Dr. Reddy’s Laboratories Inc.
WARNING: MYELOSUPPRESSION and PULMONARY TOXICITY
Carmustine 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 until blood counts recover.
Carmustine causes dose-related pulmonary toxicity. Patients receiving greater than 1400 mg/m2 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)].
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.
The recommended dose of carmustine for injection 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 carmustine is used with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted. Administer carmustine 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
The hematologic toxicity can be delayed and cumulative. Monitor blood counts weekly. Do not administer a repeat course of carmustine 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 if the creatinine clearance is less than 10 mL/min. Do not administer carmustine to patients with compromised renal function. Monitor transaminases and bilirubin periodically during treatment. [see Adverse Reactions (6)].
- Dissolve carmustine with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP).
- Aseptically add 27 mL Sterile Water for Injection, USP.
o Each mL of resulting solution contains 3.3 mg of carmustine in 10% ethanol. Such solutions should be protected from light.
o 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.
o 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.
o Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
o After reconstitution as recommended, carmustine 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.
o 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° to 8°C, 36° to 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 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. Carmustine is a cytotoxic drug. Follow applicable special handling and disposal procedures1.
- The lyophilized dosage formulation contains no preservatives and is not intended for use as a multiple dose vial.
Accidental contact of reconstituted carmustine 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. Immediately wash the skin or mucosa thoroughly with soap and water if carmustine lyophilized material or solution contacts the skin or mucosa1.
For injection: 100 mg of carmustine USP, as a lyophilized powder in a single-dose vial for reconstitution and a vial containing 3 mL sterile diluent (Dehydrated Alcohol Injection, USP).
Carmustine is contraindicated in patients with previous hypersensitivity to carmustine or its components.
Bone marrow toxicity is a dose-limiting, common and severe toxic effect of carmustine occurring 4 to 6 weeks after drug administration (thrombocytopenia occurs at about 4 weeks post-administration persisting for 1 to 2 weeks; leukopenia occurs at 5 to 6 weeks after a dose of carmustine persisting for 1 to 2 weeks; thrombocytopenia is generally more severe than leukopenia; anemia is less frequent and less severe compared to thrombocytopenia and/or leukopenia) Complete blood count should therefore be monitored weekly for at least six weeks after a dose. Repeat doses of carmustine should not be given more frequently than every six weeks.
The bone marrow toxicity of carmustine is cumulative and therefore the dosage adjustment must be considered on the basis of nadir blood counts from prior dose [see Adverse Reactions (6)]. Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine [see Drug Interactions (7)].
Cases of fatal pulmonary toxicity with carmustine have been reported. Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported to occur from 9 days to 43 months after treatment with carmustine and related nitrosoureas. Pulmonary toxicity from carmustine is dose-related. Patients receiving greater than 1400 mg/m2 cumulative dose are at significantly higher risk than those receiving less. However, there have been reports of pulmonary fibrosis in patients receiving lower total doses. Interstitial fibrosis (with lower doses) occurred rarely. Additionally, delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received carmustine (in cumulative doses ranging from 770 to 1800 mg/m2 combined with cranial radiotherapy for intracranial tumors) in childhood and early adolescence. Other risk factors include past history of lung disease and duration of treatment. Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) are particularly at risk.
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