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All about: Avastin

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Generic Name: bevacizumab
Dosage Form: Injection

For Intravenous Use

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.)

Avastin Description

Avastin® (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework regions and the complementarity‑determining regions of a murine antibody that binds to VEGF ( 1). Bevacizumab is produced in a Chinese Hamster Ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin and has a molecular weight of approximately 149 kilodaltons. Avastin is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion. Avastin is supplied in 100 mg and 400 mg preservative‑free, single‑use vials to deliver 4 mL or 16 mL of Avastin (25 mg/mL). The 100 mg product is formulated in 240 mgα,α‑trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg α,α‑trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP.

Avastin - Clinical Pharmacology

MECHANISM OF ACTION

Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt‑1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitromodels of angiogenesis. Administration of Bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

PHARMACOKINETICS

The pharmacokinetic profile of Bevacizumab was assessed using an assay that measures total serum Bevacizumab concentrations (i.e., the assay did not distinguish between free Bevacizumab and Bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of Avastin weekly, every 2 weeks, or every 3 weeks, the estimated half‑life of Bevacizumab was approximately 20 days (range 11–50 days). The predicted time to reach steady state was 100 days. The accumulation ratio following a dose of 10 mg/kg of Bevacizumab every 2 weeks was 2.8.

The clearance of Bevacizumab varied by body weight, by gender, and by tumor burden. After correcting for body weight, males had a higher Bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc (3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median value of tumor surface area) had a higher Bevacizumab clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens below the median. In a randomized study of 813 patients (Study 1), there was no evidence of lesser efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated with Avastin as compared to females and patients with low tumor burden. The relationship between Bevacizumab exposure and clinical outcomes has not been explored.

SPECIAL POPULATIONS

Analyses of demographic data suggest that no dose adjustments are necessary for age or sex.

Patients with renal impairment. No studies have been conducted to examine the pharmacokinetics of Bevacizumab in patients with renal impairment.

Patients with hepatic dysfunction. No studies have been conducted to examine the pharmacokinetics of Bevacizumab in patients with hepatic impairment.

Clinical Studies

Avastin® In Metastatic Colorectal Cancer (mCRC)

The safety and efficacy of Avastin in the treatment of patients with metastatic carcinoma of the colon or rectum were studied in three randomized, controlled clinical trials in combination with intravenous 5‑fluorouracil‑based chemotherapy. The activity of Avastin in patients with metastatic colorectal cancer that progressed on or after receiving both irinotecan based- and oxaliplatin based‑chemotherapy regimens was evaluated in an open‑access trial in combination with intravenous 5‑fluorouracil‑based chemotherapy.

Avastin in Combination with Bolus‑IFL

Study 1 was a randomized, double‑blind, active‑controlled clinical trial evaluating Avastin as first‑line treatment of metastatic carcinoma of the colon or rectum. Patients were randomized to bolus‑IFL (irinotecan 125 mg/m2 IV, 5‑fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), bolus‑IFL plus Avastin (5 mg/kg every 2 weeks) (Arm 2), or 5‑FU/LV plus Avastin (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 was discontinued, as pre‑specified, when the toxicity of Avastin in combination with the bolus‑IFL regimen was deemed acceptable.

Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 40% were female, and 79% were Caucasian. Fifty‑seven percent had an ECOG performance status of 0. Twenty‑one percent had a rectal primary and 28% received prior adjuvant chemotherapy. In the majority of patients, 56%, the dominant site of disease was extra‑abdominal, while the liver was the dominant site in 38% of patients. Results are presented in Table 1 and Figure 1.

Table 1: Study 1 Efficacy Results
IFL + Placebo IFL + Avastin
5 mg/kg q 2 wks
*
p < 0.001 by stratified logrank test.
p < 0.01 byχ2 test
Number of Patients 411 402
Overall Survival*
 Median (months) 15.6 20.3
 Hazard ratio 0.66
Progression‑free Survival*
Median (months) 6.2 10.6
 Hazard ratio 0.54
Overall Response Rate
 Rate (percent) 35% 45%
Duration of Response
 Median (months) 7.1 10.4
Figure 1: Duration of Survival in Study 1
Error bars represent 95% confidence intervals.

The clinical benefit of Avastin, as measured by survival in the two principal arms, was seen in subgroups defined by age (<65 yrs,≥65 yrs) and gender.

Among the 110 patients enrolled in Arm 3, median overall survival was 18.3 months, median progression‑free survival was 8.8 months, overall response rate was 39%, and median duration of response was 8.5 months.

Avastin in Combination with 5‑FU/LV Chemotherapy

Study 2 was a randomized, active‑controlled clinical trial testing Avastin in combination with 5‑FU/LV as first‑line treatment of metastatic colorectal cancer. Patients were randomized to receive 5‑FU/LV (5‑fluorouracil 500 mg/m2, leucovorin 500 mg/m2 weekly for 6 weeks every 8 weeks) or 5‑FU/LV plus Avastin (5 mg/kg every 2 weeks) or 5‑FU/LV plus Avastin (10 mg/kg every 2 weeks). The primary endpoints of the trial were objective response rate and progression‑free survival. Results are presented in Table 2.

Table 2: Study 2 Efficacy Results
5-FU/LV 5‑FU/LV + Avastin 5 mg/kg 5‑FU/LV+ Avastin 10 mg/kg
Number of Patients 36 35 33
Overall Survival
 Median (months) 13.6 17.7 15.2
Progression‑free Survival
 Median (months) 5.2 9.0 7.2
Overall Response Rate
 Rate (percent) 17 40 24

Progression‑free survival was significantly longer in patients receiving 5‑FU/LV plus Avastin at 5 mg/kg when compared to those not receiving Avastin. However, overall survival and overall response rate were not significantly different. Outcomes for patients receiving 5‑FU/LV plus Avastin at 10 mg/kg were not significantly different than for patients who did not receive Avastin.

Avastin in Combination with 5‑FU/LV and Oxaliplatin Chemotherapy

Study 3 was an open‑label, randomized, 3-arm, active-controlled, multicenter clinical trial evaluating Avastin alone, Avastin in combination with 5‑FU/LV and oxaliplatin (FOLFOX4), and FOLFOX4 alone in the second‑line treatment of metastatic carcinoma of the colon or rectum. Patients were previously treated with irinotecan and 5‑FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized to FOLFOX4 (Day 1: oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 concurrently IV, then 5-FU 400 mg/m2 IV bolus followed by 600 mg/m2 continuously IV; Day 2: leucovorin 200 mg/m2 IV, then 5‑FU 400 mg/m2 IV bolus followed by 600 mg/m2 continuously IV; repeated every 2 weeks), FOLFOX4 plus Avastin, or Avastin monotherapy. Avastin was administered at a dose of 10 mg/kg every 2 weeks and for patients in the FOLFOX4 plus Avastin arm, prior to the FOLFOX4 chemotherapy on Day 1.

Of the 829 patients randomized to the three arms, the median age was 61 years, 40% were female, 87% were Caucasian, and 49% had an ECOG performance status of 0. Twenty-six percent had received prior radiation therapy, and 80% received prior adjuvant chemotherapy. Ninety‑nine percent received prior irinotecan, with or without 5‑FU for metastatic colorectal cancer, and 1% received prior irinotecan and 5‑FU as adjuvant therapy.

The Avastin monotherapy arm of Study 3 was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee (DMC), based on evidence of decreased survival in the Avastin alone arm as compared to the FOLFOX4 alone arm. In the two remaining study arms, overall survival (OS) was significantly longer in patients receiving Avastin in combination with FOLFOX4 as compared to those receiving FOLFOX4 alone (median OS 13.0 mos vs. 10.8 mos; hazard ratio 0.75 [95% CI 0.63, 0.89], p=0.001 stratified logrank test). In addition, patients treated with Avastin in combination with FOLFOX4 were reported to have significantly longer progression-free survival and a higher overall response rate based on investigator assessment. The clinical benefit of Avastin, as measured by survival, was seen in the subgroups defined by age (<65 yrs,≥65 yrs) and gender.

Avastin in Third‑Line Metastatic Colorectal Cancer

Study 4 was an open access, multicenter, single arm study that evaluated the activity of Avastin in combination with bolus or infusional 5‑FU/LV in 339 patients with metastatic colorectal cancer with disease progression following both irinotecan‑ and oxaliplatin‑containing chemotherapy regimens. The majority (73%) of patients received concurrent 5‑FU/LV according to a bolus regimen.

There was one objective partial response in the first 100 evaluable patients for an overall response rate of 1% (95% CI 0–5.5%).

Avastin® In Unresectable Non‑Squamous, Non‑Small Cell Lung Cancer (NSCLC)

The safety and efficacy of Avastin as first line treatment of patients with locally advanced, metastatic, or recurrent non‑squamous, NSCLC was studied in a single, large, randomized, active‑controlled, open‑label, multicenter study (Study 5, n=878), supported by a randomized, dose ranging, active controlled Phase 2 study (Study 6, n=98).

In Study 5, chemotherapy‑naïve patients with locally advanced, metastatic or recurrent non‑squamous NSCLC were randomized (1:1) to receive six cycles of paclitaxel 200 mg⁄m2 and carboplatin AUC=6.0, both by IV infusion on day 1 (PC) or PC in combination with Avastin at a dose of 15 mg⁄kg by IV infusion on day 1 (PC plus Avastin). After completion or upon discontinuation of chemotherapy, patients in the PC plus Avastin arm continued to receive Avastin alone until disease progression or until unacceptable toxicity. Cycles were repeated every 21 days. Patients with predominant squamous histology (mixed cell type tumors only), central nervous system (CNS) metastasis, gross hemoptysis (≥1⁄2 tsp of red blood), or unstable angina and those receiving therapeutic anticoagulation were excluded. The main outcome measure of the study was duration of survival.

Among the 878 patients randomized to the two treatment arms, the median age was 63, 46% were female, 43% were ≥ age 65, and 28% had≥ 5% weight loss at study entry. Eleven percent had recurrent disease and of the remaining 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease. The survival curves are presented in Figure 2. Overall survival was statistically significantly higher among patients receiving PC plus Avastin compared with those receiving PC alone; median OS was 12.3 mos vs. 10.3 mos (hazard ratio 0.80 [repeated 95% CI 0.68, 0.94], final p‑value 0.013, stratified log‑rank test). Based on investigator assessment which was not independently verified, patients were reported to have longer progression‑free survival with Avastin in combination with PC compared to PC alone.

Figure 2: Duration of Survival in Study 5

In an exploratory analyses across patient subgroups, the impact of Avastin on overall survival was less robust in the following: women [HR = 0.99 (95% CI: 0.79, 1.25)], age≥ 65 years [HR = 0.91 (95% CI: 0.72, 1.14)] and patients with ≥5% weight loss at study entry [HR = 0.96 (95% CI: 0.73, 1.26)].

Indications and Usage for Avastin

Avastin®, in combination with intravenous 5‑fluorouracil‑based chemotherapy, is indicated for first- or second‑line treatment of patients with metastatic carcinoma of the colon or rectum.

Avastin®, in combination with carboplatin and paclitaxel, is indicated for first‑line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.

Contraindications

None.

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 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.

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 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. Twenty‑four 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‑

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