DACARBAZINE 600 MG POWDER FOR SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Dacarbazine 600 mg, powder for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single-dose vial contains 600 mg of dacarbazine.

When reconstituted each ml of solution contains 10 mg of dacarbazine.

The use of dacarbazine should be confined to physicians experienced in oncology or haematology. See also section 4.4.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection.

A white or pale yellow powder or plug.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

Further indications for dacarbazine as part of combination chemotherapy are:

Hodgkin’s disease

Advanced adult soft tissue sarcomas (except mesothelioma, Kaposi sarcoma)

4.2 Posology and method of administration

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

Dosage

The following regimes can be used.

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 intravenousin­fusion.

Dacarbazine is administered in a daily dose of 375 mg/m2 body surface area i.v. on day 1 and day 15 in combination with doxorubicin, bleomycin and vinblastine for each cycle of ABVD regimen.

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).

Restriction of food intake for 4–6 hours prior to treatment may reduce the severity of the nausea and vomiting which occurs in most patients particularly during the first two days of treatment.

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 (see section 4.4).

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 adverse effects of dacarbazine. In Hodgkin’s disease, the recommended cycles for administration of ABVD combination therapy ranges between 3 to 8 cycles of therapy based on the stage of disease and the treatment response. 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 use in elderly patients can be given.

Method of Administration

Administration is by the intravenous route only.

If extravasation occurs, the injection should be discontinued immediately (see section 4.4).

It is recommended to test the patency of the vein first with a 5– to 10-ml flush of sodium chloride infusion solution or glucose 5 %. The same solutions should be used after infusion to flush any remaining drug from the tubing.

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 1530 minutes.

After reconstitution with water for injection without further dilution with sodium chloride infusion solution or glucose 5 %, 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.

For instructions on reconstitution and dilution of the medicinal product before administration, (see section 6.6).

4.3 Contraindications

This medicinal product IS CONTRAINDICATED in cases of:

Patients who have demonstrated hypersensitivity to dacarbazine, or to any of the excipients listed in section 6.1, in the past

Patients with severe liver or kidney diseases

Pregnancy and lactation

In combination with yellow fever vaccine.

4.4 Special warnings and precautions for useWarnings

Haemopoietic depression is the most common toxic side effect of dacarbazine and involves primarily the leucocytes and platelets, although mild anaemia may sometimes occur. Leucopenia and thrombocytopenia may be severe enough to cause death.

Long-term therapy can cause cumulative bone marrow toxicity.

Possible bone marrow depression requires careful monitoring of white blood cells, red blood cells and platelet levels. Such toxicity may necessitate temporary suspension or cessation of 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.

Hepatic toxicity, accompanied by hepatic vein thrombosis and hepatocellular necrosis resulting in death, has been reported. The incidence of such reactions has been low. This toxicity has been observed mostly when dacarbazine has been administered concomitantly with other anti-neoplastic drugs; however, it has also been reported in some patients treated with dacarbazine alone. Therefore frequent monitoring of liver size, function and blood counts (especially eosinophils) is required (see section 4.8).

It is recommended that dacarbazine be administered by physicians experienced in the use of cytotoxic therapy. Laboratory facilities should be available for blood monitoring.

The drug can produce severe and possibly fatal, haematologic or hepatic toxicity and severe GI reactions and should be administered to patients preferably within the hospital setting, where they can be observed frequently during and after therapy, particularly with regards to the haemopoietic toxicity.

The concomitant use of dacarbazine with phenytoin, or live attenuated vaccines is not recommended (see section 4.5).

Precautions for use

Hepatotoxic drugs and alcohol should be avoided during chemotherapy.

Administration of an anti-emetic may also reduce the severity of gastrointestinal effects.

Impairment of renal and liver function: See dosage in impaired renal and liver function.

If extravasation occurs, tissue damage and severe pain may occur.

Care should be taken to avoid contact with the skin and eyes when reconstituting or administering dacarbazine.

Paediatric use

No recommendations for the use of dacarbazine in paediatric patients are available.

Excipient information

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions common to all cytotoxics

Due to the increase of thrombotic risk in case of tumeral diseases, the use of anticoagulative treatment is frequent. The high variability of the coagulability during diseases, and the eventuality of interaction between oral anticoagulants and anticancer chemotherapy require, if it is decided to treat the patient with oral anticoagulants, to increase frequency of the INR monitoring.

Concomitant use not recommended (see also section 4.4)

Yellow fever vaccine: risk of fatal systemic vaccinal disease.

Live attenuated vaccines: risk of systemic, possible fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease.

Use an inactivated vaccine where this exists (poliomyelitis).

Phenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin (see section 4.4)

Concomitant use to take into consideration

Ciclosporin (and by extrapolation tacrolimus): Excessive immunosuppression with risk of lymphoprolife­ration.

Dacarbazine can enhance the effects of methoxypsoralen because of photosensitization.

Specific interactions of dacarbazine (high dose) requiring precautions of use Fotemustine: can cause acute lung toxicity (adult respiratory distress syndrome). Fotemustine and dacarbazine should not be used concomitantly. Dacarbazine should be administered over one week after fotemustine administration.

Metabolic interactions

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

4.6 Fertility, pregnancy and lactation

Pregnancy

For dacarbazine no clinical data on exposed pregnancy are available. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Dacarbazine is contraindicated during pregnancy (see section 4.3).

Breastfeeding

Dacarbazine is contraindicated during lactation (see section 4.3).

Contraceptive measures

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

Women of childbearing age should use effective methods of contraception during the treatment.

4.7. Effects on Ability to Drive and Use Machines

Dacarbazine may influence the ability to drive or operate machinery in cases of nausea and vomiting or rare adverse reactions affecting the nervous system.

4.8 Undesirable effects

Adverse event frequencies have been categorised as follows: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

*Symptoms of hepatic necrosis included fever, eosinophilia, abdominal pain, enlarged liver, jaundice and shock.

Blood and lymphatic system disorders

Bone marrow depression, leucopenia, thrombocytopenia and anaemia (see section 4.4). Clinical consequences of leucopenia may be fever, infections and sepsis.

Gastrointestinal disorders

Symptoms of anorexia, nausea, and vomiting are the most frequent side-effects. Vomiting may last for 1–12 hours. Rarely have intractable nausea and vomiting necessitated discontinuation of therapy.

Hepatobiliary disorders

Increases in transaminases (AST, ALT), alkaline phosphatase, LDH. Levels usually return to normal within two weeks.

General disorders and administration site conditions

Infrequently some patients have experienced an influenza type syndrome of fever, myalgias and malaise. This syndrome usually occurs after large single doses and approximately seven days after treatment with dacarbazine and lasts 7–21 days, and may reoccur with successive treatments. Venous irritation and some of the systemic adverse reactions are thought to result from formation of photodegradation products.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9

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 overdosage is only suspected, long-term careful haematological monitoring is essential and supportive measures, e.g. appropriate transfusions for bone marrow suppression may be required. There is no known antidote for dacarbazine overdose. Therefore, special care has to be taken to avoid overdose of this drug.

5.1 Pharmacodynamic properties

ATC: L01AX04

Dacarbazine is an imidazole dimethyltriazene with reproducible activity in patients with metastatic melanoma. The structure of dacarbazine bears a striking resemblance to the metabolite 5-aminoimidazole-4-carboxamide (AIC) which is converted to inosinic acid by enzymes involved in purine synthesis.

It was therefore initially thought to act as an antimetabolite, by inhibiting purine metabolism and nucleic acid synthesis. However the similarity of structure is of little relevance since dacarbazine is extensively metabolised by the cytochrome P450 system in the liver by N-demethylation reaction. The monomethyl derivative then spontaneously cleaves to yield AIC and an intermediate compound, probably diazomethane, which decomposes to produce the methyl carbonium ion. This ion attached to nucleophilic groups on nucleic acids and other macromolecules, thus acting as an alkylating agent. The 7-position of guanine on DNA is especially susceptible to alkylation.

Dacarbazine is thought to act as an alkylating agent in man. It interferes with the synthesis of DNA, RNA and proteins but its cytotoxicity is not specific for any phase of the cell cycle. In general, it is most effective in inhibiting synthesis of RNA. Dacarbazine kills cells slowly and no immunosuppressive action has been shown in man. There are no systemic studies of dose-response effects but one anecdotal report has suggested that there may be an increased chance of response as the dose increases.

Dacarbazine undergoes spontaneous photodegradation in light, decomposing into 5-diazoimidazole-4-carboxamide and dimethylamine. 5-Diazoimidazole-4-carboxamide can attack nucleophilic groups of DNA and also undergoes structural rearrangement to form 2-azahypoxanthine. However, the products of photodegradation of dacarbazine probably do not contribute greatly to its cytotoxicity, although they may be implicated in the local burning pain on intravenous injection and systemic problems associated with the drug.

5.2 Pharmacokinetic properties

The volume of distribution of dacarbazine exceeds body water content, suggesting localisation in some body tissues, probably the liver. Dacarbazine is only slightly (approximately 5%) bound to plasma proteins. Its plasma half-life after intravenous administration is approximately 35 minutes. In animal studies, approximately 46% of radio-labelled dose was recovered from the urine after 6 hours. Of this 46%, almost half, was unchanged dacarbazine and a similar quantity was amino-imidazole carboxamide, a metabolite. Dacarbazine is subject to renal tubular secretion rather than glomerular filtration.

Dacarbazine crosses the blood-brain barrier to a limited extent; CSF concentrations are reported to be about 14% of plasma concentrations. It is not known if dacarbazine crosses the placenta or distributes into milk.

5.3 Preclinical safety data

Because of its pharmacodynamic properties, dacarbazine shows mutagenic, carcinogenic and teratogenic effects which are detectable in experimental test systems.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid monohydrate,

Mannitol (E421),

Sodium hydroxide.

6.2 Incompatibilities

Dacarbazine is incompatible with hydrocortisone sodium succinate in solution, forming an immediate precipitate. It is also incompatible with L-cysteine and sodium hydrogen carbonate.

It has been reported to be incompatible with heparin, although only with concentrated solutions (25 mg/ml).

Dacarbazine must not be mixed with other medicinal products except those mentioned in 6.6.

6.3 Shelf life

Before use: 3 years.

6.4 Special precautions for storage

Store at 2–8°C. Keep vial in the outer carton.

The reconstituted and diluted solutions should be protected from light.

Physical and chemical in-use stability:

Storage conditions

Reconstituted solution                         ­24 hours at 2–8°C

Further diluted with 5% dextrose or

0.9% sodium chloride                         ­24 hours at 2–8°C

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 not be longer than 24 hours at 2 to 8°C, unless reconstitution or dilution has taken place in controlled and validated aseptic conditions.

6.5 Nature and contents of container

1368,6 mg of powder in 100 ml amber type I glass vials with 20 mm west type

I 1816

S87J freeze-drying rubber closure and aluminium cap with plastic flip-off top, and with

or without Onco-tain shrink wrapping.

6.6 Special precautions for disposalInstructions for handling

The handling of this cytotoxic agent by nursing or medical personnel requires every precaution to guarantee the protection of the handler and their surroundings.

The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicines used, in conditions that guarantee the protection of the environment and, in particular, the protection of the personnel handling the medicines. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area.

Personnel must be provided with appropriate handling materials, notably long sleeved gowns, protection masks, caps, protective goggles, sterile single-use gloves, protective covers for the work area and collection bags for waste.

In case of contact of the medicinal product with the eye, wash the eye thoroughly with water. If the substance is splashed accidentally onto the skin, wash the skin with large amounts of water and then with a soft soap. Rinse thoroughly.

Excreta and vomit must be handled with care.

Pregnant women must be warned to avoid handling cytotoxic agents.

Any broken container must be treated as contaminated waste (see Disposal).

All operations such as reconstitution and dilution should be carried out only under aseptic conditions in a suite or cabinet dedicated for the assembly of cytotoxics.

Dacarbazine 600 mg vials should be reconstituted with 59.1 ml of Water for Injections BP. Aseptically transfer the required amount of water for injections into the vial and shake until a solution is obtained. The resulting solution contains the equivalent of 10 mg/ml of dacarbazine and have a pH of 3 to 4. The resulting solution is hypo-osmolar and therefore should be given by slow intravenous injection over one to two minutes.

Dacarbazine is sensitive to light. Reconstituted solutions should be suitably protected from light.

If desired the reconstituted solution can be further diluted under aseptic conditions with 125–250 ml of Dextrose Injection BP 5% or Sodium Chloride Injection BP 0.9% and administered by intravenous infusion over 15–30 minutes. During administration, the infusion set should be protected from exposure to daylight e.g. by using lightresistant PVC infusion sets. If normal infusion sets are used, then these should be covered to protect from light.

Doses up to 200 mg/m2 may be given as slow intravenous injection. Larger doses (ranging from 200 to 850 mg/m2) should be administered as an i.v. infusion over 1530 minutes.

Before being injected, the solution should be visually inspected in order to detect particulate matter or discolouration. Dacarbazine is photosensitive, with exposure to light causing a colour change from pale yellow to pink. The product should not be used if it appears pink in colour. Intravenous infusions should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration. Infusions showing haziness, particulate matter, precipitation, discolouration or leakage should not be used.

Discard any unused portion.

Disposal

Vials, materials that have been utilised for dilution, and any other contaminated material should be placed in a thick plastic bag or other impervious container and incinerated.

7.

Hospira UK Limited Horizon

Honey Lane Hurley Maidenhead

SL6 6RJ

UK

04515/0122

Date of first authorisation: 29 November 2000

Date of latest renewal: 29 November 2005