Avastin Side Effects, and Drug Interactions - Bevacizumab

Avastin Side Effects, and Drug Interactions - Bevacizumab

SIDE EFFECTS

The most serious adverse events associated with AVASTIN were:

• Gastrointestinal Perforations/Wound Healing Complications (see WARNINGS)

• Hemorrhage (see WARNINGS)

• Hypertensive Crises (see WARNINGS)

• Nephrotic Syndrome (see WARNINGS)

• Congestive Heart Failure (see WARNINGS)

The most common severe (NCI-CTC Grade 3-4) adverse events among 1032 patients receiving AVASTIN in Genentech-sponsored studies were asthenia, pain, hypertension, diarrhea, and leukopenia.

The most common adverse events of any severity among the 742 patients receiving AVASTIN in Genentech-sponsored studies were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

A total of 1032 patients with metastatic colorectal cancer (n = 568) and with other cancers (n = 464) received AVASTIN either as a single agent (n = 157) or in combination with chemotherapy (n = 875) in Genentech-sponsored clinical trials. All adverse events were collected in 742 of the 1032 patients; for the remaining 290, all NCI-CTC Grade 3 and 4 adverse events and only selected Grade 1 and 2 adverse events (hypertension, proteinuria, thromboembolic events) were collected.

Adverse events across all Genentech-sponsored studies were used to further characterize specific adverse events. (See WARNINGS: Hemorrhage, Hypertension, Proteinuria, Congestive Heart Failure and PRECAUTIONS: Geriatric Use.)

Comparative data on adverse experiences, except where indicated, are limited to Study 1, a randomized, active-controlled study in 897 patients receiving initial treatment for metastatic colorectal cancer. All NCI-CTC Grade 3 and 4 adverse events and selected Grade 1 and 2 adverse events (hypertension, proteinuria, thromboembolic events) were reported for the overall study population. In Study 1, the median age was 60, 60% were male, 78% had colon primary lesion, and 29% had prior adjuvant or neoadjuvant chemotherapy. The median duration of exposure to AVASTIN in Study 1 was 8 months in Arm 2 and 7 months in Arm 3. All adverse events, including all NCI-CTC Grade 1 and 2 events, were reported in a subset of 309 patients. The baseline entry characteristics in the 309 patient safety subset were similar to the overall study population and well-balanced across the three study arms.

Severe and life-threatening (NCI-CTC Grade 3 and 4) adverse events, which occurred at a higher incidence (³ 2%) in patients receiving bolus-IFL plus AVASTIN as compared to bolus-IFL plus placebo, are presented in Table 4.

Adverse events of any severity, which occurred at a higher incidence ( > 5%) in the initial phase of the study in patients receiving AVASTIN (bolus-IFL plus AVASTIN or 5-FU/LV plus AVASTIN) as compared to the bolus-IFL plus placebo arm, are presented in Table 5.

In Study 1, both serious and non-serious hemorrhagic events occurred at a higher incidence in patients receiving AVASTIN. (See WARNINGS: Hemorrhage.) In the 309 patients in which Grade 1-4 events were collected, epistaxis was common and reported in 35% of patients receiving bolus-IFL plus AVASTIN compared with 10% of patients receiving bolus-IFL plus placebo. These events were generally mild in severity (NCI-CTC Grade 1) and resolved without medical intervention. Other mild to moderate hemorrhagic events reported more frequently in patients receiving bolus-IFL plus AVASTIN when compared to those receiving bolus-IFL plus placebo included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%).

In Study 1, 18% of patients receiving bolus-IFL plus AVASTIN and 15% of patients receiving bolus-IFL plus placebo experienced a Grade 3-4 thromboembolic event. The incidence of the following Grade 3 and 4 thromboembolic events were higher in patients receiving bolus-IFL plus AVASTIN as compared to patients receiving bolus-IFL plus placebo: cerebrovascular events (4 vs. 0 patients), myocardial infarction (6 vs. 3), deep venous thrombosis (34 vs. 19), and intra-abdominal thrombosis (13 vs. 5). In contrast, the incidence of pulmonary embolism was higher in patients receiving bolus-IFL plus placebo (16 vs. 20).

In Study 1, 53 of 392 (14%) patients who received bolus-IFL plus AVASTIN and 30 of 396 (8%) patients who received bolus-IFL plus placebo had a thromboembolic event and received full-dose warfarin. Two patients in each treatment arm (four total) developed bleeding complications. In the two patients treated with full-dose warfarin and AVASTIN, these events were associated with marked elevations in their INR. Eleven of 53 (21%) patients receiving bolus-IFL plus AVASTIN and one of 30 (3%) patients receiving bolus-IFL developed an additional thromboembolic event.

The following other serious adverse events are considered unusual in cancer patients receiving cytotoxic chemotherapy and occurred in at least one subject treated with AVASTIN in clinical studies.

No formal drug interaction studies with anti-neoplastic agents have been conducted. In Study 1, patients with colorectal cancer were given irinotecan/5-FU/leucovorin (bolus-IFL) with or without AVASTIN. Irinotecan concentrations were similar in patients receiving bolus-IFL alone and in combination with AVASTIN. The concentrations of SN38, the active metabolite of irinotecan, were on average 33% higher in patients receiving bolus-IFL in combination with AVASTIN when compared with bolus-IFL alone. In Study 1, patients receiving bolus-IFL plus AVASTIN had a higher incidence of Grade 3-4 diarrhea and neutropenia. Due to high inter-patient variability and limited sampling, the extent of the increase in SN38 levels in patients receiving concurrent irinotecan and AVASTIN is uncertain.