Zaltrap100 mg/4 ml

Zaltrap 100 mg/4 ml, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Cytotoxic Chemotherapy

Ablibercept is a recombinant fusion protein that acts as a decoy receptor for the ligands, vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF). It prevents these ligands to binding to endothelial receptors, VEGFR-1 and VEGFR-2, to suppress neovascularization and decrease vascular permeability. This ultimately will slow vision loss or the progression of metastatic colorectal cancer.

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. Zaltrap 100 mg/4 ml 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 Zaltrap 100 mg/4 ml 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 Zaltrap 100 mg/4 ml 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 Zaltrap 100 mg/4 ml 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 Zaltrap 100 mg/4 ml with other drugs in the same infusion bag or intravenous line.

No dedicated drug-drug interaction studies have been conducted for Zaltrap 100 mg/4 ml. No clinically important pharmacokinetic drug-drug interactions were found between ziv-Zaltrap 100 mg/4 ml and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses.

Most common adverse reactions (all grades, ≥20% incidence and at least 2% greater incidence for the Zaltrap 100 mg/4 ml/FOLFIRI regimen) were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache

Pregnancy category C. There are no adequate and well-controlled studies with Zaltrap 100 mg/4 ml in pregnant women. Zaltrap 100 mg/4 ml was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. Zaltrap 100 mg/4 ml should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.It is not known whether Zaltrap 100 mg/4 ml is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Zaltrap 100 mg/4 ml, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Adverse reactions, sometimes severe and life-threatening or fatal, have been seen in clinical trials with Zaltrap 100 mg/4 ml, including: Fistula Formation: Discontinue Zaltrap 100 mg/4 ml if fistula occurs. Hypertension: Monitor blood pressure and treat hypertension. Temporarily suspend Zaltrap 100 mg/4 ml if hypertension is not controlled. Discontinue Zaltrap 100 mg/4 ml if hypertensive crisis develops. Arterial Thromboembolic Events (ATE) (e.g., transient ischemic attacks, cerebrovascular accident, angina pectoris): Discontinue Zaltrap 100 mg/4 ml if ATE develops. Proteinuria: Monitor urine protein. Suspend Zaltrap 100 mg/4 ml when proteinuria ≥ 2 grams per 24 hours. Discontinue Zaltrap 100 mg/4 ml if nephrotic syndrome or thrombotic microangiopathy (TMA) develops. Neutropenia and Neutropenic Complications: Delay administration of Zaltrap 100 mg/4 ml/FOLFIRI until neutrophil count is ≥ 1.5 × 109/L. Diarrhea and Dehydration: Incidence of severe diarrhea and dehydration is increased. Monitor elderly patients more closely. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue Zaltrap 100 mg/4 ml.

There have been no cases of overdose reported with Zaltrap 100 mg/4 ml. There is no information on the safety of Zaltrap 100 mg/4 ml given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks.

Store Zaltrap 100 mg/4 ml vials in a refrigerator at 2 to 8° C . Keep the vials in the original outer carton to protect from light.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established. In a dose-escalation, safety, and tolerability study, 21 patients ages 2 to 21 years (median age 12.9) with solid tumors received Zaltrap 100 mg/4 ml at doses ranging from 2 to 3 mg/kg, IV, every two weeks. The pharmacokinetics of free ziv-Zaltrap 100 mg/4 ml were evaluated in 8 of these patients (ages 5 to 17 years). The maximum tolerated dose in the study was 2.5 mg/kg, below the dose known to be safe and effective in adults with mCRC.Geriatric Use: Of the 611 patients with mCRC, patients treated with Zaltrap 100 mg/4 ml/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydrationThe effect of Zaltrap 100 mg/4 ml on overall survival was similar in patients <65 years old and ≥65 years old who received Zaltrap 100 mg/4 ml/FOLFIRI. No dose adjustment of Zaltrap 100 mg/4 ml is recommended for patients greater than or equal to 65 years of age.Hepatic Impairment: No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-Zaltrap 100 mg/4 ml. Based on a population PK analysis with data from 1507 patients, ziv-Zaltrap 100 mg/4 ml exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function. There are no data available for patients with severe hepatic impairment.Renal Impairment: No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-Zaltrap 100 mg/4 ml. Based on a population PK analysis with data from 1507 patients, ziv-Zaltrap 100 mg/4 ml exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology.Females and Males of Reproductive Potential: Male and female reproductive function and fertility may be compromised during treatment with Zaltrap 100 mg/4 ml, as suggested by findings in monkeys [see Nonclinical Toxicology. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment.

Cytotoxic Chemotherapy

Ablibercept is a recombinant fusion protein that acts as a decoy receptor for the ligands, vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF). It prevents these ligands to binding to endothelial receptors, VEGFR-1 and VEGFR-2, to suppress neovascularization and decrease vascular permeability. This ultimately will slow vision loss or the progression of metastatic colorectal cancer.

Pregnancy category C. There are no adequate and well-controlled studies with Zaltrap 100 mg/4 ml in pregnant women. Zaltrap 100 mg/4 ml was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. Zaltrap 100 mg/4 ml should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.It is not known whether Zaltrap 100 mg/4 ml is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Zaltrap 100 mg/4 ml, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established. In a dose-escalation, safety, and tolerability study, 21 patients ages 2 to 21 years (median age 12.9) with solid tumors received Zaltrap 100 mg/4 ml at doses ranging from 2 to 3 mg/kg, IV, every two weeks. The pharmacokinetics of free ziv-Zaltrap 100 mg/4 ml were evaluated in 8 of these patients (ages 5 to 17 years). The maximum tolerated dose in the study was 2.5 mg/kg, below the dose known to be safe and effective in adults with mCRC.Geriatric Use: Of the 611 patients with mCRC, patients treated with Zaltrap 100 mg/4 ml/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydrationThe effect of Zaltrap 100 mg/4 ml on overall survival was similar in patients <65 years old and ≥65 years old who received Zaltrap 100 mg/4 ml/FOLFIRI. No dose adjustment of Zaltrap 100 mg/4 ml is recommended for patients greater than or equal to 65 years of age.Hepatic Impairment: No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-Zaltrap 100 mg/4 ml. Based on a population PK analysis with data from 1507 patients, ziv-Zaltrap 100 mg/4 ml exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function. There are no data available for patients with severe hepatic impairment.Renal Impairment: No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-Zaltrap 100 mg/4 ml. Based on a population PK analysis with data from 1507 patients, ziv-Zaltrap 100 mg/4 ml exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology.Females and Males of Reproductive Potential: Male and female reproductive function and fertility may be compromised during treatment with Zaltrap 100 mg/4 ml, as suggested by findings in monkeys [see Nonclinical Toxicology. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment.