These Highlights Do Not Include All The Information Needed To Use Zirabev Safely And Effectively. See Full Prescribing Information For Zirabev.

Limitations of Use: ZIRABEV is not indicated for adjuvant treatment of colon cancer [see Clinical Studies (14.2)].

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light. Do not freeze or shake the vial or carton.

Bevacizumab-bvzr is a vascular endothelial growth factor inhibitor. Bevacizumab-bvzr is a recombinant humanized monoclonal IgG1 antibody that contains human framework regions and murine complementarity-determining regions. Bevacizumab-bvzr has an approximate molecular weight of 149 kDa. Bevacizumab-bvzr is produced in a mammalian cell (Chinese Hamster Ovary) expression system.

ZIRABEV (bevacizumab-bvzr) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brown solution in a single-dose vial for intravenous use. ZIRABEV contains bevacizumab-bvzr at a concentration of 25 mg/mL in either 100 mg/4 mL or 400 mg/16 mL single-dose vials.

Each mL of solution contains 25 mg bevacizumab-bvzr, edetate disodium dihydrate (0.05 mg), polysorbate 80 (0.2 mg), succinic acid (2.36 mg), sucrose (85 mg), and Water for Injection, USP. Sodium hydroxide is added to adjust the pH. The pH is 5.5.

Bevacizumab products can result in two distinct patterns of bleeding: minor hemorrhage, which is most commonly Grade 1 epistaxis, and serious hemorrhage, which in some cases has been fatal. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to 5-fold more frequently in patients receiving bevacizumab compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3–5 hemorrhagic events ranged from 0.4% to 7% in patients receiving bevacizumab [see Adverse Reactions (6.1)].

Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous NSCLC and 4% of patients with non-squamous NSCLC receiving bevacizumab with chemotherapy compared to none of the patients receiving chemotherapy alone.

Do not administer ZIRABEV to patients with recent history of hemoptysis of 1/2 teaspoon or more of red blood. Discontinue in patients who develop a Grades 3–4 hemorrhage.

Severe hypertension occurred at a higher incidence in patients receiving bevacizumab products as compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3–4 hypertension ranged from 5% to 18%.

Monitor blood pressure every two to three weeks during treatment with ZIRABEV. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with ZIRABEV-induced or -exacerbated hypertension after discontinuing ZIRABEV. Withhold ZIRABEV in patients with severe hypertension that is not controlled with medical management; resume once controlled with medical management. Discontinue in patients who develop hypertensive crisis or hypertensive encephalopathy.

The safety and effectiveness of bevacizumab products in pediatric patients have not been established. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years who received bevacizumab. Bevacizumab products are not approved for use in patients under the age of 18 years.

Antitumor activity was not observed among eight pediatric patients with relapsed GBM who received bevacizumab and irinotecan. Addition of bevacizumab to standard of care did not result in improved event-free survival in pediatric patients enrolled in two randomized clinical studies, one in high grade glioma (n=121) and one in metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma (n=154).

Based on the population pharmacokinetics analysis of data from 152 pediatric and young adult patients with cancer (7 months to 21 years of age), bevacizumab clearance normalized by body weight in pediatrics was comparable to that in adults.

In an exploratory, pooled analysis of 1745 patients from five randomized, controlled studies, 35% of patients were ≥65 years old. The overall incidence of ATE was increased in all patients receiving bevacizumab with chemotherapy as compared to those receiving chemotherapy alone, regardless of age; however, the increase in the incidence of ATE was greater in patients ≥65 years (8% vs. 3%) as compared to patients <65 years (2% vs. 1%) [see Warnings and Precautions (5.4)].

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and the 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 bevacizumab products may be misleading.

In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies as detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-bevacizumab antibodies is not known.

None.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• •
  Gastrointestinal Perforations and Fistulae [see Warnings and Precautions (5.1)].
• •
  Surgery and Wound Healing Complications [see Warnings and Precautions (5.2)].
• •
  Hemorrhage [see Warnings and Precautions (5.3)].
• •
  Arterial Thromboembolic Events [see Warnings and Precautions (5.4)].
• •
  Venous Thromboembolic Events [see Warnings and Precautions (5.5)].
• •
  Hypertension [see Warnings and Precautions (5.6)].
• •
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.7)].
• •
  Renal Injury and Proteinuria [see Warnings and Precautions (5.8)].
• •
  Infusion-Related Reactions [see Warnings and Precautions (5.9)].
• •
  Ovarian Failure [see Warnings and Precautions (5.11)].
• •
  Congestive Heart Failure [see Warnings and Precautions (5.12)].

The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving bevacizumab with chemotherapy as compared to those receiving chemotherapy alone for adjuvant treatment of a solid tumor. After discontinuing bevacizumab, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% of women receiving bevacizumab. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or an FSH level <30 mIU/mL during the post-treatment period. Long-term effects of bevacizumab products on fertility are unknown. Inform females of reproductive potential of the risk of ovarian failure prior to initiating ZIRABEV [see Adverse Reactions (6.1), Use in Specific Populations (8.3)].

The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of bevacizumab every week, every 2 weeks, or every 3 weeks, bevacizumab pharmacokinetics are linear and the predicted time to reach more than 90% of steady state concentration is 84 days. The accumulation ratio following a dose of 10 mg/kg of bevacizumab once every 2 weeks is 2.8.

Population simulations of bevacizumab exposures provide a median trough concentration of 80.3 mcg/mL on Day 84 (10^th, 90^th percentile: 45, 128) following a dose of 5 mg/kg once every two weeks.

ZIRABEV is a vascular endothelial growth factor inhibitor indicated for the treatment of:

• •
  Metastatic colorectal cancer, in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment. (1.1)
• •
  Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab product-containing regimen. (1.1)

Limitations of Use: ZIRABEV is not indicated for adjuvant treatment of colon cancer. (1.1)

• •
  Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment. (1.2)
• •
  Recurrent glioblastoma in adults. (1.3)
• •
  Metastatic renal cell carcinoma in combination with interferon alfa. (1.4)
• •
  Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan. (1.5)
• •
  Epithelial ovarian, fallopian tube, or primary peritoneal cancer:
  • o
    in combination with carboplatin and paclitaxel, followed by ZIRABEV as a single agent, for stage III or IV disease following initial surgical resection. (1.6)
  • o
    in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens. (1.6)
  • o
    in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by ZIRABEV as a single agent, for platinum-sensitive recurrent disease. (1.6)

Bevacizumab products bind VEGF and prevent the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

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

The recommended dosage is 10 mg/kg intravenously every 2 weeks.

• •
  Gastrointestinal Perforations and Fistula: Discontinue for gastrointestinal perforations, tracheoesophageal fistula, grade 4 fistula, or fistula formation involving any organ. (5.1)
• •
  Surgery and Wound Healing Complications: 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 ZIRABEV for at least 28 days following a major surgery, and until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complication has not been established. Discontinue for wound healing complications of necrotizing fasciitis. (5.2)
• •
  Hemorrhage: Severe or fatal hemorrhages have occurred. Do not administer for recent hemoptysis. Discontinue for Grade 3–4 hemorrhage. (5.3)
• •
  Arterial Thromboembolic Events (ATE): Discontinue for severe ATE. (5.4)
• •
  Venous Thromboembolic Events (VTE): Discontinue for Grade 4 VTE. (5.5)
• •
  Hypertension: Monitor blood pressure and treat hypertension. Withhold if not medically controlled; resume once controlled. Discontinue for hypertensive crisis or hypertensive encephalopathy. (5.6)
• •
  Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue. (5.7)
• •
  Renal Injury and Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome. Withhold until less than 2 grams of protein in urine. (5.8)
• •
  Infusion–Related Reactions: Decrease rate for infusion-related reactions. Discontinue for severe infusion-related reactions and administer medical therapy. (5.9)
• •
  Embryo-Fetal Toxicity: May cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. (5.10, 8.1, 8.3)
• •
  Ovarian Failure: Advise females of the potential risk. (5.11, 8.3)
• •
  Congestive Heart Failure (CHF): Discontinue ZIRABEV in patients who develop CHF. (5.12)

Based on its mechanism of action and findings from animal studies, bevacizumab products may cause fetal harm when administered to pregnant women. Congenital malformations were observed with the administration of bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10 mg/kg.

Furthermore, animal models link angiogenesis and VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZIRABEV and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

Withhold for at least 28 days prior to elective surgery. Do not administer ZIRABEV for 28 days following major surgery and until adequate wound healing. (2.1)

Metastatic colorectal cancer. (2.2)

• •
  5 mg/kg every 2 weeks with bolus-IFL.
• •
  10 mg/kg every 2 weeks with FOLFOX4.
• •
  5 mg/ kg every 2 weeks or 7.5 mg/kg every 3 weeks with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin based chemotherapy after progression on a first-line bevacizumab product containing regimen.

First-line non−squamous non−small cell lung cancer. (2.3)

• •
  15 mg/kg every 3 weeks with carboplatin and paclitaxel.

Recurrent glioblastoma. (2.4)

• •
  10 mg/kg every 2 weeks.

Metastatic renal cell carcinoma. ( 2.5)

• •
  10 mg/kg every 2 weeks with interferon alfa.

Persistent, recurrent, or metastatic cervical cancer. (2.6)

• •
  15 mg/kg every 3 weeks with paclitaxel and cisplatin or paclitaxel and topotecan.

Stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection. (2.7)

• •
  15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles.

Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. (2.7)

• •
  10 mg/kg every 2 weeks with paclitaxel, pegylated liposomal doxorubicin, or topotecan given every week.
• •
  15 mg/kg every 3 weeks with topotecan given every 3 weeks

Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. (2.7)

• •
  15 mg/kg every 3 weeks with carboplatin and paclitaxel for 6–8 cycles, followed by 15 mg/kg every 3 weeks as a single agent.
• •
  15 mg/kg every 3 weeks with carboplatin and gemcitabine for 6–10 cycles, followed by 15 mg/kg every 3 weeks as a single agent.

Administer as an intravenous infusion after dilution. See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. (2.8, 2.9)

Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) clear to slightly opalescent, colorless to pale brown solution in a single-dose vial

The following adverse reactions have been identified during postapproval use of bevacizumab products. 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.

General: Polyserositis

Cardiovascular: Pulmonary hypertension, Mesenteric venous occlusion

Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Hepatobiliary disorders: Gallbladder perforation

Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw

Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)

Respiratory: Nasal septum perforation

Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

Lactation: Advise not to breastfeed. (8.2)

Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion-related reactions with the first dose occurred in <3% of patients and severe reactions occurred in 0.4% of patients.

Decrease the rate of infusion for mild, clinically insignificant 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 (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen).

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety data in Warnings and Precautions and described below reflect exposure to bevacizumab in 4463 patients including those with mCRC (AVF2107g, E3200), non-squamous NSCLC (E4599), GBM (EORTC 26101), mRCC (BO17705), cervical cancer (GOG-0240), epithelial ovarian, fallopian tube, or primary peritoneal cancer (MO22224, AVF4095, GOG-0213, and GOG-0218) or another cancer at the recommended dose and schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving bevacizumab as a single agent or in combination with other anti-cancer therapies at a rate >10% were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Across clinical studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies (14)].

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.

The recommended dosage when ZIRABEV is administered in combination with intravenous fluorouracil-based chemotherapy is:

• •
  5 mg/kg intravenously every 2 weeks in combination with bolus-IFL.
• •
  10 mg/kg intravenously every 2 weeks in combination with FOLFOX4.
• •
  5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy in patients who have progressed on a first-line bevacizumab product-containing regimen.

An increased risk of venous thromboembolic events (VTE) was observed across clinical studies [see Adverse Reactions (6.1)]. In Study GOG-0240, Grades 3–4 VTE occurred in 11% of patients receiving bevacizumab with chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the incidence of Grades 3–4 VTE was 5% in patients receiving bevacizumab with chemotherapy compared to 2% in patients receiving chemotherapy alone.

Discontinue ZIRABEV in patients with a Grade 4 VTE, including pulmonary embolism.

The incidence and severity of proteinuria was higher in patients receiving bevacizumab as compared to patients receiving chemotherapy. Grade 3 (defined as urine dipstick 4+ or >3.5 grams of protein per 24 hours) to Grade 4 (defined as nephrotic syndrome) ranged from 0.7% to 7% in clinical studies.

The overall incidence of proteinuria (all grades) was only adequately assessed in Study BO17705, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (15 days to 37 months) after initiating bevacizumab. Median time to resolution was 6.1 months (95% CI: 2.8, 11.3). Proteinuria did not resolve in 40% of patients after median follow-up of 11.2 months and required discontinuation of bevacizumab in 30% of the patients who developed proteinuria [see Adverse Reactions (6.1)].

In an exploratory, pooled analysis of patients from seven randomized clinical studies, 5% of patients receiving bevacizumab with chemotherapy experienced Grades 2–4 (defined as urine dipstick 2+ or greater or >1 gram of protein per 24 hours or nephrotic syndrome) proteinuria. Grades 2–4 proteinuria resolved in 74% of patients.

Bevacizumab was reinitiated in 42% of patients. Of the 113 patients who reinitiated bevacizumab, 48% experienced a second episode of Grades 2–4 proteinuria.

Nephrotic syndrome occurred in <1% of patients receiving bevacizumab across clinical studies, in some instances with fatal outcome. In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy. Results of a retrospective analysis of 5805 patients who received bevacizumab with chemotherapy and 3713 patients who received chemotherapy alone, showed higher rates of elevated serum creatinine levels (between 1.5 to 1.9 times baseline levels) in patients who received bevacizumab. Serum creatinine levels did not return to baseline in approximately one-third of patients who received bevacizumab.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during ZIRABEV therapy. Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Withhold for proteinuria greater than or equal to 2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome.

Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24-hour urine protein [Pearson Correlation 0.39 (95% CI: 0.17, 0.57)].

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina, occurred at a higher incidence in patients receiving bevacizumab compared to patients receiving chemotherapy. Across clinical studies, the incidence of Grades 3–5 ATE was 5% in patients receiving bevacizumab with chemotherapy compared to ≤2% in patients receiving chemotherapy alone; the highest incidence occurred in patients with GBM. The risk of developing ATE was increased in patients with a history of arterial thromboembolism, diabetes, or ≥65 years [see Use in Specific Populations (8.5)].

Discontinue in patients who develop a severe ATE. The safety of reinitiating bevacizumab products after an ATE is resolved is not known.

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

The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with interferon alfa.

ZIRABEV is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade ≥3 left ventricular dysfunction was 1% in patients receiving bevacizumab compared to 0.6% of patients receiving chemotherapy alone. Among patients who received prior anthracycline treatment, the rate of CHF was 4% for patients receiving bevacizumab with chemotherapy as compared to 0.6% for patients receiving chemotherapy alone.

In previously untreated patients with a hematological malignancy, the incidence of CHF and decline in left ventricular ejection fraction (LVEF) were increased in patients receiving bevacizumab with anthracycline-based chemotherapy compared to patients receiving placebo with the same chemotherapy regimen. The proportion of patients with a decline in LVEF from baseline of ≥20% or a decline from baseline of 10% to <50%, was 10% in patients receiving bevacizumab with chemotherapy compared to 5% in patients receiving chemotherapy alone. Time to onset of left-ventricular dysfunction or CHF was 1 to 6 months after the first dose in at least 85% of the patients and was resolved in 62% of the patients who developed CHF in the bevacizumab arm compared to 82% in the placebo arm. Discontinue ZIRABEV in patients who develop CHF.

ZIRABEV (bevacizumab-bvzr) injection is a clear to slightly opalescent, colorless to pale brown, sterile solution for intravenous infusion supplied in a carton containing one single-dose vial in the following strengths:

• •
  100 mg/4 mL (25 mg/mL) (NDC 0069-0315-01)
• •
  400 mg/16 mL (25 mg/mL) (NDC 0069-0342-01)

Withhold for at least 28 days prior to elective surgery. Do not administer ZIRABEV until at least 28 days following major surgery and until adequate wound healing.

NDC 0069-0315-01

Rx only

Zirabev™

(bevacizumab–bvzr)

Injection

100 mg/4 mL

(25 mg/mL)

For Intravenous Infusion

After Dilution

One SINGLE-DOSE VIAL

DISCARD UNUSED PORTION.

Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.

NDC 0069-0342-01

Rx only

Zirabev™

(bevacizumab–bvzr)

Injection

400 mg/16 mL

(25 mg/mL)

For Intravenous Infusion

After Dilution

One SINGLE-DOSE VIAL

DISCARD UNUSED PORTION.

NDC 0069-0315-01

Zirabev™

(bevacizumab–bvzr)

Injection

100 mg/4 mL

(25 mg/mL)

For Intravenous Infusion

After Dilution

One SINGLE-DOSE VIAL

DISCARD UNUSED PORTION.

Rx only

Pfizer Oncology

In a controlled clinical study in which bevacizumab was not administered within 28 days of major surgical procedures, the incidence of wound healing complications, including serious and fatal complications, was 15% in patients with mCRC who underwent surgery while receiving bevacizumab and 4% in patients who did not receive bevacizumab. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who received bevacizumab and 0.7% in patients who did not receive bevacizumab [see Adverse Reactions (6.1)].

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 [see Dosage and Administration (2.7)].

Necrotizing fasciitis including fatal cases, has been reported in patients receiving bevacizumab usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue ZIRABEV in patients who develop necrotizing fasciitis.

NDC 0069-0342-01

Zirabev™

(bevacizumab–bvzr)

Injection

400 mg/16 mL

(25 mg/mL)

For Intravenous Infusion

After Dilution

One SINGLE-DOSE VIAL

DISCARD UNUSED PORTION.

Rx only

Pfizer Oncology

Table 1 describes dosage modifications for specific adverse reactions. No dose reductions for ZIRABEV are recommended.

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, with the highest incidence in patients with a history of prior pelvic radiation. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of perforations occurred within 50 days of the first dose [see Adverse Reactions (6.1)].

Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. The incidence ranged from <1% to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a gastrointestinal vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a diverting ostomy.

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 in patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue in patients with fistula formation involving any internal organ.

Posterior reversible encephalopathy syndrome (PRES) was reported in <0.5% of patients across clinical studies. The onset of symptoms occurred from 16 hours to 1 year after the first dose. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES.

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. The safety of reinitiating bevacizumab products in patients who developed PRES is not known.

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).

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel.

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.

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin or in combination with paclitaxel and topotecan.

No studies have been conducted to assess potential of bevacizumab products for carcinogenicity or mutagenicity.

Bevacizumab products may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrested follicular development or absent corpora lutea, as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident.

Lack of efficacy of bevacizumab as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical studies.

The first study [BO17920 (NCT00112918)] was conducted in 3451 patients with high-risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent. Patients were randomized to receive bevacizumab at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule with FOLFOX4 (N=1155) or on a 3-weekly schedule with XELOX (N=1145) or FOLFOX4 alone (N=1151). The main outcome measure was disease free survival (DFS) in patients with stage III colon cancer.

The median age was 58 years; 54% were male, 84% were White and 29% were ≥65 years. Eighty-three percent had stage III disease.

The addition of bevacizumab to chemotherapy did not improve DFS. As compared to FOLFOX4 alone, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher for patients receiving bevacizumab with FOLFOX4 or with XELOX. The hazard ratios for DFS were 1.17 (95% CI: 0.98, 1.39) for bevacizumab with FOLFOX4 versus FOLFOX4 alone and 1.07 (95% CI: 0.90, 1.28) for bevacizumab with XELOX versus FOLFOX4 alone. The hazard ratios for OS were 1.31 (95% CI: 1.03, 1.67) and 1.27 (95% CI: 1, 1.62) for the comparison of bevacizumab with FOLFOX4 versus FOLFOX4 alone and bevacizumab with XELOX versus FOLFOX4 alone, respectively. Similar lack of efficacy for DFS was observed in the bevacizumab-containing arms compared to FOLFOX4 alone in the high-risk stage II cohort.

In a second study [NSABP-C-08 (NCT00096278)], patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either bevacizumab administered at a dose equivalent to 2.5 mg/kg/week with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% White. Seventy-five percent had stage III disease. The main outcome was DFS among stage III patients. The HR for DFS was 0.92 (95% CI: 0.77, 1.10). OS was not significantly improved with the addition of bevacizumab to mFOLFOX6 [HR 0.96 (95% CI: 0.75, 1.22)].

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.

Limitations of Use: ZIRABEV is not indicated for adjuvant treatment of colon cancer [see Clinical Studies (14.2)].

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light. Do not freeze or shake the vial or carton.

Bevacizumab-bvzr is a vascular endothelial growth factor inhibitor. Bevacizumab-bvzr is a recombinant humanized monoclonal IgG1 antibody that contains human framework regions and murine complementarity-determining regions. Bevacizumab-bvzr has an approximate molecular weight of 149 kDa. Bevacizumab-bvzr is produced in a mammalian cell (Chinese Hamster Ovary) expression system.

ZIRABEV (bevacizumab-bvzr) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brown solution in a single-dose vial for intravenous use. ZIRABEV contains bevacizumab-bvzr at a concentration of 25 mg/mL in either 100 mg/4 mL or 400 mg/16 mL single-dose vials.

Each mL of solution contains 25 mg bevacizumab-bvzr, edetate disodium dihydrate (0.05 mg), polysorbate 80 (0.2 mg), succinic acid (2.36 mg), sucrose (85 mg), and Water for Injection, USP. Sodium hydroxide is added to adjust the pH. The pH is 5.5.

Bevacizumab products can result in two distinct patterns of bleeding: minor hemorrhage, which is most commonly Grade 1 epistaxis, and serious hemorrhage, which in some cases has been fatal. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to 5-fold more frequently in patients receiving bevacizumab compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3–5 hemorrhagic events ranged from 0.4% to 7% in patients receiving bevacizumab [see Adverse Reactions (6.1)].

Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous NSCLC and 4% of patients with non-squamous NSCLC receiving bevacizumab with chemotherapy compared to none of the patients receiving chemotherapy alone.

Do not administer ZIRABEV to patients with recent history of hemoptysis of 1/2 teaspoon or more of red blood. Discontinue in patients who develop a Grades 3–4 hemorrhage.

Severe hypertension occurred at a higher incidence in patients receiving bevacizumab products as compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3–4 hypertension ranged from 5% to 18%.

Monitor blood pressure every two to three weeks during treatment with ZIRABEV. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with ZIRABEV-induced or -exacerbated hypertension after discontinuing ZIRABEV. Withhold ZIRABEV in patients with severe hypertension that is not controlled with medical management; resume once controlled with medical management. Discontinue in patients who develop hypertensive crisis or hypertensive encephalopathy.

The safety and effectiveness of bevacizumab products in pediatric patients have not been established. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years who received bevacizumab. Bevacizumab products are not approved for use in patients under the age of 18 years.

Antitumor activity was not observed among eight pediatric patients with relapsed GBM who received bevacizumab and irinotecan. Addition of bevacizumab to standard of care did not result in improved event-free survival in pediatric patients enrolled in two randomized clinical studies, one in high grade glioma (n=121) and one in metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma (n=154).

Based on the population pharmacokinetics analysis of data from 152 pediatric and young adult patients with cancer (7 months to 21 years of age), bevacizumab clearance normalized by body weight in pediatrics was comparable to that in adults.

In an exploratory, pooled analysis of 1745 patients from five randomized, controlled studies, 35% of patients were ≥65 years old. The overall incidence of ATE was increased in all patients receiving bevacizumab with chemotherapy as compared to those receiving chemotherapy alone, regardless of age; however, the increase in the incidence of ATE was greater in patients ≥65 years (8% vs. 3%) as compared to patients <65 years (2% vs. 1%) [see Warnings and Precautions (5.4)].

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and the 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 bevacizumab products may be misleading.

In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies as detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-bevacizumab antibodies is not known.

None.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• •
  Gastrointestinal Perforations and Fistulae [see Warnings and Precautions (5.1)].
• •
  Surgery and Wound Healing Complications [see Warnings and Precautions (5.2)].
• •
  Hemorrhage [see Warnings and Precautions (5.3)].
• •
  Arterial Thromboembolic Events [see Warnings and Precautions (5.4)].
• •
  Venous Thromboembolic Events [see Warnings and Precautions (5.5)].
• •
  Hypertension [see Warnings and Precautions (5.6)].
• •
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.7)].
• •
  Renal Injury and Proteinuria [see Warnings and Precautions (5.8)].
• •
  Infusion-Related Reactions [see Warnings and Precautions (5.9)].
• •
  Ovarian Failure [see Warnings and Precautions (5.11)].
• •
  Congestive Heart Failure [see Warnings and Precautions (5.12)].

The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving bevacizumab with chemotherapy as compared to those receiving chemotherapy alone for adjuvant treatment of a solid tumor. After discontinuing bevacizumab, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% of women receiving bevacizumab. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or an FSH level <30 mIU/mL during the post-treatment period. Long-term effects of bevacizumab products on fertility are unknown. Inform females of reproductive potential of the risk of ovarian failure prior to initiating ZIRABEV [see Adverse Reactions (6.1), Use in Specific Populations (8.3)].

The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of bevacizumab every week, every 2 weeks, or every 3 weeks, bevacizumab pharmacokinetics are linear and the predicted time to reach more than 90% of steady state concentration is 84 days. The accumulation ratio following a dose of 10 mg/kg of bevacizumab once every 2 weeks is 2.8.

Population simulations of bevacizumab exposures provide a median trough concentration of 80.3 mcg/mL on Day 84 (10^th, 90^th percentile: 45, 128) following a dose of 5 mg/kg once every two weeks.

ZIRABEV is a vascular endothelial growth factor inhibitor indicated for the treatment of:

• •
  Metastatic colorectal cancer, in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment. (1.1)
• •
  Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab product-containing regimen. (1.1)

Limitations of Use: ZIRABEV is not indicated for adjuvant treatment of colon cancer. (1.1)

• •
  Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment. (1.2)
• •
  Recurrent glioblastoma in adults. (1.3)
• •
  Metastatic renal cell carcinoma in combination with interferon alfa. (1.4)
• •
  Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan. (1.5)
• •
  Epithelial ovarian, fallopian tube, or primary peritoneal cancer:
  • o
    in combination with carboplatin and paclitaxel, followed by ZIRABEV as a single agent, for stage III or IV disease following initial surgical resection. (1.6)
  • o
    in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens. (1.6)
  • o
    in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by ZIRABEV as a single agent, for platinum-sensitive recurrent disease. (1.6)

Bevacizumab products bind VEGF and prevent the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

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

The recommended dosage is 10 mg/kg intravenously every 2 weeks.

• •
  Gastrointestinal Perforations and Fistula: Discontinue for gastrointestinal perforations, tracheoesophageal fistula, grade 4 fistula, or fistula formation involving any organ. (5.1)
• •
  Surgery and Wound Healing Complications: 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 ZIRABEV for at least 28 days following a major surgery, and until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complication has not been established. Discontinue for wound healing complications of necrotizing fasciitis. (5.2)
• •
  Hemorrhage: Severe or fatal hemorrhages have occurred. Do not administer for recent hemoptysis. Discontinue for Grade 3–4 hemorrhage. (5.3)
• •
  Arterial Thromboembolic Events (ATE): Discontinue for severe ATE. (5.4)
• •
  Venous Thromboembolic Events (VTE): Discontinue for Grade 4 VTE. (5.5)
• •
  Hypertension: Monitor blood pressure and treat hypertension. Withhold if not medically controlled; resume once controlled. Discontinue for hypertensive crisis or hypertensive encephalopathy. (5.6)
• •
  Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue. (5.7)
• •
  Renal Injury and Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome. Withhold until less than 2 grams of protein in urine. (5.8)
• •
  Infusion–Related Reactions: Decrease rate for infusion-related reactions. Discontinue for severe infusion-related reactions and administer medical therapy. (5.9)
• •
  Embryo-Fetal Toxicity: May cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. (5.10, 8.1, 8.3)
• •
  Ovarian Failure: Advise females of the potential risk. (5.11, 8.3)
• •
  Congestive Heart Failure (CHF): Discontinue ZIRABEV in patients who develop CHF. (5.12)

Based on its mechanism of action and findings from animal studies, bevacizumab products may cause fetal harm when administered to pregnant women. Congenital malformations were observed with the administration of bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10 mg/kg.

Furthermore, animal models link angiogenesis and VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZIRABEV and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

Withhold for at least 28 days prior to elective surgery. Do not administer ZIRABEV for 28 days following major surgery and until adequate wound healing. (2.1)

Metastatic colorectal cancer. (2.2)

• •
  5 mg/kg every 2 weeks with bolus-IFL.
• •
  10 mg/kg every 2 weeks with FOLFOX4.
• •
  5 mg/ kg every 2 weeks or 7.5 mg/kg every 3 weeks with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin based chemotherapy after progression on a first-line bevacizumab product containing regimen.

First-line non−squamous non−small cell lung cancer. (2.3)

• •
  15 mg/kg every 3 weeks with carboplatin and paclitaxel.

Recurrent glioblastoma. (2.4)

• •
  10 mg/kg every 2 weeks.

Metastatic renal cell carcinoma. ( 2.5)

• •
  10 mg/kg every 2 weeks with interferon alfa.

Persistent, recurrent, or metastatic cervical cancer. (2.6)

• •
  15 mg/kg every 3 weeks with paclitaxel and cisplatin or paclitaxel and topotecan.

Stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection. (2.7)

• •
  15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles.

Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. (2.7)

• •
  10 mg/kg every 2 weeks with paclitaxel, pegylated liposomal doxorubicin, or topotecan given every week.
• •
  15 mg/kg every 3 weeks with topotecan given every 3 weeks

Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. (2.7)

• •
  15 mg/kg every 3 weeks with carboplatin and paclitaxel for 6–8 cycles, followed by 15 mg/kg every 3 weeks as a single agent.
• •
  15 mg/kg every 3 weeks with carboplatin and gemcitabine for 6–10 cycles, followed by 15 mg/kg every 3 weeks as a single agent.

Administer as an intravenous infusion after dilution. See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. (2.8, 2.9)

Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) clear to slightly opalescent, colorless to pale brown solution in a single-dose vial

The following adverse reactions have been identified during postapproval use of bevacizumab products. 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.

General: Polyserositis

Cardiovascular: Pulmonary hypertension, Mesenteric venous occlusion

Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Hepatobiliary disorders: Gallbladder perforation

Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw

Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)

Respiratory: Nasal septum perforation

Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

Lactation: Advise not to breastfeed. (8.2)

Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion-related reactions with the first dose occurred in <3% of patients and severe reactions occurred in 0.4% of patients.

Decrease the rate of infusion for mild, clinically insignificant 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 (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen).

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety data in Warnings and Precautions and described below reflect exposure to bevacizumab in 4463 patients including those with mCRC (AVF2107g, E3200), non-squamous NSCLC (E4599), GBM (EORTC 26101), mRCC (BO17705), cervical cancer (GOG-0240), epithelial ovarian, fallopian tube, or primary peritoneal cancer (MO22224, AVF4095, GOG-0213, and GOG-0218) or another cancer at the recommended dose and schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving bevacizumab as a single agent or in combination with other anti-cancer therapies at a rate >10% were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Across clinical studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies (14)].

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.

The recommended dosage when ZIRABEV is administered in combination with intravenous fluorouracil-based chemotherapy is:

• •
  5 mg/kg intravenously every 2 weeks in combination with bolus-IFL.
• •
  10 mg/kg intravenously every 2 weeks in combination with FOLFOX4.
• •
  5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy in patients who have progressed on a first-line bevacizumab product-containing regimen.

An increased risk of venous thromboembolic events (VTE) was observed across clinical studies [see Adverse Reactions (6.1)]. In Study GOG-0240, Grades 3–4 VTE occurred in 11% of patients receiving bevacizumab with chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the incidence of Grades 3–4 VTE was 5% in patients receiving bevacizumab with chemotherapy compared to 2% in patients receiving chemotherapy alone.

Discontinue ZIRABEV in patients with a Grade 4 VTE, including pulmonary embolism.

The incidence and severity of proteinuria was higher in patients receiving bevacizumab as compared to patients receiving chemotherapy. Grade 3 (defined as urine dipstick 4+ or >3.5 grams of protein per 24 hours) to Grade 4 (defined as nephrotic syndrome) ranged from 0.7% to 7% in clinical studies.

The overall incidence of proteinuria (all grades) was only adequately assessed in Study BO17705, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (15 days to 37 months) after initiating bevacizumab. Median time to resolution was 6.1 months (95% CI: 2.8, 11.3). Proteinuria did not resolve in 40% of patients after median follow-up of 11.2 months and required discontinuation of bevacizumab in 30% of the patients who developed proteinuria [see Adverse Reactions (6.1)].

In an exploratory, pooled analysis of patients from seven randomized clinical studies, 5% of patients receiving bevacizumab with chemotherapy experienced Grades 2–4 (defined as urine dipstick 2+ or greater or >1 gram of protein per 24 hours or nephrotic syndrome) proteinuria. Grades 2–4 proteinuria resolved in 74% of patients.

Bevacizumab was reinitiated in 42% of patients. Of the 113 patients who reinitiated bevacizumab, 48% experienced a second episode of Grades 2–4 proteinuria.

Nephrotic syndrome occurred in <1% of patients receiving bevacizumab across clinical studies, in some instances with fatal outcome. In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy. Results of a retrospective analysis of 5805 patients who received bevacizumab with chemotherapy and 3713 patients who received chemotherapy alone, showed higher rates of elevated serum creatinine levels (between 1.5 to 1.9 times baseline levels) in patients who received bevacizumab. Serum creatinine levels did not return to baseline in approximately one-third of patients who received bevacizumab.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during ZIRABEV therapy. Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Withhold for proteinuria greater than or equal to 2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome.

Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24-hour urine protein [Pearson Correlation 0.39 (95% CI: 0.17, 0.57)].

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina, occurred at a higher incidence in patients receiving bevacizumab compared to patients receiving chemotherapy. Across clinical studies, the incidence of Grades 3–5 ATE was 5% in patients receiving bevacizumab with chemotherapy compared to ≤2% in patients receiving chemotherapy alone; the highest incidence occurred in patients with GBM. The risk of developing ATE was increased in patients with a history of arterial thromboembolism, diabetes, or ≥65 years [see Use in Specific Populations (8.5)].

Discontinue in patients who develop a severe ATE. The safety of reinitiating bevacizumab products after an ATE is resolved is not known.

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

The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with interferon alfa.

ZIRABEV is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade ≥3 left ventricular dysfunction was 1% in patients receiving bevacizumab compared to 0.6% of patients receiving chemotherapy alone. Among patients who received prior anthracycline treatment, the rate of CHF was 4% for patients receiving bevacizumab with chemotherapy as compared to 0.6% for patients receiving chemotherapy alone.

In previously untreated patients with a hematological malignancy, the incidence of CHF and decline in left ventricular ejection fraction (LVEF) were increased in patients receiving bevacizumab with anthracycline-based chemotherapy compared to patients receiving placebo with the same chemotherapy regimen. The proportion of patients with a decline in LVEF from baseline of ≥20% or a decline from baseline of 10% to <50%, was 10% in patients receiving bevacizumab with chemotherapy compared to 5% in patients receiving chemotherapy alone. Time to onset of left-ventricular dysfunction or CHF was 1 to 6 months after the first dose in at least 85% of the patients and was resolved in 62% of the patients who developed CHF in the bevacizumab arm compared to 82% in the placebo arm. Discontinue ZIRABEV in patients who develop CHF.

ZIRABEV (bevacizumab-bvzr) injection is a clear to slightly opalescent, colorless to pale brown, sterile solution for intravenous infusion supplied in a carton containing one single-dose vial in the following strengths:

• •
  100 mg/4 mL (25 mg/mL) (NDC 0069-0315-01)
• •
  400 mg/16 mL (25 mg/mL) (NDC 0069-0342-01)

Withhold for at least 28 days prior to elective surgery. Do not administer ZIRABEV until at least 28 days following major surgery and until adequate wound healing.

NDC 0069-0315-01

Rx only

Zirabev™

(bevacizumab–bvzr)

Injection

100 mg/4 mL

(25 mg/mL)

For Intravenous Infusion

After Dilution

One SINGLE-DOSE VIAL

DISCARD UNUSED PORTION.

Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.

NDC 0069-0342-01

Rx only

Zirabev™

(bevacizumab–bvzr)

Injection

400 mg/16 mL

(25 mg/mL)

For Intravenous Infusion

After Dilution

One SINGLE-DOSE VIAL

DISCARD UNUSED PORTION.

NDC 0069-0315-01

Zirabev™

(bevacizumab–bvzr)

Injection

100 mg/4 mL

(25 mg/mL)

For Intravenous Infusion

After Dilution

One SINGLE-DOSE VIAL

DISCARD UNUSED PORTION.

Rx only

Pfizer Oncology

In a controlled clinical study in which bevacizumab was not administered within 28 days of major surgical procedures, the incidence of wound healing complications, including serious and fatal complications, was 15% in patients with mCRC who underwent surgery while receiving bevacizumab and 4% in patients who did not receive bevacizumab. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who received bevacizumab and 0.7% in patients who did not receive bevacizumab [see Adverse Reactions (6.1)].

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 [see Dosage and Administration (2.7)].

Necrotizing fasciitis including fatal cases, has been reported in patients receiving bevacizumab usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue ZIRABEV in patients who develop necrotizing fasciitis.

NDC 0069-0342-01

Zirabev™

(bevacizumab–bvzr)

Injection

400 mg/16 mL

(25 mg/mL)

For Intravenous Infusion

After Dilution

One SINGLE-DOSE VIAL

DISCARD UNUSED PORTION.

Rx only

Pfizer Oncology

Table 1 describes dosage modifications for specific adverse reactions. No dose reductions for ZIRABEV are recommended.

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, with the highest incidence in patients with a history of prior pelvic radiation. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of perforations occurred within 50 days of the first dose [see Adverse Reactions (6.1)].

Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. The incidence ranged from <1% to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a gastrointestinal vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a diverting ostomy.

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 in patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue in patients with fistula formation involving any internal organ.

Posterior reversible encephalopathy syndrome (PRES) was reported in <0.5% of patients across clinical studies. The onset of symptoms occurred from 16 hours to 1 year after the first dose. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES.

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. The safety of reinitiating bevacizumab products in patients who developed PRES is not known.

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).

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel.

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.

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin or in combination with paclitaxel and topotecan.

No studies have been conducted to assess potential of bevacizumab products for carcinogenicity or mutagenicity.

Bevacizumab products may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrested follicular development or absent corpora lutea, as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident.

Lack of efficacy of bevacizumab as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical studies.

The first study [BO17920 (NCT00112918)] was conducted in 3451 patients with high-risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent. Patients were randomized to receive bevacizumab at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule with FOLFOX4 (N=1155) or on a 3-weekly schedule with XELOX (N=1145) or FOLFOX4 alone (N=1151). The main outcome measure was disease free survival (DFS) in patients with stage III colon cancer.

The median age was 58 years; 54% were male, 84% were White and 29% were ≥65 years. Eighty-three percent had stage III disease.

The addition of bevacizumab to chemotherapy did not improve DFS. As compared to FOLFOX4 alone, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher for patients receiving bevacizumab with FOLFOX4 or with XELOX. The hazard ratios for DFS were 1.17 (95% CI: 0.98, 1.39) for bevacizumab with FOLFOX4 versus FOLFOX4 alone and 1.07 (95% CI: 0.90, 1.28) for bevacizumab with XELOX versus FOLFOX4 alone. The hazard ratios for OS were 1.31 (95% CI: 1.03, 1.67) and 1.27 (95% CI: 1, 1.62) for the comparison of bevacizumab with FOLFOX4 versus FOLFOX4 alone and bevacizumab with XELOX versus FOLFOX4 alone, respectively. Similar lack of efficacy for DFS was observed in the bevacizumab-containing arms compared to FOLFOX4 alone in the high-risk stage II cohort.

In a second study [NSABP-C-08 (NCT00096278)], patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either bevacizumab administered at a dose equivalent to 2.5 mg/kg/week with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% White. Seventy-five percent had stage III disease. The main outcome was DFS among stage III patients. The HR for DFS was 0.92 (95% CI: 0.77, 1.10). OS was not significantly improved with the addition of bevacizumab to mFOLFOX6 [HR 0.96 (95% CI: 0.75, 1.22)].

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.