Vegzelma Dailymed

1 Indications And Usage

VEGZELMA 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: VEGZELMA 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:
  • in combination with carboplatin and paclitaxel, followed by VEGZELMA as a single agent, for stage III or IV disease following initial surgical resection (1.6)
  • 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)
  • in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by VEGZELMA as a single agent, for platinum-sensitive recurrent disease (1.6)

1.1Metastatic Colorectal Cancer

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

VEGZELMA, 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.

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

1.2First-Line Non-Squamous Non-Small Cell Lung Cancer

VEGZELMA, 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).

1.3Recurrent Glioblastoma

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

1.4Metastatic Renal Cell Carcinoma

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

1.5Persistent, Recurrent, or Metastatic Cervical Cancer

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

1.6Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

VEGZELMA, in combination with carboplatin and paclitaxel, followed by VEGZELMA 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.

VEGZELMA, 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.

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

Withhold for at least 28 days prior to elective surgery. Do not administer VEGZELMA 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 Informatio for preparation and administration instructions and dosage modifications for adverse reactions. (2.8 and 2.9 )

2.1Important Administration Information

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

2.2Metastatic Colorectal Cancer

The recommended dosage when VEGZELMA 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.

2.3First-Line Non-Squamous Non-Small Cell Lung Cancer

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

2.4Recurrent Glioblastoma

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

2.5Metastatic Renal Cell Carcinoma

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

2.6Persistent, 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.

2.7Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Stage III or IV Disease Following Initial Surgical Resection

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel for up to 6 cycles, followed by VEGZELMA 15 mg/kg every 3 weeks as a single agent for a total of up to 22 cycles or until disease progression, whichever occurs earlier.

Recurrent Disease

Platinum Resistant

The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan (every week).

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with topotecan (every 3 weeks).

Platinum Sensitive

The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and paclitaxel for 6 to 8 cycles, followed by VEGZELMA 15 mg/kg every 3 weeks as a single agent until disease progression.

The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and gemcitabine for 6 to 10 cycles, followed by VEGZELMA 15 mg/kg every 3 weeks as a single agent until disease progression.

2.8Dosage Modifications for Adverse Reactions

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

Table 1: Dosage Modifications for Adverse Reactions

Adverse Reaction	Severity	Dosage Modification
Gastrointestinal Perforations and Fistulae [see Warnings and Precautions (5.1)].	Gastrointestinal perforation, any grade Tracheoesophageal fistula, any grade Fistula, Grade 4 Fistula formation involving any internal organ	Discontinue VEGZELMA
Wound Healing Complications [see Warnings and Precautions (5.2)].	Any	Withhold VEGZELMA until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complications has not been established.
	Necrotizing fasciitis	Discontinue VEGZELMA
Hemorrhage [see Warnings and Precautions (5.3)].	Grade 3 or 4	Discontinue VEGZELMA
	Recent history of hemoptysis of 1/2 teaspoon (2.5 mL) or more	Withhold VEGZELMA
Thromboembolic Events [see Warnings and Precautions (5.4, 5.5)].	Arterial thromboembolism, severe	Discontinue VEGZELMA
	Venous thromboembolism, Grade 4	Discontinue VEGZELMA
Hypertension [see Warnings and Precautions (5.6)].	Hypertensive crisis Hypertensive encephalopathy	Discontinue VEGZELMA
	Hypertension, severe	Withhold VEGZELMA if not controlled with medical management; resume once controlled
Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.7)].	Any	Discontinue VEGZELMA
Renal Injury and Proteinuria [see Warnings and Precautions (5.8)].	Nephrotic syndrome	Discontinue VEGZELMA
	Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome	Withhold VEGZELMA until proteinuria less than 2 grams per 24 hours
Infusion-Related Reactions [see Warnings and Precautions (5.9)].	Severe	Discontinue VEGZELMA
	Clinically significant	Interrupt infusion; resume at a decreased rate of infusion after symptoms resolve
	Mild, clinically insignificant	Decrease infusion rate
Congestive Heart Failure [see Warnings and Precautions (5.12)].	Any	Discontinue VEGZELMA

2.9Preparation and Administration

Preparation

• Use appropriate aseptic technique.
• Use sterile needle and syringe to prepare VEGZELMA.
• Visually inspect vial for particulate matter and discoloration prior to preparation for administration. Discard vial if solution is cloudy, discolored, or contains particulate matter.
• Withdraw necessary amount of VEGZELMA and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION.
• Discard any unused portion left in a vial, as the product contains no preservatives.
• Diluted VEGZELMA solution may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours, or at room temperature up to 30°C (86°F) for up to 4 hours, if not used immediately.
• No incompatibilities between VEGZELMA and polyolefin (polypropylene and polyethylene) bag have been observed.

Administration

• Administer as an intravenous infusion.
• First infusion: Administer infusion over 90 minutes.
• Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated. Administer all subsequent infusions over 30 minutes if second infusion over 60 minutes is tolerated.

3 Dosage Forms And Strengths

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


Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) in a single-dose vial (3)

4 Contraindications

None.


None (4)

5 Warnings And Precautions

• 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 VEGZELMA treatment, withhold VEGZELMA until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer VEGZELMA for at least 28 days following a major surgery, and until adequate wound healing. The safety of resumption of VEGZELMA 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 VEGZELMA in patients who develop CHF. (5.12)

5.1Gastrointestinal 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, 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 VEGZELMA 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.

5.2Surgery and Wound Healing Complications

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 [seeAdverse Reactions (6.1) ].

In patients who experience wound healing complications during VEGZELMA treatment, withhold VEGZELMA 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 [seeDosage and Administration (2.8) ].

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

5.3Hemorrhage

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 VEGZELMA 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.

5.4Arterial Thromboembolic Events

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.

5.5Venous Thromboembolic Events

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

5.6Hypertension

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 VEGZELMA. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with VEGZELMA-induced or -exacerbated hypertension after discontinuing VEGZELMA. Withhold VEGZELMA 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.

5.7Posterior Reversible Encephalopathy Syndrome

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 VEGZELMA 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.

5.8Renal Injury and Proteinuria

The incidence and severity of proteinuria was higher in patients receiving bevacizumab products 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 VEGZELMA 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)].

5.9Infusion-Related Reactions

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, anaphylatoid/anaphylactic reacionts, 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).

5.10Embryo-Fetal Toxicity

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 VEGZELMA and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

5.11Ovarian Failure

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 VEGZELMA [see Adverse Reactions (6.1), Use in Specific Populations (8.3)].

5.12Congestive Heart Failure (CHF)

VEGZELMA 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 VEGZELMA in patients who develop CHF.

6 Adverse Reactions

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)].

Most common adverse reactions incidence (incidence >10%) are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION Inc. at 1-833-938-2021 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

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)].

Metastatic Colorectal Cancer

In Combination with bolus-IFL

The safety of bevacizumab was evaluated in 392 patients who received at least one dose of bevacizumab in a double-blind, active-controlled study (AVF2107g), which compared bevacizumab (5 mg/kg every 2 weeks) with bolus-IFL to placebo with bolus-IFL in patients with mCRC [see Clinical Studies (14.1)]. Patients were randomized (1:1:1) to placebo with bolus-IFL, bevacizumab with bolus-IFL, or bevacizumab with fluorouracil and leucovorin. The demographics of the safety population were similar to the demographics of the efficacy population. All Grades 3-4 adverse reactions and selected Grades 1-2 adverse reactions (i.e., hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Adverse reactions are presented in Table 2.

Table 2: Grades 3–4 Adverse Reactions Occurring at Higher Incidence (≥2%) in Patients Receiving Bevacizumab vs. Placebo in Study AVF2107g

Adverse ReactionNCI-CTC version 3	Bevacizumab with IFL(N=392)	Placebo with IFL(N=396)
Hematology
  Leukopenia	37%	31%
  Neutropenia	21%	14%
Gastrointestinal
  Diarrhea	34%	25%
  Abdominal pain	8%	5%
  Constipation	4%	2%
Vascular
  Hypertension	12%	2%
  Deep vein thrombosis	9%	5%
  Intra-abdominal thrombosis	3%	1%
  Syncope	3%	1%
General
  Asthenia	10%	7%
  Pain	8%	5%

In Combination with FOLFOX4

The safety of bevacizumab was evaluated in 521 patients in an open-label, active-controlled study (E3200) in patients who were previously treated with irinotecan and fluorouracil for initial therapy for mCRC. Patients were randomized (1:1:1) to FOLFOX4, bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) with FOLFOX4, or bevacizumab alone (10 mg/kg every 2 weeks). Bevacizumab was continued until disease progression or unacceptable toxicity.

The demographics of the safety population were similar to the demographics of the efficacy population.

Selected Grades 3–5 non-hematologic and Grades 4–5 hematologic occurring at a higher incidence (≥2%) in patients receiving bevacizumab with FOLFOX4 compared to FOLFOX4 alone 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 under-estimate the true adverse reaction rates due to the reporting mechanisms.

First-Line Non Squamous Non-Small Cell Lung Cancer

The safety of bevacizumab was evaluated as first-line treatment in 422 patients with unresectable NSCLC who received at least one dose of bevacizumab in an active-controlled, open-label, multicenter trial (E4599) [see Clinical Studies (14.3)]. Chemotherapy naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel and carboplatin with or without bevacizumab (15 mg/kg every 3 weeks). After completion or upon discontinuation of chemotherapy, patients randomized to receive bevacizumab continued to receive bevacizumab alone until disease progression or until unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors only), CNS metastasis, gross hemoptysis (1/2 teaspoon or more of red blood), unstable angina, or receiving therapeutic anticoagulation. The demographics of the safety population were similar to the demographics of the efficacy population.

Only Grades 3–5 non-hematologic and Grades 4–5 hematologic adverse reactions were collected. Grades 3–5 non-hematologic and Grades 4–5 hematologic adverse reactions occurring at a higher incidence (≥2%) in patients receiving bevacizumab with paclitaxel and carboplatin compared with patients receiving chemotherapy alone 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%).

Recurrent Glioblastoma

The safety of bevacizumab was evaluated in a multicenter, randomized, open-label study (EORTC 26101) in patients with recurrent GBM following radiotherapy and temozolomide of whom 278 patients received at least one dose of bevacizumab and are considered safety evaluable [see Clinical Studies (14.4)]. Patients were randomized (2:1) to receive bevacizumab (10 mg/kg every 2 weeks) with lomustine or lomustine alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. In the bevacizumab with lomustine arm, 22% of patients discontinued treatment 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.

Metastatic Renal Cell Carcinoma

The safety of bevacizumab was evaluated in 337 patients who received at least one dose of bevacizumab in a multicenter, double-blind study (BO17705) in patients with mRCC. Patients who had undergone a nephrectomy were randomized (1:1) to receive either bevacizumab (10 mg/kg every 2 weeks) or placebo with interferon alfa [see Clinical Studies (14.5)]. Patients were treated until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–5 adverse reactions occurring at a higher incidence (>2%) 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). Adverse reactions are presented in Table 3.

Table 3: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥5%) of Patients Receiving Bevacizumab vs. Placebo with Interferon Alfa in Study BO17705

Adverse Reaction*	Bevacizumab with Interferon Alfa(N=337)	Placebo with Interferon Alfa(N=304)
Metabolism and nutrition
  Decreased appetite	36%	31%
  Weight loss	20%	15%
General
  Fatigue	33%	27%
Vascular
  Hypertension	28%	9%
Respiratory, thoracic and mediastinal
  Epistaxis	27%	4%
  Dysphonia	5%	0%
Nervous system
  Headache	24%	16%
Gastrointestinal
  Diarrhea	21%	16%
Renal and urinary
  Proteinuria	20%	3%
Musculoskeletal and connective tissue
  Myalgia	19%	14%
  Back pain	12%	6%

The following adverse reactions were reported at a 5-fold greater incidence in patients receiving bevacizumab with interferon-alfa compared to patients receiving placebo with interferon-alfa and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs. 0); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs. 1); tinnitus (7 vs. 1); tooth abscess (7 vs. 0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

Persistent, Recurrent, or Metastatic Cervical Cancer

The safety of bevacizumab was evaluated in 218 patients who received at least one dose of bevacizumab in a multicenter study (GOG-0240) in patients with persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.6)]. Patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without bevacizumab (15 mg/kg every 3 weeks), or paclitaxel and topotecan with or without bevacizumab (15 mg/kg every 3 weeks). The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in 218 patients receiving bevacizumab with chemotherapy compared to 222 patients receiving chemotherapy alone were abdominal pain (12% vs. 10%), hypertension (11% vs. 0.5%), thrombosis (8% vs. 3%), 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%), 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%). Adverse reactions are presented in Table 4.

Table 4: Grades 1–4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240

Adverse Reaction*	Bevacizumab with Chemotherapy(N=218)	Chemotherapy(N=222)
General
  Fatigue	80%	75%
  Peripheral edema	15%	22%
Metabolism and nutrition
  Decreased appetite	34%	26%
  Hyperglycemia	26%	19%
  Hypomagnesemia	24%	15%
  Weight loss	21%	7%
  Hyponatremia	19%	10%
  Hypoalbuminemia	16%	11%
Vascular
  Hypertension	29%	6%
  Thrombosis	10%	3%
Infections
  Urinary tract infection	22%	14%
  Infection	10%	5%
Nervous system
  Headache	22%	13%
  Dysarthria	8%	1%
Psychiatric
  Anxiety	17%	10%
Respiratory, thoracic and mediastinal
  Epistaxis	17%	1%
Renal and urinary
  Increased blood creatinine	16%	10%
  Proteinuria	10%	3%
Gastrointestinal
  Stomatitis	15%	10%
  Proctalgia	6%	1%
  Anal fistula	6%	0%
Reproductive system and breast
  Pelvic pain	14%	8%
Hematology
  Neutropenia	12%	6%
  Lymphopenia	12%	5%

Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Stage III or IV Following Initial Surgical Resection

The safety of bevacizumab was evaluated in GOG-0218, a multicenter, randomized, double-blind, placebo controlled, three arm study, which evaluated the addition of bevacizumab to carboplatin and paclitaxel for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection [see Clinical Studies (14.7)]. Patients were randomized (1:1:1) to carboplatin and paclitaxel without bevacizumab (CPP), carboplatin and paclitaxel with bevacizumab for up to six cycles (CPB15), or carboplatin and paclitaxel with bevacizumab for six cycles followed by bevacizumab as a single agent for up to 16 additional doses (CPB15+). Bevacizumab was given at 15 mg/kg every three weeks. On this trial, 1215 patients received at least one dose of bevacizumab. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3-4 adverse reactions occurring at a higher incidence (2%) in either of the bevacizumab arms versus the control 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%). Adverse reactions are presented in Table 5.

Table 5: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0218

Adverse ReactionNCI-CTC version 3	Bevacizumab with carboplatin and paclitaxel followed by bevacizumab aloneCPB15+ (N=608)	Bevacizumab with carboplatin and paclitaxelCPB15 (N=607)	Carboplatin and paclitaxelCPP (N=602)
General
  Fatigue	80%	72%	73%
Gastrointestinal
  Nausea	58%	53%	51%
  Diarrhea	38%	40%	34%
  Stomatitis	25%	19%	14%
Musculoskeletal and connective tissue
  Arthralgia	41%	33%	35%
  Pain in extremity	25%	19%	17%
  Muscular weakness	15%	13%	9%
Nervous system
  Headache	34%	26%	21%
  Dysarthria	12%	10%	2%
Vascular
  Hypertension	32%	24%	14%
Respiratory, thoracic and mediastinal
  Epistaxis	31%	30%	9%
  Dyspnea	26%	28%	20%
  Nasal mucosal disorder	10%	7%	4%

Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

The safety of bevacizumab was evaluated in 179 patients who received at least one dose of bevacizumab in a multicenter, open-label study (MO22224) in which patients were randomized (1:1) to bevacizumab with chemotherapy or chemotherapy alone in patients with platinum resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within <6 months from the most recent platinum based therapy [see Clinical Studies (14.8)]. Patients were randomized to receive bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks. Patients had received no more than 2 prior chemotherapy regimens. The trial excluded patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Patients were treated until disease progression or unacceptable toxicity. Forty percent of patients on the chemotherapy alone arm received bevacizumab alone upon progression. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in 179 patients receiving bevacizumab with 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%). Adverse reactions are presented in Table 6.

Table 6: Grades 2–4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study MO22224

Adverse ReactionNCI-CTC version 3	Bevacizumab with Chemotherapy(N=179)	Chemotherapy(N=181)
Hematology
  Neutropenia	31%	25%
Vascular
  Hypertension	19%	6%
Nervous system
  Peripheral sensory neuropathy	18%	7%
General
  Mucosal inflammation	13%	6%
Renal and urinary
  Proteinuria	12%	0.6%
Skin and subcutaneous tissue
  Palmar-plantar erythrodysaesthesia	11%	5%
Infections
  Infection	11%	4%
Respiratory, thoracic and mediastinal
  Epistaxis	5%	0%

Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

6.2 Immunogenicity

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.

6.3 Postmarketing Experience

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