DACARBAZINE
DESCRIPTION:
WARNING
It is recommended that Dacarzine
(dacarbazine) 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 Dacarzine (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.
Dacarzine Sterile (dacarbazine) is a colorless to an ivory colored solid which
is light sensitive. Each vial contains 100 mg of dacarbazine, or 200 mg of
dacarbazine (the active ingredient), anhydrous citric acid and mannitol. DTIC-
Dome is reconstituted and administered intravenously (pH 3-4). Dacarzine is an
anticancer agent. Chemically, Dacarzine is 5-(3,3-dimethyl-el- triazeno)-
imidazole-4-carboxamide (DTIC).
ACTIONS/CLINICAL PHARMACOLOGY:
After intravenous administration of Dacarzine, 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. (REF. 1) In a
patient with renal and hepatic dysfunctions, the half-lives were lengthened to
55 minutes and 7.2 hours. (REF. 1) The average cumulative excretion of unchanged
DTIC in the urine is 40% of the injected dose in 6 hours. (REF. 1) DTIC is
subject to renal tubular secretion rather than glomerular filtration. At
therapeutic concentrations DTIC is not appreciably bound to human plasma
protein.
In man, DTIC is extensively degraded. Besides unchanged DTIC, 5-aminoimidazole -
4 carboxamide (AIC) is a major metabolite of DTIC excreted in the urine. AIC is
not derived endogenously but from the injected DTIC, because the administration
of radioactive DTIC labeled with 14C in the imidazole portion of the molecule
(DTIC-2-14C) gives rise to AIC-2-14C. (REF. 1)
Although the exact mechanism of action of Dacarzine 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
INDICATIONS AND USAGE:
Dacarzine is indicated in the treatment of metastatic malignant melanoma. In
addition, Dacarzine is also indicated for Hodgkin's disease as a secondary-line
therapy when used in combination with other effective agents.
CONTRAINDICATIONS:
Dacarzine is contraindicated in patients who have demonstrated a
hypersensitivity to it in the past.
WARNINGS:
It is recommended that Dacarzine
(dacarbazine) 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 Dacarzine (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.
Hemopoietic depression is the most common toxicity with Dacarzine 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 Dacarzine.
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 Dacarzine has been administered concomitantly with other
anti- neoplastic drugs; however, it has also been reported in some patients
treated with Dacarzine alone.
Anaphylaxis can occur following the administration of Dacarzine.
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 DTIC was studied in rats and mice. Proliferative endocardial
lesions, including fibrosarcomas and sarcomas were induced by DTIC in rats. In
mice, administration of DTIC resulted in the induction of angiosarcomas of the
spleen.
PREGNANCY CATEGORY C. Dacarzine has been shown to be teratogenic in rats when
given in doses 20 times the human daily dose on day 12 of gestation. DTIC 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, DTIC 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. Dacarzine 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 Dacarzine 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.
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 1-12 hours and is incompletely and unpredictably palliated
with phenobarbital and/or prochlorperazine. Rarely, intractable nausea and
vomiting have necessitated discontinuance of therapy with Dacarzine. Rarely,
Dacarzine has caused diarrhea. Some helpful suggestions include restricting the
patient's oral intake of food for 4-6 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 deg 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 Dacarzine. Rarely, photosensitivity reactions may occur.
OVERDOSAGE:
Give supportive treatment and monitor blood cell counts.
DOSAGE AND ADMINISTRATION:
MALIGNANT MELANOMA: The recommended dosage is 2 to 4.5mg/kg/day for 10 days.
Treatment may be repeated at 4 week intervals. (REF. 2)
An alternate recommended dosage is 250mg/square meter body surface/day I.V. for
5 days. Treatment may be repeated every 3 weeks. (REF. 3,4)
HODGKIN'S DISEASE: The recommended dosage of Dacarzine in the treatment of
Hodgkin's Disease is 150mg/square meter body surface/day for 5 days, in
combination with other effective drugs. Treatment may be repeated every 4 weeks.
(REF. 5) An alternative recommended dosage is 375mg/square meter body surface on
day 1, in combination with other effective drugs, to be repeated every 15 days.
(REF. 6)
Dacarzine (dacarbazine) 100mg/vial and 200mg/vial are reconstituted with 9.9 mL
and 19.7 mL, respectively, of Sterile Water for Injection, U.S.P. The resulting
solution contains 10mg/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,
U.S.P. or sodium chloride injection, U.S.P. and administered as an intravenous
infusion.
After reconstitution and prior to use, the solution in the vial may be stored at
4 deg 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, U.S.P. or sodium chloride injection, U.S.P., the resulting
solution may be stored at 4 deg 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. (REF. 7-12)
There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate.
REFERENCES:
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-el-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, D.C. 20402.
8. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA,
March 15, 1985.
9. National Study Commission on Cytotoxic Exposure--Recommendations for Handling
Cytotoxic Agents. Available from Louis P. Jeffrey, Sc. D., Director of Pharmacy
Services, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island
02902.
10. Clinical Oncological Society of Australia: Guidelines and recommendations
for safe handling of antineoplastic agents. Med. J. Australia 1: 426-428, 1983.
11. Jones, R.B., Et Al.: Safe handling of chemotherapeutic agents: A report from
the Mount Sinai Medical Center. Ca-A Cancer Journal for Clinicians Sept./Oct.
258-263, 1983.
12. American Society of Hospital Pharmacists technical assistance bulletin on
handling cytotoxic drugs in hospitals. Am. J. Hosp. Pharm. 42: 131-137, 1985.
************************************************************************