Bleomycin for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Bleomycin for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Lymphoma, Malignant Pleural Effusion, Squamous Cell Carcinoma, Testicular Cancer
Class: Antibiotics/antineoplastics
Form: Liquid solution, Subcutaneous (SC), Intramuscular (IM), Intravenous (IV)
Ingredients: bleomycin sulfate

Pharmaceutical Information

Drug Substance

Proper Name:

Bleomycin Sulfate

Chemical Name: N'-[3-(dimethylsulfonio)-propyl] bleomycinamide
Molecular Formula:

C55H84N17O21S3

Structural Formula:


Bleomycin A2: R=[-(CH2)3-S+-(CH3)2]

Bleomycin B2: R=[-(CH2)4-NH-C(=NH)-NH2]

Main Component: Bleomycin A2, in which R=[(CH3)2S+CH2CH2CH2-]
Molecular Weight:

Bleomycin Sulfate: Approximately 1400

Bleomycin A2: 1414

Bleomycin B2: 1424

Description:

Bleomycin sulfate is a white lyophilized powder. It is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus which vary only in the terminal amine portion of the molecule. Over 60% of the bleomycin mixture is represented by bleomycin A2, a complex glycopeptide. It is highly soluble in water. It has a pH of 4.5 − 6.0.

Composition

Each vial contains sterile bleomycin sulfate equivalent to bleomycin 15 units.

Note: A unit of bleomycin is equal to the formerly used milligram activity.

Stability and Storage Recommendations

Bleomycin for Injection dry powder should be stored between 2 °C and 8 °C. Protect from light. Single-dose vial. Discard unused portion.

Stability of Reconstituted Solutions

Reconstituted Bleomycin for Injection solution may be stored in refrigerator above freezing point for up to 48 hours.

Diluted Bleomycin for Injection is stable at 25 °C for 24 hours in 0.9% Sodium Chloride Injection, USP in PVC bags.

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.

Availability of Dosage Forms

C103610Bleomycin for Injection is supplied in vials containing sterile bleomycin sulfate equivalent to bleomycin 15 units. Individually packaged.

Note: Vial stoppers do not contain natural rubber latex.

Pharmacology

Animal Pharmacology

Bleomycin sulfate is well absorbed upon intramuscular, intraperitoneal and subcutaneous administration.

After administration of bleomycin, high concentrations are found in the skin, lungs, kidneys, peritoneum, lymphatic system and tumors, and this distribution is considered to have some relation to its effectiveness in the squamous cell carcinoma of human patients and to its toxicity. Bleomycin sulfate is excreted mainly by the kidney, with 69% of a dose (in rabbits) being eliminated, as active bleomycin, within 8 hours. In pregnant mice, bleomycin sulfate is recovered in high concentration in the amniotic fluid and to a lesser extent in the foetus.

Human Pharmacology

Blood concentrations have been studied in a few patients after intravenous or intramuscular injections of 15 units bleomycin. Although intravenous administration gives, as expected, higher initial levels, these are more sustained after intramuscular injection.

Toxicology

  1. The acute toxicity has been thoroughly investigated in mice, rats and dogs.
    Acute Toxicity (units/kg of Copper-Free Bleomycin)
    Animal Sex IV IP SC
    Mice M 210 312 200
    Mice F F 187 190 188
    Rats M   168 168
    Rats F   143 226
    Dogs M < 100    
  2. The subacute toxicity has been studied in groups of 20 Wistar rats for 30 days. Daily intraperitoneal doses of 0.3 units/kg and 0.9 units/kg were well tolerated; no significant changes were observed in the blood picture, histopathology, or in the biochemical tests. Above this level, toxic effects on lung and skin began to appear.
  3. Various chronic studies utilizing rats, dogs and monkeys showed that the principal toxic effect of bleomycin is epithelial in nature, affecting the lungs, skin, and kidneys. Hematopoietic toxicity, however, is only associated with high doses.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of bleomycin in humans is unknown. Given its mechanism of action, it should be considered to be a possible carcinogen in man. Bleomycin has been shown to be mutagenic in both in vitro and in vivo test systems. Bleomycin is teratogenic in rats and mice given the drug during organogenesis. The effects of bleomycin on fertility have not been established.