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Dacarbazine

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: DIC; DTIC; Dacarbazina; Dacarbazinum; Dakarbatsiini; Dakarbazin; Imidazole Carboxamide; NSC-45388; WR-139007
BAN: Dacarbazine
USAN: Dacarbazine
INN: Dacarbazine [rINN (en)]
INN: Dacarbazina [rINN (es)]
INN: Dacarbazine [rINN (fr)]
INN: Dacarbazinum [rINN (la)]
INN: Дакарбазин [rINN (ru)]
Chemical name: 5-(3,3-Dimethyltriazeno)imidazole-4-carboxamide
Molecular formula: C6H10N6O =182.2
CAS: 4342-03-4 (dacarbazine); 64038-56-8 (dacarbazine citrate)
ATC code: L01AX04
Read code: y02mE; y07io; y08gb

Pharmacopoeias. In Europe, International, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Dacarbazine). A white or slightly yellowish, crystalline powder. Slightly soluble in water and in anhydrous alcohol; practically insoluble in dichloromethane. Store at 2° to 8°. Protect from light.

The United States Pharmacopeia 31, 2008 (Dacarbazine). Store in airtight containers at 2° to 8°. Protect from light.

Incompatibility. Dacarbazine has been reported to be incompatible with hydrocortisone sodium succinate but not with the sodium phosphate. It has been reported to be incompatible with heparin, although only with concentrated dacarbazine solutions (25 mg/mL).

Stability. References to the photodegradation of dacarbazine solution. Dacarbazine is more sensitive to direct sunlight than to artificial lighting or diffuse daylight.

Adverse Effects, Treatment, and Precautions

For general discussions see Antineoplastics.

Leucopenia and thrombocytopenia with dacarbazine, although usually moderate, may be severe. The nadir of the white cell count usually occurs 21 to 25 days after a dose. Anorexia, nausea, and vomiting occur in more than 90% of patients initially but tolerance may develop after repeated doses. Less frequent adverse effects include diarrhoea, skin reactions, alopecia, a flulike syndrome, facial flushing and paraesthesia, headache, blurred vision, seizures, and rare but potentially fatal hepatotoxicity. There may be local pain at the injection site; extravasation produces pain and tissue damage. Anaphylaxis has occurred occasionally.

Dacarbazine should be used with caution in hepatic and renal impairment, and consideration given to reducing the dose. Haematological monitoring is required during therapy. Dacarbazine is potentially carcinogenic, mutagenic, and teratogenic.

Effects on the bladder. A report of haemorrhagic cystitis associated with dacarbazine treatment for melanoma. The patient developed gross haematuria with inflammation and oedema of the bladder wall 2 weeks after completing 3 cycles of monotherapy with dacarbazine; the condition responded to symptomatic management with saline lavage and oral and intravenous hydration. Two subsequent transient episodes of haematuria resolved spontaneously.

Effects on the liver. Dacarbazine has been associated with fatal hepatic vascular toxicity, caused by thrombosis of the hepatic veins, necrosis, and extensive haemorrhage. As the reaction usually occurs during the second course of dacarbazine it is thought to be immune mediated, and early corticosteroid treatment has been tried with a few reported cases of patient survival. Other adverse hepatic effects have included necrosis without inflammation, granulomatous hepatitis, and acute toxic hepatitis during the first course of dacarbazine. Morphological studies have suggested that dacarbazine may exert a toxic effect on the microfilamentous cytoskeleton of the hepatocytes.

Handling. Dacarbazine is irritant; avoid contact with skin and mucous membranes.

Interactions

For a general outline of antineoplastic drug interactions.

Levodopa. For a report of dacarbazine reducing the effects of levodopa, see Antineoplastics.

Pharmacokinetics

Dacarbazine is poorly absorbed from the gastrointestinal tract. On intravenous injection it is rapidly distributed with an initial plasma half-life of about 20 minutes; the terminal half-life is reported to be about 5 hours. The volume of distribution is larger than body water content, suggesting localisation in some body tissues, probably mainly the liver. Only about 5% is bound to plasma protein. It crosses the blood-brain barrier to a limited extent; concentrations in CSF are about 14% of those in plasma. Dacarbazine is extensively metabolised in the liver by the cytochrome P450 isoenzymes CYP1A2 and CYP2E1 (and possibly in the tissues by CYP1A1) to its active metabolite 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC), which spontaneously decomposes to the major metabolite 5-aminoimidazole-4-carboxamide (AIC). About half of a dose is excreted unchanged in the urine by tubular secretion.

Uses and Administration

Dacarbazine is a cell-cycle non-specific antineoplastic that is thought to function as an alkylating agent after it has been activated in the liver. Dacarbazine is used mainly in the treatment of metastatic malignant melanoma. It is also given to patients with Hodgkin’s disease, notably with doxorubicin, bleomycin, and vinblastine (ABVD). Dacarbazine is used with other drugs in the treatment of soft-tissue sarcoma, and may be given in neuroblastoma, Kaposi’s sarcoma, and other tumours. Dacarbazine is given by the intravenous route. Injections may be given over 1 to 2 minutes. The reconstituted solution can be further diluted with up to 300 niL of glucose 5% or sodium chloride 0.9% and given by infusion over 15 to 30 minutes. Dacarbazine is licensed for use as a single agent for metastatic melanoma in doses of 2 to 4.5 mg/kg daily for 10 days, repeated at intervals of 4 weeks, or 200 to 250 mg/m daily for 5 days, repeated at intervals of 3 weeks. It can also be given in a dose of 850 mg/m by intravenous infusion at 3-week intervals. In the treatment of Hodgkin’s disease doses of 150 mg/m daily for 5 days repeated every 4 weeks, or 375 mg/m every 15 days have been given with other agents. In the treatment of soft-tissue sarcoma, dacarbazine 250 mg/m is given daily for 5 days repeated every 3 weeks; it is usually given with doxorubicin.

Preparations

British Pharmacopoeia 2008: Dacarbazine Injection;

The United States Pharmacopeia 31, 2008: Dacarbazine for Injection.

Proprietary Preparations

Argentina: Deticene ; Oncocarbil;

Australia: DTIC;

Austria: DTIC-Dome;

Brazil: Asercit ; Dacarb;

Canada: DTIC ;

Chile: Deticene;

Finland: Dacatic;

France: Deticene;

Germany: Detimedac;

Greece: Dacarbion; Deticene;

India: Dacarin; Decarb; DTIC ;

Israel: Deticene;

Italy: Deticene;

Malaysia: DTI ;

Mexico: Deticene ; Detilem; Ifadac;

The Netherlands: Deticene;

New Zealand: DTIC-Dome ;

Philippines: Duticin;

Portugal: Deticene; Fauldetic;

South Africa: DTIC-Dome;

Sweden: DTIC;

Switzerland: Dacin; DTIC;

Turkey: Deticene;

United Kingdom (UK): DTIC-Dome ;

United States of America (US and USA): DTIC-Dome

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