DACARBAZINE Powder for solution for injection or infusion Ref.[2694] Active ingredients: Dacarbazine

Posology

The use of dacarbazine should be confined to physicians experienced in oncology or haematology.

Dacarbazine is sensitive to light exposure. All reconstituted solutions should be suitably protected from light also during administration (light-resistant infusion set).

Care should be taken when administering 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.

The following regimes may be used. For further details see current scientific literature.

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 haematological disturbances can occur an extremely careful benefit-risk analysis has to be made before every course of therapy with dacarbazine.

Duration of therapy

The treating physician should individually decide about the duration of therapy 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 advanced Hodgkin’s disease, a usual recommendation is to administer 6 cycles of ABVD combination therapy. In metastasised malignant melanoma and in advanced tissue sarcoma, the duration of treatment depends on the efficacy and tolerability in the individual patient.

Patients with kidney / liver insufficiency

If there is mild to moderate renal or hepatic insufficiency alone, a dose reduction is not usually required. In patients with combined renal and hepatic impairment elimination of dacarbazine is prolonged. However, no validated recommendations on dose reductions can be given currently.

Elderly patients

As limited experience in elderly patients is available no special instructions for the use in elderly patients can be given.

Paediatric population

The safety and efficacy of dacarbazine in children/adolescents aged <15 years have not yet been established. No special recommendations for the use of dacarbazine in the paediatric age group can be given until further data become available.

Method of administration

Rate of administration

Doses up to 200 mg/m² may be given as a slow intravenous injection. Larger doses (ranging from 200 to 850 mg/m²) should be administered as an i.v. infusion over 15-30 minutes.

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.

After reconstitution with water for injections without further dilution with 0.9% sodium chloride or 5% glucose infusion solution, dacarbazine 100 mg and 200 mg preparations are hypo-osmolar (ca. 100 mOsmol/kg) and should therefore be given by slow intravenous injection e.g. over 1 minute rather than rapid intravenous bolus over a few seconds.

Precautions to be taken before handling or administering the medicinal product

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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.

Shelf life: 3 years.

Shelf life of the reconstituted solution of Dacarbazine medac 100 mg (200 mg): Chemical and physical in-use stability has been demonstrated for 24 hours at 20°C protected from light.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally be no longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Shelf life of the reconstituted and further diluted solution of Dacarbazine medac 100 mg (200 mg): The reconstituted and further diluted solution must be used immediately.

Shelf life of the reconstituted and further diluted solution of Dacarbazine medac 500 mg (1000 mg): The reconstituted and further diluted solution must be used immediately.

Do not store above 25°C.

Keep the vial in the outer carton in order to protect from light. Reconstituted solutions should also be protected from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Dacarbazine medac 100 mg (200 mg) is supplied as a sterile powder for solution for injection/infusion in single-dose vials made of amber glass (Type I, Ph.Eur.) and closed with butyl rubber stoppers. Each carton of Dacarbazine medac 100 mg (200 mg) contains 10 vials.

Dacarbazine medac 500 mg (1000 mg) is supplied as a sterile powder for solution for infusion in single-dose vials made of amber glass (Type I, Ph.Eur.) and closed with butyl rubber stoppers. Each carton of Dacarbazine medac 500 mg (1000 mg) contains one vial.

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.

Preparation for intravenous administration

Dacarbazine-solutions are prepared immediately before use.

Dacarbazine is sensitive to light exposure. During administration, the infusion container and administration set should be protected from exposure to daylight, e.g. by using light-resistant PVC-infusion sets. Normal infusion sets should be wrapped up in e.g. UV-resistant foils.

a) Preparation of Dacarbazine medac 100 mg:

Aseptically transfer 10 ml of water for injections into the vial and shake until a solution is obtained. This freshly prepared solution containing 10 mg/ml dacarbazine (density of the solution: ρ = 1.007 g/ml) is administered as a slow injection.

For preparation of Dacarbazine medac 100 mg for i.v. infusion the freshly prepared solution is further diluted with 200-300 ml 0.9% sodium chloride or 5% glucose infusion solution. This solution is given as a short term infusion over a period between 15-30 minutes.

b) Preparation of Dacarbazine medac 200 mg:

Aseptically transfer 20 ml of water for injections into the vial and shake until a solution is obtained. This freshly prepared solution, containing10 mg/ml of dacarbazine, (density of the solution: ρ = 1.007 g/ml) is administered as a slow injection.

For preparation of Dacarbazine medac 200 mg for i.v. infusion the freshly prepared solution is further diluted with 200-300 ml 0.9% sodium chloride or 5% glucose infusion solution. This solution is given as a short term infusion over a period between 15-30 minutes.

c) Preparation of Dacarbazine medac 500 mg:

Aseptically transfer 50 ml water for injections into the vial and shake until a solution is obtained. The resulting solution, containing 10 mg/ml of dacarbazine (density of solution: ρ = 1.007 g/ml) has to be further diluted with 200-300 ml sodium chloride or 5% glucose infusion solution. The obtained infusion solution, containing 1.4-2.0 mg/ml of dacarbazine, is ready for i.v. infusion and should be given within 20-30 minutes.

d) Preparation of Dacarbazine medac 1000 mg:

Aseptically transfer 50 ml water for injections into the vial and shake until a solution is obtained. The resulting solution, containing 20 mg/ml of dacarbazine (density of solution: ρ = 1.015 g/ml) has to be further diluted with 200-300 ml 0.9% sodium chloride or 5% glucose infusion solution. The obtained infusion solution, containing 2.8-4.0 mg/ml of dacarbazine, is ready for i.v. infusion and should be given within 20-30 minutes.

Dacarbazine medac 100 mg (200 mg, 500 mg, 1000 mg) is for single use only.

The diluted solution for infusion should be visually inspected and only clear solutions practically free from particles should be used. Do not use the solution if particles are present.

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.