Usage
Dacarbazine is primarily used in the treatment of metastatic malignant melanoma. It is also used, in combination with other chemotherapeutic agents, for Hodgkin’s disease (Hodgkin’s lymphoma) and soft tissue sarcomas. It belongs to the alkylating agent class of antineoplastic drugs. Dacarbazine acts as a prodrug, requiring metabolic activation in the liver to its active metabolite, MTIC (5-(3-methyltriazen-1-yl)imidazole-4-carboxamide). MTIC methylates DNA at the O6 position of guanine, leading to DNA cross-linking and strand breaks, ultimately disrupting cell division and causing cell death.
Alternate Names
Dacarbazine is also known as DTIC (an abbreviation for its chemical name, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide). Brand names for dacarbazine include DTIC-Dome.
How It Works
Pharmacodynamics: Dacarbazine’s primary mechanism of action involves alkylation of DNA. Its active metabolite, MTIC, methylates DNA at the O6 position of guanine. This methylation leads to cross-linking and strand breaks in DNA, inhibiting DNA replication and RNA and protein synthesis. These actions cause cell cycle arrest and apoptosis (programmed cell death), particularly in rapidly dividing cells like cancer cells.
Pharmacokinetics: Dacarbazine is administered intravenously and is rapidly distributed throughout the body. It undergoes hepatic metabolism through both CYP-mediated oxidation and non-CYP pathways to form several metabolites, including the active metabolite MTIC and the inactive metabolite AIC (5-aminoimidazole-4-carboxamide). Both MTIC and AIC are primarily eliminated through renal excretion. Dacarbazine has a short half-life of approximately 5 hours.
Dosage
Standard Dosage
Adults:
- Malignant Melanoma: 200-250 mg/m² IV daily for 5 days, repeated every 3 weeks, OR 850 mg/m² IV every 3 weeks, OR 2-4.5 mg/kg IV daily for 10 days, repeated every 4 weeks.
- Hodgkin’s Disease: 150 mg/m² IV daily for 5 days, repeated every 4 weeks, OR 375 mg/m² IV on day 1 and day 15 of each cycle, as part of a combination regimen like ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine), OR 375 mg/m² IV every 15 days in combination with other antineoplastic agents.
- Soft Tissue Sarcomas: 250 mg/m² IV daily for 5 days in combination with doxorubicin every 3 weeks (ADIC regimen).
Children:
The safety and efficacy of dacarbazine in children have not been established.
Special Cases:
- Elderly Patients: Limited data suggest that dose adjustments may be necessary in elderly patients due to age-related decline in renal function.
- Patients with Renal Impairment: Dose reduction is recommended based on creatinine clearance. Generally, for mild to moderate renal impairment, a dose reduction is not required. For more severe impairment, dose reductions or discontinuation should be considered.
- Patients with Hepatic Dysfunction: As dacarbazine is metabolized in the liver, patients with hepatic dysfunction may require dose adjustments and close monitoring for toxicity.
- Patients with Comorbid Conditions: Careful consideration is required in patients with pre-existing conditions that might be exacerbated by dacarbazine’s side effects.
Clinical Use Cases Dosage recommendations are based on established protocols for specific cancer types (melanoma, Hodgkin’s disease, soft tissue sarcomas) and are not typically used in settings like intubation, surgical procedures, mechanical ventilation, or the ICU for indications other than managing these cancers or their complications. It’s not used in emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
Dose modifications are required based on patient-specific factors like renal or hepatic impairment, myelosuppression, and other toxicities. Close monitoring of blood counts and organ function is crucial during treatment.
Side Effects
Common Side Effects
Nausea, vomiting, loss of appetite, diarrhea, fatigue, flu-like symptoms, hair loss, flushing, injection site reactions (pain, burning, redness, swelling).
Rare but Serious Side Effects
Severe myelosuppression (neutropenia, thrombocytopenia, anemia), hepatotoxicity (jaundice, liver failure), allergic reactions (anaphylaxis, rash), secondary malignancies.
Long-Term Effects
Infertility, secondary malignancies.
Adverse Drug Reactions (ADR)
Anaphylaxis, severe myelosuppression, severe hepatotoxicity.
Contraindications
Hypersensitivity to dacarbazine, pregnancy, breastfeeding, severe myelosuppression.
Drug Interactions
Dacarbazine can interact with a wide range of medications, including other myelosuppressive agents (increased risk of bone marrow suppression), live vaccines (reduced immune response), and drugs that affect liver function. Fotemustine is contraindicated with dacarbazine. Consult a comprehensive drug interaction resource for a detailed list.
Pregnancy and Breastfeeding
Dacarbazine is contraindicated in pregnancy (Pregnancy Category D) and breastfeeding due to its teratogenic and potential for other harmful effects on the developing fetus and nursing infant.
Drug Profile Summary
- Mechanism of Action: Alkylating agent; disrupts DNA replication and function.
- Side Effects: Nausea, vomiting, myelosuppression, hepatotoxicity, allergic reactions.
- Contraindications: Hypersensitivity, pregnancy, breastfeeding, severe myelosuppression.
- Drug Interactions: Numerous; consult a drug interaction database.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Varies depending on indication and patient factors; see dosage section.
- Monitoring Parameters: Complete blood counts, liver function tests, renal function tests.
Popular Combinations
Dacarbazine is often used in combination regimens, such as ABVD for Hodgkin’s lymphoma and ADIC (Adriamycin, Dacarbazine) for soft tissue sarcomas.
Precautions
Monitor blood counts, liver function, and renal function regularly. Administer antiemetics to prevent nausea and vomiting. Avoid extravasation during intravenous administration. Patient counseling regarding contraception and potential long-term effects is important.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Dacarbazine?
A: The dosage varies depending on the indication and patient-specific factors. Please refer to the detailed dosage guidelines provided above.
Q2: How is Dacarbazine administered?
A: Dacarbazine is administered intravenously, either as a bolus injection or infusion.
Q3: What are the most common side effects of Dacarbazine?
A: Nausea, vomiting, and bone marrow suppression are the most common side effects.
Q4: Is Dacarbazine safe to use during pregnancy or breastfeeding?
A: No, Dacarbazine is contraindicated during pregnancy and breastfeeding.
Q5: What are the key drug interactions to be aware of with Dacarbazine?
A: Dacarbazine can interact with numerous medications; consult a comprehensive drug interaction database for a detailed list. Fotemustine is contraindicated with dacarbazine.
Q6: Are there any specific monitoring parameters for patients receiving Dacarbazine?
A: Yes, regular monitoring of blood counts, liver function, and renal function is crucial.
Q7: What precautions should be taken when administering Dacarbazine intravenously?
A: Care should be taken to avoid extravasation, as it can cause tissue damage. Administering the drug through a diluted infusion can help mitigate this risk.
Q8: What is the mechanism of action of Dacarbazine?
A: Dacarbazine is an alkylating agent, meaning its active metabolite damages cancer cell DNA, preventing cell division and growth.
Q9: Can Dacarbazine cause long-term side effects?
A: Yes, potential long-term side effects include infertility and secondary malignancies.
A: Dacarbazine is a prodrug activated by hepatic metabolism to its active metabolite, MTIC.
