Avastin safety profile

Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions.

Gastrointestinal (GI) perforations and fistulae (see Boxed WARNINGS in full Prescribing Information)

  • Serious, and sometimes fatal, GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation, some fatal, in Avastin-treated patients range from 0.3% to 3.2% across clinical trials  
  • From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer, GI perforations were reported in 3.2% of Avastin-treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of Avastin-treated patients
  • In a platinum-resistant ovarian cancer trial, the incidence of GI perforation was 1.7% (3/179). In this trial, patients who had evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded
  • The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin
  • 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. Permanently discontinue Avastin in patients with GI perforation
  • In Avastin clinical trials, GI fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer. In a cervical cancer trial, the incidence of GI vaginal fistulae was 8.3% in Avastin-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies
  • Discontinue Avastin in patients with GI perforations (GI perforation, fistula formation in the GI tract, intra-abdominal abscess)

Non-gastrointestinal fistulae (Warnings and Precautions)

  • Serious and sometimes fatal fistula formation involving tracheo esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls  
  • Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in postmarketing experience. Most events occurred within the first 6 months of Avastin therapy
  • From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer, 1.8% of Avastin treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, vesical, or female genital tract fistulae     
  • Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any grade 4 fistula
  • Discontinue Avastin in patients with fistula formation involving an internal organ

Surgery and wound healing complications (see Boxed WARNINGS in full Prescribing Information)

  • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • In a controlled clinical trial in MCRC patients who underwent surgery, the incidence of wound healing complications, including serious and fatal complications, was 15% vs 4% in patients who did not receive Avastin
  • Avastin therapy should not be initiated for at least 28 days following major surgery. The surgical incision should be fully healed prior to initiation of Avastin
  • The appropriate interval between discontinuation of Avastin and subsequent elective surgery required to reduce the risk of impaired wound healing/wound dehiscence has not been determined. The calculated half-life of Avastin (~20 days; range 11–50 days) should be taken into consideration. Suspend Avastin for at least 28 days prior to elective surgery
  • Discontinue Avastin in patients with wound dehiscence and wound healing complications requiring medical intervention
  • Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin in patients who develop necrotizing fasciitis

Hemorrhage (see Boxed WARNINGS in full Prescribing Information)

  • Avastin can result in 2 distinct patterns of bleeding: minor hemorrhage, most commonly grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events
  • Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9%
  • Serious or fatal pulmonary hemorrhage occurred in 4 of 13 (31%) patients with squamous cell histology and 2 of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone
  • In clinical studies in non-small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic grade 2 CNS hemorrhage was documented in 1 of 83 Avastin-treated patients (rate 1.2%, 95% CI, 0.06%–5.93%)
  • Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; 2 patients had grade 3–4 hemorrhage
  • Do not administer Avastin to patients with recent hemoptysis (≥1/2 tsp of red blood)
  • Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Arterial thromboembolic events (ATEs) (Warnings and Precautions)

  • Serious, and sometimes fatal, ATEs, including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATEs, occurred at a higher incidence in patients receiving Avastin compared to the control arms
  • Across indications, the incidence of grade ≥3 ATEs in the Avastin-containing arms was 2.6% compared to 0.8% in the control arms
  • Among patients receiving Avastin in combination with chemotherapy, the risk of developing an ATE during therapy was increased in patients with a history of ATE, diabetes, or age greater than 65 years
  • Permanently discontinue Avastin in patients who experience a severe ATE. The safety of resumption of Avastin therapy after resolution of an ATE has not been studied

Venous thromboembolism (Warnings and Precautions)

  • Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE)
  • From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer, grade ≥3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone 
  • Permanently discontinue Avastin in patients with life threatening (grade 4) VTE, including pulmonary embolism

Hypertension (Warnings and Precautions)

  • The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies, the incidence of grade 3 or 4 hypertension ranged from 5% to 18%
  • Blood pressure monitoring should be conducted every 2 to 3 weeks during treatment. Treat with antihypertensive therapy and monitor blood pressure regularly
  • Patients with Avastin-induced or -exacerbated hypertension who discontinue Avastin should continue to have their blood pressure monitored at regular intervals
  • Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management

Posterior reversible encephalopathy syndrome (PRES) (Warnings and Precautions)

  • PRES has been reported with an incidence of <0.5% in clinical studies 
  • 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 (MRI) is necessary to confirm the diagnosis of PRES
  • The onset of symptoms has been reported to occur from 16 hours to 1 year after initiation of Avastin
  • Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin in patients previously experiencing PRES is unknown

Proteinuria (Warnings and Precautions)

  • The incidence and severity of proteinuria are increased in patients receiving Avastin compared to controls
  • Grade 3 and 4 proteinuria ranged from 0.7% to 7.4% across clinical trials
    • The overall incidence of proteinuria (all grades) was only adequately assessed in mRCC, in which the incidence was 20%
    • In mRCC, median onset of proteinuria was 5.6 months (range 15 days to 37 months) and median time to resolution was 6.1 months (95% CI, 2.8 months–11.3 months). Proteinuria did not resolve in 40% of patients after median follow-up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria 
  • Nephrotic syndrome occurred in <1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome
  • In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy
  • Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection
  • Suspend Avastin administration for ≥2 grams of proteinuria/24 hours and resume when proteinuria is <2 g/24 hours
  • Discontinue Avastin in patients with nephrotic syndrome

Infusion reactions (Warnings and Precautions)

  • In clinical studies, infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
  • Infusion reactions in clinical trials and in postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis  
  • Avastin infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered

Embryo-fetal toxicity (Warnings and Precautions)

  • Avastin may cause fetal harm based on the drug’s mechanism of action and findings from animal studies. Limited postmarketing reports describe cases of fetal malformations with use of Avastin in pregnancy; however, these reports are insufficient to determine drug associated risks
  • 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 VEGF Receptor 2 (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 and for 6 months after the last dose of Avastin

Ovarian failure/fertility (Warnings and Precautions, Use in Specific Populations)

  • Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long-term effects of Avastin exposure on fertility are unknown
  • The incidence of ovarian failure was higher (34% vs 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone as adjuvant treatment for colorectal cancer, a use for which Avastin is not approved 

Nursing mothers (Use in Specific Populations)

  • No data are available regarding the presence of bevacizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts  
  • Because of the potential for serious adverse reactions in breastfed infants from bevacizumab, advise a nursing woman that breastfeeding is not recommended during treatment with Avastin

Most common adverse events

  • Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were

— Epistaxis
— Headache
— Hypertension
— Rhinitis

— Proteinuria
— Taste alteration
— Dry skin
— Rectal hemorrhage

— Lacrimation disorder
— Back pain
— Exfoliative dermatitis

  • Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

NSCLC Study Adverse Events

mRCC Study Adverse Events

CC Study Adverse Events

prOC Study Adverse Events

rGBM Study Adverse Events

Proteinuria: Monitoring and managing with Avastin

Incidence of proteinuria in Avastin clinical trials

  • The incidence and severity of proteinuria are increased in patients receiving Avastin [1]
  • In Studies 1, 2, 4, 5, 8 and 10, the incidence of grade 3 and 4 proteinuria, characterized as urine protein levels >3.5 g/24 hours, ranged from 0.7% to 7.4% in Avastin-treated patients [1,10,11]
  • Across clinical trials, nephrotic syndrome occurred in <1% of patients receiving Avastin, in some instances with fatal outcome [1]
  • In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy [1]

Monitoring and managing proteinuria with Avastin [1]

  • Patients receiving Avastin should be monitored for the development or worsening of proteinuria using serial urinalyses
  • Data from a postmarketing safety study showed poor correlation between urine protein/creatinine ratio and 24-hour urine protein level
  • Patients with a 2+ or greater urine dipstick reading should undergo further assessment with 24-hour urine collection
  • Suspend Avastin administration for urine protein levels ≥2 g/24 hours and resume when the protein level is <2 g/24 hours
  • Avastin should be temporarily suspended in patients with moderate to severe proteinuria
  • Patients with moderate to severe proteinuria based on 24-hour collections should be monitored regularly until improvement and/or resolution is observed
  • Discontinue Avastin in patients with nephrotic syndrome

Proteinuria: Monitoring and managing with Avastin [1]

Monitoring and Managing Proteinuria While Taking Avastin

Hypertension: Monitoring and managing with Avastin

Incidence of hypertension in Avastin clinical trials [1,4]

Tumor type Study Grade Regimen Incidence (%)
MCRC* First-line Study 2107 3–4 Avastin + IFL 12
Placebo + IFL 2
Second-line Avastin-naive
Study E3200
3–5 Avastin + FOLFOX4 9
FOLFOX4 alone 2
NSCLC First-line Study E4599 3–5 Avastin + PC 8
PC alone 0.7
mRCC AVOREN study 3–5 Avastin + IFN 6
Placebo + IFN 1
CC GOG 240 study 3–4 Avastin + chemotherapy 11.5
Chemotherapy alone 0.5
prOC AURELIA study 3–4 Avastin + chemotherapy§ 6.7
Chemotherapy§ alone 1.1
2–4 Avastin + chemotherapy§ 19
Chemotherapy§ alone 5.5
rGBM BRAIN study 3–5 Avastin alone 8
Avastin alone or Avastin + irinotecan|| 5

MCRC=metastatic colorectal cancer; IFL=5-fluorouracil (5-FU)/leucovorin (LV)/irinotecan; FOLFOX4=5-FU/LV/oxaliplatin; NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; mRCC=metastatic renal cell carcinoma; IFN=interferon alfa; CC=persistent, recurrent, or metastatic cervical cancer; prOC=platinum-resistant recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer; rGBM=recurrent glioblastoma.
*When continued beyond first progression in MCRC, no new safety signals were observed in the TML study.

These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study. [1]
Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. [1]
§Chemotherapy included paclitaxel, pegylated liposomal doxorubicin, or topotecan. [1]
||In rGBM, Avastin is not approved for use in combination with irinotecan or any other combination regimens. [1]

Monitoring blood pressure (BP) [1]

  • The incidence of severe hypertension is increased in patients receiving Avastin
  • BP monitoring should be conducted every 2 to 3 weeks during treatment with Avastin
  • Patients with Avastin-induced or -exacerbated hypertension who discontinue Avastin should continue to have their BP monitored at regular intervals

Managing hypertension with Avastin

  • In clinical trials, appropriate antihypertensives were used to help manage hypertension [2,4,6]
  • Avastin should be temporarily suspended in patients with severe hypertension that is not controlled with medical management, and discontinued in patients with hypertensive crisis or hypertensive encephalopathy [1]

Hypertension: Monitoring and managing with Avastin [1]

Chart: Monitoring and Managing Hypertension During Avastin Clinical Trials

Indications

Glioblastoma (GBM)
Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Metastatic colorectal cancer (MCRC)
Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Non-squamous non-small cell lung cancer (NSCLC)
Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

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

Persistent, recurrent, or metastatic cervical cancer (CC)
Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix.

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

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls
    • The incidences of GI perforation ranged from 0.3% to 3.2% across clinical studies
    • Discontinue Avastin in patients with GI perforation
  • Surgery and wound healing complications
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9% 
    • Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) 
    • Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included
    • GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients)
    • Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) 
    • Arterial thromboembolic events (grade ≥3, 2.6%)
    • Proteinuria (nephrotic syndrome, <1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included 
    • GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
    • Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with Avastin
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
  • Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
  • Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin 
  • Avoid use 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

Pregnancy warning

  • Based on the mechanism of action and animal studies, Avastin may cause fetal harm
  • Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy 
  • Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin
  • Advise nursing women that breastfeeding is not recommended during treatment with Avastin
  • Avastin may impair fertility

Most common adverse events

  • Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were

— Epistaxis
— Headache
— Hypertension
— Rhinitis

— Proteinuria
— Taste alteration
— Dry skin
— Rectal hemorrhage

— Lacrimation disorder
— Back pain
— Exfoliative dermatitis

  • Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Indication-specific adverse events

  • In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection 
  • In GBM patients receiving Avastin alone or Avastin plus irinotecan,a the incidences of Avastin-related adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and PRES (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage

aAvastin is not approved for use in combination with irinotecan or any other combination regimens.

  • In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
  • In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
  • When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC
  • In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
  • In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)
  • In CC, grade 3 or 4 adverse reactions in Study GOG 240, occurring at a higher incidence (≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone, were abdominal pain (11.9% vs 9.9%), diarrhea (5.5% vs 2.7%), anal fistula (3.7% vs 0%), proctalgia (2.8% vs 0%), urinary tract infection (8.3% vs 6.3%), cellulitis (3.2% vs 0.5%), fatigue (14.2% vs 9.9%), hypertension (11.5% vs 0.5%), thrombosis (8.3% vs 2.7%), hypokalemia (7.3% vs 4.5%), hyponatremia (3.7% vs 1.4%), dehydration (4.1% vs 0.5%), neutropenia (7.8% vs 4.1%), lymphopenia (6.0% vs 3.2%), back pain (5.5% vs 3.2%), and pelvic pain (5.5% vs 1.4%). There were no grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone
  • In prOC, grade 3–4 adverse events occurring at a higher incidence (≥2%) in 179 patients receiving Avastin plus 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%). There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at (888) 835-2555.

Please see full Prescribing Information, including Boxed WARNINGS, for additional important safety information.