Carmustine Drug Information

Carmustine for injection, USP 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.

Dosage

The recommended dose of carmustine for injection, USP as a single agent in previously untreated patients is 150 to 200 mg/m 2 intravenously every 6 weeks. Administer as a single dose or divided into daily injections such as 75 to 100 mg/m 2 on two successive days. Lower the dose when carmustine for injection, USP is used with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted.

Administer carmustine for injection, USP for the duration according to the established regimen. Premedicate each dose with anti-emetics. 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: The hematologic toxicity can be delayed and cumulative. Monitor blood counts weekly. Do not administer a repeat course of carmustine for injection, USP 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, USP if the creatinine clearance is less than 10 mL/min. Do not administer carmustine for injection, USP to patients with compromised renal function. Monitor transaminases and bilirubin periodically during treatment.

Preparation and Administration of Intravenous Solution

Dissolve carmustine for injection, USP 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 for injection, USP 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, USP is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F) in glass container. 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, USP 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 /min See Section 16.2 for important instructions on the storage and handling of the injection. Carmustine for injection, USP 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, USP 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, USP lyophilized material or solution contacts the skin or mucosa 1.

The following serious adverse reactions are described elsewhere in the labeling: Myelosuppression Pulmonary toxicity Administration Reactions Carcinogenicity Ocular Toxicity The following adverse reactions associated with the use of carmustine for injection, USP 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 To report SUSPECTED ADVERSE REACTIONS, contact Navinta LLC, Ewing NJ 08618 at +1-609-883-1135 or FDA at +1-800-FDA-1088 or www.fda.gov/medwatch.

• Effects of other drugs on carmustine for injection, USP Cimetidine: Greater myelosuppression (e.g., leukopenia and neutropenia) has been reported when oral cimetidine has been coadministered with carmustine. Consider alternative drugs to cimetidine.
• Phenobarbital: Phenobarbital induces the metabolism of carmustine and may compromise antitumor activity of carmustine for injection, USP. Consider alternative drugs to phenobarbital.

Effects of carmustine for injection, USP on other drugs Phenytoin: Carmustine for injection, USP when coadministered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

Pregnancy Risk Summary Carmustine for injection, USP can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animals. Limited available data with carmustine for injection, USP use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Carmustine was embryotoxic in rats and rabbits and teratogenic in rats (thoracoabdominal closure, neural tube, and eye defects and malformations of the skeletal system of the fetus) when given in doses lower than the maximum cumulative human dose based on body surface area.

Consider the benefits and risks of carmustine for injection, USP for the mother and possible risks to the fetus when prescribing carmustine for injection, USP to a pregnant woman. 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.

In the U.S. 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 ), approximately 0.1 times the maximum cumulative human dose of 1400 mg/m 2, resulted in pre-implantation loss, increased resorptions (including completely resorbed litters), and reduced the number of live births in the presence of maternal toxicity. Carmustine administered IP to pregnant rats during the period of organogenesis at cumulative doses ≥ 4 mg/kg (24 mg/m 2 ), approximately 0.02 times the maximum cumulative human dose based on a mg/m 2 basis, resulted in reduced fetal weight and various malformations, which included thoracoabdominal closure defects, neural tube defects, and eye defects, including microphthalmia/anophthalmia, and skeletal anomalies in the skull, sternebra, vertebrae and ribs, and reduced skeletal ossification in the presence of maternal toxicity.

Carmustine administered IV to rabbits during the period of organogenesis resulted in spontaneous abortions in mothers and growth defects in the fetus, mainly at cumulative doses ≥ 13 mg/kg (156 mg/ m 2 ), approximately 0.1 times the maximum cumulative human dose on a mg/ m 2 basis.

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, USP in childhood and early adolescence (1-16 years).

Carmustine for injection, USP is contraindicated in patients with previous hypersensitivity to carmustine for injection, USP or its components. Hypersensitivity

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