Trazimera · 4.1 Therapeutic indications · 1

HOS-098367 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Amongst the most serious and/or common adverse reactions reported in trastuzumab usage (intravenous and subcutaneous formulations) to date are cardiac dysfunction, infusion-related reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions. 10 Tabulated list of adverse reactions In this section, the following categories of frequency have been used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Presented in Table 1 are adverse reactions that have been reported in association with the use of intravenous trastuzumab alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting. All the terms included are based on the highest percentage seen in pivotal clinical trials. In addition, terms reported in the post-marketing setting are included in Table 1. Table 1 Undesirable effects reported with intravenous trastuzumab monotherapy or in combination with chemotherapy in pivotal clinical trials (N=8386) and in post-marketing System organ class Adverse reaction Frequency Infections and infestations Infection Very common Nasopharyngitis Very common Neutropenic sepsis Common Cystitis Common 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 known malignant and unspecified Neoplasm progression Not known (incl. cysts and polyps)

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HOS-098363 · has-contraindication-information · PDF-Seite 5

• Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients listed in section 6.1 • Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.

HOS-098362 · has-indication-information · PDF-Seite 2

Breast cancer Metastatic breast cancer Trazimera 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. 2 - 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 Trazimera 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 Trazimera therapy, for locally advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 4.4 and 5.1). Trazimera 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). Metastatic gastric cancer Trazimera in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of adult patients with HER2-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anti-cancer treatment for their metastatic disease. Trazimera should only be used in patients with metastatic gastric cancer (MGC) whose tumours have HER2 overexpression

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HOS-098365 · has-interaction-information · PDF-Seite 9

No formal drug interaction studies have been performed. Clinically significant interactions between trastuzumab and the concomitant medicinal products used in clinical trials have not been observed. Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous dose, 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 trastuzumab (4 mg/kg intravenous loading dose and 2 mg/kg intravenous dose weekly) and docetaxel (60 mg/m2 intravenous dose) in Japanese women with HER2-positive MBC, suggested that concomitant administration of trastuzumab had no effect on the single-dose pharmacokinetics of docetaxel. Study JP19959 was a 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 trastuzumab. 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 trastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab. Pharmacokinetic data from study H4613g/GO01305 in patients with metastatic or locally advanced inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin. Effect of antineoplastic agents on trastuzumab pharmacokinetics By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy (4 mg/kg loading/2 mg/kg q1w intravenous) and observed serum concentrations in Japanese women with HER2-positive MBC (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on th

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HOS-098366 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/Contraception Women of childbearing potential should be advised to use effective contraception during treatment with Trazimera and for 7 months after treatment has concluded (see section 5.2). Pregnancy Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg trastuzumab intravenous formulation and have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early (days 20–50 of gestation) and late (days 120–150 of gestation) foetal development period was observed. It is not known whether trastuzumab can affect reproductive capacity. As animal reproduction studies are not always predictive of human response, trastuzumab should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. In the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving trastuzumab. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with trastuzumab, or if a patient becomes pregnant while receiving trastuzumab or within 7 months following the last dose of trastuzumab, close monitoring by a multidisciplinary team is desirable. Breast-feeding A study conducted in Cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg trastuzumab 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 Trazimera therapy and for 7 months after the last dose. Fertility There is no fertility data available.

HOS-098364 · has-warning-information · PDF-Seite 5

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. 5 HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see section 5.1). Currently no data from clinical trials are available on re-treatment of patients with previous exposure to trastuzumab in the adjuvant setting. Cardiac dysfunction General considerations Patients treated with Trazimera are at increased risk for developing CHF (New York Heart Association [NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving trastuzumab therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin) containing chemotherapy. These may be moderate to severe and have been associated with death (see section 4.8). In addition, caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, LVEF of <55%, older age. All candidates for treatment with Trazimera, but especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Trazimera. A careful risk-benefit assessment should be made before deciding to treat with Trazimera. Trastuzumab may persist in the circulation for up to 7 months after stopping treatment based on population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive anthracyclines after stopping trastuzumab may possibly be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. If anthracyclines are used, the patient’s cardiac function should be monitored carefully. Formal cardiological assessment should be considered in patients in whom there are cardiov

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