SUMMARY OF PRODUCT 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 600mg of dacarbazine.

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

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

For 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

Dosage

The following regimes can be used.

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. on day 1

and day 15 in combination with doxorubicin, bleomycin and vinblastine for each cycle of 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).

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 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 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.

Administration

See section 4.4 Precautions for Use

If extravasation occurs, the injection should be discontinued immediately.

Dacarbazine is sensitive to light exposure. All reconstituted solutions should be suitably

protected from light during administration (light-resistant infusion set). Administration is by the intravenous route only.

Dacarbazine 600 mg vials should be reconstituted with 59.1 ml of Water for Injection

BP. The resulting solutions contain the equivalent of 10 mg/ml of dacarbazine and have

a pH of 3 to 4. The resultant solution is hypo-osmolar and therefore should be given by

slow intravenous injection over one to two minutes.

If desired the reconstituted solution can be further diluted 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.

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 15-30

minutes.

Instructions for handling

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.

Excreta and vomit must be handled with care.

Pregnant women must be warned to avoid handling cytotoxic agents.

Any broken container must be treated with the same precautions and considered as

contaminated waste. Contaminated waste should be incinerated in suitably

labelled rigid

containers.

4.3 Contraindications

This medicinal product IS CONTRAINDICATED in cases of:

•    Patients who have demonstrated a hypersensitivity to dacarbazine 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 use

Warnings

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.

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.

Hepatic toxicity, accompanied by hepatic vein thrombosis and hepatocellular necrosis resulting in death, have 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, particulary 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.

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

Cyclosporin (and by extrapolation Tacrolimus): Excessive immunosuppression with risk of lymphoproliferation.

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.

4.6. Pregnancy and lactation

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.

Pregnancy

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

Dacarbazine is contraindicated during pregnancy (see 4.3).

Lactation

Dacarbazine is contraindicated during lactation (see 4.3).

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).

Blood and lymphatic system disorders	Common Anaemia, leukopenia, thrombocytopenia, bone marrow depression
Immune system disorders	Very rare Anaphylaxis, hypersensitivity reactions
Metabolism and nutrition disorders	Common Anorexia
Psychiatric disorders	Uncommon Confusion
Nervous system disorders	Uncommon Headache, seizures, facial paraesthesia, lethargy
Eye disorders	Uncommon Blurred vision
Vascular disorders	Uncommon Facial flushing
Gastrointestinal disorders	Common Nausea, vomiting Rare Diarrhoea
Hepatobiliary disorders	Uncommon Hepatotoxicity, hepatic vein thrombosis, hepatic necrosis, Budd-Chiari Syndrome with potentially fatal outcome
Skin and subcutaneous tissue disorders	Uncommon Alopecia, rash (transient) Rare Photosensitivity Very rare Erythema, urticaria, maculopapular exanthema
Renal and urinary disorders	Uncommon Impaired renal function with increased blood creatinine and increased blood urea
General disorders and administration site conditions	Uncommon Influenza like illness, malaise. Rare Injection site irritation.
Investigations	Uncommon Increased transaminases (AST, ALT), increased alkaline phosphatase, increased lactate dehydrogenase (LDH).

Blood and lymphatic system disorders:

Bone marrow depression, leucopenia, thrombocytopenia and anaemia (see 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.

4.9. Overdose

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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 halflife 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.

6.1    List of excipients

Citric acid monohydrate, mannitol and 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 (25mg/ml).

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

6.3 Shelf life

Before use: 36 months

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.

The 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.

Warning: As with all parenteral products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration. Solution showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

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 disposal

The handling of this cytotoxic agent by nursing or medical personnel requires every precaution to guarantee the protection of the handler and their surroundings (see 4.2 Posology and Method of Administration).

In case of contact of the drug 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.

Before being administered, injectable solution should be visually inspected in order to detect possible presence of particles of discolouration.

Preparation Guidelines

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

Dacarbazine solutions should be prepared immediately before use. Before being administered, injectable solution should be visually inspected in order to detect possible presence of particles of 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.

Aseptically transfer the required amount of water for injections into the vial and shake until a solution is obtained. The solution should be clear, colourless and free from visible particles. The resultant solution should be injected intravenously over one to two minutes.

If desired the reconstituted solution can be further diluted with 125-250m1 of Dextrose Injection 5% or Sodium Chloride Injection 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 light-resistant PVC infusion sets. If normal infusion sets are used, then these should be covered to protect from light.

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.

MARKETING AUTHORISATION HOLDER

Hospira UK Limited

Horizon

Honey Lane

Hurley

Maidenhead

SL6 6RJ

UK

8    MARKETING AUTHORISATION NUMBER

04515/0122

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/11/2005

10    DATE OF REVISION OF THE TEXT

21/12/2015