ZALTRAP should be administered under the supervision of a physician experienced in the use of antineoplastic 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 treatment cycle.
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-FU 2400 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.
Dose modification
ZALTRAP should be discontinued for (see section 4.4):
• Severe haemorrhage
• Gastrointestinal (GI) perforation
• Fistula formation
• Hypertension that is not adequately controlled with anti-hypertensive therapy or occurrence of hypertensive crisis or hypertensive encephalopathy
• Arterial thromboembolic events (ATE)
• Grade 4 venous thromboembolic events (including pulmonary embolism)
• Nephrotic syndrome or thrombotic microangiopathy (TMA)
• Severe hypersensitivity reactions (including bronchospasm, dyspnoea, angioedema, and anaphylaxis) (see sections 4.3 and 4.4)
• Compromised wound healing requiring medical intervention
• Posterior reversible encephalopathy syndrome (PRES) (also known as reversible posterior leukoencephalopathy syndrome (RPLS))
ZALTRAP should be temporarily suspended for at least 4 weeks prior to elective surgery (see section 4.4).
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ZALTRAP/FOLFIRI Treatment delay or dose modification
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Neutropenia or thrombocytopenia
(see sections 4.4 and 4.8)
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Administration of ZALTRAP/FOLFIRI should be delayed until neutrophil count is ≥1.5 x 109/L or platelet count is ≥75 x 109/L.
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Febrile neutropenia or neutropenic sepsis
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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.
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Mild to moderate hypersensitivity reactions to ZALTRAP (including flushing, rash, urticaria, and pruritus)
(see section 4.4)
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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.
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Severe hypersensitivity reactions (including bronchospasm, dyspnoea, angioedema, and anaphylaxis)
(see sections 4.3 and 4.4)
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ZALTRAP/FOLFIRI should be discontinued and appropriate medical therapy should be administered.
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ZALTRAP Treatment delay and dose modification
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Hypertension
(see section 4.4)
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ZALTRAP should be temporarily suspended until hypertension is controlled.
In case of recurrent medically significant or severe hypertension, despite optimal treatment, ZALTRAP should be suspended until the hypertension is controlled and the dose reduced to 2 mg/kg for subsequent cycles.
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Proteinuria
(see section 4.4)
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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 to 2 mg/kg.
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FOLFIRI Dose modification when used in combination with ZALTRAP
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Severe stomatitis and Palmar-Plantar Erythrodysaesthesia syndrome
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5-FU bolus should be reduced and the infusion dose reduced by 20%.
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Severe diarrhoea
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Irinotecan dose should be reduced by 15-20%.
If severe diarrhoea recurs on a subsequent cycle, the 5-FU bolus and infusion dose should also be reduced by 20%.
If severe diarrhoea persists with both dose reductions, FOLFIRI should be discontinued.
Treatment with anti-diarrhoeal medicinal products and rehydration can be used as needed.
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For additional toxicities related to irinotecan, 5-FU, or folinic acid, refer to the current respective summary of product characteristics.
Special populations
Older people
In the pivotal MCRC study, 28.2% of patients were aged ≥65 and <75 and 5.4% of patients were aged ≥75. No dose adjustments of ZALTRAP is required in the older people.
Hepatic impairment
There have been no formal studies with ZALTRAP in patients with hepatic impairment (see section 5.2). Clinical data suggest that no change in aflibercept dose is required in patients with mild to moderate hepatic impairment. There are no data regarding the administration of aflibercept in patients with severe hepatic impairment.
Renal impairment
There have been no formal studies with ZALTRAP in patients with renal impairment (see section 5.2). Clinical data suggest that no change in starting dose is required in patients with mild to moderate renal impairment. There are very limited data in patients with severe renal impairment; therefore, these patients should be treated with caution.
Paediatric population
There is no relevant use of ZALTRAP in the paediatric population for the indication of metastatic colorectal cancer.
Method of administration
ZALTRAP is to be administered only as an intravenous infusion over 1 hour. Due to hyperosmolality (1000 mOsmol/kg) of the ZALTRAP concentrate, undiluted ZALTRAP concentrate must not be administered as an intravenous push or bolus. ZALTRAP must not be administered as an intravitreal injection (see sections 4.3 and 4.4).
Each vial of concentrate for solution for infusion is for single use (single-dose) only.
Diluted solutions of ZALTRAP should be administered using infusion sets containing a 0.2 micron polyethersulfone filter.
The infusion sets should be made of one of the following materials:
• polyvinyl chloride (PVC) containing bis(2-ethylhexyl) phthalate (DEHP)
• DEHP free PVC containing trioctyl-trimellitate (TOTM)
• polypropylene
• polyethylene lined PVC
• polyurethane
Filters made of polyvinylidene fluoride (PVDF) or nylon must not be used.
Precautions to be taken before handling or administering the medicinal product
For instructions on dilution of the medicinal product before administration, see section 6.6.
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 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 if hypertensive crisis or hypertensive encephalopathy occurs (see section 4.2).
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.
Thrombotic and embolic events
Arterial thromboembolic events (ATE)
ATE (including transient ischaemic attack, cerebrovascular accident, angina pectoris, intracardiac thrombus, myocardial infarction, arterial embolism, and ischaemic colitis) have been observed in patients treated with aflibercept (see section 4.8).
Aflibercept treatment should be discontinued in patients who experience an ATE (see section 4.2).
Venous thromboembolic events (VTE)
VTE including deep vein thrombosis (DVT) and pulmonary embolism (infrequently fatal) have been reported in patients treated with aflibercept (see section 4.8).
ZALTRAP should be discontinued in patients with life-threatening (Grade 4) thromboembolic events (including pulmonary embolism) (see section 4.2). Patients with Grade 3 DVT should be treated with anticoagulation as clinically indicated, and aflibercept therapy should be continued. In the event of recurrence, despite appropriate anticoagulation, aflibercept treatment should be discontinued. Patients with thromboembolic events of Grade 3 or lower need to be closely monitored.
Proteinuria
Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) have been observed in patients treated with aflibercept (see section 4.8).
Proteinuria should be monitored by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria before each aflibercept administration. Patients with a dipstick of ≥2+ for protein or a UPCR >1 should undergo a 24-hour urine collection.
Aflibercept administration should be suspended for ≥2 grams of proteinuria/24 hours and restarted when proteinuria is <2 grams/24 hours. If there is recurrence, the administration should be suspended until <2 grams/24 hours and then the dose reduced to 2 mg/kg. Aflibercept treatment should be discontinued in patients who develop nephrotic syndrome or TMA (see section 4.2).
Neutropenia and neutropenic complications
A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).
Monitoring of complete blood count (CBC) with differential count is recommended at baseline and prior to initiation of each cycle of aflibercept. Administration of ZALTRAP/FOLFIRI should be delayed until neutrophil count is ≥1.5 x 109/L (see section 4.2). Therapeutic use of G-CSF at first occurrence of grade ≥3 neutropenia and secondary prophylaxis may be considered in patients who may be at increased risk for neutropenia complications.
Diarrhoea and dehydration
A higher incidence of severe diarrhoea has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).
Dose modification of FOLFIRI regimen (see section 4.2), anti-diarrhoeal medicinal products, and rehydration as needed should be instituted.
Hypersensitivity reactions
In the pivotal study of MCRC patients, severe hypersensitivity reactions have been reported in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).
In the event of a severe hypersensitivity reaction (including bronchospasm, dyspnoea, angioedema, and anaphylaxis), aflibercept should be discontinued and appropriate medical measures should be administered (see section 4.2).
In the event of a mild to moderate hypersensitivity reaction to ZALTRAP (including flushing, rash, urticaria, and pruritus), aflibercept should be temporarily suspended until the reaction is resolved. Treatment with corticosteroids and/or antihistamines can be initiated as clinically indicated. Pre-treatment with corticosteroids and/or antihistamines may be considered in subsequent cycles (see section 4.2). Caution should be used when retreating patients with prior hypersensitivity reactions as recurrent hypersensitivity reactions have been observed in some patients despite prophylaxis, including corticosteroids.
Compromised wound healing
Aflibercept impaired wound healing in animal models (see section 5.3).
Potential for compromised wound healing (wound dehiscence, anastomotic leakage) has been reported with aflibercept (see section 4.8).
Aflibercept should be suspended for at least 4 weeks prior to elective surgery.
It is recommended that aflibercept not be initiated for at least 4 weeks following major surgery and not until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, aflibercept may be initiated/restarted once the surgical wound is fully healed. Aflibercept should be discontinued in patients with compromised wound healing requiring medical intervention (see section 4.2).
Posterior reversible encephalopathy syndrome (PRES)
PRES was not reported in the pivotal phase III study of MCRC patients. In other studies, PRES was reported in patients treated with aflibercept as monotherapy and in combination with other chemotherapies (see section 4.8).
PRES may present with altered mental status, seizure, nausea, vomiting, headache, or visual disturbances. The diagnosis of PRES is confirmed by brain Magnetic Resonance Imaging (MRI).
Aflibercept should be discontinued in patients that develop PRES (see section 4.2).
Older people
Older people patients ≥65 years had an increased risk of diarrhoea, dizziness, asthenia, weight loss and dehydration. Careful monitoring is recommended in order to rapidly detect and treat signs and symptoms of diarrhoea and dehydration and to minimize potential risk (see section 4.8).
Renal impairment
There are very limited data available for patients with severe renal impairment treated with aflibercept. No dose adjustment is required for aflibercept (see sections 4.2, 4.8 and 5.2).
Performance status and co-morbidities
Patients with ECOG performance status ≥2 or having s
