Avastin (Bevacizumab)
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Avastin (Bevacizumab)

AVASTIN®
(bevacizumab)

WARNING

GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Gastrointestinal Perforations

The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]

Surgery and Wound Healing Complications

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]

Hemorrhage

Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]

DRUG 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. 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.

What are the possible side effects of bevacizumab (Avastin)?

Bevacizumab can cause a rare but serious neurologic disorder affecting the brain. Symptoms include headache, confusion, vision problems, feeling very weak or tired, fainting, and seizure (blackout or convulsions). These rare symptoms may occur within hours of your first dose of bevacizumab, or they may not appear for up to a year after your treatment started. Call your doctor at once if you have any of these side effects.

Some people receiving a bevacizumab injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you...

Read All Potential Side Effects and See Pictures of Avastin »

What are the precautions when taking bevacizumab (Avastin)?

Before using bevacizumab, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

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...

Read All Potential Precautions of Avastin »

Last reviewed on RxList: 11/6/2012
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

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.

Limitation of Use

Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies]

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.

Glioblastoma

Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients 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.

DOSAGE AND ADMINISTRATION

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.

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]

HOW SUPPLIED

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.

Avastin® (bevacizumab), Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990. Rev: Oct 2012

Last reviewed on RxList: 11/6/2012
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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

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 3795 patients with CRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies.] Data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, an indication for which Avastin is not approved. The population was aged 18-88 years (median 59), 43.2% male and 85.3% white. The population included 1783 first- and second-line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first-line metastatic NSCLC patients who 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 5, 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 hemorrhagic 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, WARNINGS AND PRECAUTIONS, WARNINGS AND PRECAUTIONS]

Venous Thromboembolic Events

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, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. 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 (VTE). 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.

In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See DOSAGE AND ADMINISTRATION]

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 5, 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 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, 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 7). [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 metastatic breast cancer MBC, an indication for which Avastin is not approved, 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.

Ovarian Failure

The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum P-HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84 or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% (7/32) of the Avastin-treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post-treatment period. Long term effects of Avastin exposure on fertility are unknown. [See WARNINGS AND PRECAUTIONS, Use in Specific Populations]

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 IFLD + Placebo
(n = 396)
Arm 2 IFLD + 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/Aroendases
  Alopecia   26% 32% 6%
  Skin Ulcer   1% 6% 6%
Special Senses
  Taste Disorder 9% 14% 21%
Urosenital
  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%).

Glioblastoma

All adverse events were collected in 163 patients enrolled in Study 5 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 7. 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-a 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-a plus Avastin compared to the IFN-α plus placebo arm are presented in Table 3.

Table 3: NCI-CTC Grades 1-5 Adverse Events in Study 7 (Occurring at Higher Incidence [ ≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo)

System Organ Class/Preferred terma 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%
aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the IFN-a plus Avastin arm compared to IFN-a alone and not represented in Table 3: 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 an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment-emergent anti-bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-product antibody responses to bevacizumab is unknown.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and 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, Mesenteric venous occlusion

Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort

Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Musculoskeletal: Osteonecrosis of the jaw

Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)

Respiratory: Nasal septum perforation, dysphonia

Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

Read the Avastin (bevacizumab) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

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

Last reviewed on RxList: 11/6/2012
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 ≥ 1/2 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 2.6% compared to 0.8% 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]

Ovarian Failure

The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See ADVERSE REACTIONS, Use In Specific Populations ]

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 adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated 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 ]

Because of the observed teratogenic effects of bevacizumab in animals and of other 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. Human IgG is excreted in human milk, but 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.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

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]

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]

Females of Reproductive Potential

Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin-treated patients. [See WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]

Last reviewed on RxList: 11/6/2012
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

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.

CONTRAINDICATIONS

None.

Last reviewed on RxList: 11/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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 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 4 and Figure 1.

Table 4 : 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
Proeression-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

Duration of Survival in Study 1 - Illustration

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) to2 IV FOLFOX4 (Day 1: oxalip2 latin 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/m 2, 2th 2e n 5-FU 400 mg/m bolus followed by 600 mg/m 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%).

Lack of Efficacy in Adjuvant Treatment of Colon Cancer

Lack of efficacy of Avastin as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical trials.

The first study conducted in 3451 patients with high risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent, was a 3-arm study of Avastin administered at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule in combination with FOLFOX4, or on a 3-weekly schedule in combination with XELOX and FOLFOX4 alone. Patients were randomized as follows: 1151 patients to FOLFOX4 arm, 1155 to FOLFOX4 plus Avastin arm, and 1145 to XELOX plus Avastin arm. The median age was 58 years, 54% were male, 84% were Caucasian and 29% were ≥ age 65. Eighty-three percent had stage III disease.

The main efficacy outcome of the study was disease free survival (DFS) in patients with stage III colon cancer. Addition of Avastin to chemotherapy did not improve DFS. As compared to the control arm, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher in the FOLFOX4 plus Avastin and in the XELOX plus Avastin arms. The hazard ratios for DFS were 1.17 (95% CI: 0.98-1.39) for the FOLFOX4 plus Avastin versus FOLFOX4 and 1.07 (95% CI: 0.90-1.28) for the XELOX plus Avastin versus FOLFOX4. The hazard ratios for overall survival were 1.31 (95% CI=1.03, 1.67) and 1.27 (95% CI=1.00, 1.62) for the comparison of Avastin plus FOLFOX4 versus FOLFOX4 and Avastin plus XELOX versus FOLFOX4, respectively. Similar lack of efficacy for DFS were observed in the Avastin-containing arms compared to control in the high-risk stage II cohort.

In a second study, 2710 patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either Avastin administered at a dose equivalent to 2.5 mg/kg/week in combination with mFOLFOX6 (N=1356) or mFOLFOX6 alone (N=1354). The median age was 57 years, 50% were male and 87% Caucasian. Seventy-five percent had stage III disease. The main efficacy outcome was DFS among stage III patients. The hazard ratio for DFS was 0.92 (95% CI: 0.77, 1.10). Overall survival, an additional efficacy outcome, was not significantly improved with the addition of Avastin to mFOLFOX6 (HR=0.96, 95% CI=[0.75,1.22].

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-naive 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 ( ≥ 1/2 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

Duration of Survival in Study 4 - Illustration

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)].

The safety and efficacy of Avastin in patients with locally advanced, metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy was studied in another randomized, double-blind, placebo controlled, three-arm study of Avastin in combination with cisplatin and gemcitabine (CG) versus placebo and CG. A total of 1043 patients were randomized 1:1:1 to receive placebo plus CG, Avastin 7.5 mg/kg plus CG or Avastin 15.0 mg/kg plus CG. The median age was 58 years, 36% were female, and 29% were ≥ age 65. Eight percent had recurrent disease and 77% had Stage IV disease. Progression-free survival, the main efficacy outcome measure, was significantly higher in both Avastin containing arms compared to the placebo arm [HR 0.75 (95% CI 0.62, 0.91), p = 0.0026 for the Avastin 7.5 mg/kg plus CG arm and HR 0.82 (95% CI 0.68; 0.98), p = 0.0301 for the Avastin 15.0 mg/kg plus CG arm]. The addition of Avastin to CG chemotherapy failed to demonstrate an improvement in the duration of overall survival, an additional efficacy outcome measure, [HR 0.93 (95% CI 0.78; 1.11), p = 0.4203 for the Avastin 7.5 mg/kg plus CG arm and HR 1.03 (95% CI 0.86; 1.23), p = 0.7613 for the Avastin 15.0 mg/kg plus CG arm].

Glioblastoma

Study 5

The efficacy and safety of Avastin was evaluated in Study 5, 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 6

Study 6, 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 5. Median duration of response was 3.9 months (95% CI 2.4, 17.4).

Metastatic Renal Cell Carcinoma (mRCC)

Study 7

Patients with treatment-naive 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 measurable 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-a2a plus placebo arm [HR 0.86, (95% CI 0.72, 1.04)].

Figure 3: Progression-Free Survival in Study 7

Progression-Free Survival in Study 7 -  Illustration

Last reviewed on RxList: 11/6/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

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.
  • Of the increased risk for ovarian failure following Avastin treatment.

Last reviewed on RxList: 11/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

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.
  • Of the increased risk for ovarian failure following Avastin treatment.

Last reviewed on RxList: 11/6/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Avastin Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

BEVACIZUMAB - INJECTION

(BE-va-SIZ-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 to treat kidney, colon, and rectal cancer. Bevacizumab is also used to treat lung cancer (non-small cell type) and certain types of brain tumors. 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.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat a certain serious eye condition (age-related macular degeneration).

HOW TO USE: This medication is given by infusion into a vein by a health care professional. The first dose is usually given over 90 minutes. If you tolerate the first dose well, then later infusions may be given over a shorter time (60 or 30 minutes).

The dosage is based on your medical 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.

Disclaimer

Avastin Consumer (continued)

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 right away if you have any serious side effects, including: 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, calf pain/swelling, muscle cramps, severe stomach/abdominal pain, frothy/dark urine, yellowing eyes/skin, muscle loss, decreased amount of urine.

Symptoms of a severe infusion reaction that may occur during bevacizumab treatment include difficulty breathing, flushing, severe dizziness, nausea/vomiting, shaking, or chest pain. Tell your healthcare professional if you have any of these symptoms during your treatment. Your doctor will monitor you closely and will temporarily stop your treatment if a reaction occurs.

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).

This medication may cause high blood pressure. This reaction can be severe enough to require blood pressure treatment. Learn to check your blood pressure regularly and share the results with your doctor.

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

This medication may affect the ovaries, possibly reducing fertility and causing hormone changes. Talk to your doctor for more details.

A serious allergic reaction to this drug is unlikely, but get medical help right away if it occurs. Symptoms of a serious allergic reaction include: rash, itching/swelling (especially of the face/tongue/throat), 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.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Avastin (bevacizumab) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before using bevacizumab, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

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.

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.

Disclaimer

Avastin Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: sunitinib.

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: 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: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule.

STORAGE: Not applicable. This medication is given in a clinic and will not be stored at home.

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 May 2012. Copyright(c) 2012 First Databank, Inc.

Avastin Patient Information Including Side Effects

Brand Names: Avastin

Generic Name: bevacizumab (Pronunciation: bev a CIZ oo mab)

What is bevacizumab (Avastin)?

Bevacizumab is a cancer medicine that interferes with the growth of cancer cells and slows their growth and spread in the body.

Bevacizumab is used to treat a certain type of brain tumor, and certain types of cancers of the kidney, lung, colon and rectum. It is usually given as part of a combination of cancer medicines.

Bevacizumab may also be used for purposes not listed in this medication guide.

What are the possible side effects of bevacizumab (Avastin)?

Bevacizumab can cause a rare but serious neurologic disorder affecting the brain. Symptoms include headache, confusion, vision problems, feeling very weak or tired, fainting, and seizure (blackout or convulsions). These rare symptoms may occur within hours of your first dose of bevacizumab, or they may not appear for up to a year after your treatment started. Call your doctor at once if you have any of these side effects.

Some people receiving a bevacizumab injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, or have a headache, wheezing, or chest pain during the injection.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • any wound that will not heal;
  • severe stomach pain with fever, vomiting, and constipation;
  • blood in your urine or stools, vomit that looks like blood or coffee grounds;
  • easy bruising, unusual bleeding (nose, mouth, vagina, rectum), purple or red pinpoint spots under your skin, or any bleeding that will not stop;
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • sudden numbness or weakness, severe headache, confusion, or problems with vision, speech, or balance;
  • pain, swelling, warmth, or redness in one or both legs;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
  • dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, shortness of breath, uneven heartbeats, seizure);
  • puffy eyes, swelling in your stomach, arms, or legs;
  • rapid weight gain, urinating less than usual or not at all;
  • urine that looks foamy;
  • pain or burning when you urinate, loss of bladder or bowel control;
  • ongoing vaginal discharge, itching, or other irritation; or
  • missed menstrual periods.

Less serious side effects may include:

  • mild headache;
  • back pain;
  • diarrhea, loss of appetite;
  • cold symptoms such as stuffy nose, sneezing, sore throat;
  • dry or watery eyes;
  • dry or flaky skin, hair loss;
  • changes in your sense of taste; or
  • jaw pain, swelling, numbness, loose teeth, gum infection.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Avastin (bevacizumab) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about bevacizumab (Avastin)?

Treatment with bevacizumab may cause you to have problems with wound healing, which could result in bleeding or infection. If you need to have any type of surgery, you will need to stop receiving bevacizumab at least 4 weeks ahead of time. Do not start using bevacizumab for at least 4 weeks after surgery, or until your surgical incision heals.

Before being treated with bevacizumab, tell your doctor if you have a bleeding or blood-clotting disorder, heart disease, congestive heart failure, high blood pressure, or a history of heart attack, stroke, blood clots, or stomach or intestinal bleeding (including perforation).

Some people receiving a bevacizumab injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, itchy, or have a fast heartbeat, chills, wheezing, or chest pain during the injection.

Call your doctor at once if you have: any unusual bleeding or bruising, blood in your urine or stools, coughing up blood, any bleeding that will not stop, severe stomach pain with fever and vomiting, sudden numbness or weakness, leg pain or swelling, chest pain, severe headache, problems with speech or balance, swelling or rapid weight gain, urinating less than usual, loss of bladder or bowel control, or missed menstrual periods.

Bevacizumab can cause a rare but serious neurologic disorder affecting the brain. Symptoms include headache, confusion, vision problems, feeling very weak or tired, fainting, and seizure (blackout or convulsions). These rare symptoms may occur within hours of your first dose of bevacizumab, or they may not appear for up to a year after your treatment started. Call your doctor at once if you have any of these side effects.

To be sure this medication is not causing harmful effects, your blood pressure will need to be checked often. Your urine may also need to be tested. Visit your doctor regularly.

Bevacizumab may cause a woman's ovaries to stop working correctly. Symptoms of ovarian failure include 3 or more missed menstrual periods in a row. This may affect your fertility (ability to have children). Talk to your doctor about your specific risks.

Side Effects Centers

Avastin Patient Information including How Should I Take

What should I discuss with my healthcare provider before receiving bevacizumab (Avastin)?

You should not use bevacizumab if you are allergic to it, or if you have:

  • untreated or uncontrolled high blood pressure;
  • severe or uncontrolled bleeding;
  • an open skin wound;
  • an open surgical incision;
  • if you have had surgery within the past 4 weeks (28 days);
  • if you have recently been coughing up blood; or
  • if you plan to have surgery within the next 4 weeks (28 days).

To make sure you can safely receive bevacizumab, tell your doctor if you have any of these other conditions:

  • a bleeding or blood-clotting disorder;
  • a history of stomach or intestinal bleeding;
  • a history of perforation (a hole or tear) in your esophagus, stomach, or intestines;
  • heart disease, congestive heart failure;
  • high blood pressure; or
  • a history of heart attack, stroke, or blood clots.

FDA pregnancy category C. It is not known whether bevacizumab will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Bevacizumab may cause a woman's ovaries to stop working correctly. Symptoms of ovarian failure include 3 or more missed menstrual periods in a row. This may affect your fertility (ability to have children). Talk to your doctor about your specific risks.

It is not known whether bevacizumab passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are being treated with bevacizumab.

Older adults may be more likely to have side effects from this medication.

How is bevacizumab used (Avastin)?

Treatment with bevacizumab may cause you to have problems with wound healing, which could result in bleeding or infection. If you need to have any type of surgery, you will need to stop receiving bevacizumab at least 4 weeks ahead of time. Do not start using bevacizumab for at least 4 weeks after surgery, or until your surgical incision heals.

Bevacizumab is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Bevacizumab must be given slowly, and the IV infusion can take up to 90 minutes to complete.

Bevacizumab is usually given once every 2 weeks.

To be sure this medication is not causing harmful effects, your blood pressure will need to be checked often. Your urine may also need to be tested. Visit your doctor regularly.

Bevacizumab must be stored in a refrigerator and kept from freezing. Bevacizumab bottles should never be shaken.

Side Effects Centers

Avastin Patient Information including If I Miss a Dose

What happens if I miss a dose (Avastin)?

Call your doctor for instructions if you miss an appointment for your bevacizumab injection.

What happens if I overdose (Avastin)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of bevacizumab may cause a severe headache.

What should I avoid while using bevacizumab (Avastin)?

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

What other drugs will affect bevacizumab (Avastin)?

There may be other drugs that can interact with bevacizumab. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about bevacizumab.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 12.01. Revision date: 11/30/2011.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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