Consumer medicine information

DBL Dacarbazine for Injection

Dacarbazine

BRAND INFORMATION

Brand name

DBL Dacarbazine for Injection

Active ingredient

Dacarbazine

Schedule

SUMMARY CMI

DBL™ Dacarbazine for Injection

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being treated with DBL Dacarbazine for Injection?

DBL Dacarbazine for Injection contains the active ingredient dacarbazine. DBL Dacarbazine for Injection is used to treat some types of cancers: melanoma (skin cancer) that have spread and sarcoma (cancer which occurs in bone and/or soft tissue).

For more information, see Section 1. Why am I being treated with DBL Dacarbazine for Injection? in the full CMI.

2. What should I know before treatment with DBL Dacarbazine for Injection?

You should not be given DBL Dacarbazine for Injection if you have ever had an allergic reaction to dacarbazine or any of the ingredients listed at the end of the CMI, are pregnant, or are breastfeeding. Talk to your doctor if you have any other medical conditions, take any other medicines, or plan to become pregnant.

For more information, see Section 2. What should I know before treatment with DBL Dacarbazine for Injection? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DBL Dacarbazine for Injection and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is DBL Dacarbazine for Injection given?

The dose of medicine given to you will depend on your condition, weight, height, how well your kidneys and liver are working and whether you are being given any other medicines at the same time.

More instructions can be found in Section 4. How is DBL Dacarbazine for Injection given? in the full CMI.

5. What should I know while being treated with DBL Dacarbazine for Injection?

Things you should do	Remind any doctor, dentist, pharmacist and nurse who are treating you that you are being given this medicine. If you plan to be vaccinated within a year of being given DBL Dacarbazine for Injection, tell the doctor before you are vaccinated. Males should use effective contraception during and for at least 3 months after stopping treatment. Females should use effective contraception while receiving this medicine and for at least 6 months after stopping treatment. If you become pregnant while you are being given DBL Dacarbazine for Injection, tell your doctor immediately. Keep all of your doctor's appointments so your progress can be checked.
Things you should not do	Do not breastfeed while you are being treated with DBL Dacarbazine for Injection.
Driving or using machines	Do not drive or operate machinery until you know how DBL Dacarbazine for Injection affects you. Dacarbazine may affect your ability to drive or operate machinery as it can cause nausea, vomiting, dizziness, tiredness and confusion in some people.

For more information, see Section 5. What should I know while being treated with DBL Dacarbazine for Injection? in the full CMI.

6. Are there any side effects?

Side effects include nausea, vomiting, diarrhoea, skin rash or itching, hair loss, headache, tiredness, flushing in the face, dizziness upon standing, blurred vision; confusion; tingling, numbness of the skin or pins and needles sensation. Serious side effects include severe allergic reaction (shortness of breath; wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin); signs of infection (fever, chills, muscle pain, sore or inflamed mouth); unusual bleeding or bruising (including black stools, blood in your stools or urine or pinpoint red spots on your skin); pain or irritation at the injection site; seizures; severe abdominal pain or swelling and yellowing of the skin or eyeballs.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

DBL™ Dacarbazine for Injection

Active ingredient(s): dacarbazine

Consumer Medicine Information (CMI)

This leaflet provides important information about using DBL Dacarbazine for Injection. You should also speak to your doctor, nurse or pharmacist if you would like further information or if you have any concerns or questions about using DBL Dacarbazine for Injection.

Where to find information in this leaflet:

1. Why am I being treated with DBL Dacarbazine for Injection?
2. What should I know before treatment with DBL Dacarbazine for Injection?
3. What if I am taking other medicines?
4. How is DBL Dacarbazine for Injection given?
5. What should I know during treatment with DBL Dacarbazine for Injection?
6. Are there any side effects?
7. Product details

1. Why am I being treated with DBL Dacarbazine for Injection?

DBL Dacarbazine for Injection contains the active ingredient dacarbazine. DBL Dacarbazine for Injection belongs to a group of medicines known as antineoplastic or cytotoxic agents. You may also hear it referred to as a chemotherapy medicine. Dacarbazine works by killing cancer cells and stopping cancer cells from growing and multiplying.

DBL Dacarbazine for Injection is used to treat some types of cancers: melanoma (skin cancer) that have spread and sarcoma (cancer which occurs in bone and/or soft tissue).

2. What should I know before treatment with DBL Dacarbazine for Injection?

Warnings

DBL Dacarbazine for Injection should not be given to you if:

you are allergic to dacarbazine, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

you are pregnant or breastfeeding.
you have had any blood disorder with low numbers of red blood cells, white blood cells, or platelets.

Check with your doctor if you have:

any problems with your liver.
any problems with your kidney.
an infection, including shingles and chickenpox or a recent exposure to chickenpox.
a low immune system due to other medicines or treatments.

Tell your doctor if you have an infection or high temperature.

Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

Tell your doctor or dentist if you intend having any dental work while being treated with DBL Dacarbazine for Injection.

DBL Dacarbazine for Injection may increase the incidence of infection, delay healing and gum bleeding. It is therefore recommended that any dental work be completed prior to starting dacarbazine treatment or delayed until blood counts have returned to normal.

Tell your doctor if you intend to receive any vaccinations. Do not receive certain vaccines while you are being treated with DBL Dacarbazine for Injection, and for at least one year after you stop treatment.

DBL Dacarbazine for Injection may lower your body's resistance and if you receive certain vaccines with it, you may get the serious infection the vaccination is meant to prevent.

In addition, other people in close contact with you (such as other persons living in your home) should not take oral polio vaccine (sabin) since there is a chance they could pass the polio virus on to you.

It may be helpful to restrict food intake for 4 - 6 hours prior to being treated with DBL Dacarbazine for Injection as this may reduce the severity of nausea and vomiting you may experience, especially during the first two days of treatment. Discuss medicines that may also help with sickness with your doctor prior to treatment with DBL Dacarbazine for Injection.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Talk to your doctor if you are pregnant or plan to become pregnant.

You should not be given DBL Dacarbazine for Injection if you are pregnant or intend to become pregnant.

DBL Dacarbazine for Injection may cause birth defects. It is recommended that females use effective contraception while receiving this medicine and for at least 6 months after stopping treatment. Males should use effective contraception during and for at least 3 months after stopping treatment.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

You should not breastfeed while you are being treated with DBL Dacarbazine Injection.

It is not known whether dacarbazine passes into breast milk.

3. What if I am taking other medicines?

Tell your doctor, nurse or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines/treatments may interfere with DBL Dacarbazine for Injection and affect how it works.

any medicines which suppress your immune system such as azathioprine, ciclosporin and tacrolimus.
some medicines used to treat gout, such as allopurinol.
medicines used to treat epilepsy such as phenytoin.
barbiturates (such as phenobarbitone, primidone and thiopental sodium) used to treat seizures, help with sleep or as a general anaesthetic for surgery.
rifampicin, an antibiotic used to treat tuberculosis (TB).
levodopa, a medicine used in the treatment of Parkinson's disease.
other medicines used to treat cancers (such as mercaptopurine, fotemustine or interleukin-2), radiation therapy or any other treatment which lowers your immune system.
certain vaccines (such as live vaccines).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DBL Dacarbazine for Injection.

4. How is DBL Dacarbazine for Injection given?

How much is given

Your doctor will decide what dose, how often and how long you will receive it. This depends on your condition and other factors, such as your weight, height, how well your kidneys and liver are working and whether you are being given any other medicines at the same time.

How long it is given for

DBL Dacarbazine for Injection may be given alone or in combination with other drugs.

Several courses of dacarbazine therapy may be needed, depending on your response to treatment. Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any uncontrolled effects have been controlled.

How it is given

DBL Dacarbazine for Injection is given as slow infusion ("drip") into a vein by a doctor or nurse over the period of about one minute.

If you believe you have been given too much DBL Dacarbazine for Injection

As DBL Dacarbazine for Injection will be given to you in hospital or under the supervision of your doctor, it is very unlikely that you will receive an overdose.

If you think that you have been given too much DBL Dacarbazine for Injection or experience severe side effects, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know during treatment with DBL Dacarbazine for Injection?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given DBL Dacarbazine for Injection.

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given this medicine.

If you are going to have surgery, tell the surgeon, anaesthetist or dentist that you are taking this medicine. It may affect other medicines used during surgery.

If you plan to be vaccinated within a year of being given DBL Dacarbazine for Injection, tell the doctor before you are vaccinated.

If you become pregnant while you are being given DBL Dacarbazine for Injection, tell your doctor immediately.

Keep all of your doctor's appointments, and ensure you have all tests your doctor asks you to, so your progress can be checked.

Things you should not do

You should not breastfeed while you are being treated with DBL Dacarbazine for Injection.

Things to be careful of

DBL Dacarbazine for Injection can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

Avoid people who are unwell or have infections.
Be careful when using a toothbrush, dental floss or toothpick. Your doctor, dentist or nurse may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work done.
Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
Avoid contact sports or other situations where bruising or injury may occur.

Your body breaks down dacarbazine and uses it to fight cancer. The breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomit and semen.

In general, precautions to protect other people should be taken while you are receiving chemotherapy and for one week after the treatment period by:

Flushing the toilet twice to dispose of any body fluids and waste.
Wearing gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet.
Wash linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water.
Place soiled disposable nappies and other pads in a plastic bag, seal and dispose into the garbage.
For sexual intercourse, use a barrier method such as a condom.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how DBL Dacarbazine for Injection affects you.

DBL Dacarbazine for Injection may affect your ability to drive or operate machinery as it can cause nausea, vomiting, dizziness, tiredness and confusion in some people. Make sure you know how you react to dacarbazine before you drive a car, operate machinery, or do anything else that could be dangerous.

Drinking alcohol

No information is available.

Looking after your medicine

DBL Dacarbazine for Injection will be stored appropriately in the hospital ward or in the pharmacy.

6. Are there any side effects?

All medicines can have side effects. Some side effects may need medical attention.

See the information below and, if you need to, ask your doctor, nurse or pharmacist if you have any further questions about side effects.

Side effects

Side effects	What to do
nausea, vomiting diarrhoea skin rash or itching hair loss, particularly on the scalp headache tiredness flushing in the face dizziness upon standing (due to a fall in blood pressure) blurred vision confusion tingling, numbness of the skin or pins and needles sensation increased sensitivity of skin to the sun which means you may burn more easily	Speak to your doctor if you have any of these side effects and they worry you.

Serious side effects

Serious side effects

What to do

shortness of breath; wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin (severe allergic reaction)
signs of infection, such as fever, chills, muscle pain, sore, ulcerated or inflamed mouth
unusual bleeding or bruising (including black stools, blood in your stools or urine or pinpoint red spots on your skin)
pain or irritation at the injection site
seizures
severe abdominal pain or swelling
yellowing of the skin or eyeballs

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or nurse or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Some of these side effects (for example, changes in blood cell count, blood pressure, heart and liver function) can only be found when your doctor does tests from time to time to check your progress.

The benefits and side effects of dacarbazine may take some time to occur. Therefore, even after you have finished your treatment with DBL Dacarbazine for Injection you should tell your doctor immediately if you notice any of the side effects listed in this section.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/safety/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What DBL Dacarbazine for Injection contains

Active ingredient (main ingredient)	dacarbazine
Other ingredients (inactive ingredients)	citric acid monohydrate mannitol

Do not take this medicine if you are allergic to any of these ingredients.

What DBL Dacarbazine for Injection looks like

DBL Dacarbazine for Injection is a white or very pale yellow powder. It contains 200 mg dacarbazine supplied in an amber glass vial. It is available in single packs of 1 vial.

AUST R 39954.

Who distributes DBL Dacarbazine for Injection

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedicalinformation.com.au

This leaflet was prepared in November 2024.

™ = Trademark

Published by MIMS February 2025

BRAND INFORMATION

Brand name

DBL Dacarbazine for Injection

Active ingredient

Dacarbazine

Schedule

1 Name of Medicine

Dacarbazine.

2 Qualitative and Quantitative Composition

Each vial contains dacarbazine 200 milligrams.
When reconstituted as directed each mL of the solution contains dacarbazine 10 milligrams.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.
White or very pale yellow powder or plug.

4 Clinical Particulars

4.1 Therapeutic Indications

Chemotherapy of metastatic malignant melanoma and various sarcomas. In other cancers, the available evidence shows dacarbazine to be ineffective or less effective than established regimens.

Note.

The use of dacarbazine is restricted to hospitals with an oncology service.

4.2 Dose and Method of Administration

Dosage.

Adult. There are two commonly used dose regimens.
1. 4.5 milligram/kg/day for 10 days; the 10 day course may be repeated every 4 weeks.

Note.

2 milligram/kg/day for 10 days has been used by one investigator and found to be equally as effective as the higher dose.
2. 250 milligram/m²/day for 5 days; the 5 day course may be repeated every 3 weeks.
In general, effectiveness is likely to be evident after the second course of dacarbazine. Of the 1427 patients with metastatic malignant melanoma treated with dacarbazine, 81 patients (5.7%) had complete remissions and 208 patients (14.6%) had partial remissions with a total response rate of 20.3%. The duration of remissions (partial and complete combined) varied from 5 to 100 weeks. The median remission duration obtained by three principal investigators was about 6 months. Once a patient has relapsed it is unlikely that subsequent courses of dacarbazine will be effective.
Paediatric. No special information submitted to indicate whether or not children require a different dosage range or whether they metabolise the drug differently or react differently to the drug.
Geriatric. As for paediatric use.

Combination therapy.

Combinations of cancer chemotherapeutic agents have often shown an improved response over the use of single agents. This has not been the case in metastatic malignant melanoma except at a very high and toxic dosage of the combinations in small numbers of patients. However, in treatment of various soft tissue sarcomata combinations with doxorubicin and/or vincristine have increased the remission rates. The user should be familiar with the current cancer chemotherapeutic literature.

Method of administration.

Administration is by the intravenous route only.
Reconstitute vial contents by adding 19.7 mL of water for injections to the 200 milligram vial.
The resulting solution is hypotonic and will contain 10 milligram/mL of dacarbazine with a pH of 3 to 4.
Intravenous injection may be given over about one minute. Extravasation of the drug into the surrounding tissue during intravenous administration may result in tissue damage and severe pain.
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.

Dosage adjustments.

With impaired hepatic function.

As the drug partly undergoes metabolism in the liver impairment of liver function is likely to necessitate a variation in dosage (see Section 5.2 Pharmacokinetic Properties).

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 variation in dosage (see Section 5.2 Pharmacokinetic Properties).

Handling precautions.

As with all antineoplastic agents, trained personnel should prepare DBL Dacarbazine for Injection. This should be performed in a designated area (preferably a cytotoxic laminar flow cabinet). Protective gown, mask, gloves and appropriate eye protection should be worn when handling dacarbazine. Where solution accidentally contacts skin or mucosa, the affected area should be immediately washed, thoroughly with soap and water. It is recommended that pregnant personnel not handle cytotoxic agents such as dacarbazine.
Luer-Lock fitting syringes are recommended. Large bore needles are recommended to minimise pressure and possible formation of aerosols. Aerosols may also be reduced by using a venting needle during preparation.
Items used to prepare DBL Dacarbazine for Injection, or articles associated with body waste should be disposed off by placing in a double sealed polythene bag and incinerated at 1100°C.

4.3 Contraindications

Patients who are pregnant or are breastfeeding.
Patients with known hypersensitivity to dacarbazine or any of the excipients.
Patients who have previously had severe myelosuppression.

4.4 Special Warnings and Precautions for Use

Toxicity.

In the treatment of each patient, the physician must weigh carefully the possibility of achieving therapeutic benefit against the risk of toxicity (see below; see Section 4.8 Adverse Effects (Undesirable Effects)).
The drug can produce severe and possibly fatal, haematologic or hepatic toxicity. Administer only to patients in hospitals with an oncology service so that they can be observed carefully and frequently during and after therapy particularly for haematopoietic toxicity.
Haematopoietic depression is the most serious form of toxicity and involves primarily the leucocytes and megakaryocytes causing depression of platelets, but also other blood forming elements. 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 red blood cells, white blood cells and platelet levels. Haematotoxicity may warrant temporary suspension or termination of therapy. The bone marrow depressant effects of dacarbazine may result in an increased incidence of microbial infection, delayed healing and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of dacarbazine therapy, or deferred until blood counts have returned to normal. Patients should be instructed on proper oral hygiene during treatment, including caution in the use of toothbrushes, dental floss and toothpicks.
Hepatic toxicity accompanied by hepatic vein thrombosis and hepatocellular necrosis (Budd-Chiari syndrome) resulting in death has been reported. The incidence of such reactions has been low, approximately 0.01% of patients treated. This toxicity has been observed when dacarbazine has been administered concomitantly with other antineoplastic 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 Adverse Effects (Undesirable Effects)).
Restriction of food intake for 4 to 6 hours prior to treatment may reduce the severity of nausea and vomiting which occurs in most patients particularly during the first 2 days of treatment. In rare cases, intractable nausea and vomiting have necessitated discontinuation of therapy. Administration of an antiemetic may also reduce the severity of these effects.

Impairment of liver and renal disease.

See Section 4.2 Dose and Method of Administration.
Care should be taken to avoid contact with the skin and eyes when reconstituting or administering dacarbazine.
Immunisation with live virus vaccines should only be undertaken with extreme caution (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including dacarbazine, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving dacarbazine. Immunisation with oral poliovirus vaccines should be postponed in people in close contact with the patient, especially family members. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Dacarbazine is metabolised by cytochrome P450 (CYP1A1, CYP1A2, and CYP2E1). This has to be taken into account if other drugs are coadministered which are metabolised by the same hepatic enzymes. Microsomal liver enzyme inducers, e.g. barbiturates, rifampicin, phenytoin, may theoretically hasten the activation of dacarbazine to aminoimidazole-carboxamide (AIC).
The concomitant use of dacarbazine with phenytoin is not recommended due to the 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. It may be advisable to administer an anticonvulsant benzodiazepine (see Section 4.4 Special Warnings and Precautions for Use).

Mercaptopurine, azathioprine, allopurinol.

Dacarbazine inhibits xanthine oxidase and may theoretically potentiate the activity of these medicines.
The incidence or severity of side effects may be altered when dacarbazine is used in combination with other antineoplastic agents. The leucopenic and/or thrombocytopenic effects of dacarbazine may be increased with concurrent or recent therapy with other medications which cause these effects. Additive bone marrow depression may occur if dacarbazine is administered with other bone marrow depressants or with radiation therapy. Dosage adjustment of dacarbazine may be necessary.
Fotemustine and dacarbazine should not be used concomitantly. Sequential administration of dacarbazine (400-1000 milligram/m²) and fotemustine (100 milligram/m²) has been associated with acute lung toxicity, in the form of adult respiratory distress syndrome. Dacarbazine should be administered over one week after fotemustine administration.
It has been reported that dacarbazine reduced the response to levodopa in a patient with Parkinson's disease. The mechanism of this interaction is unclear, but since the plasma levels of levodopa were unchanged, it is unlikely to be due to pharmacokinetic changes.
Administration of dacarbazine may potentiate the replication of live virus vaccines, increase the adverse effects of the vaccine, or decrease the antibody response to the vaccine. Dacarbazine may also suppress the antibody response to killed virus vaccines. Viral vaccines should not be administered for 3 to 12 months after discontinuing immunosuppressive drug treatment (see Section 4.4 Special Warnings and Precautions for Use).
Ciclosporin (and by extrapolation tacrolimus) given with dacarbazine may cause excessive immunosuppression with risk of lymphoproliferation.
It has been noted that administration of dacarbazine and interleukin-2 may result in alterations to the pharmacokinetics of dacarbazine. An increased clearance (of approximately 38%) and volume of distribution (of approximately 36%) have been reported when doses of 2 to 4 x 10⁶ U/m² interleukin-2 were used. This alteration appears to correlate with the dose of interleukin-2 and should be taken into account, particularly when high doses of interleukin-2 are combined with dacarbazine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
Category D: this category specifies drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
The drug is teratogenic and carcinogenic when used in animals. When administered intraperitoneally to rats at doses of 50 or 70 milligram/kg/day (approximately 11 times the human dose), teratogenic effects have been observed, including anomalies of the skeletal system, eyes, cardiovascular system and abdominal wall. Teratogenic effects have also been observed in rabbits administered 10 milligram/kg intraperitoneally. No adequate and well controlled studies have been performed in pregnant women.
Dacarbazine for injection is therefore contraindicated in patients who are pregnant.

Advice on contraception in males and females.

Based on reproductive toxicity and genetic toxicity findings, women of childbearing potential should be advised to use effective contraception during treatment with dacarbazine and for at least 6 months after the last dose.
Based on genetic toxicity findings, male patients should be advised to use effective contraception during treatment with dacarbazine and for at least 3 months after the last dose.
It is not known whether dacarbazine is distributed into breast milk. Due to the potential risk to the infant, dacarbazine is contraindicated in breastfeeding mothers.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. Caution should be taken when driving or using machinery while on this medication as it may cause some undesirable effects (e.g. nausea, vomiting or neurological side effects).

4.8 Adverse Effects (Undesirable Effects)

More common reactions.

Gastrointestinal.

90% of patients experience nausea and vomiting in the first two days of treatment. Diarrhoea may also occur. A degree of tolerance may develop to these effects after about 2 days of treatment. Vomiting lasts 1 to 12 hours. Prophylactic antiemetic therapy with a 5HT₃-blocker or dexamethasone is usually required. Rarely, intractable nausea and vomiting have necessitated discontinuance of dacarbazine therapy.

Haematological.

Bone marrow depression (25%) (see Section 4.8 Adverse Effects (Undesirable Effects), Life threatening reactions).
Leucocytopenia was usually seen 14 days after commencement of therapy but was noted as early as day 10 and, in 10% of patients, as late as day 30 (i.e. 25 days after completion of therapy). The average length of duration was 1 week and the longest, 3 weeks.
Thrombocytopenia was most frequently seen 18 days after commencement of therapy but in 43% of patients it was noted by day 12 and in 10% not until after day 30. The average length of duration was 1 week and the longest 3 weeks.
Eosinophilia has been reported in one patient receiving dacarbazine.
Pancytopenia and anaemia have been reported in patients receiving dacarbazine, frequency unknown.

Less common reactions.

Cardiovascular.

Facial flushing, ECG abnormalities, orthostatic hypotension. Hypotension appears to be associated with high doses (> 850 mg/m²) of dacarbazine and may be dose limiting.

Dermatological.

(1%, usually transient) Rash, alopecia. Photosensitivity reactions have occurred rarely.

General.

(3%) Flu-like syndrome with fever to 39°C, severe myalgias and malaise. This syndrome usually occurs after large single doses approximately 7 days after treatment with dacarbazine and lasts 7 to 21 days. It may recur with successive treatments.

Hepatic.

(5%, usually transient). Increases in transaminases (AST and ALT), alkaline phosphatase, LDH. Levels usually return to normal within 2 weeks. Hepatic toxicity accompanied by hepatic vein thrombosis and hepatocellular necrosis (Budd-Chiari syndrome) resulting in death has been reported (see Section 4.4 Special Warnings and Precautions for Use) (0.01%). A case of acute hepatitis has been reported during the first course of dacarbazine. Granulomatous hepatitis has also occurred.

Nervous system.

(3%, usually transient) Blurred vision, seizures, headache, paraesthesia, confusion, malaise, lethargy.

Local reactions.

Injection of concentrated dacarbazine solutions may cause severe pain along the vein. Extravasation of the drug into surrounding tissue may cause severe pain, tissue damage and cellulitis.

Hypersensitivity.

Anaphylaxis has occurred occasionally.

Dental effects.

Dacarbazine may adversely affect dental procedures (see Section 4.4 Special Warnings and Precautions for Use).

Other.

Dacarbazine may rarely cause stomatitis.

Life threatening reactions.

Bone marrow depression.

Death due to agranulocytosis or thrombocytopenia occurred in about 0.4% of patients in clinical trials.

Fatal hepatotoxicity.

Budd-Chiari syndrome (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

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

Treatment.

There is no specific antidote to dacarbazine poisoning. Cease dacarbazine administration and institute supportive measures, e.g. appropriate transfusions, for bone marrow depression (see Section 4.8 Adverse Effects (Undesirable Effects), Haematological).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia). In New Zealand call 0800 764 766.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Relationship to other drugs: Dacarbazine is a structural analogue of 5-amino-imidazole-4-carboxamide which is an intermediate in purine biosynthesis.

Mechanism of action.

This drug inhibits cell replication by an unknown mechanism. However, three possible mechanisms have been postulated.
1. Since dacarbazine is an analogue of 5-amino-imidazole-4-carboxamide, an intermediate in the de novo biosynthesis of purine, it might interfere with purine biosynthesis and hence DNA biosynthesis. This appears to be true at high concentrations of the drug, but low concentrations appear to enhance DNA, RNA and protein biosynthesis.
2. One metabolite of dacarbazine, diazomethane, is an alkylating agent and may act in the same way as the nitrogen mustards.
3. The drug might act as a sulphydryl reagent since the inhibition of bacterial growth by dacarbazine can be prevented by glutathione.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Dacarbazine is poorly and erratically absorbed from the gastrointestinal tract, which could result in unpredictable tumour responses and possible increased toxicity. Therefore the drug is recommended for intravenous administration only. Peak plasma concentrations of about 8 microgram per mL are reached immediately following administration of dacarbazine 4.5 milligram/kg by intravenous push.

Distribution.

The volume of distribution of dacarbazine exceeds total body water content, suggesting localisation in some body tissue, probably the liver. The drug is only slightly bound to plasma proteins. 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 human placenta or distributes into milk.

Metabolism.

Dacarbazine is N-demethylated by liver microsomal enzymes to yield CO₂ which is excreted in expired air and aminoimidazole-carboxamide (AIC) which is excreted in the urine. About half the drug remains unchanged and is rapidly excreted by tubular secretion.

Excretion.

As dacarbazine is approximately 50% metabolised by the liver and the remaining unchanged drug and metabolites are excreted in the urine, impairment of hepatic or renal function may require a reduction in dosage to avoid toxicity.
Plasma concentrations of dacarbazine appear to decline in a biphasic manner. The initial phase half-life (t_1/2_α) is very short, with one study reporting t_1/2_α as 2.9 minutes. The terminal phase half-life (t_1/2_β) is consistently longer 41.4 to 75 minutes. In one patient with renal and hepatic dysfunction, the t_1/2_α was 55 minutes and the t_1/2_β was 7.2 hours.

5.3 Preclinical Safety Data

Genotoxicity.

Dacarbazine has been shown to be mutagenic in bacteria and produced evidence of both clastogenicity and mutagenicity in mammalian cells in vitro. In addition, dacarbazine has shown clastogenicity to mouse bone marrow in vivo. These results are consistent with the pharmacological activity of dacarbazine, which is a methylating cytostatic drug.

Carcinogenicity.

The drug is carcinogenic when used in animals.

6 Pharmaceutical Particulars

6.1 List of Excipients

Citric acid monohydrate, Mannitol.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Reconstituted vials are chemically stable for up to 8 hours if stored at 25°C and up to 24 hours if stored at 2°C to 8°C, protected from light.
However, in order to reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2°C - 8°C for not more than 24 hours.

6.4 Special Precautions for Storage

Store between 2°C and 8°C. Refrigerate. Do not freeze. Protect from light.

6.5 Nature and Contents of Container

DBL Dacarbazine for Injection is available in size 20 mL amber glass vial, single packs.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
If spill occurs, restrict access to the affected area. Wear two pairs of latex rubber gloves, a suitable mask, a protective gown and safety glasses. Limit the spread of the spill by covering with a suitable material such as absorbent towels or adsorbent granules. Spills may also be treated with 5% sodium hypochlorite. Collect the absorbent/adsorbent and other debris from the spill and place in a leak proof plastic container and label accordingly. Cytotoxic waste should be regarded as toxic and hazardous and clearly labelled 'Cytotoxic waste for incineration at 1100°C'. Waste material should be incinerated at 1100°C for at least 1 second. Clean the remaining spill area with copious amounts of water.

6.7 Physicochemical Properties

Dacarbazine is a colourless or pale yellow crystalline powder, sensitive to light. It is slightly soluble in water and alcohol.

Chemical structure.

The molecular formula of dacarbazine is C₆H₁₀N₆O. Its molecular weight is 182.2. The structural formula of dacarbazine appears below:

CAS number.

4342-03-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

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