ZALTRAP Concentrate for solution for infusion Ref.[7452] Active ingredients: Aflibercept

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
• Cardiac failure and ejection fraction decreased
• 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).

ZALTRAP/FOLFIRI Treatment delay or dose modification:

ZALTRAP Treatment delay and dose modification:

FOLFIRI Dose modification when used in combination with ZALTRAP:

For additional toxicities related to irinotecan, 5-FU, or folinic acid, refer to the current respective summary of product characteristics.

Special populations

Elderly

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 elderly 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.

Precautions to be taken before handling or administering the medicinal product

For instructions on dilution of the medicinal product before administration, and on infusion sets for administration, see section 6.6.

There is no information on the safety of aflibercept given at doses exceeding 7 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. The most commonly observed adverse reactions at these doses were similar to those observed at the therapeutic dose.

There is no specific antidote to ZALTRAP overdose. Cases of overdose should be managed by appropriate supportive measures particularly with regard to monitoring and treatment of hypertension and proteinuria. The patient should remain under close medical supervision to monitor any adverse reactions (see section 4.8).

Shelf life

Unopened vial: 3 years.

After dilution in the infusion bag: Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C and for 8 hours at 25°C.

From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C–8°C).

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

• 4 ml of concentrate in a 5 ml clear borosilicate glass vial (type I) sealed by a flanged stopper with flip-off cap and inserted coated sealing disc. Pack size of 1 vial or 3 vials.
• 8 ml of concentrate in a 10 ml clear borosilicate glass vial (type I) sealed by a flanged stopper with flip-off cap and inserted coated sealing disc. Pack size of 1 vial.

Not all pack sizes may be marketed.

ZALTRAP is a sterile, preservative-free and non-pyrogenic concentrate, therefore the solution for infusion should be prepared by a healthcare professional using safe-handling procedures and aseptic technique.

Caution should be exercised when handling ZALTRAP, taking into account the use of containment devices, personal protective equipment (e.g. gloves), and preparation procedures.

Preparation of the infusion solution

• Inspect the ZALTRAP vial visually prior to use. The concentrate solution must be clear and without particles.
• Based on the required dose for the patient, withdraw the necessary volume of ZALTRAP concentrate from the vial. More than one vial could be needed for the preparation of the infusion solution.
• Dilute it to the required administration volume with sodium chloride 9 mg/ml (0.9%) solution or 5% glucose solution for infusion. The concentration of the final ZALTRAP solution for intravenous infusion should be kept within the range of 0.6 mg/ml to 8 mg/ml of aflibercept.
• PVC containing DEHP infusion bags or polyolefin infusion bags should be used.
• The diluted solution should be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution should be discarded.
• ZALTRAP is a single-use vial. Do not re-enter the vial after the initial puncture. Any unused concentrate should be discarded.

Administration of the infusion solution

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.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.