Consumer medicine information

Myleran

Busulfan

BRAND INFORMATION

Brand name

Myleran

Active ingredient

Busulfan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Myleran.

What is in this leaflet

This leaflet answers some common questions about MYLERAN tablets. It does not contain all of the available information. It 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 taking MYLERAN tablets against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor.

Keep this leaflet with the medicine. You may need to read it again.

What MYLERAN is used for

MYLERAN contains busulfan as the active ingredient. It belongs to a group of medicines called cytotoxics.

MYLERAN is used to treat certain blood disorders.

It works by reducing the amount of certain types of blood cells in your body.

Ask your doctor if you have any questions about why MYLERAN has been prescribed for you. Your doctor may have prescribed it for another purpose.

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

There is no evidence that it is addictive.

Before you take it

When you must not take it

Do not take MYLERAN if you have ever had an allergic reaction to:

  • busulphan
  • any of the tablet ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other parts of the body; rash, itching or hives on the skin.

Do not take MYLERAN if you are planning to become pregnant or father a child unless you and your doctor have discussed the risks and benefits involved. MYLERAN may harm eggs and sperm and may cause sterility in both men and women. Reliable contraceptive methods must be taken to avoid pregnancy whilst you or your partner is taking this medicine.

Do not take MYLERAN if you are pregnant unless you and your doctor have discussed the risks and benefits involved. It may affect your developing baby if you take it during pregnancy.

Do not take this medicine whilst breast feeding.

Do not take it after the expiry date (EXP) printed on the pack. If you take it after the expiry date has passed, it may not work as well.

Do not take MYLERAN if the bottle shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines or any other foods, dyes or preservatives.

Tell your doctor if you have or have had any of the following conditions:

  • you have recently received or are receiving radiotherapy or chemotherapy
  • you have recently been vaccinated or are planning to be vaccinated
  • kidney, lung or liver disease
  • gout.

If you have not told your doctor about any of the above, tell them before you start taking MYLERAN.

Taking other medicines

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

Some medicines may be affected by MYLERAN or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines. These include:

  • phenytoin
  • itraconazole or metronidazole
  • thioguanine
  • other cytotoxic drugs
  • vaccinations with ‘live’ organism vaccines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking this medicine.

How to take it

How much to take

Take MYLERAN tablets exactly as directed by your doctor. Your doctor will decide what dose and for how long you will be taking MYLERAN. This depends on factors such as your weight, any pre-existing conditions and your response to the treatment. Your doctor may change the dose and frequency of your medicine as your condition changes.

Your doctor may order regular blood tests while you are taking MYLERAN in order to monitor your blood cell count and to change your dose if necessary.

How to take it

Swallow each tablet whole with water.

Do not break, crush or chew the tablets.

If you forget to take it

Tell your doctor if you forget to take a dose.

Do not take a double dose to make up for the dose that you missed.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 131126) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much MYLERAN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking it

Things you must do

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

It is important that you visit your doctor regularly, so your doctor can check your progress and make sure your medicine is working.

Tell any other specialist, doctor, dentist or pharmacist that you are taking MYLERAN, especially if you are about to be started on any new medicines, immunisations, vaccinations or radiotherapy.

If you are about to undergo surgery or an operation, tell your doctor that you are taking MYLERAN tablets.

Tell your doctor if you become pregnant, are trying to become pregnant or trying to father a child.

Things you must not do

Do not stop taking MYLERAN or change the dose without first checking with your doctor.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use MYLERAN to treat any other complaints unless your doctor says to.

Things to be careful of

Do not break, crush or chew the tablet. Provided the outer coating of the tablet is intact, there is no risk in handling MYLERAN tablets.

Be careful driving or operating machinery until you know how MYLERAN affects you.

Do not have any vaccinations without your doctor’s approval.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are taking MYLERAN.

All medicines can cause some side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

The following side effects have been reported with MYLERAN:

  • production of bone marrow cells may be reduced. You may notice an increase in infections. Your doctor will do regular blood tests, but you should tell him at once if you notice any signs of fever or infection or any unexpected bruising, bleeding or signs of blood in your urine
  • in women, ovarian failure, periods may stop
  • in men, sperm production may be reduced or stop. The testes may reduce in size and may not function.
  • in girls, the onset of puberty may be delayed or stop.

Tell your doctor if you notice any of the following side effects:

  • nausea and vomiting
  • diarrhoea
  • darker areas of skin
  • weight loss
  • jaundice, a yellowing of the whites of the eyes or the skin
  • pain in the liver
  • gaining weight quickly
  • swelling of arms, legs and stomach
  • unusual tiredness, looking pale, feeling weaker or dizzy
  • skin rash or itching
  • hair loss
  • frequent infections such as fever, sore throat or mouth ulcers
  • bruisingorbleedingmore easily than normal, nose bleeds
  • blood in the urine
  • convulsions
  • persistentcoughor breathlessness
  • muscle weakness
  • problems with your eyesight
  • in men, breast enlargement.

Tell your doctor immediately if you notice any of the following allergic-type symptoms:

  • wheezing
  • swelling of the lips/mouth
  • difficulty in breathing
  • hay fever
  • lumpy rash ("hives")
  • fainting

Tell your doctor if you notice anything else that is making you feel unwell, even if you think the problems are not connected with this medicine and are not referred to in this leaflet. Other side effects not listed above may occur in some people.

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

After taking it

Things to be aware of

Because of the way this medicine works there is a chance it might cause other unwanted effects that may not occur until months or years after the medicine is used. These delayed effects may include certain types of cancer such as leukaemia.

Discuss these possible effects with your doctor.

Storage

Keep MYLERAN tablets in a cool, dry place where it stays below 25°C.

Keep your tablets in the bottle until it is time to take them. If you take the medicine out of the bottle it may not keep as well.

Do not leave it in the car, on window sills, near a sink or in the bathroom. Heat and dampness can destroy some medicines.

Keep this medicine where young children cannot reach it. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Product description

What it looks like

MYLERAN tablets are white, film-coated, round and biconvex. They are engraved “GX EF3”on one side and “M” on the other.

Available in bottles of 100 tablets.

Ingredients

Active ingredient:

Each tablet contains 2 mg busulfan.

Inactive ingredients:

  • lactose anhydrous
  • starch – pregelatinised maize
  • magnesium stearate
  • hypromellose
  • titanium dioxide
  • glycerol triacetate.

Sponsor

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065

Australian Registration Number: AUST R 68028

This leaflet was revised in July 2017

Published by MIMS October 2017

BRAND INFORMATION

Brand name

Myleran

Active ingredient

Busulfan

Schedule

S4

 

1 Name of Medicine

Busulfan.

2 Qualitative and Quantitative Composition

Myleran tablets each contain 2 mg busulfan.
List of excipients with known effect: sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Myleran tablets are round biconvex white film coated tablets engraved GX EF3 on one face and M on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of chronic granulocytic leukaemia. It has been shown to be superior to splenic irradiation when judged by survival times, control of spleen size and maintenance of haemoglobin levels. Although not curative, busulfan reduces the total granulocyte mass, relieves disease symptoms and improves the clinical state of the patient. Busulfan is not useful once blast transformation has occurred.
Busulfan produces prolonged remission in polycythaemia vera. It is especially useful in cases resistant to radiophosphorus (32P) and where there is marked thrombocytosis.
Busulfan is useful in selected cases of essential thrombocythaemia and myelofibrosis.

4.2 Dose and Method of Administration

Chronic granulocytic leukaemia.

Remission induction.

The dosage is 0.06 mg/kg daily with a maximum daily dose of 4 mg which may be given as a single dose. Administration of Myleran should be discontinued when the white blood cell count has fallen to between 20,000 to 25,000/mm3 or earlier if the platelet count falls below 100,000/mm3, otherwise there is a considerable risk of causing irreversible bone marrow aplasia since the counts may continue to fall for some time after treatment is stopped. The blood count should be monitored at least weekly during the induction phase and the dose should be increased only if the response after three weeks is inadequate.

Maintenance therapy.

Although the white count may be controlled without further therapy for long periods after induction therapy, most clinicians use some form of maintenance treatment.
Dosage is usually between 0.5 to 2 mg/day but individual requirements may be much less. The aim is to maintain a white blood count of 10,000 to 15,000/mm3 and blood counts should be performed at least every four weeks.

Polycythaemia vera and essential thrombocythaemia.

Remission induction.

The dosage is 4 to 6 mg daily. The total dose required to produce remission varies so that very careful haematological control is essential.

Maintenance therapy.

The dosage is approximately half the induction dose but the exact amount must be assessed individually for each patient. Prolonged treatment is necessary, requiring close supervision and frequent blood counts.

Myelofibrosis.

The usual initial dosage is 2 to 4 mg/day, with a lower dose for maintenance. Very careful haematological control is required because of the great sensitivity of the bone marrow in this condition. Myleran is very rarely indicated in children. Provided the outer coating is intact there is no risk in handling Myleran tablets. The tablets should not be divided.

4.3 Contraindications

In view of the seriousness of the indications there are no absolute contraindications.

4.4 Special Warnings and Precautions for Use

Myleran is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.

Immunisation with live vaccines.

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.

Lung toxicity.

Myleran should be discontinued if lung toxicity develops.
If anaesthesia is required in patients with possible pulmonary toxicity, the concentration of inspired oxygen should be kept as low as safely possible and careful attention given to postoperative respiratory care.

Monitoring of blood counts.

Careful attention should be paid to the monitoring of blood counts to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia.
The main side effect of Myleran treatment is bone marrow depression, particularly thrombocytopenia. Special care must be taken when the initial platelet count is low and when the count falls during treatment. Administration of Myleran should be stopped immediately at any stage of treatment if there is a sharp fall in the platelet count or if purpura develops.

Prophylactic anticonvulsant therapy.

If high dose Myleran is prescribed, patients should be given prophylactic anticonvulsant therapy with preferably a benzodiazepine rather than phenytoin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Co-administration with itraconazole or metronidazole.

Patients coprescribed itraconazole or metronidazole with Myleran should be monitored closely for signs of busulfan toxicity. Weekly measurements of blood counts are recommended when co-administering these drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hepatic veno-occlusive disease.

Hepatic veno-occlusive disease is a major complication that can occur during treatment with busulfan. Patients who have received prior radiation therapy or prior progenitor cell transplant may be at an increased risk (see Section 4.8 Adverse Effects (Undesirable Effects)).

Oogenesis and spermatogenesis.

Busulfan interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Men treated with busulfan should be informed about sperm preservation prior to treatment (see Section 4.6 Fertility, Pregnancy and Lactation, Effects on fertility).

Monitoring.

Busulfan should not be given to patients who have recently received radiotherapy or other cytotoxic drugs.
Hyperuricaemia and/or hyperuricosuria are not uncommon in untreated patients with chronic granulocytic leukaemia and should be corrected before starting therapy with busulfan. During treatment, hyperuricaemia and the risk of uric acid nephropathy should be prevented by adequate prophylaxis.

Use in hepatic impairment.

Busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolized through the liver, caution should be observed when busulfan is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment.

Use in renal impairment.

Studies in renally impaired patients have not been conducted, however, as busulfan is moderately excreted in the urine, dose modification is not recommended in these patients. However, caution is recommended.

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

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special Warnings and Precautions for Use).
The combination of Myleran and thioguanine has resulted in the development of nodular regenerative hyperplasia, portal hypertension and oesophageal varices. The effects of other cytotoxics producing pulmonary toxicity may be additive.
The administration of phenytoin to patients receiving high dose Myleran may result in a decrease in the myeloablative effect.
The concomitant systemic administration of itraconazole to patients receiving Myleran may result in reduced busulfan clearance. Metronidazole has been reported to increase trough levels of busulfan by approximately 80%. Fluconazole had no effect on busulfan clearance. Consequently, busulfan in combination with itraconazole or metronidazole is reported to be associated with an increased risk of busulfan toxicity (see Section 4.4 Special Warnings and Precautions for Use).
Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore decrease busulfan clearance when used in combination.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Busulfan can lead to suppression of ovarian function and amenorrhoea with menopausal symptoms in premenopausal women and suppression of spermatogenesis in men. It may cause sterility in both sexes. In women busulfan may cause severe and persistent ovarian failure, including failure to achieve puberty after administration to young girls and pre-adolescents at high-dose. It may also cause male infertility, azoospermia and testicular atrophy in male patients receiving busulfan.
Treatment with high dose Myleran has been associated with severe and persistent ovarian failure, including failure to achieve puberty, after administration to young girls and pre-adolescents.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Myleran.
Busulfan interferes with spermatogenesis in experimental animals and there have been clinical reports of sterility, azoospermia and testicular atrophy in man.
(Category D)
Busulfan is potentially teratogenic and embryotoxic. Although there have been a number of reported cases where apparently normal children have been born after busulfan treatment during pregnancy, Myleran should be avoided during pregnancy, particularly during the first trimester. In every case, the potential benefit to the mother must be weighed against the risk to the fetus.
 Mothers receiving busulfan should not breastfeed.

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.

4.8 Adverse Effects (Undesirable Effects)

The most common side effect is bone marrow depression, particularly thrombocytopenia. Secondary acute leukaemia is common (see Section 5.3 Preclinical Safety Data, Genotoxicity and carcinogenicity).
Gastrointestinal effects such as nausea, vomiting, diarrhoea and dry mouth have been reported rarely. Such intolerance is not a significant problem and can be controlled by giving the daily treatment in divided doses.
At high dose: cardiac tamponade in patients with thalassaemia is common.
At high dose: idiopathic pneumonia syndrome is very common.
At high dose: in combination with cyclophosphamide, cystitis haemorrhagic is common.
Hyperpigmentation is the most common skin reaction and occurs in 5 to 10% of patients, particularly those with a dark complexion. In a few cases a clinical syndrome resembling adrenal insufficiency and characterised by weakness, severe fatigue, anorexia, weight loss, nausea and vomiting and hyperpigmentation of the skin has developed after prolonged busulfan therapy. The syndrome has sometimes resolved when busulfan has been withdrawn.
Interstitial pneumonitis may occur following conventional dose use and lead to pulmonary fibrosis. Diffuse pulmonary fibrosis with progressive dyspnoea and a persistent nonproductive cough has occurred rarely, usually after prolonged treatment over a number of years. Histological features include atypical changes of the alveolar and bronchiolar epithelium, and the presence of giant cells with large hyperchromatic nuclei. Once pulmonary toxicity is established the prognosis is poor despite Myleran withdrawal and there is little evidence that corticosteroids are helpful. The onset is usually insidious but may also be acute. In a single case pulmonary ossification also occurred.
The lung pathology may be complicated by superimposed infections. It is possible that subsequent radiotherapy can augment subclinical lung injury caused by busulfan. Lens changes and cataracts, which may be bilateral, have been reported during busulfan therapy.
Corneal thinning has been reported after bone marrow transplantation preceded by high dose Myleran treatment.
Other reported adverse reactions include urticaria, erythema multiforme, erythema nodosum, alopecia, porphyria cutanea tarda, excessive dryness and fragility of the skin with complete anhydrosis, dryness of the oral mucous membranes and cheilosis, gynaecomastia, cholestatic jaundice, endocardial fibrosis and myasthenia gravis. Most of these are single case reports, and in many a clear cause and effect relationship with busulfan has not been demonstrated. Sjögren's syndrome has also been reported.

Gastrointestinal disorders.

In paediatric transplant recipients, dental developmental anomalies (such as tooth hypoplasia, microdontia and absence of permanent teeth) have been observed with busulfan-based conditioning regimens.
An increased cutaneous radiation effect has been observed in patients receiving radiotherapy soon after high dose Myleran.
A retrospective review of postmortem reports of patients who had been treated with low dose Myleran for at least two years for chronic granulocytic leukaemia showed evidence of centrilobular sinusoidal fibrosis.
Hyperbilirubinaemia, jaundice, hepatic veno-occlusive disease and centrilobular sinusoidal fibrosis with hepatocellular atrophy and necrosis have been observed after high dose Myleran treatment.
Convulsions have been observed in adults who have received high dose Myleran.
Many histological and cytological changes have been observed in patients treated with Myleran, including widespread dysplasia affecting uterine, cervical, bronchial and other epithelia. Most reports relate to long-term treatment but transient epithelial abnormalities have been observed following short-term, high dose treatment.

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

Treatment.

The principal toxic effect is on the bone marrow. Survival after a single large dose has been reported, but haematological toxicity is likely to be more profound with chronic overdosage. As there is no known antidote, the blood picture should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Myleran, in small daily doses of 4 mg administered orally, depresses both normal and abnormal myeloid tissue. It is this property which has proved to be of value in the treatment of a proportion of cases of chronic myelogenous leukaemia. The drug is more selective than nitrogen mustard or the folic acid antagonists in its effect on the myeloid cells and may be somewhat safer in use; certain patients have received daily doses of 4 mg for as long as a year. In such doses, although it depresses myelopoiesis, it has little effect upon the lymphocytes and platelets, and side effects are absent.
Larger doses, however, depress the platelet count and cause haemorrhagic symptoms, and there is a danger of causing an irreversible depression of the bone marrow which may not become obvious for 4 to 6 months. These effects show the necessity for careful haematological control. The most favourable effects, seen in some cases of chronic myelogenous leukaemia, are a rise in the haemoglobin levels, a selective reduction or even disappearance of immature myeloid cells from the blood, a reduction in the cellularity of the bone marrow, a diminution in the size of the enlarged spleen, and pronounced subjective improvement.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

No data available.

5.3 Preclinical Safety Data

Genotoxicity and carcinogenicity.

Various chromosome aberrations have been noted in cells from patients receiving busulfan. Widespread epithelial dysplasia has been reported.
The possibility that busulfan is carcinogenic should be borne in mind. A number of malignant tumours have been reported in patients receiving busulfan.
Although acute leukaemia is probably part of the natural history of polycythaemia vera, prolonged alkylating agent therapy may increase the incidence.
Very careful consideration should be given to the use of Myleran for the treatment of polycythaemia vera and essential thrombocythaemia in view of the drug's carcinogenic potential. The use of Myleran for these indications should be avoided in younger or asymptomatic patients. If the drug is considered necessary, treatment courses should be kept as short as possible.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Myleran tablet also contains lactose, pregelatinised maize starch, magnesium stearate and Opadry White OY-S-7322.

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.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Myleran tablets are available in a bottle containing 25* and 100 tablets.
(*not currently distributed in Australia).

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

Busulfan is a white, crystalline powder. It is very slightly soluble in water and ethanol (96%), freely soluble in acetone, in acetonitrile and in chloroform. It has a melting point of 115-118°C.
The chemical name for busulfan is 1,4-butanediol dimethanesulfonate, it has a molecular weight of 246.29 and its molecular formula is C6H14O6S2.

Chemical structure.


CAS number.

55-98-1.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes