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Bevacizumab

(rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

BevacizumabDate of monograph revision: 01-Mar-2004; 05-Oct-2004; 29-Apr-2005; 01-Jun-2006; (last modified: 04-Jun-2006)
Synonyms: Bevacizumab; rhuMAb-VEGF
INN: Bevacizumab [rINN (en)]
INN: Bevacizumab [rINN (es)]
INN: Bévacizumab [rINN (fr)]
INN: Bevacizumabum [rINN (la)]
INN: Бевацизумаб [rINN (ru)]
CAS: 216974-75-3
ATC code: L01XC07

Stability. UK licensed product information states that bevacizumab is chemically and physically stable for 48 hours at 2° to 30° in sodium chloride 0.9%, although immediate use is recommended from a microbiological point of view. If the solution is not used immediately, storage for longer than 24 hours at 2° to 8° cannot be recommended, unless dilution has taken place in controlled and validated aseptic conditions. In the USA, licensed product information states that bevacizumab solutions for infusion may be stored at 2° to 8° for up to 8 hours. Bevacizumab should not be mixed with glucose.

Adverse Effects, Treatment, and Precautions

For general discussions see Antineoplastics.

Bevacizumab may impair wound healing; therapy should not be started for at least 28 days after major surgery or until the surgical incision is fully healed; it should also be withheld before elective surgery. Gastrointestinal perforation complicated by intra-abdominal abscesses or fistula formation is more common in patients receiving bevacizumab; fatalities have been reported. Bevacizumab should be stopped permanently in patients who develop gastrointestinal perforation, or fistulas, or wound dehiscence needing medical intervention. Very rare cases of nasal septum perforation have been reported.

Leucopenia, anaemia, neutropenia, thrombocytopenia, and febrile neutropenia have also occurred; severe neutropenia with infection has caused fatalities. Haemorrhage may occur; fatal pulmonary haemorrhage presenting as haemoptysis has been reported. There is an increased risk of serious thromboembolic events associated with the use of bevacizumab including stroke, transient ischaemic attacks, myocardial infarction, angina, and death. Bevacizumab may cause congestive heart failure; the risk is higher in those patients who have concurrent or previous treatment with anthracyclines.

Hypertension, possibly dose-dependent, has occurred; blood pressure should be monitored, and therapy stopped in patients who develop hypertensive crisis or hypertensive encephalopathy Proteinuria may develop; bevacizumab should be stopped in patients who develop nephrotic syndrome. Other adverse effects include asthenia, pain, abdominal pain, gastrointestinal disturbances, stomatitis, headache, epistaxis, dyspnoea, upper respiratory infection, and exfoliative dermatitis. Peripheral sensory neuropathy, syncope, somnolence, supraventricular tachycardia, palmar-plantar erythrodysesthesia syndrome, and muscular weakness have been commonly reported.

Infusion reactions, manifesting as hypertension, wheezing, chest pain, headaches, rigors, and diaphoresis may occur rarely with the first dose of bevacizumab; treatment should be interrupted. There have been rare reports of reversible posterior leukoencephalopathy syndrome, a neurological disorder; this may present as seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. Bevacizumab therapy should be stopped, and patients treated symptomatically

Effects on the cardiovascular system

For a discussion of the incidence of hypertension associated with use of bevacizumab, see Effects on the Kidneys, below.

Effects on the kidneys

A systematic review and subsequent meta-analysis of 7 studies in 1850 patients with various cancers estimated the incidence and risk of developing hypertension and proteinuria with bevacizumab therapy. The relative risk (RR) of developing proteinuria was 1.4 with low-dose bevacizumab (95% confidence interval 1.1 to 1.7) and even higher with high-dose therapy (RR 2.2; 95% confidence interval 1.6 to 2.9). For hypertension, the RR was 3.0 for low-dose bevacizumab (95% confidence interval 2.2 to 4.2) and 7.5 for high-dose therapy (95% confidence interval 4.2 to 13.4). US licensed product information states that hypertension can persist after stopping bevacizumab; therapy should be stopped permanently in those with hypertensive crisis or hypertensive encephalopathy. (For the suggestion that hypertension is a problem with angiogenesis inhibitors in general see Effects on the Cardiovascular System in Sorafenib)

The safety of continued treatment in patients with moderate to severe proteinuria has not been evaluated; therapy should be interrupted if proteinuria is equal to or greater than 2 g per 24 hours, and may be resumed when it is less than this. Nephrotic syndrome has also been reported with use of bevacizumab; therapy should be stopped in these patients. In one case, there was evidence of a haemolytic-uraemic syndrome; renal biopsy revealed a glomerular thrombotic microangiopathy. Bevacizumab was stopped, with favourable response; however, sunitinib therapy was started but had to be stopped due to a recurrence of severe haemolytic-uraemic syndrome. A patient who received 3 doses of bevacizumab was diagnosed with acute renal failure secondary to interstitial nephritis. His renal function resolved slowly after stopping therapy; haemodialysis was required.

Effects on the nervous system

There are reports of reversible posterior leukoencephalopathy syndrome (RPLS) attributed to bevacizumab. Presenting symptoms included lethargy, seizures, hypertension, acute bilateral loss of vision, headache, and confusion. Recovery was rapid after symptomatic treatment. The symptoms of RPLS may be difficult to distinguish from those of uncontrolled hypertension, and patients presenting with the above signs and symptoms should be examined neurologically.

Effects on the spleen

Splenic infarction has been reported in a patient given bevacizumab, fluorouracil, folinic acid, and irinotecan. Bevacizumab was stopped. Four further chemotherapy cycles were given. The splenic infarcts partially regressed, although the patient died from metastatic progression. The authors attributed the splenic infarction to bevacizumab, which has been associated with arterial thromboembolic events.

Fistula formation

US licensed product information for bevacizumab states that the incidence of gastrointestinal perforation, including fistula formation and/or intra-abdominal abscess, in bevacizumab-treated patients with colorectal cancer or non-small cell lung cancer was 2.4% and 0.9%, respectively. The Canadian manufacturer (Roche, Canada) has stated that there have been uncommon reports of other types of fistulas such as bron-chopleural, urogenital, and biliary fistulas, across various indications. While cancer itself might have been a risk factor for fistula formation, a role for bevacizumab could not be excluded; most events occurred within the first 6 months of therapy. There have been reports of tracheo-oesophageal fistula formation in association with use of bevacizumab, including some fatalities. Therapy should be permanently stopped in patients with trachea-oesophageal or gastrointestinal fistulas.

Interactions

The US manufacturer of bevacizumab has recommended that it should not be used with sunitinib after several patients receiving the combination had developed microangiopathic haemolytic anaemia.

Pharmacokinetics

Bevacizumab has an initial half-life of 1.4 days and a terminal half-life of about 20 days. The predicted time to steady state is about 100 days. Male patients and those with a higher tumour burden have higher clearances of bevacizumab than females and those with tumour burdens below the median, respectively; although no evidence of lesser efficacy has been seen due to this higher clearance, the relationship between exposure to bevacizumab and clinical outcome is not known.

Uses and Administration

Bevacizumab is a recombinant humanised monoclonal antibody that binds to vascular endothelial growth factor (VEGF), thereby inhibiting the angiogenesis that occurs during tumour growth. Bevacizumab is used with fluoropyrimidine-based chemotherapy in the treatment of metastatic colorectal cancer. It is also used with paclitaxel for the first-line treatment of patients with metastatic breast cancer, and with platinum-based chemotherapy in the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic, non-squamous, non-small cell lung cancer.

Bevacizumab is used with interferon alfa for the first-line treatment of advanced and/or metastatic renal cell cancer. Bevacizumab is usually given diluted in 100 mL of sodium chloride 0.9%; the final concentration should be kept within the range of 1.4 to 16.5 mg/mL. The first dose should be given as an intravenous infusion over 90 minutes; if this is well tolerated the second dose should be given over 60 minutes, and if this is well tolerated then subsequent doses may be given over 30 minutes.

In the treatment of colorectal cancer, bevacizumab is given in a dose of 5 or 10 mg/kg once every 2 weeks, or 7.5 or 15 mg/kg once every 3 weeks; doses depend on the combination of drugs used in the regimen. For breast cancer, the recommended dose of bevacizumab is 10 mg/kg given once every 2 weeks, or 15 mg/kg given once every 3 weeks. For non-small cell lung cancer, the recommended dose of bevacizumab is 7.5 or 15 mg/kg given once every 3 weeks. In the UK, combination therapy is given for up to 6 cycles, followed by bevacizumab mono-therapy until disease progression. For renal cell carcinoma, bevacizumab is given in a dose of 10 mg/kg once every 2 weeks. There are no recommended dose reduction regimens should adverse effects occur with bevacizumab; therapy should either be permanently stopped or temporarily suspended.

Bevacizumab is under investigation for various other neoplasms, such as head and neck, ovarian, and prostate cancer. A related monoclonal antibody, ranibizumab has been developed for the treatment of neovascular (wet) age-related macular degeneration, and it has been suggested that bevacizumab might also be of benefit.

Administration

It has been suggested that bevacizumab may be safely given at an infusion rate of 500 micrograms/kg per minute; this means a dose of 5 mg/kg could be given over 10 minutes.

Age-related macular degeneration

Short-term results with intravenous or intravitreal bevacizumab to treat age-related macular degeneration are promising, although it is unlicensed for this use. Ranibizumab is a humanised antibody fragment derived from bevacizumab that is used for the treatment of this disease.

Proprietary Preparations

Argentina: Avastin;

Australia: Avastin;

Belgium: Avastin;

Brazil: Avastin;

Canada: Avastin;

Chile: Avastin;

Czech Republic: Avastin;

Denmark: Avastin;

Finland: Avastin;

France: Avastin;

Germany; Avastin;

Greece: Avastin;

Hong Kong; Avastin;

Hungary: Avastin;

Indonesia: Avastin;

Ireland: Avastin;

Israel: Avastin;

Italy: Avastin;

Japan: Avastin;

Mexico: Avastin;

The Netherlands: Avastin;

Norway: Avastin;

New Zealand: Avastin;

Philippines: Avastin;

Poland: Avastin;

Portugal: Avastin;

Russia: Avastin;

South Africa; Avastin;

Singapore: Avastin;

Spain: Avastin;

Sweden: Avastin;

Switzerland: Avastin;

Thailand: Avastin;

United Kingdom (UK): Avastin;

United States of America (US and USA): Avastin.

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