DTlC-Dome 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. DTlC-Dome is reconstituted and administered intravenously (pH 3–4). DTlC-Dome is an anticancer agent. Chemically, DTlC-Dome is 5-(3, 3-dimethyl-l-triazeno)-imidazole-4-carboxamide (DTlC) with the following structural formula:

Last updated on RxList: 11/5/2008

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

MaIignant Melanoma: The recommended dosage is 2 to 4.5mg/kg/day for 10 days. Treatment may be repeated at 4 week intervals.²

An alternate recommended dosage is 250mg/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 DTIC-Dome 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.⁵ An alternative recommended dosage is 375mg/square meterbody surface on day 1, in combination with other effective drugs, to be repeated every 15 days.⁶

DTlC-Dome (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°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°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.^7-12 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

20 mL vials containing 200 mg of DTlC-Dome as sterile dacarbazine in boxes of 12. Store in a refrigerator 2°C to 8°C (36°F to 46°F).

REFERENCES

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-l-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.

Manufactured by: Ben Venue Laboratories, Bedford, Ohio 44146. Distributed by: Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven, CT 06516 USA. FDA Rev date: 9/24/1998

Last updated on RxList: 11/5/2008

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 DTlC-Dome. Rarely, DTlC-Dome 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°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 DTIC-Dome. Rarely, photosensitivity reactions may occur.

No information provided.

Last updated on RxList: 11/5/2008

Hemopoietic depression is the most common toxicity with DTlC-Dome 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 DTlC-Dome.

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 DTIC-Dome has been administered concomitantly with other anti-neoplastic drugs; however, it has also been reported in some patients treated with DTlC-Dome alone.

Anaphylaxis can occur following the administration of DTlC-Dome.

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 injectlon may be relieved by locally applied hot packs.

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

Pregnancy Category C. DTIC-Dome has been shown to be teratogenic in rats when given in doses 20 times the human daily dose on day 12 of gestation. DTlC 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, DTlC 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. DTlC-Dome 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 DTIC-Dome 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.

Last updated on RxList: 11/5/2008

Give supportive treatment and monitor blood cell counts.

DTlC-Dome is contraindicated in patients who have demonstrated a hypersensitivity to it in the past.

Last updated on RxList: 11/5/2008

After intravenous administration of DTlC-Dome, 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 DTlC in the urine is 40% of the injected dose in 6 hours.1 DTlC is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations DTIC is not appreciably bound to human plasma protein.

In man, DTlC is extensively degraded. Besides unchanged DTlC, 5-aminoimidazole -4 carboxamide (AlC) is a major metabolite of DTlC excreted in the urine. AlC is not derived endogenously but from the injected DTlC, because the administration of radioactive DTlC labeled with ¹⁴C in the imidazole portion of the molecule (DTlC-2-¹⁴C) gives rise to AIC-2-¹⁴C¹.

Although the exact mechanism of action of DTIC-Dome 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

REFERENCES

1. Loo, T.J., et al.: Mechanism of action and pharmacology studies with DTlC (NSC-45388). Cancer Treatment Reports 60: 149–152, 1976.

Last updated on RxList: 11/5/2008

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last updated on RxList: 11/5/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DACARBAZINE - INJECTION

(duh-KAR-buh-zeen)

COMMON BRAND NAME(S): DTIC-Dome

WARNING: This medication may often cause serious blood disorders (decreased bone marrow function leading to a low number of red blood cells, white blood cells, and platelets). These effects can cause anemia, lower your body's ability to fight an infection, and increase your risk of bleeding. Dacarbazine may also cause rare but serious liver problems. These side effects may rarely be life-threatening. Your doctor will monitor you closely while you are receiving this medication.

Tell your doctor immediately if you develop any of the following symptoms: unusual tiredness, pale skin, easy bruising/bleeding, signs of infection (e.g., fever, chills, persistent sore throat), persistent nausea/vomiting, dark urine, yellowing eyes/skin, stomach/abdominal pain.

USES: Dacarbazine is used to treat certain types of cancer, such as skin cancer that has spread (metastatic malignant melanoma) and Hodgkin's disease. It is a cancer chemotherapy drug that is used alone or with other medications to slow or stop cancer cell growth.

HOW TO USE: This medication is given by injection into a vein by a health care professional. It is given on a schedule as directed by your doctor. Follow all instructions for proper mixing with IV solutions. Before using, check the medication visually for particles or discoloration. If either is present, do not use the solution. If you have any questions about the use of this medication, consult your doctor or pharmacist.

Dosage is based on your medical condition, body size, and response to treatment.

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, and loss of appetite commonly occur. Vomiting may last up to 12 hours. Your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals, not eating for 4 to 6 hours before treatment, or limiting activity may help lessen these effects. These symptoms usually decrease after 1 to 2 days. Diarrhea, flu-like symptoms (e.g., discomfort, uneasiness, body aches, headache), blurred vision, or flushing/numbness/tingling of the face may also occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended.

Many people using this medication have serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.

If this medication leaks out of the vein into the tissue under the skin, it may cause serious tissue damage. Tell your doctor immediately if you experience pain, burning, redness, or swelling at the injection site.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mouth sores, confusion, seizures, sunburn (sun sensitivity).

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using dacarbazine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, blood disorders, decreased bone marrow function, current infections.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received polio vaccine by mouth or flu vaccine inhaled through the nose.

Since this medication can increase your risk of developing serious infections, wash your hands well to prevent the spread of infections. Avoid contact with people who have illnesses that may spread to others (e.g., flu, chickenpox).

To lower the chance of getting cut, bruised, or injured, use caution with sharp objects like safety razors and nail cutters, and avoid activities such as contact sports.

This drug may infrequently cause blurred vision. Use caution while driving, using machinery, or taking part in any other activity that requires alertness. Limit alcoholic beverages.

This medication may rarely make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known if this drug passes into breast milk. Due to the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

This medication can affect sperm production in men. Therefore, reliable forms of birth control should be used during treatment and for some time afterwards. Consult your doctor for more details.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs that may decrease bone marrow function (e.g., azathioprine, trimethoprim/sulfamethoxazole).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Laboratory and/or medical tests (e.g., complete blood counts) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: It is important that you receive each dose of this medication as scheduled. If you miss a dose, contact your doctor to establish a new dosing schedule.

STORAGE: Store the vials in the refrigerator between 36-46 degrees F (2-8 degrees C) away from light. Once the medication is mixed, consult your pharmacist about the expiration date of the solution.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.