Usage
Carmustine is used as palliative therapy for:
- Brain tumors (glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors)
- Multiple myeloma (in combination with prednisone)
- Hodgkin’s disease (as secondary therapy)
- Non-Hodgkin’s lymphomas (as secondary therapy)
It is also used off-label for mycosis fungoides.
Pharmacological Classification: Alkylating agent; Nitrosourea.
Mechanism of Action: Carmustine is a bifunctional alkylating agent. It alkylates DNA and RNA, causing cross-linking of DNA strands, which inhibits DNA replication and RNA transcription. This leads to cell death. It is cell-cycle phase non-specific and is generally not cross-resistant with other alkylating agents, except possibly lomustine.
Alternate Names
International Nonproprietary Name (INN): Carmustine
Brand Names: BiCNU®, Gliadel®
How It Works
Pharmacodynamics: Carmustine’s primary effect is cytotoxicity via alkylation of DNA and RNA, leading to cell death. It is cell cycle phase nonspecific.
Pharmacokinetics:
- Absorption: Administered intravenously or implanted directly into the brain (Gliadel wafer).
- Distribution: Highly lipophilic; crosses the blood-brain barrier readily, achieving CSF levels approximately 50% of plasma levels.
- Metabolism: Metabolized to active alkylating species. Phenobarbital increases its metabolism.
- Elimination: 60-70% excreted in urine within 96 hours, 10% as respiratory CO2. Elimination half-life is approximately 0.25-0.75 h.
Mode of Action (Cellular/Molecular Level): Alkylates DNA and RNA at the O6 position of guanine, causing crosslinking of DNA strands. This inhibits DNA synthesis and function, ultimately leading to cell death.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: No known specific receptor binding or neurotransmitter modulation. Inhibits several enzymes by carbamoylation.
Elimination Pathways: Renal and pulmonary excretion, metabolism primarily hepatic, CYP enzymes are not significantly involved.
Dosage
Standard Dosage
Adults (IV):
- Single Agent: 150-200 mg/m² every 6 weeks, as a single dose or divided into 75-100 mg/m² on two successive days.
- Combination Therapy: Dose adjustments are necessary; consult specific protocols.
Children (IV):
Use with extreme caution in children due to the high risk of pulmonary toxicity. Dosage 200-250 mg/m² every 4-6 weeks may be utilized depending upon the child’s individual tolerance.
Special Cases:
- Elderly Patients: Start at the lower end of the dosing range due to increased risk of organ dysfunction. Monitor renal function.
- Patients with Renal Impairment: Reduce dose based on creatinine clearance.
- Patients with Hepatic Dysfunction: Dose adjustment may be necessary; monitor closely.
- Patients with Comorbid Conditions: Evaluate on a case-by-case basis, especially for lung disease.
Clinical Use Cases:
Dosing is determined by established protocols for specific cancers.
- Brain Tumor (Gliadel Wafer): Up to 8 wafers are implanted in the surgical resection cavity after tumor removal.
Dosage Adjustments:
Adjustments are made based on hematologic response to the previous dose:
- Leukocytes > 4,000/mm³ and Platelets > 100,000/mm³: 100% of prior dose
- Leukocytes 3,000-3,999/mm³ and Platelets 75,000-99,999/mm³: 100% of prior dose
- Leukocytes 2,000-2,999/mm³ and Platelets 25,000-74,999/mm³: 70% of prior dose
- Leukocytes < 2,000/mm³ and Platelets < 25,000/mm³: 50% of prior dose
Side Effects
Common Side Effects:
Nausea, vomiting, myelosuppression (leukopenia, thrombocytopenia, anemia), fatigue, anorexia.
Rare but Serious Side Effects:
Pulmonary fibrosis (acute and delayed onset, up to 17 years later), renal toxicity, secondary malignancies (leukemia).
Long-Term Effects:
Pulmonary fibrosis, secondary malignancies.
Adverse Drug Reactions (ADR):
Severe myelosuppression, pulmonary toxicity, hepatic dysfunction, renal failure.
Contraindications
- Hypersensitivity to carmustine or nitrosoureas
- Severe bone marrow suppression
- Severe renal impairment
- Pregnancy and breastfeeding
- Children and adolescents (< 18 years old)
Drug Interactions
- Cimetidine: Increased myelosuppression
- Phenobarbital: Decreased carmustine efficacy due to increased metabolism
- Phenytoin: Decreased phenytoin levels
- CYP450 Interactions: Does not significantly interact with CYP enzymes, but may impact metabolism of other drugs metabolized by these enzymes.
- Other Interactions: Anticoagulants, NSAIDs, and platelet inhibitors may increase the risk of bleeding due to carmustine’s thrombocytopenic effects.
Pregnancy and Breastfeeding
Pregnancy Safety Category: Contraindicated in pregnancy (risk of teratogenicity and embryotoxicity).
Breastfeeding: Contraindicated as carmustine is present in breast milk.
Drug Profile Summary
- Mechanism of Action: Alkylating agent causing DNA cross-linking, resulting in cell death.
- Side Effects: Myelosuppression, nausea, vomiting, pulmonary fibrosis (acute and delayed), renal toxicity.
- Contraindications: Hypersensitivity, severe bone marrow suppression, severe renal impairment, pregnancy, breastfeeding, children <18 years.
- Drug Interactions: Cimetidine, phenobarbital, phenytoin, anticoagulants, NSAIDs, platelet inhibitors.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 150-200 mg/m² every 6 weeks IV (adult). Dose adjustments based on hematological response.
- Monitoring Parameters: CBC with differential weekly for at least 6 weeks post-dose, pulmonary function tests (PFTs), renal function tests.
Popular Combinations
Carmustine is often used in combination chemotherapy regimens for specific cancers, such as multiple myeloma (with prednisone). Combinations vary based on the specific cancer type and treatment protocol.
Precautions
- General Precautions: Monitor blood counts, renal and pulmonary function.
- Specific Populations: Contraindicated in pregnancy, breastfeeding, and children < 18 years. Use cautiously in the elderly.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Carmustine?
A: For adults, 150-200 mg/m² IV every 6 weeks as a single agent. Dosages are adjusted based on previous hematological response and for combination therapy. Pediatric use is contraindicated due to high risk of pulmonary toxicity.
Q2: How is Carmustine administered?
A: Intravenously over at least 2 hours or via implanted wafers (Gliadel) directly into the brain.
Q3: What are the most serious side effects of Carmustine?
A: Pulmonary toxicity (both acute and delayed onset), severe myelosuppression, and secondary malignancies.
Q4: What should be monitored during Carmustine treatment?
A: Complete blood counts weekly for at least 6 weeks following each dose, pulmonary function tests (PFTs), and renal function.
Q5: Can Carmustine be used during pregnancy or breastfeeding?
A: No, it is contraindicated in both pregnancy and breastfeeding due to potential harm to the fetus/infant.
Q6: What are the key drug interactions with Carmustine?
A: Cimetidine, phenobarbital, phenytoin, anticoagulants, NSAIDs, and platelet inhibitors.
Q7: How does renal impairment affect Carmustine dosing?
A: The dose should be reduced based on creatinine clearance.
Q8: What is the mechanism of action of Carmustine?
A: Carmustine alkylates DNA and RNA, leading to DNA crosslinking and ultimately cell death.
Q9: What is the role of Carmustine in treating brain tumors?
A: It is used to treat various types of brain tumors, including glioblastoma and metastatic brain tumors, both intravenously and through direct implantation (Gliadel wafer). It can cross the blood-brain barrier.
