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.
(5.1) Surgery and Wound Healing Complications:
Discontinue in patients who develop wound healing complications that require medical intervention. Withhold 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.
(5.2) Hemorrhage: Severe or fatal hemorrhages have occurred. Do not administer for recent hemoptysis. Discontinue for Grade 3-4
5.4 Arterial Thromboembolic Events
Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina, occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy.
Across clinical studies, the incidence of Grades 3-5 ATE was 5% in patients receiving Avastin with chemotherapy compared to
≤ 2% in patients receiving chemotherapy alone; the highest incidence occurred in patients with GBM. The risk of developing ATE was increased in patients with a history of arterial thromboembolism, diabetes, or greater than 65 years old
5.5 Venous Thromboembolic Events
An increased risk of venous thromboembolic events (VTE) was observed across clinical studies. In Study GOG-0240, Grade 3-4
VTE was reported in 11% of patients receiving Avastin with chemotherapy compared with 5% of patients receiving chemotherapy alone. VTE –
- Deep vein thrombosis (DVT) Deep vein thrombosis is a clot in a deep vein, usually in the leg. DVT sometimes affects the arm or other veins.
- Pulmonary embolism (PE) A pulmonary embolism occurs when a DVT clot breaks free from a vein wall, travels to the lungs and then blocks some or all of the blood supply. Blood clots originating in the thigh are more likely to break off and travel to the lungs than blood clots in the lower leg or other parts of the body.
In EORTC 26101, the incidence of Grade 3-4 VTE was 5% in patients receiving Avastin with chemotherapy compared to 2% in patients receiving chemotherapy alone.
5.7 Posterior Reversible Encephalopathy Syndrome (PRES)
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.
5.8 Renal Injury and Proteinuria
The incidence and severity of proteinuria are 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. The median time to resolution was 6.1 months (95% CI: 2.8, 11.3). Proteinuria did not resolve in 40% of patients after a median follow-up of 11.2 months and required discontinuation of Avastin in 30% of the patients who developed 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
the baseline in approximately one-third of patients who received Avastin.
5.10 Embryo-Fetal Toxicity
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 VEGFR 2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development.