Bleomycin

BLEOMYCIN- bleomycin sulfate injection, powder, lyophilized, for solution
Amneal Pharmaceuticals LLC

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. Institutions should confirm that barcode systems do not provide incorrect information when the product is scanned. Alternative procedures should be followed to assure that the correct drug product is being used and administered to individual patients.

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 or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178.

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

DESCRIPTION

Bleomycin sulfate is a white or yellowish white or cream colored amorphous hygroscopic powder. It is very soluble in water slightly soluble in dehydrated alcohol, and practically insoluble in acetone and ether.

It is a purified mixture of glycopeptides produced by a fermentation process employing the actinomycetes Streptoverticillium species. The bleomycin mixture contains predominantly the A2 , and B2 , peptides. When reconstituted in water for injection, the pH of the solution is approximately 5. Each vial contains 55 to 70% of bleomycin A2 , and 25 to 32% of bleomycin B2 .

Bleomycin injection contains the excipients: hydrochloric acid and sodium hydroxide, both for pH adjustment.

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 and shows no significant inhibition of immune response in patients treated with the drug. Bleomycin inactivating enzyme has been detected in both normal and malignant cells and is particularly prominent in

Pharmacokinetics

Absorption

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. 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.

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