Carmustine

Approved Indications:

• Brain Tumors (including glioblastoma multiforme, astrocytoma, medulloblastoma, and metastatic brain tumors) – used alone or in combination with other chemotherapeutics.
• Multiple Myeloma – usually as part of combination chemotherapy regimens.
• Hodgkin’s Lymphoma – especially in relapsed or refractory cases.
• Non-Hodgkin’s Lymphoma – for progressive, recurrent, or resistant forms.
• Malignant Gliomas – including recurrent or newly diagnosed cases in high-grade gliomas (e.g., GBM).

Off-label/Clinically Accepted Uses:

• Melanoma (metastatic) – investigational use in combination regimens.
• Secondary CNS Involvement by Lymphoma or Leukemia – as part of conditioning regimens prior to autologous stem cell transplant.

General Guidelines (Intravenous Injection):

• Adult (standard): 150–200 mg/m² total dose IV, divided over 2 days (e.g., 75–100 mg/m²/day on days 1 and 2) every 6–8 weeks.
• Brain tumors (as wafer implant): Each wafer contains 7.7 mg Carmustine. Up to 8 wafers may be implanted into the resection cavity.

Pediatric:

• Limited data; dosing typically based on body surface area (mg/m²) and used with extreme caution.

Elderly:

• Use with caution. Consider renal and hepatic function when adjusting dose.

Renal Impairment:

• Use with caution; increased toxicity risk. Consider dose reduction or extended intervals.

Hepatic Impairment:

• Monitor closely; no specific dose adjustment guidelines but hepatotoxicity may be exacerbated.

Route & Administration:

• IV Infusion: Reconstituted and diluted Carmustine should be administered via a free-flowing IV line over 1–2 hours.
• Wafer Implant (Gliadel®): Implanted into the resection cavity during craniotomy.

Precautions:

• Avoid extravasation due to risk of local necrosis.
• Monitor blood counts weekly for at least 6 weeks post-administration.

Carmustine is a nitrosourea alkylating agent that acts by forming covalent linkages with DNA and RNA strands through alkylation. It alkylates the O6 position of guanine, leading to interstrand DNA crosslinking and inhibition of DNA replication and transcription. Carmustine also carbamoylates proteins, potentially inhibiting DNA repair enzymes and other key cellular functions. Its lipophilic nature allows it to cross the blood-brain barrier effectively, making it highly useful in treating brain tumors.

• Absorption: Not applicable orally; administered intravenously or via implant.
• Distribution: Widely distributed; penetrates cerebrospinal fluid and brain tissue effectively.
• Protein Binding: 60–70%
• Metabolism: Rapidly metabolized in the liver and tissues; undergoes both spontaneous decomposition and enzymatic metabolism.
• Active Metabolites: Yes (toxic and cytotoxic metabolites contribute to antineoplastic effects).
• Half-life: Biphasic; initial t½ ≈ 15–30 minutes, terminal t½ ≈ 1–3 hours.
• Excretion: Primarily via urine (60–70% within 96 hours); also exhaled as CO₂.

• Pregnancy: Category D (FDA) – Positive evidence of human fetal risk. Carmustine is teratogenic and embryotoxic in animals. Should not be used during pregnancy unless life-threatening circumstances outweigh fetal risks.
• Lactation: Unknown if excreted into human milk. Due to potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for at least 7 days after the last dose.

• Primary Class: Alkylating Agent
• Subclass: Nitrosourea derivative; cell-cycle non-specific chemotherapeutic

• Known hypersensitivity to Carmustine or any of its excipients
• Pre-existing severe bone marrow suppression
• Active infection or sepsis
• Pregnancy (unless life-threatening condition)
• Concurrent use with high-dose radiation therapy or other myelosuppressants without appropriate timing

• Bone Marrow Suppression: Delayed and dose-limiting; nadir at 4–6 weeks post-dose. Frequent CBC monitoring required.
• Pulmonary Toxicity: Interstitial fibrosis and pulmonary infiltrates may occur, especially with prolonged use or high cumulative doses (>1200 mg/m²).
• Hepatic/Renal Toxicity: Monitor LFTs and renal function before and during therapy.
• Secondary Malignancies: Increased risk of leukemia and other neoplasms.
• Hypersensitivity Reactions: Anaphylaxis, urticaria, and other serious allergic reactions reported.
• Extravasation Risk: May cause local necrosis; ensure proper IV administration.

Hematologic:

• Thrombocytopenia
• Leukopenia
• Anemia
• Delayed marrow suppression

Pulmonary:

• Pulmonary fibrosis
• Interstitial pneumonitis

Gastrointestinal:

• Nausea and vomiting (high incidence; can be prolonged)
• Anorexia

Hepatic:

• Elevated liver enzymes
• Hepatotoxicity

Renal:

• Elevated BUN and creatinine
• Nephrotoxicity (especially with cumulative high doses)

Others:

• Pain at injection site
• Local tissue necrosis (if extravasation occurs)
• Secondary malignancies (e.g., AML)

Rare/Serious:

• Anaphylaxis
• CNS toxicity (confusion, ataxia)
• Visual disturbances

• Myelosuppressive Agents: Additive bone marrow suppression; avoid or schedule cautiously.
• Live Vaccines: Risk of infection due to immunosuppression; avoid during and after therapy.
• Phenytoin/Warfarin: Possible altered plasma levels; monitor closely.
• Cimetidine: May alter hepatic metabolism; monitor for toxicity.
• CYP450 Interactions: While Carmustine undergoes hepatic metabolism, specific CYP isoenzyme involvement is not fully characterized.

• Wafer Implant (Gliadel®) Recommendations Updated: Recent oncology guidelines reaffirm use of Carmustine wafers in high-grade gliomas for localized therapy.
• FDA Safety Warning: Reinforced caution on pulmonary fibrosis risk with cumulative doses exceeding 1200 mg/m².
• New Recommendations in High-dose Conditioning: Carmustine included as part of high-dose regimens for hematopoietic stem cell transplant in relapsed lymphoma per updated ASCO/EBMT guidelines.

For Injectable Form:

• Store refrigerated at 2°C to 8°C.
• Protect from light.
• Reconstituted solution is unstable; must be used within 8 hours at room temperature.

For Wafer Implant (Gliadel®):

• Store frozen at -20°C or below.
• Do not refreeze after thawing.
• Use immediately after removal from freezer and implantation.

Handling Precautions:

• Carmustine is a cytotoxic agent; use protective gloves and gown.
• Follow proper disposal procedures for chemotherapy waste.