Bleomycin 15 [USP'U]/1 Injection, Powder, Lyophilized, For Solution, 1 vial — NDC 63323-136-10 (Billing 63323-0136-10)

WARNINGS: Patients receiving bleomycin must be observed carefully and frequently during and after therapy. It should be used with extreme caution in patients with significant impairment of renal function or compromised pulmonary function. Pulmonary toxicities occur in 10% of treated patients.

In approximately 1%, the nonspecific pneumonitis induced by bleomycin progresses to pulmonary fibrosis and death. Although this is age and dose related, the toxicity is unpredictable. Frequent roentgenograms are recommended (see ADVERSE REACTIONS, Pulmonary ).

A severe idiosyncratic reaction (similar to anaphylaxis) consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin. Since these reactions usually occur after the first or second dose, careful monitoring is essential after these doses (see ADVERSE REACTIONS, Idiosyncratic Reactions ). Renal or hepatic toxicity, beginning as a deterioration in renal or liver function tests, have been reported.

These toxicities may occur at any time after initiation of therapy. Usage in Pregnancy Pregnancy “Category D” Bleomycin can cause fetal harm when administered to a pregnant woman. It has been shown to be teratogenic in rats.

Administration of intraperitoneal doses of 1.5 mg/kg/day to rats (about 1.6 times the recommended human dose on a unit/m 2 basis) on days 6 to 15 of gestation caused skeletal malformations, shortened innominate artery and hydroureter. Bleomycin is abortifacient but not teratogenic in rabbits at intravenous doses of 1.2 mg/kg/day (about 2.4 times the recommended human dose on a unit/m 2 basis) given on gestation days 6 to 18. There have been no studies in pregnant women.

If bleomycin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with bleomycin.

Usage in Pregnancy Pregnancy “Category D” Bleomycin can cause fetal harm when administered to a pregnant woman. It has been shown to be teratogenic in rats. Administration of intraperitoneal doses of 1.5 mg/kg/day to rats (about 1.6 times the recommended human dose on a unit/m 2 basis) on days 6 to 15 of gestation caused skeletal malformations, shortened innominate artery and hydroureter.

Bleomycin is abortifacient but not teratogenic in rabbits at intravenous doses of 1.2 mg/kg/day (about 2.4 times the recommended human dose on a unit/m 2 basis) given on gestation days 6 to 18. There have been no studies in pregnant women. If bleomycin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential should be advised to avoid becoming pregnant during therapy with bleomycin.

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 bleomycin has been extremely difficult. The earliest symptom associated with bleomycin pulmonary toxicity is dyspnea.

The earliest sign is fine rales. Radiographically, bleomycin-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 bleomycin toxicity include bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous edema, and interstitial fibrosis. The acute stage may involve capillary changes and subsequent fibrinous exudation into alveoli producing a change similar to hyaline membrane formation and progressing to a diffuse interstitial fibrosis resembling the Hamman-Rich syndrome.

These microscopic findings are nonspecific; e.g., similar changes are seen in radiation pneumonitis and pneumocystic pneumonitis. To monitor the onset of pulmonary toxicity, roentgenograms of the chest should be taken every 1 to 2 weeks (see WARNINGS ). If pulmonary changes are noted, treatment should be discontinued until it can be determined if they are drug related.

Recent studies have suggested that sequential measurement of the pulmonary diffusion capacity for carbon monoxide (DL co ) during treatment with bleomycin may be an indicator of subclinical pulmonary toxicity. It is recommended that the DL co be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DL co falls below 30% to 35% of the pretreatment value. Because of bleomycin’s sensitization of lung tissue, patients who have received bleomycin are at greater risk of developing pulmonary toxicity when oxygen is administered in surgery.

While long exposure to very high oxygen concentrations is a known cause of lung damage, after bleomycin administration, lung damage can occur at lower concentrations that are usually considered safe. Suggested preventive measures are: 1. Maintain FlO 2 at concentrations approximating that of room air (25%) during surgery and the postoperative period.

2. Monitor carefully fluid replacement, focusing more on colloid administration rather than crystalloid. Sudden onset of an acute chest pain syndrome suggestive of pleuropericarditis has been reported during bleomycin infusions.

Although each patient must be individually evaluated, further courses of bleomycin do not appear to be contraindicated. Pulmonary adverse events which may be related to the intrapleural administration of bleomycin have been reported. Idiosyncratic Reactions In approximately 1% of the lymphoma patients treated with bleomycin, an idiosyncratic reaction, similar to anaphylaxis clinically, has been reported.

The reaction may be immediate or delayed for several hours, and usually occurs after the first o… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS: General Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Lower doses of bleomycin may be required in these patients than those with normal renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of bleomycin 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/m 2 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 bleomycin therapy.

Pediatric Use Safety and effectiveness of bleomycin 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.

General Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Lower doses of bleomycin may be required in these patients than those with normal renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of bleomycin 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/m 2 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 bleomycin therapy.

Pediatric Use Safety and effectiveness of bleomycin 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 betw… [Excerpted — this section continues on DailyMed.]