CARMUSTINE- carmustine

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. The exposure-response relationship for efficacy or safety is unknown. 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 CO 2.

Carmustine for Injection is a nitrosourea indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following: Brain tumors glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors (1) Multiple myeloma-in combination with prednisone (1) Relapsed or refractory Hodgkin's lymphoma in combination with other approved drugs (1) Relapsed or refractory Non-Hodgkin's lymphomas in combination with other approved drugs (1) Carmustine for injection is indicated as palliative therapy as a single agent or in established combination therapy in the following: Brain tumors glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors. Multiple myeloma in combination with prednisone. Relapsed or refractory Hodgkin's lymphoma in combination with other approved drugs. Relapsed or refractory Non-Hodgkin's lymphomas in combination with other approved drugs.

Recommended Dosage: As a single agent, 150 to 200 mg/m 2 2 The recommended dose of Carmustine for Injection as a single agent in previously untreated patients is 150 to 200 mg/m 2 2 Adjust doses subsequent to the initial dose according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment: Nadir After Prior Dose Percentage of Prior Dose to Leukocytes/mm 3 Platelets/mm 3 >4000 >100,000 100% 3000-3999 75,000-99,999 100% 2000-2999 25,000-74,999 70% <2000 <25,000 50% The hematologic toxicity can be delayed and cumulative. Monitor blood counts weekly. Do not administer a repeat course of Carmustine for Injection until circulating blood elements have returned to acceptable levels (platelets above 100 Gi/L, leukocytes above 4 Gi/L and absolute neutrophil count above 1 Gi/L). The usual interval between courses is 6 weeks. Evaluate renal function prior to administration and periodically during treatment. For patients with compromised renal function, monitor for toxicity more frequently. Discontinue Carmustine for Injection if the creatinine clearance is less than 10 mL/min. Do not administer Carmustine for Injection to patients with compromised renal function. Monitor transaminases and bilirubin periodically during treatment. [see Adverse Reactions (6) Dissolve carmustine for injection with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP). Aseptically add 27 mL Sterile Water for Injection, USP. Each mL of resulting solution contains 3. 3 mg of carmustine in 10% ethanol. Such solutions should be protected from light. The reconstituted solution is a clear, colorless to yellowish solution. Once reconstituted, the solution must be further diluted with Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Examine reconstituted vials for crystal formation prior to use. If crystals are observed, they may be re-dissolved by warming the vial to room temperature with agitation. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After reconstitution as recommended, carmustine for injection is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F) in glass container. If crystals are observed, they may be redissolved by warming the vial to room temperature with agitation. Vials reconstituted as directed and further diluted with 500 mL Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, in glass or polypropylene containers to a concentration of 0. 2 mg/mL, should be stored at room temperature, protected from light and utilized within 8 hours. These solutions are also stable 24 hours under refrigeration (2°-8°C, 36°-46°F) and an additional 6 hours at room temperature protected from light. Administer reconstituted solution by slow intravenous infusion over at least two hours. Administration of carmustine for injection over a period of less than two hours can lead to pain and burning at the site of injection. Monitor the injected area during the administration. The rate of administration of the intravenous infusion should not be more than 1. 66 mg/m 2 See Section 16. 2 for important instructions on the storage and handling of the injection. carmustine for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 The lyophilized dosage formulation contains no preservatives and is not intended for use as a multiple dose via. Accidental contact of reconstituted carmustine for injection with the skin has caused transient hyperpigmentation of the affected areas. Wear impervious gloves to minimize the risk of dermal exposure impervious gloves when handling vials containing carmustine for injection. Immediately wash the skin or mucosa thoroughly with soap and water if carmustine for injection lyophilized material or solution contacts the skin or mucosa 1.

The following serious adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5. 1) Pulmonary toxicity [see Warnings and Precautions (5. 2) Administration Reactions [see Warnings and Precautions (5. 3) Carcinogenicity [see Warnings and Precautions (5. 4) Ocular Toxicity [see Warnings and Precautions (5. 5) The following adverse reactions associated with the use of carmustine for injection were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders Tachycardia and chest pain. Eye Disorders Conjunctival edema, conjunctival hemorrhage, blurred vision and loss of depth perception Gastrointestinal Toxicity Nausea, vomiting, anorexia, and diarrhea Hepatotoxicity Increased transaminase, increased alkaline phosphatase, increased bilirubin levels Infections and Infestations Opportunistic infection (including with fatal outcome). Neoplasms Benign, Malignant and Unspecified (including cysts and polyps) Acute leukemia, bone marrow dysplasias. Nephrotoxicity Progressive azotemia, decrease in kidney size, renal failure Nervous System Disorders Headaches, encephalopathy, and seizures Pulmonary Toxicity Pneumonitis, interstitial lung disease Reproductive System and Breast Disorders Gynecomastia Skin and Subcutaneous Tissue Disorders Burning sensation, hyperpigmentation, swelling, pain, erythema, skin necrosis, alopecia, allergic reaction Vascular Disorders Veno-occlusive disease. Most common adverse reactions (>1%) are nausea, vomiting, renal toxicity, pneumonitis, pulmonary toxicity, myelosuppression ( 6 To report SUSPECTED ADVERSE REACTIONS, contact STI Pharma LLC at 1-888-301-9680 or FDA at 1-800-FDA-1088 or www. gov/medwatch.

Hypersensitivity (4) Carmustine for Injection is contraindicated in patients with previous hypersensitivity to carmustine or its components.

Lactation: Advise lactating females not to breastfeed (8. 2) Risk Summary Carmustine for Injection can cause fetal harm when administered to a pregnant woman based on the mechanism of action [ see Clinical Pharmacology (12. 1) [see Data] Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Intraperitoneal (IP) administration of carmustine to pregnant rats 14 days prior to mating and during the period of organogenesis at cumulative doses >= 26 mg/kg (158 mg/ m 2 2 Carmustine administered IP to pregnant rats during the period of organogenesis at cumulative doses >= 4 mg/kg (24 mg/m 2 2 2 2 2 2 2 2 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. , carcinogenicity and myelosuppression) in nursing infants, nursing should be discontinued while taking Carmustine for Injection. 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) 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 (1-16 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) 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.

Cimetidine: Increased myelosuppression with concomitant use. 1) Phenobarbital: Induces carmustine metabolism, reducing exposure. May lead to reduced efficacy. 1) Phenytoin: Carmustine for Injection may reduce the efficacy of phenytoin. 2) Cimetidine: Phenobarbital: Phenytoin:.

OVERDOSAGE
The main result of overdose is myeloablation. No proven antidotes have been established for Carmustine for Injection overdosage.
NONCLINICAL TOXICOLOGY
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/ m 2 2
REFERENCES
1. "OSHA Hazardous Drugs." OSHA http://www.osha.gov/SLTC/hazardousdrugs/index.html

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