BLEOMYCIN

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 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 is effective as a sclerosing agent for the treatment of malignant pleural effusion and prevention of recurrent pleural effusions.

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 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: Patient CrCL (mL/min) Bleomycin for Injection, USP 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 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. Administration Bleomycin for Injection may be given by the intramuscular, intravenous, subcutaneous or intrapleural routes. Administration Precautions Caution should be exercised when handling Bleomycin for injection. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published. 1–4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Bleomycin for injection. If Bleomycin for injection contacts the skin, immediately wash the skin thoroughly with soap and water. If contact with mucous membranes occurs, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below. Intramuscular or Subcutaneous The Bleomycin for Injection, USP 15 units vial should be reconstituted with 1 to 5 mL of Sterile Water for Injection, USP, Sodium Chloride for Injection, 0.9%, USP, or Sterile Bacteriostatic Water for Injection, USP. The Bleomycin for Injection, USP 30 units vial should be reconstituted with 2 to 10 mL of the above diluents. Intravenous The contents of the 15 units or 30 units vial should be dissolved in 5 mL or 10 mL, respectively of Sodium Chloride for Injection, 0.9%, USP, and administered slowly over a period of 10 minutes. Intrapleural Sixty units of Bleomycin are dissolved in 50 to 100 mL Sodium Chloride for Injection, 0.9%, USP, and administered through a thoracostomy tube following drainage of excess pleural fluid and confirmation of complete lung expansion. The literature suggests that successful pleurodesis is, in part, dependent upon complete drainage of the pleural fluid and reestablishment of negative intrapleural pressure prior to instillation of a sclerosing agent. Therefore, the amount of drainage from the chest tube should be as minimal as possible prior to instillation of Bleomyc …

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

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 …

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.

Mechanism of Action Although the exact mechanism of action of bleomycin 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, Bleomycin acts as a sclerosing agent.

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. It is available as a lyophilized powder for intramuscular, intravenous or subcutaneous injection. Each vial contains sterile bleomycin sulphate equivalent to 15 units or 30 units of bleomycin. Sulfuric acid or Sodium hydroxide used, if necessary to adjust the pH. Bleomycins are a group of related basic glycopeptides which differ in the terminal amine substituent of the common structural unit, bleomycin acid. The main components of Bleomycin for Injection are bleomycins A 2 and B 2 . Chemically, bleomycin A 2 is N 1 -[3-(dimethylsulfonio)propyl]-bleomycinamide and bleomycin B 2 is N 1 -[4-(aminoiminomethyl)amino]butyl]-bleomycinamide. The molecular formula of bleomycin A 2 is C 55 H 84 N 17 O 21 S 3 and a calculated molecular weight of 1414. The molecular formula of bleomycin B 2 is C 55 H 84 N 20 O 21 S 2 and a calculated molecular weight of 1425. The structural formula of bleomycins A 2 and B 2 are shown below. 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. structural formula bleomycin

HOW SUPPLIED: Bleomycin for Injection, USP is available as follows: Product No. NDC No. 103610 63323-136-10 15 units per vial, individually packaged. 103720 63323-137-20 30 units per vial, individually packaged. Stability The sterile powder is stable under refrigeration 2°C to 8°C (36°F to 46°F) and should not be used after the expiration date is reached. Bleomycin for Injection 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 demonstrates a loss of A 2 and B 2 potency that does not occur when Bleomycin for Injection is reconstituted in Sodium Chloride for Injection, 0.9%, USP. Bleomycin for Injection is stable for 24 hours at room temperature in Sodium Chloride. The container closure is not made with natural rubber latex.

Stability The sterile powder is stable under refrigeration 2°C to 8°C (36°F to 46°F) and should not be used after the expiration date is reached. Bleomycin for Injection 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 demonstrates a loss of A 2 and B 2 potency that does not occur when Bleomycin for Injection is reconstituted in Sodium Chloride for Injection, 0.9%, USP. Bleomycin for Injection is stable for 24 hours at room temperature in Sodium Chloride. The container closure is not made with natural rubber latex.