Dacarbazine is a chemotherapeutic cytotoxic (non-cell cycle specific) drug that is used to treat patients with hodgkins lymphoma and malignant melanoma in combination with other chemotherapeutic agents.

Dacarbazine Uses:

• Hodgkin lymphoma:

  • It is used in the management of Hodgkin lymphoma (in combination with other chemotherapeutic agents)

• Metastatic malignant melanoma:

  • It can be used in the treatment of metastatic malignant melanoma

• Use: Off-Label: Adult

  • Advanced Medullary thyroid cancer
  • Advanced Pancreatic neuroendocrine tumors
  • Malignant Pheochromocytoma
  • Advanced Soft-tissue sarcomas

Dacarbazine Dose in Adults

Note: Dacarbazine is associated with high emetic adverse effects. Antiemetics are recommended to prevent vomiting and nausea. 

Dacarbazine Dose in the treatment of Hodgkin lymphoma:

• ABVD regimen:

  • 375 mg/m² intravenously on days 1 and 15 every month combined with doxorubicin, bleomycin, and vinblastine for 2 to 4 cycles.

• A-AVD regimen:

  • 375 mg/m² intravenously on days 1 and 15 every 4 weeks combined with brentuximab vedotin, doxorubicin, and vinblastine for up to 6 cycles.
  • Administer primary prophylaxis with G-CSF (filgrastim), beginning with cycle 1.

Dacarbazine Dose in the treatment of metastatic malignant Melanoma:

• 250 mg/m² intravenously over 30 minutes once a day, on days 1 to 5 every 3 weeks.

Dacarbazine Dose in the treatment of stage IIIA-N2a to stage IIIC-N3, high-risk melanoma (off-label dosing/combinations):

• IV: Bio-chemotherapy regimen:
  • 800 mg/m² infused intravenously over one hour on day 1 every 3 weeks (in combination with cisplatin, vinblastine, interleukin-2, and interferon alfa-2b) for a total of three cycles.

Dacarbazine Dose in the treatment of advanced Medullary thyroid cancer (off-label):

• 200 mg/m² intravenously once a day for 5 days every 6 weeks (in combination with fluorouracil and streptozocin) OR
• 600 mg/m² once daily for 2 days every 3 or 4 weeks (in combination with cyclophosphamide and vincristine) OR
• 250 mg/m² over 15 to 30 minutes once a day for 5 days every 30 days (in combination with fluorouracil).

Dacarbazine Dose in the treatment of advanced Pancreatic neuroendocrine tumors (off-label):

• 850 mg/m² intravenously over 60 to 90 minutes on day 1 every 30 days.

Dacarbazine Dose in the treatment of malignant Pheochromocytoma (off-label):

• 600 mg/m² intravenously once a day for 2 days every 20-30 days (in combination with cyclophosphamide and vincristine).

Dacarbazine Dose in the treatment of advanced Soft tissue sarcoma (off-label): IV:

• AD regimen:

  • 250 mg/m²/day as a continuous intravenous infusion for 4 days 3-weeky (total of 1,000 mg/m²/cycle) (in combination with doxorubicin) OR
  • 187.5 mg/m² /day as a continuous intravenous infusion for 4 days every 3 weeks (total of 750 mg/m² /cycle) (in combination with doxorubicin).

• MAID regimen:

  • 250 mg/m²/day as a continuous intravenous infusion for 4 days 3-weekly (total of 1,000 mg/m²/cycle) (in combination with mesna, doxorubicin, and ifosfamide).

Dacarbazine Dose in Childrens

Note:

• For oncology uses, details concerning dosing in combination regimens should also be reviewed.
• It is associated with a high emetic potential. Antiemetics are recommended to prevent nausea and vomiting.

Dacarbazine Dose in the treatment of High-Risk Hodgkin lymphoma: Limited data available:

• ABVD regimen:

  • Children and Adolescents:
  • 375 mg/m² intravenously over 30 to 60 minutes on Days 1 and 15 of a 28-day treatment cycle for 2 to 6 cycles in combination with doxorubicin, vinblastine, and bleomycin.

Dacarbazine Dose in the treatment of High-risk Melanoma: Limited data available:

• Children ≥10 years and Adolescents:

  • IV: 800 mg/m² over one hour on Day 1 only after vinblastine and in combination with cisplatin and interferon alfa-2b every 3 weeks for 3 cycles.

Pregnancy Risk Factor C

• [US Boxed Warning] The drug has been shown in animal reproduction studies as being carcinogenic and/or toxic to animals.
• Animal trials have been conducted to determine potential harmful effects.
• Treatment should not be performed on females in their reproductive years.
• The European Society for Medical Oncology published guidelines for management of pregnancy-related cancer.
• These guidelines recommend that you refer to a cancer center during pregnancy.
• They also encourage the use of a multidisciplinary team, including an obstetrician and neonatologist.
• If chemotherapy is necessary, it should not be given during the first trimester.
• There should be a 21-day time gap between the last dose of chemotherapy and the delivery date. The 33-week gestation limit should also be considered.
• Guidelines for treatment of hematologic malignancies in pregnancy have been published by an international consensus panel.
• Dacarbazine can be used in Hodgkin’s disease as part of the ABVD treatment regimen.
• ABVD can be given in the final trimester of pregnancy if treatment is not possible for patients with Hodgkin lymphoma in its early stages. This is based on limited data.
• ABVD may be given in the second or third trimester to patients with advanced-stage diseases.

Use of dacarbazine while breastfeeding

• It is unknown whether the drug is secreted into breast milk.
• The risk of serious adverse reactions in breastfed infants should be considered. It is best to decide whether to stop breastfeeding or discontinue dacarbazine.

Dose in Kidney disease:

There are no dosage adjustments provided in the manufacturer's labeling.

• The following adjustments have been recommended:

  • CrCl 46 to 60 mL/minute:
    • Reduce dose to 80% of the usual dose
  • CrCl 31 to 45 mL/minute:
    • Reduce dose to 75% of the usual dose
  • CrCl ≤30 mL/minute:
    • Reduce dose to 70% of the usual dose

Dose in Liver disease:

• There are no dose adjustments have been provided in the manufacturer's labeling.
• It may cause hepatotoxicity. Patients should be monitored closely for the clinical signs of toxicity.

Side effects of Dacarbazine:

• Central nervous system:

  • Infusion-site pain

• Dermatologic:

  • Alopecia

• Gastrointestinal:

  • Nausea and vomiting
  • Anorexia

• Hematologic & oncologic:

  • Bone marrow depression
  • Leukopenia
  • Thrombocytopenia

Contraindications to Dacarbazine:

• Canadian labeling: Additional contraindications not in the US labeling
  • Severe allergic reactions.
  • Previous myelosuppressive diseases

Warnings and precautions

• Anaphylaxis

  • It has been reported that severe allergic reactions, including anaphylactic reactions, have been observed.

• Suppression of bone marrow: [US Boxed Warning]

  • The most common toxicity is bone marrow suppression;
  • Leukopenia or thrombocytopenia may occur in patients. This may lead to treatment interruptions or delays.
  • Treatment may result in anemia. Monitoring blood CBC and differential levels is important.
  • Leukopenia can begin in about 2 weeks, with a range of 10 to 30 days. The total duration is approximately 1 to 3 weeks.
  • The average time it takes to get thrombocytopenia started is 18 days. However, the duration of the disease can vary from 12 to 30 day.

• [US Boxed Warning] Carcinogenic/teratogenic

  • Animal studies have shown that this agent is carcinogenic and/or toxic to animals.

• Extravasation

  • It can cause skin irritations and local reactions. Extravasation can cause severe tissue and pain, according to the manufacturer.

• Gastrointestinal toxicities:

  • This can cause severe nausea and vomiting. Antiemetics should be taken before the infusion to prevent nausea or vomiting.

• Hepatic effects: [US Boxed Warning]

  • Reports of hepatic necrosis have been made.
  • Hepatotoxicity can also be associated with hepatic vein embolism and hepatocellular necrosis, which can be fatal and potentially deadly.
  • Hepatotoxicity is most common with combination chemotherapy. However, it can also occur with dacarbazine monotherapy.

• Hepatic impairment

  • Patients with liver disease should be cautious as the drug's half-life is higher. You should monitor the patient for signs of toxicity and reduce dosage.

• Renal impairment

  • Patients with kidney impairment should be cautious as this can alter half-life. You should monitor the patient for toxicities and reduce dosage.

Dacarbazine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• CBC with differential counts.
• Liver function

How to administer Dacarbazine?

• It is administered as a slow intravenous infusion over 15 to 60 minutes.
• Severe venous irritation may follow rapid infusions.
• Monitor the site for extravasation as it is an irritant and causes local reactions.
• Prior to administration, administer antiemetic drugs to prevent infusion-related nausea and vomiting.

Mechanism of action of Dacarbazine:

• It is an alkylating agent with no cell cycle specificity that is converted by the cytochrome 450 system to the active alkylating compound MTIC [(methyl triazene-1,yl)-imidazole-4 carboxamide]. MTIC can cause cytotoxic effects by alkylation (methylation of DNA at O-6 and N-7 positions, leading to DNA double-strand breakage and apoptosis.

Distribution:

• Exceeds total body water; suggesting binding to some tissue (probably liver).

Metabolism:

• Extensively hepatic to the active metabolite MTIC [(methyl-triazene-1-yl)-imidazole4-carboxamide]

Half-life elimination: Biphasic:

• Initial: 19 minutes, 55 minutes (renal and hepatic dysfunction);
• Terminal: 5 hours, 7.2 hours (renal and hepatic dysfunction)

Excretion:

• Urine (~40%; as unchanged drug)

International Brands of Dacarbazine:

• Acocard
• Arzi
• Arzi-100
• Arzi-200
• Bazipar
• T.I.C.
• T.I.C.Dome
• Dabaz
• DAC
• Dacarb
• Dacarbazin
• Dacarbazina
• Dacarbazine
• Dacarbazine DBL
• Dacarbazine Dome
• Dacarbazine For Injection
• Dacarzin
• Dacatic
• Dacimed
• Dacin
• Decarb
• Deticene
• Deticine
• Detilem
• Detimedac
• DTI
• DTIC
• DTIC-Dome
• Duticin
• Oncocarbil
• Tiferomed

Dacarbazine Brand Names in Pakistan: