Dacarbazine for Injection, USP

It is recommended that dacarbazine for injection be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.

1. Hemopoietic depression is the most common toxicity with dacarbazine for injection. (See WARNINGS.)
2. Hepatic necrosis has been reported. (See WARNINGS.)
3. Studies have demonstrated this agent to have a carcinogenic and teratogenic effect when used in animals.
4. In treatment of each patient, the physician must weigh carefully the possibility of achieving therapeutic benefit against the risk of toxicity.

Dacarbazine for Injection, USP is a white to an ivory colored solid which is light sensitive. Each 20 mL vial contains 200 mg of dacarbazine, USP (active ingredient). Each vial also contains anhydrous citric acid and mannitol. Dacarbazine for Injection, USP is reconstituted and administered intravenously (pH 3.0 to 4.0). Dacarbazine for Injection, USP is an anticancer agent. Chemically, Dacarbazine for Injection, USP is 5-(3,3-Dimethyl-1-triazeno) imidazole-4-carboxamide (dacarbazine) with the following structural formula:

C₆H₁₀N₆O M.W. 182.19

After intravenous administration of dacarbazine for injection, 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 dacarbazine in the urine is 40% of the injected dose in 6 hours.¹

Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein.

In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine. AIC is not derived endogenously but from the injected dacarbazine, because the administration of radioactive dacarbazine labeled with ¹⁴C in the imidazole portion of the molecule (dacarbazine-2-¹⁴C) gives rise to AIC-2-¹⁴C.¹

Although the exact mechanism of action of dacarbazine for injection is not known, three hypotheses have been offered:

1. Inhibition of DNA synthesis by acting as a purine analog
2. Action as an alkylating agent
3. Interaction with SH groups

Dacarbazine for injection is indicated in the treatment of metastatic malignant melanoma. In addition, Dacarbazine for injection is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other effective agents.

Dacarbazine for injection is contraindicated in patients who have demonstrated a hypersensitivity to it in the past.

Hemopoietic depression is the most common toxicity with dacarbazine for injection and involves primarily the leukocytes and platelets, although anemia may sometimes occur. Leukopenia and thrombocytopenia may be severe enough to cause death. The possible bone marrow depression requires careful monitoring of white blood cells, red blood cells, and platelet levels. Hemopoietic toxicity may warrant temporary suspension or cessation of therapy with dacarbazine for injection.

Hepatic toxicity accompanied by hepatic vein thrombosis and hepatocellular necrosis resulting in death, has been reported. The incidence of such reactions has been low; approximately 0.01% of patients treated. This toxicity has been observed mostly when dacarbazine for injection has been administered concomitantly with other anti-neoplastic drugs; however, it has also been reported in some patients treated with dacarbazine for injection alone.

Anaphylaxis can occur following the administration of dacarbazine for injection.

Hospitalization is not always necessary but adequate laboratory study capability must be available. Extravasation of the drug subcutaneously during intravenous administration may result in tissue damage and severe pain. Local pain, burning sensation, and irritation at the site of injection may be relieved by locally applied hot packs.

Carcinogenicity of dacarbazine was studied in rats and mice. Proliferative endocardial lesions, including fibrosarcomas and sarcomas were induced by dacarbazine in rats. In mice, administration of dacarbazine resulted in the induction of angiosarcomas of the spleen.

Symptoms of anorexia, nausea, and vomiting are the most frequently noted of all toxic reactions. Over 90% of patients are affected with the initial few doses. The vomiting lasts 1 to 12 hours and is incompletely and unpredictably palliated with phenobarbital and/or prochlorperazine. Rarely, intractable nausea and vomiting have necessitated discontinuance of therapy with dacarbazine for injection. Rarely, dacarbazine for injection has caused diarrhea. Some helpful suggestions include restricting the patient's oral intake of food for 4 to 6 hours prior to treatment. The rapid toleration of these symptoms suggests that a central nervous system mechanism may be involved, and usually these symptoms subside after the first 1 or 2 days.

There are a number of minor toxicities that are infrequently noted. Patients have experienced an influenza-like syndrome of fever to 39°C, myalgias and malaise. These symptoms occur usually after large single doses, may last for several days, and they may occur with successive treatments.

Alopecia has been noted as has facial flushing and facial paresthesia. There have been few reports of significant liver or renal function test abnormalities in man. However, these abnormalities have been observed more frequently in animal studies.

Erythematous and urticarial rashes have been observed infrequently after administration of dacarbazine for injection. Rarely, photosensitivity reactions may occur.

To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Give supportive treatment and monitor blood cell counts.

Sterile Dacarbazine for Injection, USP is available as follows:

1. Loo, T.J., et al.: Mechanism of action and pharmacology studies with DTIC (NSC-45388). Cancer Treatment Reports 60: 149–152, 1976.
2. Nathanson, L., et al.: Characteristics of prognosis and response to an imidazole carboxamide in malignant melanoma. Clinical Pharmacology and Therapeutics 12: 955–962, 1971.
3. Costanza, M.E., et al.: Therapy of malignant melanoma with an imidazole carboxamide and bischloroethyl nitrosourea. Cancer 30: 1457–1461, 1972.
4. Luce, J.K., et al.: Clinical trials with the antitumor agent 5-(3, 3-dimethyl-1-triazeno) imidazole-4-carboxamide (NSC-45388). Cancer Chemotherapy Reports 54: 119–124, 1970.
5. Bonadonna, G., et al.: Combined Chemotherapy (MOPP or ABVD)—radiotherapy approach in advanced Hodgkin's disease. Cancer Treatment Reports 61: 769–777, 1977.
6. Santoro, A., and Bonadonna, G.: Prolonged disease-free survival in MOPP-resistant Hodgkin's disease after treatment with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD).
   Cancer Chemotherapy Pharmacol. 2: 101–105, 1979.
7. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.
8. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA, 1985; 253 (11):1590–1592.
9. National Study Commission on Cytotoxic Exposure—Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
10. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med. J. Australia, 1983; 1:426–428.
11. Jones, RB, et al.: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA—A Cancer Journal for Clinicians, 1983; (Sept/Oct) 258–263.
12. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am. J. Hosp. Pharm, 1990; 47: 1033–1049.
13. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am. J. Hosp. Pharm, 1986; 43:1193–1204.

Distributed by:
Teva Pharmaceuticals USA, Inc.
Parsippany, NJ 07054

Rev. B 2/2020

NDC 0703-5075-01

Rx only

Dacarbazine for Injection, USP

200 mg

Prepared as the citrate salt

For Intravenous Use Only

Single-Dose Vial

Discard Unused Portion.

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