Dacarbazine

Dacarbazine is a cytostatic agent. It has no antitumour effect of its own; the effect comes from metabolites formed in the liver. The SmPC attributes it to inhibition of cell growth that does not depend on the cell cycle and to inhibition of DNA synthesis, with an alkylating effect also shown.

Mechanism of Action

• Activation: by microsomal N-demethylation, catalysed by CYP1A1, CYP1A2 and CYP2E1, dacarbazine forms the reactive N-demethylated compounds HMMTIC and MTIC. MTIC is then broken down to 5-aminoimidazole-4-carboxamide (AIC) and a methyl cation, which is responsible for the alkylating effect.
• Cell-cycle independence: the growth-inhibiting effect is not specific to a phase of the cell cycle.
• DNA synthesis: dacarbazine inhibits DNA synthesis, and other cytostatic mechanisms may also be influenced. DrugBank notes that the exact mechanism is not known and that dacarbazine is a synthetic analogue of the purine precursor AIC.

Pharmacokinetics

• Absorption: dacarbazine is given intravenously, so the dose enters the circulation directly.
• Distribution: rapid distribution into tissue after an intravenous dose. About 5% is bound to plasma proteins. Plasma kinetics are biphasic: the initial (distribution) half-life is about 20 minutes and the terminal half-life is 0.5–3.5 hours.
• Metabolism: mainly in the liver, by hydroxylation and demethylation. Dacarbazine is inactive until cytochrome P450 (CYP1A1, CYP1A2, CYP2E1) forms HMMTIC and MTIC; MTIC is in turn metabolised to AIC. Hydroxylation to metabolites with antitumour activity has also been identified.
• Elimination: the kidney excretes about 20–50% of the dose unchanged, by renal tubular secretion.
• Special populations: in combined renal and hepatic impairment elimination is prolonged; the SmPC gives no recommendation on dose reduction.

Dacarbazine is authorised nationally. The indications below are those of the Spanish SmPC for Dacarbazina medac.

• Metastatic malignant melanoma: treatment of patients with metastatic malignant melanoma.
• Advanced Hodgkin’s disease: as part of combination chemotherapy.
• Advanced soft-tissue sarcoma in adults: as part of combination chemotherapy, with the exception of mesothelioma and Kaposi’s sarcoma.

• Hypersensitivity to dacarbazine or to any of the excipients.
• Pregnancy and breastfeeding.
• Leucopenia and/or thrombocytopenia.
• Severe liver or kidney disease.
• Hepatic veno-occlusion: if it develops, continuing treatment is contraindicated (SmPC section 4.4).

The most frequent reactions are gastrointestinal (anorexia, nausea and vomiting) and blood disorders (anaemia, leucopenia and thrombocytopenia). The blood count changes depend on the dose and appear with a delay, the lowest level often being reached only after 3 to 4 weeks. No reactions are listed as very common or of unknown frequency.

Common (≥1/100 to <1/10): blood and lymphatic system (anaemia, leucopenia, thrombocytopenia); gastrointestinal (anorexia, nausea, vomiting).

Uncommon (≥1/1,000 to <1/100): infections; skin (alopecia, hyperpigmentation, photosensitivity); general (flu-like symptoms).

Rare (≥1/10,000 to <1/1,000): blood and lymphatic system (pancytopenia, agranulocytosis); immune system (anaphylactic reactions); nervous system (headache, impaired vision, confusion, lethargy, convulsions, facial paraesthesia); vascular (sudden hot flush or facial flushing); gastrointestinal (diarrhoea); liver (hepatic necrosis caused by occlusion of intrahepatic veins, veno-occlusive disease; Budd-Chiari syndrome, potentially fatal); kidney (impaired renal function); skin (erythema, maculopapular rash, urticaria); general (irritation at the application site); investigations (raised liver enzymes such as alkaline phosphatase, AST and ALT, and raised blood lactate dehydrogenase, creatinine and urea).

Flu-like symptoms (exhaustion, chills, fever, muscle pain) can appear during the administration or only some days later, and may return with the next infusion. Hepatic veno-occlusive disease mostly arose in the second phase of therapy, with fever, eosinophilia, abdominal pain, enlarged liver, jaundice and shock that worsened within hours or days; fatal outcomes have been described. Venous irritation and some systemic reactions are thought to be due to photodegradation products. Facial paraesthesia and flushing can follow shortly after the injection, and allergic skin reactions are rare. Accidental injection outside the vein can cause local pain and necrosis.

• Phenytoin: avoid. Dacarbazine can reduce the absorption of phenytoin from the gut, which may predispose the patient to convulsions.
• Fotemustine: must not be used at the same time; the combination can cause acute lung toxicity (adult respiratory distress syndrome), which can be fatal.
• Other bone-marrow-suppressing treatment: prior or concurrent cytostatics or irradiation can cause myelotoxic interactions.
• Medicines metabolised by CYP1A1, CYP1A2 or CYP2E1: dacarbazine uses the same enzymes, which should be kept in mind when such medicines are given together.
• Methoxypsoralen: dacarbazine can increase its effects through photosensitisation.
• Live vaccines: avoid during treatment because of the risk of serious and potentially fatal infections; if used after chemotherapy, give no earlier than 3 months after the last dose. An inactivated vaccine is recommended where available.
• Oral anticoagulants: the INR should be checked more often, because of the large variability in coagulation between patients and the possible interaction with cytostatics.
• Ciclosporin (in some cases tacrolimus): use together should be considered carefully, as these medicines may cause excessive immunosuppression and lymphoproliferation.
• Alcohol and hepatotoxic medicines: avoid during chemotherapy.
• Food: DrugBank notes that fasting for four to six hours before treatment may help reduce nausea and vomiting; the SmPC advises antiemetic and supportive measures.

Use is restricted to physicians experienced in oncology or haematology. The regimens below can be used; for more detail the SmPC refers to the current scientific literature. Blood parameters and liver and kidney function are checked frequently, and antiemetic and supportive measures are advised because severe gastrointestinal reactions are frequent. Each treatment must be preceded by an extremely careful benefit–risk analysis.

Doses by Indication

• Malignant melanoma: as a single agent, 200–250 mg/m² body surface area per day as an intravenous injection for 5 days every 3 weeks. Instead of an intravenous bolus it can be given as a rapid infusion over 15–30 minutes. Another option is 850 mg/m² on the first day and then once every 3 weeks as an intravenous infusion.
• Hodgkin’s disease: 375 mg/m² of body surface area intravenously every 15 days, in combination with doxorubicin, bleomycin and vinblastine (ABVD regimen). Six cycles of ABVD are usually recommended for advanced disease.
• Adult soft-tissue sarcoma: 250 mg/m² intravenously on days 1 to 5, in combination with doxorubicin, every 3 weeks (ADIC regimen).
• Duration: set by the physician for each patient, taking into account the type and stage of the disease, the combination therapy, the response and the side effects. In metastatic melanoma and advanced soft-tissue sarcoma it depends on efficacy and tolerability.

Method of Administration

• Dacarbazine is sensitive to light. All reconstituted solutions must be protected from light, also during administration (light-resistant infusion set).
• Extravasation must be avoided: it causes local pain and tissue injury. If it happens, the injection is stopped at once and the rest of the dose is given into another vein.
• Doses up to 200 mg/m² can be given by slow intravenous injection; higher doses (200 to 850 mg/m²) are given as an intravenous infusion over 15–30 minutes.
• Vein patency is checked first with 5–10 mL of 0.9% sodium chloride or 5% glucose solution, and the same solutions are used afterwards to flush the line. For reconstitution and handling, see SmPC section 6.6.

Special Populations

• Renal or hepatic impairment: when impairment is only mild to moderate, a dose reduction is normally not needed. In combined renal and hepatic impairment elimination is prolonged, but there are no dose reduction recommendations. Severe liver or kidney disease is a contraindication.
• Elderly: experience is limited, so no special instructions can be given.
• Children and adolescents: safety and efficacy have not been established under 15 years of age, and use in the paediatric age group is not recommended until more data are available.

Supervision and Monitoring

• Treatment is given under the supervision of an oncology specialist who can monitor clinical, biochemical and haematological effects during and after treatment.
• Treatment is stopped at once if symptoms of impaired liver or kidney function or of a hypersensitivity reaction appear.
• Long-term therapy can cause cumulative bone-marrow toxicity, so white cells, red cells and platelets are monitored carefully. Haematopoietic toxicity may justify temporary or permanent discontinuation.

Hepatic Veno-Occlusive Disease

• A serious but rare complication is hepatic necrosis due to occlusion of the intrahepatic veins. Liver size and function and the blood count (especially eosinophils) are monitored often.
• In individual cases of suspected veno-occlusive disease, early treatment with high-dose corticosteroids (for example hydrocortisone 300 mg a day), with or without fibrinolytic agents such as heparin or tissue plasminogen activator, is effective. If venous occlusion of the liver occurs, continuing dacarbazine is contraindicated.

Extravasation

Leakage of the medicine during intravenous administration can damage tissue and cause severe pain (see Administration and Dosage).

Vaccines and Immunosuppression

Dacarbazine is a moderate immunosuppressant. Live vaccines given to patients made immunocompromised by chemotherapy can cause serious and potentially fatal infections, so they are avoided during treatment. After chemotherapy they should be used with caution, taking the patient’s immune status, disease and other treatments into account, and not before at least 3 months after the end of chemotherapy. Inactivated vaccines can be used if available.

Other Cautions

• Hepatotoxic medicines and alcohol are avoided during chemotherapy.
• Phenytoin and fotemustine must not be used with dacarbazine (see Drug Interactions).

Pregnancy, Breastfeeding and Fertility

• Pregnancy and breastfeeding: contraindicated. Dacarbazine was mutagenic, teratogenic and carcinogenic in animals, and an increased teratogenic risk in humans must be presumed.
• Contraception: because of its genotoxic potential, women of childbearing potential should use effective contraception during treatment and for 6 months after it ends. Men should use effective contraception and not father a child during treatment and for 3 months after it ends. Patients who are planning a pregnancy should seek genetic counselling.
• Fertility: patients should seek advice on fertility preservation before starting treatment.

Effect on Driving

Dacarbazine can affect the ability to drive and use machines, because of its effects on the central nervous system or because of nausea and vomiting.

Do not store above 25 °C. Keep the vial in the outer carton to protect it from light; reconstituted solutions must also be protected from light. Dacarbazine does not need cold-chain storage. For storage after reconstitution, see Shelf Life.

• Unopened vial: 3 years.
• Reconstituted solution: chemically and physically stable for 48 hours at 2–8 °C protected from light. From a microbiological point of view it should be used at once; otherwise in-use times and conditions are the user’s responsibility and normally should not exceed 24 hours at 2–8 °C, unless reconstitution was done under validated, controlled aseptic conditions.
• Reconstituted and further diluted solution: stable for 2 hours at 25 °C in polyethylene containers, and for 24 hours at 2–8 °C protected from light in polyethylene containers and glass bottles. From a microbiological point of view it should be used at once.

Prescription only (Rx), for use under a physician experienced in oncology or haematology. Dacarbazine is given by intravenous injection or infusion in hospital, so it is supplied to the hospital or clinic that administers it.