Avastin safety profile

Gastrointestinal (GI) Perforations and Fistulae (Warnings and Precautions)

• 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 (Warnings and Precautions)

• 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 complications, including serious and fatal complications, was 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
• 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
• 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 (Warnings and Precautions)

• Avastin can result in 2 distinct patterns of bleeding: minor hemorrhage, which is 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 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 ≥1/2 teaspoon or more of red blood. Discontinue Avastin in patients who develop a Grade 3-4 hemorrhage
• 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
  

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 Thromboembolic Events (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 occurred 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)

• Severe hypertension occurred at a higher incidence 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 was 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 protein 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 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 ≥2 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-Related Reactions (Warnings and Precautions)

• In clinical studies, infusion-related reactions with the first dose of Avastin occurred in <3% of patients and severe reactions occurred in 0.4% of patients
  
• Infusion-related 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, anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors, and diaphoresis
  
• 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)
  

Embryo-Fetal Toxicity (Warnings and Precautions)

• 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 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 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

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% 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