There have been no cases of overdose reported with Залтрап. There is no information on the safety of Залтрап given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks.
None
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The safety of Залтрап in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with Залтрап 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of Залтрап/FOLFIRI or 8 cycles of placebo/FOLFIRI.
The most common adverse reactions (all grades, ≥ 20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the Залтрап/FOLFIRI arm , in order of decreasing frequency, 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 (see Table 1).
The most common Grade 3-4 adverse reactions ( ≥ 5%) reported at a higher incidence (2% or greater between-arm difference) in the Залтрап/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1).
The most frequent adverse reactions leading to permanent discontinuation in ≥ 1% of patients treated with Залтрап/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.
The Залтрап dose was reduced and/or omitted in 17% of patients compared to placebo-dose modification in 5% of patients. Cycle delays > 7 days occurred in 60% of patients treated with Залтрап/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI.
The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥ 5% (all grades) in patients receiving Залтрап in combination with FOLFIRI and which occurred at ≥ 2% higher frequency in patients treated with Залтрап/FOLFIRI compared to placebo/FOLFIRI are shown in Table 1.
Table 1: Selected Adverse Reactions and Laboratory Findings in Study 1:
| Primary System Organ Class Preferred Term (%) | Placebo/ FOLFIRI (N=605) | Залтрап/ FOLFIRI (N=611) | ||
| All grades | Grades 3-4 | All grades | Grades 3-4 | |
| Infections and infestations | ||||
| Urinary Tract Infection | 6% | 0.8% | 9% | 0.8% |
| Blood and lymphatic system disorders | ||||
| Leukopenia | 72% | 12% | 78% | 16% |
| Neutropenia | 57% | 30% | 67% | 37% |
| Thrombocytopenia | 35% | 2% | 48% | 3% |
| Metabolism and nutrition disorders | ||||
| Decreased Appetite | 24% | 2% | 32% | 3% |
| Dehydration | 3% | 1% | 9% | 4% |
| Nervous system disorders | ||||
| Headache | 9% | 0.3% | 22% | 2% |
| Vascular disorders | ||||
| Hypertension | 11% | 1.5% | 41% | 19% |
| Respiratory, thoracic and mediastinal disorders | ||||
| Epistaxis | 7% | 0 | 28% | 0.2% |
| Dysphonia | 3% | 0 | 25% | 0.5% |
| Dyspnea | 9% | 0.8% | 12% | 0.8% |
| Oropharyngeal Pain | 3% | 0 | 8% | 0.2% |
| Rhinorrhea | 2% | 0 | 6% | 0 |
| Gastrointestinal disorders | ||||
| Diarrhea | 57% | 8% | 69% | 19% |
| Stomatitis | 33% | 5% | 50% | 13% |
| Abdominal Pain | 24% | 2% | 27% | 4% |
| Abdominal Pain Upper | 8% | 1% | 11% | 1% |
| Hemorrhoids | 2% | 0 | 6% | 0 |
| Rectal Hemorrhage | 2% | 0.5% | 5% | 0.7% |
| Proctalgia | 2% | 0.3% | 5% | 0.3% |
| Skin and subcutaneous tissue disorders | ||||
| Palmar-Plantar Erythrodysesthesia Syndrome | 4% | 0.5% | 11% | 3% |
| Skin Hyperpigmentation | 3% | 0 | 8% | 0 |
| Renal and urinary disorders | ||||
| Proteinuria* | 41% | 1% | 62% | 8% |
| Serum creatinine increased | 19% | 0.5% | 23% | 0 |
| General disorders and administration site conditions | ||||
| Fatigue | 39% | 8% | 48% | 13% |
| Asthenia | 13% | 3% | 18% | 5% |
| Investigations | ||||
| AST increased | 54% | 2% | 62% | 3% |
| ALT increased | 39% | 2% | 50% | 3% |
| Weight decreased | 14% | 0.8% | 32% | 3% |
| Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 * Compilation of clinical and laboratory data | ||||
Infections occurred at a higher frequency in patients receiving Залтрап/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.
In patients with mCRC, severe hypersensitivity reactions have been reported with Залтрап/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 Залтрап/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3-4 VTE occurred in 8% of patients treated with Залтрап/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with Залтрап/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI.
ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo.
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.
Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Залтрап with the incidence of antibodies to other products may be misleading.
Post Marketing ExperienceThe following adverse reactions have been identified during post-approval use of Залтрап. 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
Залтрап, 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.
Plasma concentrations of free and VEGF-bound ziv-aflibercept were measured using specific enzyme-linked immunosorbent assays (ELISAs). Free ziv-aflibercept concentrations appear to exhibit linear pharmacokinetics in the dose range of 2-9 mg/kg. Following 4 mg/kg every two weeks intravenous administration of Залтрап, the elimination half-life of free ziv-aflibercept was approximately 6 days (range 4-7 days). Steady state concentrations of free ziv-aflibercept were reached by the second dose. The accumulation ratio for free ziv-aflibercept was approximately 1.2 after administration of 4 mg/kg every two weeks.
Included as part of the PRECAUTIONS section.
PRECAUTIONS HemorrhagePatients treated with Залтрап have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) were reported in 38% of patients treated with Залтрап/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3-4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving Залтрап/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving Залтрап.
Monitor patients for signs and symptoms of bleeding. Do not initiate Залтрап in patients with severe hemorrhage. Discontinue Залтрап in patients who develop severe hemorrhage.
Gastrointestinal PerforationGastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving Залтрап. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with Залтрап and 0.3% for patients treated with placebo. Grade 3-4 GI perforation events occurred in 0.8% of patients treated with Залтрап and 0.2% of patients treated with placebo.
Monitor patients for signs and symptoms of GI perforation. Discontinue Залтрап therapy in patients who experience GI perforation.
Compromised Wound HealingЗалтрап impairs wound healing in animal models. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with Залтрап/FOLFIRI regimen and in none of the patients treated with placebo/FOLFIRI regimen.
Suspend Залтрап for at least 4 weeks prior to elective surgery. Do not resume Залтрап for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, Залтрап may be initiated/resumed once the surgical wound is fully healed. Discontinue Залтрап in patients with compromised wound healing.
Fistula FormationFistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with Залтрап. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with Залтрап/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with Залтрап (0.3%) and in 1 placebo-treated patient (0.2%).
Discontinue Залтрап therapy in patients who develop fistula.
HypertensionЗалтрап increases the risk of Grade 3-4 hypertension. There is no clinical trial experience administering Залтрап to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% of patients treated with Залтрап/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with Залтрап/FOLFIRI. Among those patients treated with Залтрап/FOLFIRI developing Grade 3-4 hypertension, 54% had onset during the first two cycles of treatment.
Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with Залтрап. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend Залтрап in patients with uncontrolled hypertension until controlled, and permanently reduce Залтрап dose to 2 mg per kg for subsequent cycles. Discontinue Залтрап in patients with hypertensive crisis or hypertensive encephalopathy.
Arterial Thromboembolic EventsArterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received Залтрап. In patients with mCRC, ATE was reported in 2.6% of patients treated with Залтрап/FOLFIRI and 1.7% of patients treated with placebo/FOLFIRI. Grade 3-4 events occurred in 11 patients (1.8%) treated with Залтрап/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI.
Discontinue Залтрап in patients who experience an ATE.
ProteinuriaSevere proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with Залтрап. In patients with mCRC, proteinuria was reported in 62% patients treated with Залтрап/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3-4 proteinuria occurred in 8% of patients treated with Залтрап/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI. Nephrotic syndrome occurred in 2 patients (0.5%) treated with Залтрап/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies.
Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during Залтрап therapy. Patients with a dipstick of ≥ 2+ for protein or a UPCR greater than 1 should undergo a 24-hour urine collection.
Suspend Залтрап administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the Залтрап dose to 2 mg per kg. Discontinue Залтрап in patients who develop nephrotic syndrome or TMA.
Neutropenia And Neutropenic ComplicationsA higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving Залтрап. In patients with mCRC, Grade 3-4 neutropenia occurred in 37% of patients treated with Залтрап/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI. Grade 3-4 febrile neutropenia occurred in 4% of patients treated with Залтрап/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3-4 neutropenic infection/sepsis occurred in 1.5% of patients treated with Залтрап/FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI.
Monitor CBC with differential count at baseline and prior to initiation of each cycle of Залтрап. Delay Залтрап/FOLFIRI until neutrophil count is at or above 1.5 x 109/L.
Diarrhea And DehydrationThe incidence of severe diarrhea is increased in patients treated with Залтрап/FOLFIRI. In patients with mCRC, Grade 3-4 diarrhea was reported in 19% of patients treated with Залтрап/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3-4 dehydration was reported in 4% of patients treated with Залтрап/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age. Monitor elderly patients closely for diarrhea.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with Залтрап monotherapy or in combination with chemotherapy.
Confirm the diagnosis of RPLS with MRI and discontinue Залтрап in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityNo studies have been conducted to evaluate carcinogenicity or mutagenicity of ziv-aflibercept.
Ziv-aflibercept impaired reproductive function and fertility in monkeys. In a 6-month repeat-dose toxicology study in sexually mature monkeys, ziv-aflibercept inhibited ovarian function and follicular development, as evidenced by: decreased ovary weight, decreased amount of luteal tissue, decreased number of maturing follicles, atrophy of uterine endometrium and myometrium, vaginal atrophy, abrogation of progesterone peaks and menstrual bleeding. Alterations in sperm morphology and decreased sperm motility were noted in male monkeys. These effects were observed at all doses tested including the lowest dose tested, 3 mg per kg. Reversibility was observed within 18 weeks after cessation of treatment. Systemic exposure (AUC) with a 3 mg per kg per dose in monkeys was approximately 60% of the AUC in patients at the recommended dose.
Use In Specific Populations PregnancyPregnancy Category C
Risk SummaryThere are no adequate and well-controlled studies with Залтрап in pregnant women. Залтрап 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. Залтрап should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal DataZiv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose.
Nursing MothersIt is not known whether Залтрап 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 Залтрап, 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 UseThe 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 Залтрап at doses ranging from 2 to 3 mg/kg, IV, every two weeks. The pharmacokinetics of free ziv-aflibercept 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 UseOf the 611 patients with mCRC, patients treated with Залтрап/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 dehydration.
The effect of Залтрап on overall survival was similar in patients < 65 years old and ≥ 65 years old who received Залтрап/FOLFIRI.
No dose adjustment of Залтрап is recommended for patients greater than or equal to 65 years of age.
Hepatic ImpairmentNo dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept.
Based on a population PK analysis with data from 1507 patients, ziv-aflibercept 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 ImpairmentNo dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept.
Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function.
Females And Males Of Reproductive PotentialMale and female reproductive function and fertility may be compromised during treatment with Залтрап, as suggested by findings in monkeys. 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.
Administer Залтрап 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer Залтрап prior to any component of the FOLFIRI regimen on the day of treatment.
Continue Залтрап until disease progression or unacceptable toxicity.
Dose Modification/Treatment Delay Recommendations Discontinue Залтрап forFor toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information.
Preparation For AdministrationInspect vials visually prior to use. Залтрап 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 Залтрап and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP 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 Залтрап at 2°-8°C (36°-46°F) for up to 24 hours, or at controlled room temperature 20°-25°C (68°-77°F) for up to 8 hours. Discard any unused portion left in the infusion bag.
AdministrationAdminister the diluted Залтрап 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 Залтрап with other drugs in the same infusion bag or intravenous line.
Administer Залтрап using an infusion set made of one of the following materials:
