Dacarbazine

Registered South African indications:

• Metastatic malignant myeloma
• Malignant sarcoma
  - In combination with other chemotherapeutic medicines
• Hodgkin's disease
• Other malignant diseases, including carcinomas of the colon, ovary, breast and lung and testicular teratoma
  - When used in combination with other cytotoxic agents

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• Further therapy if veno-occlusive disease of the liver occurs
• Leukopenia and/or thrombocytopenia
• Coadministration with yellow fever vaccine
• Coadministration with hepatotoxic medicines and alcohol

South African recommendations

Caution in the following patient groups

• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Elderly

Administration precautions

• It is recommended that dacarbazine should only be administered under the supervision of a medical practitioner specialised in oncology, having the facilities for the necessary regular monitoring of clinical, biochemical and haematological effects, during and after therapy

Monitoring precautions

• During dacarbazine treatment frequent monitoring of blood counts should be conducted as well as monitoring of hepatic and renal function
• As severe gastrointestinal and haematological disturbances can occur, a very careful benefit-risk analysis must be carried out before each treatment with dacarbazine (See Monitoring)

Haemopoietic depression

• Long-term therapy with dacarbazine can lead to cumulative bone marrow toxicity, potentially causing severe leukopenia and thrombocytopaenia. Careful and frequent monitoring of red and white blood cells and platelets is required

Hepatotoxicity

• Hepatic toxicity, including hepatic vein thrombosis and hepatocellular necrosis, has been reported, sometimes leading to death. Frequent monitoring of liver size, function, and blood counts (especially eosinophils) is essential, particularly during the second cycle of dacarbazine therapy
• Dacarbazine is contraindicated if veno-occlusive disease occurs, and hepatotoxic medicines and alcohol are also contraindicated during chemotherapy

Immunosuppression

• Dacarbazine can cause immunosuppression, leading to a reduced capacity to cope with infections
• It should be avoided in patients with acute infections where possible, and dosage reduction or withdrawal should be considered if infections develop. Live vaccines must be avoided

Thrombotic risk

• The presence of tumoural disease increases thrombotic risk, often requiring anticoagulant treatment. If using oral anticoagulants, the high intra-individual variability in coagulation and interactions with chemotherapy necessitate increased frequency of International Normalised Ratio (INR) monitoring

Gastro-intestinal effects

• Severe gastrointestinal reactions are frequent, so anti-emetic and supportive measures are recommended. Extravasation of the medicine must be avoided as it can cause tissue damage and severe pain
• Concomitant use with phenytoin should be avoided due to the risk of exacerbation of convulsions from decreased phenytoin absorption

Women of childbearing potential/contraception in men and women

• Due to the genotoxic potential of dacarbazine, women of childbearing potential must use effective contraception during treatment and for 6 months after completion
• Men are recommended to use effective contraception and avoid fathering a child during treatment and for 3 months after completion. Patients considering pregnancy should seek genetic counselling after the required contraceptive period

Paediatric population

• Dacarbazine is not recommended for use in children and adolescents as its safety and efficacy have not been established

Effects on ability to drive and use machines

• Dacarbazine may influence the ability to drive or operate machines because of its central nervous side effects or because of nausea and vomiting

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Metastatic malignant myeloma
Malignant sarcoma
- In combination with other chemotherapeutic medicines
Hodgkin's disease
Other malignant diseases, including carcinomas of the colon, ovary, breast and lung and testicular teratoma
- When used in combination with other cytotoxic agents

• IV: 2-4.5mg/kg/day; Treatment duration: 10 days; May be repeated at 3-week intervals

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It has been found that dacarbazine may be as efficacious at the lower dosage as at the higher dosage

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Combinations of cancer chemotherapeutic agents have often shown an improved response over the use of a single agent

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Therapy duration
The treating medical practitioner should decide about the duration of therapy to the individual taking into account the type and stage of the underlying disease, the combination therapy administered, and the response to, and adverse effects of dacarbazine
In metastatic malignant melanoma and in advanced soft tissue sarcoma the duration of treatment depends on the efficacy and tolerability in the individual patient

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See Additional Prescriber Points for method of administration

Not established for use in children and adolescents

Pregnancy

South African recommendations

• Contraindicated
• Dacarbazine has been shown to be mutagenic, teratogenic and carcinogenic in animals
• It must therefore be assumed that there is an increased risk for teratogenic effects exists in humans. For this reason, dacarbazine must not be used during pregnancy
• It is not known if dacarbazine crosses the placenta

Women of childbearing potential

• Women of childbearing age must use effective methods of contraception while being treated with dacarbazine and for 6 months following completion of treatment

Contraceptive measures for men

• Men are advised to take contraceptive measures during and for 3 months after cessation of therapy

Breastfeeding

South African recommendations

• Contraindicated
• Dacarbazine must not be used while breastfeeding
• It is not known if dacarbazine distributes into milk

Fertility

South African recommendations

• Due to the genotoxic potential of dacarbazine, patients are advised to seek advice on fertility preservation options before starting treatment with dacarbazine. After treatment with dacarbazine, patients planning pregnancy are advised to seek genetic counselling

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

South African recommendations

• Caution; no information available

Infections and Infestations

Less frequent

• Infections

Blood and Lymphatic System Disorders

Frequent

• Anaemia
• Leukopenia
• Thrombocytopenia
• Bone marrow suppression

Less frequent

• Pancytopenia
• Agranulocytosis

Immune System Disorders

Less frequent

• Anaphylaxis
• Hypersensitivity reactions

Psychiatric Disorders

Less frequent

• Confusion

Nervous System Disorders

Less frequent

• Headache
• Lethargy
• Convulsions
• Facial paraesthesia

Eye Disorders

Less frequent

• Blurred vision
• Impaired vision

Vascular Disorders

Less frequent

• Facial flushing

Gastrointestinal Disorders

Frequent

• Anorexia
• Nausea
• Vomiting

Less frequent

• Diarrhoea

Hepato-biliary Disorders

Less frequent

• Hepatotoxicity
• Hepatic vein thrombosis
• Hepatic necrosis due to veno-occlusive disease (VOD) of the liver
• Budd-Chiari syndrome with potentially fatal outcome

Skin and Subcutaneous Tissue Disorders

Less frequent

• Alopecia
• Hyperpigmentation
• Photosensitivity
• Transient rash
• Erythema
• Maculopapular exanthema
• Urticaria

Renal and Urinary Disorders

Less frequent

• Impaired renal function with increased blood creatinine
• Increased blood urea

General Disorders and Administration Site Conditions

Less frequent

• Flu-like symptoms
• Malaise
• Injection site irritation

Investigations

Less frequent

• Elevation of liver enzymes
• Increased transaminases (AST, ALT)
• Increased alkaline phosphatase
• Increased lactate dehydrogenase (LDH)

• Yellow fever vaccine
• Live-attenuated vaccine
• Hepatotoxic medicines
• Alcohol
• Phenytoin
• Oral anticoagulants
• Warfarin
• Cyclosporin
• Tacrolimus
• Digoxin
• Fotemustine
• Other treatment modalities having adverse effects on the bone marrow
• Cytostatic agents
• Irradiation
• Suxamethonium
• CYP450 substrates
• Methoxypsoralen

• Full blood count with differential
• Hepatic function
• Renal function

Additional Observations

• Signs of extravasation
• Gastrointestinal effects
  - Observe for and manage severe gastrointestinal reactions (e.g., anorexia, nausea, and vomiting) which occur frequently
• Signs of liver/kidney dysfunction or hypersensitivity
  - Therapy must be immediately discontinued if symptoms of a liver or kidney functional disorder or symptoms of a hypersensitivity reaction are observed
• Signs of veno-occlusive disease (VOD) of the liver
• Infections
  - Monitor for signs of infections, as dacarbazine can cause immunosuppression
• Flu-like symptoms
  - Monitor for flu-like symptoms (exhaustion, chills, fever, and muscular pain) which are occasionally observed during or days after administration and may recur
• Central nervous system effects
  - Monitor for central nervous side effects such as headaches, impaired vision, confusion, lethargy, and convulsions, which may occur less frequently

Method of administration

• Care should be taken during the administration of the injection to avoid extravasation into tissues, since this will cause local pain and tissue damage
• If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should be introduced into another vein
• Food intake prior to administration of dacarbazine should be avoided to reduce the severity of nausea and vomiting. Excreta and vomit should be handled with care
• Testing the patency of the vein first is recommended with a 5-10ml flush of isotonic sodium chloride infusion solution or glucose 5%
• The same solutions should be used after infusion to flush any remaining medicine from the tubing
• After reconstitution with water for injections and without further dilution with isotonic sodium chloride solution or glucose 5%, dacarbazine preparations are hypo-osmolar and should therefore be given by slow intravenous injection, e.g., over 1 minute and not as an i.v. bolus injection over a few seconds

Instructions for preparation and reconstitution

Recommendations for safe handling

• Dacarbazine is sensitive to light exposure. All reconstituted solutions should be suitably protected from light also during administration (light-resistant infusion set)
• Dacarbazine is an antineoplastic agent. Before preparing a solution, local cytotoxic guidelines should be referred to regarding handling of cytotoxic agents
• Dacarbazine should only be opened by trained staff. As with all cytotoxic agents, precautions should be taken to avoid exposing staff
• Handling of cytotoxic medicines should be avoided during pregnancy. Preparation of the solution for administration should be carried out in a designated handling area, working over a washable tray or disposable plastic-backed absorbent paper
• It is recommended that suitable eye protection, disposable gloves, face mask and a disposable apron are worn. Syringes and infusion sets should be assembled carefully to avoid leaks (use of Luer lock fittings is recommended)
• Once completed, any exposed surfaces should be thoroughly cleaned and the hands and face washed. In the event of spillage, operators should put on gloves, face masks, eye protection and a disposable apron and mop up the spilled material with an absorbent material laid out in the area for that purpose
• The area should then be cleaned and all contaminated material transferred to a cytotoxic spillage bag or sealed for incineration

Handling of dacarbazine

• Dacarbazine should be handled according to standard procedures for cytostatics that have mutagenic, carcinogenic and teratogenic effects

Preparation and administration of the solution for injection or infusion

• Dacarbazine 200mg should be reconstituted with 19.7ml of water for injections. The resulting solution contains 10mg/ml dacarbazine and has a pH of 3.0 to 4.0
• For preparation of infusion solutions, the reconstituted solution should be diluted with 200ml glucose 5% or sodium chloride solution 0.9%
• The resulting solution contains 1.0mg/ml of dacarbazine. The solutions prepared by reconstitution or by reconstitution and dilution must be clear and free from visible particles
• All prepared solutions must be protected from light; the administration should also take place without exposure to daylight

Dacarbazine is a cytostatic agent. The antineoplastic effect is due to an inhibition of cell growth which is independent of the cell cycle and due to an inhibition of DNA synthesis, by acting as a purine analogue. An alkylating effect has also been shown and further cytostatic mechanisms may also be influenced by dacarbazine. Dacarbazine probably does not have an antineoplastic effect by itself. However by microsomal N-demethylation it is converted to 5-amino-imidazole-4-carboxamide and a methyl cation, which is responsible for the alkylating effects.