Zaltrap · 4.8 Undesirable effects · 1

HOS-155541 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1,216 patients previously treated for metastatic colorectal cancer, of which 611 patients were treated with ZALTRAP 4 mg/kg every two weeks (one cycle) and 605 patients were treated with placebo/FOLFIRI in a phase III study. Patients received a median number of 9 cycles of the ZALTRAP/FOLFIRI regimen. The most common adverse reactions (all grades, ≥ 20 % incidence) reported at least 2 % greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency were leucopenia, diarrhoea, neutropenia, proteinuria, increased aspartate aminotransferase (AST), stomatitis, fatigue, thrombocytopenia, increased alanine aminotransferase (ALT), hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache (see Table 1). The most common reported grades 3-4 reactions ( ≥5 % incidence) reported at least 2 % greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency, were neutropenia, diarrhoea, hypertension, leucopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1). The most frequent adverse reactions leading to permanent discontinuation in ≥ 1 % of patients treated with the ZALTRAP/FOLFIRI regimen were vascular disorders (3.8 %) including hypertension (2.3 %), infections (3.4 %), asthenia/fatigue (1.6 %, 2.1 %),diarrhoea (2.3 %), dehydration (1 %), stomatitis (1.1 %), neutropenia (1.1 %), proteinuria (1.5 %), and pulmonary embolism (1.1 %). Tabulated summary of adverse reactions Adverse reactions and laboratory abnormalities reported in patients treated with the ZALTRAP/FOLFIRI regimen compared to patients treated with the placebo/FOLFIRI regimen are listed in Table 1 according to MedDRA system organ class and frequency categories. Adverse reactions in Table 1 are defined as either any adverse clinical reaction or laboratory abnormality 9 having ≥ 2 % greater incidence (all grades) in the aflibercept treatment group in comparison to the placebo treatment group in the MCRC study including those that do not meet this threshold but were consistent with the anti-VEGF class and were seen in any study with aflibercept. Intensity of the adverse reactions is graded according to NCI CTC version 3.0 (grade ≥ 3 = G ≥ 3). Within each f

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HOS-155537 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to aflibercept or to any of the excipients listed in section 6.1. Ophthalmic / intravitreal use due to hyperosmotic properties of ZALTRAP (see section 4.4). For contraindications related to FOLFIRI components (irinotecan, 5-FU, and folinic acid), refer to the current respective summary of product characteristics.

HOS-155536 · has-indication-information · PDF-Seite 2

ZALTRAP in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy is indicated in adults with metastatic colorectal cancer (MCRC) that is resistant to or has progressed after an oxaliplatin-containing regimen.

HOS-155539 · has-interaction-information · PDF-Seite 8

Population pharmacokinetics analysis and inter study comparisons did not reveal any pharmacokinetic drug-drug interaction between aflibercept and the FOLFIRI regimen.

HOS-155540 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential / Contraception in females Women of childbearing potential should be advised to avoid becoming pregnant while on ZALTRAP, and should be informed of the potential hazard to the foetus. Women of childbearing potential treated with ZALTRAP must use effective contraception during treatment and for 3 months after the last dose of treatment. Pregnancy There are no data from the use of aflibercept in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). As angiogenesis is critical to foetal development, the inhibition 8 of angiogenesis following administration of ZALTRAP may result in adverse effects on pregnancy. ZALTRAP should be used only if the potential benefit justifies the potential risk during pregnancy. If the patient becomes pregnant while taking ZALTRAP, she should be informed of the potential hazard to the foetus. Breast-feeding No studies have been conducted to assess the impact of ZALTRAP on milk production, its presence in breast milk or its effects on the breast-fed child. It is unknown whether aflibercept is excreted in human milk. A risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ZALTRAP therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Male and female fertility are likely to be compromised during treatment with aflibercept based on studies in monkeys (see section 5.3).

HOS-155538 · has-warning-information · PDF-Seite 5

Haemorrhage An increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events has been reported in patients treated with aflibercept (see section 4.8). Patients should be monitored for signs and symptoms of GI bleeding and other severe bleeding. Aflibercept should not be administered to patients with severe haemorrhage (see section 4.2). Thrombocytopenia has been reported in patients treated with the ZALTRAP/FOLFIRI regimen. Monitoring of complete blood count (CBC) with platelets is recommended at baseline, prior to initiation of each cycle of aflibercept, and as clinically necessary. Administration of the ZALTRAP/FOLFIRI should be delayed until platelet count is ≥75 x 109 / L (see section 4.2). Gastrointestinal perforation GI perforation including fatal GI perforation has been reported in patients treated with aflibercept (see section 4.8). Patients should be monitored for signs and symptoms of GI perforation. Aflibercept treatment should be discontinued in patients who experience GI perforation (see section 4.2). Fistula formation Fistula formation involving GI and non-GI sites has occurred in patients treated with aflibercept (see section 4.8). Aflibercept treatment should be discontinued in patients who develop fistula (see section 4.2). Hypertension An increased risk of grade 3-4 hypertension (including hypertension and one case of essential hypertension) has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8). Pre-existing hypertension must be adequately controlled before starting aflibercept. If hypertension cannot be adequately controlled, treatment with aflibercept should not be initiated. It is recommended to monitor blood pressure every two weeks, including before each administration or as clinically 5 indicated during treatment with aflibercept. In the event of hypertension on aflibercept treatment, blood pressure should be controlled with appropriate anti-hypertensive therapy and blood pressure should be monitored regularly. In case of recurrent medically significant or severe hypertension, despite optimal treatment, aflibercept should be suspended until the hypertension is controlled and the aflibercept dose should be reduced to 2 mg/kg for subsequent cycles. Aflibercept should be permanently discontinued if hypertension cannot be adequately managed with appropriate anti-hypertensive therapy or aflibercept dose reduction, or

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