Poherdy · 4.6 Fertility, pregnancy and lactation · 1

HOS-101033 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile 8 The safety of pertuzumab has been evaluated in more than 6,000 patients in Phase I, II, and III trials in patients with various malignancies and predominantly treated with pertuzumab in combination with other antineoplastic agents. Those studies included the pivotal trials CLEOPATRA (n=808), NEOSPHERE (n=417), TRYPHAENA (n=225), and APHINITY (n=4804) [pooled in Table 2]. The safety of pertuzumab was generally consistent across studies, although the incidence and most common adverse drug reactions (ADRs) varied depending on whether pertuzumab was administered as monotherapy or with concomitant anti-neoplastic agents. Tabulated list of adverse reactions Table 2 summarizes the ADRs from the pertuzumab-treated groups of the following pivotal clinical trials: • CLEOPATRA, in which pertuzumab was given in combination with docetaxel and trastuzumab to patients with metastatic breast cancer (n=453) • NEOSPHERE (n=309) and TRYPHAENA (n=218), in which neoadjuvant pertuzumab was given in combination with trastuzumab and chemotherapy to patients with locally advanced, inflammatory, or early breast cancer • APHINITY, in which adjuvant pertuzumab was given in combination with trastuzumab and anthracycline-based or non-anthracycline-based, taxane-containing chemotherapy to patients with early breast cancer (n=2364) In addition, ADRs reported in the post-marketing setting are included in Table 2. As pertuzumab was used with trastuzumab and chemotherapy in these trials, it is difficult to ascertain the causal relationship of an adverse event to a particular medicinal product. The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency: 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 and SOC, ADRs are presented in the order of decreasing seriousness. The most common ADRs (≥30%) from this pooled data were diarrhoea, alopecia, nausea, fatigue, neutropenia, and vomiting. The most common NCI-CTCAE Grade 3-4 ADRs (≥10%) were neutropenia and febrile neutropenia. Table 2 Summary of ADRs in patients treated with Pertuzumab in clinical trials^, and in the Post-marketing setting† System organ

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HOS-101029 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Poherdy is contraindicated in subjects with hereditary fructose intolerance (HFI). Prior to initiating treatment HFI should be excluded via medical history or on clinical grounds (see section 4.4). 5

HOS-101028 · has-indication-information · PDF-Seite 2

Early breast cancer Poherdy is indicated for use in combination with trastuzumab and chemotherapy in: • the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence (see section 5.1) • the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of recurrence (see section 5.1) Metastatic breast cancer Poherdy is indicated for use in combination with trastuzumab and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.

HOS-101031 · has-interaction-information · PDF-Seite 8

No pharmacokinetic (PK) interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel in a sub-study of 37 patients in the randomised, pivotal trial CLEOPATRA in metastatic breast cancer. In addition, in the population PK analysis, no evidence of a drug-drug interaction has been shown between pertuzumab and trastuzumab or between pertuzumab and docetaxel. This absence of drug-drug interaction was confirmed by pharmacokinetic data from the NEOSPHERE and APHINITY studies. Five studies evaluated the effects of pertuzumab on the PK of co-administered cytotoxic agents, docetaxel, paclitaxel, gemcitabine, capecitabine, carboplatin and erlotinib. There was no evidence of any PK interaction between pertuzumab and any of these agents. The PK of pertuzumab in these studies was comparable to those observed in single-agent studies.

HOS-101032 · has-pregnancy-information · PDF-Seite 8

Contraception Women of childbearing potential should use effective contraception while receiving Poherdy and for 6 months following the last dose of Poherdy. Pregnancy There is limited amount of data from the use of pertuzumab in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Poherdy is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding Because human IgG is secreted in human milk and the potential for absorption and harm to the infant is unknown, a decision should be made to discontinue breast-feeding or to discontinue treatment, taking into account the benefit of breast-feeding for the child and the benefit of Poherdy therapy for the woman (see section 5.2). Fertility No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. In repeated dose toxicity studies in cynomolgus monkeys, no definitive conclusions could be drawn on the adverse effect on male reproductive organs. No adverse reactions were observed in sexually mature female cynomolgus monkeys exposed to pertuzumab (see section 5.3).

HOS-101030 · has-warning-information · PDF-Seite 6

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Left ventricular dysfunction (including congestive heart failure) Decreases in LVEF have been reported with medicinal products that block HER2 activity, including pertuzumab. The incidence of symptomatic left ventricular systolic dysfunction (LVD) [congestive heart failure] was higher in patients treated with pertuzumab in combination with trastuzumab and chemotherapy compared with trastuzumab and chemotherapy. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of LVEF declines. The majority of cases of symptomatic heart failure reported in the adjuvant setting were in patients who received anthracycline-based chemotherapy (see section 4.8). Pertuzumab has not been studied in patients with: a pre-treatment LVEF value of < 50%; a prior history of congestive heart failure (CHF); LVEF declines to < 50% during prior trastuzumab adjuvant therapy; or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of pertuzumab and at regular intervals during treatment with pertuzumab (e.g. once during neoadjuvant treatment and every 12 weeks in the adjuvant or metastatic setting) to ensure that LVEF is within normal limits. If the LVEF has declined as indicated in section 4.2 and has not improved, or has declined further at the subsequent assessment, discontinuation of pertuzumab and trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. Cardiac risk should be carefully considered and balanced against the medical need of the individual patient before use of pertuzumab with an anthracycline. Based on the pharmacological actions of HER2-targeted agents and anthracyclines, the risk of cardiac toxicity might be expected to be higher with concomitant use of pertuzumab and anthracyclines than with sequential use. Sequential use of pertuzumab (in combination with trastuzumab and a taxane) has been evaluated following the epirubicin or doxorubicin component of many anthracycline-based regimens in the APHINITY and BERENICE studies. However, only l

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