DACARBAZINE: 5,105 Adverse Event Reports & Safety Profile

DESCRIPTION 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: C 6 H 10 N 6 O M.W. 182.19 structural formula

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION Malignant Melanoma The recommended dosage is 2 to 4.5 mg/kg/day for 10 days. Treatment may be repeated at 4 week intervals. 2 An alternate recommended dosage is 250 mg/square meter body surface/day I.V. for 5 days. Treatment may be repeated every 3 weeks. 3,4 Hodgkin's Disease The recommended dosage of Dacarbazine for Injection, USP in the treatment of Hodgkin’s disease is 150 mg/square meter body surface/day for 5 days, in combination with other effective drugs. Treatment may be repeated every 4 weeks. 5 An alternative recommended dosage is 375 mg/square meter body surface on day 1, in combination with other effective drugs, to be repeated every 15 days. 6 Dacarbazine for Injection, USP 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, of Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and administered only intravenously. The reconstituted solution may be further diluted with 5% Dextrose Injection or Sodium Chloride Injection and administered as an intravenous infusion. After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is further diluted in 5% Dextrose Injection or Sodium Chloride Injection, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 7-13 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Malignant Melanoma

The recommended dosage is 2 to 4.5 mg/kg/day for 10 days. Treatment may be repeated at 4 week intervals. 2 An alternate recommended dosage is 250 mg/square meter body surface/day I.V. for 5 days. Treatment may be repeated every 3 weeks. 3,4

Hodgkin's Disease The recommended dosage of Dacarbazine for Injection, USP in the treatment of Hodgkin’s disease is 150 mg/square meter body surface/day for 5 days, in combination with other effective drugs. Treatment may be repeated every 4 weeks. 5 An alternative recommended dosage is 375 mg/square meter body surface on day 1, in combination with other effective drugs, to be repeated every 15 days. 6 Dacarbazine for Injection, USP 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, of Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and administered only intravenously. The reconstituted solution may be further diluted with 5% Dextrose Injection or Sodium Chloride Injection and administered as an intravenous infusion. After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is further diluted in 5% Dextrose Injection or Sodium Chloride Injection, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 7-13 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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

ADVERSE REACTIONS 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 Meitheal Pharmaceuticals, Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

WARNINGS 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 antineoplastic 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.

PRECAUTIONS 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.

Pregnancy Teratogenic

Effects, Pregnancy Category C. Dacarbazine has been shown to be teratogenic in rats when given in doses 20 times the human daily dose on day 12 of gestation. Dacarbazine when administered in 10 times the human daily dose to male rats (twice weekly for 9 weeks) did not affect the male libido, although female rats mated to male rats had higher incidence of resorptions than controls. In rabbits, dacarbazine daily dose 7 times the human daily dose given on Days 6-15 of gestation resulted in fetal skeletal anomalies. There are no adequate and well controlled studies in pregnant women. Dacarbazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for dacarbazine in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pregnancy Teratogenic

Effects, Pregnancy Category C. Dacarbazine has been shown to be teratogenic in rats when given in doses 20 times the human daily dose on day 12 of gestation. Dacarbazine when administered in 10 times the human daily dose to male rats (twice weekly for 9 weeks) did not affect the male libido, although female rats mated to male rats had higher incidence of resorptions than controls. In rabbits, dacarbazine daily dose 7 times the human daily dose given on Days 6-15 of gestation resulted in fetal skeletal anomalies. There are no adequate and well controlled studies in pregnant women. Dacarbazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for dacarbazine in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.