Warnings and Precautions

• Gastrointestinal Perforations and Fistulae. Serious and sometimes fatal gastrointestinal perforation occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. The incidence ranged from 0.3% to 3% across clinical studies. Non-GI fistulae incidence ranged from <1% to 1.8%, and was highest in patients with cervical cancer. Avoid ZIRABEV in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Discontinue for gastrointestinal perforations, tracheoesophageal fistula, grade 4 fistula, or fistula formation involving any internal organ
• Surgery and Wound Healing Complications. The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab-treated patients. In patients who experience wound healing complications during ZIRABEV treatment, withhold ZIRABEV until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following major surgery and until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complications has not been established. Discontinue for wound healing complications of necrotizing fasciitis
• Hemorrhage. Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding occurred up to 5-fold more frequently in patients receiving bevacizumab. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 7%. Do not administer ZIRABEV to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood). Discontinue ZIRABEV in patients who develop grade 3-4 hemorrhage
• Additional serious and sometimes fatal adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:
  • Arterial thromboembolic events (ATE) (grade ≥3, 5%, highest in patients with GBM). Discontinue in patients who develop a severe ATE
  • Renal injury and proteinuria. Monitor proteinuria during ZIRABEV therapy. Patients with a 2+ or greater urine dipstick reading should undergo
    24-hour urine collection. Withhold for
    proteinuria ≥2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome
  • Grade 3-4 proteinuria ranged from 0.7% to 7% in clinical studies
  • Nephrotic syndrome (<1%)
• Additional serious adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:
  • Venous thromboembolism events (VTE) (grade ≥3, 11% seen in Study GOG-0240). Discontinue ZIRABEV in patients with a grade 4 VTE, including pulmonary embolism
  • Hypertension (grade 3-4, 5%-18%). Monitor blood pressure during treatment and, for
    ZIRABEV-associated hypertension, continue monitoring after discontinuation. Withhold for severe hypertension. Discontinue for hypertensive crisis or hypertensive encephalopathy
  • Posterior reversible encephalopathy syndrome (PRES) (<0.5%). Discontinue ZIRABEV in patients who develop PRES. Symptoms usually resolve or improve within days after discontinuing bevacizumab products, although some patients have experienced ongoing neurologic sequelae
  • Congestive heart failure (CHF) (grade ≥3 left ventricular dysfunction, 1%). Discontinue ZIRABEV in patients who develop CHF
• Infusion-related reactions. Infusion-related reactions with the first dose of bevacizumab occurred in <3% of patients, and severe reactions occurred in 0.4% of patients. Decrease the rate of infusion for mild infusion-related reactions. Interrupt the infusion in patients with clinically significant infusion-related reactions and consider resuming at a slower rate following resolution. Discontinue in patients who develop a severe infusion-related reaction and administer appropriate medical therapy
• Ovarian failure. Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with ZIRABEV

Pregnancy Warning

• Based on the mechanism of action and animal studies, bevacizumab products may cause fetal harm
• Advise female patients that bevacizumab products may cause fetal harm and to inform their health care provider of a known or suspected pregnancy
• Advise females of reproductive potential to use effective contraception during treatment with ZIRABEV and for 6 months after the last dose of ZIRABEV
• Advise nursing women that breastfeeding is not recommended during treatment with ZIRABEV and for 6 months following their last dose of treatment
• Bevacizumab products may impair fertility

Most Common Adverse Events

• Across studies, the most common adverse reactions observed in bevacizumab patients at a rate >10% were:
  • Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
• Across all studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions

Indication-Specific Adverse Events

• In first-line metastatic colorectal cancer (mCRC), the most common grade 3-4 events in Study 2107, which occurred at a (≥2%) higher incidence in the bevacizumab plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
• In second-line mCRC, the most common grade 3-5 (nonhematologic) and 4-5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the bevacizumab plus FOLFOX4 vs FOLFOX4 groups, were fatigue (19% vs 13%), diarrhea (18% vs 13%), sensory neuropathy (17% vs 9%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), hypertension (9% vs 2%), abdominal pain (8% vs 5%), hemorrhage (5% vs 1%), other neurological (5% vs 3%), ileus (4% vs 1%), and headache (3% vs 0%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
• In non-small cell lung cancer (NSCLC), grade 3-5 (nonhematologic) and grade 4-5 (hematologic) adverse events in Study E4599 occurring at a (≥2%) higher incidence in bevacizumab-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thromboembolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
• In recurrent glioblastoma (rGBM) Study EORTC 26101, 22% of patients discontinued treatment in the bevacizumab with lomustine arm due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adverse reaction profile was similar to that observed in other approved indications
• In metastatic renal cell carcinoma (mRCC), the most common grade 3-5 adverse events in Study BO17705, occurring at a (≥2%) higher incidence in bevacizumab-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%, including hypertension and hypertensive crisis), and hemorrhage (3% vs 0.3%, including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)
• In persistent, recurrent, or metastatic cervical cancer, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (≥2%) in 218 patients receiving bevacizumab plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), diarrhea (6% vs 3%), anal fistula (4% vs 0%), proctalgia (3% vs 0%), urinary tract infection (8% vs 6%), cellulitis (3% vs 0.5%), fatigue (14% vs 10%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), hypokalemia (7% vs 4%), hyponatremia (4% vs 1%), dehydration (4% vs 0.5%), neutropenia (8% vs 4%), lymphopenia (6% vs 3%), back pain (6% vs 3%), and pelvic pain (6% vs 1%)
• In stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer after primary surgery:
  • 608 patients received carboplatin and paclitaxel plus bevacizumab followed by bevacizumab (CPB15+), 607 patients received carboplatin and paclitaxel plus bevacizumab followed by placebo (CPB15), and 602 patients received carboplatin and paclitaxel plus placebo followed by placebo (CPP)
  • Grade 3-4 adverse reactions occurring at a higher incidence (≥2%) in either of the bevacizumab arms vs the chemotherapy-only arm were fatigue (CPB15+, 9%; CPB15, 6%; CPP, 6%), hypertension (CPB15+, 10%; CPB15, 6%; CPP, 2%), thrombocytopenia (CPB15+, 21%; CPB15, 20%; CPP, 15%), and leukopenia (CPB15+, 51%; CPB15, 53%; CPP, 50%)
• In platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psOC), grade 3-4 adverse reactions in Study AVF4095g, occurring at a higher incidence (≥2%) in 247 patients receiving bevacizumab plus carboplatin and gemcitabine (chemotherapy) compared to 233 patients receiving placebo plus chemotherapy, were thrombocytopenia (40% vs 34%), nausea (4% vs 1.3%), fatigue (6% vs 4%), headache (4% vs 0.9%), proteinuria (10% vs 0.4%), dyspnea (4% vs 1.7%), epistaxis (5% vs 0.4%), and hypertension (17% vs 0.9%)
• In platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, grade 3-4 adverse reactions in Study GOG-0213, occurring at a higher incidence (≥2%) in 325 patients receiving bevacizumab plus carboplatin and paclitaxel (chemotherapy) compared to 332 patients receiving chemotherapy alone, were hypertension (11% vs 0.6%), fatigue (8% vs 3%), febrile neutropenia (6% vs 3%), proteinuria (8% vs 0%), abdominal pain (6% vs 0.9%), hyponatremia (4% vs 0.9%), headache (3% vs 0.9%), and pain in extremity (3.0% vs 0%)
• In platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (prOC), grade 3-4 adverse reactions in Study MO22224, occurring at a higher incidence (≥2%) in 179 patients receiving bevacizumab plus chemotherapy compared to 181 patients receiving chemotherapy alone, were hypertension (6.7% vs 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs 1.7%)

INDICATIONS

Metastatic Colorectal Cancer

ZIRABEV, in combination with intravenous
fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer (mCRC).

ZIRABEV, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen.

Limitation of Use: ZIRABEV is not indicated for adjuvant treatment of colon cancer.

First-Line Non-Squamous Non-Small Cell Lung Cancer

ZIRABEV, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC).

Recurrent Glioblastoma

ZIRABEV is indicated for the treatment of recurrent glioblastoma (GBM) in adults.

Metastatic Renal Cell Carcinoma

ZIRABEV, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC).

Persistent, Recurrent, or Metastatic Cervical Cancer

ZIRABEV, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

ZIRABEV, in combination with carboplatin and paclitaxel, followed by ZIRABEV as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.

ZIRABEV, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan, is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.

ZIRABEV, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by ZIRABEV as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Please see full Prescribing Information for additional Important Safety Information.

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/MedWatch.