Avastin safety profile

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

  • Serious and sometimes fatal gastrointestinal perforation occurred at a higher incidence in patients treated with Avastin compared to patients treated with 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 (tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occurred at a higher incidence in patients treated with Avastin compared to patients treated with chemotherapy. The incidence ranged from <1% to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a gastrointestinal vaginal fistula may also have bowel obstructions and require surgical intervention, as well as a diverting ostomy
  • Avoid 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 Avastin in patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving any internal organ

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

  • In clinical studies, administration of Avastin was not allowed until at least 28 days after surgery. Do not initiate Avastin for at least 28 days following surgery and until the surgical wound is fully healed
  • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • In a controlled clinical study in MCRC patients who underwent surgery while receiving Avastin, 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% vs 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 Avastin for at least 28 days prior to elective surgery. Do not administer Avastin 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

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, hemorrhage
  • 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 chemotherapy alone. Across clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7%
  • Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous cell histology and 4% of patients with 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 ≥1/2 teaspoon or more of red blood. Discontinue Avastin in patients who develop a hemorrhage

Arterial thromboembolic events (ATEs) (Warnings and Precautions)

  • Serious, sometimes fatal, ATEs including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina, occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy
  • In clinical studies, the incidence of grade ≥3 ATEs in the Avastin-containing arms was 5% compared to ≤2% in patients receiving chemotherapy alone; the highest incidence occurred in patients with GBM
  • The risk of developing an ATE was increased in patients with a history of arterial thromboembolism, diabetes, or age >65 years
  • The safety of reinitiating Avastin after an ATE is resolved is not known. Discontinue Avastin in patients who develop a severe ATE

Venous thromboembolism (Warnings and Precautions)

  • An increased risk of venous thromboembolic events (VTEs) was observed in clinical studies across indications
  • In Study GOG-0240, Grade 3-4 VTEs were 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 VTEs 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   

Hypertension (Warnings and Precautions)

  • The incidence of severe hypertension is increased in patients receiving Avastin as compared to patients receiving chemotherapy alone. In clinical studies, the incidence of grade 3-4 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
  • 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 Avastin in patients who develop hypertensive crisis or hypertensive encephalopathy

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

  • 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 (MRI) 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

Renal Injury and Proteinuria (Warnings and Precautions)

  • The incidence and severity of proteinuria is higher in patients receiving Avastin compared to patients receiving chemotherapy
  • Grade 3 (defined as urine dipstick 4+ or >3.5 grams of protein per 24 hours) and 4 (defined as nephrotic syndrome) proteinuria ranged from 0.7% to 7% across clinical studies
    • The overall incidence of proteinuria (all grades) was only adequately assessed in BO17705, in which the incidence was 20%
    • In mRCC, median onset of proteinuria after initiating Avastin 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 discontinuation of Avastin in 30% of the patients who developed proteinuria
  • In an exploratory, pooled analysis from seven randomized clinical studies, 5% of patients receiving Avastin with chemotherapy experienced Grade 2-4 (defined as urine dipstick 2+ or greater or >1 gram of proteinuria per 24 hours or nephrotic syndrome) proteinuria. Grade 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 <1% of patients receiving Avastin in 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 (ranging between 1.5 to 1.9 times baseline levels) in patients who had 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 ³2 grams per 24 hours and resume when proteinuria is <2 grams per 24 hours. Discontinue Avastin 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)]

Infusion reactions (Warnings and Precautions)

  • In clinical studies, infusion reactions with the first dose of Avastin occurred in <3% of patients and severe reactions occurred in 0.2% of patients
  • Infusion reactions reported in the 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
  • Decrease the rate of infusion for mild, clinically significant 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, diphenhydramine, bronchodilators and/or oxygen)

Embryo-fetal toxicity (Warnings and Precautions)

  • Avastin may cause fetal harm based on its mechanism of action and findings from animal studies
  • 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 and for 6 months after the last dose of Avastin

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

  • 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% (7/32) of women receiving Avastin. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a 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

Congestive Heart Failure (CHF) (Warnings and Precautions)

  • 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 10.4% 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 month to 6 months after the first dose of Avastin 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

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 suggests 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 women not to breastfeed during treatment with Avastin and for 6 months following the final dose

Most common adverse events

  • Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% 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% to 22% of patients because of adverse reactions

NSCLC Study Adverse Events

mRCC Study Adverse Events

CC Study Adverse Events

psOC 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 is higher in patients receiving Avastin as compared to patients receiving chemotherapy [1]
  • 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 [1]
  • 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 [Pearson Correlation 0.39 (95% CI: 0.17–0.57)]
  • 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® (bevacizumab)

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-0240 study 3–4 Avastin + chemotherapy 11.5
Chemotherapy alone 0.5
psOC OCEANS study 3–4 Avastin + chemotherapy§ 16.2
Placebo + chemotherapy§
0.4
GOG-0213 study
3–4 Avastin + chemotherapy|| 11
Chemotherapy|| alone  0.6
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
EORTC study ≥3 Avastin + lomustine 15.1

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; psOC=platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; prOC=platinum-resistant recurrent epithelial ovarian, fallopian tube or 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 carboplatin/gemcitabine. [1]
||Chemotherapy included carboplatin/paclitaxel. [1]
Chemotherapy included paclitaxel, pegylated liposomal doxorubicin, or topotecan. [1]

Monitoring blood pressure (BP) [1]

  • The incidence of severe hypertension is increased in patients receiving Avastin compared to those receiving chemotherapy alone
  • 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]
  • Withhold Avastin 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]

Monitoring and Managing Hypertension During Avastin® (bevacizumab) Clinical Trials

Indications

Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (rOC)
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.

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

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

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

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

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

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

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.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to patients treated with chemotherapy
    • The incidence of GI perforation ranged from 0.3% to 3% 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
    • Withhold Avastin for 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
    • Discontinue 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. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7%
    • Do not administer Avastin to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients who develop grade 3-4 hemorrhage

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM)
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Venous thromboembolism (grade ≥3, 11% seen in GOG-0240)
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
    • Congestive heart failure (CHF) (1%)
  • Infusion reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.2% of patients
  • 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
  • Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with Avastin

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 and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse events

  • Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% 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% to 22% of patients because of adverse reactions

Indication-specific adverse events

  • In psOC, grade 3 or 4 adverse reactions in the OCEANS study occurring at a higher incidence (≥2%) in 247 patients receiving Avastin plus carboplatin and gemcitabine (chemotherapy), compared to 233 patients receiving placebo plus 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%)
  • In psOC, grade 3 or 4 adverse reactions in the GOG-0213 study occurring at a higher incidence (≥2%) in 325 patients receiving Avastin plus carboplatin and paclitaxel (chemotherapy), compared to 332 patients receiving 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 (3.4% vs 0%)
  • In prOC, grade 3-4 adverse reactions in AURELIA 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%)
  • In CC, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (≥2%) in 218 patients receiving Avastin plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), 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%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), 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%)
  • 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%, 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)
  • In rGBM Study EORTC 26101, 22% of patients discontinued treatment in the Avastin with lomustine arm 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
  • 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 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%)
  • 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 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 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 MCRC5

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.