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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(da KAR ba zeen)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Treatment of malignant melanoma, Hodgkin's disease
Use: Unlabeled
Treatment of soft-tissue sarcomas, islet cell tumors, pheochromocytoma, medullary carcinoma of the thyroid
Pregnancy Risk Factor
C
Pregnancy Considerations
[U.S. Boxed Warning]: This agent is carcinogenic and/or teratogenic when used in animals; adverse effects have been observed in animal studies. There are no adequate and well-controlled trials in pregnant women; use in pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.
Contraindications
Hypersensitivity to dacarbazine or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Carcinogenic/teratogenic: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
• Hepatic effects: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Anaphylaxis: May occur following dacarbazine administration.
• Bone marrow suppression: [U.S. Boxed Warning]: Bone marrow suppression is a common toxicity; leukopenia and thrombocytopenia may be severe; may result in treatment delays or discontinuation; monitor closely.
• Carcinogenic/teratogenic: [U.S. Boxed Warning]: May be carcinogenic and/or teratogenic.
• Extravasation: May result in tissue damage and severe pain.
• Hepatic effects: [U.S. Boxed Warning]: Hepatotoxicity with hepatocellular necrosis and hepatic vein thrombosis has been reported (rare), usually with combination chemotherapy, but may occur with dacarbazine alone.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; half-life is increased, monitor for toxicity and consider dosage reduction.
• Renal impairment: Use with caution in patients with renal impairment; half-life is increased, monitor for toxicity and consider dosage reduction.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician. Carefully evaluate the potential benefits of therapy against the risk for toxicity.
Adverse Reactions
Frequency not always defined.
Dermatologic: Alopecia
Gastrointestinal: Nausea and vomiting (>90%), anorexia
Hematologic: Myelosuppression (onset: 5-7 days; nadir: 7-10 days; recovery: 21-28 days), leukopenia, thrombocytopenia
Local: Pain on infusion
Infrequent, postmarketing, and/or case reports: Anaphylactic reactions, anemia, diarrhea, eosinophilia, erythema, facial flushing, facial paresthesia, flu-like syndrome (fever, myalgia, malaise), hepatic necrosis, hepatic vein occlusion, liver enzymes increased (transient), paresthesia, photosensitivity, rash, renal functions test abnormalities, taste alteration, urticaria
Metabolism/Transport Effects
Substrate of CYP1A2 (major), CYP2E1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
CYP2E1 Inhibitors (Moderate): May decrease the metabolism of CYP2E1 Substrates. Risk C: Monitor therapy
CYP2E1 Inhibitors (Strong): May decrease the metabolism of CYP2E1 Substrates. Risk D: Consider therapy modification
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
SORAfenib: May decrease the serum concentration of Dacarbazine. Sorafenib may also increase the concentration of dacarbazine's active metabolite. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI irritation).
Herb/Nutraceutical: Avoid dong quai, St John's wort (may also cause photosensitization).
Storage
Store intact vials under refrigeration (2°C to 8°C). Protect from light. The following stability information has also been reported: Intact vials are stable for 3 months at room temperature (Cohen, 2007). Reconstituted solution is stable for 24 hours at room temperature (20°C) and 96 hours under refrigeration (4°C) when protected from light, although the manufacturer recommends use within 72 hours if refrigerated and 8 hours at room temperature. Solutions for infusion (in D5W or NS) are stable for 24 hours at room temperature if protected from light. Decomposed drug turns pink.
Reconstitution
Use appropriate precautions for handling and disposal. The manufacturer recommends reconstituting 100 mg and 200 mg vials with 9.9 mL and 19.7 mL SWFI, respectively, to a concentration of 10 mg/mL; some institutions use different standard dilutions (eg, 20 mg/mL).
Standard I.V. dilution: Dilute in 250-1000 mL D5W or NS.
Compatibility
Stable in NS, sterile water for injection; variable stability (consult detailed reference) in D5W.
Y-site administration: Compatible: Amifostine, aztreonam, doxorubicin liposomal, etoposide phosphate, filgrastim, fludarabine, granisetron, melphalan, ondansetron, paclitaxel, palonosetron, sargramostim, teniposide, thiotepa, vinorelbine. Incompatible: Allopurinol, cefepime, piperacillin/tazobactam. Variable (consult detailed reference): Heparin.
Mechanism of Action
Alkylating agent which is converted to the active alkylating metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide] via the cytochrome P450 system. The cytotoxic effects of MTIC are manifested through alkylation (methylation) of DNA at the O6, N7 guanine positions which lead to DNA double strand breaks and apoptosis. Non-cell cycle specific.
Pharmacodynamics/Kinetics
Distribution: Vd: 0.6 L/kg, exceeding total body water; suggesting binding to some tissue (probably liver)
Protein binding: ~5%
Metabolism: Extensively hepatic to the active metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide]
Half-life elimination: Biphasic: Initial: 20-40 minutes, Terminal: 5 hours; Patients with renal and hepatic dysfunction: Initial: 55 minutes, Terminal: 7.2 hours
Excretion: Urine (~40% as unchanged drug)
Dosage
Details concerning dosing in combination regimens should also be consulted. I.V.:
Children: Hodgkin's disease (combination chemotherapy): 375 mg/m2/dose days 1 and 15 every 4 weeks (ABVD regimen; Hutchinson, 1998)
Adults:
Hodgkin's disease (combination chemotherapy): 375 mg/m2/dose days 1 and 15 every 4 weeks (ABVD regimen)
Metastatic melanoma: 250 mg/m2/dose days 1-5 every 3 weeks
Metastatic melanoma (unlabeled dosing; in combination with cisplatin and vinblastine): 800 mg/m2 on day 1 every 3 weeks (Atkins, 2008; Eton, 2002)
Soft tissue sarcoma (unlabeled use; MAID regimen): 250 mg/m2/day continuous infusion for 4 days every 3 weeks (total of 1000 mg/m2/cycle) (Antman, 1993; Antman, 1998)
Dosage adjustment in renal impairment: The FDA-approved labeling does not contain dosage adjustment guidelines. The following guidelines have been used by some clinicians (Kintzel, 1995):
Clcr 46-60 mL/minute: Administer 80% of dose
Clcr 31-45 mL/minute: Administer 75% of dose
Clcr <30 mL/minute: Administer 70% of dose
Dosage adjustment in hepatic impairment: The FDA-approved labeling does not contain adjustment guidelines. May cause hepatotoxicity; monitor closely for signs of toxicity.
Dosage: Combination Regimens
Lymphoma, Hodgkin:
ABVD Early Stage (Hodgkin)
ABVD (Hodgkin)
MOPP/ABVD (Hodgkin)
Melanoma:
BOLD
BOLD + Interferon
BOLD (Melanoma)
Cisplatin-Dacarbazine-Interferon Alfa-2b-Aldesleukin
Cisplatin-Vinblastine-Dacarbazine (Melanoma)
CVD-Interleukin-Interferon (Melanoma)
Dartmouth Regimen
Sarcoma:
CYVADIC
MAID (Sarcoma)
Sarcoma, soft tissue: AD (Soft Tissue Sarcoma)
Administration: I.V.
Irritant. Infuse over 30-60 minutes; may also be administered as a continuous infusion (unlabeled administration rate) depending on the protocol
Administration: I.V. Detail
Rapid infusion may cause severe venous irritation.
Extravasation management: Local pain, burning sensation, and irritation at the injection site may be relieved by local application of hot packs. If extravasation occurs, apply cold packs. Protect exposed tissue from light following extravasation.
pH: 3-4
Monitoring Parameters
CBC with differential, liver function
Patient Education
This drug can only be given by infusion. Report immediately any pain, burning, or swelling at infusion site; chest pain; or difficulty breathing or swallowing. Limit oral intake for 4-6 hours before infusion. Maintain adequate nutrition and hydration, unless instructed to restrict fluid intake. You will be more susceptible to infection. May cause nausea, vomiting, loss of appetite, hair loss (reversible), headache, fever, sinus congestion, or muscle aches. Report immediately any numbness in extremities or change in gait, respiratory distress or respiratory difficulty, change in urinary pattern, rash, easy bruising or bleeding, yellowing of eyes or skin, change in color of urine, or blackened stool.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Metallic taste.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause headache
Mental Health: Effects on Psychiatric Treatment
May cause myelosuppression; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
To be administered under the supervision of an experienced cancer chemotherapy physician. Use with caution and monitor for toxicity in presence of renal and/or hepatic impairment. Premedicate with antiemetic (emetic potential is moderately high). Patient must be monitored closely for anaphylactic reaction; emergency treatment should be available. Infusion site must be closely monitored; extravasation can cause severe cellulitis or tissue necrosis. Assess results of CBC with differential and LFTs prior to each treatment and throughout therapy.
Oncology: Emetic Potential
High (>90%)
Oncology: Vesicant
May be an irritant
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution: 100 mg, 200 mg
References
Antman K, Crowley J, Balcerzak SP, et al, “An Intergroup Phase III Randomized Study of Doxorubicin and Dacarbazine With or Without Ifosfamide and Mesna in Advanced Soft Tissue and Bone Sarcomas,” J Clin Oncol, 1993, 11(7):1276-85.
Antman K, Crowley J, Balcerzak SP, et al, “A Southwest Oncology Group and Cancer and Leukemia Group B phase II Study of Doxorubicin, Dacarbazine, Ifosfamide, and Mesna in Adults With Advanced Osteosarcoma, Ewing's Sarcoma, and Rhabdomyosarcoma,” Cancer, 1998, 82(7):1288-95.
Atkins MB, Hsu J, Lee S, et al, “Phase III Trial Comparing Concurrent Biochemotherapy With Cisplatin, Vinblastine, Dacarbazine, Interleukin-2, and Interferon Alfa-2b With Cisplatin, Vinblastine, and Dacarbazine Alone in Patients With Metastatic Malignant Melanoma (E3695): A Trial Coordinated by the Eastern Cooperative Oncology Group,” J Clin Oncol, 2008, 26(35):5748-54.
Bonfante V, Santoro A, Viviani S, et al, “ABVD in the Treatment of Hodgkin's Disease,” Semin Oncol, 1992, 19(2 Suppl 5):38-44.
Buesa JM and Urrechaga E, “Clinical Pharmacokinetics of High-Dose DTIC,” Cancer Chemother Pharmacol, 1991, 28(6):475-9.
Cohen V, Jellinek SP, Teperikidis L, et al, “Room-Temperature Storage of Medications Labeled for Refrigeration,” Am J Health-Syst Pharm, 2007, 64(16):1711-15.
Engert A, Franklin J, Eich HT, et al, “Two Cycles of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine Plus Extended-Field Radiotherapy is Superior to Radiotherapy Alone in Early Favorable Hodgkin's Lymphoma: Final Results of the GHSG HD7 Trial,” J Clin Oncol, 2007, 25(23):3495-502.
Eton O, Legha SS, Bedikian AY, et al, “Sequential Biochemotherapy Versus Chemotherapy for Metastatic Melanoma: Results From a Phase III Randomized Trial,” J Clin Oncol, 2002, 20(8):2045-52.
Hutchinson RJ, Fryer CJ, Davis PC, et al, “MOPP or Radiation in Addition to ABVD in the Treatment of Pathologically Staged Advanced Hodgkin's Disease in Children: Results of the Children's Cancer Group Phase III Trial,” J Clin Oncol, 1998, 16(3):897-906.
Kintzel PE and Dorr RT, "Anticancer Drug Renal Toxicity and Elimination: Dosing Guidelines for Altered Renal Function," Cancer Treat Rev, 1995, 21(1):33-64.
Meyer RM, Gospodarowicz MK, Connors JM, et al, “Randomized Comparison of ABVD Chemotherapy With a Strategy That Includes Radiation Therapy in Patients With Limited-Stage Hodgkin's Lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group,” J Clin Oncol, 2005, 23(21):4634-42.
Middleton MR, Grob JJ, Aaronson N, et al, “Randomized Phase III Study of Temozolomide Versus Dacarbazine in the Treatment of Patients With Advanced Metastatic Malignant Melanoma,” J Clin Oncol, 2000, 18(1):158-66.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Hodgkin Disease/Lymphoma,” Version 1.2010. Available at http://www.nccn.org/professionals/physician_gls/PDF/hodgkins.pdf
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Melanoma,” Version 2.2010. Available at http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf
National Comprehensive Cancer Network® (NCCN) “Practice Guidelines in Oncology™: Neuroendocrine Tumors,” Version 2.2009. Available at http://www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Soft Tissue Sarcoma,” Version 3.2010. Available at http://www.nccn.org/professionals/physician_gls/PDF/sarcoma.pdf
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Thyroid Carcinoma,” Version 1.2010. Available at http://www.nccn.org/professionals/physician_gls/PDF/thyroid.pdf
Nocera M, Baudin E, Pellegriti G, et al, “Treatment of Advanced Medullary Thyroid Cancer With an Alternating Combination of Doxorubicin-Streptozocin and 5 FU-Dacarbazine, Groupe d'Etude des Tumeurs à Calcitonine (GETC),” Br J Cancer, 2000, 83(6):715-8.
Ramanathan RK, Cnaan A, Hahn RG, et al, “Phase II Trial of Dacarbazine (DTIC) in Advanced Pancreatic Islet Cell Carcinoma, Study of the Eastern Cooperative Oncology Group-E6282,” Ann Oncol, 2001, 12(8):1139-43.
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(7):2083-90.
Straus DJ, Portlock CS, Qin J, et al, “Results of a Prospective Randomized Clinical Trial of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD) Followed by Radiation Therapy (RT) Versus ABVD Alone for Stages I, II, and IIIA Nonbulky Hodgkin Disease,” Blood, 2004, 104(12):3483-9.
International Brand Names
Lexi-Comp.com
Last full review/revision February 2012
Content last modified February 2012
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