4.1. Therapeutic indications

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 chemotherapy regimens for their metastatic disease. Prior chemotherapy must have included at least an anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor positive patients must also have failed hormonal therapy, unless patients are unsuitable for these treatments.

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

- in combination with docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.

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

Early breast cancer

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) (see section 5.1).

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

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

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

Herceptin should only be used in patients with metastatic or early breast cancer whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay (see sections 4.4 and 5.1).

4.2. Posology and method of administration

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

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

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

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

Posology

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

In the pivotal trial (BO22227) Herceptin subcutaneous formulation was administered in the neoadjuvant/adjuvant setting in patients with early breast cancer. The preoperative chemotherapy regimen 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.

Duration of treatment

Patients with MBC should be treated with Herceptin until progression of disease. Patients with EBC should 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).

Dose reduction

No reductions in the dose of Herceptin were made during clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-induced myelosuppression butthey should be monitored carefully for complications of neutropenia during this time. Refer to the Summary of Product Characteristics (SmPC) for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.

If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 points from baseline AND to below 50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure (CHF) has developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.

Missed doses

If the patient misses a dose of Herceptin subcutaneous formulation, it is recommended to administer the 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.

Special populations

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

Paediatric population

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

Method of administration

The 600 mg dose should be administered as a subcutaneous injection only over 2-5 minutes every three weeks. The injection site should be alternated between the left and right thigh. New injections should 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 medicinal products for subcutaneous administration should preferably be injected at different sites. Patients should be observed for 30 minutes after the first injection and for 15 minutes after subsequent injections 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.

4.3. Contraindications

• Hypersensitivity to trastuzumab, murine proteins, hyaluronidase or to any of the other excipients listed in section 6.1.

• Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.

4.4. Special warnings and precautions for use

Traceability

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

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

Currently no data from clinical trials are available on re-treatment of patients with previous exposure to 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 in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. These may be moderate to severe and have been associated with death (see section 4.8). In addition, caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, LVEF of <55%, older age.

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

Trastuzumab may persist in the circulation for up to 7 months after stopping Herceptin treatment based on population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping Herceptin. If anthracyclines are used, the patient's cardiac function should be monitored carefully.

Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. In all patients cardiac function should be monitored during treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6-8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has been seen.

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

If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with standard medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy 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 dysfunction with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines.

Early breast cancer

For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin. In patients who receive anthracycline-containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration 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, cardiac arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled hypertension (hypertension controlled by standard medical treatment eligible), and hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC pivotal trials with 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 events was observed when Herceptin (intravenous formulation) was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was more marked when Herceptin (intravenous formulation) was administered concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of 5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events was observed (up to 2.37 %) in patients who were administered Herceptin concurrently with a taxane following anthracycline therapy, compared to approximately 1 % in the two comparator arms (anthracycline plus cyclophosphamide followed 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 cardiac dysfunction 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 used concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose anthracycline regimens, i.e., with maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin 360 mg/m2.

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

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

In the pivotal trial MO16432, Herceptin was administered concurrently with neoadjuvant chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2) . The incidence of symptomatic cardiac dysfunction was 1.7% in the Herceptin arm .

In the pivotal trial BO22227, Herceptin was administered concurrently with neoadjuvant chemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m2); at a median follow-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 lower body weights (<59 kg, the lowest body weight quartile) the fixed dose used in the Herceptin subcutaneous 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 subcutaneous formulation. 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 with the intravenous formulation. Patients should be observed for ARRs for 30 minutes after the first injection and for 15 minutes after subsequent injections. ARRs considered mild in severity can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. Serious reactions to intravenous Herceptin have been treated successfully with supportive therapy such as oxygen, beta-agonists, and corticosteroids. In rare cases, these reactions were associated with a clinical course culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal 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 have been reported with the use of the intravenous formulation in the post-marketing setting (see section 4.8). These events have occasionally been fatal and may occur as part of an infusion-related reaction or with delayed onset. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Herceptin (see section 4.3). Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.

Excipients with known effect

Sodium

Herceptin contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially sodium-free.

Polysorbate 20

Herceptin contains 2.0 mg of polysorbate 20 in each 600 mg/5 mL vial, which is equivalent to 0.4 mg/mL. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

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 MBC suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg 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-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite was unclear.

Data from study JP16003, a single-arm study of Herceptin (4 mg/kg IV loading dose and 2 mg/kg IV weekly) and docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggested that concomitant administration of Herceptin had no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and cisplatin when used with or without Herceptin. The results of this substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus Herceptin. However, capecitabine itself showed higher concentrations and a longer half-life when combined with Herceptin. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus Herceptin.

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

Effect of antineoplastic agents on trastuzumab pharmacokinetics

By comparison of simulated serum trastuzumab concentrations after Herceptin monotherapy (4 mg/kg loading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with HER2- positive MBC (study JP16003) no evidence of a PK effect of concurrent administration 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 Herceptin and paclitaxel and two Phase II studies in which Herceptin was administered as monotherapy (W016229 and MO16982), in women with HER2-positive MBC indicates that individual and mean trastuzumab trough serum concentrations varied within and across studies but there was no clear effect of the concomitant administration of paclitaxel on the pharmacokinetics of trastuzumab. Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with Herceptin, paclitaxel and doxorubicin to trastuzumab PK data in studies where Herceptin was administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab.

Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the PK of trastuzumab.

The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of trastuzumab.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception

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

Pregnancy

Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation and have revealed no evidence of impaired fertility or harm to the fetus. Placental transfer of trastuzumab during the early (days 20‑50 of gestation) and late (days 120‑150 of gestation) fetal development period was observed. It is not known whether Herceptin can affect reproductive capacity. As animal reproduction studies are not always predictive of human response, Herceptin should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus.

In the post-marketing setting, cases of fetal renal growth and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus, have been reported in pregnant women receiving Herceptin. Women who become pregnant should be advised of the possibility of harm to the fetus. If a pregnant woman is treated with Herceptin, or if a patient becomes pregnant while receiving Herceptin or within 7 months following last dose of Herceptin, close monitoring by a multidisciplinary team is desirable.

Breast-feeding

A study conducted in Cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation from days 120 to 150 of pregnancy demonstrated that trastuzumab is secreted in the milk postpartum. The exposure to trastuzumab in utero and the presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age. It is not known whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the potential for harm to the infant is unknown, women should not breast-feed during Herceptin therapy and for 7 months after the last dose.

Fertility

There is no fertility data available.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

Amongst the most serious and/or common adverse reactions reported in Herceptin usage (intravenous and 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 treated with the intravenous and subcutaneous formulations respectively) from the pivotal trial in EBC was overall similar to the known safety profile of the intravenous formulation.

Severe adverse events (defined according to National Cancer Institute Common Terminology Criteria for 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 subcutaneous formulation respectively).

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

• Serious adverse events (most of which were identified because of in-patient hospitalisation or prolongation of existing hospitalisation): 14.1 % for the intravenous formulation versus 21.5 % for the subcutaneous formulation. The difference in serious adverse event rates between formulations was mainly due to infections with or without neutropenia (4.4 % versus 8.1 %) and cardiac disorders (0.7 % versus 1.7 %);

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

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

• Hypertension: 4.7 % versus 9.8 % for the intravenous formulation versus subcutaneous formulation 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Presented in Table 1 are adverse reactions that have been reported in association with the use of intravenous Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting.

All the terms included are based on the highest percentage seen in pivotal clinical trials. In addition, terms reported in the post marketing setting are included in Table 1.

Table 1: Undesirable effects reported with intravenous Herceptin monotherapy or in combination with chemotherapy in pivotal clinical trials (N = 8386) and in post-marketing

System organ class

Adverse reaction

Frequency

Infections and infestations

Infection

Very common

Nasopharyngitis

Very common

Neutropenic sepsis

Common

Cystitis

Common

Influenza

Common

Sinusitis

Common

Skin infection

Common

Rhinitis

Common

Upper respiratory tract infection

Common

Urinary tract infection

Common

Pharyngitis

Common

Neoplasms benign, malignant and unspecified (incl. Cysts and polyps)

Malignant neoplasm progression

Not known

Neoplasm progression

Not known

Blood and lymphatic system disorders

Febrile neutropenia

Very common

Anaemia

Very common

Neutropenia

Very common

White blood cell count decreased/leukopenia

Very common

Thrombocytopenia

Very common

Hypoprothrombinaemia

Not known

Immune thrombocytopenia

Not known

Immune system disorders

Hypersensitivity

Common

+Anaphylactic reaction

Rare

+Anaphylactic shock

Rare

Metabolism and nutrition disorders

Weight decreased/Weight loss

Very common

Anorexia

Very common

Tumour lysis syndrome

Not known

Hyperkalaemia

Not known

Psychiatric disorders

Insomnia

Very common

Anxiety

Common

Depression

Common

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 common

1 Blood pressure increased

Very common

1 Heart beat irregular

Very common

1Cardiac flutter

Very common

Ejection fraction decreased*

Very common

+Cardiac failure (congestive)

Common

+1Supraventricular tachyarrhythmia

Common

Cardiomyopathy

Common

1Palpitation

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 mediastinal disorders

+Dyspnoea

Very common

Cough

Very common

Epistaxis

Very common

Rhinorrhoea

Very common

+Pneumonia

Common

Asthma

Common

Lung disorder

Common

+Pleural effusion

Common

+1Wheezing

Uncommon

Pneumonitis

Uncommon

+Pulmonary fibrosis

Not known

+Respiratory distress

Not known

+Respiratory failure

Not known

+Lung infiltration

Not known

+Acute pulmonary oedema

Not known

+Acute respiratory distress syndrome

Not known

+Bronchospasm

Not known

+Hypoxia

Not known

+Oxygen saturation decreased

Not known

Laryngeal oedema

Not known

Orthopnoea

Not known

Pulmonary oedema

Not known

Interstitial lung disease

Not known

Gastrointestinal disorders

Diarrhoea

Very common

Vomiting

Very common

Nausea

Very common

1 Lip swelling

Very common

Abdominal pain

Very common

Dyspepsia

Very common

Constipation

Very common

Stomatitis

Very common

Haemorrhoids

Common

Dry mouth

Common

Hepatobiliary disorders

Hepatocellular Injury

Common

Hepatitis

Common

Liver Tenderness

Common

Jaundice

Rare

Skin and subcutaneous tissue disorders

Erythema

Very common

Rash

Very common

1 Swelling face

Very common

Alopecia

Very common

Nail disorder

Very common

Palmar-plantar erythrodysaesthesia syndrome

Very common

Acne

Common

Dry skin

Common

Ecchymosis

Common

Hyperhydrosis

Common

Maculopapular rash

Common

Pruritus

Common

Onychoclasis

Common

Dermatitis

Common

Urticaria

Uncommon

Angioedema

Not known

Musculoskeletal and connective tissue disorders

Arthralgia

Very common

1Muscle tightness

Very common

Myalgia

Very common

Arthritis

Common

Back pain

Common

Bone pain

Common

Muscle spasms

Common

Neck pain

Common

Pain in extremity

Common

Renal and urinary disorders

Renal disorder

Common

Glomerulonephritis membranous

Not known

Glomerulonephropathy

Not known

Renal failure

Not known

Pregnancy, puerperium and perinatal conditions

Oligohydramnios

Not known

Renal hypoplasia

Not known

Pulmonary hypoplasia

Not known

Reproductive system and breast disorders

Breast inflammation/mastitis

Common

General disorders and administration site conditions

Asthenia

Very common

Chest pain

Very common

Chills

Very common

Fatigue

Very common

Influenza-like symptoms

Very common

Infusion related reaction

Very common

Pain

Very common

Pyrexia

Very common

Mucosal inflammation

Very common

Peripheral oedema

Very common

Malaise

Common

Oedema

Common

Injury, poisoning and procedural complications

Contusion

Common

+ Denotes adverse reactions that have been reported in association with a fatal outcome.

1 Denotes adverse reactions that are reported largely in association with administration-related reactions. Specific percentages for these are not available.

* Observed with combination therapy following anthracyclines and combined with taxanes

Description of selected adverse reactions

Cardiac dysfunction

Congestive heart failure (NYHA Class II-IV) is a common adverse reaction to Herceptin. It has been associated 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 with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (specifically symptomatic congestive heart 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 dose anthracycline regimen is limited (see section 4.4).

When Herceptin was administered after completion of adjuvant chemotherapy NYHA Class III-IV heart failure was observed in 0.6 % of patients in the one-year arm after a median follow-up of 12 months. In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA Class III & IV) in the Herceptin 1 year treatment arm was 0.8 %, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6 %.

Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥50 % after the event) was evident for 71.4 % of Herceptin-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5 % of patients. Approximately 17 % of cardiac dysfunction related events occurred after completion of Herceptin.

In the pivotal metastatic trials of intravenous Herceptin, the incidence of cardiac dysfunction varied between 9 % and 12 % when it was combined with paclitaxel compared with 1 % – 4 % for paclitaxel alone. For monotherapy, the rate was 6 % – 9 %. The highest rate of cardiac dysfunction was seen in patients receiving Herceptin concurrently with anthracycline/cyclophosphamide (27 %), and was significantly higher than for anthracycline/cyclophosphamide alone (7 % – 10 %). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2 % in patients receiving Herceptin and docetaxel, compared with 0 % in patients receiving docetaxel alone. Most of the patients (79 %) who developed cardiac dysfunction in these trials experienced an improvement after receiving standard treatment for CHF.

Administration-related reactions/hypersensitivity

Administration-related reactions (ARRs)/hypersensitivity reactions such as chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress, 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 collection methodology, and whether trastuzumab was given concurrently with chemotherapy or as monotherapy.

Anaphylactoid reactions have been observed in isolated cases.

Haematotoxicity

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

Pulmonary events

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

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 formulation and 47.8 % with the Herceptin subcutaneous formulation; severe grade 3 reactions were reported in 2.0 % and 1.7 % of the patients, respectively during the treatment phase; no severe grade 4 or 5 reactions were observed. All of the severe ARRs with the Herceptin subcutaneous formulation occurred during concurrent administration with chemotherapy. The most frequent severe reaction was drug hypersensitivity.

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

Infections

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

The rate of serious infections (most of which were identified because of in-patient hospitalisation or prolongation of existing hospitalisation) was 4.4 % in the Herceptin intravenous formulation arm and 8.1 % in the Herceptin subcutaneous formulation arm. The difference between formulations was mainly observed during the adjuvant treatment phase (monotherapy) and was mainly due to postoperative 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 intravenous treatment 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 grade hypertension with the Herceptin subcutaneous formulation (4.7 % versus 9.8 % in the intravenous and subcutaneous 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. All but one patient who reported severe hypertension had a history of hypertension before they entered the study. Some of the severe events occurred on the day of the injection.

Immunogenicity

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 patients receiving Herceptin subcutaneous vial developed antibodies against trastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in the Herceptin intravenous 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 antibodies had no impact on pharmacokinetics, efficacy (determined by pathological Complete Response [pCR] and event free survival [EFS]) and safety determined by occurrence of administration related reactions (ARRs) of Herceptin intravenous and Herceptin subcutaneous.

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

Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulation and vice versa

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Single doses of up to 960 mg of Herceptin subcutaneous formulation have been administered with no reported untoward effects.