Carmustine – BiCNU®

Carmustine - BiCNU®

Usual Diluents

Dilution Data

Stability

Only use glass or polyolefin containers for BiCNU administration.

Stability:
The unopened vial of the dry drug must be stored in a refrigerator (2°-8°C, 36°-46°F). The diluent ampules may be stored at controlled room temperature (59°-86°F, 15°-30°C) or 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. After reconstitution as recommended, BiCNU is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F). Reconstituted vials should be examined 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 to a concentration of 0.2 mg/mL in 5% Dextrose Injection, USP, should be stored at room temperature, protected from light and utilized within 8 hours.

Dilution examples:
[Dose < 20mg]  [100ml ]  [1 -2 hours]
[Dose 20 - 50mg]  [250 ml ]  [1 -2 hours]
[Dose > 50 mg]  [500ml ]  [1 -2 hours]

Reconstitution:
First, dissolve BiCNU with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP). Second, 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.

Administration:
The reconstituted solution should be used intravenously only and should be administered by IV drip. Injection of BiCNU over shorter periods of time than 1 to 2 hours may produce intense pain and burning at the site of injection1.
Infusion through a free-flowing saline or dextrose infusion, or administration through a central catheter can alleviate venous pain/irritation. 2
High-dose carmustine: Maximum rate of infusion of ≤3 mg/m2/minute to avoid excessive flushing, agitation, and hypotension; infusions should run over at least 2 hours; some investigational protocols dictate shorter infusions. (High-dose carmustine is fatal if not followed by bone marrow or peripheral stem cell infusions.)2

CLINICAL PHARMACOLOGY
Although it is generally agreed that 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.

Intravenously administered carmustine is rapidly degraded, with no intact drug detectable after 15 minutes. However, in studies with 14C-labeled drug, prolonged levels of the isotope were detected in the plasma and tissue, probably representing radioactive fragments of the parent compound.

It is thought that the antineoplastic and toxic activities of carmustine may be due to metabolites. Approximately 60% to 70% of a total dose is excreted in the urine in 96 hours and about 10% as respiratory CO2. The fate of the remainder is undetermined.

Because of the high lipid solubility and the relative lack of ionization at physiological pH, carmustine crosses the blood-brain barrier quite effectively. Levels of radioactivity in the CSF are ≥50% of those measured concurrently in plasma.

INDICATIONS AND USAGE
BiCNU is 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. Multiple myeloma—in combination with prednisone. Hodgkin’s Disease—as secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy. Non-Hodgkin’s lymphomas—as secondary therapy in combination with other approved drugs for patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy. CONTRAINDICATIONS
BiCNU should not be given to individuals who have demonstrated a previous hypersensitivity to it.

DOSAGE AND ADMINISTRATION
The recommended dose of BiCNU as a single agent in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. This may be given as a single dose or divided into daily injections such as 75 to 100 mg/m2 on 2 successive days. When BiCNU is used in combination with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted, the doses should be adjusted accordingly.

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose.
The following schedule is suggested as a guide to dosage adjustment:

A repeat course of BiCNU should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3, leukocytes above 4,000/mm3), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.

Administration Precautions
As with other potentially toxic compounds, caution should be exercised in handling BiCNU and preparing the solution of BiCNU. Accidental contact of reconstituted BiCNU with the skin has caused transient hyperpigmentation of the affected areas. The use of gloves is recommended. If BiCNU lyophilized material or solution contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

The reconstituted solution should be used intravenously only and should be administered by IV drip. Injection of BiCNU over shorter periods of time than 1 to 2 hours may produce intense pain and burning at the site of injection.

Preparation of Intravenous Solutions
First, dissolve BiCNU with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP). Second, 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.

Reconstitution as recommended results in a clear, colorless to yellowish solution which may be further diluted with 5% Dextrose Injection, USP. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Important Note
The lyophilized dosage formulation contains no preservatives and is not intended for use as a multiple dose vial.

Stability
The unopened vial of the dry drug must be stored in a refrigerator (2°-8°C, 36°-46°F). The diluent ampules may be stored at controlled room temperature (59°-86°F, 15°-30°C) or 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. After reconstitution as recommended, BiCNU is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F). Reconstituted vials should be examined 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 to a concentration of 0.2 mg/mL in 5% Dextrose Injection, USP, should be stored at room temperature, protected from light and utilized within 8 hours.

Glass containers were used for the stability data provided in this section.
Only use glass containers for BiCNU administration.

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.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing BiCNU. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.

HOW SUPPLIED
BiCNU® (carmustine for injection). Each package includes a vial containing 100 mg carmustine and an ampule containing 3 mL sterile diluent.

NDC 0015-3012-60

STORAGE
Store in a refrigerator (2°-8°C, 36°-46°F).

Store diluent at controlled room temperature (59°-86°F, 15°-30°C) or in a refrigerator (2°-8°C, 36°-46°F).

2) Solimando, Dominic A. Drug Information Handbook for Oncology: A Complete Guide to Combination Chemotherapy Regimens, 8th ed. Hudson, OH: Lexi-Comp, Inc.; 2010.

Proper handling and disposal of anticancer drugs: ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41. Recommendations for the safe handling of cytotoxic drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992. US Dept of Health and Human Services, Public Health Service Publication NIH 92-2621. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1592. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983;1:426-428. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J Clin. 1983;33:258-263. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. Controlling occupational exposure to hazardous drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:166