Imuger 25 mg & 50 mg Film-coated Tablets

3. PHARMACEUTICAL FORM
 
Film-coated tablet

Pale-yellow, film-coated, round,  biconvex tablet, marked ‘AE’ over ‘25’ on one side and ‘G’ on the reverse.

Pale- yellow, film-coated, round, biconvex tablet, marked ‘AE’ over ‘50’ on one side and breakline on the reverse. The tablet can be divided into equal doses.

4.1 Therapeutic indications

Azathioprine is indicated in combination with other immunosuppressive agents for the prophylaxis of transplant rejection in patients receiving allogenic kidney, liver, heart, lung, or pancreas transplants. Azathioprine is usually indicated in immunosuppressive regimens as an adjunct to immunosuppressive agents that form the mainstay of treatment (basis immunosuppression).

Azathioprine is indicated in severe cases of the following diseases, in patients who are intolerant to steroids or who are dependent on steroids and in whom the therapeutic response is inadequate despite treatment with high doses of steroids:
• severe active rheumatoid arthritis that cannot be kept under control by less toxic agents (disease-modifying anti-rheumatic drugs (DMARDs))
• severe or moderately severe inflammatory intestinal disease (Crohn’s disease or ulcerative colitis)
• systemic lupus erythematosus
• dermatomyositis
• autoimmune hepatitis
• polyarteritis nodosa
• refractory warm auto-immune autoimmune haemolytic anaemia
• chronic refractory idiopathic thrombocytopenic purpura

4.2  Posology and method of administration

Posology

Use in patients with renal and/ or hepatic impairment
In patients with renal and/ or mild to moderate hepatic dysfunction, dosages should be given at the lower end of the normal range. Azathioprine is contraindicated in severe hepatic impairment (see section 4.3).

Paediatric population:
There are insufficient data to recommend the use of azathio¬prine for the treatment of juvenile idiopathic arthritis, systemic lupus erythematosus, dermatomyositis, and polyar-teriitis polyarteritis nodosa (in children and adolescents < 18 years).
 
Concerning the other indications, the given dose recommendations apply for children and adolescents as well as for adults.

Use in the elderly: 
There is no specific information on how elderly patients tolerate azathioprine.  It is advisable to monitor renal and hepatic functions and consider a dose reduction if there is a functional impact (see section 4.2). It is recommended that the dosages used should be at the lower end of the normal range (for monitoring of blood count see section 4.4).

Drug interactions:
When allopurinol, oxipurinol or thiopurinol is given conco¬mitantly with azathioprine, the dose of azathioprine must be reduced to a quarter of the original dose (see sections 4.4 and 4.5).

It can take weeks or months before a therapeutic effect is seen.

The medicinal product may be given over the long term unless the patient cannot tolerate the preparation.

Use in TPMT-deficient patients:
Patients with rare hereditary problems of small or non-existent thiopurine S methyltransferase (TPMT) activity are at an increased risk of severe azathioprine toxicity from conventional doses of azathioprine, and usually require a significant dose reduction. The optimal starting dose for homozygous patients with TPMT deficiency has not been established (see sections 4.4 and. 5.2).

Most patients with heterozygous TPMT deficiency tolerate the recommended azathioprine doses, but some of them may require dose reduction. Tests of genotype and phenotype of TPMT are available (see sections 4.4 and 5.2).

Patients with NUDT15 variant:
Patients with an inherited, mutated NUDT15 gene have an increased risk of serious azathioprine toxicity (see section 4.4). These patients generally require a dose reduction, particularly those patients who are homozygous for the NUDT15 variant (see section 4.4). Genotypical testing of NUDT15 variants may be considered before starting treatment with azathioprine. In every case it is necessary to monitor the blood count carefully.

4.4 Special warnings and precautions for use

Immunisation with live vaccines is not recommended as they may cause infection in immunocompromised hosts (see section 4.5).

Patients with NUDT15 variant:
Patients with an inherited mutated NUDT15 gene have an increased risk of serious azathioprine toxicity, such as early leukopenia and alopecia, from conventional doses in thiopurine treatment. A dose reduction is generally required, particularly for those patients who are homozygous for the NUDT15 variant (see section 4.2). The frequency of NUDT15 c.415C>T has an ethnic variability: approx. 10% in Asians, 4% in Latin Americans, 0.2% in Europeans and 0% in Africans. In every case it is necessary to monitor the blood count carefully.

Fertility:
Contraceptive measures must be used by both male and female patients of reproductive age during azathioprine therapy and for at least three months thereafter. This also applies to patients with impaired fertility due to chronic uraemia, since fertility usually returns to normal after transplantation.

Relief of chronic renal insufficiency by renal transplantation involving the administration of azathioprine has been accompanied by increased fertility in both male and female transplant recipients.

Azathioprine has been reported to interfere with the effectiveness of intrauterine contraceptive devices. It is therefore recommended that alternative or additional contraceptive measures be used.

4.6 Fertility, pregnancy and lactation

This also applies to patients with impaired fertility due to chronic uraemia, since that fertility usually returns to normal after transplantation. Azathioprine has been reported to interfere with the effectiveness of intrauterine contraceptive devices. It is therefore recommended that alternative or additional contraceptive measures be used.

4.8 Undesirable effects

Infections and infestations
Patients treated with azathioprine alone or in combination with other immunesuppressants immunosuppressants, primarily corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe and atypical varicella, herpes zoster and other infectious agents (see section 4.4).

5.1 Pharmacodynamic properties
 
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents. Immunosuppressants. Other immunosuppressants, ATC code: L04 AX 01

Azathioprine is used as an immunosuppressive antimetabolite either alone or

1. NAME OF THE MEDICINAL PRODUCT

Imuger 25 mg Film-coated Tablets film-coated tablets
Imuger 50 mg Film-coated Tablets film-coated tablets

4.4 Special warnings and precautions for use

Carcinogenicity:
Patients receiving immunosuppressive therapy, including azathioprine are at an increased risk of developing non-Hodgkin's lymphomas lymphoproliferative disorders and other malignancies, notably mainly skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer carcinoma in situ. The increased risk appears to be is probably related to the degree intensity and duration of immunosuppression.treatment, and not the individual product. It has been reported that reduction or discontinuation of immunosuppression immunosuppressive therapy may provide result in partial or complete regression of the lymphoproliferative disorder non-Hodgkin's lymphoma and Kaposi's sarcoma.

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.

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

	Very common (>1/10)	Common (>1/100to <1/10)	Uncommon (>1/1000to <1/100)	Rare (>1/10000to <1/1000)	Very rare (<1/10000),	Not known (cannot be estimated from the available data)
Infections and infestations	Viral, fungal and bacterial infections in transplant patients receiving azathioprine in combination with other immunosuppressants. In 20% of kidney transplant patients.	Susceptibility to infection in patients with inflammatory bowel disease	Viral, fungal and bacterial infections in other patient populations. In <1% of rheumatoid arthritis (RA) patients		Cases of PML associated with JC virus has been reported following use of azathioprine in combination with other immunosuppressive agents (see section 4.4).
Neoplasms benign, malignant and unspecified (including cysts and polyps)		In up to 2.8% of kidney transplant patients, significantly fewer cases (or none at all) in other indications (in decreasing frequency): squamous cell carcinoma of the skin, non-Hodgkin lymphomas, cervical cancer, Kaposi’s sarcoma, vulval cancer.	Post-transplantation lymphoproliferative disease.	Neoplasms including lymphoproliferative disorders, skin cancers (melanomas and non-melanomas), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ (see section 4.4)	Acute myeloid leukaemia and myelo-dysplastic syndromes.
Blood and lymphatic system disorders	Depression of bone marrow function; leukopenia   - in >50% of kidney transplant patients (significant in 16%), - in 28% of RA patients, - in 15% of Crohn’s disease patients.	Thrombocytopenia. Significant leukopenia in 5.3% in RA patients.	Anaemia	Agranulocytopenia, pancytopenia and aplastic anaemia, megaloblastic anaemia, ery­throid hypoplasia.	Haemolytic anaemia
Immune system disorders			Hypersensitivity reac­tions including general malaise, hypotension, dizziness, leukocytosis, exanthema, severe nau­sea and vomiting, di­arrhoea, fever, rigors, chills, rash, myalgia, arthra­lgia, vasculitis, renal dysfunction, elevations in liver enzymes.		Hypersensitivity reactions with lethal outcome.
Nervous system disorders						Meningism
Respiratory, thoracic and mediastinal disorders				Interstitial pneumonitis (reversible).

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.

Ireland
Pharmacovigilance Section
Irish Medicines Board
Kevin O’Malley House
Earlsfort Centre
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6767836
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie

6.6  Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

In section 6.5, additional pack size of 90 for blisters

PVC/Aluminium foil blister packs – 20, 30, 50,

90, 100

 

Extensive updates to the SPC in line with the brand leader and QRD template.

Section 3: description chanaged from...
25mg: Pale yellow, film coated, biconvex tablet approximately 6mm in diameter             marked “AE 25” on one side and “G” on reverse. Pale-yellow, film-coated, biconvex tablets marked ‘AE over 25’ on one side and ‘G’ on the reverse.

50mg: Pale yellow, film coated, biconvex tablet approximately 8mm in diameter             marked “AE 50” on one side and breakline on reverse.Pale- yellow, film-coated, round, biconvex tablets marked “AE over 50” on one side and breakline on the reverse.