as long as three weeks. a therapeutic response should be observed as the total dose approaches 150,000 iu, if this is not seen, consideration should be given to other therapy. note. when bleomycin is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses (see precautions, pulmonary toxicity and interactions). intra-arterial administration. intra-arterial infusion/ perfusion is employed when increased drug concentrations at the cancer site are desired. the suggested dosage schedule is 30,000 to 60,000 iu once or twice a week until the total recommended dose of 300,000 iu is reached. repeat treatment. in patients for whom a course of bleomycin treatment provides an initial but incomplete response, a repeat course is suggested. patients who show superficial improvement after one course, e.g. in cases of squamous cell carcinoma, may benefit from a second course of treatment to prevent recurrence. a repeat course may be commenced after a minimum of three to four weeks following completion of the first course, providing no sign of pulmonary toxicity has been observed (see contraindications). a total dose of 150,000 iu for repeat treatment is recommended. use in children no information available. use in the elderly adult dose should be used with caution, particularly in patients over 70 years (see adverse effects, pulmonary toxicity). impaired hepatic function use adult dose with caution. impaired renal function as bleomycin is mostly excreted unchanged and as there is a high correlation between renal bleomycin clearance and creatinine clearance, impairment of function may require reduction in dosage and careful monitoring for toxicity. dosage reductions of 40 to 75% have been recommended for patients with creatinine clearance values of less than or equal to 40 ml/minute reconstitution intramuscular, subcutaneous injection. for intramuscular or subcutaneous injection, dissolve the contents of the vial in 1 to 5 ml of sterile water for injection or sodium chloride intravenous infusion 0.9%. intravenous, intra-arterial injection. for intravenous or intra-arterial injection, dissolve the contents of the vial in 5 to 10 ml of diluent and administer slowly over a period of 10 minutes. suitable diluents are water for injections, bacteriostatic water for injection and sodium chloride intravenous infusion 0.9%. although glucose intravenous infusion 5% has been used in the past, recent data suggests that it is not the diluent of choice, as over the concentration range of 300 to 15,000 iu/ml the content of bleomycin a2 + b2 was consistently lower when glucose intravenous infusion 5% was used. reconstituted solutions containing bleomycin 150 to 15,000 iu/ml prepared using the recommended diluents remain stable for periods of at least 24 hours when stored in the dark, at temperatures of 2 to 8°c. solutions of bleomycin sulfate in sodium chloride intravenous 0.9% stored in the dark at 2 to 8°c for ten days were chemically stable. however, in order to reduce the possibility of microbiological contamination, reconstituted injections should be used as soon as practicable after preparation. if storage of the reconstituted solution is necessary, store at 2 to 8°c for no more than 24 hours. any unused portions must be discarded in compliance with acceptable procedures for the disposal of anticancer medicines.

mycin pulmonary toxicity are not easily distinguished from other syndromes commonly observed in cancer patient, including progressive metastatic tumor (especially lymphangitic tumor), infectious processes such as pneumocystsis carinii or cytomegalovirus, or radiation injury. the first symptoms to appear are dyspnea, with cough and low grade fever, commonly occurring four to ten weeks after initiation of therapy, although the time of onset of pulmonary toxicity may vary from during therapy to up to six months after the cessation of therapy. the microscopic tissue changes due to bleomycin toxicity are frequently present as 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 and are similar to the changes produced in radiation pneumonitis, pneumocystic pneumonitis, and at times reaction to long standing malignant pulmonary disease. pulmonary function tests have revealed some alteration in the pulmonary status such as decreased total lung volume and decreased vital capacity, but these tests have proved to be of limited value in predicting pulmonary fibrosis. it has been suggested that bleomycin should be discontinued it forced vital capacity decreases rapidly. pulmonary toxicity is seen more commonly in smokers. idiosyncratic effects . hypersensitivity reactions consisting of hypotension, lever, chills, mental confusion and wheezing have occurred in approximately 1% of patients receiving bleomycin. this idiosyncratic reaction occurs mainly in lymphoma patients (5%), may be immediate or delayed for several hours, and usually occurs after the first or second dose. the reaction has resulted in death. treatment of anaphylactic reactions is supportive and symptomatic and may include volume expansion, vas0pressor therapy, antihistamines and corticosteroids. cardiovascular. vascular toxicities coincident with the use of bleomycin in combination with other antineoplastic agents have been reposed rarely. the events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic uremic syndrome) or cerebrovascular arteritis. acute chest pain syndrome, acute pericarditis, fulminant fatal hyperpyrexia and fulminate, fatal angioedema have been reported. more common reactions body as a whole. fever, chills and headache frequently follow parenteral administration of bleomycin (20 to 50%). these reactions have been reported to occur most frequently with large single doses and occur within a few hours of administration lasting 4 to 12 hours. usually, febrile reactions become less frequent with continued use of the drug but may occur sporadically and reoccur later in the treatment course. gastrointestinal. anorexia, nausea and vomiting (20 to 50%) (anorexia and weight loss may persist after discontinuing therapy), tiredness. mucocutaneous (50%). hypoesthesia which may progress to hyperesthesia, urticaria, erythematous swelling, tenderness, pruritus, hyperpigmentation (particularly in those areas subject to friction or pressure and in skin folds, nail cuticles, scars, and intramuscular injection sites), patchy hyperkeratosis, alopecia, ichthyosis, rash, striae, vesiculation, peeling, and bleeding, stomatitis, ulcerations of the tongue and lips. this toxicity is usually evident within one to three weeks following initiation of therapy and appears to be reversible and dose related, usually after 150,000 to 200,000 iu of bleomycin has been administered and, in general, is related to total cumulative dose. in 0.2% of patients it was necessary to discontinue treatment because of this toxicity. when bleomycin is administered intra-arterially, dermal lesions are most common in the region supplied by the artery used. the incidence of mucocutaneous adverse events is increased when bleomycin sulfate is given in combination with radiotherapy to head and neck. less common reactions body as a whole. idiosyncratic reactions occurring in 1% of patients (5% of lymphoma patients) (see severe/ life threatening reactions). cardiovascular. diverse vascular toxicities (see severe/ life-threatening reactions), hypotension (more common after intrapleural administration), sudden onset of an acute chest pain syndrome, suggestive of pleuropericarditis (although each patient must be individually evaluated, further courses of bleomycin do not appear to be contraindicated), ocular hemorrhage. there are isolated reports of raynaud's phenomenon occurring in patients treated with a combination of bleomycin and vinblastine with or without cisplatin or, in a few cases, with bleomycin as a single agent. it is currently unknown if the cause of the raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, cisplatin induced hypomagnesaemia or a combination of any or all of these. central nervous system. cns toxicity is rare, but monitoring is advised. disorientation and aggressive behavior have been reported. hematological. thrombocytopenia, leucopenia, slight depression of hemoglobin levels. bleomycin does not frequently produce serious bone marrow toxicity. hepatic. liver toxicity beginning as deterioration in liver function tests has been reported infrequently. injection site. pain at injection site, phlebitis, other local reactions. renal. renal toxicity beginning as deterioration in renal function tests has been reported infrequently. hematuria and cystitis have been reported. respiratory. pulmonary toxicity (10%) (see severe/ life threatening reactions).

distribution in mice, bleomycin diffusing from the blood produces high concentrations in the skin, lungs, kidneys, peritoneum, lymphatic system and susceptible tumour tissue if present. bleomycin crosses the placenta, but does not cross the blood brain barrier. equilibrium dialysis and gel permeation experiments suggest that less than 1.0% of the drug is protein bound after incubation with normal human serum in vitro. metabolism the majority of a bleomycin dose is not readily metabolised. the highest rate of metabolism occurs in the liver and gastrointestinal tract. a lower rate of metabolism also occurs in skin, lungs, kidneys, muscle and serum. the products of bleomycin metabolism are not known. excretion bleomycin is primarily excreted in the urine. after intravenous injection an average of 40% of the administered dose is recovered unchanged in the urine within 24 hours. after intramuscular injection 20% is recovered in the urine after six hours. the plasma half-lives have varied from 15 to 60 minutes in patients with normal renal function following intravenous administration. the serum half-life is prolonged in patients with renal dysfunction. in one patient with severe renal dysfunction the biological half-life was 21 hours when the creatinine clearance was 10.7 ml/minute, and 13 hours when the creatinine clearance was 15.2 ml/minute. there were undetectable serum levels of bleomycin 72 hours after the intravenous dose. interactions with other medicines -pharmacodynamic interactions anaesthetics, general and oxygen. use in patients previously treated with bleomycin may result in rapid pulmonary deterioration, since bleomycin causes sensitisation of lung tissue to oxygen. radiation therapy. radiation therapy, especially to the chest area, either prior to, during or after bleomycin therapy may result in increased bleomycin toxicity. dosage adjustment may be necessary. antineoplastic agents. concurrent use may result in increased bleomycin toxicity, or in occurrence of pulmonary toxicity at lower doses of bleomycin (see precautions). combination therapy. pulmonary toxicity may be observed at lower doses of bleomycin when bleomycin is administered as part of a multidrug treatment regimen. patients should be closely monitored for signs of pulmonary toxicity (see precautions). granulocyte colony stimulating factor. it has been suggested that concomitant administration of g-csf and bleomycin may increase the risk of bleomycin induced pulmonary toxicity, especially at higher doses, although this has not been confirmed in clinical trials. if g-csf is added to bleomycin containing treatment regimens, patients should be closely observed for signs of pulmonary toxicity (see precautions). -pharmacokinetic interactions cisplatin. cisplatin induced renal function impairment may result in delayed clearance and bleomycin toxicity even at low doses. an increased incidence of bleomycin induced pulmonary toxicity has been observed when these two agents are administered as part of an antineoplastic treatment regimen. dosage reduction may be required (see precautions). digoxin. serum levels of digoxin may be reduced and its actions may be decreased. it is thought that drug induced alterations of the intestinal mucosa may be involved in the reduced gastrointestinal absorption. phenytoin. serum concentrations of phenytoin may be decreased due to decreased absorption or increased metabolism of phenytoin.

f bleomycin metabolism are not known. excretion bleomycin is primarily excreted in the urine. after intravenous injection an average of 40% of the administered dose is recovered unchanged in the urine within 24 hours. after intramuscular injection 20% is recovered in the urine after six hours. the plasma half-lives have varied from 15 to 60 minutes in patients with normal renal function following intravenous administration. the serum half-life is prolonged in patients with renal dysfunction. in one patient with severe renal dysfunction the biological half-life was 21 hours when the creatinine clearance was 10.7 ml/minute, and 13 hours when the creatinine clearance was 15.2 ml/minute. there were undetectable serum levels of bleomycin 72 hours after the intravenous dose. interactions with other medicines -pharmacodynamic interactions anaesthetics, general and oxygen. use in patients previously treated with bleomycin may result in rapid pulmonary deterioration, since bleomycin causes sensitisation of lung tissue to oxygen. radiation therapy. radiation therapy, especially to the chest area, either prior to, during or after bleomycin therapy may result in increased bleomycin toxicity. dosage adjustment may be necessary. antineoplastic agents. concurrent use may result in increased bleomycin toxicity, or in occurrence of pulmonary toxicity at lower doses of bleomycin (see precautions). combination therapy. pulmonary toxicity may be observed at lower doses of bleomycin when bleomycin is administered as part of a multidrug treatment regimen. patients should be closely monitored for signs of pulmonary toxicity (see precautions). granulocyte colony stimulating factor. it has been suggested that concomitant administration of g-csf and bleomycin may increase the risk of bleomycin induced pulmonary toxicity, especially at higher doses, although this has not been confirmed in clinical trials. if g-csf is added to bleomycin containing treatment regimens, patients should be closely observed for signs of pulmonary toxicity (see precautions). -pharmacokinetic interactions cisplatin. cisplatin induced renal function impairment may result in delayed clearance and bleomycin toxicity even at low doses. an increased incidence of bleomycin induced pulmonary toxicity has been observed when these two agents are administered as part of an antineoplastic treatment regimen. dosage reduction may be required (see precautions). digoxin. serum levels of digoxin may be reduced and its actions may be decreased. it is thought that drug induced alterations of the intestinal mucosa may be involved in the reduced gastrointestinal absorption. phenytoin. serum concentrations of phenytoin may be decreased due to decreased absorption or increased metabolism of phenytoin.