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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. Avastin has an approximate molecular weight of 149 kD. Bevacizumab is produced in a mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.

Avastin is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous 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 mg α,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.

Last updated on RxList: 8/12/2009

Metastatic Colorectal Cancer (mCRC)

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

Non-Squamous Non–Small Cell Lung Cancer (NSCLC)

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

Metastatic Breast Cancer (MBC)

Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies.]

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Glioblastoma

Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies.]

Metastatic Renal Cell Carcinoma (mRCC)

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Administration

Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion.

• Do not initiate Avastin until at least 28 days following major surgery. Administer Avastin after the surgical incision has fully healed.
• First infusion: Administer infusion over 90 minutes.
• Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated; administer all subsequent infusions over 30 minutes if infusion over 60 minutes is tolerated.

Recommended Doses and Schedules

Patients should continue treatment until disease progression or unacceptable toxicity.

Metastatic Colorectal Cancer (mCRC)

The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy.

• Administer 5 mg/kg when used in combination with bolus-IFL.
• Administer 10 mg/kg when used in combination with FOLFOX4.

Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

The recommended dose is 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel.

Metastatic Breast Cancer (MBC)

The recommended dose is 10 mg/kg every 2 weeks in combination with paclitaxel.

Glioblastoma

The recommended dose is 10 mg/kg every 2 weeks.

Metastatic Renal Cell Carcinoma (mRCC)

The recommended dose is 10 mg/kg every 2 weeks in combination with interferon alfa.

Preparation for Administration

Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of Avastin and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives.

DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION.

Dose Modifications

There are no recommended dose reductions.

Discontinue Avastin for:

• Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ [See BOXED WARNING, WARNINGS AND PRECAUTIONS.]
• Wound dehiscence and wound healing complications requiring medical intervention [See WARNINGS AND PRECAUTIONS.]
• Serious hemorrhage (i.e., requiring medical intervention) [See BOXED WARNING, WARNINGS AND PRECAUTIONS.]
• Severe arterial thromboembolic events [See WARNINGS AND PRECAUTIONS.]
• Hypertensive crisis or hypertensive encephalopathy [See WARNINGS AND PRECAUTIONS.]
• Reversible posterior leukoencephalopathy syndrome (RPLS) [See WARNINGS AND PRECAUTIONS.]
• Nephrotic syndrome [See WARNINGS AND PRECAUTIONS.]

Temporarily suspend Avastin for:

• At least 4 weeks prior to elective surgery [See WARNINGS AND PRECAUTIONS.]
• Severe hypertension not controlled with medical management [See WARNINGS AND PRECAUTIONS.]
• Moderate to severe proteinuria pending further evaluation [See WARNINGS AND PRECAUTIONS.]
• Severe infusion reactions [See WARNINGS AND PRECAUTIONS.]

Dosage Forms And Strengths

100 mg per 4 mL single-use vial

400 mg per 16 mL single-use vial

Storage And Handling

Avastin vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-061-01)] are stable at 2-8°C (36-46°F). Avastin vials should be protected from light. Do not freeze or shake.

Diluted Avastin solutions may be stored at 2-8°C (36-46°F) for up to 8 hours. Store in the original carton until time of use. No incompatibilities between Avastin and polyvinylchloride or polyolefin bags have been observed.

Manufactured by: Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080-4990. Revision Date: July 2009

Last updated on RxList: 8/12/2009

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Gastrointestinal Perforations [SEE BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS.]
• Surgery and Wound Healing Complications [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS.]
• Hemorrhage [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS.]
• Non-Gastrointestinal Fistula Formation [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS.]
• Arterial Thromboembolic Events [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS.]
• Hypertensive Crisis [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS.]
• Reversible Posterior Leukoencephalopathy Syndrome [See DOSAGE AND ADMINISTRATION,WARNINGS AND PRECAUTIONS]
• Proteinuria [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS.]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

Clinical Trial Experience

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 data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies.] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications

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 Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS.]

Hemorrhage

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. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagi events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS.]

Venous Thromboembolic Events

The incidence of 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. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was 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 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 Grade 3-4 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).

Neutropenia and Infection

The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (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 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%)].

In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

Proteinuria

Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See WARNINGS AND PRECAUTIONS.]

Congestive Heart Failure

The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3-4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC)

The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3-4 adverse events and selected Grade 1-2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3-4) 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 1.

Table 1 : NCI-CTC Grade 3-4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2%] Avastin vs. Control)

	Arm 1 IFL + Placebo (n = 396)	Arm 2 IFL + Avastin (n = 392)
NCI-CTC Grade 3-4 Events	74%	87%
Body as a Whole
Asthenia	7%	10%
Abdominal Pain	5%	8%
Pain	5%	8%
Cardiovascular
Hypertension	2%	12%
Deep Vein Thrombosis	5%	9%
Intra-Abdominal Thrombosis	1%	3%
Syncope	1%	3%
Digestive
Diarrhea	25%	34%
Constipation	2%	4%
Hemic/Lymphatic
Leukopenia	31%	37%
Neutropeniaa	14%	21%
a Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

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 2. Grade 1-4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.

Table 2 : NCI-CTC Grade 1-4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 5%] in IFL+Avastin vs. IFL)

	Arm 1 IFL + Placebo (n = 98)	Arm 2 IFL + Avastin (n = 102)	Arm 3 5-FU/LV + Avastin (n = 109)
Body as a Whole
Pain	55%	61%	62%
Abdominal Pain	55%	61%	50%
Headache	19%	26%	26%
Cardiovascular
Hypertension	14%	23%	34%
Hypotension	7%	15%	7%
Deep Vein Thrombosis	3%	9%	6%
Digestive
Vomiting	47%	52%	47%
Anorexia	30%	43%	35%
Constipation	29%	40%	29%
Stomatitis	18%	32%	30%
Dyspepsia	15%	24%	17%
GI Hemorrhage	6%	24%	19%
Weight Loss	10%	15%	16%
Dry Mouth	2%	7%	4%
Colitis	1%	6%	1%
Hemic/Lymphatic
Thrombocytopenia	0%	5%	5%
Nervous
Dizziness	20%	26%	19%
Respiratory
Upper Respiratory Infection	39%	47%	40%
Epistaxis	10%	35%	32%
Dyspnea	15%	26%	25%
Voice Alteration	2%	9%	6%
Skin/Appendages
Alopecia	26%	32%	6%
Skin Ulcer	1%	6%	6%
Special Senses
Taste Disorder	9%	14%	21%
Urogenital
Proteinuria	24%	36%	36%

Avastin in Combination with FOLFOX4 in Second-line mCRC

Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events) occurring at a higher incidence ( ≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events (occurring at a higher incidence ( ≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Metastatic Breast Cancer (MBC)

Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 5. Grade 3-4 adverse events occurring at a higher incidence ( ≥ 2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%).

Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.

Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).

Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1-4 events which occurred at a higher incidence ( ≥ 5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 : NCI-CTC Grade 1-4 Adverse Events in Study 6 (Occurring at Higher Incidence [ ≥ 5%] in Capecitabine + Avastin vs. Capecitabine Alone)

	Capecitabine (n = 215)	Capecitabine + Avastin (n = 229)
Body as a Whole
Asthenia	47%	57%
Headache	13%	33%
Pain	25%	31%
Cardiovascular
Hypertension	2%	24%
Digestive
Stomatitis	19%	25%
Metabolic/Nutrition
Weight loss	4%	9%
Musculoskeletal
Myalgia	8%	14%
Respiratory
Dyspnea	18%	27%
Epistaxis	1%	16%
Skin/Appendages
Exfoliative dermatitis	75%	84%
Urogenital
Albuminuria	7%	22%

Glioblastoma

All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1-4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3-5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC)

All grade adverse events were collected in Study 9. Grade 3-5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1-5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN-α plus Avastin compared to the IFN-α plus placebo arm are presented in Table 4.

Table 4 : NCI-CTC Grades 1-5 Adverse Events in Study 9 (Occuring at Higher Incidence [ ≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo)

System Organ Class/Preferred term*	IFN-α + Placebo (n = 304)	IFN-α +Avastin (n = 337)
Gastrointestinal disorders
Diarrhea	16%	21%
General disorders and administration site conditions
Fatigue	27%	33%
Investigations
Weight decreased	15%	20%
Metabolism and nutrition disorders
Anorexia	31%	36%
Musculoskeletal and connective tissue disorders
Myalgia	14%	19%
Back pain	6%	12%
Nervous system disorders
Headache	16%	24%
Renal and urinary disorders
Proteinuria	3%	20%
Respiratory, thoracic and mediastinal disorders
Epistaxis	4%	27%
Dysphonia	0%	5%
Vascular disorders
Hypertension	9%	28%
*Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

Immunogenicity

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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Polyserositis

Cardiovascular: Pulmonary hypertension, RPLS

Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)

Respiratory: Nasal septum perforation, dysphonia

A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, 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.

In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

Last updated on RxList: 8/12/2009

Included as part of the PRECAUTIONS section.

Gastrointestinal Perforations

Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See ADVERSE REACTIONS.]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See BOXED WARNING, DOSAGE AND ADMINISTRATION.]

Surgery and Wound Healing Complications

Avastin impairs wound healing in animal models. [See Nonclinical Toxicology.] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See ADVERSE REACTIONS.]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

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. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See BOXED WARNING, DOSAGE AND ADMINISTRATION.]

Hemorrhage

Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See ADVERSE REACTIONS.]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non-small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%-5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3-4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥ ½ teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See BOXED WARNING, DOSAGE AND ADMINISTRATION.]

Non-Gastrointestinal Fistula Formation

Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See DOSAGE AND ADMINISTRATION.]

Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations.]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See DOSAGE AND ADMINISTRATION.]

Hypertension

The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See DOSAGE AND ADMINISTRATION.]

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. 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. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.

Discontinue Avastin in patients developing RPLS. 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. [See DOSAGE AND ADMINISTRATION.]

Proteinuria

The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See ADVERSE REACTIONS.] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations.] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See DOSAGE AND ADMINISTRATION.]

Infusion Reactions

Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon ( < 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See DOSAGE AND ADMINISTRATION.]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity studies of bevacizumab have been conducted.

Bevacizumab may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrested follicular development or absent corpora lutea as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. 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; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology.]

Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11-50 days]) and the importance of the drug to the mother. [See CLINICAL PHARMACOLOGY.]

Pediatric Use

The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

Geriatric Use

In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients 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 2, patients aged ≥ 65 years 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 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See WARNINGS AND PRECAUTIONS.]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with 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 aged ≥ 65 years and 1127 patients < 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 aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See WARNINGS AND PRECAUTIONS.]

Last updated on RxList: 8/12/2009

The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

None.

Last updated on RxList: 8/12/2009

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 vitro models 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, gender, and 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 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.

Animal Toxicology and/or Pharmacology

In cynomolgus monkeys, when bevacizumab was administered at doses of 0.4 to 20 times the weekly human exposure, anatomical pathology revealed several adverse effects on general growth and skeletal development, fertility and wound healing capacity. Severe physeal dysplasia was consistently reported in juvenile monkeys with open growth plates receiving 0.4 to 20 times the human dose. The physeal dysplasia was characterized by a linear cessation of growth line and chondrocyte hyperplasia which did not completely resolve after the 4 to 12 weeks recovery period without drug exposure.

Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.

Reproductive and Developmental Toxicology

Pregnant rabbits dosed with 1 to 12 times the human dose of bevacizumab every three days during the period of organogenesis (gestation day 6-18) exhibited teratogenic effects, decreases in maternal and fetal body weights, and increased number of fetal resorptions. Teratogenic effects included: reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws; meningocele; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges. There are no data available regarding the level of bevacizumab exposure in the offspring.

Clinical Studies

Metastatic Colorectal Cancer (mCRC)

Study 1

In this double-blind, active-controlled study, patients were randomized (1:1:1) to IV bolus-IFL (irinotecan 125 mg/m², 5-FU 500 mg/m², and leucovorin (LV) 20 mg/m² 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. The main outcome measure was overall survival (OS).

Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 40% were female, 79% were Caucasian, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prior adjuvant chemotherapy. In 56% of the patients, the dominant site of disease was extra-abdominal, while the liver was the dominant site in 38% of patients.

The addition of Avastin resulted in an improvement in survival across subgroups defined by age ( < 65 yrs, ≥ 65 yrs) and gender. Results are presented in Table 5 and Figure 1.

Table 5 : Study 1 Efficacy Results

	IFL + Placebo	IFL + Avastin 5 mg/kg q 2 wks
Number of Patients	411	402
Overall Survivala
Median (months)	15.6	20.3
Hazard ratio		0.66
Progression-free Survivala
Median (months)	6.2	10.6
Hazard ratio		0.54
Overall Response Rateb
Rate (percent)	35%	45%
Duration of Response
Median (months)	7.1	10.4
a p < 0.001 by stratified log rank test. b p < 0.01 by χ² test.

Figure 1 : Duration of Survival in Study 1

Among the 110 patients enrolled in Arm 3, median OS was 18.3 months, median progression-free survival (PFS) was 8.8 months, objective response rate (ORR) was 39%, and median duration of response was 8.5 months.

Study 2

Study 2 was a randomized, open-label, active-controlled trial in patients who were previously treated with irinotecan +/- 5-FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized (1:1:1) to IV FOLFOX4 (Day 1: oxaliplatin 85 mg/m² and LV 200 mg/m² concurrently, then 5-FU 400 mg/m² bolus followed by 600 mg/m² continuously; Day 2: LV 200 mg/m², then 5-FU 400 mg/m² bolus followed by 600 mg/m² continuously; repeated every 2 weeks), FOLFOX4 plus Avastin (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1), or Avastin monotherapy(10 mg/kg every 2 weeks). The main outcome measure was OS.

The Avastin monotherapy arm was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee based on evidence of decreased survival compared to FOLFOX4 alone.

Of the 829 patients randomized to the three arms, the median age was 61 years, 40% were female, 87% were Caucasian, 49% had an ECOG performance status of 0, 26% received prior radiation therapy, and 80% received prior adjuvant chemotherapy, 99% received prior irinotecan, with or without 5-FU as therapy for metastatic disease, and 1% received prior irinotecan and 5-FU as adjuvant therapy.

The addition of Avastin to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone (median OS 13.0 months vs. 10.8 months; hazard ratio 0.75 [95% CI 0.63, 0.89], p = 0.001 stratified log rank test) with clinical benefit seen in subgroups defined by age ( < 65 yrs, ≥ 65 yrs) and gender. PFS and ORR based on investigator assessment were higher in the Avastin plus FOLFOX4 arm.

Study 3

The activity of Avastin in combination with bolus or infusional 5-FU/LV was evaluated in a single arm study enrolling 339 patients with mCRC with disease progression following both irinotecan- and oxaliplatin-containing chemotherapy regimens. Seventy-three percent of patients received concurrent bolus 5-FU/LV. One objective partial response was verified in the first 100 evaluable patients for an overall response rate of 1% (95% CI 0-5.5%).

Unresectable Non–Squamous Non–Small Cell Lung Cancer (NSCLC)

Study 4

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.

Chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel 200 mg/m² and carboplatin AUC=6.0, by IV on day 1 (PC) or PC in combination with Avastin 15 mg/kg by IV 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. Patients with predominant squamous histology (mixed cell type tumors only), central nervous system (CNS) metastasis, gross hemoptysis ( ≥ ½ tsp of red blood), unstable angina, or receiving therapeutic anticoagulation were excluded. The main outcome measure was duration of survival.

Of the 878 patients randomized, 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 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease.

The results are presented in Figure 2. OS was statistically significantly higher among patients receiving PC plus Avastin compared with those receiving PC alone; median OS was 12.3 months vs. 10.3 months [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 PFS with Avastin in combination with PC compared to PC alone.

Figure 2 : Duration of Survival in Study 4

In an exploratory analyses across patient subgroups, the impact of Avastin on OS 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)].

Metastatic Breast Cancer (MBC)

Study 5

The efficacy and safety of Avastin as first-line treatment of patients with MBC was studied in a single, open-label, randomized, multicenter study. Patients who had not received chemotherapy for locally recurrent or MBC were randomized (1:1) to receive paclitaxel (90 mg/m² IV once weekly for 3 out of 4 weeks) alone or in combination with Avastin (10 mg/kg IV infusion every 2 weeks). Patients were treated until disease progression or unacceptable toxicity. In situations where paclitaxel was discontinued or held, treatment with Avastin alone could be continued until disease progression. Patients with breast cancer overexpressing HER2 were not eligible unless they had received prior therapy with trastuzumab.

Prior hormonal therapy for the treatment of metastatic disease was allowed, as was prior adjuvant chemotherapy or hormonal therapy. Adjuvant taxane therapy, if received, must have been completed 12 or more months prior to study entry. Patients with central nervous system metastasis were excluded. The main outcome measure of the study was PFS as assessed by independent radiographic review. Secondary outcome measures were OS and ORR.

Of the 722 patients randomized, the median age was 55 years, 76% were white, 55% were postmenopausal, and 64% were ER and/or PR positive. Patient characteristics were similar across treatment arms. Thirty-six percent had received prior hormonal therapy for advanced disease, and 66% had received adjuvant chemotherapy, including 20% with prior taxane use and 50% with prior anthracycline use. Efficacy results are summarized in Table 6.

Table 6 : Avastin Efficacy Results from Study 5

Efficacy Parameter	Avastin + Paclitaxel (n=368)	Paclitaxel Alone (n=354)	p-value	HR (95% CI)
Progression-free Survival	11.3	5.8		0.48
[median, months (95% CI)]	(10.5, 13.3)	(5.4, 8.2)	< 0.0001	(0.39, 0.61)
Overall Survival	26.5	24.8		0.87
[median, months (95% CI)]	(23.7, 29.2)	(21.4, 27.4)	0.14	(0.72, 1.05)
Partial Response Rate1 (PR)	48.9%2	22.2%	< 0.001	-
1 Includes only patients with measurable disease. 2 The difference in partial response rates is 26.7% with a 95% CI (18.4%, 35.0%).

The addition of Avastin to paclitaxel resulted in an improvement in PFS with no significant improvement in OS. Partial response rates in patients with measurable disease were higher with Avastin plus paclitaxel. No complete responses were observed.

Thirty-four percent of the patients had incomplete follow-up for disease progression; therefore an exploratory analysis using similar imputation between arms was performed, which yielded a hazard ratio of 0.57.

Study 6

The efficacy and safety of Avastin as second- and third-line treatment of patients with MBC was studied in a single open-label randomized study. Patients who had received prior anthracycline and taxane therapy in the adjuvant setting or for their MBC were randomized (1:1) to receive capecitabine alone or in combination with Avastin. Of the 462 enrolled patients, the median age was 51 years, 81% were white, and 50% were ER positive. Patient characteristics were similar across the treatment arms.

The study failed to demonstrate a statistically significant effect on PFS or OS. The median PFS was 4.2 months in the capecitabine arm and 4.9 months in the capecitabine plus Avastin arm (log-rank p-value = 0.86, hazard ratio 0.98). The median OS was 14.5 months in the capecitabine arm and 15.1 months in the capecitabine plus Avastin arm (hazard ratio of 1.08).

Glioblastoma

Study 7

The efficacy and safety of Avastin was evaluated in Study 7, an open-label, multicenter, randomized, non-comparative study of patients with previously treated glioblastoma. Patients received Avastin (10 mg/kg IV) alone or Avastin plus irinotecan every 2 weeks until disease progression or until unacceptable toxicity. All patients received prior radiotherapy (completed at least 8 weeks prior to receiving Avastin) and temozolomide. Patients with active brain hemorrhage were excluded.

Of the 85 patients randomized to the Avastin arm, the median age was 54 years, 32% were female, 81% were in first relapse, Karnofsky performance status was 90-100 for 45% and 70-80 for 55%.

The efficacy of Avastin was demonstrated using response assessment based on both WHO radiographic criteria and by stable or decreasing corticosteroid use, which occurred in 25.9% (95% CI 17.0%, 36.1%) of the patients. Median duration of response was 4.2 months (95% CI 3.0, 5.7). Radiologic assessment was based on MRI imaging (using T1 and T2/FLAIR). MRI does not necessarily distinguish between tumor, edema, and radiation necrosis.

Study 8

Study 8, was a single-arm, single institution trial with 56 patients with glioblastoma. All patients had documented disease progression after receiving temozolomide and radiation therapy. Patients received Avastin 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity.

The median age was 54, 54% were male, 98% Caucasian, and 68% had a Karnofsky Performance Status of 90-100.

The efficacy of Avastin was supported by an objective response rate of 19.6% (95% CI 10.9%, 31.3%) using the same response criteria as in Study 7. Median duration of response was 3.9 months 95% CI 2.4, 17.4).

Metastatic Renal Cell Carcinoma (mRCC)

Study 9

Patients with treatment-naïve mRCC were evaluated in a multicenter, randomized, double-blind, international study comparing Avastin plus interferon alfa 2a (IFN- α2a) versus placebo plus IFN-α2a. A total of 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either Avastin (10 mg/kg IV infusion every 2 weeks; n = 327) or placebo (IV every 2 weeks; n = 322) in combination with IFN-α2a (9 MIU subcutaneously three times weekly, for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure of the study was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 60 years (range 18-82), 96% were white, and 70% were male. The study population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate (1-2), 8% poor (3-5), and 7% missing.

The results are presented in Figure 3. PFS was statistically significantly prolonged among patients receiving Avastin plus IFN-α2a compared to those receiving IFN-α2a alone; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95% CI 0.49, 0.72), p-value < 0.0001, stratified log-rank test]. Among the 595 patients with measureable disease, ORR was also significantly higher (30% vs. 12%, p < 0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the Avastin plus IFN-α2a arm and 21 months in the IFN-α2a plus placebo arm [HR 0.86, (95% CI 0.72, 1.04)].

Figure 3 : Progression-Free Survival in Study 9

Last updated on RxList: 8/12/2009

Advise patients:

• To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated.
• To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting.
• Of increased risk of wound healing complications during and following Avastin.
• Of increased risk of an arterial thromboembolic event.
• Of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following last dose of Avastin.

Last updated on RxList: 8/12/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

BEVACIZUMAB - INJECTION

(bev-ah-CIZ-oo-mab)

COMMON BRAND NAME(S): Avastin

WARNING: This medication can rarely cause a tear in the stomach/intestines (gastrointestinal perforation and wound dehiscence), bloody vomit, or bleeding in the lungs, which sometimes can be fatal. Seek immediate medical attention if you develop: severe stomach/abdominal pain, constipation with vomiting, fever, black/bloody stools, blood in vomit, or coughing up blood.

Tell your surgeon that you are taking this medication before having any type of surgery (see also Precautions section).

USES: This medication is a man-made antibody (IgG1) used along with chemotherapy to treat patients who have colon and rectal cancer, which has spread to other parts of the body. Bevacizumab is also used along with chemotherapy to treat patients who have lung cancer (non-small cell type). This drug works by blocking a certain protein (vascular endothelial growth factor-VEGF) thereby decreasing the blood supply to the tumor and slowing tumor growth.

HOW TO USE: The first dose of this medication is administered by infusion into a vein over 90 minutes by a health care professional. Follow all instructions for proper mixing and dilution with the correct IV fluids. If you have questions regarding the use of this medication, consult your pharmacist. Do not shake. It is usually given once every 2 weeks. If this medication is tolerated, then later infusions can be given over a shorter time (60 or 30 minutes).

The dosage is based on your condition, response to previous therapy, and your weight. Tell your doctor if your weight changes.

Use this medication regularly in order to get the most benefit from it. Try not to miss any doses.

Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.

SIDE EFFECTS: Dry mouth, cough, voice changes, loss of appetite, diarrhea, vomiting, constipation, mouth sores, nausea, headache may occur. If any of these effects persist or worsen, notify your doctor or pharmacist immediately.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these serious side effects occur: trouble breathing, swelling of ankles/feet, sudden weight gain, unusual tiredness, fast heartbeat, fainting, signs of infection (e.g., fever, persistent sore throat), difficulty urinating.

Tell your doctor immediately if any of these unlikely but serious side effects occur: calf pain/swelling, muscle cramps.

Tell your doctor immediately if any of these highly unlikely but very serious side effects occur: severe stomach/abdominal pain, frothy/dark urine, yellowing eyes/skin, muscle loss, decreased amount of urine.

Bevacizumab infrequently may cause blood clots to form, leading to serious medical conditions (heart attack/angina, stroke/TIA). Seek immediate medical attention if you develop chest pain/tightness, sudden vision changes, weakness on one side of the body, confusion, or slurred speech. If any of these conditions occur, you should not be given this medication again.

This medication can cause bleeding. Some episodes may be minor including nosebleeds, minor gum bleeding, and vaginal bleeding. If these persist or worsen, notify your doctor or pharmacist promptly. Other episodes may be more serious including stomach bleeding or bleeding in the lungs (see also Warning section).

Have your blood pressure checked regularly while taking this medication. Learn how to monitor your own blood pressure at home, and share the results with your doctor.

Rarely, bevacizumab may cause a condition called RPLS (reversible posterior leukoencephalopathy syndrome). Seek immediate medical attention if you develop persistent headache, seizures, sudden vision changes, mental/mood changes (e.g., confusion).

A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, swelling, severe dizziness, severe trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using bevacizumab, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: stomach/intestinal ulcers, recent bloody vomiting or coughing up blood, recent major surgery, a fistula (an abnormal tunnel connecting two body cavities such as the bladder and the vagina).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high blood pressure, heart disease or blood clots (arterial vessels), kidney disease, brain tumors, lung tumors.

Before having any surgery (including dental), tell your doctor that you are using this medication. Bevacizumab has been shown to slow wound healing. Do not begin using this medication until at least 28 days after any major surgery, unless directed otherwise by your doctor.

Do not have immunizations/vaccinations without your doctor's consent and avoid contact with people who have recently received oral polio vaccine.

Use caution with sharp objects like safety razors or nail cutters and avoid activities such as contact sports to lower the chance of getting cut, bruised, or injured.

Caution is advised when using this drug in the elderly because they may be at greater risk for side effects (e.g., blood clots, kidney effects such as protein in the urine). See also Side Effects section.

This medication should be used only when clearly needed during pregnancy. Bevacizumab may cause harm to an unborn baby. If you become pregnant or think you may be pregnant, inform your doctor immediately. Women of child-bearing age should use an effective form of birth control while using this medication and for an extended period after stopping this drug. Discuss the risks, benefits and any other concerns with your doctor.

Based on information from related drugs, this medication may pass into breast milk. Therefore, breast-feeding while using this medication is not recommended. Also, do not breast-feed for extended period after stopping this drug. Consult your doctor or pharmacist before breast-feeding and if more details are needed.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: sunitinib.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: severe headache.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood pressure monitoring, urine tests for protein, kidney function tests, bilirubin levels, complete blood counts-CBC) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, contact your doctor or pharmacist to immediately to establish a new dosing schedule.

STORAGE: Refrigerate between 36-46 degrees F (2-8 degrees C). Do not freeze. Keep all medicines away from children and pets.

Once mixed, the drug may be stored for up to 8 hours in the refrigerator. Discard if not used within the 8 hours.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.