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4.4       Special warnings and precautions for use

Conventional dose Treatment

Patients co-administered who are concurrently treated with the conventional dose of busulfan and itraconazole or metronidazole with conventional dose busulfan should be closely monitored closely for signs of busulfan toxicity. At concomitant use of these agents with busulfan Weekly measurements of blood counts are recommended when co-administering these drugs (see section 4.5).

4.5       Interaction with other medicinal products and other forms of interaction

In patients receiving high-dose busulfan it has been reported that co-administration of itraconazole decreases clearance of busulfan by approximately 20 % with corresponding increases in plasma busulfan levels. In combination with metronidazole (1200 mg, given as 400 mg three times daily) busulfan values are increased in approximately 80% (see section 4.4). Metronidazole has been reported to increase trough levels of busulfan by approximately 80 %. Fluconazole had no effect on busulfan clearance. Consequently, high-dose busulfan in combination with itraconazole or metronidazole is reported to be associated with an increased risk of busulfan toxicity (see section 4.4).

4.8       Undesirable effects

The following convention has been utilised for the classification of frequency:  Very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000) and, very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Not known        Tooth hypoplasia

10.       DATE OF  REVISION OF THE TEXT

January November  2017

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 4.2      Posology and method of administration

Obese patients

4.4       Special warnings and precautions for use

Hepatic veno-occlusive disease is a major complication that can occur during treatment with busulfan. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk (see section 4.8).

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 (section 4.6 and 4.8).

4.5       Interaction with other medicinal products and other forms of interaction

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4).

The effects of other cytotoxics producing pulmonary toxicity may be additive (see section 4.8).

In the paediatric population, for the combined Busulfan-Melphalan (BuMel) regimen it has been reported that the administration of melphalan less than 24 hours after the last oral busulfan administration may influence the development of toxicities. 

4.6       Fertility, pregnancy and lactation

Fertility

Myleran can lead to suppression of ovarian function and amenorrhoea in 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 (see section 4.8 and 5.3).

4.8       Undesirable effects

Nervous system disorders           Rare      At high-dose:seizure convusion (see section 4.4 and 4.5)

Musculoskeletal and connective tissue disorders               Rare      Sjögren’s syndrome

Injury, poisoning and procedural complications   Rare      Radiation skin injury is increased in patients receiving radiotherapy soon after high-dose busulfan

Uncommon      Ovarian disorder and amenorrhoea with menopausal symptoms in pre-menopausal patients at conventional dose. In very rare cases, recovery of ovarian function has been reported with continuing treatment

4.9       Overdose

Treatment:

There is no known antidote. Dialysis should be considered in the management of overdose as there is one report of successful dialysis of busulfan.

Appropriate supportive treatment should be given during the period of haematological toxicity.

Since, busulfan is metabolised through conjugation with glutathione, administration of glutathione might be considered.

10.       DATE OF  REVISION OF THE TEXT

January 2017 November 2015

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2 mg of the active substance busulfan.

Excipient with known effect:

Each tablet also contains 92.5 mg of lactose.

3. Pharmaceutical Form

Film-coated tablet.

White, film-coated, biconvex tablets engraved 'GX EF3' on one side and 'M' on the other.

. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Myleran is indicated for the palliative treatment of the chronic phase of chronic granulocytic myeloid leukaemia.

Myleran is effective in producing prolonged remission in polycythaemia vera, particularly in cases with marked thrombocytosis.

4.2 Posology and method of administration

General Posology

The relevant literature should be consulted for full details of treatment schedules.

Use in the elderly

No special comment.

Chronic granulocyticmyeloid leukaemia



The usual maintenance dosage is 0.5‑2 mg/day, but individual requirements may be much less. The aim is to maintain a leucocyte count of 10‑15 x 10⁹ per litre and blood counts must be performed at least every 4 weeks. Should a patient require an average daily dose of less than the content of one tablet, the maintenance dose may also be adjusted by reducing the number of treatment days per week.

Note: Lower doses of Myleran should be used if it is administered with other cytotoxic agents.

Paediatric population:

Chronic granulocyticmyeloid leukaemia is very rare in the paediatric age group. Myleran may be used to treat Philadelphia chromosome positive (Ph' positive) disease, but the Ph' negative juvenile variant responds poorly.

4.4 Special warnings and precautions for use

Hyperuricaemia and/or hyperuricosuria are not uncommon in patients with chronic granulocytic myeloid leukaemia and should be corrected before starting treatment with Myleran. During treatment, hyperuricaemia and the risk of uric acid nephropathy should be prevented by adequate prophylaxis, including adequate hydration and the use of allopurinol.

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.

Myleran 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.

The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Conventional dose Treatment

Patients co-administered itraconazole or metronidazole with conventional dose busulfan 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).

High-dose Treatment (used for Haemopoietic Stem Cell Transplantation)

If high-dose Myleran is prescribed (see section 4.9), patients should be given prophylactic anticonvulsant therapy with preferably a benzodiazepine rather than phenytoin (see section 4.5 and 4.8).

Concomitant administration of itraconazole or metronidazole with high-dose busulfan has been reported to be associated with an increased risk of busulfan toxicity (see section 4.5). Co administration of metronidazole and high-dose busulfan is not recommended. Co administration of itraconazole with high-dose busulfan should be at the discretion of the prescribing physician and should be based on a risk/benefit assessment.

Mutagenicity

Various chromosome aberrations have been noted in cells from patients receiving bulsulpha busulfan.

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 (see section 5.3). 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.

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

Fertility

Myleran can lead to suppression of ovarian function and amenorrhoea in women and suppression of spermatogenesis in men (see section 4.8 and 5.3).

The use of Myleran should be avoided whenever possible during pregnancy, particularly during the first trimester. In every individual case the expected benefit of treatment to the mother must be weighed against the possible risks to the foetus.

It is not known whether Myleran or its metabolites are excreted in human breast milk. Mothers receiving Myleran should not breast-feed their infants.

Breastfeeding

4.8 Undesirable effects

For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.

The following convention has been utilised for the classification of frequency: Very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000) and very rare (< 1/10,000).

The following table of adverse reactions originated from the use of busulfan, or busulfan in combination with other therapeutic agents.

* Description of selected adverse events

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

5. Pharmacological Properties

5.1 Pharmacodynamic properties

Group and ATC code: Antineoplastic and Immunomodulating agents, alkyl sulfonates: L01AB01.

Mechanism of action

Busulfan (1,4-butanediol dimethanesulfonate) is a bifunctional alkylating agent. Binding to DNA is believed to play a role in its mode of action, and di-guanyl derivatives have been isolated, but interstrand crosslinking has not been conclusively demonstrated.

The basis for the uniquely selective effect of busulfan on granulocytopoiesis is not fully understood. Although not curative, Myleran is very effective in reducing the total granulocyte mass, relieving the symptoms of disease and improving the clinical state of the patient. Myleran has been shown to be superior to splenic irradiation when judged by survival times and maintenance of haemoglobin levels and is as effective in controlling spleen size.

5.2 Pharmacokinetic properties

Absorption

The bioavailability of oral busulfan shows large intraindividual variation ranging from 47 % to 103 % (mean 80 %) in adults.

Following oral administration of high-dose busulfan (1 mg/kg every 6 h for 4 days), AUC and Cmax in adults are highly variable but have been reported to be 8260 nanograms.h/ml (range 2484 to 21090)

Distribution

Busulfan is reported to have a volume of distribution of 0.64 ± 0.12 L/kg in adults.

Busulfan given in high doses has been shown to enter the cerebrospinal fluid (CSF) in concentrations comparable to those found in plasma, with a mean CSF:plasma ratio of 1.3 : 1. The saliva:plasma distribution of busulfan was 1.1 : 1.

Biotransformation

Busulfan metabolism involves a reaction with glutathione, which occurs via the liver and is mediated by glutathione-S­transferase.

The urinary metabolites of busulfan have been identified as 3-hydroxysulpholane, tetrahydrothiophene 1-oxide and sulpholane, in patients treated with high-dose busulfan.

Elimination

Special patient populations

Paediatric population

The bioavailability of oral busulfan shows large intra-individual variation ranging from 22 % to 120 % (mean 68 %) in children.

Fertility

Busulfan interferes with spermatogenesis in experimental animals. Limited studies in female animals indicate busulfan has a marked and irreversible effect on fertility via oocyte depletion.

6.6 Special precautions for disposal and other handling

Safe handling of Myleran tablets

8. Marketing Authorisation Number

PA 1691/008/001

9. Date of First Authorisation/Renewal of THE Authorisation

Date of first authorisation: 1 April 1979

Date of last renewal: 1 April 2009

10. Date of Revision of THE Text

November 2015 April 2014

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7 MARKETING AUTHORISATION HOLDER

12/13 Exchange Place

I.F.S.C Dublin 1

3016 Lake Drive,

Citywest Business Campus

Dublin 24

10 DATE OF REVISION OF THE TEXT

February April 20143

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Aspen Europe GmbH

Industriestrasse 32-36,

D-23843 Bad Oldesloe

Germany

Aspen Pharma Trading Limited

12/13 Exchange Place

I.F.S.C Dublin 1,

Ireland

8.    marketing authoriSation number

PA 1568/9/1

PA 1691/8/1

10.  date of (PARTIAL) REVision of the Text

March 2010

November 2010

Myleran Changes in red

1.   name of the medicinal product

Myleran 2mg Film-coated Tablets

2.   qualitative and QUantitative composition

Each tablet contains 2mg of the active substance busulphan.

Each tablet also contains 92.5mg of Lactose

For a full list of excipients, see Section 6.1.

3.   pharmaceutical form

White, film-coated round biconvex tablets engraved ‘GX EF3’ on one side and ‘M’ on the other.

9.   date of first authoriSation/renewal of the AUTHORISATION

1^st April 1979 / 1^st April 2009

10. date of (PARTIAL) REVision of the Text

October 2009