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Special Alerts
Avastin®: Intravitreal Use (Unapproved) Associated with Serious Ophthalmic Adverse Effects
December 2011
Hoffman-La Roche Limited, in collaboration with Health Canada, has notified healthcare professionals regarding serious ophthalmic adverse events in patients treated with intravitreal bevacizumab (Avastin©) injections. Cases of acute ocular inflammation, endophthalmitis, and infectious endophthalmitis, some resulting in blindness or near-blindness, have been reported in clusters. In the past, cases of sterile endophthalmitis, uveitis, vitritis, and other inflammatory adverse events, some leading to blindness, have also been reported (individual and cluster reports) following use of bevacizumab repackaged from a single vial into multiple syringes. Additionally, the U.S. Food and Drug Administration (FDA) has identified a group of streptococcal endophthalmitis cases in Florida that has led to investigation of aseptic technique breaches associated with repackaging bevacizumab for use in ophthalmic procedures.
Clinicians are reminded that bevacizumab is not approved for intravitreal use. The manufacturer and Health Canada will continue investigation into ophthalmic adverse events and will provide updates as warranted.
Information from Health Canada may be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/avastin_8_hpc-cps-eng.php.
Information from the U.S. FDA may be found at http://www.fda.gov/Drugs/DrugSafety/ucm270296.htm.
Avastin®: FDA and Health Canada Remove Breast Cancer Indication from the Product Labeling - Updated
November 2011
On November 18, 2011, the U.S. Food and Drug Administration (FDA) announced the removal of the metastatic breast cancer indication from bevacizumab (Avastin®) labeling, citing a lack of demonstrated safety and efficacy in metastatic breast cancer. A similar announcement was recently made by Health Canada in regards to the Canadian product labeling. After review of clinical trial data, both regulatory agencies determined that use of bevacizumab in patients with metastatic breast cancer did not prolong overall survival, quality of life, or provide a sufficient benefit in slowing disease progression to outweigh significant risks associated with treatment (eg, severe hypertension, hemorrhage, myocardial infarction, heart failure, GI perforation).
Bevacizumab (Avastin®) continues to be an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).
Information from the FDA regarding this issue may be found at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280536.htm.
Information from Health Canada regarding this issue may be found at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_159-eng.php.
Avastin®: Rate of Ovarian Failure Increased in Premenopausal Women
November 2011
Hoffman-La Roche Limited, in conjunction with Health Canada, has issued notice to Canadian healthcare professionals regarding an increased incidence of ovarian failure in premenopausal women treated with bevacizumab (Avastin®). In a phase III study of colon cancer patients, the incidence of ovarian failure was 39% in premenopausal patients receiving bevacizumab concomitantly with chemotherapy versus ~3% in those receiving chemotherapy alone. Ovarian function recovered in ~86% of affected women following discontinuation of bevacizumab. Chemotherapy is a risk factor for ovarian failure; however, when bevacizumab is used as an adjuvant treatment, the risk is higher. Avastin® Canadian product monograph has been updated to include this new important safety information.
Further information may be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/avastin_6_hpc-cps-eng.php.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(be vuh SIZ uh mab)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of metastatic colorectal cancer; treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous, nonsmall cell lung cancer; treatment of progressive glioblastoma; treatment of metastatic renal cell cancer (not an approved use in Canada)
Note: For the treatment of glioblastoma, effectiveness is based on improvement in objective response rate.
Use: Unlabeled
Treatment of metastatic breast cancer, recurrent cervical cancer, recurrent ovarian cancer, soft tissue sarcomas (angiosarcoma or hemangiopericytoma/solitary fibrous tumor), age-related macular degeneration (AMD)
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects have been observed in animal reproduction studies. Angiogenesis is of critical importance to human fetal development, and bevacizumab inhibits angiogenesis. Adequate contraception during therapy is recommended (and for ≥6 months following last dose of bevacizumab). Patients should also be counseled regarding prolonged exposure following discontinuation of therapy due to the long half-life of bevacizumab. Based on animal studies, bevacizumab may disrupt normal menstrual cycles and impair fertility by several effects, including reduced endometrial proliferation and follicular developmental arrest. Some parameters do not recover completely, or recover very slowly following discontinuation.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Immunoglobulins are excreted in breast milk, and it is assumed that bevacizumab may appear in breast milk. According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother. The half-life of bevacizumab is up to 50 days (average 20 days), and this should be considered when decisions are made concerning breast-feeding resumption.
Note: Canadian labeling recommends to discontinue breast-feeding during treatment and to avoid breast-feeding a minimum of 6 months following discontinuation of treatment.
Contraindications
There are no contraindications listed in the FDA-approved manufacturer's labeling.
Canadian labeling: Hypersensitivity to bevacizumab, any component of the formulation, Chinese hamster ovary cell products or other recombinant human or humanized antibodies; untreated CNS metastases
Warnings/Precautions
Boxed warnings:
• Gastrointestinal perforation: See “Concerns related to adverse effects” below.
• Hemorrhage: See “Concerns related to adverse effects” below.
• Wound dehiscence: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Fistula/abscess formation: Gastrointestinal fistula (including enterocutaneous, esophageal, duodenal, and rectal fistulas), and intra-abdominal abscess have been reported in patients receiving bevacizumab for colorectal cancer and other cancers (not related to treatment duration). Nongastrointestinal fistula formation (including tracheoesophageal, bronchopleural, biliary, vaginal,renal, and bladder fistulas) has been observed, most commonly within the first 6 months of treatment. Permanently discontinue in patients who develop internal organ fistulas.
• Gastrointestinal perforation: [U.S. Boxed Warning]: Gastrointestinal (GI) perforation, (sometimes fatal) has occurred in 0.3% to 2.4% of clinical study patients receiving bevacizumab; discontinue if GI perforation occurs. Most cases occur within 50 days of treatment initiation; monitor patients for signs/symptoms (eg, fever, abdominal pain with constipation and/or nausea/vomiting).
• Heart failure: Among all approved indications, the incidence of heart failure (HF) and/or left ventricular dysfunction is higher in patients receiving bevacizumab plus chemotherapy when compared to chemotherapy alone. Use with caution in patients with cardiovascular disease. The safety of therapy resumption or continuation in patients with cardiac dysfunction has not been studied. In studies of patients with metastatic breast cancer (an unlabeled use), the incidence of grades 3 or 4 HF was increased in patients receiving bevacizumab plus paclitaxel when compared to the control arm. Patients with metastatic breast cancer who received prior anthracycline therapy had a higher rate of HF compared to those receiving paclitaxel alone (3.8% vs 0.6% respectively). A meta-analysis of 5 studies which enrolled patients with metastatic breast cancer who received bevacizumab suggested an association with an increased risk of heart failure; all trials included in the analysis enrolled patients who either received prior or were receiving concurrent anthracycline therapy (Choueiri, 2011).
• Hemorrhage: [U.S. Boxed Warning]: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous system hemorrhage, epistaxis, and vaginal bleeding have been reported (up to 5 times more frequently if receiving bevacizumab). Avoid use in patients with serious hemorrhage or recent hemoptysis (≥2.5 mL blood). Serious pulmonary hemorrhage has been reported in patients receiving bevacizumab (primarily in patients with nonsmall cell lung cancer with squamous cell histology [not an FDA-approved indication]). Intracranial hemorrhage, including cases of grade 3 or 4 hemorrhage, has occurred in patients with previously treated glioblastoma. Treatment discontinuation is recommended in all patients with intracranial bleeding or other serious hemorrhage. Use with caution in patients at risk for thrombocytopenia.
• Hypertension: May cause and/or worsen hypertension; use caution in patients with pre-existing hypertension and monitor BP closely in all patients. Permanent discontinuation is recommended in patients who experience a hypertensive crisis or encephalopathy. Temporarily discontinue in patients who develop uncontrolled hypertension.
• Infusion reactions and hypersensitivity: Infusion reactions (eg, hypertension, hypertensive crisis, wheezing, oxygen desaturation, hypersensitivity [including anaphylactic/anaphylactoid reactions], chest pain, rigors, headache, diaphoresis) may occur with the first infusion (uncommon). Interrupt therapy in patients experiencing severe infusion reactions; there are no data to address routine premedication use or reinstitution of therapy in patients who experience severe infusion reactions.
• Mortality: Bevacizumab, in combination with chemotherapy (or biologic therapy), is associated with an increased risk of treatment-related mortality; a higher risk of fatal adverse events was identified in a meta-analysis of 16 trials in which bevacizumab was used for the treatment of various cancers (breast cancer, colorectal cancer, non small cell lung cancer, pancreatic cancer, prostate cancer, and renal cell cancer) and compared to chemotherapy alone (Ranpura, 2011).
• Ovarian failure: In premenopausal women receiving bevacizumab in combination with mFOLFOX (fluorouracil/oxaliplatin based chemotherapy) the incidence of ovarian failure (amenorrhea ≥3 months) was higher (34%) compared to women who received mFOLFOX alone (2%). Ovarian function recovered in some patients after treatment was discontinued. Premenopausal women should be informed of the potential risk of ovarian failure.
• Proteinuria/nephrotic syndrome: Proteinuria and/or nephrotic syndrome have been associated with use; risks may be increased in patients with history of hypertension. Thrombotic microangiopathy has been associated with bevacizumab-induced proteinuria. Withhold treatment for ≥2 g proteinuria/24 hours and resume when proteinuria is <2 g/24 hours; discontinue in patients with nephrotic syndrome.
• Reversible posterior leukoencephalopathy syndrome: Cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Symptoms (which include headache, seizure, confusion, lethargy, blindness and/or other vision, or neurologic disturbances) may occur from 16 hours to 1 year after treatment initiation. Resolution of symptoms usually occurs within days after discontinuation; however, neurologic sequelae may remain. RPLS may be associated with hypertension; discontinue therapy and begin management of hypertension, if present.
• Thromboembolism: Bevacizumab is associated with an increased risk for arterial thromboembolic events (ATE), including cerebral infarction, stroke, MI, TIA, angina, and other ATEs, when used in combination with chemotherapy. History of ATE or ≥65 years of age may present an even greater risk; permanently discontinue with serious ATE; the safety of treatment reinitiation after ATE has not been studied. Although patients with cancer are at risk for venous thromboembolism (VTE), a meta-analysis of 15 controlled trials has demonstrated an increased risk for VTE in patients who received bevacizumab (Nalluri, 2008). Discontinue therapy in patients with severe arteriothrombotic event or life-threatening pulmonary embolism.
• Wound dehiscence: [U.S. Boxed Warning]: The incidence of wound healing and surgical complications is increased in patients who have received bevacizumab; discontinue with wound dehiscence. Although the appropriate interval between withholding bevacizumab and elective surgery has not been defined, bevacizumab should be discontinued at least 28 days prior to surgery and should not be reinitiated for at least 28 days after surgery and until wound is fully healed. In a retrospective review of central venous access device placements, a greater risk of wound dehiscence was observed when port placement and bevacizumab administration were separated by <14 days (Erinjeri, 2011).
Disease-related concerns:
• CNS metastases: Use with caution in patients with CNS metastases; one case of CNS hemorrhage was observed in a study of NSCLC patients with CNS metastases. Use in patients with untreated CNS metastases is contraindicated in the Canadian labeling.
• Hepatic impairment: Safety and efficacy have not been established in hepatic impairment.
• Renal impairment: Safety and efficacy have not been established in renal impairment.
Concurrent drug therapy issues:
• Anthracyclines: May potentiate cardiotoxic effects of anthracyclines. HF is more common with prior anthracycline exposure and/or left chest wall irradiation.
• Myelosuppressive chemotherapy: When used in combination with myelosuppressive chemotherapy, increased rates of severe or febrile neutropenia and neutropenic infection were reported.
• Sorafenib: The incidence of hand-foot syndrome is increased in patients treated with bevacizumab plus sorafenib in comparison to those treated with sorafenib monotherapy.
• Sunitinib: Microangiopathic hemolytic anemia (MAHA) has been reported when bevacizumab has been used in combination with sunitinib. Concurrent therapy with sunitinib and bevacizumab is also associated with dose-limiting hypertension in patients with metastatic renal cell cancer.
Special populations:
• Elderly: Use with caution in patients ≥65 years of age; greater risk for adverse events, including arterial thrombotic events and proteinuria. Serious adverse events occurring more frequently in the elderly also include deep thrombophlebitis, sepsis, hyper-/hypotension, MI, CHF, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia.
Adverse Reactions
Percentages reported as monotherapy and as part of combination chemotherapy regimens. Some studies only reported hematologic toxicities grades ≥4 and nonhematologic toxicities grades ≥3.
>10%:
Cardiovascular: Hypertension (12% to 34%; grades 3/4: 5% to 18%), thromboembolic event (≤21%; grades 3/4: 15%; venous thrombus/embolus: 8%; grades 3/4: 5% to 7%; arterial thrombosis 6%; grades 3/4: 3%), hypotension (7% to 15%)
Central nervous system: Pain (8% to 62%), headache (24% to 37%; grades 3/4: 2% to 4%), dizziness (19% to 26%), fatigue (≤45%; grades 3/4: 4% to 19%), sensory neuropathy (grades 3/4: 1% to 17%; in combination with paclitaxel: 24%)
Dermatologic: Alopecia (6% to 32%), dry skin (7% to 20%), exfoliative dermatitis (3% to 19%), skin discoloration (2% to 16%)
Gastrointestinal: Abdominal pain (8% to 61%; grades 3/4: 8%), vomiting (47% to 52%; grades 3/4: ≤11%), anorexia (35% to 43%), constipation (4% to 40%), diarrhea (grades 3/4: 1% to 34%), stomatitis (30% to 32%), gastrointestinal hemorrhage (19% to 24%), dyspepsia (17% to 24%), taste disorder (14% to 21%), weight loss (15% to 20%), flatulence (11% to 19%), nausea (grades 3/4: ≤12%)
Hematologic: Hemorrhage (≤40%; grades 3/4: 1% to 5%), leukopenia (grades 3/4: 37%), neutropenia (grade 4: 21% to 27%)
Neuromuscular & skeletal: Myalgia (8% to 19%), back pain (≤12%)
Renal: Proteinuria (4% to 36%; grades 3/4: ≤7%; median onset: 5.6 months; median time to resolution: 6.1 months)
Respiratory: Upper respiratory infection (40% to 47%), epistaxis (19% to 35%), dyspnea (25% to 26%), rhinitis
Miscellaneous: Infection (≤55%; serious: 7% to 14%; pneumonia, catheter, or wound infections)
1% to 10%:
Cardiovascular: DVT (6% to 9%; grades 3/4: 9%), HF (grades 3/4: 1% to 4%), syncope (grades 3/4: 3%), intra-abdominal venous thrombosis (grades 3/4: 3%), cardio-/cerebrovascular arterial thrombotic event (2% to 4%), left ventricular dysfunction (grades 3/4: 1%)
Central nervous system: CNS hemorrhage (1% to 5%; grades 3/4: 1%), dysphonia (≤5%)
Dermatologic: Skin ulcer (≤6%), wound dehiscence (1% to 6%), acne (≤1%)
Endocrine & metabolic: Dehydration (grades 3/4: ≤10%), hyponatremia (grades 3/4: 4%)
Gastrointestinal: Xerostomia (4% to 7%), colitis (1% to 6%), ileus (grades 3/4: 4% to 5%), gingival bleeding (2% to 4%), fistula (1%), gastrointestinal perforation (≤4%), gastroesophageal reflux (≤2%), gingivitis (≤2%), mouth ulceration (≤2%), tooth abscess (≤2%), intra-abdominal abscess (1%), gastritis (≤1%), gingival pain (≤1%)
Genitourinary: Vaginal hemorrhage (4%)
Hematologic: Neutropenic fever/infection (5%; grades 3 and/or 4: 4% to 5%), thrombocytopenia (5%)
Neuromuscular & skeletal: Weakness (10%), neuropathy (other than sensory: grades 3/4: 1% to 5%)
Ocular: Blurred vision (≤2%)
Otic: Tinnitus (≤2%), deafness (≤1%)
Respiratory: Voice alteration (5% to 9%), pneumonitis/pulmonary infiltrates (grades 3/4: 5%), hemoptysis (nonsquamous histology 2%), pulmonary embolism (≤1%)
Miscellaneous: Infusion reactions (<3%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Anaphylaxis, anastomotic ulceration, angina, bladder perforation, cerebral infarction; fistula (biliary, bladder, bronchopleural, duodenal, enterocutaneous, esophageal, gastrointestinal, rectal, renal, tracheoesophageal [TE] and vaginal); gastrointestinal ulcer, hemorrhagic stroke, hypersensitivity, hypertensive crises, hypertensive encephalopathy, intestinal necrosis, intestinal obstruction, mesenteric venous occlusion, microangiopathic hemolytic anemia (when used in combination with sunitinib), MI, nasal septum perforation, nephrotic syndrome, osteonecrosis (jaw), ovarian failure, pancytopenia, polyserositis, pulmonary hemorrhage, pulmonary hypertension, renal failure, renal thrombotic microangiopathy, reversible posterior leukoencephalopathy syndrome (RPLS), sepsis, subarachnoid hemorrhage, toxic anterior segment syndrome (TASS), transient ischemic attack, ureteral stricture wound healing complications
Reported from unlabeled use: Eye disorders: Endophthalmitis (infectious and sterile), hemorrhage (conjunctival, retinal or vitreous), intraocular inflammation (iritis, vitritis), intraocular pressure increased, ocular hyperemia, ocular pain/discomfort, permanent vision loss, retinal detachment, visual disturbance, vitreous floaters
Metabolism/Transport Effects
None known.
Drug Interactions
Antineoplastic Agents (Anthracycline, Systemic): Bevacizumab may enhance the cardiotoxic effect of Antineoplastic Agents (Anthracycline, Systemic). Risk C: Monitor therapy
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Irinotecan: Bevacizumab may enhance the adverse/toxic effect of Irinotecan. Risk C: Monitor therapy
SORAfenib: Bevacizumab may enhance the adverse/toxic effect of SORAfenib. Specifically, the risk for hand-foot skin reaction may be increased. Risk C: Monitor therapy
SUNItinib: May enhance the adverse/toxic effect of Bevacizumab. Specifically, the risk for a specific form of anemia, microangiopathic hemolytic anemia (MAHA), may be increased. Bevacizumab may enhance the hypertensive effect of SUNItinib. Risk X: Avoid combination
Storage
Store vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light; do not shake. Diluted solutions are stable for up to 8 hours under refrigeration. Discard unused portion of vial.
Reconstitution
Prior to I.V. infusion, dilute prescribed dose of bevacizumab in a total volume of 100 mL NS. Do not mix with dextrose-containing solutions.
Mechanism of Action
Bevacizumab is a recombinant, humanized monoclonal antibody which binds to, and neutralizes, vascular endothelial growth factor (VEGF), preventing its association with endothelial receptors, Flt-1 and KDR. VEGF binding initiates angiogenesis (endothelial proliferation and the formation of new blood vessels). The inhibition of microvascular growth is believed to retard the growth of all tissues (including metastatic tissue).
Pharmacodynamics/Kinetics
Distribution: Vd: 46 mL/kg
Half-life elimination: ~20 days (range: 11-50 days)
Excretion: Clearance: 2.75-5 mL/kg/day
Dosage
Adults: Details concerning dosing in combination regimens should also be consulted.
I.V.:
Colorectal cancer, metastatic: 5 or 10 mg/kg every 2 weeks (in combination with fluorouracil-based chemotherapy)
Canadian labeling: 5 mg/kg every 2 weeks (in combination with fluorouracil-based chemotherapy)
Glioblastoma: 10 mg/kg every 2 weeks as monotherapy or (unlabeled) 10 mg/kg every 2 weeks (in combination with irinotecan) (Vredenburgh, 2007)
Nonsmall cell lung cancer (nonsquamous cell histology): 15 mg/kg every 3 weeks (in combination with carboplatin and paclitaxel) for 4-6 cycles followed by maintenance treatment (unlabeled use) of bevacizumab 15 mg/kg every 3 weeks as monotherapy until disease progression or unacceptable toxicity (Sandler, 2006)
Renal cell cancer, metastatic: 10 mg/kg every 2 weeks (in combination with interferon alfa) or (unlabeled) 10 mg/kg every 2 weeks as monotherapy (Yang, 2003)
Breast cancer, metastatic (unlabeled use): 10 mg/kg every 2 weeks (in combination with paclitaxel) (Miller, 2007)
Ovarian cancer (unlabeled use): 15 mg/kg every 3 weeks (Burger, 2007; Cannistra, 2007)
Intravitreal: Age-related macular degeneration (unlabeled use): 1.25 mg (0.05 mL) monthly until improvement/resolution, usually ~1-3 injections (Avery, 2006) or 2.5 mg (0.1 mL) every 4 weeks for 3 doses (Bashshur, 2006)
Dosage adjustment for toxicity: I.V. administration (systemic): There are no recommended dosage reductions. Temporary suspension is recommended for severe infusion reactions, at least 4 weeks prior to (and after) elective surgery, in moderate-to-severe proteinuria (in most studies, treatment was withheld for ≥2 g proteinuria/24 hours), or in patients with severe hypertension which is not controlled with medical management. Permanent discontinuation is recommended (by the manufacturer) in patients who develop wound dehiscence and wound healing complications requiring intervention, fistula (gastrointestinal and nongastrointestinal), gastrointestinal perforation, intra-abdominal abscess, hypertensive crisis, hypertensive encephalopathy, serious bleeding/hemorrhage, severe arterial thromboembolic event, nephrotic syndrome, or RPLS.
Dosage adjustment in renal impairment: There are no dosage adjustments provided in manufacturer's labeling
Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in manufacturer's labeling
Dosage: Combination Regimens
Brain tumors: Bevacizumab-Irinotecan (Glioblastoma)
Breast cancer:
Bevacizumab-Capecitabine (Breast Cancer)
Docetaxel-Bevacizumab
Paclitaxel-Bevacizumab
Colorectal cancer:
Bevacizumab-Fluorouracil-Leucovorin
Bevacizumab + FOLFIRI (Colorectal)
Bevacizumab-Oxaliplatin-Fluorouracil-Leucovorin
Bevacizumab + XELOX (Colorectal)
Lung cancer (nonsmall cell):
Bevacizumab-Cisplatin-Gemcitabine
Paclitaxel-Carboplatin-Bevacizumab
Renal cell cancer:
Bevacizumab-Interferon Alfa (RCC)
Bevacizumab (RCC Regimen)
Administration: I.V.
I.V. infusion, usually after the other antineoplastic agents. Infuse the initial dose over 90 minutes. The second infusion may be shortened to 60 minutes if the initial infusion is well tolerated. The third and subsequent infusions may be shortened to 30 minutes if the 60-minute infusion is well tolerated. Monitor closely during the infusion for signs/symptoms of an infusion reaction. Some Some institutions use a 10-minute infusion (0.5 mg/kg/minute) for bevacizumab dosed at 5 mg/kg (after tolerance at the 90-, 60-, and 30-minute infusion rates has been established; Reidy, 2007). Do not administer I.V. push.
Administration: Other
Intravitreal injection (unlabeled use): Adequate local anesthesia and a topical broad-spectrum antimicrobial agent should be administered prior to the procedure; administer topical ophthalmic antibiotics for 3 days after procedure (Avery, 2006; Bashshur, 2006).
Administration: I.V. Detail
pH: 6.2
Monitoring Parameters
Monitor closely during the infusion for signs/symptoms of an infusion reaction. Monitor CBC with differential; signs/symptoms of gastrointestinal perforation, fistula, or abscess (including abdominal pain, constipation, vomiting, and fever); signs/symptoms of bleeding, including hemoptysis, gastrointestinal, and/or CNS bleeding, and/or epistaxis. Monitor blood pressure every 2-3 weeks; more frequently if hypertension develops during therapy. Continue to monitor blood pressure after discontinuing due to bevacizumab-induced hypertension. Monitor for proteinuria/nephrotic syndrome with urine dipstick; collect 24 hour urine in patients with ≥2+ reading.
AMD: Monitor intraocular pressure and retinal artery perfusion
Patient Education
This medication can only be administered by infusion; you will be closely monitored during infusion. Report immediately unusual back or abdominal pain; acute headache; difficulty breathing or chest tightness; difficulty swallowing; itching or rash; or redness, swelling, or pain at infusion site. Between treatments, maintain adequate nutrition and hydration, unless instructed to restrict fluid intake. You may experience loss of appetite, nausea, dry mouth, taste changes, loss of hair (will grow back when therapy is completed), or muscle or skeletal pain. Report immediately any unusual bleeding (blood in urine or tarry stool, nose bleeds, vaginal bleeding, bleeding from wound); abdominal pain, vomiting, constipation, or diarrhea; acute headache, dizziness, or confusion; seizure, vision changes, or unusual lethargy; changes in urinary pattern; pain, redness, swelling, or sudden loss of sensation in extremities; skin rash or hives; or unusual infection (fever or chills, cough, sore throat, pain or difficulty passing urine).
Geriatric Considerations
Elderly patients ≥65 years of age had an increased incidence of arterial thromboembolic events; an increased risk for proteinuria; other serious adverse events occurring often include weakness, sepsis, hyper-/hypotension, CHF, constipation, anorexia, anemia, hyper-/hypokalemia, and diarrhea.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), stomatitis, taste disorder, and gingival bleeding.
Cases of osteonecrosis of the jaw (ONJ) have been associated with bevacizumab exposure. ONJ presents clinically as exposed necrotic bone of at least 8 weeks duration with or without the presence of pain, infection, or previous trauma in a patient who has not received radiation to the jaw. Since ONJ is also associated with bisphosphonate exposure and bisphosphonates are known to have antiangiogenic properties, inhibition of angiogenesis may play a role in ONJ associated with these two classes of drugs. Patients developing ONJ while on bevacizumab therapy should receive care by an oral surgeon. See Dental Health Professional Considerations.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
Three case reports describe the development of ONJ in association with bevacizumab therapy. All three cases were cancer patients treated with bevacizumab 10 mg/kg every 2 weeks and 15 mg/kg every 3 weeks (Estilo, 2009; Greuter, 2008). Another report showed that a combination of bisphosphonates and antiangiogenic factors (primarily bevacizumab) induces ONJ more frequently than bisphosphonates alone. Of the 25 patients receiving concurrent treatment with bisphosphonates and the antiangiogenic drug bevacizumab, four developed ONJ (16%). Of the 91 patients receiving bisphosphonates without antiangiogenic factors, one developed ONJ (1.1%), a significant statistical difference (Christodoulou, 2009).
Mental Health: Effects on Mental Status
Dizziness is common; may cause confusion
Mental Health: Effects on Psychiatric Treatment
Gastrointestinal side effects are common; these effects may be additive with concurrent use of SSRIs, acetylcholinesterase inhibitors, aripiprazole, or ziprasidone. Hematologic adverse effects are common; use caution with clozapine, carbamazepine, valproate, mirtazapine. May cause hypokalemia; use caution with ziprasidone.
Nursing: Physical Assessment/Monitoring
Assess patient for recent abdominal surgery, arterial thromboembolism, cardiovascular disease, hemoptysis, and CNS metastases prior to beginning treatment. Patient must be monitored closely during each infusion for infusion reaction (eg, hypertension, chest pain, wheezing, diaphoresis). In event of infusion reaction, infusion should be discontinued and patient assessed. Monitor for gastrointestinal perforation (abdominal pain, constipation, vomiting), serious bleeding, arterial thrombotic event, nephrotic syndrome, encephalopathy, and heart failure.
Oncology: Emetic Potential
Very low <10%
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [preservative free]:
Avastin®: 25 mg/mL (4 mL, 16 mL) [derived from or manufactured using Chinese hamster ovary cells]
Pricing: U.S. (www.drugstore.com)
Solution (Avastin)
100 mg/4 mL (4): $645.96
400 mg/16 mL (16): $2525.85
References
Allegra CJ, Yothers G, O'Connell MJ, et al, “Initial Safety Report of NSABP C-08: A Randomized Phase III Study of Modified FOLFOX6 With or Without Bevacizumab for the Adjuvant Treatment of Patients With Stage II or III Colon Cancer,” J Clin Oncol, 2009, 27(20):3385-90.
Avery RL, Pieramici DJ, Rabena MD, et al, “Intravitreal Bevacizumab (Avastin) for Neovascular Age-Related Macular Degeneration,” Ophthalmology, 2006, 113(3):363-72.
Azad NS, Aragon-Ching JB, Dahut WL, et al, “Hand-Foot Skin Reaction Increases With Cumulative Sorafenib Dose and With Combination Anti-Vascular Endothelial Growth Factor Therapy,” Clin Cancer Res, 2009, 15(4):1411-16.
Bansal N and Hoffman M, “Bladder Perforation in a Patient With Recurrent Epithelial Ovarian Cancer After Treatment With Bevacizumab,” Gynecol Oncol, 2011, 120(2):313-4.
Bashshur AF, Bazarbachi A, Schakal A, et al, “Intravitreal Bevacizumab for the Management of Choroidal Neovascularization in Age-Related Macular Degeneration,” Am J Ophthalmol, 2006, 142(1):1-9.
Bracarda S, Bellmunt J, Melichar B, et al, "Overall Survival in Patients With Metastatic Renal Cell Carcinoma Initially Treated With Bevacizumab Plus Interferon-α2a and Subsequent Therapy With Tyrosine Kinase Inhibitors: A Retrospective Analysis of the Phase III AVOREN Trial," BJU Int, 2011, 107(2):214-9.
Burger RA, Brady MF, Bookman MA, et al, “Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer,” N Engl J Med, 2011, 365(26):2473-83. PMID: 22204724
Burger RA, Sill MW, Monk BJ, et al, “Phase II Trial of Bevacizumab in Persistent or Recurrent Epithelial Ovarian Cancer or Primary Peritoneal Cancer: A Gynecologic Oncology Group Study,” J Clin Oncol, 2007, 25(33):5165-71.
Cannistra SA, Matulonis UA, Penson RT, et al, “Phase II Study of Bevacizumab in Patients With Platinum-Resistant Ovarian Cancer or Peritoneal Serous Cancer,” J Clin Oncol, 2007, 25(33):5180-6.
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Last full review/revision March 2012
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