Last Updated on eMC 09-11-2017 View medicine  | Aspen Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:29-09-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Text in red = new text

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4.4       Special warnings and precautions for use

 

Conventional dose Treatment

 

 

Conventional dose Treatment

 

Patients who are concurrently treatedco-administered itraconazole or metronidazole with the conventional dose of busulfan and itraconazole or metronidazole 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

September 2017  25/02/2016

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.1 - List of excipients
  • Change to section 6.2 - Incompatibilities
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:25-02-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Text in red = new text
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2.        Qualitative and Quantitative Composition

 

Each 2 mg tablet contains 2 mg of the active substance busulfan

 

Excipient with known effect: lactose

 

For the full list of excipients, see section 6.1.

 

4.1      Therapeutic indications

 

Busulfan is indicated as conditioning treatment prior to haemopoietic  haematopoietic progenitor cell transplantation in patients when the combination of high dose busulfan and cyclophosphamide is considered the best available option.

 

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

 

4.8      Undesirable effects

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

 

System organ class

Frequency

Side effects

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

Common

Leukaemia secondary to oncology chemotherapy (see section 4.4)

Blood and lymphatic system disorders *

Very common

Dose-related bone marrow failure, manifesting as leukopenia and particularly thrombocytopenia

Rare

Aplastic anaemia

Nervous system disorders

Rare

At high-dose: convulsion (see section 4.4 and 4.5)

Very rare

Myasthenia gravis

Eye disorders

Rare

Lens disorder and cataract (which may be bilateral) corneal thinning (reported after bone marrow transplantation preceded by high-dose Busulfan treatment)

Cardiac disorders

Common

At high-dose: cardiac tamponade in patients with thalassaemia

Respiratory, thoracic and mediastinal disorders *

Very common

At high-dose: idiopathic pneumonia syndrome

Common

Interstitial lung disease following long term conventional dose use

Gastrointestinal disorders

Very common

At high-dose: nausea, vomiting, diarrhoea, mouth ulceration

Rare

At conventional dose: nausea, vomiting, diarrhoea, mouth ulceration, which may possibly be ameliorated by using divided doses. Dry mouth

Hepatobiliary disorders *

Very common

At-high-dose: hyperbilirubinaemia, jaundice, venoocclusive liver disease (see section 4.4 and 4.5) and biliary fibrosis with hepatic atrophy and necrosis

Rare

Jaundice and abnormal hepatic function, at conventional dose. Biliary fibrosis

Skin and subcutaneous tissue disorders *

Common

Alopecia at high-dose. Skin hyperpigmentation (see also General disorders and administration site conditions)

Rare

Alopecia at conventional dose, skin reactions including urticaria, erythema multiforme, erythema nodosum, porphyrianon-acute, rash, dry skin and fragility of the skin with complete anhydrosis cheilosis, Sjögren’s syndrome. An increased radiation skin injury in patients receiving radiotherapy soon after high-dose Busulfan

Renal and urinary disorders

Common

At high-dose: in combination with cyclophosphamide cystitis haemorrhagic

Reproductive system and breast disorders *

 

Very common

Ovarian disorder and amenorrhoea with menopausal symptoms in pre-menopausal patients at high-dose; severe and persistent ovarian failure, including failure to achieve puberty after administration to young girls and pre-adolescents at high-dose. Male infertility, azoospermia and testicular atrophy in male patients receiving 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

Very rare

Gynaecomastia

General disorders and administration site conditions *

Rare

Dysplasia

 

* Description of selected adverse events

 

General disorders and administration site conditions

 

Clinical syndrome (weakness, severe fatigue, anorexia, weight loss, nausea and vomiting and hyperpigmentation of the skin) resembling adrenal insufficiency (Addison’s disease) but without biochemical evidence of adrenal suppression, mucous membrane hyperpigmentation or hair loss (see Skin and subcutaneous tissue disorders) has been seen in a few cases following prolonged Busulfan therapy. The syndrome has sometimes resolved when busulfan has been withdrawn.

 

 

The following table of adverse reactions originated from the intravenous use of busulfan in combination with cyclophosphamide or melphalan.

 

System organ class

Frequency

Side effects

Immune system disorders

Very common

Hypersensitivity

Metabolism and nutrition disorders

Very common

Hyperglycaemia, hypocalcaemia, hypokalaemia, hypomagnesaemia, hypophosphataemia

Common

Hyponatraemia

Psychiatric disorders

Very common

Anxiety, depression, insomnia

Common

Confusional state

Uncommon

Delirium, nervousness, hallucination, agitation

Nervous system disorders

Very common

Headache, dizziness

Uncommon

Encephalopathy, cerebral haemorrhage

Cardiac disorders

Very common

Tachycardia

Common

Arrhythmia, atrial fibrillation, cardiomegaly, pericarditis

Uncommon

Ventricular extrasystoles, bradycardia

Vascular disorders

Very common

Hypertension, hypotension, thrombosis, vasodilation

Uncommon

Femoral artery thrombosis, capillary leak syndrome

Respiratory, thoracic and mediastinal disorders

Common

Hyperventilation, respiratory failure, asthma, atelectasis, pleural effusion

Gastrointestinal disorders

Very common

Abdominal pain, dyspepsia, ascites, constipation, anorectal discomfort

Common

Haematemesis, ileus, oesophagitis

Uncommon

Gastrointestinal haemorrhage

Hepatobiliary disorders

Very common

Hepatomegaly

Musculoskeletal and connective tissue disorders

Very common

Myalgia, back pain, arthralgia

Renal and urinary disorders

Very common

Dysuria, oliguria

Common

Haematuria, moderate renal insufficiency

General disorders and administration site conditions

Very common

Chills, pyrexia, chest pain, oedema, general oedema, pain

Investigations

Very common

Weight increased, abnormal breath sounds, blood creatinine increased

Common

Blood urea increased, decreased ejection fraction

 

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

 

4.9      Overdose

 

Symptoms and signs

 

The acute dose-limiting toxicity of Busulfan in man is myelosuppression (see section 4.8 Undesirable Effects).

 

 

 

Metabolism Biotransformation

 

5.2      Pharmacokinetic properties

 

Absorption

 

The bioavailability of oral Busulfan shows large intra-individual variations ranging from 47 % to 103 % (mean 80 68%) in adults.

 

 

 

 

Special Patient Populations

 

Children Paediatric population

 

The bioavailability of oral busulfan shows large intra-individual variation ranging from 22 % to 120 % (mean 80 68 %) in children.

 

5.3         Preclinical safety data

 

Carcinogenicity

 

There is limited evidence from preclinical studies that Busulfan is carcinogenic in animals (see section 4.4 Special Warnings and Precautions for Use).

 

6.1      List of excipients

 

Tablet core:                      

Lactose, anhydrous

Pregelatinised starch

Magnesium stearate

 

 

6.2      Incompatibilities

 

Not applicable  Not Known

 

9.        DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

 

22 January 2002

Date of first authorisation: 13 January 1986

Date of latest renewal: 30 June 2003

 

10.      DATE OF (PARTIAL) REVISION OF TEXT

 

25/02/2016 November

Reasons for adding or updating:

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Date of revision of text on the SPC:01-11-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Text in red = new
Text strikethrough = deleted


4.4       Special Warnings and Precautions for Use

Monitoring:


Hepatic veno-occlusive disease is a major complication that can occur during treatment with Busulfphan.


5.2 Pharmacokinetic Properties

Metabolism:


The urinary metabolites of busulfan have been identified as 3-hydroxysulpholane, tetrahydrothiophene 1-oxide and sulpholane, in patients treated with high-dose Busulfan. Very little busulfane is excreted unchanged in the urine.

7          Marketing Authorisation Holder

 

Aspen Pharma Trading Limited

3016 Lake Drive

Citywest Business Campus

Dublin 24

Ireland

12/13 Exchange Place
I.F.S.C.
Dublin 1
Ireland

10        Date of (Partial) Revision of Text

November May 2013

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:03-05-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



The following text has been inserted (in green and underlined) or deleted (in red) to section 4.2, 4.4, 4.5 and 10.
4.2       Posology and Method of Administration

 

General:

           

The bioavailability of oral Busulfan shows large intra-individual variations ranging from 47% to 103% (mean 68%) in adults and from 22% to 120% (mean 80%) in children. (See Section 5.2 Pharmacokinetics).

 

There are other formulations available which may be more suitable for paediatric patients.

 

Busulfan tablets are usually given in courses or administered continuously.  The dose must be adjusted for the individual patient under close clinical and haematological control.  Should a patient require an average daily dose of less than the content of the available Busulfan tablets, this can be achieved by introducing one or more busulfan free days between treatment days.  The tablets should not be divided (see 6.6 Instructions for Use/Handling). 

 


4.4       Special Warnings and Precautions for Use

 

 

 

Monitoring:

 

Careful attention must be paid to monitoring the blood counts throughout treatment to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia (see also 4.8 Undesirable Effects).

 

Hepatic veno-occlusive disease is a major complication that can occur during treatment with Busulphan. Patients who have received prior radiation therapy, for three or more cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk of developing hepatic veno-occlusive disease (see section 4.8 Undesirable Effects).

 

High-dose Treatment:

 

If high-dose Busulfan is prescribed, patients should be given prophylactic anticonvulsant therapy, preferably with a benzodiazepine rather than phenytoin.

4.5       Interactions with other medicinal products and other forms of interaction

  

A reduced incidence of hepatic veno-occlusive disease and other regimen-related toxicities have been observed in adult and paediatric patients treated with high-dose Busulfan and cyclophosphamide when the first dose of cyclophosphamide has been delayed for > 24 hours after the last dose of busulfan.

10.       Date of (Partial) Revision of Text

 

November 2012January 2013

Reasons for adding or updating:

  • Change to section 1 - Name of the medicinal product
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:17-12-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Change from Brand Name Myleran to Busulfan
Revision of text 17-Dec-2012

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder
  • Change to section 8 - MARKETING AUTHORISATION NUMBER(S)
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-05-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



7.         Marketing Authorisation Holder changed from ALKOPHARMA SARL, 45-47, rte d’Arlon, L – 1140 Luxembourg  to

Aspen Pharma Trading Limited, 12/13 Exchange Place, I.F.S.C, Dublin 1, Ireland

 

8.         Marketing Authorisation Number changed from PL 36637/0008 to PL 39699/ 0042

 

10.       Date of (Partial) Revision of Text changed from September 2010 to May 2012

Reasons for adding or updating:

  • New SPC for eMC ie an SPC for an existing product, but one that is new for the eMC

Date of revision of text on the SPC:01-01-0001

Legal Category:POM

Black Triangle (CHM): NO