in humans is unknown. A study in F344-type male rats demonstrated an increased incidence of nodular hyperplasia after induced lung carcinogenesis by nitrosamines, followed by treatment with bleomycin. In another study where the drug was administered to rats by subcutaneous injection at 0.35 mg/kg weekly (3.82 units/m2 weekly or about 30% at the recommended human dose), necropsy findings included dose-related injection site fibrosarcomas as well as various renal tumors. Bleomycin has been shown to be mutagenic both in vitro and in vivo. The effects of bleomycin on fertility have not been studied.
Pregnancy
Pregnancy Category D
See WARNINGS.
Nursing Mothers
It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued by women receiving BLENOXANE therapy.
Pediatric Use
Safety and effectiveness of BLENOXANE in pediatric patients have not been established.
Geriatric Use
In clinical trials, pulmonary toxicity was more common in patients older than 70 years than in younger patients (see BOXED WARNING, WARNINGS, and ADVERSE REACTIONS: Pulmonary). Other reported clinical experience has not identified other differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Bleomycin is 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 it may be useful to monitor renal function.
ADVERSE REACTIONS
Pulmonary
The most serious side effects are pulmonary adverse reactions, occurring in approximately 10% of treated patients. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Approximately 1% of patients treated have died of pulmonary fibrosis. Pulmonary toxicity is both dose and age related, being more common in patients over 70 years of age and in those receiving over 400 units total dose. This toxicity, however, is unpredictable and has been seen in young patients receiving low doses. Some published reports have suggested that the risk of pulmonary toxicity may be increased when bleomycin is used in combination with G-CSF (filgrastim) or other cytokines. However, randomized clinical studies completed to date have not demonstrated an increased risk of pulmonary complications in patients treated with bleomycin and G-CSF.
Because of lack of specificity of the clinical syndrome, the identification of patients with pulmonary toxicity due to BLENOXANE has been extremely difficult. The earliest symptom associated with BLENOXANE pulmonary toxicity is dyspnea. The earliest sign is fine rales.
Radiographically, BLENOXANE-induced pneumonitis produces nonspecific patchy opacities, usually of the lower lung fields. The most common changes in pulmonary function tests are a decrease in total lung volume and a decrease in vital capacity. However, these changes are not predictive of the development of pulmonary fibrosis.
The microscopic tissue changes due to BLENOXANE toxicity include bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous edema, and interstitial fibrosis. The acute stage may in |
