Dacarbazine - Drug Monograph

Introduction

Dacarbazine is an alkylating agent and synthetic antineoplastic medication belonging to the class of triazenes. First approved by the FDA in 1975, it remains a cornerstone in the treatment of certain malignancies, particularly metastatic malignant melanoma and Hodgkin lymphoma. As a cytotoxic chemotherapy drug, dacarbazine requires careful administration and monitoring under specialist oncology supervision.

Mechanism of Action

Dacarbazine functions through multiple cytotoxic mechanisms. Primarily, it acts as an alkylating agent after metabolic activation in the liver, where it is converted to the active metabolite MTIC (5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide). This metabolite alkylates DNA primarily at the N-7 position of guanine, leading to DNA cross-linking, strand breaks, and miscoding errors during replication. Additionally, dacarbazine functions as a purine analog and inhibits DNA, RNA, and protein synthesis. The drug is cell cycle phase-nonspecific but demonstrates greatest activity during the S phase.

Indications

Dacarbazine is FDA-approved for:

• Treatment of metastatic malignant melanoma
• Second-line treatment of Hodgkin lymphoma (as part of combination regimens such as ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine)

Off-label uses include:

• Treatment of soft tissue sarcomas
• Neuroendocrine tumors
• Medullary thyroid carcinoma
• Certain pediatric malignancies

Dosage and Administration

• Malignant melanoma: 2-4.5 mg/kg/day IV for 10 days, repeated every 4 weeks OR 250 mg/m²/day IV for 5 days, repeated every 3 weeks
• Hodgkin lymphoma: 375 mg/m² IV on days 1 and 15 of each 28-day cycle (as part of ABVD regimen)

• Route: Intravenous infusion only
• Reconstitution: Dilute with sterile water for injection or 5% dextrose solution
• Infusion time: Typically administered over 15-30 minutes
• Vesicant properties: Considered a moderate irritant; ensure proper IV access and monitoring during administration

• Renal impairment: Dose reduction recommended for CrCl <50 mL/min
• Hepatic impairment: Use with caution; consider dose reduction
• Elderly: Monitor closely due to increased risk of toxicity
• Pediatrics: Safety and efficacy not established in children

Pharmacokinetics

Contraindications

• Hypersensitivity to dacarbazine or any component of the formulation
• Severe bone marrow suppression
• Pregnancy (unless potential benefit justifies potential risk to fetus)
• Breastfeeding

Warnings and Precautions

• Hematologic toxicity: Severe myelosuppression may occur
• Hepatic toxicity: Hepatic necrosis has been reported
• Carcinogenicity: Dacarbazine is mutagenic and carcinogenic

• Extravasation risk: May cause tissue damage; administer through secure IV line
• Photosensitivity: Patients should avoid excessive sun exposure
• Anaphylaxis: Rare but serious hypersensitivity reactions reported
• Hepatic veno-occlusive disease: Monitor liver function closely
• Embryo-fetal toxicity: Women of childbearing potential should use effective contraception

Drug Interactions

• Live vaccines: Increased risk of infection; avoid concomitant administration
• Phenytoin: May reduce dacarbazine efficacy
• CYP1A2 inducers (e.g., omeprazole, smoking): May increase metabolism of dacarbazine
• CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin): May decrease metabolism of dacarbazine
• Other myelosuppressive agents: Additive bone marrow toxicity
• Warfarin: Possible enhanced anticoagulant effect

Adverse Effects

• Myelosuppression (leukopenia, thrombocytopenia, anemia)
• Nausea and vomiting (90% of patients; often severe)
• Anorexia
• Flu-like symptoms (fever, myalgia, malaise)
• Alopecia

• Diarrhea
• Hepatic toxicity (elevated transaminases)
• Photosensitivity reactions
• Local tissue damage with extravasation

• Anaphylaxis
• Hepatic necrosis
• Hepatic veno-occlusive disease
• Secondary malignancies
• Severe neurotoxicity

Monitoring Parameters

• Complete blood count: Weekly during treatment and until recovery
• Liver function tests: Before each cycle and as clinically indicated
• Renal function: Baseline and periodic assessment
• Vital signs: During infusion for hypersensitivity reactions
• IV site: Continuous monitoring for extravasation
• Pregnancy status: For women of childbearing potential
• Response assessment: CT/MRI scans per treatment protocol

Patient Education

• Report immediately: Fever ≥38°C, chills, unusual bleeding/bruising, severe nausea/vomiting, yellowing of skin/eyes, dark urine, or injection site pain/swelling
• Use effective contraception during and for at least 6 months after treatment
• Avoid breastfeeding during treatment
• Limit sun exposure and use high-SPF sunscreen/protective clothing
• Maintain adequate hydration, especially around treatment days
• Do not receive live vaccines without consulting oncology team
• Alert all healthcare providers about dacarbazine treatment
• Expect hair loss; consider wig or head covering
• Manage nausea with prescribed antiemetics and dietary modifications

References

1. National Cancer Institute. Dacarbazine - Cancer Drug Information. Accessed 2023. 2. Micromedex Solutions. Dacarbazine Drug Information. Truven Health Analytics. 2023. 3. FDA Prescribing Information: Dacarbazine Injection. Revised 2022. 4. NCCN Guidelines: Melanoma Version 3.2023. 5. NCCN Guidelines: Hodgkin Lymphoma Version 2.2023. 6. Flannery MT, Harris R, Caskey FJ, et al. Dacarbazine: a review of its efficacy in the treatment of metastatic melanoma. Cancer Management and Research. 2013;5:11-31. 7. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine. 2010;363(8):711-723. 8. American Society of Health-System Pharmacists. AHFS Drug Information. Bethesda, MD. 2023.