DTIC-Dome

Generic Name: Dacarbazine
Class: Antineoplastic Agents
VA Class: AN300
CAS Number: 4342-03-4

Warning(s)

  • Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.100 Carefully weigh risks/benefits of therapy in each patient.100

  • Myelosuppression occurs commonly.100 (See Hematologic Effects under Cautions.)

  • Hepatic necrosis reported.100 (See Hepatic Effects under Cautions.)

  • Known carcinogen and teratogen in animals.100 (See Carcinogenicity and also Fetal/Neonatal Morbidity and Mortality, under Cautions.)

Introduction

Antimetabolite antineoplastic agent; a purine analog.100

Uses for DTIC-Dome

Melanoma

A systemic treatment of choice for the palliative treatment of metastatic melanoma.100 101 105 106 107 108 111 135 138 Has been used alone and in combination regimens.105 106 107 108 111 135 Optimal regimen remains to be established.105 107 138

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Hodgkin’s Disease

Treatment of advanced Hodgkin’s disease in combination with other antineoplastic agents.100 101 102 103 104 Often used with doxorubicin, bleomycin, and vinblastine (ABVD regimen).101 102 103 104

DTIC-Dome Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.100

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer only by IV injection or infusion.100 b Extremely irritating to tissues; avoid extravasation.100 (See Local Effects under Cautions.)

Reconstitution

Reconstitute vial containing 100 or 200 mg of dacarbazine powder with 9.9 or 19.7 mL, respectively, of sterile water for injection to provide a solution containing 10 mg/mL.100 c d

Dilution

Reconstituted solution may be further diluted with 5% dextrose or 0.9% sodium chloride injection and infused IV.100 c d

Rate of Administration

IV injection: Administer over 1 minute.100 b

IV infusion: Infuse diluted solution over 15–30 minutes.100 b

Dosage

Optimize results and minimize adverse effects by basing dose on clinical and hematologic response, patient tolerance, and other chemotherapy or irradiation being used.100 b

Consult published protocols for dosages in combination regimens and method and sequence of administration.b

Adults

Melanoma
Metastatic Melanoma
IV

2–4.5 mg/kg daily for 10 days; may repeat at 4-week intervals.100

Alternatively, 250 mg/m2 daily for 5 days; may repeat at 3-week intervals.100

Hodgkin’s Disease
IV

150 mg/m2 daily for 5 days in combination with other antineoplastic agents; may repeat every 4 weeks.100

Alternatively, 375 mg/m2 on day 1, in combination with other antineoplastic agents; repeat every 15 days.100

Cautions for DTIC-Dome

Contraindications

  • Hypersensitivity to dacarbazine or any ingredient in the formulation.100

Warnings/Precautions

Warnings

Administer only under supervision of a qualified clinician experienced in therapy with antineoplastic agents.100 (See Boxed Warning.)

Hematologic Effects

Myelosuppression (principally severe leukopenia and thrombocytopenia) occurs commonly, generally 2–4 weeks after the last dose;100 b fatal leukopenia and thrombocytopenia reported.100 Anemia can occur.100 b

Carefully monitor hematologic status during therapy; evaluate leukocyte, erythrocyte, and platelet counts at frequent intervals.100

Hematopoietic toxicity (generally leukocyte count <3000/mm3 and platelet count <100,000/mm3) may require temporary withdrawal or discontinuance of the drug.100 b

Hepatic Effects

Hepatotoxicity complicated by hepatic vein thrombosis and hepatocellular necrosis resulting in death has been reported.100 More common with combination regimens but also occurs with dacarbazine alone.100

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.100

Sensitivity Reactions

Hypersensitivity Reactions

Possible hypersensitivity reactions, including anaphylaxis.100

Photosensitivity

Photosensitivity reactions reported rarely.100

General Precautions

Carcinogenicity

Carcinogenic effects reported in animals; importance in humans not known.100 b

Local Effects

Extravasation may result in tissue damage and severe pain.100

Undiluted solutions administered by IV injection may cause severe pain and phlebitis; some clinicians recommend dilution and infusion.b

Hot packs may relieve local pain, burning sensation, and irritation at the injection site.100

Specific Populations

Pregnancy

Category C.100

Lactation

Not known whether dacarbazine is distributed into milk; discontinue nursing or the drug.100

Common Adverse Effects

Anorexia, nausea, vomiting, leukopenia, thrombocytopenia.100

Interactions for DTIC-Dome

Metabolized by hepatic microsomal enzymes.b

Drugs Affecting Hepatic Microsomal Enzymes

Enzyme inducers: Possible increased metabolism of dacarbazine.b

Specific Drugs

Drug

Interaction

Phenobarbital

Possible increased dacarbazine metabolismb

Phenytoin

Possible increased dacarbazine metabolismb

DTIC-Dome Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed from the GI tract.b

Distribution

Extent

Volume of distribution exceeds total body water content, suggesting localization in a body tissue, probably the liver.100

Crosses blood-brain barrier to a limited extent; CSF concentrations approximately 14% of plasma concentrations.100

Not known whether dacarbazine crosses the placenta or is distributed into milk.100

Plasma Protein Binding

Slightly bound.100

Elimination

Metabolism

Extensively metabolized; hepatic microsomal enzymes are involved.100 b Some metabolites may contribute to the antineoplastic effect of the drug.b

Elimination Route

Excreted in urine by tubular secretion; about 46% of an administered dose is excreted in urine within 6 hours (about 50% as unchanged drug and 50% as 5-amino-1H-imidazole-4-carboxamide [AIC]). (See Actions.)100 b

Half-life

Biphasic; initial-phase half-life averages 19 minutes; terminal half-life averages 5 hours.100

Stability

Storage

Parenteral

Powder for Injection

2–8°C; protect from light.100

Use reconstituted solutions containing 10 mg/mL in sterile water for injection within 8 hours if stored at room temperature or 72 hours if stored at 4°C.100 d

Use solutions further diluted with ≤500 mL of 5% dextrose or 0.9% sodium chloride injection within 8 hours if stored at room temperature or 24 hours if stored at 4°C.100 b d

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Variable

Dextrose 5% in waterHID

Sodium chloride 0.9%b

Drug Compatibility
Admixture CompatibilityHID

Compatible

Ondansetron HCl

Variable

Ondansetron HCl with doxorubicin HCl

Incompatible

Hydrocortisone sodium succinateb

Y-Site CompatibilityHID

Compatible

Amifostine

Aztreonam

Doxorubicin HCl liposome injection

Etoposide phosphate

Filgrastim

Fludarabine phosphate

Granisetron HCl

Melphalan HCl

Ondansetron HCl

Paclitaxel

Palonosetron HCl

Sargramostim

Teniposide

Thiotepa

Vinorelbine tartrate

Incompatible

Allopurinol sodium

Hydrocortisone sodium succinate

Piperacillin sodium–tazobactam sodium

Variable

Heparin sodium

Actions

  • Appears to exert cytotoxic effect by acting as an alkylating agent.100

  • Does not exhibit cell cycle-phase specificity.b

  • Synthetic analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC).100

Advice to Patients

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.100

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Dacarbazine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use

100 mg*

Dacarbazine for Injection

200 mg*

Dacarbazine for Injection

DTIC-Dome

Bayer

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 20, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Bayer Corporation. DTIC-Dome (dacarbazine) prescribing information. West Haven, CT; 1998 Sep.

101. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]

102. Urba WJ, Longo DL. Hodgkin’s disease. N Engl J Med. 1992; 326:678-687. [IDIS 292239] [PubMed 1736106]

103. DeVita VT Jr, Hubbard SM. Hodgkin’s disease. N Engl J Med. 1993; 328:560-5. [IDIS 309839] [PubMed 8426624]

104. Adult Hodgkin’s disease. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Sep.

105. Melanoma. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jun.

106. Duran Garcia E, Santolaya R, Requena T. Treatment of malignant melanoma. Ann Pharmacother. 1999; 33:730-8. [IDIS 428254] [PubMed 10410188]

107. Cohen GL, Falkson CI. Current treatment options for malignant melanoma. Drugs. 1998; 55:791-9. [PubMed 9617594]

108. Houghton A, Coit D, Bloomer W et al. NCCN melanoma practice guidelines. National Comprehensive Cancer Network. Oncology (Huntingt). 1998; 12:153-77.

109. Agarwala SS, Ferri W, Gooding W et al. A phase III randomized trial of dacarbazine and carboplatin with and without tamoxifen in the treatment of patients with metastatic melanoma. Cancer. 1999; 85:1979-84. [IDIS 427693] [PubMed 10223239]

110. Rosenberg SA, Yang JC, Schwartzentruber DJ et al. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol. 1999; 17:968-75. [IDIS 425420] [PubMed 10071291]

111. Falkson CI, Ibrahim J, Kirkwood JM et al. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1998; 16:1743-51. [IDIS 406115] [PubMed 9586887]

112. Jungnelius U, Ringborg U, Aamdal S et al. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma. A randomised phase III trial. Eur J Cancer. 1998; 34:1368-74. [PubMed 9849419]

113. Johnston SR, Constenla DO, Moore J et al. Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma. Br J Cancer. 1998; 77:1280-6. [PubMed 9579834]

114. Legha SS, Ring S, Bedikian A et al. Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha. Ann Oncol. 1996; 7:827-35. [PubMed 8922197]

115. Rusthoven JJ, Quirt IC, Iscoe NA et al. Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1996; 14:2083-90. [IDIS 370184] [PubMed 8683240]

116. Cocconi G, Bella M, Calabresi F et al. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992; 327:516-23. [IDIS 300796] [PubMed 1635566]

117. Guerry IV D, Schuchter LM. Disseminated melanoma—is there a new standard therapy? N Engl J Med. 1992; 327:560-1. Editorial.

118. Margolin KA, Liu PY, Flaherty LE et al. Phase II study of carmustine, dacarbazine, cisplatin, and tamoxifen in advanced melanoma: a Southwest Oncology Group study. J Clin Oncol. 1998; 16:664-9. [IDIS 401191] [PubMed 9469356]

119. Balch CM, Buzaid AC. Finally, a successful adjuvant therapy for high-risk melanoma. J Clin Oncol. 1996; 14:1-3. [IDIS 358662] [PubMed 8558183]

120. Cole BF, Gelber RD, Kirkwood JM et al. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1996; 14:2666-73. [IDIS 373949] [PubMed 8874325]

121. Haluska FG. Adjuvant interferon for stage II melanoma. J Clin Oncol. 1998; 16:3205-6. [IDIS 414262] [PubMed 9738597]

122. Kirkwood JM. Adjuvant IFNα2 therapy of melanoma. Lancet. 1998; 351:1901-3. [IDIS 408457] [PubMed 9654253]

123. Ascierto PA, Palmieri G. Adjuvant therapy of cutaneous melanoma. Lancet. 1999; 353:328. [PubMed 9929057]

124. Kirkwood JM, Ibrahim J, Sondak V et al. Preliminary analysis of the E1690/S9111/C9190 Intergroup postoperative adjuvant trial of high- and low-dose IFNa2b (HDI and LDI) in high-risk primary or lymph node metastatic melanoma. Proc Am Soc Clin Oncol. 1999; 18:A2072.

125. Bajetta E, Di Leo A, Zampino MG et al. Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. J Clin Oncol. 1994; 12:806-11. [IDIS 328755] [PubMed 8151323]

126. Thomson DB, Adena M, McLeod GR et al. Interferon-alpha 2a does not improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian randomized trial. Melanoma Res. 1993; 3:133-8. [PubMed 8518552]

127. Falkson CI, Falkson G, Falkson HC Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma. J Clin Oncol. 1991; 9:1403-8.

128. Koops HS, Vaglini M, Suciu S et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol. 1998; 16:2906-12. [IDIS 414236] [PubMed 9738557]

129. Tan JK, Ho VC. Pooled analysis of the efficacy of bacille Calmette-Guerin (BCG) immunotherapy in malignant melanoma. J Dermatol Surg Oncol. 1993; 19:985-90. [PubMed 8245304]

130. Wallack MK, Sivanandham M, Balch CM et al. Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J Am Coll Surg. 1998; 187:69-79. [IDIS 409461] [PubMed 9660028]

131. Hafstrom L, Rudenstam CM, Blomquist E et al. Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities. Swedish Melanoma Study Group. J Clin Oncol. 1991; 9:2091-4. [PubMed 1960549]

132. Quirt IC, Shelley WE, Pater JL et al. Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1991; 9:729-35. [PubMed 2016615]

133. Spitler LE. A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma. J Clin Oncol. 1991; 9:736-40. [PubMed 2016616]

134. Creagan ET, Suman VJ, Dalton RJ et al. Phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma. J Clin Oncol. 1999; 17:1884-90. [IDIS 429715] [PubMed 10561229]

135. Chapman PB, Einhorn LH, Meyers ML et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999; 17:2745-51. [IDIS 435276] [PubMed 10561349]

136. Legha SS, Ring S, Eton O et al. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol. 1998; 16:1752-9. [IDIS 406116] [PubMed 9586888]

137. Atkins MB, Flaherty LE, Sosman JA, principal investigators. Phase III study of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (summary last modified 10/1999). Protocol ID: E-E3695. From CancerNet: PDQ Clinical Trials (database). Bethesda, MD: National Cancer Institute; accessed 1999 Nov 29.

138. Reviewers’ comments (personal observations) on melanoma.

139. Kirkwood JM, Strawderman MH, Ernstoff MS et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996; 14:7-17. [IDIS 358664] [PubMed 8558223]

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:327-9.

b. AHFS Drug Information 2004. McEvoy GK, ed. Dacarbazine. American Society of Health-System Pharmacists; 2004: 956-8.

c. Bayer Corporation. DTIC-Dome (dacarbazine) prescribing information. West Haven, CT; 2003 May.

d. American Pharmaceutical Partners. Dacarbazine (for injection) prescribing information. Schaumburg, Illinois; 2002 April.

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