Zaltrap

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.

• 4 mg per kg as an intravenous infusion over 1 hour every 2 weeks. (
  2.1 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.
  ,
  2.3 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.

  Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to achieve a final concentration of 0.6 mg/mL to 8 mg/mL.

  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
  )
• Do not administer as an intravenous push or bolus. (
  2.3 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.

  Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to achieve a final concentration of 0.6 mg/mL to 8 mg/mL.

  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
  )

ZALTRAP is a clear, colorless to pale-yellow solution available as:

• Injection: 100 mg/4 mL (25 mg/mL) solution in a single-dose vial
• Injection: 200 mg/8 mL (25 mg/mL) solution in a single-dose vial

• Lactation: Advise not to breastfeed. (
  8.2 Lactation

  Risk Summary

  There are no data on the presence of ziv-aflibercept in human milk, or the effects of ziv-aflibercept on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with ZALTRAP and for 1 month following the last dose.
  )

• Hemorrhage
  : Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in patients who have received ZALTRAP. Do not administer ZALTRAP to patients with severe hemorrhage. (
  5.1 Hemorrhage

  Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) was reported in 38% of patients treated with ZALTRAP/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 ZALTRAP/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 ZALTRAP.

  Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage

  [see Dosage and Administration (2.2)]

  .
  )
• Gastrointestinal Perforation
  : Discontinue ZALTRAP therapy in patients who experience GI perforation. (
  5.2 Gastrointestinal Perforation

  Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo.

  Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation

  [see Dosage and Administration (2.2)]

  .
  )
• Impaired Wound Healing
  : Withhold ZALTRAP for at least 4 weeks prior to elective surgery. Do not administer for at least 4 weeks following major surgery and until wounds have adequately healed. Discontinue ZALTRAP in patients with impaired wound healing. The safety of resumption of ZALTRAP after resolution of wound healing complications has not been established. (
  5.3 Impaired Wound Healing

  Grade 3 impaired wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI regimen.

  Withhold ZALTRAP for at least 4 weeks prior to elective surgery. Do not administer ZALTRAP for at least 4 weeks after major surgery and until wounds have adequately healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with impaired wound healing. The safety of resumption of ZALTRAP after resolution of wound healing complications has not been established

  [see Dosage and Administration (2.2)]

  .
  )
• Fistula Formation
  : Discontinue ZALTRAP if fistula occurs. (
  2.2 Dosage Modifications for Adverse Reactions

  Discontinue ZALTRAP for:

  • Severe hemorrhage
    [see Warnings and Precautions (5.1)]
  • Gastrointestinal perforation
    [see Warnings and Precautions (5.2)]
  • Impaired wound healing
    [see Warnings and Precautions (5.3)]
  • Fistula formation
    [see Warnings and Precautions (5.4)]
  • Hypertensive crisis or hypertensive encephalopathy
    [see Warnings and Precautions (5.5)]
  • Arterial thromboembolic events (ATE)
    [see Warnings and Precautions (5.6)]
  • Nephrotic syndrome or thrombotic microangiopathy (TMA)
    [see Warnings and Precautions (5.7)]
  • Reversible posterior leukoencephalopathy syndrome (RPLS)
    [see Warnings and Precautions (5.10)]

  Temporarily suspend ZALTRAP:

  • At least 4 weeks prior to elective surgery
    [see Warnings and Precautions (5.3)].
  • For uncontrolled hypertension until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg
    [see Warnings and Precautions (5.5)]
    .
  • 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
    [see Warnings and Precautions (5.7)]
    .
  ,
  5.4 Fistula Formation

  Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/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 ZALTRAP (0.3%) and in 1 patient treated with placebo (0.2%).

  Discontinue ZALTRAP therapy in patients who develop fistula

  [see Dosage and Administration (2.2)]

  .
  )
• Hypertension
  : Monitor blood pressure and treat hypertension. Temporarily suspend ZALTRAP if hypertension is not controlled. Discontinue ZALTRAP if hypertensive crisis develops. (
  2.2 Dosage Modifications for Adverse Reactions

  Discontinue ZALTRAP for:

  • Severe hemorrhage
    [see Warnings and Precautions (5.1)]
  • Gastrointestinal perforation
    [see Warnings and Precautions (5.2)]
  • Impaired wound healing
    [see Warnings and Precautions (5.3)]
  • Fistula formation
    [see Warnings and Precautions (5.4)]
  • Hypertensive crisis or hypertensive encephalopathy
    [see Warnings and Precautions (5.5)]
  • Arterial thromboembolic events (ATE)
    [see Warnings and Precautions (5.6)]
  • Nephrotic syndrome or thrombotic microangiopathy (TMA)
    [see Warnings and Precautions (5.7)]
  • Reversible posterior leukoencephalopathy syndrome (RPLS)
    [see Warnings and Precautions (5.10)]

  Temporarily suspend ZALTRAP:

  • At least 4 weeks prior to elective surgery
    [see Warnings and Precautions (5.3)].
  • For uncontrolled hypertension until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg
    [see Warnings and Precautions (5.5)]
    .
  • 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
    [see Warnings and Precautions (5.7)]
    .
  ,
  5.5 Hypertension

  ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing antihypertensive 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 ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/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 ZALTRAP. Treat with appropriate antihypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled and permanently reduce the ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy

  [see Dosage and Administration (2.2)]

  .
  )
• Arterial Thromboembolic Events (ATE)
  : Discontinue ZALTRAP if ATE develops. (
  5.6 Arterial Thromboembolic Events

  ATE, including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI.

  Discontinue ZALTRAP in patients who experience an ATE

  [see Dosage and Administration (2.2)]

  .
  )
• Proteinuria
  : Monitor urine protein. Suspend ZALTRAP for proteinuria of 2 grams per 24 hours or more. Discontinue ZALTRAP if nephrotic syndrome or thrombotic microangiopathy (TMA) develops. (
  2.2 Dosage Modifications for Adverse Reactions

  Discontinue ZALTRAP for:

  • Severe hemorrhage
    [see Warnings and Precautions (5.1)]
  • Gastrointestinal perforation
    [see Warnings and Precautions (5.2)]
  • Impaired wound healing
    [see Warnings and Precautions (5.3)]
  • Fistula formation
    [see Warnings and Precautions (5.4)]
  • Hypertensive crisis or hypertensive encephalopathy
    [see Warnings and Precautions (5.5)]
  • Arterial thromboembolic events (ATE)
    [see Warnings and Precautions (5.6)]
  • Nephrotic syndrome or thrombotic microangiopathy (TMA)
    [see Warnings and Precautions (5.7)]
  • Reversible posterior leukoencephalopathy syndrome (RPLS)
    [see Warnings and Precautions (5.10)]

  Temporarily suspend ZALTRAP:

  • At least 4 weeks prior to elective surgery
    [see Warnings and Precautions (5.3)].
  • For uncontrolled hypertension until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg
    [see Warnings and Precautions (5.5)]
    .
  • 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
    [see Warnings and Precautions (5.7)]
    .
  ,
  5.7 Proteinuria

  Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC, proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI

  [see Adverse Reactions (6.1)]

  . Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/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 ZALTRAP therapy. Patients with a dipstick of ≥2+ for protein or a UPCR greater than 1 should undergo a 24-hour urine collection.

  Suspend ZALTRAP 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 ZALTRAP dose to 2 mg per kg. Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA

  [see Dosage and Administration (2.2)]

  .
  )
• Neutropenia and Neutropenic Complications
  : Delay administration of ZALTRAP/FOLFIRI until neutrophil count is 1.5 × 10⁹/L or higher. (
  5.8 Neutropenia and Neutropenic Complications

  A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI

  [see Adverse Reactions (6.1)]

  . Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/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 ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 10⁹/L.
  )
• Diarrhea and Dehydration
  : Incidence of severe diarrhea and dehydration is increased. Monitor elderly patients more closely. (
  5.9 Diarrhea and Dehydration

  The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI

  [see Adverse Reactions (6.1)]

  . 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

  [see Use in Specific Populations (8.5)]

  . Monitor elderly patients closely for diarrhea.
  ,
  8.5 Geriatric Use

  Of the 611 patients with mCRC, patients treated with ZALTRAP/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

  [see Warnings and Precautions (5.9)].

  The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI.
  )
• Reversible Posterior Leukoencephalopathy Syndrome
  : Discontinue ZALTRAP. (
  5.10 Reversible Posterior Leukoencephalopathy Syndrome

  RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy.

  Confirm the diagnosis of RPLS with magnetic resonance imaging (MRI) and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death

  [see Dosage and Administration (2.2)]

  .
  )
• Embryo-Fetal Toxicity
  : Can cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. (
  5.11 Embryo-Fetal Toxicity

  Based on findings from animal studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women. 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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZALTRAP and for 3 months following the last dose

  [see Use in Specific Populations (8.1, 8.3)]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal reproduction studies and its mechanism of action

  [see Clinical Pharmacology (12.1)]

  , 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 2% to 4% and 15% to 20%, 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).
  ,
  8.3 Females and Males of Reproductive Potential

  ZALTRAP can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)].

  Pregnancy Testing

  Verify the pregnancy status in females of reproductive potential prior to initiating ZALTRAP

  [see Use in Specific Populations (8.1)]

  .

  Contraception

  Females

  Based on data from animal studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women

  [see Use in Specific Populations (8.1)]

  .

  Advise female patients of reproductive potential to use effective contraception during treatment with ZALTRAP and for 3 months following the last dose.

  Infertility

  Advise female and male patients of reproductive potential that ZALTRAP may impair reproductive function and fertility

  [see Nonclinical Toxicology (13.1)]

  .
  )