Consumer medicine information

Muphoran

Fotemustine

BRAND INFORMATION

Brand name

Muphoran

Active ingredient

Fotemustine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Muphoran.

What is in this leaflet

This leaflet answers some of the common questions about MUPHORAN. It does not contain all the available information. Reading this leaflet does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being treated with MUPHORAN against the expected benefits for you.

If you have any concerns about being treated with this medicine, ask your doctor, pharmacist, or oncology nurse.

Keep this leaflet in a safe place. You may need to read it again.

What MUPHORAN is

The name of your medicine is MUPHORAN. The active ingredient of MUPHORAN is called fotemustine. Fotemustine is a type of chemotherapy that belongs to a group of anti-cancer agents called nitrosoureas (pronounced ni-tro-so-u-ree-as).

What MUPHORAN is used for

You have been prescribed MUPHORAN for melanoma (also known as malignant melanoma). MUPHORAN is available only with a prescription - usually from an experienced cancer specialist (also known as an oncologist).

Why MUPHORAN is used for melanoma

Melanoma is a type of skin cancer. Sometimes melanoma spreads from the skin to the lung, liver, bowel, or brain.

MUPHORAN works by stopping the rapid growth of some types of cancer cells.

MUPHORAN treatment can shrink and slow the growth of melanoma tumours for some patients. Other patients may not have a useful treatment response from MUPHORAN.

Ask your doctor if you have any questions about why you are being treated with MUPHORAN.

Before you are treated with MUPHORAN

There are some people who shouldn't be treated with MUPHORAN. Please read the following lists. If you think any of these situations apply to you or you have any questions, please consult your doctor, pharmacist, or oncology nurse.

When you must not be treated with MUPHORAN

  • You are allergic to fotemustine or any other nitrosourea.
    Symptoms of an allergic reaction to MUPHORAN may include 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
  • You are pregnant or trying to become pregnant.
    The effect of MUPHORAN on your developing baby if you are treated with it during pregnancy is unknown. Other medicines similar to MUPHORAN have been shown to affect the developing baby.
  • You are breast-feeding or plan to breast-feed.
    It is unknown whether MUPHORAN is excreted in breast milk and therefore the risk to the breast-fed baby is unknown.
  • You have been or are intending to be vaccinated with the yellow fever vaccine.
    The combination of MUPHORAN and the vaccine can result in a fatal reaction.
  • If you are a child or adolescent.

Before you start to be treated with MUPHORAN

Tell your doctor if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • You become pregnant while taking MUPHORAN.
  • You have problems with the number of white cells or platelets in your blood which you may notice as bleeding or bruising more easily than normal.
  • You have had other chemotherapy in the last 4-6 weeks.
  • You have other health problems, including kidney disease.
  • You drink substantial quantities of alcohol or have an alcohol-related disorder.
  • You have received or are intending to receive any vaccine.

Tell your doctor if you are breast-feeding or plan to breastfeed. Your doctor or pharmacist will discuss the possible risks and benefits of using MUPHORAN during breastfeeding.

Taking other medicines

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

Some medicines and MUPHORAN may interfere with each other. These include:

  • Phenytoin (a medicine used to treat epilepsy and/or convulsions).
  • Certain vaccines while you are being treated with MUPHORAN is not recommended.
  • Immunosuppressants (medicines which lower the body's resistance to disease).
  • Dacarbazine (another medicine used to treat skin cancers).
  • Medicines used to prevent blood clots, e.g. warfarin.

Being treated with MUPHORAN may change the effect of some medicines, and some medicines may affect how well MUPHORAN works. You may need different amounts of your medicine, or you may need to take different medicines.

Your doctor or pharmacist may have more information about which medicines to be careful with or avoid while you are being treated with MUPHORAN.

For older people

Older people can generally be treated with MUPHORAN however, additional care may be required to minimise side effects of treatment.

How MUPHORAN is given

Only experienced cancer specialists treat patients with MUPHORAN. They select a dose depending on your height and weight. MUPHORAN may be given alone or with other chemotherapy drugs.

Treatment is divided into phases.

First phase of treatment:

  • When MUPHORAN is the only chemotherapy used during treatment, then the first phase of treatment consists of one slow injection of MUPHORAN (a "drip") into a vein or an artery once a week for 3 consecutive weeks.
  • When MUPHORAN is used with other chemotherapy then the first phase of treatment consists of one slow injection of MUPHORAN (as above) once a week for 2 consecutive weeks.

Rest period:

  • The first phase of treatment is followed by a period of 4 - 5 weeks where no MUPHORAN is given.

Second phase of treatment

  • The second phase of treatment consists of one slow injection of MUPHORAN (as above) every 3 weeks for as long as the specialist thinks it is necessary.

Overdosage

As MUPHORAN is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you experience any side effects after being given MUPHORAN tell your doctor immediately or go to Accident and Emergency at your nearest hospital. You may need urgent medical attention.

While you are being treated with MUPHORAN

Things you must do

Tell all doctors, dentists and pharmacists who are involved with your treatment that you are being treated with MUPHORAN. You are likely to have regular tests to check that your liver is working properly when you are treated with MUPHORAN.

If you become pregnant while taking MUPHORAN tell your doctor.

Ensure you are using effective contraception if you are a women of childbearing potential.

If you are male, you should use effective contraception while taking MUPHORAN.

Keep follow-up appointments with your doctor. It is important to have your follow-up doses of MUPHORAN at the appropriate times to get the best effects from your treatments.

If you feel that your medicine is not helping your condition, talk to your doctor.

Things to be careful of

Driving is not advisable immediately following the administration of MUPHORAN. Be careful driving or operating machinery until you know how MUPHORAN affects you.

Side effects

If you do not feel well while you are being treated with MUPHORAN then tell your doctor, pharmacist, or oncology nurse as soon as possible.

All medicines including MUPHORAN, can have side effects. Sometimes they are serious, most of the time they are not. Side effects may happen at the start of treatment or they may happen after you have been taking your medicine for some time. You may need medical treatment if you get some of the side effects. These can include:

  • Feeling quite sick or vomiting during the 2 hours following an injection.
  • A reduced number of white cells in your blood - making you more vulnerable to infections.
  • A reduced number of platelets in your blood - making you more vulnerable to bleeding or bruising.

Patients being treated with MUPHORAN have sometimes experienced:

  • Swelling, redness and soreness at the site of injection.
  • A rise in temperature.
  • An itching sensation.
  • Pain in the stomach.
  • Diarrhoea.
  • Feeling drowsy for a short time.
  • Having temporary tingling feelings, numbness, or altered taste sensation.
  • Hepatitis (a serious liver condition) which may cause nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, light coloured bowel motions and/or, dark coloured urine.
  • Lung toxicity.

Anti-cancer medicines have a potential risk of blood disorders caused by a lack of new blood cells (myelodysplasic syndrome) and acute myeloid leukaemia. At high cumulated doses, rare cases of cancers have been reported following treatment with MUPHORAN. Some side effects may not be apparent to you but may be seen on the results of tests. These may include moderate transient and reversible increases in liver enzymes (transaminases, alkaline phosphatases), bilirubin or transient increases in blood urea. You will usually have regular blood tests and your eyes examined regularly during treatment - more frequently if you have kidney problems or are an older person.

If you want to know more about the side effects of MUPHORAN ask your doctor, pharmacist or oncology nurse.

The possibility of a severe allergic reaction (anaphylaxis) exists with any medication.

While very rare, these are very serious side effects. You may need urgent medical attention or hospitalisation.

The following are general signs and symptoms of an allergic reaction

  • itching, skin rash or hives
  • shortness of breath, wheezing or trouble breathing
  • swelling of the face, lips, tongue or other parts of the body.

Other side effects not listed above may also occur in some patients. Tell your doctor, pharmacist or oncology nurse if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

What MUPHORAN looks like

MUPHORAN is a pale yellow powder packed inside a brown glass vial. It is dissolved in a liquid in the hospital pharmacy and usually diluted into a bag of weak glucose (sugar) solution before it is given to a patient. The solution is handled carefully and protected from light.

Ingredients

Each brown vial of MUPHORAN contains 208mg of fotemustine powder as the active ingredient.

Manufacturer

MUPHORAN is a product discovered by Servier Research International.

It is distributed in Australia by:

Servier Laboratories (Aust.) Pty. Ltd.
Level 4, Building 9,
588A Swan Street
Burnley 3121 Victoria
Telephone: 1800 153 590
Internet: www.servier.com.au

The New Zealand contact address for Servier Laboratories is:

Servier Laboratories (NZ) Ltd
12th Floor, Citibank building
23 Customs Street
Auckland

MUPHORAN is registered on the Australian Register of Therapeutic Goods. Australian Register Number: AUST R 44019

This leaflet was last revised in July 2022

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Muphoran

Active ingredient

Fotemustine

Schedule

S4

 

1 Name of Medicine

Fotemustine.

2 Qualitative and Quantitative Composition

Each vial contains 208 mg of fotemustine. The reconstituted solution has a volume of 4.16 mL (i.e. 200 mg of fotemustine in 4 mL of solution).

Diluent with known effects.

Ethanol, (see Section 6.5 Nature and Contents of Container).
Fotemustine is a pale yellow powder that in accordance with the standards of the European Pharmacopoeia, is slightly soluble in water and soluble in 95% ethanol. An infrared spectrophotometric study carried out on several batches showed no polymorphism.
Fotemustine is a cytostatic anticancer agent of the nitrosourea family with an alkylating and carbamoylating effect with a wide spectrum of experimental antitumoral activity.

3 Pharmaceutical Form

Sterile powder, and 4 mL diluent for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

The indication "disseminated malignant melanoma", including cerebral metastases is currently the preferential indication for fotemustine, administered alone or in combination with other anticancer agents.

4.2 Dose and Method of Administration

Prepare the solution immediately prior to administration (see Section 4.4 Special Warnings and Precautions for Use; Section 6.4 Special Precautions for Storage). Solutions of fotemustine are unstable when exposed to light.
To avoid microbial contamination, the diluted solution must be used as soon as practicable after preparation and any unused solution discarded.
Before starting the fotemustine infusion, verify that the intravenous tube has been placed correctly in the patient in order to avoid extravasation. In case of extravasation, stop the infusion, wash the vein abundantly with 5% glucose solution (4 mL/min), immobilise the limb and cool with an ice bag to avoid the diffusion of the infusion solution. Aspire the extravasated volume as much as possible and immobilise the limb in an elevated position.
Dissolve the vial of fotemustine with the ampoule of 4 mL of sterile alcohol solution, then, after calculating the dose to be injected, dilute the solution in 5% isotonic glucose solution for administration by intravenous infusion.
The solution prepared in this way must be administered, protected from light:
by intravenous infusion over one hour;
by intra-arterial infusion over four hours.

In single agent chemotherapy.

Treatment consists of:

Induction treatment.

Three consecutive administrations at one week intervals, followed by a therapeutic rest period of four to five weeks.

Maintenance treatment.

One administration every three weeks.
Blood counts should be performed frequently (see Section 4.4 Special Warnings and Precautions for Use). It is also recommended to regularly monitor liver function tests during or following induction treatment.

Combination chemotherapy.

In combination chemotherapy, the third administration of the induction treatment is omitted. The dose remains 100 mg/m2.

Combination with dacarbazine.

Simultaneous administration with dacarbazine should be avoided as rare cases of pulmonary toxicity (adult acute respiratory distress syndrome) have been observed when Muphoran (fotemustine) is combined simultaneously, on the same day, with high doses of dacarbazine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.3 Contraindications

Muphoran (fotemustine) is contraindicated:
in children and adolescents as the benefit/risk ratio has not been established in this population;
in pregnant women due to the known mutagenic and carcinogenic potential of nitrosoureas (see Section 4.6 Fertility, Pregnancy and Lactation);
for lactating women (see Section 4.6 Fertility, Pregnancy and Lactation);
in combination with the yellow fever vaccine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
in patients with a hypersensitivity to fotemustine, any of the excipients or to nitrosoureas.

4.4 Special Warnings and Precautions for Use

Avoid any contact with skin, mucosa and any absorption of the reconstituted solution. It is recommended to wear a protective mask and gloves during the preparation of the solution. In event of contact with Muphoran (fotemustine), rinse affected area thoroughly with water. Contaminated equipment should be disposed of appropriately (see Section 4.2 Dose and Method of Administration).
Use of Muphoran (fotemustine) with live attenuated vaccines or phenytoin is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Muphoran (fotemustine) should only be used by experienced cancer physicians in institutions with facilities for the monitoring and management of any post-treatment adverse effects.
Treatment should only be considered when the platelet count and/or granulocyte count is acceptable, with minimum values of 100,000/mm3 and 2,000/mm3, respectively.

Haematological status.

Administration of Muphoran (fotemustine) to patients who have already received chemotherapy in the previous four weeks (or six weeks in the case of previous treatment with a nitrosourea) is not recommended.
Blood counts should be performed before each new administration and doses should be adjusted according to the haematological status. Table 1 may be used as a guide.
An interval of eight weeks is recommended between the start of induction treatment and the start of maintenance treatment. An interval of three weeks is recommended between two cycles of maintenance treatment.
Maintenance treatment should only be considered when the platelet count and/or granulocyte count is acceptable, with minimum values of 100,000/mm3 and 2,000/mm3, respectively.

Liver function tests.

Regular monitoring of liver function tests during or following induction treatment is recommended.

Use in patients with alcohol-related disorders.

A single vial of Muphoran (fotemustine) reconstituted contains 3.35 mL of 96% ethanol (equivalent to 1.3 g of alcohol per 100 mg of fotemustine, equivalent to 32 mL of beer, 13.3 mL of wine) this quantity of alcohol may be harmful to patients suffering from alcoholism and should be taken into consideration in patients with liver disease or epilepsy.

Extravasation.

Before commencing the fotemustine infusion, check that the intravenous tube has been placed correctly in the patient in order to avoid extravasation. In case of extravasation, stop the infusion, aspire the extravasated volume as fast as possible and immobilise the limb in an elevated position (see Section 4.2 Dose and Method of Administration).

Preclinical ophthalmoscopic observations.

Fotemustine caused retinal atrophy in rats and retinal detachment in monkeys, at plasma concentrations similar to those observed following IV infusion of the therapeutic dose to patients. The significance of this to humans is unknown. Ophthalmoscopic examinations should be carried out routinely during treatment.

Use in hepatic impairment.

There have been no specific studies of Muphoran (fotemustine) in this population.
Regular monitoring of liver function tests during or following induction treatment is recommended (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Liver function tests).

Use in renal impairment.

Standard doses of Muphoran (fotemustine) in a small number of patients presenting with renal impairment did not result in any changes in urea or creatinine. However in the absence of long-term experience in a wider patient population it is recommended that patients with impaired renal function be closely monitored.

Use in the elderly.

The toxicity of Muphoran (fotemustine) has been compared in patients below and above the age of 60 years. Thrombopenia (grade 3), leukopenia (grade 3) and gastrointestinal toxicity (grade 3) were significantly more frequent in patients over 60 years.

Paediatric use.

Muphoran is contraindicated in children and adolescents as the benefit/risk ratio has not been established in this population (see Section 4.3 Contraindications).

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Muphoran (fotemustine).
No interaction has been observed between Muphoran (fotemustine) and medicines acting on the central nervous system such as analgesics, neuroleptics, anxiolytics and those for Parkinson's disease. No interaction with metoclopramide has been reported and there is no data concerning interaction between antiemetic 5HT3 antagonists. The low gastrointestinal toxicity of fotemustine does not usually require such therapy.

Combined use which is contraindicated.

(See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Combination of Muphoran (fotemustine) and yellow fever vaccine is contraindicated due to the risk of fatal systemic vaccine induced disease (see Section 4.3 Contraindications).

Combined use not recommended.

(See Section 4.4 Special Warnings and Precautions for Use).

Phenytoin.

Combination of Muphoran (fotemustine) and phenytoin is not recommended due to the risk of seizures through decreased gastrointestinal absorption of phenytoin by Muphoran (fotemustine), or risk of enhanced toxicity or loss of efficacy of Muphoran (fotemustine) through an increase in its hepatic metabolism by phenytoin.

Live attenuated vaccines (except yellow fever).

Combination of Muphoran (fotemustine) and live attenuated vaccines is not recommended due to the risk of systemic vaccine induced disease, which can be fatal. This risk is increased in subjects who are already immunosuppressed due to the underlying disease. Use an inactivated vaccine when such a vaccine exists.

Combined use which requires caution.

Immunosuppressants.

Caution is recommended with the combination of Muphoran (fotemustine) and immunosuppressants due to the possibility of excessive immunosuppression with risk of lymphoproliferation.

Combined use specific to Muphoran (fotemustine).

Dacarbazine.

Do not administer Muphoran (fotemustine) and dacarbazine simultaneously. An interval of one week should be left between the last administration of Muphoran (fotemustine) and the first day of a course of dacarbazine (see Section 4.2 Dose and Method of Administration).

With high doses of dacarbazine.

As pulmonary toxicity (acute respiratory distress syndrome) has been observed following the sequential administration of dacarbazine - fotemustine, likely due to O6 alkyltransferase inhibition provoked by a high dose of dacarbazine, this mode of administration should be avoided.

Combined use common to cytotoxics.

Anticoagulants.

Anticoagulant treatments are commonly used in neoplastic disease due to the increased risk of thrombosis. If patients are treated with oral anticoagulants, the INR should be checked more frequently because of the considerable variation in blood clotting during the course of these diseases, which is complicated by the risk of interaction that exists between oral anticoagulants and antineoplastic chemotherapy.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fotemustine affected fertility in male dogs. Complete azoospermia was observed at doses of ≥ 3.5 mg/kg (about 70 mg/m2) IV in a one year study, using the clinical therapeutic protocol. Testicular atrophy was seen in rats given ≥ 22.5 mg/kg/week for four weeks.
(Category D)
Use of Muphoran (fotemustine) is contraindicated in pregnant women and women of childbearing potential who are not using effective contraception (see Section 4.3 Contraindications). Muphoran (fotemustine) should be used in conjunction with effective contraception in women of childbearing potential.
No reproductive studies have been carried out with fotemustine because of its reactivity. However, related nitrosoureas have been shown to be teratogenic and embryotoxic in animal studies.

Information for male patients.

Male patients should be advised to use effective contraception while taking Muphoran (fotemustine).
 Use of Muphoran (fotemustine) in lactating women is contraindicated (see Section 4.3 Contraindications).
There is no data on the effects of Muphoran (fotemustine) in lactating women. As it is unknown whether fotemustine or its metabolites are excreted in human milk, the risk to newborns/infants cannot be excluded.

4.7 Effects on Ability to Drive and Use Machines

While no studies on the effects on the ability to drive vehicles and use machines have been performed, driving is not advisable immediately following the administration of Muphoran (fotemustine).

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The main adverse effects observed during clinical trials were haematological, and could affect the three blood lines. This toxicity is delayed and characterised by anaemia, thrombocytopenia and leukopenia (all commonly observed) with nadirs occurring respectively four to five weeks and five to six weeks after the first dose of the induction treatment. Pancytopenia may also occur.
The haematological toxicity may be accentuated in patients who have previously received chemotherapy and/or in combination with other drugs likely to induce haematopoietic toxicity.
Increased haematological and gastrointestinal toxicity may be observed in the elderly.

Tabulated list of adverse effects.

The following undesirable effects have been observed during treatment with Muphoran (fotemustine) and ranked under the following frequency: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000), not known (cannot be estimated from the available data). See Table 2.

Respiratory, thoracic and mediastinal disorders.

Rare cases of lung toxicity (adult acute respiratory distress syndrome) have been observed in combination with dacarbazine) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Pulmonary toxicity (interstitial pneumopathy) has also been reported with fotemustine.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Antineoplastic agents and in particular alkylating agents were associated with a potential risk of myelodysplastic syndrome and acute myeloid leukaemia. At high cumulated doses, rare cases were reported with fotemustine either alone or in combination with other chemotherapies, and with or without radiotherapy.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
Increased haematological surveillance is recommended in cases of overdose.
There is no known antidote.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fotemustine is a cytostatic antineoplastic agent whose chemical formula includes a bioisostere of alanine (1-amino ethylphosphonic acid) in order to facilitate cellular penetration and passage across the blood brain barrier.
In animal pharmacology, its spectrum of anticancer activity is very wide and is exerted on tumours of various histological types and in various anatomical sites, particularly cerebral and visceral.
As a result of its alkylating and carbamoylating effect, it exerts a potent cytostatic activity on cells in cycle, inducing accumulation of cells in G2M phase.
It does not have any hepatic, pulmonary or renal glutathione reductase inhibitory activity. Immunotoxicity studies demonstrate sparing of NK cellular activity.

Clinical trials.

In man, clinical studies in the indication of "disseminated malignant melanoma" have demonstrated the efficiency of Muphoran (fotemustine) both in terms of the response rate and the duration of responses and by the responses obtained on cerebral metastatic sites.

5.2 Pharmacokinetic Properties

Distribution and metabolism.

In animals, the tissue distribution is rapid and very extensive. Fotemustine crosses the blood brain barrier; (two to five minutes after bolus administration in the rat, it is detected in the brain at sufficiently high levels to be active).
In man, during administration by intravenous infusion, the plasma levels of fotemustine are close to the steady-state value after 45 minutes. After the end of the infusion, plasma levels go down rapidly and three hours later the molecule can no longer be detected in the blood.
The binding to plasma proteins is quantitatively low (25 to 30%) and essentially concerns acid alpha-1-glycoprotein and albumin.

Excretion.

After administration in man of the drug labelled with 14C on the chloroethyl group, the radioactivity is slowly eliminated with a terminal half-life of 83 hours. About 50 to 60% of the radioactivity administered is detected in the urine, 30 to 40% of which is detected during the first 24 hours, but the unchanged molecule is not detected in the urine. 5% of the radioactivity is eliminated in the faeces and less than 0.2% in the form of expired CO2.

5.3 Preclinical Safety Data

Genotoxicity.

Fotemustine is both mutagenic (Salmonella typhimurium, E. coli reverse mutation tests) and clastogenic (mouse micronucleus test, in vitro human lymphocyte assay). Fotemustine had significant transforming effects in cell transformation studies (Syrian hamster embryo cells, BALB/3T3 cells).

Carcinogenicity.

Antineoplastic agents and in particular alkylating agents were associated with a potential risk of myelodysplastic syndrome and acute myeloid leukaemia. At high cumulated doses, rare cases were reported with fotemustine, either alone or in combination with other chemotherapies, and with or without radiotherapy (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)).

6 Pharmaceutical Particulars

6.1 List of Excipients

There are no excipients.

Diluent with known effects.

Solvent: ethanol 80% V/V (i.e. ethanol 96% V/V with water for injections).

6.2 Incompatibilities

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

6.3 Shelf Life

Shelf life of the powder in the sterile vial: 2 years.
The diluted solution for intravenous administration must be used immediately.

6.4 Special Precautions for Storage

Storage.

Keep in the refrigerator at a temperature of between +2°C and +8°C.
After reconstitution, the diluted solution for intravenous administration must be protected from light.

Handling and spill procedures.

Items used to prepare Muphoran (fotemustine), or articles associated with body waste should be placed in a closed system and disposed of in a manner such that personnel and the environment are not contaminated. Relevant regulations and practice standards concerning the disposal of cytotoxic waste should be followed.
If a spill occurs, restrict access to the affected area. Wear protective clothing and footwear, suitable gloves, a mask and eye protection and follow relevant spill cleaning procedures. Relevant regulations and practice standards concerning the disposal of cytotoxic waste should be followed.

6.5 Nature and Contents of Container

A cardboard box containing:
A 10 mg brown vial sealed with a chlorobutyl elastomere seal, containing 208 mg of the active compound fotemustine;
A 5 mL fine tipped clear glass bottle ampoule containing the solvent (3.35 mL of 96% ethanol and water for injections q.s. to 4 mL).
Solvent: ethanol 80% V/V (i.e. ethanol 96% V/V with water for injections).
The reconstituted solution has a volume of 4.16 mL (i.e. 200 mg of fotemustine in 4 mL of solution).
All or part of this volume (depending on the dose administered) is diluted in 250 to 400 mL of 5% glucose solution for intravenous or intra-arterial administration.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

The active component of Muphoran is fotemustine which has the chemical name, (RS)-diethyl {1-[3-(2-chloroethyl)-3-nitrosoureido]ethyl} phosphonate. Fotemustine is a nitrosurea derivative. It is a pale yellow powder slightly soluble in water and soluble in 95% ethanol. It has a pH of 6.3 (0.3% aqueous solution), a pKa of 10.4 for the acid group and a partition coefficient octanol/water of 15.7-17.9 (pH 2.1- 7.4).

Chemical structure.


Molecular formula: C9H19ClN3O5P.
Molecular weight (relative): 315.7.

CAS number.

92118-27-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes