Dacarbazine

Dacarbazine is an antineoplastic and alkylating agent belonging to the pharmacological class of Triazines.

Dacarbazine, also known as DTIC, is approved by the FDA to treat malignant melanoma and Hodgkin's disease.

Dacarbazine swiftly absorbs into the bloodstream after injection. It distributes rapidly in tissues, potentially localizing in the liver, crosses the blood-brain barrier, and is primarily metabolized in the liver before elimination via urine.

The most common side effects of dacarbazine include nausea, vomiting, decreased white blood cell count, and injection site pain.

Dacarbazine is available as a powder for injection.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Dacarbazine is an antineoplastic and alkylating agent belonging to the pharmacological class of Triazines.

The purine precursor imidazole carboxamide has a structural analogue in dacarbazine. Dacarbazine is converted to the reactive substance methyltriazenoimidazole carboxamide (MTIC) in the liver by cytochrome P450. It is considered that the production of methylammonium ions, which target nucleophilic groups in DNA, is the leading cause of MTIC's cytotoxicity. Dacarbazine functions as a purine analogue and interacts with sulfhydryl groups to potentially inhibit DNA and RNA synthesis. Temozolomide and dacarbazine are prodrugs of MTIC. Dacarbazine has a mild immunosuppressive effect and is not phase-specific in the cell cycle.

At a dosage of 4.5 mg/kg, the peak plasma concentration reaches 8 mcg/mL.

Dacarbazine is available as a powder for injection.

Powder for injection: To be administered intravenously over a short period, typically every 3 weeks after appropriate dilution.

Parenterally: Administer dacarbazine parenterally via intravenous infusion after dissolving the drug in sterile water for injection. The infusion typically lasts 15 to 30 minutes, but durations may vary. Ensure thorough flushing of the intravenous line post-infusion to prevent drug residue. Maintain strict aseptic techniques during preparation and administration to avoid infections. Consider premedicating patients with antiemetics or antinauseants before administering dacarbazine to manage potential side effects. Caution must be exercised during intravenous infusion to prevent tissue damage in case of leakage. Monitor for signs of extravasation or local irritation at the injection site to ensure safe and effective administration.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Dacarbazine is available as a powder for injection.

Combined other antineoplastics, such as ABVD

IV 150 mg/m² every day for 5 days; repeat every 4 weeks OR

Start IV 375 mg/m² on Day 1 and repeat every 15 days.

CBC and LFTs should be monitored.

2-4.5 mg/kg IV every day for ten days; repeat every 4 weeks

Repeat the IV dose of 250 mg/m² every three weeks for five days.

CBC and LFTs should be monitored.

When taking dacarbazine, prioritize dietary adherence for better safety. Include a variety of nutrient-rich foods like leafy vegetables, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, cauliflower, cabbage, broccoli, beans, and herbs. Individuals with chronic illnesses, including cancer, benefit from a diet rich in protein, whole grains, healthy fats, vitamins, and minerals. Avoid smoking and alcohol intake for optimal health.

The dietary restriction should be individualized as per patient requirements.

Dacarbazine for injection commonly causes hemopoietic depression, predominantly affecting leukocytes and platelets, with potentially fatal outcomes. Closely monitoring white blood cells, red blood cells, and platelet levels is essential due to the risk of severe leukopenia and thrombocytopenia. Hemopoietic toxicity may necessitate temporary suspension or discontinuation of therapy.

Hepatic toxicity, including hepatic vein thrombosis and hepatocellular necrosis leading to fatalities, has been rarely reported (approximately 0.01% of patients). This toxicity has been observed when dacarbazine for injection is administered alongside other antineoplastic drugs or as a single agent.

Anaphylactic reactions can occur post-administration of dacarbazine for injection, warranting immediate medical attention.

Ensure access to adequate laboratory facilities, although hospitalization might not always be necessary. Extravasation of the drug during intravenous administration may cause severe pain and tissue damage if it infiltrates subcutaneously. Consider applying hot packs directly to the affected area to relieve local pain, burning sensation, and irritation at the injection site.

Studies in rats and mice have shown the potential carcinogenicity of dacarbazine. Rats exhibited proliferative endocardial lesions, including fibrosarcomas and sarcomas, while mice developed angiosarcomas of the spleen upon dacarbazine administration.

It is unsafe to consume dacarbazine with alcohol.

Consume nutritious foods avoid saturated fats; and exercise regularly.

The adverse reactions related to dacarbazine can be categorized as:

Common Adverse Effects: Nausea, vomiting, alopecia, injection site pain, leukopenia, and thrombocytopenia

Less Common Adverse Effects: Anorexia, metallic taste, flu-like symptoms, Erythematous and urticarial rashes.

Rare Adverse Effects: In men, liver or renal function test abnormalities and photosensitivity reactions.

The clinically relevant drug interactions of dacarbazine are briefly summarized here.

Increased metabolism when combined with drugs that induce enzymes, such as phenytoin, rifampicin, and barbiturates. Allopurinol, azathioprine, and mercaptopurine may have an increased effect. It could reduce the body's ability to respond to vaccinations. May intensify the photosensitization-induced effects of methoxsalen.

The common side effects of dacarbazine include:

Injection site pain

Decreased white blood cell count

Loss of appetite

Dizziness

Sore throat

Headache

Fever

Chills

Cough

Nausea

Vomiting

Bruising or bleeding gums

FDA Pregnancy Category C: Animal studies have shown fetal risks, and there are no controlled studies on women. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

When given to rats on day 12 of pregnancy at doses 20 times the daily dose of humans, dacarbazine has been demonstrated to be teratogenic. When male rats were given dacarbazine at ten times the human daily dose (twice weekly for nine weeks), it did not affect the male libido; however, female rats that mated with male rats experienced a higher incidence of resorptions than the control group. Fetal skeletal abnormalities were observed in rabbits when dacarbazine was administered daily on Days 6–15 of gestation, seven times the daily dose given to humans. There aren't enough reliable studies on expectant mothers. Dacarbazine should only be used if the possible advantages outweigh the potential risks to the developing foetus.

It is unknown if the drug is eliminated in human milk. As many medications are excreted in human milk and that dacarbazine has been shown in animal studies to have tumorigenicity, the mother's need for the drug should be taken into consideration when deciding whether to stop nursing or to stop taking it altogether.

The safety and efficacy of dacarbazine in pediatric populations have yet to be conclusively established. Further research must determine its appropriateness, optimal dosage, and potential risks in children and adolescents.

With additional antineoplastics, such as ABVD

150 mg/m² IV every day for five days, then every four weeks

IV 375 mg/m² on Day 1 and repeat every 15 days afterwards.

Off-label Combination Therapy for Neuroblastoma

Once on day 1, 800-900 mg/m² IV; repeat every three to four weeks

The safety and efficacy of dacarbazine in the geriatric population have yet to be thoroughly established. Efficacy and safety in this group may vary, requiring cautious dosing and close monitoring for potential side effects. Further studies are needed to ascertain its optimal use and risk-benefit profile in older individuals.

With additional antineoplastics, such as ABVD

150 mg/m² IV every day for five days, then every four weeks

IV 375 mg/m² on Day 1 and repeat every 15 days afterwards.

CBC and LFTs should be noted.

2-4.5 mg/kg IV every day for ten days; repeat every four weeks OR

IV 250 mg/m² daily for 5 days; repeat every 3 weeks.

CBC and LFTs should be noted.

46–60 mL/min CrCl: 80% of the standard dosage

31–45 mL/min CrCl: 75% of the standard dosage

<30 mL/min CrCl: 70% of the standard dosage

Unknown; for liver toxicity symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of dacarbazine.

Overconsumption of Dacarbazine could lead to severe bone marrow suppression, nausea, vomiting, and diarrhoea.

There is no specific antidote or treatment for overdosage of dacarbazine, so treatment typically involves symptomatic and supportive measures. Monitor blood counts for at least six weeks due to its myelosuppressive effects. Manage severe hematological toxicity with necessary supportive measures such as hematopoietic growth factors and transfusions. Regularly assess liver function and monitor hepatic enzymes. Consider gastric lavage if recent ingestion is evident. Timely medical intervention plays an essential role in managing Dacarbazine overdose, ensuring careful monitoring and proper care to address symptoms and prevent complications.

Dacarbazine is a synthetic derivative of 5-amino-1H-imidazole-4-carboxamide (AIC), a naturally occurring purine precursor. Dacarbazine is administered intravenously, and the volume of distribution afterwards surpasses the body's total water content, indicating that the drug is localized in body tissue—likely the liver. Its biphasic elimination from the plasma has a terminal half-life of five hours and an initial half-life of nineteen minutes. Half-lives in patients with hepatic and renal dysfunction were extended to 7.2 hours and 55 minutes, respectively. On average, 40% of the injected dose is excreted cumulatively in the urine in six hours when unchanged DTIC is excreted. Rather than glomerular filtration, DTIC is subject to renal tubular secretion. Dacarbazine is not significantly bound to human plasma protein at therapeutic concentrations.