ctrough during the neoadjuvant treatment phase, at the pre dose Cycle 8 time point, washigher in the Herceptin subcutaneous arm (78.7 µg/mL) than the Herceptin intravenous arm(57.8 µg/mL) of the study. During the adjuvant phase of treatment, at the pre-dose Cycle 13 timepoint, the mean Ctrough values were 90.4 µg/mL and 62.1 µg/mL, respectively. Based on the observeddata in study BO22227, steady state with the intravenous formulation was reached at cycle 8. With

Herceptin subcutaneous formulation, concentrations were approximately at steady-state following

Cycle 7 dose (pre-dose Cycle 8) with small increase in concentration (<15%) up to cycle 13. The mean

Ctrough at the subcutaneous pre- dose cycle 18 was 90.7 µg/mL and is similar to that of cycle 13,suggesting no further increase after cycle 13.

The median Tmax following subcutaneous administration was approximately 3 days, with highinterindividual variability (range 1-14 days). The mean Cmax was expectedly lower in the Herceptinsubcutaneous formulation (149 μg/mL) than in the intravenous arm (end of infusion value: 221μg/mL).

The mean AUC0-21 days following the Cycle 7 dose was approximately 10 % higher with the Herceptinsubcutaneous formulation as compared to the Herceptin intravenous formulation, with mean AUCvalues of 2268 µg/mL*day and 2056 µg/mL*day, respectively. The AUC0-21 days following Cycle 12dose was approximately 20 % higher with the Herceptin subcutaneous formulation than the Herceptinintravenous dose, with mean AUC values of 2610 µg/mL*day and 2179 µg/mL*day, respectively. Dueto the significant impact of body weight on trastuzumab clearance and the use of a fixed dose for thesubcutaneous administration the difference in exposure between subcutaneous and intravenousadministration was dependent on body weight: in patients with a body weight < 51 kg, mean steadystate AUC of trastuzumab was about 80% higher after subcutaneous than after intravenous treatmentwhereas in the highest BW group (> 90 kg) AUC was 20% lower after subcutaneous than afterintravenous treatment.

A population PK model with parallel linear and nonlinear elimination from the central compartmentwas constructed using pooled Herceptin SC and Herceptin IV PK data from the phase III study

BO22227 to describe the observed PK concentrations following Herceptin IV and Herceptin SCadministration in EBC patients. Bioavailability of trastuzumab given as the subcutaneous formulationwas estimated to be 77.1%, and the first order absorption rate constant was estimated to be 0.4 day-1.

Linear clearance was 0.111 L/day and the central compartment volume (Vc) was 2.91 L. The

Michaelis-Menten parameter values were 11.9 mg/day and 33.9 µg/mL for Vmax and Km, respectively.

Body weight and serum alanine aminotransferase (SGPT/ALT) showed a statistically significantinfluence on PK, however, simulations demonstrated that no dose adjustments are required in EBCpatients. The population predicted PK exposure parameter values (median with 5th - 95th Percentiles)for Herceptin SC dosing regimens in EBC patients are shown in Table 13 below.

Table 13 Population Predicted PK Exposure Values (median with 5th - 95th Percentiles) for the

Herceptin SC 600 mg Q3W Dosing Regimen in EBC patients

Primary tumor Ctype and Cycle N min Cmax AUC0-21days

Regimen (µg/mL) (µg/mL) (µg.day/mL)28.2 79.3 1065

Cycle 1 297(14.8 - 40.9) (56.1 - 109) (718 - 1504)

EBC 600 mg

Herceptin SC q3w Cycle 7 75.0 149 2337(steady 297state) (35.1 - 123) (86.1 - 214) (1258 - 3478)

Trastuzumab washout

Trastuzumab washout period was assessed following subcutaneous 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.

Herceptin Intravenous

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. Herceptin 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 Herceptin,or to determine its effects on fertility in males.

Herceptin Subcutaneous

A single dose study in rabbits and a 13-week repeat dose toxicity study in Cynomolgus monkeys wereconducted. The rabbit study was performed to specifically examine local tolerance aspects. The 13-week study was performed to confirm that the change in route of administration and the use of thenovel excipient recombinant human hyaluronidase (rHuPH20) did not have an effect on the Herceptinsafety characteristics. Herceptin subcutaneous formulation was locally and systemically well tolerated.

Hyaluronidase is found in most tissues of the human body. Non-clinical data for recombinant humanhyaluronidase reveal no special hazard for humans based on conventional studies of repeated dosetoxicity including safety pharmacology endpoints. Reproductive toxicology studies with rHuPH20revealed embryofetal toxicity in mice at high systemic exposure, but did not show teratogenicpotential.

Recombinant human hyaluronidase (rHuPH20)

L-histidine

L-histidine hydrochloride monohydrateα,α-trehalose dihydrate

L-methionine

Polysorbate 20

Water for injections

Herceptin subcutaneous formulation is a ready to use solution which should not be mixed or dilutedwith other products.

No incompatibilities between Herceptin subcutaneous formulation and polypropylene orpolycarbonate syringe material or stainless steel transfer and injection needles and polyethylene Luercone stoppers have been observed.

21 months.

Once transferred from the vial to the syringe the medicinal product is physically and chemically stablefor 28 days at 2°C - 8°C and for 6 hours (cumulative time in the vial and the syringe) at ambienttemperature (max. 30°C) in diffused daylight.

As Herceptin does not contain any antimicrobial-preservative, from a microbiological point of view,the medicine should be used immediately.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

Once removed from the refrigerator Herceptin subcutaneous formulation must be administered within6 hours and should not be kept above 30°C.

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

One 6 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin filmcontaining 5 mL of solution (600 mg of trastuzumab).

Each carton contains one vial.

Herceptin should be inspected visually to ensure there is no particulate matter or discolouration priorto administration.

Herceptin is for single-use only.

As Herceptin does not contain any antimicrobial-preservative, from a microbiological point of view,the medicine should be used immediately. If not used immediately, preparation should take place incontrolled and validated aseptic conditions. After transfer of the solution to the syringe, it isrecommended to replace the transfer needle by a syringe closing cap to avoid drying of the solution inthe needle and not compromise the quality of the medicinal product. The hypodermic injection needlemust be attached to the syringe immediately prior to administration followed by volume adjustment to5 mL.

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

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/00/145/002

Date of first authorisation: 28 August 2000

Date of latest renewal: 28 July 2010

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

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