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Drug Safety-related Labeling Changes (SrLC)

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AVASTIN (BLA-125085)

(BEVACIZUMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/18/2022 (SUPPL-340)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Infusion-Related Reactions

Newly added reaction:

Anaphylactoid/anaphylactic reactions

10/09/2020 (SUPPL-336)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Surgery and Wound Healing Complications

(Additions and/or revisions underlined)

In a controlled clinical study in which Avastin 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 Avastin and 4% in patients who did not receive Avastin. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who received Avastin and 0.7% in patients who did not receive Avastin [see Adverse Reactions (6.1)].

In patients who experience wound healing complications during Avastin treatment, withhold Avastin 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 AVASTIN after resolution of wound healing complications has not been established [see Dosage and Administration (2.9)].

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Gastrointestinal Perforations and Fistulae: Avastin may increase the risk of developing gastrointestinal perforations and fistulae. Advise patients to immediately contact their health care provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, or vomiting [see Warnings and Precautions (5.1)].

Surgery and Wound Healing Complications: Avastin can increase the risk of wound healing complications. Instruct patients not to undergo surgery without first discussing this potential risk with their healthcare provider [see Warnings and Precautions (5.2)].

Hemorrhage: Avastin can increase the risk of hemorrhage. Advise patients to immediately contact their health care provider for signs and symptoms of serious or unusual bleeding including coughing or spitting blood [see Warnings and Precautions (5.3)].

Arterial and Venous Thromboembolic Events: Avastin increases the risk of arterial and venous thromboembolic events. Advise patients to immediately contact their health care provider for signs and symptoms of arterial or venous thromboembolism [see Warnings and Precautions (5.4, 5.5)].

Hypertension: Avastin can increase blood pressure. Advise patients that they will undergo routine blood pressure monitoring and to contact their healthcare provider if they experience changes in blood pressure [see Warnings and Precautions (5.6)].

Posterior Reversible Leukoencephalopathy Syndrome: Posterior reversible encephalopathy syndrome (PRES) has been associated with Avastin treatment. Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see Warnings and Precautions (5.7)].

Renal Injury and Proteinuria: Avastin increases the risk of proteinuria and renal injury, including nephrotic syndrome. Advise patients that treatment with Avastin requires regular monitoring of renal function and to contact their health care provider for proteinuria or signs and symptoms of nephrotic syndrome [see Warnings and Precautions (5.8)].

Infusion-Related Reactions: Avastin can cause infusion-related reactions. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.9)].

Congestive Heart Failure: Avastin can increase the risk of developing congestive heart failure. Advise patients to contact their healthcare provider immediately for signs and symptoms of CHF [see Warnings and Precautions (5.12)].

Embryo-Fetal Toxicity: Advise female patients that Avastin may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose [see Use in Specific Populations (8.3)].

Ovarian Failure: Avastin may lead to ovarian failure. Advise patients of potential options for preservation of ova prior to starting treatment [see Warnings and Precautions (5.11)].

Lactation: Advise women not to breastfeed during treatment with Avastin and for 6 months after the last dose [see Use in Specific Populations (8.2)].

09/30/2020 (SUPPL-334)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

(Newly added information)

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

05/29/2020 (SUPPL-332)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Hemorrhage

Additions and/or revisions underlined:

An evaluation for the presence of varices is recommended within 6 months of initiation of Avastin in patients with HCC. There is lack of clinical data to support the safety of Avastin in patients with variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding because these patients were excluded from clinical trials of Avastin in HCC [see Clinical Studies (14.10)].

Do not administer Avastin 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… The safety data in Warnings and Precautions and described below reflect exposure to Avastin 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 HCC (IMbrave150) at the recommended dose and schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving Avastin as a single agent or in combination with other anti-cancer therapies at a rate greater than or equal to 10% were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Newly added information following Table 8: Grades 1?5 Adverse Reactions Occurring at Higher Incidence (greater than or equal to 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213:

Hepatocellular Carcinoma (HCC)

The safety of Avastin in combination with atezolizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment [see Clinical Studies (14.10)]. Patients received 1,200 mg of atezolizumab intravenously followed by 15 mg/kg Avastin (n=329) every 3 weeks, or 400 mg of sorafenib (n=156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to Avastin was 6.9 months (range: 0-16 months) and to atezolizumab was 7.4 months (range: 0-16 months).

Fatal adverse reactions occurred in 4.6% of patients in the Avastin and atezolizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%).

Serious adverse reactions occurred in 38% of patients in the Avastin and atezolizumab arm. The most frequent serious adverse reactions (greater than or equal to 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1%).

Adverse reactions leading to discontinuation of Avastin occurred in 15% of patients in the Avastin and atezolizumab arm. The most common adverse reactions leading to Avastin discontinuation were hemorrhages (4.9%), including bleeding varicose vein, hemorrhage and gastrointestinal, subarachnoid, and pulmonary hemorrhages; and increased transaminases or bilirubin (0.9%).

Adverse reactions leading to interruption of Avastin occurred in 46% of patients in the Avastin and atezolizumab arm; the most common (greater than or equal to 2%) were proteinuria (6%); infections (6%); hypertension (6%); liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline phosphatate (4.6%); gastrointestinal hemorrhages (3%); thrombocytopenia/decreased platelet count (4.3%); and pyrexia (2.4%).

Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received Avastin and atezolizumab in IMbrave150.

Newly added tables; please refer to label for complete information:

Table 9: Adverse Reactions Occurring in greater than or equal to 10% of Patients with HCC Receiving Avastin in IMbrave150

Table 10: Laboratory Abnormalities Worsening from Baseline Occurring in greater than or equal to 20% of Patients with HCC Receiving Avastin in IMbrave150

06/20/2019 (SUPPL-331)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

Based on its mechanism of action and findings from animal studies, Avastin 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 Avastin and for 6 months after the last dose.


5.3 Hemorrhage

(Additions and/or revisions underlined)

Avastin 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 Avastin 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 Avastin.


5.7 Posterior Reversible Encephalopathy Syndrome

(Additions and/or revisions underlined)

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.


6 Adverse Reactions

6 ADVERSE REACTIONS

(Additions and/or revisions underlined):

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

·       Infusion-Related Reactions


6.1 Clinical Trials Experience

(Extensive Revisions; please refer to label for complete information)


6.2 Immunogenicity

(Additions and/or revisions underlined)

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 to bevacizumab in the studies described below with the incidence of antibodies in other studies or to other bevacizumab products may be misleading.


8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

Based on findings from animal studies and its mechanism of action, Avastin may cause fetal harm in pregnant women. Limited postmarketing reports describe cases of fetal malformations with use of Avastin in pregnancy; however, these reports are insufficient to determine drug- associated risks…


8.4 Pediatric Use

(Additions and/or revisions underlined)

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.


Juvenile Animal Toxicity Data

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.


17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Lactation: Advise women not to breastfeed during treatment with Avastin and for 6 months after the last dose.


06/13/2018 (SUPPL-323)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trial Experience

(Additions and/or revisions are underlined)

The safety data below reflect exposure to Avastin in 4134 patients with mCRC, non-squamous NSCLC, glioblastoma, mRCC, cervical cancer, and epithelial ovarian, fallopian tube, or primary peritoneal cancer, including controlled studies (AVF2107g, E3200, E4599, EORTC 26101, BO17705, GOG-0240, MO22224, AVF4095, GOG -0213, and GOG-0218) at the recommended dose and schedule for a median of 6 to 23 doses.

Across clinical studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions.

Stage III or IV Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer Following Initial Surgical Resection

GOG-0218 was a multicenter, randomized, double-blind, placebo controlled, three arm study evaluating the addition of Avastin 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. Patients were randomized (1:1:1) to be treated with carboplatin and paclitaxel without Avastin (CPP), carboplatin and paclitaxel with Avastin for up to six cycles (CPB15), or carboplatin and paclitaxel with Avastin for six cycles followed by Avastin as a single agent for up to 16 additional doses (CPB15+). Avastin was given at 15 mg/kg every three weeks. On this trial, 1215 patients received at least one dose of Avastin. The demographics of the safety population were similar to the demographics of the efficacy population. Adverse reactions are presented in Table 2.

Table 2: Grade 1-5 Adverse Reactions Occuring at Higher Incidence ( greater than or equal to 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0218.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Antitumor activity was not observed among eight pediatric patients with relapsed glioblastoma receiving bevacizumab and irinotecan. Addition of Avastin to standard of care did not result in improved event-free survival in pediatric patients enrolled in two randomized clinical trials, 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 patients with cancer (7 months to 21 years of age), bevacizumab clearance normalized by body weight in pediatrics was comparable to that in adults.

04/30/2018 (SUPPL-324)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness of Avastin 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 have received Avastin. Avastin is not approved for use in patients under the age of 18 years.

Antitumor activity was not observed among eight pediatric patients with relapsed glioblastoma who received bevacizumab and irinotecan. Addition of Avastin to standard of care did not result in improved event-free survival in pediatric patients enrolled in two randomized clinical trials, 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 patients with cancer (7 months to 21 years of age), bevacizumab clearance normalized by body weight in pediatrics was comparable to that in adults.

 …

12/05/2017 (SUPPL-319)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Gastrointestinal Perforations: The incidence of gastrointestinal perforation, some fatal, in patients receiving Avastin ranges from 0.3% to 3%. Discontinue Avastin in patients who develop gastrointestinal perforation Surgery and Wound Healing Complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in patients receiving Avastin. Discontinue Avastin in patients who develop wound healing complications that require medical intervention. Withhold Avastin at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery, and until the wound is fully healed.

Hemorrhages: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with a recent history of hemoptysis. Discontinue in patients who develop Grade 3-4 hemorrhage.

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Gastrointestinal Perforations and Fistulae

Serious and sometimes fatal gastrointestinal perforation occur at a higher incidence in patients receiving Avastin 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.

Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occur at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. The incidence ranged from less than 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 use of Avastin 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.

5.2 Surgery and Wound Healing Complications

In a controlled clinical study in which Avastin 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 Avastin and 4% in patients who did not receive Avastin. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who received Avastin and 0.7% in patients who did not receive Avastin.

Discontinue Avastin in patients with wound healing complications requiring medical intervention. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following surgery and until the wound is fully healed.

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

5.3 Hemorrhage

Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases, fatal hemorrhage. 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 Avastin compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-5 hemorrhagic events among ranged from 0.4% to 7% in patients receiving Avastin.

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

Do not administer Avastin to patients with recent history of hemoptysis of greater than or equal to 1/2 teaspoon or more of red blood. Discontinue Avastin in patients who develop a Grade 3-4 hemorrhage.

5.4 Arterial 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 Avastin compared to patients receiving chemotherapy. Across clinical studies, the incidence of Grades 3-5 ATE was 5% in patients receiving Avastin with chemotherapy compared to less than or equal 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 greater than 65 years old. Discontinue in patients who develop a severe ATE. The safety of reinitiating Avastin after an ATE is resolved is not known.

5.5 Venous Thromboembolic Events

An increased risk of venous thromboembolic events (VTEF) was observed across clinical studies. In Study GOG-0240, Grade 3-4 VTE was reported in 11% of patients receiving Avastin with chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the incidence of Grade 3-4 VTE was 5% in patients receiving Avastin with chemotherapy compared to 2% in patients receiving chemotherapy alone.

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

5.6 Hypertension

The incidence of severe hypertension is increased in patients receiving Avastin as compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grade 3-4 hypertension ranged from 5% to 18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuing Avastin. Withhold Avastin 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.

5.7 Posterior Reversible Encephalopathy Syndrome (PRES)

PRES was reported in less than 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 Avastin in patients who develop PRES. Symptoms usually resolve or improve within days after discontinuing Avastin, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin in patients who developed PRES is not known.

5.8 Renal Injury and Proteinuria

The incidence and severity of proteinuria is higher in patients receiving Avastin as compared to patients receiving chemotherapy. Grade 3 (defined as urine dipstick 4+ or greater than 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 Avastin. 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 Avastin in 30% of the patients who developed proteinuria.

In an exploratory, pooled analysis of patients from seven randomized clinical studies, 5% of patients receiving Avastin with chemotherapy experienced Grades 2-4 (defined as urine dipstick 2+ or greater or greater than 1 gram of protein per 24 hours or nephrotic syndrome) proteinuria. Grades 2-4 proteinuria resolved in 74% of patients. Avastin was reinitiated in 42% of patients. Of the 113 patients who reinitiated Avastin, 48% experienced a second episode of Grade 2-4 proteinuria.

Nephrotic syndrome occurred in less than 1% of patients receiving Avastin 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 Avastin 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 Avastin. Serum creatinine levels did not return to baseline in approximately one-third of patients who received Avastin.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 plus 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)].

5.9 Infusion Reactions

Infusion reactions reported across clinical studies and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose occurred in less than 3% of patients and severe reactions occurred in 0.2% of patients.

Decrease the rate of infusion for mild, clinically insignificant infusion reactions. Interrupt the infusion in patients with clinically significant infusion reactions and consider resuming at a slower rate following resolution. Discontinue in patients who develop a severe infusion reaction and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen).

5.11 Ovarian Failure

The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone for adjuvant treatment of a solid tumor. After discontinuing Avastin, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% of women receiving Avastin. Recovery of ovarian function is defined as resumption of menses, a positive serum ?-HCG pregnancy test, or a FSH level less than 30 mIU/mL during the post-treatment period. Long-term effects of Avastin on fertility are unknown. Inform females of reproductive potential of the risk of ovarian failure prior to initiating Avastin.

Newly added subsection:

5.12 Congestive Heart Failure (CHF)

Avastin is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade greater than or equal to 3 left ventricular dysfunction was 1% in patients receiving Avastin 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 Avastin 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 Avastin 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 greater than or equal to 20% or a decline from baseline of 10% to less than 50%, was 10% in patients receiving Avastin 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 Avastin arm compared to 82% in the placebo arm. Discontinue Avastin in patients who develop CHF.

 

6 Adverse Reactions

Additions and/or revisions underlined:

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

  • Renal Injury and Proteinuria

  • Congestive Heart Failure

6.1 Clinical Trial Experience

The most common adverse reactions observed in patients receiving Avastin as a single agent or in combination with chemotherapy at a rate greater than 10%, are epistaxis, headache …

… The safety data below reflect exposure to Avastin in 2919 patients with mCRC, non-squamous NSCLC, glioblastoma, mRCC, cervical cancer, platinum-resistant or platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, including controlled studies (AVF2107g, E3200, E4599, EORTC 26101, BO17705, GOG-0240, MO22224, AVF4095, GOG-0213) at the recommended dose and schedule for a median of 6 to 23 doses.

Across clinical studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions.

Platinum-Resistant Recurrent Epithelia Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: The safety of Avastin was evaluated in 179 patients who received at least one dose of Avastin in a multicenter, open-label study (MO22224) in which patients were randomized (1:1) to Avastin with chemotherapy or chemotherapy alone in patients with platinum resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within less than 6 months from the most recent platinum based therapy. Patients were randomized to receive Avastin (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 Avastin alone upon progression. The demographics of the safety population were similar to the demographics of the efficacy population. Adverse reactions are presented in Table 2.

Table 2: Grade 2?4 Adverse Reactions Occurring at Higher Incidence (greater than or equal to 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study MO22224; See label for complete information.

Grade 3-4 adverse reactions occurring at a higher incidence (greater than or equal to 2%) in 179 patients receiving Avastin 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%). Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer The safety of Avastin was evaluated in 247 patients who received at least one dose of Avastin in a double-blind study (AVF4095g) in patients with platinum sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Patients were randomized (1:1) to receive Avastin (15 mg/kg) or placebo every 3 weeks with carboplatin and gemcitabine for 6 to 10 cycles followed by Avastin or placebo alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Adverse reactions are presented in Table 3.

Table 3: Grade 1?5 Adverse Reactions Occurring at a Higher Incidence (greater than or equal to 5%) in Patients Receiving Avastin with Chemotherapy vs. Placebo with Chemotherapy in Study AVF4095g See label for complete information.

Grade 3-4 adverse reactions occurring at a higher incidence (greater than or equal to 2%) in patients receiving Avastin with chemotherapy compared to placebo with chemotherapy were: thrombocytopenia (40% vs. 34%), nausea (4% vs. 1.3%), fatigue (6% vs. 4%), headache (4% vs. 0.9%), proteinuria (10% vs. 0.4%), dyspnea (4% vs. 1.7%), epistaxis (5% vs. 0.4%), and hypertension (17% vs. 0.9%).

The safety of Avastin was evaluated in an open-label, controlled study, GOG-0213, in 325 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy. Patients were randomized (1:1) to receive carboplatin and paclitaxel for 6 to 8 cycles or Avastin (15 mg/kg every 3 weeks) with carboplatin and paclitaxel for 6 to 8 cycles followed by Avastin as a single agent until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Adverse reactions are presented in Table 4.

 

Table 4: Grade 1?5 Adverse Reactions Occurring at Higher Incidence (greater than or equal to 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213; See label for complete information.

Grade 3-4 adverse reactions occurring at a higher incidence (greater than or equal to 2%) in patients receiving Avastin with chemotherapy compared to chemotherapy alone were: hypertension (11% vs. 0.6%), fatigue (8% vs. 3%), febrile neutropenia (6% vs. 3%), proteinuria (8% vs. 0%), abdominal pain (6% vs. .94 n%), hyponatremia (4% vs. 0.9%), headache (3% vs. 0.9%), and pain in extremity (3% vs. 0%).

Metastatic Renal Cell Carcinoma (mRCC)

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

Grade 3-5 adverse reactions occurring at a higher incidence (greater than 2%) were fatigue ... Adverse reactions are presented in Table 5.

Grades 1-5 Adverse Reactions Occurring at Higher Incidence (greater than or equal to 5%) of Patients Receiving Avastin vs. Placebo with Interferon Alfa in Study BO17705

The following adverse reactions were reported at a 5-fold greater incidence in patients receiving Avastin with interferon-alfa compared to patients receiving placebo with interferon-alfa and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient)

Persistent, Recurrent, or Metastatic Cervical Cancer

The safety of Avastin was evaluated in 218 patients who received at least one dose of Avastin in a multicenter study (GOG-0240) in patients with persistent, recurrent, or metastatic cervical cancer. Patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without Avastin (15 mg/kg every 3 weeks), or paclitaxel and topotecan with or without Avastin (15 mg/kg every 3 weeks). The demographics of the safety population were similar to the demographics of the efficacy population. Adverse reactions are presented in Table 6.

Table 6: Grades 1-4 Adverse Reactions Occurring at Higher Incidence (greater than or equal to 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240 See label for complete information.

Grade 3-4 adverse reactions occurring at a higher incidence (greater than or equal to 2%) in 218 patients receiving Avastin 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%).

Metastatic Colorectal Cancer (mCRC)

The safety of Avastin was evaluated in 392 patients who received at least one dose of Avastin in a double-blind, active-controlled study (AVF2107g), which compared Avastin (5 mg/kg every 2 weeks) with bolus-IFL to placebo with bolus IFL in patients with mCRC. Patients were randomized (1:1:1) to placebo with bolus IFL, Avastin with bolus IFL, or Avastin with 5 fluorouracil and leucovorin. The demographics of the safety population were similar to the demographics of the efficacy population.

All Grade 3-4 adverse reactions and selected Grade 1-2 adverse reactions (i.e., hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Adverse reactions are presented in Table 7.

Table 7: Grade 3-4 Adverse Reactions (Occurring at Higher Incidence (greater than or equal to 2%) in Patients Receiving Avastin vs. Placebo in Study AVF2107g Please refer to label for complete information.

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

The demographics of the safety population were similar to the demographics of the efficacy population. The most frequent adverse reactions (selected Grade 3-5 non-hematologic and Grade 4-5 hematologic) occurring at a higher incidence (greater than or equal to 2%) in patients receiving Avastin 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 event rates due to the reporting mechanisms.

First-Line Non Squamous Non Small Cell Lung Cancer (NSCLC)

The safety of Avastin was evaluated as first-line treatment in 422 patients with unresectable NSCLC who received at least one dose of Avastin in an active-controlled, open-label, multicenter trial (E4599). 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 Avastin (15 mg/kg every 3 weeks). After completion or upon discontinuation of chemotherapy, patients randomized to receive Avastin continued to receive Avastin 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 Grade 3-5 non hematologic and Grade 4-5 hematologic adverse reactions were collected. Grade 3-5 non hematologic and Grade 4-5 hematologic adverse reactions occurring at a higher incidence (greater than or equal to 2%) in patients receiving Avastin 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 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

EORTC 26101 was a multicenter, randomized, open-label study in patients with recurrent GBM following radiotherapy and temozolomide of whom 278 patients received at least one dose of Avastin and are considered safety evaluable. Patients were randomized (2:1) to receive Avastin (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 Avastin with lomustine arm, 22% of patients discontinued treatment due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving Avastin with lomustine, the adverse reaction profile was similar to that observed in other approved indications.

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 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 to bevacizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2323) 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

Addition of the following:

Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia

7 Drug Interactions

Additions and/or revisions underlined:

No clinically meaningful effect on the pharmacokinetics of irinotecan or its active metabolite SN38I, interferon alfa, carboplatin or paclitaxel was observed when Avastin was administered in combination with these drugs; however, 3 of the 8 patients receiving Avastin with paclitaxel and carboplatin had lower paclitaxel exposure after four cycles of treatment (at Day 63) …

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

Data

Animal Data

Pregnant rabbits dosed with 10 mg/kg to 100 mg/kg bevacizumab (approximately 1 to 10 times the clinical dose of 10 mg/kg) every three days during the period of organogenesis (gestation day 6-18) exhibited decreases in maternal and fetal body weights and increased number of fetal resorptions. There were dose-related increases in the number of litters containing fetuses with any type of malformation (42% for the 0 mg/kg dose, 76% for the 30 mg/kg dose, and 95% for the 100 mg/kg dose) or fetal alterations (9% for the 0 mg/kg dose, 15% for the 30 mg/kg dose, and 61% for the 100 mg/kg dose).

8.2 Lactation

Risk Summary

… Because of the potential for serious adverse reactions in breastfed infants from bevacizumab, advise women not to breastfeed during treatment with Avastin and for 6 months following the final dose.

8.3 Females and Males of Reproductive Potential

Infertility

Females

In a clinical study of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in patients who received Avastin with chemotherapy (34%) compared patients who received chemotherapy alone (2%). After discontinuing Avastin with chemotherapy,

8.5 Geriatric Use

In an exploratory, pooled analysis of 1745 patients from five randomized, controlled studies, 35%

patients were greater than or equal to 65 years old. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age; however, the increase in the incidence of ATE was greater in

patients greater than or equal to 65 years (8% vs. 3%) as compared to patients less than 65 years (2% vs. 1%)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Gastrointestinal Perforations and Fistulae: Avastin may increase the risk of developing gastrointestinal perforations and fistulae. Advise patients to immediately contact their health care provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, or vomiting.

Surgery and Wound Healing Complications: Avastin can increase the risk of wound healing complications. Advise patients that Avastin should not be used for at least 28 days before or after surgery and until surgical wounds are fully healed.

Hemorrhage: Avastin can increase the risk of hemorrhage. Advise patients to immediately contact their health care provider for signs and symptoms of serious or unusual bleeding including coughing or spitting blood.

Arterial and Venous Thromboembolism: Avastin increases the risk of arterial and venous thromboembolic events. Advise patients to immediately contact their health care provider for signs and symptoms of arterial or venous thromboembolism.

Hypertension: Avastin can increase blood pressure. Advise patients that they will undergo routine blood pressure monitoring and to contact their healthcare provider if they experience changes in blood pressure.

Posterior Reversible Leukoencephalopathy Syndrome: Posterior reversible encephalopathy syndrome (PRES) has been associated with Avastin treatment. Advise patients to immediately contact their health care provider for new onset or worsening neurological function.

Renal Injury and Proteinuria: Avastin increases the risk of proteinuria and renal injury, including nephrotic syndrome. Advise patients that treatment with Avastin requires regular monitoring of renal function and to contact their health care provider for proteinuria or signs and symptoms of nephrotic syndrome.

Infusion Reactions: Avastin can cause infusion reactions. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions.

Congestive Heart Failure: Avastin can increase the risk of developing congestive heart failure. Advise patients to contact their healthcare provider immediately for signs and symptoms of CHF.

Embryo-Fetal Toxicity: Advise female patients that Avastin may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin.

Ovarian Failure: Avastin may lead to ovarian failure. Advise patients of potential options for preservation of ova prior to starting treatment.

Lactation: Advise lactating women not to breastfeed while taking Avastin or within 6 months following their last dose of treatment.

12/06/2016 (SUPPL-317)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trial Experience

…The data below reflect exposure to Avastin in more than 5500 patients with CRC, non-squamous NSCLC, glioblastoma, mRCC, cervical cancer, platinum-resistant or platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, including controlled (Studies 1, 2, 4, , 9, 10, 11, and 12) or …

                                                                                       

The population included … 179 platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who received a median of 6 doses of Avastin, and 572 platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who received a median of  between 12 and 16 doses of Avastin …

Congestive Heart Failure (CHF)

Ovarian Failure

Persistent, Recurrent, or Metastatic Carcinoma of the Cervix

Epsilon replaces greater than or equal to in these sections.

 

Persistent, Recurrent, or Metastatic Carcinoma of the Cervix

There were no Grade 5 events occurring at a higher incidence in (epsilon 2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone … Additional information: Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with carboplatin and gemcitabine, followed by Avastin as a single agent.

Adverse events occuring in a randomized, double-blinded study (Study 11) of chemotherapy compared to Avastin plus chemotherapy are presented in Table 6.

Table 6: Grade 1?5 Adverse Events in Study 11 (Occurring at Higher Incidence [epsilon 5%] in Chemo plus Avastin vs. Chemo plus Placebo) (newly added table; please refer to label)

Grade 3 or 4 adverse events occurring at a higher incidence (epsilon 2%) in 247 patients treated with Avastin plus chemotherapy compared to 233 patients treated with placebo plus chemotherapy were thrombocytopenia (40.1% vs. 33.9%), nausea (4.5% vs. 1.3%), fatigue (6.5% vs. 4.3%), headache (3.6% vs. 0.9%), proteinuria (9.7% vs. 0.4%), dyspnea (4.5% vs. 1.7%), epistaxis (4.9% vs. 0.4%), and hypertension (17.0% vs. 0.9%). Grade epsilon 3 Anemia (16.2% vs. 18.9%) and decreased white blood cell count (1.6% vs. 4.3%) occurred with a epsilon 2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. There were no Grade 5 adverse events occurring at a higher incidence (epsilon 2%) for the Avastin plus chemotherapy arm compared to the placebo plus chemotherapy arm.

Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with carboplatin and paclitaxel, followed by Avastin as a single agent.

Adverse events occurring in a randomized, open-label study, Study 12, of chemotherapy compared to Avastin plus chemotherapy, are presented in Table 7.

Table 7: Grade 1?5 Adverse Events in Study 12 (Occurring at Higher Incidence [epsilon 5%] in Chemo plus Avastin vs. Chemo Alone) (newly added table; please refer to label)

Grade 3 or 4 adverse events occurring at a higher incidence (epsilon 2%) in 325 patients treated with Avastin plus chemotherapy compared to 332 patients treated with chemotherapy alone were hypertension (11.1% vs. 0.6%), fatigue (7.7% vs. 2.7%), febrile neutropenia (6.2% vs. 2.7%), proteinuria (8% vs. 0%), abdominal pain (5.8% vs. 0.9%), hyponatremia (3.7% vs. 0.9%), headache (3.1% vs. 0.9%), and pain in extremity (3.4% vs. 0%). No Grade epsilon 3 adverse events occurred with a epsilon 2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. There were no Grade 5 adverse events occurring at a higher incidence (epsilon 2%) in the Avastin plus chemotherapy arm compared to the chemotherapy alone arm.

8 Use in Specific Populations

8.5 Geriatric Use

Epsilon replaces greater than or equal to in this section