BLEOMYCIN- bleomycin sulfate injection, powder, lyophilized, for solution
APP Pharmaceuticals, LLC
It is recommended that Bleomycin for Injection, USP 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 bleomycin. 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 bleomycin.
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 is provided as a sterile lyophilized powder for reconstitution containing 15 units/vial and 30 units/vial, which are intended for intramuscular, intravenous, subcutaneous or intrapleural administration.
Its chemical name is N’-[3-(dimethylsulphonio)propyl]bleomycin-amide (bleomycin A2 ) and N’-[4-(guaniodobutyl)]bleomycin-amide (bleomycin B2 ).
(Main component: Bleomycin A2 , in which R is [CH3 ]2 S+ CH2 CH2 CH2 -)
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.
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.
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 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 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.
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.
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.
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/m2 and 23 mL/min/m2 , 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.
Age, Gender, and Race
The effects of age, gender, and race on the pharmacokinetics of bleomycin have not been evaluated.
Children of less than 3 years of age have higher total body clearance than in adults, 71 mL/min/m2 versus 51 mL/min/m2 , 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 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).
The effect of hepatic insufficiency on the pharmacokinetics of bleomycin has not been evaluated.
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/m2 as the cumulative dose of cisplatin exceeded 300 mg/m2. 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.
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 treatment (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.
Bleomycin for Injection 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 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.
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