What Is Dacarbazine (Dakarbaz)? FDA Approval, Authorization and Reimbursement Status in Turkey

• FDA Approval: Yes, Initial Approval Date: May 27, 1975
• Brand Name: Dakarbaz
• Active Ingredient: Dacarbazine
• Route of Administration: Intravenous (IV) infusion
• Class: Alkylating agent (triazene compound)
• Category: Chemotherapeutic antineoplastic drug
• Manufacturer: Bayer Healthcare (DTIC-Dome). Also manufactured by numerous generic companies.
• Distribution in Turkey: Koçak Farma, Sanofi
• Cancers for Which It Is Approved: Advanced malignant melanoma, Hodgkin lymphoma, soft tissue sarcomas, medullary thyroid carcinoma; may be among palliative treatment options for rare tumors.

What Is Dacarbazine (Dakarbaz)? How Does It Work?

Dacarbazine is a chemotherapy drug used to treat various cancers. A member of the triazene class, it is particularly effective in cancers such as Hodgkin lymphoma, malignant melanoma and soft tissue sarcomas.

How Does It Work?

After administration, dacarbazine is metabolized in the liver into its active form. The resulting active metabolites add methyl groups to guanine bases in DNA, disrupting its structure. This prevents proper DNA replication and stops cell division, leading to cancer cell death.

This DNA damage causes cell-cycle arrest and apoptosis, or programmed cell death. However, some cancer cells can repair the damage through DNA repair mechanisms. In particular, the enzyme O6-methylguanine-DNA methyltransferase (MGMT) can remove methyl groups from DNA and reduce the drug's effect. Tumors with low MGMT levels are therefore more sensitive to dacarbazine.

FDA (US Food and Drug Administration) Approval History

Dacarbazine was first approved by the US Food and Drug Administration (FDA) on May 27, 1975.

Authorization in Turkey

Authorized in Turkey by Koçak Farma İlaç on 29.07.2013.

Therapeutic Indications

• Used as monotherapy for malignant melanoma.
• Used in combination for Hodgkin lymphoma, non-Hodgkin lymphoma and soft tissue sarcomas other than Kaposi sarcoma.

SGK Reimbursement

No indication requirement applies in patients diagnosed with cancer. It is among the drugs that may be used without an indication-match requirement, based on a specialist physician's report describing the treatment protocol. It is therefore reimbursed by SGK.

Price: Dakarbaz 100 mg vial: 1000, 23 lira; Dakarbaz 200 mg vial: 1672.68 lira.

Resistance Mechanisms

• Activation of DNA Repair Mechanisms: The enzyme O6-methylguanine-DNA methyltransferase (MGMT) can repair dacarbazine-induced DNA damage and negate the drug's effect. Dacarbazine attaches a methyl group to the guanine base at the O6 position in DNA. MGMT removes this methyl group, preventing apoptosis. Tumors with high MGMT expression are resistant to dacarbazine. Some clinical studies have therefore reported better responses in patients with low MGMT levels.
• Impaired Drug Metabolism: Dacarbazine is a prodrug activated in the liver through the CYP450 enzyme system. If this metabolic activation is inadequate (for example, because of liver failure or genetic polymorphisms), the drug cannot be sufficiently effective. This represents an indirect resistance mechanism.
• Reduced Cellular Drug Uptake / Increased Drug Efflux: Cancer cells may overexpress pump systems, such as P-glycoprotein, that reduce drug entry into cells or actively expel the drug. This prevents therapeutic intracellular concentrations and leads to lack of effectiveness.
• Disruption of Apoptosis (Programmed Cell Death) Pathways: Dacarbazine triggers apoptosis through DNA damage. However, some tumor cells can block this signal by developing mutations in tumor-suppressor proteins such as p53. Increased anti-apoptotic proteins, such as Bcl-2, can also suppress cell death and cause treatment resistance.
• Epigenetic Changes: Lack of methylation in the MGMT gene promoter keeps the gene active and increases dacarbazine resistance. Conversely, MGMT promoter methylation suppresses gene expression and makes the cell sensitive to the drug.

Absorption

• Dacarbazine is administered only intravenously (IV).
• Oral bioavailability is low, and it is not administered by mouth.
• With IV administration, it enters the systemic circulation directly and begins to act rapidly.

Distribution

• Volume of distribution (Vd): approximately 0.5–0.8 L/kg, indicating moderate distribution into body fluids and tissues.
• Plasma protein binding is low (~5%). This means a larger free drug fraction and potentially easier entry into cells.
• Central nervous system penetration is limited, but may increase if the meninges are inflamed.

Metabolism

• Dacarbazine is a prodrug converted in the liver to active metabolites through CYP1A1, CYP1A2 and CYP2E1.
• The active compounds formed through metabolism are: MTIC (5-amino-imidazole-4-carboxamide), the active agent that attaches alkyl groups to DNA; and hydroxyalkyl derivatives, which have cytotoxic effects.
• The metabolic process may vary with individual enzyme activity and liver function.

Elimination

• Elimination half-life: approximately 20–50 minutes for the parent compound. However, active metabolites have longer-lasting effects.
• The drug and its metabolites are eliminated primarily through the kidneys.
• Approximately 40% is excreted unchanged in urine.
• The remainder is eliminated as metabolites.
• Dose adjustment may be necessary in patients with renal impairment because the risk of accumulation may increase.

Dose Range

As a single agent: 150–250 mg/m²/day by IV infusion, usually for 4-5 consecutive days. The cycle is repeated every 3 weeks.

In combination therapy: 100–250 mg/m²/day by IV infusion, usually for 4-5 consecutive days. The cycle is repeated every 3 weeks.

Drug Interactions

• As a chemotherapy agent that disrupts DNA synthesis at the cellular level, dacarbazine may have clinically significant interactions with certain drugs. These may arise through pharmacokinetics (absorption, metabolism and elimination) or through pharmacodynamics, namely overlapping toxicity profiles.
• Because the drug is activated in the liver through CYP1A2, CYP1A1 and CYP2E1, concomitant drugs affecting these enzymes may alter its pharmacological effects. For example, cytochrome P450 inducers such as rifampicin, carbamazepine and cigarette smoke may accelerate dacarbazine metabolism and reduce effectiveness. In contrast, enzyme inhibitors such as fluconazole, ketoconazole and some antibiotics may slow its breakdown and increase toxicity.
• Combining dacarbazine with other cytotoxic drugs requires caution, particularly regarding bone marrow suppression. For example, combination with agents such as vincristine, bleomycin, ifosfamide or adriamycin substantially increases myelosuppression risk. Complete blood counts should be monitored regularly, with doses adjusted if necessary.
• Allopurinol may also be used with dacarbazine for conditions such as hyperuricemia caused by rapid tumor cell breakdown. However, this combination may also increase hematological adverse effects.
• Because of its immunosuppressive effects, concomitant use with live vaccines is not recommended. Live vaccines may cause serious infections in immunocompromised patients. Such vaccinations should be planned after chemotherapy is completed.
• Finally, dacarbazine can cause photosensitivity in some patients. This may be more pronounced when combined with other photosensitizing drugs, such as tetracyclines or retinoids. Sun exposure should therefore be limited and protective measures taken.

Situations Requiring Attention

• Risk of Myelosuppression (Bone Marrow Suppression): Dacarbazine may suppress bone marrow function, causing leukopenia, anemia and thrombocytopenia. These effects are dose-dependent and generally peak 1-2 weeks after treatment. Regular complete blood counts are essential; falling values require dose reduction or a treatment break.
• Liver Function: The drug may be hepatotoxic. Serious complications such as hepatic veno-occlusive disease (sinusoidal obstruction) have been reported, although rarely. Liver function tests (AST, ALT, ALP, bilirubin) should be monitored regularly during treatment. Dose adjustment may be necessary in patients with hepatic impairment.
• Kidney Function: Because many metabolites are eliminated by the kidneys, impaired kidney function (urea, creatinine) increases the risk of accumulation and toxicity. Doses should be adjusted if necessary, and urine output monitored.
• Nausea, Vomiting and Gastrointestinal Tolerability: It is highly emetogenic (causes nausea and vomiting). Antiemetic prophylaxis, such as 5-HT3 antagonists and/or dexamethasone, is recommended before treatment. Prolonged vomiting requires caution because it can disrupt fluid and electrolyte balance.
• Photosensitivity and Skin Reactions: Drug-related photosensitivity may occur. During and after treatment, patients are advised to avoid direct sun exposure and use protective clothing and sunscreen.
• Infection Risk: Opportunistic infections may develop because of immune suppression. Fever, sore throat and respiratory symptoms should be taken seriously and assessed. Live vaccines are contraindicated. Vaccination should be deferred until after treatment.
• Pregnancy and Breastfeeding: It is pregnancy category C: fetal toxicity has been observed in animal studies, but human data are inadequate. It should be used during pregnancy only if vital. Breastfeeding should be stopped during treatment.
• Anaphylactic and Infusion Reactions: Although rare, sudden allergic reactions, flushing, hypotension or bronchospasm may occur during intravenous administration. Patients should be monitored closely during initial administrations, with emergency treatment facilities available.
• Drug Interactions:  Drugs affecting CYP450 enzymes may alter dacarbazine's effectiveness and toxicity when used concomitantly. Concomitant use with other bone marrow-suppressing drugs should also be carefully planned.

Side Effects

• Nausea 90%
• Vomiting 90%
• Loss of appetite (anorexia) 90%
• Bone marrow suppression 25%
• Anemia 1–10%
• Leukopenia 1–10%
• Thrombocytopenia 1–10%
• Blurred vision 1–10%
• Hair loss (alopecia) 0.1–1%
• Hyperpigmentation 0.1–1%
• Photosensitivity 0.1–1%
• Infections 0.1–1%
• Flu-like symptoms – 0.1–1%
• Allergic reactions (including anaphylaxis) 0.01–0.1%
• Liver necrosis 0.01–0.1%
• Renal dysfunction 0.01–0.1%
• Facial flushing 0.01–0.1%
• Headache 0.01–0.1%
• Lethargy 0.01–0.1%
• Confusion 0.01–0.1%
• Convulsions 0.01–0.1%
• Facial paresthesia 0.01–0.1%