Myelosuppression: Bone marrow toxicity is a dose-limiting, common and severe toxic effect of BiCNU occurring 4-6 weeks after drug administration (thrombocytopenia occurs at about 4 weeks post-administration persisting for 1 to 2 weeks; leukopenia occurs at 5 to 6 weeks after a dose of BiCNU persisting for 1 to 2 weeks; thrombocytopenia is generally more severe than leukopenia; anemia is less frequent and less severe compared to thrombocytopenia and/or leukopenia). Complete blood count should therefore be monitored weekly for at least six weeks after a dose. Repeat doses of BiCNU should not be given more frequently than every six weeks. The bone marrow toxicity of BiCNU is cumulative and therefore the dosage adjustment must be considered on the basis of nadir blood counts from prior dose [see Adverse Reactions]. Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine [see Interactions].
Pulmonary Toxicity: Cases of fatal pulmonary toxicity with BiCNU have been reported. Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported to occur from 9 days to 43 months after treatment with BiCNU and related nitrosoureas. Pulmonary toxicity from BiCNU is dose-related. Patients receiving greater than 1400 mg/m2 cumulative dose are at significantly higher risk than those receiving less. However, there have been reports of pulmonary fibrosis in patients receiving lower total doses. Interstitial fibrosis (with lower doses) occurred rarely. Additionally, delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received BiCNU (in cumulative doses ranging from 770 to 1800 mg/m2 combined with cranial radiotherapy for intracranial tumors) in childhood and early adolescence. Other risk factors include past history of lung disease and duration of treatment. Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) are particularly at risk.
Administration Reactions: Injection site reactions may occur during the administration of BiCNU. Rapid intravenous infusion of BiCNU may produce intensive flushing of the skin and suffusion of the conjunctiva within 2 hours, lasting about 4 hours. It is also associated with burning at the site of injection although true thrombosis is rare. Given the possibility of extravasation, close monitoring of the infusion site for possible infiltration during drug administration is recommended. A specific treatment for extravasation reactions is unknown at this time.
Carcinogenicity: Long-term use of nitrosoureas, such as BiCNU, has been reported to be associated with the development of secondary malignancies. Carmustine was carcinogenic when administered to laboratory animals [see Pharmacology: Toxicology: Nonclinical Toxicity under Actions]. Nitrosourea therapy, such as BiCNU, has carcinogenic potential in humans. Patients treated with BiCNU should be monitored long-term for development of second malignancies.
Ocular Toxicity: BiCNU has been administered through an intraarterial intracarotid route; this procedure is investigational and has been associated with ocular toxicity. Safety and effectiveness of the intraarterial route have not been established.
Embryo-Fetal Toxicity: Carmustine was embryotoxic in rats and rabbits and teratogenic in rats when given in doses lower than the maximum cumulative human dose based on body surface area. There are no adequate and well-controlled studies in pregnant women. Advise pregnant women of the potential risk to the fetus [see as follows]. Advise females of reproductive potential to use highly effective contraception during and after treatment with BiCNU for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with BiCNU for at least 3 months after therapy [see as follows].
Pediatric Use: Safety and effectiveness in children have not been established. Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in a long-term study of patients who received BiCNU in childhood and early adolescence (1-16 years). Eight out of the 17 patients (47%) who survived childhood brain tumors, including all the 5 patients initially treated at less than 5 years of age, died of pulmonary fibrosis. [See Adverse Reactions.]
Geriatric Use: Clinical studies of BiCNU did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
BiCNU and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.