Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 21 April 2018

Indication(s)

1 INDICATIONS AND USAGE BiCNU 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) BiCNU®(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.

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Advisory information

contraindications
4 CONTRAINDICATIONS Hypersensitivity (4) BiCNU is contraindicated in patients with previous hypersensitivity to BiCNU or its components.
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 BiCNU 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 Heritage Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended Dosage: As a single agent, 150 to 200 mg/m2BiCNU intravenously every 6 weeks as a single dose or divided into daily injections such as 75 to 100 mg/m2on 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 BiCNU as a single agent in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. Administer as a single dose or divided into daily injections such as 75 to 100 mg/m2 on two successive days. Lower the dose when BiCNU is used with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted. Administer BiCNU 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/mm3 Platelets/mm3 >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 BiCNU 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 BiCNU if the creatinine clearance is less than 10 mL/min. Do not administer BiCNU 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 BiCNU 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 BiCNU 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, BiCNU 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 BiCNU 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/m2/min. See Section 16.2 for important instructions on the storage and handling of the injection. BiCNU 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 BiCNU 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 BiCNU. Immediately wash the skin or mucosa thoroughly with soap and water if BiCNU lyophilized material or solution contacts the skin or mucosa1.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise lactating females not to breastfeed (8.2) 8.1 Pregnancy Risk Summary BiCNU (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 BiCNU 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 BiCNU for the mother and possible risks to the fetus when prescribing BiCNU 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/ m2), approximately 0.1 times the maximum cumulative human dose of 1400 mg/m2, 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/m2), approximately 0.02 times the maximum cumulative human dose based on a mg/m2 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/m2), approximately 0.03 times the maximum cumulative human dose on a mg/ m2 basis. Intravenous (IV) administration of carmustine to rats at a cumulative dose of 50 mg/kg (300 mg/ m2), approximately 0.2 times the maximum cumulative human dose on a mg/m2 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/ m2), approximately 0.1 times the maximum cumulative human dose on a mg/ m2 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 BiCNU. 8.3 Females and Males of Reproductive Potential Contraception Advise female patients to avoid pregnancy during treatment with BiCNU 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 BiCNU treatment and for at least three months after the final dose of BiCNU [see Nonclinical Toxicology (13.1) ]. Infertility Based on nonclinical findings, male fertility may be compromised by treatment with BiCNU [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 BiCNU 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)]. 8.5 Geriatric Use Clinical studies of BiCNU 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. BiCNU 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.

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: BiCNU may reduce the efficacy of phenytoin. (7.2) 7.1 Effects of Other Drugs on BiCNU 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 BiCNU. Consider alternative drugs to phenobarbital. 7.2 Effects of BiCNU on Other Drugs Phenytoin: BiCNU when coadministered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

More information

Category Value
Authorisation number NDA017422
Orphan designation No
Product NDC 23155-261
Date Last Revised 16-04-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling 16.2 Storage and Handling Store product and diluent in a refrigerator (2°-8°C, 36°-46°F). Stability Store the unopened vial of the dry drug in a refrigerator (2°-8°C, 36°-46°F). Store the diluent vials in a refrigerator (2°-8°C, 36°-46°F). The recommended storage of unopened BiCNU vials provides a stable product for up to 3 years. Compatibility/ Incompatibility with Containers The intravenous solution is unstable in polyvinyl chloride container. DO NOT USE PVC Containers. Administer BiCNU solution from the glass bottles or polypropylene container only. Ensure the polypropylene containers used are PVC free and DEHP free. Important Note BiCNU has a low melting point (30.5°-32.0°C or 86.9°-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 BiCNU will appear as a very small amount of dry flakes or dry congealed mass. If this is evident, the BiCNU is suitable for use and should be refrigerated immediately.
Marketing authorisation holder Heritage Pharmaceuticals Inc.
Warnings WARNING: MYELOSUPPRESSION and PULMONARY TOXICITY Myelosuppression BiCNU 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 BiCNU until blood counts recover. Pulmonary Toxicity BiCNU causes dose-related pulmonary toxicity. Patients receiving greater than 1400 mg/m2cumulative 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 BiCNU. Monitor blood counts. (5, 6). • Pulmonary toxicity from BiCNU appears to be dose related. Patients receiving greater than 1400 mg/m2 cumulative dose are at significantly higher risk than those receiving less (5, 6).