Phesgo · 4.4 Special warnings and precautions for use · 1

HOS-099601 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The most common adverse drug reactions (ADRs) (≥ 30 %) reported in patients treated with Phesgo or intravenous pertuzumab in combination with trastuzumab and chemotherapy were alopecia, diarrhoea, nausea, anemia, asthenia and arthralgia. The most common serious adverse events (SAE) (≥ 1 %) reported in patients treated with Phesgo or intravenous pertuzumab in combination with trastuzumab were febrile neutropenia, cardiac failure, pyrexia, neutropenia, neutropenic sepsis, neutrophil count decreased and pneumonia. The safety profile of Phesgo was overall consistent to the known safety profile of intravenous pertuzumab in combination with trastuzumab, with an additional ADR of injection site reaction (15.3 % vs. 0.4 %). In the pivotal trial FEDERICA, SAEs were equally distributed between the Phesgo treatment arm and the intravenous pertuzumab in combination with trastuzumab treatment arm. The following adverse drug reactions were reported with a higher frequency (≥ 5 %) with Phesgo compared to intravenous pertuzumab in combination with trastuzumab: alopecia 79 % vs 73 %, myalgia 27 % vs 20.6 %, and dyspnea 12.1 % vs 6 %. Tabulated list of adverse reactions The safety of pertuzumab in combination with trastuzumab has been evaluated in 3 834 patients with HER2-positive breast cancers in the pivotal trials CLEOPATRA, NEOSPHERE, TRYPHAENA APHINITY and FEDERICA. It was generally consistent across studies, although the incidence and most common ADRs varied depending on whether pertuzumab in combination with trastuzumab were administered with or without concomitant anti-neoplastic agent. Table 2 presents, in the first column, ADRs that have been reported in association with the use of pertuzumab in combination with trastuzumab and chemotherapy in the below mentioned pivotal clinical trials (n= 3 834) and in the post-marketing setting. As pertuzumab is used in combination with trastuzumab and chemotherapy, it is difficult to ascertain the causal relationship of an adverse reaction to a particular medicinal product. The last two columns detail ADRs reported in the Phesgo arm of FEDERICA study (n=243) when Phesgo is administered with chemotherapy agent and as monotherapy. • CLEOPATRA, in which pertuzumab was given in combination with trastuzumab and docetaxel to patients with metastatic breast cancer (n= 453) • NEOSPHERE (n= 309) and TRYPHAENA (n= 218), in which neoadjuvant pertuzumab was given in combination wi

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HOS-099597 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

HOS-099596 · has-indication-information · PDF-Seite 2

Early breast cancer (EBC) Phesgo is indicated for use in combination with 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 (MBC) Phesgo is indicated for use in combination with 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. 2

HOS-099599 · has-interaction-information · PDF-Seite 8

No formal drug interaction studies have been performed. Pertuzumab No 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 PK 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 8 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. Trastuzumab 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 PK data from studies BO15935 and M77004 in women with HER2-positive metastatic breast cancer suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxylpaclitaxel, 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, 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 were unclear. Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg intravenous loading dose and 2 mg/kg intravenous weekly) and docetaxel (60 mg/m2 intravenous) in Japanese women with HER2-positive metastatic breast cancer, 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

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HOS-099600 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/contraception Women of childbearing potential should use effective contraception while receiving Phesgo and for 7 months following the last dose. Pregnancy In animal studies pertuzumab has shown reproductive toxicity. There is only a limited amount of data from the use of pertuzumab in pregnant women. From animal studies, it is not known whether trastuzumab can affect reproductive capacity (see section 5.3). However, in the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some of which resulted in fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving trastuzumab. Based on the aforementioned animal studies and post-marketing data, Phesgo should therefore be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Phesgo, or if a patient becomes pregnant while receiving Phesgo or within 7 months following the last dose of Phesgo, close monitoring by a multidisciplinary team is desirable. Breast-feeding As human IgG is secreted into human milk and the potential for absorption and harm to the infant is unknown, women should not breast-feed during Phesgo therapy and for at least 7 months following the last dose. Fertility Pertuzumab No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of pertuzumab for up to six-month duration in cynomolgus monkeys (see section 5.3). Trastuzumab Reproduction studies conducted in cynomolgus monkeys with trastuzumab revealed no evidence of impaired fertility in female cynomolgus monkeys (see section 5.3).

HOS-099598 · 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 and trastuzumab. 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 to trastuzumab and chemotherapy. In the adjuvant setting, the majority of cases of symptomatic heart failure reported were in patients who received anthracycline-based chemotherapy (see section 4.8). Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of LVEF declines based on studies with intravenous pertuzumab in combination with trastuzumab and chemotherapy. Patients with history of serious cardiac illness or medical conditions, history of ventricular dysrhythmias or risk factors for ventricular dysrhythmias were excluded from the (neo-)adjuvant EBC pivotal trial FEDERICA with Phesgo. Phesgo has not been studied in patients with: a pre-treatment LVEF value of < 55 % (EBC) or < 50 % (MBC); a prior history of congestive heart failure (CHF); 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. In addition, pertuzumab in combination with trastuzumab and chemotherapy has not been studied in patients with decreases in LVEF < 50 % during prior trastuzumab adjuvant therapy. LVEF should be assessed prior to initiation of Phesgo and at regular intervals during treatment (e.g. once during neoadjuvant treatment and every 12 weeks in the adjuvant and 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 Phesgo should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. 6 Cardiac risk should be carefully considered and balanced against the medical need of the individual patient before

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