Dacarbazine for injection BP 600mg (Hospira UK Ltd)

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1. Name Of The Medicinal Product

Dacarbazine for Injection BP 600mg

2. Qualitative And Quantitative Composition

Each vial contains 600mg of dacarbazine. When reconstituted each ml of solution contains 10mg of dacarbazine.

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

1. Metastatic malignant melanoma

2. Sarcoma

3. Hodgkin's disease.

In addition, dacarbazine has been shown, when used in combination with other cytotoxic agents, to be of use in the treatment of other malignant diseases including: carcinoma of the colon, ovary, breast, lung, testicular teratoma, and solid tumours in children.

4.2 Posology And Method Of Administration

Dosage

Standard dose: The following dosage schedules are recommended:

1. 2.0-4.5mg/kg/day for 10 days, which may be repeated at 4 week

intervals.

2. 250mg/m?/day for five days, which may be repeated at 3 week intervals.

3. A further alternative is to administer the total schedule dose on the first day.

Other schedules may be used at the discretion of the prescribing physician.

Children:

The dosage for children is calculated on a mg/kg or mg/m? basis as per the standard dosage. There is no indication that children require a different dosage range or metabolise or react differently to the drug.

Geriatric:

As for paediatric use.

With Impaired Hepatic Function

As the drug partly undergoes metabolism in the liver, impairment of liver function is likely to necessitate a reduction in dosage.

With Impaired Renal Function

As the drug is excreted 50% unchanged in the urine by tubular secretion, impairment of renal function is likely to necessitate a reduction in dosage.

Administration

Administration is by the intravenous route only.

Dacarbazine 600mg vials should be reconstituted with 59.1ml of Water for Injections BP. The resulting solution contains the equivalent of 10mg/ml of dacarbazine and has a pH of 3 to 4. The resultant solution should be injected intravenously over one to two minutes.

If desired the reconstituted solution can be further diluted with 125-250ml of Dextrose Injection BP 5% or Sodium Chloride Injection BP 0.9% and administered by intravenous infusion over 15-30 minutes.

4.3 Contraindications

Dacarbazine is contraindicated in patients who have demonstrated a hypersensitivity to Dacarbazine in the past.

Dacarbazine should not be administered to patients who are pregnant or may become pregnant or breast feeding mothers.

Patients who have previously had severe myelosuppression.

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.

Precautions

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.

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

Restriction of food and oral fluids 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. Administration of an anti-emetic may also reduce the severity of these effects.

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

Care must be taken to avoid extravasation during intravenous administration as this may cause tissue damage and severe pain.

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

Microsomal liver enzyme inducer e.g. barbiturates, rifampicin, phenytoin may theoretically hasten the activation of dacarbazine to aminoimidazole-carboxamide.

Mercaptopurine, azathioprine, allopurinol: dacarbazine inhibits xanthine oxidase and may theoretically potentiate the activity of these drugs.

Patients receiving Dacarbazine should not receive immunisation with live vaccines. Dacarbazine may impair the immunological response to the vaccine with the development of a generalised vaccinia.

4.6 Pregnancy And Lactation

Studies have demonstrated that this agent is carcinogenic and teratogenic when administered to animals. Dacarbazine therefore should not be administered to pregnant or lactating women unless the benefit clearly justifies the potential risk to the foetus.

4.7 Effects On Ability To Drive And Use Machines

Dacarbazine in appropriate doses should not impair the ability to drive. However, rare adverse reactions affecting the nervous system may cause blurred vision, seizures, headache, confusion, malaise and lethargy. Patients affected by these adverse effects should not drive or operate machinery.

4.8 Undesirable Effects

Common Reactions

Symptoms of anorexia, nausea, and vomiting are the most frequent side-effects. Vomiting may last for 1-12 hours.. Nausea and vomiting rarely necessitate discontinuation of therapy. Diarrhoea is a rarer side-effect of Dacarbazine therapy.

It is suggested that restriction of the patient's oral fluid intake and food 4-6 hours prior to treatment may be helpful. The rapid toleration of these symptoms suggests a central nervous system mechanism, and usually these symptoms subside after the first 1-2 days.

Haematological: Bone marrow depression, leucocytopenia, thrombocytopenia and occasionally anaemia.

Haemopoietic toxicity may warrant temporary suspension or cessation of Dacarbazine therapy.

Less Common Reactions:

Cardiovascular: Facial flushing

Dermatological: Transient rash, alopecia

General: 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.

Hepatic: Increases in transaminases (AST, ALT), alkaline phosphatase, LDH. Levels usually return to normal within two weeks; hepatic toxicity accompanied by hepatic vein thrombosis and hepatocellular necrosis,(Budd-Chiari Syndrome) resulting in death.

Nervous System: Blurred vision, seizures, headache, facial paraesthesia, confusion, malaise, and lethargy.

Anaphylaxis can occur very rarely following administration of Dacarbazine.

Photosensitivity reactions may occur rarely.

4.9 Overdose

Signs and Symptoms:

Severe bone marrow depression and gastrointestinal effects such as nausea, vomiting and diarrhoea may be expected.

Treatment:

Cease dacarbazine administration and institute supportive measures, e.g. appropriate transfusions for bone marrow suppression.

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 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

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Citric Acid, Mannitol, Sodium Hydroxide.

6.2 Incompatibilities

Dacarbazine is incompatible with hydrocortisone sodium succinate in solution, forming an immediate precipitate.

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

6.3 Shelf Life

The shelf life of the product as packaged for sale is 36 months.

The physical and chemical in use stability of reconstituted solutions has been demonstrated for 96 hours at 2-8°C. Solutions diluted with 5% dextrose or 0.9% sodium chloride have demonstrated physical and chemical in use stability for 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 / dilution has taken place in controlled and validated aseptic conditions.

Dacarbazine is photosensitive with exposure to light causing a colour change from pale yellow to pink. The product or reconstituted solution should not be used if it appears pink in colour.

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.

6.5 Nature And Contents Of Container

20mm West Type 1816 S87J freeze-drying rubber closure (Type 1 as defined by the Ph.Eur).

100ml amber Type1 glass vials with or without Onco-Tain™ shrink wrapping

Aluminium cap with plastic 'flip-off' top.

6.6 Special Precautions For Disposal And Other Handling

Cytotoxic Handling Guidelines

Dacarbazine for Injection should only be prepared for administration by professionals who have been trained in the safe use of the preparation. Preparation should only be carried out in an aseptic cabinet or suite dedicated for the assembly of cytotoxics.

In the event of spillage, operators should put on gloves and mop up the spilled material with an absorbent material kept in the area for that purpose. The procedure should be repeated and the area rinsed with water. Repeat if necessary. All contaminated material must be transferred to a cytotoxic spillage bag or bin and sealed for incineration.

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. Dacarbazine is sensitive to light exposure.

Aseptically transfer 59.1ml of water for injections into the Dacarbazine 600mg 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 125-250ml 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.

Administrative Data 7. Marketing Authorisation Holder

Mayne Pharma Plc

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

United Kingdom

8. Marketing Authorisation Number(S)

PL 04515/0122

9. Date Of First Authorisation/Renewal Of The Authorisation

29 November 2000

10. Date Of Revision Of The Text

15th May 2003

Dacarbazine for injection BP 600mg Hospira UK Ltd

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