Bleomycin Sulfate

Description

DESCRIPTION Bleomycin for Injection, USP is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus . It is freely soluble in water. Bleomycin for Injection, USP is provided as a sterile lyophilized powder for reconstitution containing 15 units per vial and 30 units per vial, which are intended for intramuscular, intravenous, subcutaneous or intrapleural administration. Its chemical name is N'-[3-(dimethylsulphonio)propyl]bleomycin-amide (bleomycin A 2 ) and N'-[4-(guaniodobutyl)]bleomycin-amide (bleomycin B 2 ). (Main component: Bleomycin A 2 , in which R is [CH 3 ] 2 S + CH 2 CH 2 CH 2 -) 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. Figure

What Is Bleomycin Sulfate Used For?

INDICATIONS AND USAGE Bleomycin for Injection, USP should be considered a palliative treatment. It has been shown to be useful in the management of the following neoplasms either as a single agent or in proven combinations with other approved chemotherapeutic agents: Squamous Cell Carcinoma: Head and neck (including mouth, tongue, tonsil, nasopharynx, oropharynx, sinus, palate, lip, buccal mucosa, gingivae, epiglottis, skin, larynx), penis, cervix, and vulva. The response to Bleomycin for Injection, USP is poorer in patients with previously irradiated head and neck cancer. Lymphomas: Hodgkin's disease, non-Hodgkin's lymphoma. Testicular Carcinoma: Embryonal cell, choriocarcinoma, and teratocarcinoma. Bleomycin for Injection, USP has also been shown to be useful in the management of: Malignant Pleural Effusion: Bleomycin for Injection, USP is effective as a sclerosing agent for the treatment of malignant pleural effusion and prevention of recurrent pleural effusions.

Dosage and Administration

DOSAGE AND ADMINISTRATION Because of the possibility of an anaphylactoid reaction, lymphoma patients should be treated with 2 units or less for the first 2 doses. If no acute reaction occurs, then the regular dosage schedule may be followed. The following dose schedule is recommended: Squamous cell carcinoma, non-Hodgkin's lymphoma, testicular carcinoma – 0.25 to 0.50 units/kg (10 to 20 units/m 2 ) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly. Hodgkin's Disease – 0.25 to 0.50 units/kg (10 to 20 units/m 2 ) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly. After a 50% response, a maintenance dose of 1 unit daily or 5 units weekly intravenously or intramuscularly should be given. Pulmonary toxicity of bleomycin for injection appears to be dose-related with a striking increase when the total dose is over 400 units. Total doses over 400 units should be given with great caution. Note: When bleomycin for injection is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses. Improvement of Hodgkin's disease and testicular tumors is prompt and noted within 2 weeks. If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as 3 weeks before any improvement is noted. Malignant Pleural Effusion – 60 units administered as a single dose bolus intrapleural injection (see ADMINISTRATION: Intrapleural ). Use in Patients with Renal Insufficiency The following dosing reductions are proposed for patients with creatinine clearance (CrCL) values of less than 50 mL/min: CrCL can be estimated from the individual patient's measured serum creatinine (Scr) values using the Cockcroft and Gault formula: Males CrCL = [weight × (140 – Age)]/(72 × Scr) Females CrCL = 0.85 × [weight × (140 – Age)]/(72 × Scr) Where CrCL in mL/min/1.73m 2 , weight in kg, age in years, and Scr in mg/dL. Patient CrCL (mL/min) Bleomycin for Injection Dose (%) 50 and above 100 40 to 50 70 30 to 40 60 20 to 30 55 10 to 20 45 5 to 10 40

Side Effects (Adverse Reactions)

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: Maintain FIO 2 at concentrations approximating that of room air (25%) during surgery and the postoperative period. 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 or...

Drug Interactions

Drug Interactions Drugs that Can Affect Renal Clearance Because bleomycin is eliminated predominantly through renal excretion, the administration of nephrotoxic drugs with bleomycin may affect its renal clearance. Specifically, in one report of 2 children receiving concomitant cisplatin with bleomycin, total body clearance of bleomycin decreased from 39 to 18 mL/min/m 2 as the cumulative dose of cisplatin exceeded 300 mg/m 2 . Terminal half-life of bleomycin also increased from 4.4 to 6 hours. Fatal bleomycin pulmonary toxicity has been reported in a patient with unrecognized cisplatin-induced oliguric renal failure.

Contraindications

CONTRAINDICATIONS Bleomycin for injection is contraindicated in patients who have demonstrated a hypersensitive or an idiosyncratic reaction to it.

Pregnancy and Breastfeeding

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.

How Supplied

HOW SUPPLIED Bleomycin for Injection, USP is supplied as follows: NDC Bleomycin for Injection, USP Package Factor 71288- 106 -10 15 units per vial 1 vial per carton 71288- 107 -20 30 units per vial 1 vial per carton Storage Conditions Store refrigerated between 2° and 8°C (36° and 46°F). The sterile powder is stable under refrigeration and should not be used after the expiration date is reached. Bleomycin for Injection, USP should not be reconstituted or diluted with D 5 W or other dextrose containing diluents. When reconstituted in D 5 W and analyzed by HPLC, Bleomycin for Injection, USP demonstrates a loss of A 2 and B 2 potency that does not occur when Bleomycin for Injection, USP is reconstituted in Sodium Chloride for Injection, 0.9%, USP. Bleomycin for Injection, USP is stable for 24 hours at room temperature in Sodium Chloride. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.