Zaltrap Drug Information

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

Recommended Dose and Schedule

The recommended dosage of ZALTRAP is 4 mg per kg of actual body weight as an intravenous infusion over 1 hour every two weeks in combination with FOLFIRI until disease progression or unacceptable toxicity. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment. Refer to prescribing information for irinotecan, fluorouracil, and leucovorin for the recommended dosage and dosage modifications for these drugs.

• Dosage Modifications for Adverse Reactions Discontinue ZALTRAP for: Severe hemorrhage Gastrointestinal perforation Impaired wound healing Fistula formation Hypertensive crisis or hypertensive encephalopathy Arterial thromboembolic events (ATE) Nephrotic syndrome or thrombotic microangiopathy (TMA) Reversible posterior leukoencephalopathy syndrome (RPLS) Temporarily suspend ZALTRAP: At least 4 weeks prior to elective surgery. For uncontrolled hypertension until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg. For proteinuria of 2 grams per 24 hours or more. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg.

Preparation and Administration Preparation

Inspect vials visually prior to use. ZALTRAP 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. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags.

Store diluted ZALTRAP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 8 hours. Discard any unused portion left in the infusion bag. Administration Administer the diluted ZALTRAP 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 push or bolus. Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line.

Administer ZALTRAP using an infusion set made of one of the following materials: PVC containing DEHP DEHP free PVC containing trioctyl-trimellitate (TOTM) polypropylene polyethylene lined PVC polyurethane

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ZALTRAP in combination with FOLFIRI was evaluated in VELOUR (EFC102621). Patients received ZALTRAP 4 mg per kg (N=611) or placebo (N=605) intravenously every two weeks (one cycle) in combination with FOLFIRI.

Patients received a median of 9 cycles of ZALTRAP/FOLFIRI. The most common Grade 3–4 adverse reactions (≥5%) in the ZALTRAP/FOLFIRI arm were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia. The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.

The ZALTRAP dose was reduced and/or omitted in 17% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI. The most common adverse reactions (≥20%) in the ZALTRAP/FOLFIRI arm 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.

Adverse reactions and laboratory abnormalities that occurred in ≥5% (all grades) of patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients who received ZALTRAP/FOLFIRI compared to those who received placebo/FOLFIRI in VELOUR are shown in Table 1. VELOUR was not designed to demonstrate a statistically significant difference in adverse reaction rates for ZALTRAP/FOLFIRI as compared to placebo/FOLFIRI for any adverse reactions listed below. In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%).

In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI.

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for antiproduct antibody (APA) at baseline. The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population.

The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ZALTRAP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal and connective tissue disorders: Osteonecrosis of the jaw Cardiac disorders: Cardiac failure, ejection fraction decreased Vascular disorders: Arterial (including aortic) aneurysms, dissections, and rupture

No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic interactions were found between ziv-aflibercept and irinotecan/SN-38 or fluorouracil.

Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women. There is insufficient data in pregnant women exposed to ZALTRAP to assess the risks. Administration of ziv-aflibercept during the period of organogenesis was embryotoxic and teratogenic in rabbits at exposure levels approximately 0.3 times the human exposure at the 4 mg per kg dose (see Data ).

Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal data In pregnant rabbits, administration of ziv-aflibercept during the period of organogenesis resulted in an increase in postimplantation loss and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and anal atresia), visceral (heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs, supernumerary arches and ribs, and incomplete ossification) at doses greater than or equal to 3 mg per kg, administered once every 3 days (approximately 0.3 times the human exposure at the 4 mg per kg dose based on AUC).

Pediatric Use The safety and effectiveness in pediatric patients have not been established. The mean elimination half-life of free ziv-aflibercept determined after the first dose in 8 pediatric patients aged 5 to 17 years was within the range of values previously observed in adults. The maximum tolerated dose based on body weight in these pediatric patients was lower than the dose known to be safe and effective in adults with mCRC.

Juvenile Animal Toxicity Data Weekly/every-two-weeks intravenous administration of ziv-aflibercept at dose of 3 mg per kg (approximately 0.6 times the human exposure at the 4 mg per kg dose based on AUC) to growing young adult (sexually mature) cynomolgus monkeys for up to 6 months resulted in changes in the bone (effects on growth plate and the axial and appendicular skeleton), nasal cavity (atrophy/loss of the septum and/or turbinates), kidney (glomerulopathy with inflammation), ovary (decreased number of maturing follicles, granulosa cells, and/or theca cells), and adrenal gland (decreased vacuolation with inflammation). In another study in sexually immature cynomolgus monkeys (treated intravenously for 3 months), there were similar effects. The skeletal and nasal cavity effects were not reversible after a post-dosing recovery period.