Carmustine

FDA Drug Information • Also known as: Carmustine, Gliadel

Brand Names: Carmustine, Gliadel
Dosage Form: KIT
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: MYELOSUPPRESSION and PULMONARY TOXICITY Myelosuppression Carmustine for injection causes suppression of marrow function (including thrombocytopenia and leukopenia), which may contribute to bleeding and overwhelming infections [see Warnings and Precautions (5.1) and Adverse Reactions (6) ] . Monitor blood counts weekly for at least 6 weeks after each dose. Adjust dosage based on nadir blood counts from the prior dose [see Dosage and Administration (2.1) ] . Do not administer a repeat course of carmustine for injection until blood counts recover. Pulmonary Toxicity C armustine for injection causes dose-related pulmonary toxicity. Patients receiving greater than 1,400 mg/m 2 cumulative dose are at significantly higher risk than those receiving less. Delayed pulmonary toxicity can occur years after treatment, and can result in death, particularly in patients treated in childhood [see Adverse Reactions (6) and Use in Specific Populations (8.4) ] . WARNING: MYELOSUPPRESSION and PULMONARY TOXICITY See full prescribing information for complete boxed warning Suppression of marrow function, notably thrombocytopenia and leukopenia, is the most common and severe of the toxic effects of carmustine for injection. Monitor blood counts. ( 5 , 6 ). Pulmonary toxicity from carmustine for injection appears to be dose related. Patients receiving greater than 1,400 mg/m 2 cumulative dose are at significantly higher risk than those receiving less ( 5 , 6 ).

Description

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 C 5 H 9 Cl 2 N 3 O 2 and the structural formula of carmustine is: 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. 10

What Is Carmustine Used For?

1 INDICATIONS AND USAGE 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. 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 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Recommended Dosage: As a single agent, 150 mg/m 2 to 200 mg/m 2 carmustine for injection intravenously every 6 weeks as a single-dose or divided into daily injections such as 75 mg/m 2 to 100 mg/m 2 on 2 successive days. Adjust dose for combination therapy or in patients with reduced bone marrow reserve. ( 2.1 ) Administer reconstituted solution only as a slow intravenous infusion over at least 2 hours. ( 2.2 ) 2.1 Dosage The recommended dose of carmustine for injection as a single agent in previously untreated patients is 150 mg/m 2 to 200 mg/m 2 intravenously every 6 weeks. Administer as a single-dose or divided into daily injections such as 75 mg/m 2 to 100 mg/m 2 on two successive days. Lower the dose when carmustine for injection is used with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted. Administer carmustine for injection, 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: Nadir After Prior Dose Percentage of Prior Dose to be Given Leukocytes/mm 3 Platelets/mm 3 > 4,000 > 100,000 100% 3,000 to 3,999 75,000 to 99,999 100% 2,000 to 2,999 25,000 to 74,999 70% < 2,000 < 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) ]. 2.2 Preparation and Administration of Intravenous Solution 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 for injection 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...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS 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 Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions

7 DRUG INTERACTIONS Cimetidine: Increased myelosuppression with concomitant use. ( 7.1 ) Phenobarbital: Induces carmustine metabolism, reducing exposure. May lead to reduced efficacy. ( 7.1 ) Phenytoin: Carmustine for injection may reduce the efficacy of phenytoin. ( 7.2 ) 7.1 Effects of Other Drugs on Carmustine for Injection Cimetidine Greater myelosuppression (e.g., leukopenia and neutropenia) has been reported when oral cimetidine has been co-administered with carmustine. Consider alternative drugs to cimetidine. Phenobarbital Phenobarbital induces the metabolism of carmustine and may compromise antitumor activity of carmustine for injection. Consider alternative drugs to phenobarbital. 7.2 Effects of Carmustine for Injection on Other Drugs Phenytoin Carmustine for injection when co-administered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

Contraindications

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

Pregnancy and Breastfeeding

8.1 Pregnancy 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) ] and findings in animals [see Data] . Limited available data with carmustine for injection 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, for the mother and possible risks to the fetus when prescribing carmustine for injection 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% to 4% and 15% to 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 1,400 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,...

Overdosage

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

How Supplied

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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.