DailyMed Label: Bleomycin

DailyMed Label: Bleomycin

2024

DailyMed Prescription

Bleomycin

Bleomycin

Hikma Pharmaceuticals USA Inc.

NDC: 0143-9240

NDC: 0143-9240

NDC: 0143-9241

NDC: 0143-9241

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, white to off-white, lyophilized cake or powder in vials for intramuscular, intravenous, or subcutaneous administration. Each 15 unit and 30 unit vial contains sterile bleomycin sulfate equivalent to 15 or 30 units of bleomycin, respectively. The pH range is 4.0 to 6.0 in a solution reconstituted with Sterile Water for Injection. Its chemical name is N 1 -[3-(dimethylsulphonio)propyl]bleomycin-amide (bleomycin A 2 ) and N 1 -4-(guanidobutyl)bleomycinamide (bleomycin B 2 ). 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 is shown at right: 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 for Injection, USP should be considered a palliative treatment. It has been shown to be useful in the management of the 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 is poorer in patients with previously irradiated head and neck cancer. Hodgkin's disease, non-Hodgkin's lymphoma. Embryonal cell, choriocarcinoma, and teratocarcinoma. Bleomycin for Injection, USP has also been shown to be useful in the management of: Bleomycin is effective as a sclerosing agent for the treatment of malignant pleural effusion and prevention of recurrent pleural effusions.

Because of the possibility of an anaphylactold reaction, lymphoma patients should be treated with 2 units or less for the first two 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 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. Bleomycin may be given by the intramuscular, intravenous, subcutaneous or intrapleural routes. 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. 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. 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. 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.

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

Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Lower doses of bleomycin may be required in these patients than those with normal renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). The carcinogenic potential of bleomycin in humans is unknown. A study in F344-type male rats demonstrated an increased incidence of nodular hyperplasia after induced lung carcinogenesis by nitrosamines, followed by treatment with bleomycin. In another study where the drug was administered to rats by subcutaneous injection at 0.35 mg/kg weekly (3.82 units/m 2 weekly or about 30% at the recommended human dose), necropsy findings included dose related injection site fibrosarcomas as well as various renal tumors. Bleomycin has been shown to be mutagenic both in vitro and in vivo . The effects of bleomycin on fertility have not been studied. (see WARNINGS ) 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. Safety and effectiveness of bleomycin in pediatric patients have not been established. In clinical trials, pulmonary toxicity was more common in patients older than 70 years than in younger patients (see BOXED WARNING , WARNINGS , and ADVERSE REACTIONS : Pulmonary ). Other reported clinical experience has not identified other differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Bleomycin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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 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.

Bleomycin for Injection, USP is available as follows: NDC 0143-9240-01 , 15 units of bleomycin per vial as bleomycin sulfate USP. NDC 0143-9241-01 , 30 units of bleomycin per vial as bleomycin sulfate USP. The sterile powder is stable under refrigeration 2° to 8°C (36° to 46°F) and should not be used after the expiration date is reached. Bleomycin 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 demonstrates a loss of A 2 and B 2 potency that does not occur when bleomycin is reconstituted in Sodium Chloride for Injection, 0.9%. Bleomycin is stable for 24 hours at room temperature in Sodium Chloride. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689.

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/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. 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. 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/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. 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/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 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. 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. 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.

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.

NDC 0143- 9240 -01     Rx only Bleomycin  for Injection, USP Equivalent to  15 units per vial Bleomycin For IM, IV, SC or Intrapleural use Cytotoxic 1 Single Dose Vial NDC 0143- 9240 -01     Rx only 1 Single Dose Vial Bleomycin  for Injection, USP Equivalent to  15 units per vial Bleomycin For Intramuscular, Intravenous, Subcutaneous or Intrapleural use Caution: Cytotoxic- Special handling procedures vial carton