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Carmustine

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

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

Synonyms: BCNU; BiCNU; Carmustina; Carmustinum; Karmustiini; Karmustin; Karmustinas; Karmusztin; NSC-409962; WR-139021
BAN: Carmustine
USAN: Carmustine
INN: Carmustine [rINN (en)]
INN: Carmustina [rINN (es)]
INN: Carmustine [rINN (fr)]
INN: Carmustinum [rINN (la)]
INN: Кармустин [rINN (ru)]
Chemical name: 1,3-Bis(2-chloroethyl)-1-nitrosourea
Molecular formula: C5H9Cl2N3O2 =214.0
CAS: 154-93-8
ATC code: L01AD01
Read code: y02jG; y08bi

Pharmacopoeias. In China, and Europe.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Carmustine). A yellowish, granular powder. Very slightly soluble in water; freely soluble in dehydrated alcohol; very soluble in dichloromethane. It melts at about 31° with decomposition. Store at a temperature of 2° to 8° in airtight containers. Protect from light.

Stability. The manufacturers state that, when reconstituted, resulting carmustine solutions (undiluted or further diluted in sodium chloride 0.9% or glucose 5%) are stable for 8 hours at room temperature, or 24 hours at 2° to 8°, when protected from light. There is some evidence that carmustine interacts with plastic giving sets and containers, and licensed product information recommends the use of polyethylene or glass.

A study has indicated that diluted solutions of carmustine undergo increased degradation in the presence of sodium bicarbonate, with only 73% of the original concentration of carmustine remaining after 90 minutes, much of the loss being in the first 15 minutes.

Adverse Effects and Treatment

For a general outline see Antineoplastics. Delayed and cumulative bone-marrow depression is the most frequent and serious adverse effect of intravenous carmustine. Platelets and leucocytes are mainly affected, with platelet nadirs occurring at 4 to 5 weeks after a dose and leucocyte nadirs at 5 to 6 weeks; although thrombocytopenia is usually more severe, leucopenia may also be dose-limiting. Other adverse effects include pulmonary fibrosis (mainly but not exclusively at high cumulative doses — see also Effects on the Lungs), renal and hepatic damage, and neuroretinitis. Nausea and vomiting, beginning up to 2 hours after a dose, is common but can be reduced by prophylactic antiemetic therapy. Venous irritation may follow intravenous injection and transient hyperpigmentation has been noted after contact of a solution with the skin. Flushing of the skin and suffusion of the conjunctiva may occur on rapid intravenous infusion. Hypotension, tachycardia, chest pain, headache, and hypersensitivity reactions have been reported. Convulsions, cerebral oedema, and various neurological symptoms have been reported in patients given carmustine-containing polymer implants; abnormalities of wound healing at the site of implantation, and an increased incidence of intracranial infection have also been reported.

As with other alkylating agents, carmustine is potentially carcinogenic, mutagenic, and teratogenic.

Effects on the eyes. Ocular toxicity has been reported in patients given carmustine, and seems to be more likely when given into the carotid artery, although it was also seen with high-dose intravenous therapy. There is some evidence that the alcohol diluent used to prepare carmustine solutions may contribute to the retinopathy.

Effects on the lungs. Studies have found a high incidence of fatal pulmonary fibrosis (see also Effects on the Lungs) in patients treated with carmustine for gliomas during childhood; patients who were treated before 5 or 6 years of age were more likely to die of pulmonary fibrosis than those treated at a later age. However, there are reports of pulmonary toxicity and upper lobe pulmonary fibrosis occurring in adults given carmustine and high-dose chemotherapy.

Extravasation. For mention of the use of sodium bicarbonate as a specific antidote after carmustine extravasation, see under Treatment of Adverse Effects of Antineoplastics.

Precautions

For reference to the precautions necessary with antineoplastics. Carmustine should be used with extreme caution in children, who are at particular risk of severe delayed pulmonary toxicity. It should also be used with caution in patients with reduced lung function. Lung function should be monitored before and frequently during therapy. Blood counts should be monitored weekly during therapy, and for at least 6 weeks after the last dose. Renal and hepatic function should also be monitored periodically.

Handling and disposal. Carmustine has been shown to permeate latex, PVC, and rubber gloves, the degree of permeation tending to increase with time, up to an equilibrium value. The permeation rate appears not to depend solely on glove thickness and material, and may be different for different gloves made from the same material. The time for initial penetration was reported to vary between 4.7 and 66.0 minutes in one study, and gloves could be chosen accordingly depending on the anticipated length of exposure. Double-gloving, particularly with thicker PVC or efhylmethacrylate gloves, may offer some additional protection.

Interactions

For a general outline of antineoplastic drug interactions.

Cimetidine. Reductions in white cell counts and platelet counts well below those normally attributed to treatment with carmustine alone were seen in 6 of 8 patients receiving their first course of carmustine and steroids with cimetidine given prophylactically, and in 9 patients in a further study. Cimetidine was also reported to exacerbate the neutropenia and leucopenia in a patient receiving lomustine.

Pharmacokinetics

Intravenous carmustine is rapidly metabolised, and no intact drug is detectable after 15 minutes; metabolites have a much longer half-life and are presumed to be responsible for its activity. It is primarily excreted in the urine; some is also excreted as carbon dioxide, via the lungs. Carmustine readily crosses the blood-brain barrier, appearing in CSF in substantial concentrations almost immediately after intravenous injection. Carmustine diffuses from polymer implants into surrounding brain tissue; however, tissue and plasma concentrations after implantation have not been determined.

Uses and Administration

Carmustine is a cell-cycle phase non-specific antineoplastic belonging to the nitrosourea group of compounds, which are considered to function as alkylating agents. It is believed to alkylate DNA and RNA, and may also inhibit enzymatic processes by carbamoylation of amino acids in proteins. Carmustine is used in the treatment of brain tumours, and in combination chemotherapy for multiple myeloma. It may be given as second-line therapy in Hodgkin’s disease, non-Hodgkin’s lymphoma, and some other malignancies (see below).

Carmustine is licensed for use as a single agent either as a single dose of 150 to 200 mg/m or divided into doses of 75 to 100 mg/m given on 2 successive days. Doses are given by intravenous infusion over 1 to 2 hours in sodium chloride 0.9% or glucose 5%. Lower doses are usually given in combination therapy, except for conditioning before stem-cell transplantation. Doses may be repeated every 6 weeks provided that blood counts have returned to acceptable levels. Subsequent doses must be adjusted according to the haematological response (see also Bone-marrow Depression).

Polymer implants containing carmustine have been developed for implantation into the brain in the localised treatment of high-grade malignant glioma or recurrent glioblastoma multiforme. Each implant contains 7.7 mg of carmustine: up to 8 such implants are inserted into the cavity left by surgical removal of the tumour.

Amyloidosis. For mention of chemotherapy with epirubicin, cyclophosphamide, and carmustine to suppress amyloidosis after cardiac transplantation.

Malignant neoplasms. Carmustine has been used in chemo-fherapeutic regimens for a number of malignancies. Because of its ability to pass the blood-brain barrier it has been extensively used in malignant neoplasms of the brain. As an extension of such use, carmustine-releasing wafers have been implanted directly into the brain. In a multicentre study in patients with recurrent malignant glioma, biodegradable poly(carboxyphe-noxypropane/sebacic acid)anhydride polymer wafers containing carmustine implanted into the brain after tumour resection produced a median survival of 31 weeks compared with 23 weeks for placebo. A subsequent small cohort study failed to find a clear survival benefit associated with wafer implantation in recurrent glioma, and reported a higher rate of complications including seizures, cerebral oedema, CSF leaks, sepsis, and wound infections. The limitations of this small study were acknowledged by the authors, and a review that included these studies concluded that despite limited data, carmustine wafers do provide some survival benefit. A randomised trial in 240 patients found that treatment with carmustine wafers reduced the risk of death by 28% compared with placebo; this survival advantage was maintained at 1, 2, and 3 years, with statistical significance at 3 years. The adverse effect profile was similar for carmustine and placebo groups, and a retrospective review found carmustine wafers to be well tolerated with a low incidence of surgical complications such as infection. However, it was noted that, in some patients, neurological symptoms developed during an attempted tapering of dexamefhasone dosage after carmustine with radiotherapy and that close supervision of patients is warranted. Treatment effects or necrosis can radiographically mimic recurrent tumour in a proportion of patients; implantation of wafers caused morphological changes of the brain immediately adjacent to the implants.

Other conditions in which carmustine has been employed, include malignant melanoma, Hodgkin’s disease, and multiple myeloma.

Mycosis fungoides. Topical application of carmustine has been used successfully in early mycosis fungoides. Erythema and telangiectasia were the most frequent adverse effects.

Proprietary Preparations

Argentina: BiCNU;

Australia: BiCNU; Gliadel;

Austria; Carmubris;

Belgium: Nitrumori ;

Brazil: Becenun;

Canada: BiCNU;

Chile: BiCNU; Gliadel ;

Czech Republic: BiCNU;

France: BiCNU; Gliadel;

Germany; Carmubris;

Greece: Carmubris; Gliadel; Nitrumont;

Hong Kong; BiCNU;

Hungary: BiCNU;

Ireland: BiCNU;

Israel: BiC-NU ; Gliadel;

Malaysia: BiCNU ; Gliadel;

Mexico: BiCNU;

The Netherlands: Gliadel;

New Zealand: BiCNU;

Philippines: BiCNU;

Portugal: Gliadel;

South Africa: BiCNU; Gliadel;

Singapore; BiCNU;

Spain: Gliadel;

Turkey: Nitrumon;

United Kingdom (UK): BiCNU ; Gliadel;

United States of America (US and USA): BiCNU; Gliadel.

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