Dacarbazine

DRUG NAME: Dacarbazine

SYNONYM(S): DIC,1 DTIC1,2

COMMON TRADE NAME(S): Dacarbazine for Injection

CLASSIFICATION: alkylating agent3

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

4
activation via cytochrome P450 in the liver to the reactive compound, methyltriazenoimidazole carboxamide (MTIC).
The cytotoxicity of MTIC is thought to be due primarily to the formation of methylcarbonium ions that attack
3,5
nucleophilic groups in DNA. Dacarbazine may also inhibit DNA and RNA synthesis by acting as a purine analogue
and by interacting with sulfhydryl groups.3,6 Both dacarbazine and temozolomide are prodrugs of MTIC. Dacarbazine
3
is cell cycle phase-nonspecific and is mildly immunosuppressive.

PHARMACOKINETICS:

Oral Absorption not given orally due to incomplete and variable absorption
Distribution cross blood brain barrier?7 minimal
volume of distribution5 0.6 L/kg; exceeds total body water, suggesting
localization in body tissue, likely the liver
plasma protein binding <5%
Metabolism primarily hepatic, principally via CYP 1A2, secondarily by CYP 2E1; CYP 1A1 may play a
role in extrahepatic metabolism4
active metabolite(s)4,5,8 yes; including MTIC
2,4,8
inactive metabolite(s) yes; including aminoimidazole carboxamide (AIC)
Excretion primarily renal, net tubular secretion (saturable at doses >1200 mg/m2), minor hepatobiliary
and pulmonary excretion7
urine 20-50% unchanged, 12-24% as AIC
feces no information found
terminal half life5 5h
9
clearance 15 mL/kg/min
3
Adapted from standard reference unless specified otherwise.

USES:

Primary uses: Other uses:

10
Lymphoma, Hodgkin’s Islet cell carcinoma5
*Melanoma, metastatic malignant Medullary carcinoma of the thyroid5
Sarcoma, soft tissue11-13 Neuroblastoma1
*Health Canada approved indication

BC Cancer Agency Cancer Drug Manual© Page 1 of 7 Dacarbazine

Developed: September 1994
Revised: 1 September 2007, 1 January 2011, 1 June 2013
 Dacarbazine

SPECIAL PRECAUTIONS:
3 14
Contraindicated in patients who have a history of hypersensitivity reaction to dacarbazine or temozolomide.

Caution: Monitor hepatic and renal function during therapy.3

Carcinogenicity: Dacarbazine is carcinogenic in animals.3

15
Mutagenicity: No information found regarding mutagenicity in Ames test and mammalian in vitro mutation test.
Dacarbazine is clastogenic in mammalian in vivo chromosome tests.16
17
Fertility: Does not typically cause more than transient gonadal dysfunction.
5
Pregnancy: FDA Pregnancy Category C. 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.

Breastfeeding is not recommended due to the potential secretion into breast milk.3,5

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.18,19 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%)5

blood/bone marrow/ myelosuppression
febrile neutropenia
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
20
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 reported20
cardiovascular EKG abnormalities
(arrhythmia)
cardiovascular (general) orthostatic hypotension; typically associated with doses >850 mg/m2
constitutional symptoms fatigue
dermatology/skin extravasation hazard: irritant21
alopecia (1-10%)5
erythematous, macular, papular, and/or urticarial rash (1-10%)5
facial flushing (<1%); transient1
phototoxicity22 (1-10%)5; typically occurs hours after treatment and lasts 1-4 days,23
self-limiting and does not require drug discontinuation24
reaction resembling fixed drug eruption
gastrointestinal emetogenic potential: high25

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Developed: September 1994
Revised: 1 September 2007, 1 January 2011, 1 June 2013
 Dacarbazine

ORGAN SITE SIDE EFFECT

Clinically important side effects are in bold, italics

anorexia (>90%); see paragraph following the Side Effects table

diarrhea (<1%); with high-dose,5 typically not severe
nausea and vomiting (>90%); see paragraph following the Side Effects table
stomatitis1,6
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 enzymes1 (<1%)5
neurology confusion
facial paresthesia (<1%)5; transient1
seizures
ocular/visual blurred vision
pain headache (<1%)5
injection site pain; may be minimized by administration via central line or by
infusion of diluted solution1,5
renal/genitourinary renal dysfunction
sexual/reproductive gonadal dysfunction17; transient
function
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
3
Adapted from standard reference 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.3,7 Nausea and vomiting are typically acute in onset, intense and short-lived, persisting for 1-12
3 3
hours. Restriction of food and fluid intake 4-6 h prior to treatment has been recommended. Antiemetic agents are
required for prophylaxis and treatment of N/V. (Refer to SCNAUSEA protocol.) Intractable nausea and vomiting
1,3
requiring drug discontinuation has rarely occurred.

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
1,5 3
Hepatotoxicity may be more common with combination chemotherapy. Monitor hepatic function during therapy.

INTERACTIONS:

AGENT EFFECT MECHANISM MANAGEMENT

3
aldesleukin decreased therapeutic related to aldesleukin usual monitoring;
effect of dacarbazine dose; increased clearance dacarbazine dosage
(~38%) and volume of increase may be required
distribution (~36%) of
dacarbazine

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Developed: September 1994
Revised: 1 September 2007, 1 January 2011, 1 June 2013
 Dacarbazine

AGENT EFFECT MECHANISM MANAGEMENT

26
aldesleukin hypersensitivity reactions unknown usual monitoring
have been reported when
used concurrently
levodopa3,26 reduced response to unknown; unlikely due to usual monitoring; levodopa
levodopa pharmacokinetic changes dosage increase may be
required
Dacarbazine inhibits xanthine oxidase and may theoretically potentiate the activity and toxicity of mercaptopurine
3
and azathioprine.
3
Dacarbazine inhibits xanthine oxidase and may theoretically potentiate the activity, but not the toxicity, of allopurinol.

The principle liver enzyme responsible for dacarbazine metabolism in humans is CYP 1A2, but CYP 2E1 may participate when
CYP 1A2 expression is low. CYP 1A1 is found in extrahepatic tissue and may also contribute to the metabolism of dacarbazine at
4
its site of action. Theoretically, inducers of these enzymes may increase the metabolism of dacarbazine along these pathways,
decreasing dacarbazine serum levels, but increasing the serum levels and effects of its metabolites. Conversely, inhibitors of these
enzymes may decrease the metabolism of dacarbazine along these pathways, increasing serum levels of dacarbazine, but
27
decreasing the serum levels and effects of its metabolites. . Clinical significance of these interactions is unknown. Monitor for
27
therapeutic activity of treatment and presentation of side effects during concurrent therapy.

SUPPLY AND STORAGE:

Injection: Mayne Pharma (Canada) Inc, supplies dacarbazine as 200 mg and 600 mg vials. Store in the refrigerator
and protect from light.3

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
28
harmful degradation products.

PARENTERAL ADMINISTRATION:

BCCA administration guideline noted in bold, italics

Subcutaneous no information found
Intramuscular no information found
Direct intravenous over at least 1 minute1,3 into tubing of running IV; see
Prevention and Management of Extravasation of
Chemotherapy. Intermittent infusion typically less
painful than direct IV.
Intermittent infusion over 1-2 h,10,11,29 over 15-30 minutes has been used1,3
Rapid infusion may cause severe venous irritation.1,5 If
irritation occurs, slow the rate of infusion.
Continuous infusion no information found
Intraperitoneal no information found

BC Cancer Agency Cancer Drug Manual© Page 4 of 7 Dacarbazine

Developed: September 1994
Revised: 1 September 2007, 1 January 2011, 1 June 2013
 Dacarbazine

BCCA administration guideline noted in bold, italics

Intrapleural no information found
Intrathecal investigational; has been used30
Intra-arterial investigational; has been used1,5
Intravesical no information found

DOSAGE GUIDELINES:

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.

Adults:
BCCA usual dose noted in bold, italics
Cycle Length:
Intravenous: 3 weeks5,12,13: 850 mg/m2 IV for one dose on day 1
(total dose per cycle 850 mg/m2)

4 weeks10: 375 mg/m2 IV for one dose on day 1 and 15

2
(total dose per cycle 750 mg/m )

3 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 weeks3,5: 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 weeks5,11,18,29: rarely used in doses exceeding 1.2 g/m2

Intra-arterial: n/a5: 50-400 mg/m2 IV for 5-10 days

(total dose per cycle 250-4000 mg/m2)

Concurrent radiation: no information found

Dosage in myelosuppression: modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix 6 "Dosage Modification for Myelosuppression"

Dosage in renal failure: adjustment required, no details found3,5

Dosage in hepatic failure: adjustment required,3 no details found; alternatively may monitor for toxicity5

Dosage in dialysis: no information found

Children:
Cycle Length:
Intravenous: safety and efficacy have not been established in children3; dacarbazine has been
used in pediatric patients5,31
5,31
4 weeks : 375 mg/m2 IV for one dose on day 1 and 15
2
(total dose per cycle 750 mg/m )

BC Cancer Agency Cancer Drug Manual© Page 5 of 7 Dacarbazine

Developed: September 1994
Revised: 1 September 2007, 1 January 2011, 1 June 2013
 Dacarbazine

5,31,32
3-4 weeks : 200-470 mg/m2 IV once daily for 5 consecutive days starting
on day 1
2
(total dose per cycle 1000-2350 mg/m )
5,31
3-4 weeks : 800-900 mg/m2 IV for one dose on day 1
(total dose per cycle 800-900 mg/m2)

REFERENCES:

1. McEvoy GK, editor. AHFS 2006 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc. p.
1007-1009.
2. DRUGDEX® Evaluations (database on the Internet). Dacarbazine. Thomson MICROMEDEX®, 2007. Available at:
www.micromedex.com. Accessed 26 April 2007.
3. Mayne Pharma (Canada) Inc. DACARBAZINE FOR INJECTION product monograph. Montreal, Quebec; 25 July 2003.
4. Reid JM, Kuffel MJ, Miller JK, et al. Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1,
CYP1A2, and CYP2E1. Clin Cancer Res 1999;5(8):2192-2197.
5. Rose BD editor. Dacarbazine. www.uptodate.com ed. Waltham, Massachusetts: UpToDate 15.1; 2007.
6. USPDI® Drug Information for the Health Care Professional (database on the Internet). Dacarbazine (Systemic). Thompson
MICROMEDEX®, 2007. Available at: www.micromedex.com. Accessed 26 April 2007.
7. Chabner BA, Longo DL. Cancer chemotherapy and biotherapy. 4th ed. Philadelphia, Pennsylvania: Lippincott Williams &
Wilkins; 2006. p. 317-320.
8. Pizzo P, Poplack D. Principles and practice of pediatric oncology. 5th ed. Philadelphia, Pennsylvania: Lippincott Williams &
Wilkins; 2006. p. 316-317.
9. Breithaupt H, Dammann A, Aigner K. Pharmacokinetics of dacarbazine (DTIC) and its metabolite 5-aminoimidazole-4-
carboxamide (AIC) following different dose schedules. Cancer Chemother Pharmacol 1982;9(2):103-109.
10. BC Cancer Agency Lymphoma Tumour Group. (LYABVD) BCCA Protocol Summary for Treatment of Hodgkin's Disease with
Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
11. BC Cancer Agency Sarcoma Tumour Group. (SADTIC) BCCA Protocol Summary for High Dose Single Agent Dacarbazine
(DTIC) for Metastatic Soft Tissue Sarcoma. Vancouver, British Columbia: BC Cancer Agency; 1 April 2000.
12. BC Cancer Agency Sarcoma Tumour Group. (SAAVADIC) BCCA Protocol Summary for ADRIAMYCIN® and DTIC Program
for use in Patients with Soft Tissue Sarcoma. Vancouver, British Columbia: BC Cancer Agency; 1 August 2003.
13. BC Cancer Agency Sarcoma Tumour Group. (SAAJADIC) BCCA Protocol Summary for Doxorubicin (ADRIAMYCIN®) and
Dacarbazine (DTIC) Program for Patients with Soft Tissue Sarcoma. Vancouver, British Columbia: BC Cancer Agency; 1
November 1999.
14. McEvoy GK, editor. AHFS 2006 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.
p. 1192-1193.
15. Chabner BA, Longo DL. Cancer chemotherapy and biotherapy. 4th ed. Philadelphia, Pennsylvania: Lippincott Williams &
Wilkins; 2006. p. 73-75.
16. Miele M, Bonassi S, Bonatti S, et al. Micronucleus analysis in peripheral blood lymphocytes from melanoma patients treated
with dacarbazine. Anticancer Res 1998;18(3B):1967-71.
17. REPROTOX® (database on the Internet). Dacarbazine. Thomson MICROMEDEX®, 2007. Available at:
http://www.micromedex.com/. Accessed May 4, 2007.
18. Kenneth Wilson MD. Personal communication. BCCA Melanoma Tumour Group; 7 June 2007.
19. Meg Knowling MD. Personal communication. BCCA Sarcoma Tumour Group; 19 June 2007.
20. Hospira Healthcare Corporation. Dacarbazine for Injection® product monograph. Saint-Laurent, Quebec; 4 June 2007.
21. BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and
Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 September 2006.
22. Allen JE. Drug-induced photosensitivity. Clinical Pharmacy 1993;12(8):580-587.
23. Serrano G, Aliaga A, Febrer I, et al. Dacarbazine-induced photosensitivity. Photodermatol 1989;6(3):140-141.
24. Yung CW, Winston EM, Lorincz AL. Dacarbazine-induced photosensitivity reaction. J Am Acad Dermatol 1981;4(5):541-543.
25. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting
in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.
26. 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.
27. Basow DS. Lexi-Interact™ Online Dacarbazine. UpToDate 18.1, Available at: www.uptodate.com. Accessed 22 June 2010.
28. 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.
29. 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.
30. Champagne MA, Silver HKB. Intrathecal dacarbazine treatment of leptomeningeal malignant melanoma. J Natl Cancer Inst
1992;84(15):1203-1204.

BC Cancer Agency Cancer Drug Manual© Page 6 of 7 Dacarbazine

Developed: September 1994
Revised: 1 September 2007, 1 January 2011, 1 June 2013
 Dacarbazine

31. Rose BD editor. Dacarbazine: Pediatric drug information. www.uptodate.com ed. Waltham, Massachusetts: UpToDate 15.1;
2007.
32. Pizzo P, Poplack D. Principles and practice of pediatric oncology. 5th ed. Philadelphia, Pennsylvania: Lippincott Williams &
Wilkins; 2006. p. 300.

BC Cancer Agency Cancer Drug Manual© Page 7 of 7 Dacarbazine

Developed: September 1994
Revised: 1 September 2007, 1 January 2011, 1 June 2013