DacaCedal^®

Dacarbazine is indicated for the treatment of patients with metastasised malignant melanoma.

Further indications for dacarbazine as part of a combination chemotherapy are:

• advanced Hodgkin’s disease
• advanced metastatic soft tissue sarcomas.

• Hypersensitivity to the active substance or to any of the excipients
• pregnancy or breastfeeding
• leukopenia and/or thrombocytopenia,
• severe liver or kidney diseases.

Dacarbazine should only be administered under the supervision of a physician specialised in oncology who has the facilities for regular monitoring of clinical, biochemical and haematological effects, during and after therapy.

If symptoms of a liver or kidney functional disorder or symptoms of a hypersensitivity reaction are observed immediate cessation of therapy is required. If veno-occlusive disease of the liver occurs, further therapy with dacarbazine is contraindicated.

The responsible physician should be aware of a rarely observed severe complication during therapy resulting from liver necrosis due to occlusion of intrahepatic veins. Therefore, frequent monitoring of liver size, function and blood counts (especially eosinophils) is required. In single cases of suspected veno-occlusive disease early therapy with high-dose corticosteroids (for example hydrocortisone 300 mg/day) with or without fibrinolytic agents like heparin or tissue plasminogen activator was successful.

Long-term therapy can cause cumulative bone marrow toxicity. The possible bone marrow depression requires careful monitoring of white blood cells, red blood cells and platelet levels. Haemopoietic toxicity may warrant temporary suspension or cessation of therapy.

Extravasation of the medicinal product during i.v. administration may result in tissue damage and severe pain.

Concomitant use with phenytoin should be avoided because reduced absorption of phenytoin from the gastrointestinal tract may predispose the patient to convulsions.

Dacarbazine is a moderate immunosuppressive agent. Administration of live vaccines to patients who are immunocompromised as a result of treatment with chemotherapeutics such as dacarbazine can cause serious and potentially fatal infections. Immunisation with live vaccines should therefore be avoided during dacarbazine therapy. It is generally advised to use live virus vaccines with caution after stopping chemotherapy and to take the patient’s immune status into account, depending also on the disease and other therapies. Vaccination with live vaccines should be administrated no sooner than 3 months after the completion of chemotherapy. Inactivated vaccines can be used if available.Concomitant use of fotemustine can cause acute pulmonary toxicity (adult respiratory distress syndrome), which may lead to a fatal outcome. Fotemustine and dacarbazine should not be used concomitantly. Hepatotoxic medicinal products and alcohol should be avoided during chemotherapy.

Dacacedal® should be used only under constant supervision by clinicians experienced in cancer chemotherapy.

Dosage:

Dosage of dacarbazine must be based on the clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects. Clinicians should consult published protocols for the dosage of dacarbazine and other chemotherapeutic agents and the method and sequence of administration.

Malignant melanoma

Dacarbazine can be administered as single agent in doses of 200 to 250 mg/m2 body surface area/day as an i.v. injection for 5 days every 3 weeks.

As an alternative to an intravenous bolus injection dacarbazine can be administered as a short-term infusion (over 15 – 30 minutes).

It is also possible to give 850 mg/m2 body surface area on day 1 and then once every 3 weeks as intravenous infusion.

Hodgkin’s disease

Dacarbazine is administered in a daily dose of 375 mg/m2 body surface area i.v. every 15 days in combination with doxorubicin, bleomycin and vinblastine (ABVD regimen).

Adult soft-tissue sarcoma

For adult soft tissue sarcomas dacarbazine is given in daily doses of 250 mg/m2 body surface area i.v. (days 1 – 5) in combination with doxorubicin every 3 weeks (ADIC regimen).

During dacarbazine treatment frequent monitoring of blood counts should be conducted as well as monitoring of hepatic and renal function. Since severe gastrointestinal reactions frequently occur, antiemetic and supportive measures are advisable.

Because severe gastrointestinal and hematological disturbances can occur an extremely careful benefit-risk analysis has to be made before every course of therapy with dacarbazine.

Method of administration

Preparation for intravenous administration

1. a) Preparation of Dacarbazine 100 mg:

Aseptically transfer 10 ml of water for injection into the vial and shake until a solution is obtained. This freshly prepared solution containing 10 mg/ml dacarbazine. Solutions further diluted with 200-300 mL of 5% dextrose or 0.9% sodium chloride injection.

1. b) Preparation of Dacarbazine 200 mg:

Aseptically transfer 20 ml of water for injection into the vial and shake until a solution is obtained. This freshly prepared solution, containing 10 mg/ml of dacarbazine. Solutions further diluted with 200-300 mL of 5% dextrose or 0.9% sodium chloride injection

Dacarbazine is administered by IV injection or infusion. Care should be taken to avoid extravasation of the drug. Reconstituted solutions may be administered by IV push over a 1-minute period. Alternatively, the reconstituted solution may be further diluted with 200-300 mL of 5% dextrose or 0.9% sodium chloride injection and infused IV over a 15- to 30-minute period. It is recommended to test the patency of the vein first with a 5- to 10-ml flush of 0.9 % sodium chloride or 5 % glucose infusion solution. The same solutions should be used after infusion to flush any remaining medicinal product from the tubing. The manufacturer’s labeling should be consulted for information on reconstitution and further dilution of other strengths of the powder for injection.

Frequency not defined

Central nervous system: Infusion-site pain

Dermatologic: Alopecia

Gastrointestinal: Nausea and vomiting (>90%), anorexia

Hematologic & oncologic: bone marrow depression (onset: 5 to 7 days; nadir: 7 to 10 days; recovery: 21 to 28 days), leukopenia, thrombocytopenia

<1%

postmarketing, and/or case reports: Anaphylaxis, anemia, diarrhea, dysgeusia, eosinophilia, erythema, facial flushing, facial paresthesia, flu-like symptoms (fever, myalgia, malaise), hepatic necrosis, increased liver enzymes (transient), paresthesia, renal function test abnormality, skin photosensitivity, skin rush, urticaria, venous obstruction (hepatic vein)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Please report any adverse drug reactions via contacting Cedal Nano. (1)

OVERDOSAGE:

The primary anticipated complications of overdose are severe bone marrow suppression, eventually bone marrow aplasia which may be delayed by up to two weeks. Time to occurrence of nadirs of leucocytes and thrombocytes can be 4 weeks. Even if overdose is only suspected, long-term careful haematologic monitoring is essential.

There is no known antidote for dacarbazine overdose. Therefore, special care has to be taken to avoid overdose of this medicinal product. Give supportive treatment and monitor blood cell counts.

In case of previous or concomitant treatment having adverse effects on the bone marrow (particularly cytostatic agents, irradiation) myelotoxic interactions are possible.

Studies to investigate the presence of phenotypic metabolism have not been undertaken but hydroxylation of the parent compound to metabolites with anti-tumour activity has been identified.

Dacarbazine is metabolised by cytochrome P450 (CYP1A1, CYP1A2, and CYP2E1). This has to be taken into account if other medicinal products are co-administered which are metabolised by the same hepatic enzymes.

Dacarbazine can enhance the effects of methoxypsoralen because of photosensitization.

Immunisation with live vaccines should be avoided during therapy with dacarbazine due to the risk of serious and potentially fatal infections. It is advised to use live virus vaccines with caution after stopping chemotherapy and vaccinate not sooner than 3 months after the last dose of chemotherapy. It is recommended to use an inactivated vaccine if available.

Risk of thrombosis is increased in malignant diseases; therefore, use of concomitant anticoagulation is common. If the patient is to receive oral anticoagulants, the frequency of INR monitoring must be increased due to large interindividual variability in coagulation and due to possible interaction between anticoagulants and cytostatics.

Concomitant use with phenytoin may cause reduced absorption of phenytoin from the gastrointestinal tract and may predispose the patient to convulsions.

Concomitant use of cyclosporine (and in some cases tacrolimus) must be considered carefully because these agents may cause excessive immunosuppression and lymphoproliferation. Concomitant use of fotemustine can cause acute pulmonary toxicity (adult respiratory distress syndrome). Fotemustine and dacarbazine should not be used concomitantly.

Pregnancy

Dacarbazine has been shown to be mutagenic, teratogenic and carcinogenic in animals and has been shown to be teratogenic in rats when given in doses 20 times the human daily dose on day 12 of gestation. Dacarbazine, 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, dacarbazine daily dose 7 times the human daily dose given on days 6 to 15 of gestation resulted in fetal skeletal anomalies. There are no adequate and well-controlled studies in pregnant women. Dacarbazine for injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, the potential for tumorigenicity shown for dacarbazine for injection in animal studies and because of the carcinogenic potential of dacarbazine in nursing infants, 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.

Pediatric Use

Dacarbazine is not recommended for use in the pediatric age group until further data become available.

Fertility

The effect of dacarbazine on fertility in humans is not known. Reproduction studies in male rats using dacarbazine dosages 10 times the usual human dosage have not revealed evidence of impaired fertility; however, in female rats receiving dacarbazine, fetal resorptions occurred more frequently than in rats receiving placebo. However, men are advised to take contraceptive measures during and for 6 months after cessation of therapy. Women of child-bearing potential have to use effective contraception during treatment.

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.

How Supplied

Dacacedal® is supplied as vials containing dacarbazine equivalent to 100 mg and 200 mg as a powder for solution for injection.

Store unopened vials at 2° to 8°C (36°-46°F). Keep vial in outer carton to protect from light and moisture.

Incompatibilities

Dacarbazine solution is chemically incompatible with heparin, hydrocortisone, L-cysteine and sodium succinate.

Shelf life

Shelf life of the reconstituted solution of Dacacedal® 100 mg and 200 mg

Dacarbazine solutions containing 10 mg/mL in sterile water for injection are stable for up to 8 hours when stored at 4°C and at room temperature.

Shelf life of the reconstituted and further diluted solution of Dacacedal® 100 mg and 200 mg

Solutions further diluted with up to 500 mL of 5% dextrose or 0.9% sodium chloride injection are stable for at least 8 hours when stored at 2–8°C and at room temperature (under normal room light conditions).

Special precautions for storage

– Keep the medicine in the box until it is consumed.

– Store in a refrigerator (2 to 8°C) and store away from light, heat and moisture.

– Reconstituted solutions should also be store in a refrigerator (2 to 8°C) and protected from light. 

– Keep the medicine out of the reach of children.

Special precautions for disposal and other handling

Recommendations for safe handling

Dacarbazine is an antineoplastic agent and should be handled according to standard procedures for cytostatics that have mutagenic, carcinogenic and teratogenic effects. Before commencing, local cytotoxic guidelines should be referred to.

Dacarbazine should only be opened by trained staff and as with all cytotoxic agents; precautions should be taken to avoid exposing staff. Handling of cytotoxic medicinal products should be generally avoided during pregnancy. Preparation of solution for administration should be carried out in a designated handling area and working over a washable tray or disposable plastic-backed absorbent paper.

Suitable eye protection, disposable gloves, face mask and disposable apron should be worn. Syringes and infusion sets should be assembled carefully to avoid leakage (use of Luer lock fittings is recommended). On completion, any exposed surface should be thoroughly cleaned and hands and face washed.

In the event of spillage, operators should put on gloves, face masks, eye-protection and disposable apron and mop up the spilled material with an absorbent material tapped in the area for that purpose. The area should then be cleaned and all contaminated material transferred to a cytotoxic spillage bag or bin or sealed for incineration.

Any portion of the contents remaining after use should be discarded, as well as solutions where the visual appearance of the product has changed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.