al or liver function tests, have been reported. these toxicities may occur at any time after initiation of therapy. use in pregnancy: teratogenic effects: 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.

ation 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 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 cockroft and gault formula: males crcl = [weight x (140 – age)]/(72 x scr) females crcl = 0.85 x [weight x (140 – age)]/(72 x scr) where crcl in ml/min/1.73 m 2 , weight in kg, age in years, and scr in mg/dl. administration bleomycin 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 15 units vial should be reconstituted with 1 to 5 ml of sterile water for injection, sodium chloride for injection, 0.9%, or sterilebacteriostatic water for injection. the bleomycin 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%, 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%, 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 bleomycin. although there is no conclusive evidence to support this contention, it is generally accepted that chest tube drainage should be less than 100 ml in a 24 hour period prior to sclerosis. however, bleomycin instillation may be appropriate when drainage is between 100 to 300 ml under clinical conditions that necessitate sclerosis therapy. the thoracostomy tube is clamped after bleomycin instillation. the patient is moved from the supine to the left and right lateral positions several times during the next four hours. the clamp is then removed and suction reestablished. the amount of time the chest tube remains in place following sclerosis is dictated by the clinical situation. the intrapleural injection of topical anesthetics or systemic narcotic analgesia is generally not required. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

oxicity 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 fi0 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 or second dose (see warnings ). it consists of hypotension, mental confusion, fever, chills, and wheezing. treatment is symptomatic including volume expansion, pressor agents, antihistamines, and corticosteroids. integument and mucous membranes these adverse reactions have been reported in approximately 50% of treated patients. they consist of erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of the skin. hyperkeratosis, nail changes, alopecia, pruritus, and stomatitis have also been reported. it was necessary to discontinue bleomycin therapy in 2% of treated patients because of these toxicities. scleroderma-like skin changes have been reported. skin toxicity is a relatively late manifestation usually developing in the second and third week of treatment after 150 to 200 units of bleomycin have been administered and appears to be related to the cumulative dose. intrapleural administration of bleomycin has been associated with local pain. hypotension possibly requiring symptomatic treatment has been reported. death has been reported in association with bleomycin pleurodesis in seriously ill patients. other vascular toxicities coincident with the use of bleomycin in combination with other antineoplastic agents have been reported. the events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hus) or cerebral arteritis. various mechanisms have been proposed for these vascular complications. there are also reports of raynaud's phenomenon occurring in patients treated with bleomycin in combination with vinblastine with or without cisplatin or, in a few cases, with bleomycin as a single agent. it is currently unknown if the cause of raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors. fever, chills, and vomiting have been reported. anorexia and weight loss have been reported and may persist long after termination of this medication. pain at tumor site, phlebitis, and other local reactions have been reported. malaise has been reported.

ions, compared to intravenous and bolus administration. following intramuscular doses of 1 to 10 units/m 2 , both peak plasma concentration and auc increased in proportion with the increase of dose. following intravenous bolus administration of 30 units of bleomycin 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 two 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/m 2 in patients following a 15 units/m 2 iv 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. systemic elimination of the drug by enzymatic degradation is probably only important in patients with severely compromised renal function. excretion the primary route of elimination is via the kidneys. about 65% of the administered intravenous dose is excreted in urine within 24 hours. in patients with normal renal function, plasma concentrations of bleomycin decline biexponentially with a mean terminal half-life of 2 hours following intravenous bolus administration. total body clearance and renal clearance averaged 51 ml/min/m 2 and 23 ml/min/m 2 , respectively. following intrapleural administration to patients with normal renal function, a lower percentage of drug (40%) is recovered in the urine, as compared to that found in the urine after intravenous administration. special populations age, gender, and race the effects of age, gender, and race on the pharmacokinetics of bleomycin have not been evaluated. pediatric children of less than 3 years of age have higher total body clearance than in adults, 71 ml/min/m 2 versus 51 ml/min/m 2 , respectively, following intravenous bolus administration. children of more than 8 years of age have comparable clearance as in adults. in children with normal renal function, plasma concentrations of bleomycin decline biexponentially as in adults. the volume of distribution and terminal half-life of bleomycin in children appears comparable to that in adults. renal insufficiency renal insufficiency markedly alters bleomycin elimination. the terminal elimination half-life increases exponentially as the creatinine clearance decreases. dosing reductions were proposed for patients with creatinine clearance values of <50 ml/min (see precautions and dosage and administration ). hepatic insufficiency the effect of hepatic insufficiency on the pharmacokinetics of bleomycin has not been evaluated. 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. clinical studies malignant pleural effusion the safety and efficacy of bleomycin 60 units and tetracycline (1 g) as treatment for malignant pleural effusion were evaluated in a multicenter, randomized trial. patients were required to have cytologically positive pleural effusion, good performance status (0,1,2), lung re-expansion following tube thoracostomy with drainage rates of 100 ml/24 hours or less, no prior intrapleural therapy, no prior systemic bleomycin therapy, no chest irradiation and no recent change in systemic therapy. overall survival did not differ between the bleomycin (n=44) and tetracycline (n=41) groups. of patients evaluated within 30 days of instillation, the recurrence rate was 36% (10/28) with bleomycin and 67% (18/27) with tetracycline (p=0.023). toxicity was similar between groups.

leomycin is widely distributed throughout the body with a mean volume of distribution of 17.5 l/m 2 in patients following a 15 units/m 2 iv 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. systemic elimination of the drug by enzymatic degradation is probably only important in patients with severely compromised renal function. excretion the primary route of elimination is via the kidneys. about 65% of the administered intravenous dose is excreted in urine within 24 hours. in patients with normal renal function, plasma concentrations of bleomycin decline biexponentially with a mean terminal half-life of 2 hours following intravenous bolus administration. total body clearance and renal clearance averaged 51 ml/min/m 2 and 23 ml/min/m 2 , respectively. following intrapleural administration to patients with normal renal function, a lower percentage of drug (40%) is recovered in the urine, as compared to that found in the urine after intravenous administration.