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Avastin (Bevacizumab) - Warnings and Precautions

 
 



WARNINGS

GASTROINTESTINAL PERFORATIONS

AVASTIN administration can result in the development of gastrointestinal perforation, in some instances resulting in fatality. Gastrointestinal perforation, sometimes associated with intra‑abdominal abscess, occurred throughout treatment with AVASTIN (i.e., was not correlated to duration of exposure). The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra‑abdominal abscess) in patients with colorectal cancer and in patients with non‑small cell lung cancer (NSCLC) receiving AVASTIN was 2.4% and 0.9%, respectively. The typical presentation was reported as abdominal pain associated with symptoms such as constipation and vomiting. Gastrointestinal perforation should be included in the differential diagnosis of patients presenting with abdominal pain on AVASTIN. AVASTIN therapy should be permanently discontinued in patients with gastrointestinal perforation. (See WARNINGS: Gastrointestinal Perforations and DOSAGE AND ADMINISTRATION: Dose Modifications.)

WOUND HEALING COMPLICATIONS

AVASTIN administration can result in the development of wound dehiscence, in some instances resulting in fatality. AVASTIN therapy should be permanently discontinued in patients with wound dehiscence requiring medical intervention. The appropriate interval between termination of AVASTIN and subsequent elective surgery required to avoid the risks of impaired wound healing⁄wound dehiscence has not been determined. (See WARNINGS: Wound Healing Complications and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Hemorrhage

Fatal pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and AVASTIN. The incidence of severe or fatal hemoptysis was 31% in patients with squamous histology and 2.3% in patients with NSCLC excluding predominant squamous histology. Patients with recent hemoptysis (≥1⁄2 tsp of red blood) should not receive AVASTIN. (See WARNINGS: Hemorrhage, ADVERSE REACTIONS: Hemorrhage, and DOSAGE AND ADMINISTRATION: Dose Modifications.)

 

WARNINGS

Gastrointestinal Perforations

(See DOSAGE AND ADMINISTRATION: Dose Modifications)

Gastrointestinal perforation complicated by intra‑abdominal abscesses or fistula formation and in some instances with a fatal outcome, occurs at an increased incidence in patients receiving AVASTIN as compared to controls. In Studies 1, 2, and 3, the incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra-abdominal abscess) in patients receiving AVASTIN was 2.4%. These episodes occurred with or without intra‑abdominal abscesses and at various time points during treatment. The typical presentation was reported as abdominal pain associated with symptoms such as constipation and emesis.

In post‑marketing clinical studies and reports, gastrointestinal perforation, fistula formation in the gastrointestinal tract (eg. gastrointestinal, enterocutaneous, esophageal, duodenal, rectal), and/or intra‑abdominal abscess occurred in patients receiving AVASTIN for colorectal and for other types of cancer. The overall incidence in clinical studies was 1%, but may be higher in some cancer settings. Of the reported events, approximately 30% were fatal. Patients with gastrointestinal perforation, regardless of underlying cancer, typically present with abdominal pain, nausea and fever. Events were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of AVASTIN, with most events occurring within the first 50 days.

Permanently discontinue AVASTIN therapy in patients with gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra‑abdominal abscess).

Non‑Gastrointestinal Fistula Formation

(See DOSAGE AND ADMINISTRATION: Dose Modifications)

Non-gastrointestinal fistula formation has been reported in patients treated with AVASTIN in controlled clinical studies (with an incidence of <0.3%) and in post-marketing experience, in some cases with fatal outcome. Fistula formation involving the following areas of the body other than the gastrointestinal tract have been reported: (tracheo‑esophageal, bronchopleural, biliary, vagina and bladder). Events were reported throughout treatment with Avastin, with most events occurring within the first 6 months.

Permanently discontinue AVASTIN in patients with fistula formation involving an internal organ.

Wound Healing Complications

(See DOSAGE AND ADMINISTRATION: Dose Modifications)

AVASTIN impairs wound healing in animal models. In clinical studies of AVASTIN, patients were not allowed to receive AVASTIN until at least 28 days had elapsed following surgery. In clinical studies of AVASTIN in combination with chemotherapy, there were 6 instances of dehiscence among 788 patients (0.8%).

The appropriate interval between discontinuation of AVASTIN and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined. In Study 1, 39 patients who received bolus‑IFL plus AVASTIN underwent surgery following AVASTIN therapy; of these patients, six (15%) had wound healing/bleeding complications. In the same study, 25 patients in the bolus‑IFL arm underwent surgery; of these patients, one of 25 (4%) had wound healing/bleeding complications. The longest interval between the last dose of study drug and dehiscence was 56 days; this occurred in a patient on the bolus‑IFL plus AVASTIN arm.

The interval between termination of AVASTIN and subsequent elective surgery should take into consideration the calculated half life of AVASTIN (approximately 20 days).

Discontinue AVASTIN in patients with wound healing complications requiring medical intervention.

Hemorrhage

(See DOSAGE AND ADMINISTRATION: Dose Modifications)

Two distinct patterns of bleeding have occurred in patients receiving AVASTIN. The first is minor hemorrhage, most commonly NCI‑CTC Grade 1 epistaxis. The second is serious, and in some cases fatal, hemorrhagic events.

In Study 6, four of 13 (31%) AVASTIN‑treated patients with squamous cell histology and two of 53 (4%) AVASTIN‑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. Of the patients experiencing pulmonary hemorrhage requiring medical intervention, many had cavitation and/or necrosis of the tumor, either pre‑existing or developing during AVASTIN therapy. In Study 5, the rate of pulmonary hemorrhage requiring medical intervention for the PC plus AVASTIN arm was 2.3% (10 of 427) compared to 0.5% (2 of 441) for the PC alone arm. There were seven deaths due to pulmonary hemorrhage reported by investigators in the PC plus AVASTIN arm as compared to one in the PC alone arm. Generally, these serious hemorrhagic events presented as major or massive hemoptysis without an antecedent history of minor hemoptysis during Avastin therapy. Do not administer AVASTIN to patients with recent history of hemoptysis of ≥1/2 tsp of red blood. Other serious bleeding events occurring in patients receiving AVASTIN across all indications include gastrointestinal hemorrhage, subarachnoid hemorrhage, and hemorrhagic stroke. Some of these events were fatal. (See ADVERSE REACTIONS: Hemorrhage.)

The risk of central nervous system (CNS) bleeding in patients with CNS metastases receiving AVASTIN has not been evaluated because these patients were excluded from late stage clinical studies following development of CNS hemorrhage in a patient with a CNS metastasis in a Phase 1 study.

Discontinue AVASTIN in patients with serious hemorrhage (i.e., requiring medical intervention) and initiate aggressive medical management. (See ADVERSE REACTIONS: Hemorrhage.)

Arterial Thromboembolic Events

(See DOSAGE AND ADMINISTRATION: Dose Modifications and PRECAUTIONS: Geriatric Use)

Arterial thromboembolic events (ATE) occurred at a higher incidence in patients receiving AVASTIN in combination with chemotherapy as compared to those receiving chemotherapy alone. ATE included cerebral infarction, transient ischemic attacks (TIAs), myocardial infarction (MI), angina, and a variety of other ATE. These events were fatal in some instances.

In a pooled analysis of randomized, controlled clinical trials involving 1745 patients, the incidence of ATE was 4.4% among patients treated with AVASTIN in combination with chemotherapy and 1.9% among patients receiving chemotherapy alone. Fatal outcomes for these events occurred in 7 of 963 patients (0.7%) who were treated with AVASTIN in combination with chemotherapy, compared to 3 of 782 patients (0.4%) who were treated with chemotherapy alone. The incidences of both cerebrovascular arterial events (1.9% vs. 0.5%) and cardiovascular arterial events (2.1% vs. 1.0%) were increased in patients receiving AVASTIN compared to chemotherapy alone. The relative risk of ATE was greater in patients 65 and over (8.5% vs. 2.9%) as compared to those less than 65 (2.1% vs. 1.4%). (See PRECAUTIONS: Geriatric Use.)

The safety of resumption of AVASTIN therapy after resolution of an ATE has not been studied. Permanently discontinue AVASTIN in patients who experience a severe ATE during treatment. (See DOSAGE AND ADMINISTRATION: Dose Modifications and PRECAUTIONS: Geriatric Use.)

Hypertension

(See DOSAGE AND ADMINISTRATION: Dose Modifications)

The incidence of severe hypertension was increased in patients receiving AVASTIN as compared to controls. Across clinical studies the incidence of NCI‑CTC Grade 3 or 4 hypertension ranged from 8–18%.

Medication classes used for management of patients with NCI‑CTC Grade 3 hypertension receiving AVASTIN included angiotensin‑converting enzyme inhibitors, beta blockers, diuretics, and calcium channel blockers. Development or worsening of hypertension can require hospitalization or require discontinuation of AVASTIN in up to 1.7% of patients. Hypertension can persist after discontinuation of AVASTIN. Complications can include hypertensive encephalopathy (in some cases fatal) and CNS hemorrhage.

In the post‑marketing experience, acute increases in blood pressure associated with initial or subsequent infusions of AVASTIN have been reported (see PRECAUTIONS: Infusion Reactions). Some cases were serious and associated with clinical sequelae.

Permanently discontinue AVASTIN in patients with hypertensive crisis or hypertensive encephalopathy. Temporarily suspend AVASTIN in patients with severe hypertension that is not controlled with medical management. (See DOSAGE AND ADMINISTRATION: Dose Modifications)

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

(See DOSAGE AND ADMINISTRATION: Dose Modifications)

RPLS has been reported in clinical studies (with an incidence of<0.1%) and in post‑marketing experience. RPLS 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, but is not necessary for diagnosis of RPLS. Magnetic Resonance Imaging (MRI) is necessary to confirm the diagnosis of RPLS. The onset of symptoms has been reported to occur from 16 hours to 1 year after initiation of AVASTIN.

In patients developing RPLS, discontinue AVASTIN and initiate treatment of hypertension, if present. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating AVASTIN therapy in patients previously experiencing RPLS is not known.

Neutropenia and Infection

(See PRECAUTIONS: Geriatric Use and ADVERSE REACTIONS: Neutropenia and Infection.)

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 AVASTIN. (See PRECAUTIONS: Geriatric Use and ADVERSE REACTIONS: Neutropenia and Infection.)

Proteinuria

(See DOSAGE AND ADMINISTRATION: Dose Modifications)

The incidence and severity of proteinuria is increased in patients receiving AVASTIN as compared to control. In Studies 1, 3 and 5, the incidence of NCI‑CTC Grade 3 and 4 proteinuria, characterized as >3.5 gm/24 hours, ranged up to 3.0% in AVASTIN‑treated patients.

Nephrotic syndrome occurred in seven of 1459 (0.5%) patients receiving AVASTIN in clinical studies. One patient died and one required dialysis. In three patients, proteinuria decreased in severity several months after discontinuation of AVASTIN. No patient had normalization of urinary protein levels (by 24 hour urine) following discontinuation of AVASTIN.

The highest incidence of proteinuria was observed in a dose‑ranging, placebo‑controlled, randomized study of AVASTIN in patients with metastatic renal cell carcinoma, an indication for which AVASTIN is not approved, 24‑hour urine collections were obtained in approximately half the patients enrolled. Among patients in whom 24‑hour urine collections were obtained, four of 19 (21%) patients receiving AVASTIN at 10 mg/kg every two weeks, two of 14 (14%) patients receiving AVASTIN at 3 mg/kg every two weeks, and none of the 15 placebo patients experienced NCI‑CTC Grade 3 proteinuria (>3.5 gm protein/24 hours).

Discontinue AVASTIN in patients with nephrotic syndrome. The safety of continued AVASTIN treatment in patients with moderate to severe proteinuria has not been evaluated. In most clinical studies, AVASTIN was interrupted for ≥2 grams of proteinuria/24 hours and resumed when proteinuria was <2 gm/24 hours. Patients with moderate to severe proteinuria based on 24‑hour collections should be monitored regularly until improvement and/or resolution is observed. (See DOSAGE AND ADMINISTRATION: Dose Modifications.)

Congestive Heart Failure

Congestive heart failure (CHF), defined as NCI‑CTC Grade 2–4 left ventricular dysfunction, was reported in 25 of 1459 (1.7%) patients receiving AVASTIN in clinical studies. The risk of CHF appears to be higher in patients receiving AVASTIN who have received prior or concurrent anthracyclines. In a controlled study in patients with breast cancer (an unlabelled indication), the incidence of CHF was higher in the AVASTIN plus chemotherapy arm as compared to the chemotherapy alone arm. Congestive heart failure occurred in 13 of 299 (4%) patients who received prior anthracyclines and/or left chest wall irradiation. Congestive heart failure occurred in six of 44 (14%) patients with relapsed acute leukemia (an unlabelled indication) receiving AVASTIN and concurrent anthracyclines in a single arm study.

The safety of continuation or resumption of AVASTIN in patients with cardiac dysfunction has not been studied.

PRECAUTIONS

GENERAL

Use AVASTIN with caution in patients with known hypersensitivity to AVASTIN or any component of this drug product.

INFUSION REACTIONS

In clinical studies, infusion reactions with the first dose of AVASTIN were uncommon (<3%) and severe reactions occurred in 0.2% of patients. Infusion reactions reported in the clinical trials and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, NCI‑CTC Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. Adequate information on rechallenge is not available. AVASTIN infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.

There are no data regarding the most appropriate method of identification of patients who may safely be retreated with AVASTIN after experiencing a severe infusion reaction.

SURGERY

AVASTIN therapy should not be initiated for at least 28 days following major surgery. The surgical incision should be fully healed prior to initiation of AVASTIN. Because of the potential for impaired wound healing, AVASTIN should be suspended prior to elective surgery. The appropriate interval between the last dose of AVASTIN and elective surgery is unknown; however, the half‑life of AVASTIN is estimated to be 20 days (see CLINICAL PHARMACOLOGY: Pharmacokinetics) and the interval chosen should take into consideration the half‑life of the drug. (See WARNINGS: Gastrointestinal Perforations and Wound Healing Complications.)

CARDIOVASCULAR DISEASE

Patients were excluded from participation in AVASTIN clinical trials if, in the previous year, they had experienced clinically significant cardiovascular disease. In an exploratory analysis pooling the data from five randomized, placebo‑controlled, clinical trials conducted in patients without a recent history of clinically significant cardiovascular disease, the overall incidence of arterial thromboembolic events, the incidence of fatal arterial thromboembolic events, and the incidence of cardiovascular thromboembolic events were increased in patients receiving AVASTIN plus chemotherapy as compared to chemotherapy alone.

LABORATORY TESTS

Blood pressure monitoring should be conducted every two to three weeks during treatment with AVASTIN. Patients who develop hypertension on AVASTIN may require blood pressure monitoring at more frequent intervals. Patients with AVASTIN‑induced or ‑exacerbated hypertension who discontinue AVASTIN should continue to have their blood pressure monitored at regular intervals.

Patients receiving AVASTIN should be monitored for the development or worsening of proteinuria with serial urinalyses. Patients with a 2+ or greater urine dipstick reading should undergo further assessment, e.g., a 24‑hour urine collection. (See WARNINGS: Proteinuria and DOSAGE AND ADMINISTRATION: Dose Modifications.)

DRUG INTERACTIONS

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 NCI‑CTC 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.

In Study 6, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with AVASTIN. However, 3 of the 8 patients receiving AVASTIN plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without AVASTIN had a greater paclitaxel exposure at Day 63 than at Day 0.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

No carcinogenicity data are available for AVASTIN in animals or humans.

AVASTIN may impair fertility. Dose‑related decreases in ovarian and uterine weights, endometrial proliferation, number of menstrual cycles, and arrested follicular development or absent corpora lutea were observed in female cynomolgus monkeys treated with 10 or 50 mg/kg of AVASTIN for 13 or 26 weeks. Following a 4‑ or 12‑week recovery period, which examined only the high–dose group, trends suggestive of reversibility were noted in the two females for each regimen that were assigned to recover. After the 12‑week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12‑week recovery time point, but uterine weight decreases were still notable, corpora lutea were absent in 1 out of 2 animals, and the number of menstrual cycles remained reduced (67%).

PREGNANCY CATEGORY C

AVASTIN has been shown to be teratogenic in rabbits when administered in doses that approximate the human dose on a mg/kg basis. Observed effects included decreases in maternal and fetal body weights, an increased number of fetal resorptions, and an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested.

Angiogenesis is critical to fetal development and the inhibition of angiogenesis following administration of AVASTIN is likely to result in adverse effects on pregnancy. There are no adequate and well‑controlled studies in pregnant women. AVASTIN should be used during pregnancy or in any woman not employing adequate contraception only if the potential benefit justifies the potential risk to the fetus. All patients should be counseled regarding the potential risk of AVASTIN to the developing fetus prior to initiation of therapy. If the patient becomes pregnant while receiving AVASTIN, she should be apprised of the potential hazard to the fetus and/or the potential risk of loss of pregnancy. Patients who discontinue AVASTIN should also be counseled concerning the prolonged exposure following discontinuation of therapy (half‑life of approximately 20 days) and the possible effects of AVASTIN on fetal development.

NURSING MOTHERS

It is not known whether AVASTIN is secreted in human milk. Because human IgG1 is secreted into human milk, the potential for absorption and harm to the infant after ingestion is unknown. Women should be advised to discontinue nursing during treatment with AVASTIN and for a prolonged period following the use of AVASTIN, taking into account the half‑life of the product, approximately 20 days [range 11– 50 days]. (See CLINICAL PHARMACOLOGY: Pharmacokineticss.)

PEDIATRIC USE

The safety and effectiveness of AVASTIN in pediatric patients has not been studied. However, physeal dysplasia was observed in juvenile cynomolgus monkeys with open growth plates treated for four weeks with doses that were less than the recommended human dose based on mg/kg and exposure. The incidence and severity of physeal dysplasia were dose‑related and were at least partially reversible upon cessation of treatment.

GERIATRIC USE

In Study 1, NCI‑CTC Grade 3–4 adverse events were collected in all patients receiving study drug (396 bolus‑IFL plus placebo; 392 bolus‑IFL plus AVASTIN; 109 5‑FU/LV plus AVASTIN), while NCI‑CTC Grade 1 and 2  adverse events were collected in a subset of 309 patients. There were insufficient numbers of patients 65 years and older in the subset in which NCI‑CTC Grade 1–4 adverse events were collected to determine whether the overall adverse event profile was different in the elderly as compared to younger patients. Among the 392 patients receiving bolus‑IFL plus AVASTIN, 126 were at least 65 years of age. Severe adverse events that occurred at a higher incidence (≥2%) in the elderly when compared to those less than 65 years were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of AVASTIN on overall survival was similar in elderly patients as compared to younger patients.

In Study 3, patients age 65 and older receiving AVASTIN plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

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

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients age 65 or older and 1127 patients less than 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving AVASTIN with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients 65 and over (8.5% vs. 2.9%) as compared to those less than 65 (2.1% vs. 1.4%). (See WARNINGS: Arterial Thromboembolic Events)

Page last updated: 2007-09-20

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