ZALTRAP

ZALTRAP should be administered under the supervision of a physician experienced in the use ofantineoplastic medicinal products. Posology The recommended dose of ZALTRAP, administered as an intravenous infusion over 1 hour, is 4 mg / kg of body weight, followed by the FOLFIRI regimen.

This is considered as one treatmentcycle. The FOLFIRI regimen to be used is irinotecan 180 mg/m2 intravenous infusion over 90 minutes and folinic acid (dl racemic) 400 mg/m² intravenous infusion over 2 hours at the same time on day 1 using a Y-line, followed by 5-fluorouracil (5-FU) 400 mg / m² intravenous bolus, followed by 5-FU2400 mg / m² continuous intravenous infusion over 46 hours.

The treatment cycle is repeated every 2 weeks. ZALTRAP treatment should be continued until disease progression or unacceptable toxicity occurs. 4). 5 x 109/L or platelet count is 75 x 109 /L. Febrile neutropenia or neutropenic sepsis Irinotecan dose should be reduced by 15-20 % in subsequent cycles.

If recurrence, 5-FU bolus and infusion doses should additionally be reduced by 20 % in subsequent cycles. If recurrence after irinotecan and 5-FU dose reductions, reduction of ZALTRAP dose to 2 mg/kg could be considered. The use of granulocyte colony-stimulating factor (G-CSF) may be considered.

4) The infusion should be temporarily suspended until the reaction resolves. Treatment with corticosteroids and/or antihistamines can be used as clinically indicated. Pre-treatment with corticosteroids and/or antihistamines may be considered in subsequent cycles.

4) ZALTRAP/FOLFIRI should be discontinued and appropriate medical therapy should be administered. 4) ZALTRAP should be temporarily suspended until hypertension is controlled. In case of recurrent medically significant or severe hypertension, despite optimal treatment, ZALTRAP shouldbe suspended until the hypertension is controlled and the dose reduced to 2 mg / kg for subsequent cycles.

4) ZALTRAP should be suspended when proteinuria ≥2 grams per 24 hours and resumed when proteinuria < 2 grams per 24 hours. If recurrence, the treatment should be suspended until <2 grams per 24 hours and then the dose reduces to2 mg/kg.

FOLFIRI Dose modification when used in combination with ZALTRAP Severe stomatitis and Palmar-Plantar Erythrodysaesthesia syndrome 5-FU bolus should be reduced and the infusion dose reduced by 20 %. Severe diarrhoea Irinotecan dose should be reduced by 15-20 %.

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 phaseIII 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 orderof 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 orderof decreasing frequency, were neutropenia, diarrhoea, hypertension, leucopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 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 arelisted 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 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.

8). 2). Monitoring of complete blood count (CBC) with platelets is recommended at baseline, prior to initiation of each cycle of aflibercept, and as clinically necessary. 2). 8). Patients should be monitored for signs and symptoms of GI perforation.

2). 8). 2). 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 recommendedto monitor blood pressure every two weeks, including before each administration or as clinically 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 theaflibercept dose should be reduced to 2 mg/kg for subsequent cycles.

2). Hypertension may exacerbate underlying cardiovascular disease. Caution should be exercised when treating patients with history of clinically significant cardiovascular disease such as coronary artery disease, or congestive heart failure with ZALTRAP.

Patients with NYHA class III or IV congestive heart failure should not be treated with ZALTRAP. Aneurysms and artery dissections The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections.

Before initiating ZALTRAP, this risk should becarefully considered in patients with risk factors such as hypertension or history of aneurysm. Baseline and periodic evaluations of left ventricular function should be considered while the patient isreceiving Zaltrap.

Patients should be monitored for signs and symptoms of cardiac failure and ejectionfraction decreased. Discontinue ZALTRAP in patients who experience cardiac failure and ejection fraction decreased. 8). 2). 8). 2). Patients with Grade 3 DVT should be treated withanticoagulation as clinically indicated, and aflibercept therapy should be continued.

1. 4). For contraindications related to FOLFIRI components (irinotecan, 5-FU, and folinic acid), refer to thecurrent respective summary of product characteristics.