Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Dacarbazine is a structural analogue of imidazole carboxamide, a purine precursor.1 Dacarbazine undergoes activation via cytochrome P450 in the liver to the reactive compound, methyltriazenoimidazole carboxamide (MTIC).5 The cytotoxicity of MTIC is thought to be due primarily to the formation of methylcarbonium ions that attack nucleophilic groups in DNA.3,6 Dacarbazine may also inhibit DNA and RNA synthesis by acting as a purine analogue and by interacting with sulfhydryl groups.3,7 Both dacarbazine and temozolomide are prodrugs of MTIC. Dacarbazine is cell cycle phase-nonspecific and is mildly immunosuppressive.3

PHARMACOKINETICS:

SPECIAL PRECAUTIONS:

Contraindicated in patients who have a history of hypersensitivity reaction to dacarbazine3 or temozolomide.15

Mutagenicity: No information found regarding mutagenicity in Ames test and mammalian in vitro mutation test.16 Dacarbazine is clastogenic in mammalian in vivo chromosome tests.17

Pregnancy: FDA Pregnancy Category C.6 Animal studies have shown fetal risks and there are no controlled studies in women. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.19,20 When placebo-controlled trials are available, adverse events are included if the incidence is

5% higher in the treatment group.

ORGAN SITE	SIDE EFFECT
Clinically important side effects are in bold, italics
allergy/immunology	anaphylaxis (<1%) 6
blood/bone marrow/ febrile neutropenia	myelosuppression
	leukopenia ; typically occurs 14 days after treatment, has occurred as early as 10 days and in 10% of patients is delayed as late as 30 days, typical duration 1 week but 3 weeks has been reported
	thrombocytopenia ; typically occurs 12-18 days after treatment, in 10% of patients is delayed until after day 30, typical duration 1 week but 3 weeks has been reported
cardiovascular (arrhythmia)	EKG abnormalities
cardiovascular (general)	orthostatic hypotension; typically associated with doses >850 mg/m 2
constitutional symptoms	fatigue
dermatology/skin	extravasation hazard: irritant 21
	alopecia (1-10%) 6
	erythematous, macular, papular, and/or urticarial rash (1-10%) 6
	facial flushing (<1%); transient 1
	phototoxicity 22 (1-10%) 6 ; typically occurs hours after treatment and lasts 1-4 days, 23 self-limiting and does not require drug discontinuation 24
	reaction resembling fixed drug eruption
gastrointestinal	emetogenic potential: high 25
	anorexia ( > 90%); see paragraph following the Side Effects table
	diarrhea (<1%); with high-dose, 6 typically not severe
	nausea and vomiting ( > 90%) ; see paragraph following the Side Effects table
	stomatitis 1,7
ORGAN SITE	SIDE EFFECT
Clinically important side effects are in bold, italics
hepatobiliary/pancreas	hepatotoxicity with hepatocellular necrosis and/or hepatic vascular occlusion (0.01%) 1 ; see paragraph following the Side Effects table
metabolic/laboratory	elevated liver enzymes 1 (<1%) 6
neurology	confusion
	facial paresthesia (<1%) 6 ; transient 1
	seizures
ocular/visual	blurred vision
pain	headache (<1%) 6
pain	injection site pain; may be minimized by administration via central line or by infusion of diluted solution 1,6
renal/genitourinary	renal dysfunction
sexual/reproductive function	gonadal dysfunction 18 ; transient
syndromes	influenza-like syndrome (<10%); fever, myalgia, and malaise, typically occurs after single large doses 2-7 days after treatment and persists for 7-21 days, may recur, supportive management recommended
vascular	veno-occlusive disease; see paragraph following the Side Effects table

Adapted from standard reference3 unless specified otherwise. Nausea, vomiting, and anorexia occur in >90% of patients receiving dacarbazine. GI symptoms are most common with initial doses, with tolerance developing after the first few days of successive treatment when the drug is given on a 5 day schedule.3,8 Nausea and vomiting are typically acute in onset, intense and short-lived, persisting for 1-12 hours.3 Restriction of food and fluid intake 4-6 h prior to treatment has been recommended.3 Antiemetic agents are required for prophylaxis and treatment of N/V. (Refer to SCNAUSEA protocol.) Intractable nausea and vomiting requiring drug discontinuation has rarely occurred.

1,3

Hepatotoxicity with hepatocellular necrosis and/or hepatic vascular occlusion: Vascular occlusion typically occurs during the second cycle of treatment and may be preceded by mild, transient hepatic toxicity after the first cycle.3 Eosinophilia and eosinophilic infiltrates have been reported with hepatic vascular occlusion, suggesting that a hypersensitivity mechanism may be involved. Fatalities due to dacarbazine-induced hepatotoxicity have occurred.3 Hepatotoxicity may be more common with combination chemotherapy.1,6 Monitor hepatic function during therapy.3

INTERACTIONS:

Dacarbazine inhibits xanthine oxidase and may theoretically potentiate the activity and toxicity of mercaptopurine and azathioprine.3

Dacarbazine inhibits xanthine oxidase and may theoretically potentiate the activity, but not the toxicity, of allopurinol.3

Dacarbazine is a major CYP1A2 and 2E1 substrate; therefore, drugs or herbs that are CYP 1A2 or CYP 2E1 inducers may decrease the serum levels/effects of dacarbazine. Likewise, drugs or herbs that are CYP1A2 and 2E1 inhibitors may increase the serum levels/effects of dacarbazine.26

SUPPLY AND STORAGE:

: Mayne Pharma (Canada) Inc, supplies dacarbazine as 200 mg and 600 mg vials. Store in the refrigerator and protect from light.

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.

Additional information: Dacarbazine is sensitive to light and heat; a change in colour from pale ivory to pink is a sign of decomposition.1 Protect from light to preserve activity and prevent formation of inactive and potentially harmful degradation products.27

The following are compatible via Y-site injection: amifostine, aztreonam, doxorubicin, filgrastim, fludarabine, granisetron, melphalan, ondansetron, paclitaxel, sargramostim, teniposide, thiotepa, vinorelbine.

The following are incompatible via Y-site injection: allopurinol, cefepime, piperacillin/tazobactam.

PARENTERAL ADMINISTRATION:

DOSAGE GUIDELINES:

BCCA administration guideline noted in bold, italics
Subcutaneous	no information found
Intramuscular	no information found
Direct intravenous	over at least 1 minute 1,3 into tubing of running IV; see Prevention and Management of Extravasation of Chemotherapy . Intermittent infusion typically less painful than direct IV.

BCCA administration guideline noted in bold, italics
Intermittent infusion	over 1-2 h, 11,12,29 over 15-30 minutes has been used 1,3 Rapid infusion may cause severe venous irritation. 1,6 If irritation occurs, slow the rate of infusion.
Continuous infusion	no information found
Intraperitoneal	no information found
Intrapleural	no information found
Intrathecal	investigational; has been used 30
Intra-arterial	investigational; has been used 1,6
Intravesical	no information found

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Intravenous: 3 weeks6,13,14: 850 mg/m2 IV for one dose on day 1 (total dose per cycle 850 mg/m2)

4 weeks11: 375 mg/m2 IV for one dose on day 1 and 15 (total dose per cycle 750 mg/m2) weeks3: 2-4.5 mg/kg IV once daily for 10 consecutive days starting on day 1 (total dose per cycle 20-45 mg/kg) 3-4 weeks3,6: 100-250 mg/m2 IV once daily for 5 consecutive days starting on day 1 (total dose per cycle 500-1250 mg/m2)

High-dose therapy: 3-4 weeks6,12,19,29: rarely used in doses exceeding 1.2 g/m2 Intra-arterial: n/a6: 50-400 mg/m2 IV for 5-10 days (total dose per cycle 250-4000 mg/m2)

modify according to protocol by which patient is being treated; if no guidelines

Dosage in hepatic failure: adjustment required,3 no details found; alternatively may monitor for toxicity6

Cycle Length: Intravenous: safety and efficacy have not been established in children3; dacarbazine has been used in pediatric patients6,31 weeks6,31: 375 mg/m2 IV for one dose on day 1 and 15 (total dose per cycle 750 mg/m2) 3-4 weeks6,31,32: 200-470 mg/m2 IV once daily for 5 consecutive days starting on day 1 (total dose per cycle 1000-2350 mg/m2) 3-4 weeks6,31: 800-900 mg/m2 IV for one dose on day 1 (total dose per cycle 800-900 mg/m2)

REFERENCES:

Drug Interaction Facts (database on the Internet). Dacarbazine Cancer Chemo Manual. Facts and Comparisons 4.0, Available at: http://online.factsandcomparisons.com. Accessed April 26, 2007.

El Aatmani M, Poujol S, Astre C, et al. Stability of dacarbazine in amber glass vials and polyvinyl chloride bags. Am J Health- Syst Pharm 2002; 59(14):1351-6.

Trissel L. Handbook on injectable drugs. 13th ed. Bethesda, Maryland: American Society of Health-System Pharmacists; 2005. p. 428-431.

BC Cancer Agency Melanoma Tumour Group. (SMDTIC) BCCA Protocol Summary for Palliative Therapy for Metastatic Malignant Melanoma Using High Dose Dacarbazine (DTIC). Vancouver, British Columbia: BC Cancer Agency; 1 December 2003.

Champagne MA, Silver HKB. Intrathecal dacarbazine treatment of leptomeningeal malignant melanoma. J Natl Cancer Inst 1992; 84(15):1203-1204.

Rose BD editor. Dacarbazine: Pediatric drug information. www.uptodate.com ed. Waltham, Massachusetts: UpToDate 15.1; 2007.

Pizzo P, Poplack D. Principles and practice of pediatric oncology. 5th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2006. p. 300.

Oral Absorption	not given orally due to incomplete and variable absorption
Distribution	cross blood brain barrier? 8	minimal
	volume of distribution 6	0.6 L/kg; exceeds total body water, suggesting localization in body tissue, likely the liver
	plasma protein binding	<5%
Metabolism	primarily hepatic, involves the hepatic microsomal enzyme oxidation system
	active metabolite(s) 5,6,9	yes; including MTIC
	inactive metabolite(s) 2,5,9	yes; including aminoimidazole carboxamide (AIC)
Excretion	primarily renal, net tubular secretion (saturable at doses >1200 mg/m 2 ), minor hepatobiliary and pulmonary excretion 8
	urine	20-50% unchanged, 12-24% as AIC
	feces	no information found
	terminal half life 6	5 h
	clearance 10	15 mL/kg/min

Primary uses:	Other uses:
Lymphoma, Hodgkin's 11	Islet cell carcinoma 6
* Melanoma, metastatic malignant	Medullary carcinoma of the thyroid 6
Sarcoma, soft tissue 12-14	Neuroblastoma 1

AGENT	EFFECT	MECHANISM	MANAGEMENT
aldesleukin 3	decreased therapeutic effect of dacarbazine	related to aldesleukin dose; increased clearance (~38%) and volume of distribution (~36%) of dacarbazine	usual monitoring; dacarbazine dosage increase may be required
aldesleukin 26	hypersensitivity reactions have been reported when used concurrently	unknown	usual monitoring
AGENT	EFFECT	MECHANISM	MANAGEMENT
levodopa 3,26	reduced response to levodopa	unknown; unlikely due to pharmacokinetic changes	usual monitoring; levodopa dosage increase may be required

COMMON TRADE NAME(S):