Avastin Side Effects

Generic Name: bevacizumab

Please note - some side effects for Avastin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Avastin - for the Consumer

Avastin Solution

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Avastin Solution:

Changes in taste; constipation; diarrhea; dizziness; dry mouth; dry skin; hair loss; headache; increased thirst; indigestion; loss of appetite; minor nosebleeds; mouth pain or sores; muscle pain; nausea; pain, swelling, or redness at the injection site; sluggishness; stuffy or runny nose; tiredness; voice changes; vomiting; weakness; weight loss.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blood in the urine; calf pain or tenderness; chest pain; confusion; cough; coughing or choking while eating; coughing up or vomiting blood; dark urine; difficult or painful urination; fainting; fever, chills, or persistent sore throat; frequent or urgent urination; loss of coordination; numbness of the arms or legs; one-sided weakness; peeling of skin; seizure; severe or persistent headache; severe or persistent nosebleed; severe or persistent stomach pain, constipation, or vomiting; severe or persistent weakness; shortness of breath; skin discoloration, irritation, or lesions; speech changes; sudden, severe dizziness; swelling, discoloration, or pain in the legs; swelling of the hands, ankles, or feet; trouble swallowing; unusual bruising or bleeding; unusual weight gain; vaginal pain, bleeding, or discharge; vision loss, blurred vision, or other vision changes; wheezing; wounds that do not heal.

Avastin Side Effects - for the Professional

Avastin

The most serious adverse reactions in patients receiving Avastin were:

• Gastrointestinal Perforations
• Non-Gastrointestinal Fistula Formation
• Wound Healing Complications
• Hemorrhage
• Arterial Thromboembolic Events
• Hypertensive Crises
• Reversible Posterior Leukoencephalopathy Syndrome
• Neutropenia and Infection
• Nephrotic Syndrome
• Congestive Heart Failure

The most common adverse events in patients receiving Avastin were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.

Adverse Reactions in Clinical Trails

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.

The data described below reflect exposure to Avastin in 1529 patients, including 665 receiving Avastin for at least 6 months and 199 receiving Avastin for at least one year. Avastin was studied primarily in placebo- and active‑controlled trials (n = 501, and n = 1028, respectively).

The incidence of gastrointestinal perforation across all studies ranged from 0–3.7%. The incidence of gastrointestinal perforation, in some cases fatal, in patients with mCRC receiving Avastin alone or in combination with chemotherapy was 2.4% compared to 0.3% in patients receiving only chemotherapy. The incidence of gastrointestinal perforation in NSCLC patients receiving Avastin was 0.9% compared to 0% in patients receiving only chemotherapy.

The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In the same study, the incidence of wound dehiscence was also higher in the Avastin‑treated patients (1% vs. 0.5%).

Severe or fatal hemorrhages, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in Avastin‑treated patients compared to patients treated with chemotherapy alone. NCI‑CTC Grade 3–5 hemorrhagic events occurred in 4.7% of NSCLC patients and 5.2% of mCRC patients receiving Avastin compared to 1.1% and 0.7% for the control groups respectively.

The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. These events were generally mild in severity (NCI‑CTC Grade 1) and resolved without medical intervention. Additional 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%).

The incidence of arterial thromboembolic events was increased in NSCLC patients receiving PC plus Avastin (3.0%) compared with patients receiving PC alone (1.4%). Five events were fatal in the PC plus Avastin arm, compared with 1 event in the PC alone arm. This increased risk is consistent with that observed in patients with mCRC.

The incidence of NCI‑CTC grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. In addition, in patients with mCRC, the risk of developing a second subsequent thromboembolic event in patients receiving Avastin and chemotherapy is increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

The overall incidence of NCI‑CTC Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, the incidence of the following NCI‑CTC Grade 3 and 4 venous thromboembolic events was higher in patients receiving bolus‑IFL plus Avastin as compared to patients receiving bolus‑IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

Fatal CNS hemorrhage complicating Avastin induced hypertension can occur.

In Study 1 the incidences of hypertension and of severe hypertension were increased in patients with mCRC receiving Avastin compared to those receiving chemotherapy alone.

Among patients with severe hypertension in the Avastin arms, slightly over half the patients (51%) had a diastolic reading greater than 110 mmHg associated with a systolic reading less than 200 mmHg.

Similar results were seen in patients receiving Avastin alone or in combination with FOLFOX4 or carboplatin and paclitaxel.

An increased incidence of neutropenia has been reported in patients receiving Avastin and chemotherapy compared to chemotherapy alone. In Study 1, the incidence of NCI‑CTC Grade 3 or 4 neutropenia was increased in patients with mCRC receiving IFL+Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of NCI‑CTC Grade 4 neutropenia was increased in patients with NSCLC receiving PC plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with NCI‑CTC Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

Metastatic Carcinoma of the Colon and Rectum

The data in Tables 4 and 5 were obtained in Study 1. All NCI‑CTC Grade 3 and 4 adverse events and selected NCI‑CTC Grade 1 and 2 adverse events (hypertension, proteinuria, thromboembolic events) were reported for the overall study population. The median age was 60, 60% were male, 79% were Caucasian, 78% had a colon primary lesion, 56% had extra‑abdominal disease, 29% had prior adjuvant or neoadjuvant chemotherapy, and 57% had ECOG performance status of 0. The median duration of exposure to Avastin was 8 months in Arm 2 and 7 months in Arm 3. Severe and life threatening (NCI‑CTC Grade 3 and 4) adverse events, which occurred at a higher incidence (≥2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 4.

NCI‑CTC Grade 1–4 adverse events which occurred at a higher incidence (≥5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm, are presented in Table 5.

The data in Table 6 were obtained in Study 3. Only NCI‑CTC Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were reported. The median age was 61 years, 40% were female, 87% were Caucasian, 99% received prior chemotherapy for metastatic colorectal cancer, 26% had received prior radiation therapy, and the 49% had an ECOG performance status of 0. Selected NCI‑CTC Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events which occurred at a higher incidence in patients receiving FOLFOX4 plus Avastin as compared to those who received FOLFOX4 alone, are presented in Table 6. These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 3.

Non‑Squamous, Non‑Small Cell Lung Cancer

The data in Table 7 were obtained in Study 5. Only NCI‑CTC Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were reported. The median age was 63, 46% were female, no patients had received prior chemotherapy, 76% had Stage IV disease, 12% had Stage IIIB disease with malignant pleural effusion, 11% had recurrent disease, and 40% had an ECOG performance status of 0. The median duration of exposure to Avastin was 4.9 months.

NCI CTC Grade 3, 4, and 5 adverse events that occurred at a ≥2% higher incidence in patients receiving PC plus Avastin as compared with PC alone are presented in Table 7.

Other Serious Adverse Events

The following additional serious adverse events occurred in at least one subject treated with Avastin in clinical studies or post‑marketing experience.

Body as a Whole: polyserositis

Digestive: intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration

Hemic and lymphatic: pancytopenia

Respiratory: nasal septum perforation

Side Effects by Body System

General

General side effects including asthenia (up to 74%), pain (up to 62%), abdominal pain (up to 61%), infection (55%), fatigue (45%), headache (up to 37%), nongastrointestinal fistula formation (less than 0.3%), and polyserositis have been reported. Fatigue (10.7%), infection without neutropenia (9.1%), and infection with an unknown ANC (3.0%) have been reported with the use of paclitaxel in combination with bevacizumab.

Gastrointestinal

Gastrointestinal side effects including vomiting (up to 52%), anorexia (up to 43%), constipation (up to 40%), diarrhea (up to 34%), stomatitis (up to 32%), dyspepsia (up to 24%), gastrointestinal hemorrhage (up to 24%), flatulence (up to 19%), weight loss (up to 16%), dry mouth (up to 7%), colitis (up to 6%), constipation (up to 4%), intestinal obstruction, intestinal necrosis, mesenteric venous occlusion, and anastomotic ulceration have been reported. Gastrointestinal perforation and wound dehiscence, complicated by intraabdominal abscesses were reported to occur at an increased incidence in patients receiving bevacizumab as compared to controls. Tracheoesophageal (TE) fistula formation has been reported in a recent clinical study in patients with limited-stage small cell lung cancer (SCLC). There have been two confirmed serious adverse events of TE fistula (one fatal) reported in the first 29 patients enrolled in this study. A third, fatal event (upper aerodigestive tract hemorrhage and death of unknown cause) has also reported in which TE fistula was suspected but not confirmed. Vomiting (5.5%), diarrhea (4.7%), and nausea (4.1%), have been reported with the use of paclitaxel in combination with bevacizumab.

All three TE fistulas occurred during the bevacizumab maintenance phase of the study in the context of persistent esophagitis. Additionally, six other cases of TE fistula have been reported in other lung and esophageal cancer studies using bevacizumab and chemotherapy alone or with concurrent radiation treatment.

The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intraabdominal abscess) in patients with colorectal cancer and in patients with non-small cell lung cancer (NSCLC) receiving bevacizumab was 2.4% and 0.9%, respectively.

Cardiovascular

Cardiovascular side effects including hypertension (up to 34%), hypotension (up to 15%), deep vein thrombosis (up to 9%), and congestive heart failure have been reported. An increased risk of serious arterial thromboembolic events including cerebrovascular accidents (stroke), myocardial infarctions, transient ischemic attacks, and angina related to bevacizumab has been reported. The risk of fatal arterial thrombotic events has also been increased. The risk of a serious arterial thrombotic event has been reported to be approximately twice as high in patients receiving infusional 5-FU based chemotherapy with bevacizumab, with an overall rate of up to 5%. Hypertension (16%) has been reported with the use of paclitaxel in combination with bevacizumab. Pulmonary hypertension has been reported.

Risk factors for the development of arterial thromboembolic events have included a history of arterial thromboembolism prior to bevacizumab exposure, age 65 years and above, and bevacizumab therapy. These events have occurred at a higher rate in these high-risk groups.

In one study, the rate of congestive heart failure (defined as NCI-CTC grade 3 and 4) in the bevacizumab plus paclitaxel arm was 2.2 % versus 0.3% in the control arm. Among patients receiving anthracyclines, the rate of CHF was 3.8% for bevacizumab treated patients and 0.6 % for patients receiving paclitaxel alone. Congestive heart failure occurred in six of 44 (14%) patients with relapsed acute leukemia (a non-FDA approved indication) receiving bevacizumab and concurrent anthracyclines in a single arm study. The safety of continuation or resumption of bevacizumab in patients with cardiac dysfunction has not been studied.

Nervous system

Nervous system side effects including dizziness (up to 26%), confusion (up to 6%), CNS hemorrhage (up to 5%), and abnormal gait (up to 5%) have been reported. Cases of a rare brain-capillary leak syndrome (reversible posterior leukoencephalopathy syndrome or RPLS) have also been reported. Sensory neuropathy (24.2%), headache (3.6%), and cerebrovascular ischemia (2.5%) have been reported with the use of paclitaxel in combination with bevacizumab.

Bevacizumab should not be administered to patients with a recent history of hemoptysis of greater than or equal to 1/2 teaspoon of red blood. Bevacizumab should discontinued in patients with hemorrhage.

RPLS is a neurological disorder associated with hypertension, fluid retention, and cytotoxic effects of immunosuppressive drugs on the vascular endothelium. The syndrome can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present, but is not necessary for diagnosis. The onset of symptoms has been reported to occur from sixteen hours to one year after initiation of bevacizumab. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS.

Hematologic

Hematologic side effects including leukopenia (37%), neutropenia (21%), thrombocytopenia (5%), both serious and nonserious hemorrhagic events, and pancytopenia have been reported. In one study, 18% of patients receiving bolus IFL (irinotecan, fluorouracil, and leucovorin) with bevacizumab (versus 15% of patients receiving IFL with placebo) experienced a grade 3 or grade 4 thromboembolic event. Increased rates of severe neutropenia, febrile neutropenia, and infection with severe neutropenia (including some fatalities) have been observed in patients treated with myelosuppressive chemotherapy plus bevacizumab.

Metabolic

Metabolic side effects including hypokalemia (up to 16%), bilirubinemia (up to 6%), and hyponatremia have been reported.

Musculoskeletal

Musculoskeletal side effects including myalgia (up to 15%) have been reported. Bone pain (3.9%) has been reported with the use of paclitaxel in combination with bevacizumab. A case of osteonecrosis of the jaw related to bevacizumab has also been reported.

Genitourinary

Genitourinary side effects including ureteral stricture have been reported.

Respiratory

Respiratory side effects including fatal pulmonary hemorrhage can occur in patients with non-small cell lung cancer treated with chemotherapy and bevacizumab. A 31% incidence of severe or fatal hemoptysis has been reported in patients with squamous histology and a 2.3% incidence has been reported in patients with non-small cell lung cancer excluding predominant squamous histology. Nasal septum perforation and dysphonia have also been reported.

Patients with recent hemoptysis (greater than or equal to 1/2 tsp of red blood) should not receive bevacizumab.

In study 6, four of 13 (31%) bevacizumab-treated patients with squamous cell histology and two of 53 (4%) bevacizumab-treated patients with histology other than squamous cell, experienced serious or fatal pulmonary hemorrhage as compared to none of the 32 (0%) patients receiving chemotherapy alone. In study 5, the rate of pulmonary hemorrhage requiring medical intervention for the paclitaxel, carboplatin, plus bevacizumab arm was 2.3% (10 of 427) compared to 0.5% (2 of 441) for the paclitaxel plus carboplatin alone arm. There were seven deaths due to pulmonary hemorrhage reported by investigators in the paclitaxel, carboplatin, plus bevacizumab arm as compared to one in the paclitaxel plus carboplatin alone arm. Generally, these serious hemorrhagic events presented as major or massive hemoptysis without a history of minor hemoptysis during bevacizumab therapy.

Renal

Kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

In study 5, patients age 65 and older receiving carboplatin, paclitaxel, and bevacizumab had a greater relative risk for proteinuria as compared to younger patients.

Renal side effects including an increase in the incidence (up to 3.0%) and severity of proteinuria have been reported. Nephrotic syndrome (0.5%) has been reported in patients receiving bevacizumab. Proteinuria (3.0%) has also been reported with the use of paclitaxel in combination with bevacizumab.

Ocular

Ocular side effects including cases of Charles Bonnet syndrome (visual hallucinations) have been reported after intravitreal bevacizumab injection for age-related macular degeneration.

It has been suggested that reduction in macular edema after treatment may have resulted in anatomic changes at the fovea and may have triggered the visual hallucinations.

Dermatologic

Dermatologic side effects including rash/desquamation (2.5%) have been reported with the use of paclitaxel in combination with bevacizumab.

Other

Other side effects including epistaxis (up to 26%) and wound-healing complications (6%) have been reported.

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