carmustine

1 INDICATIONS AND USAGE 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.

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.

2 DOSAGE AND ADMINISTRATION Recommended Dosage: As a single agent, 150 to 200 mg/m 2 carmustine for injection, USP intravenously every 6 weeks as a single dose or divided into daily injections such as 75 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, 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: Nadir After Prior Dose Percentage of Prior Dose to be Given 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, 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. [see Adverse Reactions (6) ]. 2.2 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. Examine reconstituted vials for crystal formation prior to use. 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, USP over a period of less than two h …

3 DOSAGE FORMS AND STRENGTHS For injection: 100 mg of carmustine lyophilized powder in a single-dose vial for reconstitution and a vial containing 3mL sterile diluent (Dehydrated Alcohol Injection, USP) (3) For injection: 100 mg of carmustine as a lyophilized powder in a single-dose vial for reconstitution and a vial containing 3 mL sterile diluent (Dehydrated Alcohol Injection, USP).

For injection: 100 mg of carmustine as a lyophilized powder in a single-dose vial for reconstitution and a vial containing 3 mL sterile diluent (Dehydrated Alcohol Injection, USP).

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

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

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, 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 ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc, Pennington, NJ 08534 at +1-877-993-8779 or FDA at +1-800-FDA-1088 or www.fda.gov/medwatch.

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 coadministered with carmustine. Consider alternative drugs to cimetidine. Phenobarbital: Phenobarbital induces the metabolism of carmustine and may compromise antitumor activity of carmustine. Consider alternative drugs to phenobarbital. 7.2 Effects of Carmustine for Injection on Other Drugs Phenytoin: Carmustine when coadministered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

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 coadministered with carmustine. Consider alternative drugs to cimetidine. Phenobarbital: Phenobarbital induces the metabolism of carmustine and may compromise antitumor activity of carmustine. Consider alternative drugs to phenobarbital.

7.2 Effects of Carmustine for Injection on Other Drugs Phenytoin: Carmustine when coadministered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise lactating females not to breastfeed (8.2) See 17 for PATIENT COUNSELING INFORMATION. Revised: 02/2024 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 2-4% 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. Embryo-fetal death was observed at cumulative doses ≥ 8 mg/kg (48 mg/m 2 ), approximately 0.03 times the maximum cumulative human dose on a mg/ m 2 basis. Intravenous (IV) administration of carmustine to rats at a cumulative dose of 50 mg/kg (300 mg/ m 2 ), approximately 0.2 times the maximum cumulative human dose on a mg/m 2 basis, during the last quarter of pregnancy resulted in the death of offspring within 4 months. 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. 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 m …

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.

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 214.06. 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, USP is administered by intravenous infusion after reconstitution, as recommended. 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. Structural Formula

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 214.06. 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, USP is administered by intravenous infusion after reconstitution, as recommended. 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. Structural Formula

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Carmustine for injection, USP. Each package includes a vial containing 100 mg carmustine, USP and a vial containing 3 mL sterile diluent. NDC 75907-327-11 16.2 Storage and Handling Store product and diluent in a refrigerator (2°C to 8°C, 36°F to 46°F). Stability Store the unopened vial of the dry drug in a refrigerator (2°C to 8°C, 36°F to 46°F). Store the diluent vials in a refrigerator (2°C to 8°C, 36°F to 46°F). The recommended storage of unopened carmustine vials provides a stable product for up to 24 months. Compatibility/ Incompatibility with Containers The intravenous solution is unstable in polyvinyl chloride container. DO NOT USE PVC Containers . Administer carmustine solution from the glass bottles or polypropylene container only. Ensure the polypropylene containers used are PVC free and DEHP free. Important Note Carmustine 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 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.

16.1 How Supplied Carmustine for injection, USP. Each package includes a vial containing 100 mg carmustine, USP and a vial containing 3 mL sterile diluent. NDC 75907-327-11

16.2 Storage and Handling Store product and diluent in a refrigerator (2°C to 8°C, 36°F to 46°F). Stability Store the unopened vial of the dry drug in a refrigerator (2°C to 8°C, 36°F to 46°F). Store the diluent vials in a refrigerator (2°C to 8°C, 36°F to 46°F). The recommended storage of unopened carmustine vials provides a stable product for up to 24 months. Compatibility/ Incompatibility with Containers The intravenous solution is unstable in polyvinyl chloride container. DO NOT USE PVC Containers . Administer carmustine solution from the glass bottles or polypropylene container only. Ensure the polypropylene containers used are PVC free and DEHP free. Important Note Carmustine 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 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.