IMPORTANT SAFETY INFORMATION AND INDICATION
IMPORTANT SAFETY INFORMATION AND INDICATIONS
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. Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer). 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. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following surgery and until the wound is fully healed. Discontinue in patients who develop wound healing complications that require medical intervention or 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
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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 0.2% 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 healthcare 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, rectal 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%)
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.
ZIRABEV is a trademark of Pfizer Inc.
Avastin is a registered trademark of Genentech, Inc.
