Avastin: Package Insert and Label Information (Page 2 of 6)

5.7 Posterior 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 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 was higher in patients receiving Avastin 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 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 [see Adverse Reactions (6.1)].

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 > 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 Grades 2-4 proteinuria.

Nephrotic syndrome occurred in < 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+ 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-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, 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 0.2% 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).

5.10 Embryo-Fetal Toxicity

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 [see Use in Specific Populations (8.1, 8.3)].

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 β-HCG pregnancy test, or an FSH level < 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 [see Adverse Reactions (6.1), Use in Specific Populations (8.3)].

5.12 Congestive Heart Failure (CHF)

Avastin is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade ≥ 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 ≥ 20% or a decline from baseline of 10% to < 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

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

6.1 Clinical 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 Avastin in 4134 patients including those with mCRC (AVF2107g, E3200), non-squamous NSCLC (E4599), GBM (EORTC 26101), mRCC (BO17705), cervical cancer (GOG-0240), and epithelial ovarian, fallopian tube, or primary peritoneal cancer (MO22224, AVF4095, GOG-0213, and GOG-0218) 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 chemotherapy at a rate > 10% were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across clinical studies, Avastin 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 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 [see Clinical Studies (14.1)]. Patients were randomized (1:1:1) to placebo with bolus-IFL, Avastin with bolus-IFL, or Avastin 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 Avastin vs. Placebo in Study AVF2107g
Adverse Reaction * Avastin with IFL (N=392) Placebo with IFL(N=396)
*
NCI-CTC version 3
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 Avastin 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, 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.

Selected Grades 3–5 non-hematologic and Grades 4–5 hematologic occurring at a higher incidence (≥ 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 reaction rates due to the reporting mechanisms.

First-Line Non Squamous Non-Small Cell Lung Cancer

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) [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 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 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 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 (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 Avastin 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 Avastin and are considered safety evaluable [see Clinical Studies (14.4)]. 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.

Metastatic Renal Cell Carcinoma

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 mRCC. 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 [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 Avastin vs. Placebo with Interferon Alfa in Study BO17705
Adverse Reaction * Avastin with Interferon Alfa(N=337) Placebo with Interferon Alfa(N=304)
*
NCI-CTC version 3
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 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); 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 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[see Clinical Studies (14.6)]. 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.

Grades 3-4 adverse reactions occurring at a higher incidence (≥ 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%). Adverse reactions are presented in Table 4.

Table 4: Grades 1-4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240
Adverse Reaction * Avastin with Chemotherapy(N=218) Chemotherapy(N=222)
*
NCI-CTC version 3
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 Avastin was evaluated in GOG-0218, a multicenter, randomized, double-blind, placebo controlled, three arm study, which evaluated 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 [see Clinical Studies (14.7)]. Patients were randomized (1:1:1) to 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.

Grades 3-4 adverse reactions occurring at a higher incidence (≥2%) in either of the Avastin 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 Avastin with Chemotherapy vs. Chemotherapy Alone in GOG-0218
Adverse Reaction * Avastin with carboplatin and paclitaxel followed by Avastin alone (N=608) Avastin with carboplatin and paclitaxel (N= 607) Carboplatin and paclitaxel §(N= 602)
*
NCI-CTC version 3,
CPB15+,
CPB15,
§
CPP
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 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 < 6 months from the most recent platinum based therapy [see Clinical Studies (14.8)]. 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.

Grades 3-4 adverse reactions occurring at a higher incidence ( ≥ 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%).

Adverse reactions are presented in Table 6.

Table 6: Grades 2–4 Adverse Reactions Occurring at Higher Incidence ( ≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study MO22224
Adverse Reaction * Avastin with Chemotherapy(N=179) Chemotherapy(N=181)
*
NCI-CTC version 3
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

Study AVF4095g

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 [see Clinical Studies (14.9]. 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.

Grades 3-4 adverse reactions occurring at a higher incidence (≥ 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%). Adverse reactions are presented in Table 7.

Table 7: Grades 1–5 Adverse Reactions Occurring at a Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Placebo with Chemotherapy in Study AVF4095g
Adverse Reaction * Avastin with Carboplatin and Gemcitabine(N=247) Placebo with Carboplatin and Gemcitabine(N=233)
*
NCI-CTC version 3
General
Fatigue 82% 75%
Mucosal inflammation 15% 10%
Gastrointestinal
Nausea 72% 66%
Diarrhea 38% 29%
Stomatitis 15% 7%
Hemorrhoids 8% 3%
Gingival bleeding 7% 0%
Hematology
Thrombocytopenia 58% 51%
Respiratory, thoracic and mediastinal
Epistaxis 55% 14%
Dyspnea 30% 24%
Cough 26% 18%
Oropharyngeal pain 16% 10%
Dysphonia 13% 3%
Rhinorrhea 10% 4%
Sinus congestion 8% 2%
Nervous system
Headache 49% 30%
Dizziness 23% 17%
Vascular
Hypertension 42% 9%
Musculoskeletal and connective tissue
Arthralgia 28% 19%
Back pain 21% 13%
Psychiatric
Insomnia 21% 15%
Renal and urinary
Proteinuria 20% 3%
Injury and procedural
Contusion 17% 9%
Infections
Sinusitis 15% 9%

Study GOG-0213

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[see Clinical Studies (14.9)]. 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.

Grades 3-4 adverse reactions occurring at a higher incidence (≥ 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. 0.9%), hyponatremia (4% vs. 0.9%), headache (3% vs. 0.9%), and pain in extremity (3% vs. 0%).

Adverse reactions are presented in Table 8.

Table 8: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213
Adverse Reaction * Avastin with Carboplatin and Paclitaxel(N=325) Carboplatin and Paclitaxel(N=332)
*
NCI-CTC version 3
Musculoskeletal and connective tissue
Arthralgia 45% 30%
Myalgia 29% 18%
Pain in extremity 25% 14%
Back pain 17% 10%
Muscular weakness 13% 8%
Neck pain 9% 0%
Vascular
Hypertension 42% 3%
Gastrointestinal
Diarrhea 39% 32%
Abdominal pain 33% 28%
Vomiting 33% 25%
Stomatitis 33% 16%
Nervous system
Headache 38% 20%
Dysarthria 14% 2%
Dizziness 13% 8%
Metabolism and nutrition
Decreased appetite 35% 25%
Hyperglycemia 31% 24%
Hypomagnesemia 27% 17%
Hyponatremia 17% 6%
Weight loss 15% 4%
Hypocalcemia 12% 5%
Hypoalbuminemia 11% 6%
Hyperkalemia 9% 3%
Respiratory, thoracic and mediastinal
Epistaxis 33% 2%
Dyspnea 30% 25%
Cough 30% 17%
Rhinitis allergic 17% 4%
Nasal mucosal disorder 14% 3%
Skin and subcutaneous tissue
Exfoliative rash 23% 16%
Nail disorder 10% 2%
Dry skin 7% 2%
Renal and urinary
Proteinuria 17% 1%
Increased blood creatinine 13% 5%
Hepatic
Increased aspartate aminotransferase 15% 9%
General
Chest pain 8% 2%
Infections
Sinusitis 7% 2%

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