BLENOXANE - bleomycin sulfate injection, powder, for solution 
E.R. Squibb & Sons, L.L.C.
----------
BLENOXANE®
(bleomycin sulfate for injection, USP)
WARNING
It is recommended that BLENOXANE be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.
Pulmonary fibrosis is the most severe toxicity associated with BLENOXANE. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses.
A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with BLENOXANE.
DESCRIPTION
BLENOXANE® (bleomycin sulfate for injection, USP) is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus. It is freely soluble in water.
Note: A unit of bleomycin is equal to the formerly used milligram activity. The term milligram activity is a misnomer and was changed to units to be more precise.
CLINICAL PHARMACOLOGY
Mechanism of Action
Although the exact mechanism of action of BLENOXANE is unknown, available evidence indicates that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis.
Bleomycin is known to cause single, and to a lesser extent, double-stranded breaks in DNA. In in vitro and in vivo experiments, bleomycin has been shown to cause cell cycle arrest in G2 and in mitosis.
When administered into the pleural cavity in the treatment of malignant pleural effusion, BLENOXANE acts as a sclerosing agent.
Pharmacokinetics
Absorption
Bleomycin is rapidly absorbed following either intramuscular, subcutaneous, intraperitoneal, or intrapleural administration reaching peak plasma concentrations in 30 to 60 minutes. Systemic bioavailability of bleomycin is 100% and 70% following intramuscular and subcutaneous administrations, respectively, and 45% following both intraperitoneal and intrapleural administrations, compared to intravenous and bolus administration.
Following intramuscular doses of 1 to 10 units/m2, both peak plasma concentration and AUC increased in proportion with the increase of dose.
Following intravenous bolus administration of 30 units of BLENOXANE to one patient with a primary germ cell tumor of the brain, a peak CSF level was 40% of the simultaneously-obtained plasma level and was attained in 2 hours after drug administration. The area under the bleomycin CSF concentration x time curve was 25% of the area of the bleomycin plasma concentration x time curve.
Distribution
Bleomycin is widely distributed throughout the body with a mean volume of distribution of 17.5 L/m2 in patients following a 15 units/m2 intravenous bolus dose. Protein binding of bleomycin has not been studied.
Metabolism
Bleomycin is inactivated by a cytosolic cysteine proteinase enzyme, bleomycin hydrolase. The enzyme is widely distributed in normal tissues with the exception of the skin and lungs, both targets of bleomycin toxicity