Avastin

HOS-093952 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The overall safety profile of Avastin is based on data from over 5 700 patients with various malignancies, predominantly treated with Avastin in combination with chemotherapy in clinical trials. The most serious adverse reactions were: • Gastrointestinal perforations (see section 4.4). • Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small cell lung cancer patients (see section 4.4). • Arterial thromboembolism (see section 4.4). The most frequently observed adverse reactions across clinical trials in patients receiving Avastin were hypertension, fatigue or asthenia, diarrhoea and abdominal pain. 10 Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with Avastin therapy are likely to be dose-dependent. Tabulated list of adverse reactions The adverse reactions listed in this section fall into the following frequency categories: 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). Tables 1 and 2 list adverse reactions associated with the use of Avastin in combination with different chemotherapy regimens in multiple indications, by MedDRA system organ class. Table 1 provides all adverse reactions by frequency that were determined to have a causal relationship with Avastin through: • comparative incidences noted between clinical trial treatment arms (with at least a 10% difference compared to the control arm for NCI-CTCAE Grade 1-5 reactions or at least a 2% difference compared to the control arm for NCI-CTCAE Grade 3-5 reactions, • post-authorisation safety studies, • spontaneous reporting, • epidemiological studies\non-interventional or observational studies, • or through an evaluation of individual case reports. Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically significant or severe. Post-marketing adverse reactions are included in both Tables 1 and 2, where applicable. Detailed information about these post-marketing reactions are provided

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HOS-093948 · has-contraindication-information · PDF-Seite 5

● Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. ● Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies. ● Pregnancy (see section 4.6).

HOS-093947 · has-indication-information · PDF-Seite 2

Bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum. Bevacizumab in combination with paclitaxel is indicated for first-line treatment of adult patients with metastatic breast cancer. For further information as to human epidermal growth factor receptor 2 (HER2) status, please refer to section 5.1. Bevacizumab in combination with capecitabine is indicated for first-line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline- containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Avastin in combination with capecitabine. For further information as to HER2 status, please refer to section 5.1. Bevacizumab, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. Bevacizumab, in combination with erlotinib, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations (see section 5.1). Bevacizumab in combination with interferon alfa-2a is indicated for first line treatment of adult patients with advanced and/or metastatic renal cell cancer. 2 Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. (See section 5.1). Bevacizumab, in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel, is indicated for treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. Bevacizumab in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin is indicated for the treatment of adult patients wit

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HOS-093950 · has-interaction-information · PDF-Seite 9

Effect of antineoplastic agents on bevacizumab pharmacokinetics No clinically relevant interaction of co-administered chemotherapy on bevacizumab pharmacokinetics was observed based on the results of population pharmacokinetic analyses. There were neither statistically significant nor clinically relevant differences in bevacizumab clearance in patients receiving Avastin monotherapy compared to patients receiving Avastin in combination with interferon alfa-2a, erlotinib or chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or cisplatin/gemcitabine). Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics of co- administered interferon alfa 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapies irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurement of free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabine pharmacokinetics cannot be drawn. Combination of bevacizumab and sunitinib malate In two clinical trials of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia (MAHA) was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two weeks) and sunitinib malate (50 mg daily) combination. MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, and thrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, and neurological symptoms were observed in some of these patients. All of these findings were reversible upon discontinuation of bevacizumab and sunitinib malate (see Hypertension, Proteinuria, PRES in section 4.4). Combination with platinum- or taxane-based therapies (see sections 4.4 and 4.8) Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed mainly in patients treated with platinum- or taxane-based therapies in the treatment of NSCLC and mBC. Radiotherapy The safety and efficacy of concomitant administration of radiotherapy and Avastin has not been established. EGFR monoclonal antibodies in combination with bevacizumab chemotherapy regimens No interaction studies have been performed. EGFR monoclonal antibodies should not be administered for the treatment of mCRC in combination with bevacizumab-containing chemothe

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HOS-093951 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment. Pregnancy There are no clinical trial data on the use of Avastin in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). IgGs are known to cross the placenta, and Avastin is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to cause serious birth defects when administered during pregnancy. In the post-marketing setting, cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see section 4.8). Avastin is contraindicated in pregnancy (see section 4.3). Breast-feeding It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milk and bevacizumab could harm infant growth and development (see section 5.3), women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of Avastin. Fertility Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility (see section 5.3). In a phase III trial in the adjuvant treatment of patients with colon cancer, a substudy with premenopausal women has shown a higher incidence of new cases of ovarian failure in the bevacizumab group compared to the control group. After discontinuation of bevacizumab treatment, ovarian function recovered in the majority of patients. Long term effects of the treatment with bevacizumab on fertility are unknown.

HOS-093949 · has-warning-information · PDF-Seite 5

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. Gastrointestinal (GI) perforations and Fistulae (see section 4.8) Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation when treated with Avastin. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with Avastin and all patients with GI perforation had a history of prior radiation. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation. 5 GI-vaginal Fistulae in study GOG-0240 Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin are at increased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal fistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and all patients with GI- vaginal fistulae had a history of prior radiation. Recurrence of cancer within the field of prior radiation is an additional important risk factor for the development of GI-vaginal fistulae. Non-GI Fistulae (see section 4.8) Patients may be at increased risk for the development of fistulae when treated with Avastin. Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula [US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3)]. Limited information is available on the continued use of Avastin in patients with other fistulae. In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of Avastin should be considered. Wound healing complications (see section 4.8) Avastin may adversely affect the wound healing process. Serious wound healing complications, including anastomotic complications, with a fatal outcome have been reported. Therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experienced wound healing complications during therapy, treatment should be withheld

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