Carmustine (Page 3 of 5)

8.2 Lactation

Risk Summary

There is no information regarding the presence of carmustine in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse events (e.g., carcinogenicity and myelosuppression) in nursing infants, nursing should be discontinued while taking carmustine for injection.

8.3 Females and Males of Reproductive Potential

Contraception

Advise female patients to avoid pregnancy during treatment with carmustine for injection because of the risk of fetal harm [see Use in Specific Populations (8.1)].

Advise female patients of reproductive potential to use highly effective contraception during and for up to six months after completion of treatment.

Advise males with female sexual partners of reproductive potential to use effective contraception during carmustine for injection treatment and for at least three months after the final dose of carmustine for injection [see Nonclinical Toxicology (13.1)].

Infertility

Based on nonclinical findings, male fertility may be compromised by treatment with carmustine for injection [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in children have not been established. Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in a long-term study of patients who received carmustine for injection in childhood and early adolescence (1 to 16 years). Eight out of the 17 patients (47%) who survived childhood brain tumors, including all the 5 patients initially treated at less than 5 years of age, died of pulmonary fibrosis [see Adverse Reactions (6.1)].

8.5 Geriatric Use

Clinical studies of carmustine for injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Carmustine for injection and its metabolites are 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 renal function should be monitored.

10 OVERDOSAGE

The main result of overdose is myeloablation. No proven antidotes have been established for carmustine for injection overdosage.

11 DESCRIPTION

The active ingredient in carmustine for injection, USP is a nitrosourea with the chemical name 1,3-bis(2-chloroethyl)-1-nitrosourea and a molecular weight of 214.05 g/mol. The drug product is supplied as sterile lyophilized pale yellow flakes or a congealed mass, and it is highly soluble in alcohol and lipids, and poorly soluble in water. Carmustine for injection is administered by intravenous infusion after reconstitution, as recommended.

The molecular formula of carmustine is C5 H9 Cl2 N3 O2 and the structural formula of carmustine is:

10
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Carmustine for injection, USP is available in 100 mg single-dose vials of lyophilized material. Sterile diluent for constitution of carmustine for injection, USP is co-packaged with the active drug product for use in constitution of the lyophile. The diluent is supplied in a vial containing 3 mL of dehydrated alcohol injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of carmustine is not fully understood. While carmustine alkylates DNA and RNA, it is not cross-resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. The metabolites may contribute to antitumor activity and toxicities of carmustine.

12.2 Pharmacodynamics

The exposure-response relationship for efficacy or safety is unknown.

12.3 Pharmacokinetics

Distribution

Carmustine crosses the blood-brain barrier. Levels of radioactivity in the CSF are greater than or equal to 50% of those measured concurrently in plasma.

Elimination

Following a short intravenous infusion, the reported elimination half-life ranges from 15 minutes to 75 minutes.

Metabolism

Carmustine may be inactivated through denitrosation reactions catalyzed by both cytosolic and microsomal enzymes, including NADPH and glutathione-S-transferase.

Excretion

Approximately 60% to 70% of a total dose is excreted in the urine within 96 hours. Approximately 10% is eliminated as respiratory CO2 .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carmustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans [see Adverse Reactions (6.1)].

Carmustine was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies.

Male rats treated with carmustine at cumulative doses ≥ 36 mg/kg (216 mg/m2), approximately 0.15 times the maximum cumulative human dose on a mg/m2 basis, showed decreases in reproductive potential when mated with untreated female rats (e.g., decreased implantations, increased resorption rate, and a decrease in viable fetuses).

15 REFERENCES

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Carmustine for Injection, USP is a lyophilized pale yellow flakes or congealed mass containing 100 mg carmustine, USP and supplied in an amber colored glass vial for single-dose use.

Each package includes a vial containing 100 mg carmustine, USP and a vial containing 3 mL sterile diluent (dehydrated alcohol injection, USP).

It is available as follows:

100 mg/vial (Carmustine, USP): NDC 70121-1668-1

3mL Sterile Diluent (Dehydrated Alcohol Injection, USP): NDC 70121-3639-1

Carton of 1 Vial Carmustine, USP and 1 Vial Sterile Diluent: NDC 70121-1482-2

16.2 Storage and Handling

Store product and diluent in a refrigerator at 2° to 8°C, (36° to 46°F).

Stability

Store the unopened vial of the dry drug in a refrigerator 2° to 8°C, (36° to 46°F). Store the diluent vials in a refrigerator 2° to 8°C, (36° to 46°F). The recommended storage of unopened carmustine for injection vials provides a stable product for up to 18 months.

Compatibility/ Incompatibility with Containers

The intravenous solution is unstable in polyvinyl chloride container. DO NOT USE PVC Containers.

Administer carmustine for injection solution from the glass bottles or polypropylene container only. Ensure the polypropylene containers used are PVC free and DEHP free.

Important Note

Carmustine for injection has a low melting point (30.5° to 32.0°C or 86.9° to 89.6°F). Exposure of the drug to this temperature or above will cause the drug to liquefy and appear as an oil film on the vials. This is a sign of decomposition and vials should be discarded. If there is a question of adequate refrigeration upon receipt of this product, immediately inspect the vial in each individual carton. Hold the vial to a bright light for inspection. The carmustine for injection will appear as a very small amount of dry flakes or dry congealed mass. If this is evident, the carmustine for injection is suitable for use and should be refrigerated immediately.

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