Aflibercept, used in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed after treatment with an oxaliplatin-containing regimen.

Aflibercept is a recombinant fusion protein that functions as a decoy receptor for vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF). By binding to these ligands, it prevents them from attaching to VEGFR-1 and VEGFR-2 receptors on endothelial cells. This action inhibits new blood vessel formation (angiogenesis) and reduces vascular permeability, thereby slowing tumor growth and disease progression.

4 mg/kg as an intravenous infusion over 1 hour every 2 weeks. Do not administer as an intravenous (IV) push or bolus.

Preparation for Administration: Inspect vials visually prior to use. Aflibercept is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles. Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial. Withdraw the prescribed dose of Aflibercept and dilute in 0.9% sodium chloride solution, 5% dextrose solution for injection, to achieve a final concentration of 0.6– 8 mg/mL.

Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags. Store diluted Aflibercept at 2°–8°C for up to 24 hours, or at controlled room temperature 20°–25°C for up to 8 hours. Discard any unused portion left in the infusion bag.

Administration: Administer the diluted Aflibercept solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Do not administer as an intravenous (IV) push or bolus. Do not combine Aflibercept with other drugs in the same infusion bag or intravenous line.

No dedicated drug-drug interaction studies have been conducted with Aflibercept. However, available pharmacokinetic analyses show no clinically significant interactions between ziv-aflibercept and irinotecan, SN-38, or 5-fluorouracil.

Most frequently reported adverse reactions (all grades, ≥20% incidence and at least 2% higher incidence with the Aflibercept/FOLFIRI regimen) included leukopenia, diarrhea, neutropenia, proteinuria, elevated AST, stomatitis, fatigue, thrombocytopenia, increased ALT, hypertension, weight loss, reduced appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache.

Pregnancy Category C, There are no sufficient and well-controlled studies of Aflibercept in pregnant women. In animal studies, Aflibercept demonstrated embryotoxic and teratogenic effects in rabbits at exposure levels lower than those observed in humans at the recommended dose, with increased rates of external, visceral, and skeletal fetal abnormalities. Aflibercept should be used during pregnancy only when the potential benefit outweighs the possible risk to the fetus.

It is unknown whether Aflibercept is excreted in human breast milk. Since many medications are excreted in human milk and due to the risk of serious adverse effects in nursing infants from Aflibercept, a decision should be made either to discontinue breastfeeding or to stop the drug, considering the importance of the treatment for the mother.

During clinical trials, Aflibercept has been associated with several adverse reactions, some of which may be serious, life-threatening, or even fatal. Important precautions include:

• Fistula Formation: If a fistula develops, treatment with Aflibercept should be permanently discontinued.
• Hypertension: Blood pressure should be monitored regularly and managed appropriately. If hypertension cannot be controlled, Aflibercept should be temporarily withheld. Therapy must be discontinued in cases of hypertensive crisis.
• Arterial Thromboembolic Events (ATE): Serious events such as transient ischemic attack, stroke, or angina may occur. Aflibercept should be discontinued if these events develop.
• Proteinuria: Urinary protein levels should be monitored. Treatment should be temporarily suspended if proteinuria reaches ≥2 g in 24 hours. Aflibercept should be discontinued if nephrotic syndrome or thrombotic microangiopathy (TMA) occurs.
• Neutropenia and Related Complications: Administration of Aflibercept with FOLFIRI should be delayed until the neutrophil count is ≥1.5 × 10⁹/L.
• Diarrhea and Dehydration: Severe diarrhea and dehydration may occur more frequently. Elderly patients should be monitored closely.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): If RPLS occurs, treatment with Aflibercept should be discontinued.

Pediatric Use: The safety and effectiveness of Aflibercept in pediatric patients have not been established. In a dose-escalation study evaluating safety and tolerability, 21 patients aged 2 to 21 years (median age 12.9 years) with solid tumors received Aflibercept intravenously every two weeks at doses ranging from 2 to 3 mg/kg. Pharmacokinetic analysis of free ziv-aflibercept was performed in 8 patients aged 5 to 17 years. The maximum tolerated dose identified in this study was 2.5 mg/kg, which is lower than the dose considered safe and effective in adults with metastatic colorectal cancer (mCRC).

Geriatric Use: Among 611 patients with mCRC treated with the Aflibercept/FOLFIRI regimen, 205 patients (34%) were aged 65 years or older and 33 patients (5%) were aged 75 years or older. Compared with younger patients, elderly patients (≥65 years) experienced higher incidences of diarrhea, dizziness, weakness, weight loss, and dehydration. Therefore, elderly patients should be monitored more closely, particularly for diarrhea and dehydration.

However, the overall survival benefit of Aflibercept was similar in patients younger than 65 years and those aged 65 years or older who received Aflibercept/FOLFIRI. No dose adjustment is recommended for patients aged 65 years or above.

Hepatic Impairment: No specific clinical studies have been conducted to assess the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept. Population pharmacokinetic analyses involving data from 1507 patients indicate that drug exposure in patients with mild or moderate hepatic impairment is comparable to those with normal liver function. There are currently no available data for patients with severe hepatic impairment.

Renal Impairment: No dedicated clinical studies have been carried out to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept. Population pharmacokinetic analyses show that patients with mild, moderate, or severe renal impairment have similar drug exposure compared to patients with normal renal function.

Females and Males of Reproductive Potential: Animal studies suggest that treatment with Aflibercept may affect male and female fertility. These effects were reversible within approximately 18 weeks after stopping treatment. Both males and females of reproductive potential should use effective contraception during treatment and for at least 3 months after the final dose.

No cases of overdose with Aflibercept have been reported so far. The safety of doses exceeding 7 mg/kg every two weeks or 9 mg/kg every three weeks has not been established.

Cytotoxic Chemotherapy

Aflibercept vials should be stored in a refrigerator at a temperature between 2°C and 8°C. Keep the vials in their original outer carton to protect them from light.