BLEOMYCIN- bleomycin_injection, powder, lyophilized, for solution

CLINICAL PHARMACOLOGY
Although the precise mechanism of action of bleomycin is not fully known, it is thought that the primary action is to produce single and double strand breaks in DNA, leading to inhibition of cell division and growth, and inhibition of DNA synthesis in the cells. Bleomycin is probably most effective against cells in the M and G2 (premitotic) phase of the cell cycle. Bleomycin has not been shown to have an immunosuppressive effect in vitro A bsorption Bleomycin is well absorbed in animals upon parenteral administration. Intramuscular injection of 15 units in humans resulted in a maximum serum concentration of 1 mU/mL 30 minutes after administration. Intravenous injection of 15 units in humans resulted in a maximum serum concentration of 3. 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. Radiation therapy. Antineoplastic agents. Combination therapy. Granulocyte colony stimulating factor. -Pharmacokinetic interactions Cisplatin.
Pharmacokinetics
A bsorption Bleomycin is well absorbed in animals upon parenteral administration. Intramuscular injection of 15 units in humans resulted in a maximum serum concentration of 1 mU/mL 30 minutes after administration. Intravenous injection of 15 units in humans resulted in a maximum serum concentration of 3.3 mU/mL. 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. Radiation therapy. Antineoplastic agents. Combination therapy. Granulocyte colony stimulating factor. -Pharmacokinetic interactions Cisplatin. Digoxin. Phenytoin.

Palliation and treatment adjutant to surgery and radiation therapy of the following neoplasms: Squamous cell carcinoma of the skin, head and neck, and esophagus (primary indication). Squamous cell carcinoma of the larynx, penis and uterine cervix. Squamous cell carcinoma of the bronchus (response infrequent). Ch0riocarcinoma and embryonal cell carcinoma of the testis. Advanced Hodgkin’s disease and Other lymphomas. Mycosis fungoides. Note

Bleomycin may be given by the intramuscular, intravenous, subcutaneous or intra-arterial routes. Note. Use in Adults Initial treatment (Intramuscular, intravenous or subcutaneous administration). 10,000 to 20,000 IU/m2 of body surface area given weekly or twice weekly. Alternatively, give 15,000 IU daily for seven days followed by three weeks off treatment and repeat twice so that a total dose of approximately 300,000 IU is administered. Improvement of lymphomas and testicular tumours is prompt, i.e. within two weeks while response by squamous cell cancers may take 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. Intra-arterial administration. Repeat treatment. 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. Intravenous, intra-arterial injection. 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.

Severe or life-threatening reactions Pulmonary toxicity. This toxicity is frequently seen in those with underlying lung disease such as emphysema and in those previously treated with pulmonary or mediastinal irradiation. The identification of patient with pulmonary toxicity due to bleomycin has been extremely difficult. The clinical symptoms and X-ray findings of bleomycin 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 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 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. Pericarditis, fulminant fatal hyperpyrexia and fulminate, fatal angioedema have been reported. More common reactions Body as a whole. Gastrointestinal. Mucocutaneous (50%). 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. (see Severe/ life threatening reactions). Cardiovascular. 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. Hematological. Hepatic. Injection site. Renal. Respiratory.

Pediatric Use
No information available
Use in pregnancy Category D:
Bleomycin has caused, is suspected to have caused or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. It may also have adverse pharmacological effects

IMPORTANT DRUG INFORMATION
July 5, 2016 Re: Temporary importation of Bleomycin Sulfate Powder for Injection, 15,000 International Units (IU) to address drug shortage issue Dear Healthcare Professional, IMPORTANT NOTE: Each vial of Amneal Biosciences’ product contains 15,000 IU of Bleomycin Sulfate Powder for Injection, which is equivalent to Bleomycin Sulfate USP 15 units (1000 IU of Bleomycin Sulfate Powder for Injection = 1 unit of Bleomycin Sulfate USP). Prescribers and pharmacists must be alert to this difference in labeled units in order to prevent medication errors. Appropriate quality assurance measures should be enacted to reduce the risk of medication errors. Due to the current critical shortage of Bleomycin Sulfate for Injection, USP, 15 units and 30 units per vial in the United States (U.S.) market, Amneal Biosciences is coordinating with the U.S. Food and Drug Administration (FDA) to increase the availability of Bleomycin Sulfate for Injection, USP, 15 units per vial. Amneal Biosciences has initiated temporary importation of a non-FDA approved product, Bleomycin Sulfate Powder for Injection 15,000 IU per vial to the U.S. market: lot numbers GE50604, GE60003, GE60012. The Bleomycin Sulfate Powder for Injection 15,000 IU product being distributed by Amneal Biosciences was manufactured by Cipla Ltd. from its FDA-inspected facility in Verna, Goa, India, for Amneal Pharma Australia Pty Ltd and was sold in Australia under the WIllow Pharmaceutical label. At this time, no other entity except Amneal Biosciences is authorized by the FDA to import or distribute Amneal Pharma Australia Pty Ltd.’s Bleomycin Sulfate Powder for Injection 15,000 IU product. FDA has not approved the Bleomycin Sulfate Powder for Injection 15,000 IU product being distributed by Amneal Biosciences in the United States. Amneal Biosciences’ Bleomycin Sulfate Powder for Injection 15,000 IU product contains the same active ingredient, bleomycin sulfate, in the same strength as the U.S. FDA-approved Bleomycin Sulfate for Injection, USP, 15 units per vial. In the U.S., the labeling for Bleomycin Sulfate for Injection includes the following indications: i) squamous cell carcinoma; ii) non-Hodgkin lymphoma; iii) testicular carcinoma; iv) Hodgkin lymphoma; v) malignant pleural effusion. Bleomycin Sulfate Powder for Injection 15,000 IU product being distributed by Amneal Biosciences is approved in Australia and is dispensed with a Medication Guide. The information on the medication guide differs from the full prescribing information for the current U.S. FDA reference listed drug (RLD). Two key differences between the two package inserts is that the U.S. FDA-approved label uses different units from the Amneal Biosciences label and the Amneal Australia label does not include an indication for malignant pleural effusions. Additionally, the U.S. FDA-approved label provides weight-based dosing information as well as body surface area-based dosage, whereas the imported product label contains only BSA-based dosing information. This letter is not intended as a complete description of the benefits and risks related to the use of Bleomycin Sulfate Powder for Injection 15,000 IU. Please refer to the package insert for the U.S. FDA-approved Bleomycin Sulfate for Injection, USP for full prescribing information. Please note that the barcode used for Amneal Biosciences’ Bleomycin Sulfate Powder for Injection, 15,000 IU product may not be appropriately recognized by scanning systems used in the United States. The Bleomycin Sulfate Powder for Injection 15,000 IU product distributed by Amneal Biosciences should be handled exactly as you have handled the U.S. FDA-approved Bleomycin Sulfate for Injection, USP. Refrigerate unopened vials at 2°C to 8°C (36°F to 46°F). The Bleomycin Sulfate Powder for Injection 15,000 IU product distributed by Amneal Biosciences should not be reconstituted or diluted with D5W or other dextrose-containing diluents. To order Bleomycin Sulfate Powder for Injection, 15,000 IU product distributed by Amneal Biosciences, health care professionals can order the product from their wholesaler/distributor of choice. To report adverse events or medication errors, or for answers to medical and technical inquiries for patients who have used Amneal Biosciences’ Bleomycin Sulfate Powder for Injection, 15,000 IU product, please contact Amneal Biosciences Drug Safety by telephone at 1-855-266-3251 Monday through Friday from 9:00-5:30 EST, or email at biosciencesdrugsafety@amneal.com Adverse events or quality problems experienced with the use of this product may also be reported to the FDA’s MedWatch Adverse Event Reporting Program either online, or regular mail, or by fax: Complete and submit the report Online: www.fda.gov/medwatch/report.htm Regular mail or Fax: Download form www.fda.gov/MedWatch/getforms.htm For full U.S. FDA reference listed drug (RLD) prescribing information for Bleomycin Sulfate for Injection, USP, including the BOXED WARNING, please visit: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5806c40-12ce-48e3-8abd-9f8997ef4428 For full prescribing information for Amneal Bioscience’s Bleomycin Sulfate Powder for Injection 15,000 IU product, please visit: http://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=157341 Sincerely, Charles D. Lucarelli President Amneal Biosciences LLC
Carcinogenesis,Mutagenesis, Impairment of Fertility
Bleomycin is mutagenic in both in vitro and in vivo test systems. It is not known whether bleomycin is a carcinogenic in humans. However, an increased incidence of Modular hyperplasia was noted in F344/N male rats with lung cancer induced by nitrosamines, after bleomycin treatment. In another study where bleomycin was administered subcutaneously to rats at a dose of 0.35 mg/kg weekly (or about 30% the recommended human dose), necropsy findings included dose related injection site fibrosarcomas and various renal tumors. The effects of bleomycin on fertility are not known.
OVERDOSAGE
Symptoms: Treatment. Bleomycin is probably not dialyzable. In case of Overdose, immediately contact the Poisons Information Centre for advice. (In Australia, call 131 126.)

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BLEOMYCIN- bleomycin_injection, powder, lyophilized, for solution Product manual source documgent