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Aspen

3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Telephone: 003531 630 8400
Medical Information Direct Line: 0080000404142 - Freephone
Medical Information e-mail: aspenmedinfo@professionalinformation.co.uk
Summary of Product Characteristics last updated on medicines.ie: 12/10/2017
SPC Imuran Tablets 25mg

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

Updated on 12/10/2017 and displayed until Current
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 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   31-Aug-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Text in red = new text

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4.2 Posology and method of administration

 

 

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe azathioprine toxicity (see 4.4). These patients generally require dose reduction; particularly those being NUDT15 variant homozygotes (see 4.4). Genotypic testing of NUDT15 variants may be considered before initiating azathioprine therapy. In any case, close monitoring of blood counts is necessary.

 

 

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established.

Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine-related severe leukocytopenia and alopecia, especially in Asian populations (see section 4.4 and 5.2).

 

 

 

4.4 Special warnings and precautions for use

 

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe azathioprine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy. They generally require dose reduction, particularly those being NUDT15 variant homozygotes (see 4.2). The frequency of NUDT15 c.415C>T has an ethnic variability of approximately 10 % in East Asians, 4 % in Hispanics, 0.2 % in Europeans and 0 % in Africans. In any case, close monitoring of blood counts is necessary.

 

 

 

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established.

Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine-related severe leukocytopenia and alopecia, especially in Asian populations (see section 4.2 and 5.2).

 

5.2 Pharmacokinetic properties

 

NUDT15 R139C (NUDT15 c.415C>T) Variant

Recent studies indicate that a strong association exists between the NUDT15 variant NUDT15 c.415C>T [p.Arg139Cys] (also known as NUDT15 R139C [rs116855232]), which is thought to lead to a loss of function of the NUDT15 enzyme, and thiopurine-mediated toxicity such as leukopenia and alopecia. The frequency of NUDT15 c.415C>T has an ethnic variability of 9.8 % in East Asians, 3.9 % in Hispanics, 0.2 % in Europeans and 0.0 % in Africans, indicating an increased risk for the Asian population. Patients who are NUDT15 variant homozygotes (NUDT15 T risk alleles) are at an excessive risk of thiopurine toxicity compared with the C homozygotes.

Reduced thiopurine doses for patients who carry the NUDT15 variants may decrease their risk of toxicity. Therefore, genotypic analysis determining NUDT15 genotype should be determined for all patients, including paediatric patients, prior to initiating thiopurine treatment (see section 4.2). The prescribing physician is advised to establish whether dose reduction is required based on patient response to treatment as well as their genetic profile.

Patients with variants in both the NUDT15 and TPMT enzymes are significantly less tolerant of thiopurines than those with risk alleles in only one of these two genes.

The precise mechanism of NUDT15-associated thiopurine-related toxicity is not understood

 

 

 

 

10 DATE OF REVISION OF THE TEXT

April August 2017

Updated on 04/05/2017 and displayed until 12/10/2017
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 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   28-Apr-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Text in red = new text
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4.2 Posology and method of administration


Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established.

Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine-related severe leukocytopenia and alopecia, especially in Asian populations (see section 4.4 and 5.2).


 

4.4 Special warnings and precautions for use



Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established.

Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine-related severe leukocytopenia and alopecia, especially in Asian populations (see section 4.2 and 5.2).

 

4.8 Undesirable effects


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.

 

5.2 Pharmacokinetic properties



NUDT15 R139C (NUDT15 c.415C>T) Variant

Recent studies indicate that a strong association exists between the NUDT15 variant NUDT15 c.415C>T [p.Arg139Cys] (also known as NUDT15 R139C [rs116855232]), which is thought to lead to a loss of function of the NUDT15 enzyme, and thiopurine-mediated toxicity such as leukopenia and alopecia. The frequency of NUDT15 c.415C>T has an ethnic variability of 9.8 % in East Asians, 3.9 % in Hispanics, 0.2 % in Europeans and 0.0 % in Africans, indicating an increased risk for the Asian population. Patients who are NUDT15 variant homozygotes (NUDT15 T risk alleles) are at an excessive risk of thiopurine toxicity compared with the C homozygotes.

Reduced thiopurine doses for patients who carry the NUDT15 variants may decrease their risk of toxicity. Therefore, genotypic analysis determining NUDT15 genotype should be determined for all patients, including paediatric patients, prior to initiating thiopurine treatment (see section 4.2). The prescribing physician is advised to establish whether dose reduction is required based on patient response to treatment as well as their genetic profile.

Patients with variants in both the NUDT15 and TPMT enzymes are significantly less tolerant of thiopurines than those with risk alleles in only one of these two genes.

The precise mechanism of NUDT15-associated thiopurine-related toxicity is not understood.


 

10 DATE OF REVISION OF THE TEXT

January April 2017

 

Updated on 11/01/2017 and displayed until 04/05/2017
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • 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:   03-Jan-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

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

 

 

 

 

Carcinogenicity (see also section 4.8 Undesirable Effects):

Patients receiving immunosuppressive therapy, including azathioprine are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.

A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.

As is usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited, and patients should wear protective clothing and use a sunscreen with a high protection factor.

Macrophage Activation Syndrome

Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD), and there could potentially be an increased susceptibility for developing the condition with the use of azathioprine. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with azathioprine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

 

 

4.8 Undesirable effects

 

The risk of developing non-Hodgkin’s lymphomas and other malignancies, notably skin cancers (melanoma and non-melanomas), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ, is increased in patients who receive immunosuppressive drugs, particularly in transplant recipients receiving aggressive treatment and such therapy should be maintained at the lowest effective levels. The increased risk of developing non-Hodgkin’s lymphomas in immunosuppressed rheumatoid arthritis patients compared with the general population appears to be related at least in part to the disease itself.

There have been rare reports of acute myeloid leukaemia and myelodysplasia (some in association with chromosomal abnormalities).

 

 

10 DATE OF REVISION OF THE TEXT

April 2014January 2017

 

Updated on 11/04/2014 and displayed until 11/01/2017
Reasons for adding or updating:
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Apr-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

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7 MARKETING AUTHORISATION HOLDER

 

3016 Lake Drive,

Citywest Business Campus,

12/13 Exchange Place

I.F.S.C Dublin 1

 

 

 

 

10 DATE OF REVISION OF THE TEXT

April 2014
September 2013

Updated on 10/01/2013 and displayed until 11/04/2014
Reasons for adding or updating:
  • Improved electronic presentation
Date of revision of text on the SPC:   01-Sep-2012
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Improved electronic presentation
Updated on 05/05/2011 and displayed until 10/01/2013
Reasons for adding or updating:
  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text
  • SPC retired pending re-submission
Date of revision of text on the SPC:   01-Jan-2011
Legal Category:   Product subject to medical prescription which may be renewed (B)

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Product ownership changed from GSK to Aspen

Updated on 22/03/2010 and displayed until 05/05/2011
Reasons for adding or updating:
  • Change to section 7 - Marketing authorisation holder
Date of revision of text on the SPC:   30-Nov-2009
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Change to section 7 - Marketing Authrisation Holder
From GlaxoSmithKline to Aspen Europe
Updated on 29/10/2008 and displayed until 22/03/2010
Reasons for adding or updating:
  • Correction of spelling/typing errors
Updated on 26/08/2008 and displayed until 29/10/2008
Reasons for adding or updating:
  • Improved electronic presentation
Updated on 03/04/2007 and displayed until 26/08/2008
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   03/2007
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Update to section 4.8 to add Steven Johnson Syndrome and toxic epidermal necrolysis

Updated on 30/01/2007 and displayed until 03/04/2007
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   01/2007
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Section 4.8

Immune System Disorders

Uncommon: hypersensitivity reactions

Very rare: Stevens-Johnson syndrome and toxic epidermal necrolysis

Updated on 25/05/2005 and displayed until 30/01/2007
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
Updated on 28/01/2005 and displayed until 25/05/2005
Reasons for adding or updating:
  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text
Updated on 07/01/2004 and displayed until 28/01/2005
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
Updated on 25/07/2003 and displayed until 07/01/2004
Reasons for adding or updating:
  • Change to section 3 - Pharmaceutical form
  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text
Updated on 30/06/2003 and displayed until 25/07/2003
Reasons for adding or updating:
  • New SPC for medicines.ie

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Active Ingredients

 
   Azathioprine