ARZI-200

Indications

• Metastatic melanoma
• Soft-tissue sarcomas (part of combination therapy)
• Hodgkin's disease (part of combination therapy)

Dosage

Children: Refer to local protocol for specific dosing guidelines.

Adults: Refer to local protocol for specific dosing guidelines.

Mechanism of action

Dacarbazine exerts its cytotoxic effects as an alkylating agent, requiring metabolic activation primarily in the liver via the cytochrome P450 system. It is demethylated to form an unstable monoalkyl derivative, which decomposes spontaneously to release alkylating moieties. This mechanism leads to inhibition of RNA and protein synthesis more than DNA synthesis, and it is not specific to any phase of the cell cycle.

Pharmacodynamics

Dacarbazine is a synthetic analog of the purine precursor 5-amino-1H-imidazole-4-carboxamide. Following intravenous administration, it displays a biphasic plasma disappearance with an initial half-life of approximately 19 minutes and a terminal half-life of about 5 hours. Its volume of distribution exceeds total body water, indicating localization in tissues, notably the liver. In patients with renal or hepatic impairment, the elimination half-life is prolonged.

Pharmacokinetics

Dacarbazine is primarily excreted unchanged in the urine, with about 40% of the administered dose eliminated within 6 hours. It undergoes renal tubular secretion rather than glomerular filtration. At therapeutic levels, it shows minimal binding to plasma proteins.

Contra-indications

• Acute infection
• Cardiac disease
• Cystitis
• Severe hepatic impairment
• Severe renal impairment

Adverse effects

• Anaemia
• Congestive heart failure
• Diarrhoea
• Fluid retention
• Headache
• Hepatic function abnormality
• Nausea
• Thrombocytopenia
• Vomiting
• Alopecia
• Appetite decreased
• Leucopenia
• Myocardial ischaemia
• Erectile dysfunction
• Depression
• Hypotension
• Confusion
• Skin reactions
• Infection reactivation

Interactions

• Calcium-containing products
• Magnesium-containing products
• Aluminium-containing products
• Other alkylating agents

Precautions

• Caution in handling due to irritant properties
• Monitor hepatic and renal function
• Caution in patients with renal impairment
• Caution in patients with hepatic impairment
• Men should use effective contraceptive methods during treatment

Pregnancy

Avoid use due to carcinogenic and teratogenic effects.

Breast-feeding

Discontinue breastfeeding during treatment.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Powder for solution for infusion (500 mg)
• Powder for solution for infusion (100 mg)

Mechanism of action

The mechanism of action is not known, but appears to exert cytotoxic effects via its action as an alkylating agent. Other theories include DNA synthesis inhibition by its action as a purine analog, and interaction with SH groups. Dacarbazine is not cell cycle-phase specific. Dacarbazine functions as an alkylating agent after metabolic activation in the liver. It appears to inhibit the synthesis of RNA and protein more than it inhibits the synthesis of DNA. It kills cells slowly, and there appears to be no phase of the cell cycle in which sensitivity is increased ... . ...FOR CHEMOTHERAPEUTIC EFFECTIVENESS, DACARBAZINE REQUIRES INITIAL ACTIVATION BY CYTOCHROME P450 SYSTEM OF LIVER THROUGH N-DEMETHYLATION REACTION. IN TARGET CELL...OCCURS SPONTANEOUS CLEAVAGE LIBERATING AIC /5-AMINOIMIDAZOLE-4-CARBOXAMIDE/ & ALKYLATING MOIETY, PRESUMABLY DIAZOMETHANE... Although the mechanism of action of dacarbazine is not known in detail, it is demethylated by liver microsomal enzymes to form an unstable monoalkyl derivative which can decompose spontaneously into alkylating moieties. In light, dacarbazine can also rapidly undergo chemical decomposition to form 4-diazoimidazole-5-carboxamide, which is highly toxic but which has no antitumor activity in vivo ... .

Pharmacodynamics

Dacarbazine is a synthetic analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). After intravenous administration of dacarbazine, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours. 1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7.2 hours. 1 The average cumulative excretion of unchanged DTIC in the urine is 40% of the injected dose in 6 hours. 1 DTIC is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein.