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Home , Azathioprine, Thiopurine

1. NAME OF THE MEDICINAL PRODUCT Azathioprin Orifarm 50 mg film-coated tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 50 mg

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Film-coated tablet

Light yellow, film-coated, circular, biconvex tablet engraved ”A50”and score line on one side and plain on the other side.

The score line is not intended for breaking the tablet.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Azathioprine is indicated in combination with other immunosuppressive agents for the prophylaxis of in patients receiving allogenic , 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 ).

Azathioprine is indicated in severe cases of systemic erythematosus, 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.

4.2 Posology and method of administration

Posology

Transplantation Depending on the immunosuppressive regime selected, a loading dose of up to 5mg/kg/body weight/day orally is usually given. The maintenance dose can range from 1-4 mg/kg body weight/day and should be adjusted according to the clinical response and haematological tolerance. To enhance the survival and function of the transplant organ azathioprine is often given in combination with . Withdrawal of treatment with azathioprine after several years of therapy entail a high risk of graft rejection.

Systemic lupus erytematosus In general, the starting dosage is 1-3mg/kg/body weight/day and should be adjusted according to the clinical response (which may not be evident for weeks or months) and haematological tolerance. The maintenance dose is usually 2-2,5 mg/kg body weight/day and should be adjusted according to the clinical response and haematological tolerance. Clinical response is expected within a few days or weeks after starting treatment with azathioprine. If a clinical effect is not reached within three months, discontinuation should be considered. Otherwise it may be continued as a long term treatment if tolerated. Since the treatment effects can have a delayed onset of action it is important to without delay adjust dosing in case of rapid fall of leukocyte counts or other signs of myelosuppression

Use in patients with renal and/ or hepatic impairment: In patients with impaired renal and/or hepatic function, it should be considered to reduce the dosage (see section 4.4). Azathioprine is contra-indicated in severe hepatic impairment. (See section 4.3).

Paediatric population There are insufficient data to recommend the use of azathioprine for the treatment of systemic lupus erythematosus (in children and adolescents < 18 years).

Concerning the other indication the given dose recommendations apply for children and adolescents as well as for adults.

Use in the elderly: There is limited experience of the administration of azathioprine in elderly patients. It is advisable to monitor renal and hepatic function, and to consider dosage reduction if there is impairment (see section 4.2 – Renal and/or hepatic impairment).

Interaction with other medicinal products When , or thiopurinol is given concomitantly 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 therapeutic effect is seen.

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

Withdrawal of azathioprine should always be a gradual process performed under close monitoring.

Treatment with azathioprine should be initiated or supervised by a physician with great experience of immunosuppressive treatment. Azathioprine should only be prescribed if sufficient follow-up concerning toxic effects can be provided throughout the treatment period.

TPMT-deficient patients Patients with inherited little or no S-methyltransferase (TPMT) activity are at increased risk for severe azathioprine toxicity from conventional doses of azathioprine and generally requires substantial dose reduction. The optimal starting dose for homozygous patients with TPMT deficiency has not been established (see section 4.4 and 5.2).

Most patients with heterozygous TPMT deficiency tolerate recommended azathioprine doses, but some may require dose reduction. Genotypic and phenotypic tests of TPMT are available (see section 4.4 and 5.2).

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

Method of administration Azathioprin Orifarm is supplied for oral administration. The tablet should be taken with at least a glass of liquid (200 ml). Azathioprin Orifarm should be taken following a meal in order to reduce the risk of nausea. Halving of the film-coated tablet should be avoided. The score line is not intended to divide the tablet into equal doses.

4.3 Contraindications

to the active substance or to any of the excipients listed in section 6.1  Hypersensitivity to 6- (6-MP)  Severe  Seriously impaired hepatic function or bone marrow function   Any live vaccine, especially BCG, smallpox or yellow fever  Lactation (see section 4.6)

4.4 Special warnings and special precautions for use

Immunisation using a live vaccine is not recommended as it has the potential to cause in immunocompromised hosts (see section 4.5).

Co-administration of ribavirin and azathioprine is not advised. Ribavirin may reduce efficacy and increase toxicity of azathioprine (see section 4.5).

Monitoring There are potential dangers in the use of azathioprine; it should therefore not be prescribed unless the patient can be adequately monitored for toxic effects throughout the duration of therapy.

Especially the haematological toxicity should be closely monitored and the maintenance dose must be reduced to the lowest dose required for a clinically response.

During the first eight weeks of treatment, a , including platelet count must be performed at least once weekly. It should be controlled more frequently:

- if high doses are used - in elderly patients - if renal function is impaired - if hepatic function is mildly to moderately impaired (see also sections 4.2 and 5.2) - if bone marrow function is mildly to moderately impaired (see also section 4.2) - in patients with hypersplenism

The frequency of the blood count controls may be reduced after 8 weeks. It is recommended that complete blood counts be repeated monthly, or at least at intervals of no longer than 3 months.

At the first signs of an abnormal fall in blood counts, treatment should be interrupted immediately as leucocytes and platelets may continue to fall after treatment is stopped.

S-alkaline phosphatase, S-transaminase and S-bilirubin should be monitored. Increase in these parameters may necessitate dose reduction or temporary discontinuation.

Patients must be advised to inform their doctor immediately about ulcerations of the throat, fever, infections, bruising, bleeding or other signs of myelosuppression. Myelosuppression is reversible if azathioprine is stopped early enough.

Azathioprine is hepatotoxic and liver function tests should be routinely monitored during treatment. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. The patient should be instructed to discontinue azathioprine immediately if jaundice becomes apparent.

There are individuals with an inherited deficiency of the enzyme thiopurine methyl transferase (TPMT) who may be unusually sensitive to the myelosuppression effect of azathioprine and prone to developing rapid bone marrow depression following the initiation of treatment with azathioprine. This problem could be exacerbated by co- administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphasalazine Also a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6– mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics (see section 4.8). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary.

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 section 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.

The dosage of azathioprine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression (see section 4.5).

Renal and/or hepatic impairment Caution is advised during the administration of azathioprine in patients with renal impairment and/or hepatic impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored (see section 4.2).

Lesch-Nyhan syndrome Limited data indicate that azathioprine is not effective in patients with hereditary --phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome). Therefore azathioprine should not be used in these patients.

Varicella Zoster Virus Infection Infection with varicella zoster virus (VZV; chickenpox and herpes zoster) may become severe during the administration of immunosuppressants. Caution should be exercised especially with respect to the following: - Before starting the administration of immunosuppressants, the prescriber should check to see if the patient has a history of VZV. Serologic testing may be useful in determining previous exposure. - Patients who have no history of exposure should avoid contact with individuals with chickenpox or herpes zoster. - If the patient is exposed to VZV, special care must be taken to avoid patients developing chickenpox or herpes zoster, and passive immunisation with varicella- zoster immunoglobulin (VZIG) may be considered. - If the patient is infected with VZV, appropriate measures should be taken, which may include antiviral therapy and supportive care.

Mutagenicity Chromosomal abnormalities have been demonstrated in both male and female patients treated with azathioprine. It is difficult to assess the role of azathioprine in the development of these abnormalities. Chromosomal abnormalities, which disappear with time, have been demonstrated in lymphocytes from the off-spring of patients treated with azathioprine. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the offspring of patients treated with azathioprine. Azathioprine and long-wave light have been shown to have a synergistic clastogenic effect in patients treated with azathioprine for a range of disorders.

Carcinogenicity Patients receiving immunosuppressive therapy, including azathioprine are at an increased risk of developing lymphoproliferative disorders and other , notably skin (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical in situ. The increased risk appears to be related to the degree

and duration of immunosuppressive treatment. It has been reported that discontinuation of immunosuppressive treatment may provide partial regression of the lymphoproliferative disorder.

A treatment regimen containing multiple immunosuppressants (including ) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with a fatal outcome. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. Due to the risk for , exposure to sunlight and UV light should be limited, and patients should wear protective clothing and use a sunscreen with a high protection factor.

Patients receiving multiple immunosuppressive agents may be at increased risk of over- immunosuppression, therefore such therapy should be maintained at the lowest effective level.

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.

Progressive Multifocal Leukoencephalopathy (PML) PML, an caused by the JC virus, has been reported in patients receiving azathioprine with other immunosuppressive agents. Immunosuppressive therapy should be withheld at the first sign or symptoms suggestive of PML and appropriate evaluation undertaken to establish a diagnosis (see section 4.8).

If allopurinol, oxipurinol and/or thiopurinol are given concomitantly with azathioprine, the dosage of azathioprine must be reduced to a quarter of the original dose (see section 4.2 and 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Vaccines The immunosuppressive activity of azathioprine can lead to an atypical and possibly harmful response to live vaccines, and therefore, for theoretical reasons, the administration of live vaccines to patients being treated with azathioprine is contraindicated (see sections 4.3 and 4.4).

A diminished response to killed vaccines is likely and such a response to hepatitis B vaccine has been observed among patients treated with a combination of azathioprine and corticosteroids.

A small clinical study has indicated that standard therapeutic doses of azathioprine do not deleteriously affect the response to polyvalent pneumococcal vaccine, as assessed on the basis of mean anti-capsular specific concentration.

Effect of concomitant drugs on azathioprine

Ribavirin: Ribavirin inhibits the enzyme, monophosphate dehydrogenase (IMPDH), leading to a lower production of the active 6-thioguanine and increased production of the active 6-mercaptopurine ribonucleotide. Severe myelosuppression has been reported following concomitant administration of azathioprine and ribavirin; therefore co-administration is not advised (see sections 4.4 and 5.2).

Cytostatic/myelosuppressive agents (see section 4.4): When possible, concomitant therapy with azathioprine and agents with myelosuppressive/cytotoxic properties, such as , should be avoided. Liver necrosis has been reported in patients who received azathioprine and then . Interaction with trimethoprim sulfate, resulting in severe haematological abnormalities, has been reported. There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, such as neutropenia and thrombocytopenia, between azathioprine and co-trimoxazole.

There have been case reports suggesting that haematological abnormalities (neutropenia and thrombocytopenia, anaemia) may develop due to concomitant therapy with azathioprine and ACE-inhibitors.

It has been suggested that cimetidine and indomethacin may have myelosuppressive effects which may be enhanced by concomitant administration of azathioprine.

Allopurinol/oxipurinol/thiopurinol: oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol which results in reduced conversion of biologically active 6- thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxipurinol and/or thiopurinol are administered concomitantly with 6-mercaptopurine or azathioprine, the dose of 6-mercaptopurine and azathioprine must be reduced to a quarter of the original dose (see sections 4.2 and 4.4).

Aminosalicylate: There is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or ) inhibit the TPMT enzyme. Therefore lower doses of azathioprine may need to be considered when administered concomitantly with aminosalicylate derivatives (see section 4.4).

Methotrexate: (20 mg/m2 orally) increased 6-mercaptopurine AUC by approximately 31 % and methotrexate (2 or 5 g/m2 intravenously) increased 6- mercaptopurine AUC by 69 and 93 %, respectively. Therefore, when azathioprine is administered concomitantly with high dose methotrexate, the dose should be adjusted to maintain a suitable count.

Immunosuppressants: If azathioprine is combined with other immunosuppressants, such as cyclosporine or , the greater risk of excessive immunosuppression must be taken into consideration.

Infliximab: An interaction has been observed in Crohn’s disease patients on continuous azathioprine treatment. Patients experienced transient increase in 6-TGN levels (6- thioguanine , an active metabolite of azathioprine) and decrease in average leucocyte levels in the first weeks after infusion, which returned to previous levels after 3 months.

Effect of azathioprine on other drugs

Anticoagulants: Inhibition of the effect of and acenocoumarol, has been reported if administered concomitantly with azathioprine and therefore increased doses of the may be necessary. Coagulation should be closely monitored when anticoagulants of the coumarin type are given concomitantly with azathioprine.

4.6 , lactation and fertility

Pregnancy Azathioprine should not be used during pregnancy without careful assessment of risks and benefits. Substantial transplacental and transamniotic transmission of azathioprine and its metabolites from the mother to the foetus have been shown to occur.

Leucopenia and thrombocytopenia have been reported in a number of neonates whose mothers received azathioprine during pregnancy. Extra care in haematological monitoring is advised during pregnancy.

Teratogenicity has been reported in animal studies (see section 5.3). There are conflicting information about teratogenicity in humans. As with all cytotoxic , adequate contraceptive precautions should be advised when either partner is receiving Azathioprin Orifarm. Azathioprine has been reported to interfere with the effectiveness of intrauterine contraceptive devices. It is therefore recommended to use another type of contraception or complementary contraception.

Breast-feeding 6-mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment. Breast-feeding and concomitant use of azathioprine are contraindicated (see section 4.3). Breast-feeding must be ceased during treatment with azathioprine.

Fertility 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.

4.7 Effects on ability to drive and use machines Studies on the effects of azathioprine on the ability to drive and use machines have not been performed.

4.8 Undesirable effects Up to 50% of patients can be expected to experience adverse effects. The type, frequency and severity of adverse reactions may depend on the dose of azathioprine and duration of therapy as well as on the patient's underlying disease or concomitant therapies.

The principal undesirable effect of azathioprine is a dose-related, generally reversible depression of bone marrow function expressed as leukopenia, thrombocytopenia and anaemia. Leukopenia may occur in more than 50% of all patients treated with conventional doses of azathioprine. Other manifestations of bone marrow depression such as thrombocytopenia, , macrocytosis or megaloblastic bone marrow changes occur less frequently.

Type and frequency of undesirable effects of azathioprine are summarised in the following table.

Very common Common Uncommon Rare Very rare Not known (≥1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) (≥1/10000 to (<1/10000) (cannot be <1/1000) estimated from the available data) Infections Viral, fungal and Viral, fungal and Cases of JC and bacterial bacterial infections virus infestations infections in in other patient associated transplant populations. PML have patients been reported receiving following the azathioprine in use of combination with azathioprine other in immunosuppres- combination sants1. with other immune- suppressants (see section 4.4). Neoplasms Vulval cancer2 Post-transplantation Neoplasms Acute benign, lymphoproliferative including myeloid malignant disease. lymphoprolife- leukaemia and rative disorders, and myelo- unspecified skin cancers dysplastic (incl cysts (melanomas and syndromes. and polyps) non-melanomas), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ (see section 4.4). Blood and Depression of Thrombocytopenia Anaemia Agranulocytosis, Haemolytic lymphatic bone marrow pancytopenia and anaemia system function3, aplastic anaemia, disorders leucopenia. megaloblastic anaemia, ery- throid hypoplasia.

Very common Common Uncommon Rare Very rare Not known (≥1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) (≥1/10000 to (<1/10000) (cannot be <1/1000) estimated from the available data) Immune Hypersensitivity system reactions4 with disorders multi-organ effects including general malaise, hypotension, dizziness, leucocytosis, exanthema, severe nausea and , diarrhoea, fever, rigors, chills, , myalgia, arthralgia, , impaired renal function, elevations in liver enzymes. Nervous Menningis- system mus disorders Respiratory, Interstitial thoracic and pneumonitis. mediastinal disorders Gastrointesti- Nausea and Pancreatitis6. Steatorrhoea, Intestinal nal disorders anorexia with diarrhoea7. haemorrhage. occasional Bowel vomiting5. perforation, colitis, diverticulitis8. Hepatobiliary Impaired hepatic Life-threatening disorders function. Different veno-occlusive pathologies liver disease10. including cholestasis, destructive chol- angitis, peliosis hepatitis, perisinusoidal fibrosis, and nodular regene- rative hyperplasia9. Skin and Alopecia11. Stevens- subcutaneous Johnson tissue syndrome disorders and toxic epidermal necrolysis. Renal and Acute renal urinary failure. disorders

1Infection and infestations Patients receiving azathioprine alone, or in combination with other immunosupressants, particularly corticosteroids, have shown increased susceptibility to viral, fungal and

bacterial infections, including severe and atypical VZV, herpes zoster and other infectious agents (see section 4.4).

2Neoplasms benign and malignant Patients receiving immunosuppressive therapy, including azathioprine, are at increased risk of developing non-Hodgkin's and other malignancies, including skin cancer (melanoma and non-melanoma), sarcoma (Kaposi’s and non-Kaposi’s) and cervical cancer in situ. Transplant patients receiving aggressive treatment are particularly vulnerable, and the dosage for these patients should therefore be at the lowest effective dose. The tumours typically occur under conditions of immunosuppression (induced by oncovirus or natural irradiation). The increased risk of developing non-Hodgkin's lymphoma in patients with , in comparison with the general population, is apparently partly due to the disease itself.

3Blood and lymphatic system disorders Azathioprine may be associated with a dose-related, generally reversible, suppression of bone marrow function, most frequently expressed as leucopenia, but also sometimes as anaemia and thrombocytopenia and in rare cases as agranulocytosis, pancytopenia and aplastic anaemia. These adverse reactions occur particularly in patients predisposed to myelotoxicity such as those with TMPT-deficiency, impaired hepatic or renal function and in patients failing to reduce the dose of azathioprine when receiving concurrent allopurinol therapy. Reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content have occurred in association with azathioprine therapy. Megaloblastic bone marrow changes have also been observed but severe megaloblastic anaemia and erythroid hypoplasia are rare.

Although adverse effects on haematopoiesis occur most commonly at the beginning of treatment with azathioprine, late occurrence has been reported. Therefore, careful monitoring of the blood cell counts is recommended even in patients in stable long-term therapy (see section 4.4).

4Immune system disorders Different clinical symptoms, which appear to be idiosyncratic manifestations of hypersensitivity, have been described following administration of azathioprine. In many cases, recommenced administration of azathioprine confirmed an association with azathioprine. Immediate discontinuation of azathioprine and institution of circulatory support where appropriate leads to recovery in the majority of cases. Other significant underlying pathology has contributed to very rare deaths reported. Following a hypersensitivity reaction to the product, the necessity for continued administration of azathioprine should be carefully considered on an individual basis.

Gastrointestinal disorders 5Some experience nausea the first time they use azathioprine. The nausea may be reduced by administering azathioprine after meals.

6Pancreatitis has been reported in a small percentage of patients in azathioprine therapy, particularly in renal transplant patients and those diagnosed as having inflammatory bowel disease. There are difficulties in relating the pancreatitis to the administration of one

particular drug, although recommenced administration of azathioprine has confirmed an association with azathioprine on occasions.

7Severe diarrhoea, recurring on recommenced administration of azathioprine, has been reported in patients treated with azathioprine for inflammatory bowel disease. The possibility that exacerbation of symptoms might be drug-related should be borne in mind when treating such patients.

8Serious complications, including colitis, diverticulitis and bowel perforation, have been described in transplant recipients receiving immunosuppressive therapy. However, the aetiology is not clearly established and high-dose corticosteroids may be implicated.

Hepatobiliary disorders 9Cholestasis and deterioration of liver function have occasionally been reported in association with azathioprine therapy. These events are usually reversible upon discontinuation of azathioprine therapy. This may be associated with symptoms of a hypersensitivity reaction (see disorders).

10A rare, but life-threatening veno-occlusive hepatic disease during chronic administration of azathioprine has been described, mainly in transplant patients. In occasional cases discontinuation of azathioprine have led to either a temporary or permanent recovery from the liver histology and the symptoms.

11Skin and subcutaneous tissue disorders Hair loss has been described a number of times in patients receiving azathioprine alone or in combination with other immunosuppressive agents. In many cases this symptom disappeared spontaneously despite continuing therapy. The association between alopecia and azathioprine is still unclear.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medical product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professional are asked to report any suspected adverse reactions via the national reporting system listed in appendix V.

4.9 Overdose Symptoms Unexplained infection, ulceration of the throat, bruising and bleeding are the main symptoms of overdosage with azathioprine and is the result of which will be maximal after 9-14 days. These symptoms are more likely to be manifested following chronic overdosage, rather than after a single acute overdose. There has been a report of a patient who ingested a single overdose of 7.5 g of azathioprine. The immediate toxic effects of this overdose were nausea, vomiting and diarrhoea, followed by mild leucopenia and minor abnormalities in liver function. Recovery was uneventful.

Treatment There is no specific antidote for azathioprine. The treatment is symptomatic. In the event of overdose, blood count should be closely monitored to assess the necessity of blood

transfusion and other relevant supportive treatment. Active treatment (such as the use of activated charcoal) may not be effective in the event of an azathioprine overdose unless the procedure can be undertaken within 60 minutes of ingestion.

The value of dialysis in patients who have taken an overdose of azathioprine is not known, though azathioprine is partially dialysable.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties Pharmacotherapeutic group: Other immunosuppressive agents, ATC code: LO4AX01

Azathioprine is a pro-drug of 6-mercaptopurine (6-MP). 6-MP is inactive but acts as a antagonist and requires cellular uptake and intracellular anabolism to thioguanine nucleotides (TGNs) for immunosuppression.

The TGNs and other metabolites (e.g. 6-methyl-mecaptopurine ribonucleotides) inhibit de novo purine synthesis and conversion to other purine nucleotides. The TGNs are also incorporated into nucleic acids and this contributes to the immunosuppressive effects of the drug. The activity of the methylnitroimidazole moiety, a metabolite of azathioprine but not 6- MP, has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP.

5.2. Pharmacokinetic Properties Absorption Azathioprine is well absorbed following oral administration.

Distribution The volume of distribution at steady state (Vdss) of azathioprine is unknown. The mean (± SD) apparent Vdss of 6-MP is 0.9 (±0.8) L/kg, although this may be an underestimate because 6-MP is eliminated throughout the body (and not just in the liver).

Concentrations of 6-MP in cerebrospinal fluid (CSF) are low or negligible after IV or oral administration of 6-MP. Only 30% of the medicinal product binds to plasma proteins. 12.5% enter the cerebrospinal fluid.

Biotransformation Azathioprine is rapidly metabolised in vivo by -S-transferase into 6-MP and a methylnitroimidazole moiety.

The 6-MP readily crosses cell membranes and is extensively metabolised by many multi- step pathways to active and inactive metabolites, not to one predominate enzyme. Because of the complex metabolism, inhibition of one enzyme does not explain all cases of lack of efficacy and/or pronounced myelosuppression. The predominantly responsible enzymes for the metabolism of 6-MP or its downstream metabolites are: the polymorphic enzyme thiopurine S-methyl transferase (TPMT) (see sections 4.4 and 4.5), (see

section 4.5), inosine monophosphate dehydrogenase (IMPDH) (see section 4.5), and hypoxanthine guanine phosphribosyltransferase (HPRT). Additional enzymes involved in the formation of active and inactive metabolites are: monophosphate synthetase (GMPS, which form TGNs) and inosine triphosphate pyrophosphatase (ITPase). Azathioprine itself is also metabolized by aldehyde oxidase to form 8-hydroxy azathioprine, which may be active. There are also multiple inactive metabolites formed via other pathways.

There is evidence that polymorphisms in the genes encoding the different enzyme systems involved with metabolism of azathioprine may predict adverse drug reactions to azathioprine therapy.

Thiopurine S-methyl transferase (TPMT): TPMT activity is inversely related to 6-MP derived thioguanine nucleotide concentration, with higher thioguanine nucleotide concentrations resulting in greater reductions in white blood cell and neutrophil counts. Individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations. Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles (TPMT*2, TPMT*3A and TPMT*3C) account for about 95% of individuals with reduced levels of TPMT activity. Approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable enzyme activity. Approximately 10% of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate TPMT activity and 90% of individuals have normal TPMT activity with two functional alleles. There may also be a group of approximately 2% who have very high TPMT activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in red blood cells and can also be informative (see section 4.4). Genotypic testing is not enough to avoid adverse reactions and therefore monitoring should still be performed.

Elimination After oral administration of 100 mg 35S-azathioprine, 50% of the radioactivity was excreted in the urine and 12% in the faeces after 24 hours. In the urine, the major compound was the inactive oxidised metabolite thiouric acid. Less than 2% was excreted in the urine as azathioprine or 6-MP. Azathioprine has a high extraction ratio with a total clearance greater than 3 L/min in healthy volunteers. There are no data on the renal clearance or half-life of azathioprine. The renal clearance of 6-MP and the half-life of 6- MP are 191 mL/min/m2 and 0.9 hr respectively.

Special patient populations Elderly No specific studies have been carried out in the elderly (see section 4.2).

Renal impairment Studies with azathioprine have shown no difference in 6-MP in uremic patients compared to renal transplant patients. Since little is known about the active metabolites of azathioprine in renal impairment, consideration should be given to reducing the dosage in patients with impaired renal function (see section 4.2).

Azathioprine and/or its metabolites are eliminated by haemodialysis, with approximately 45% of radioactive metabolites eliminated during 8 hours dialysis.

Hepatic impairment A study with azathioprine was performed in three groups of renal transplant patients: those without liver disease, those with hepatic impairment (but no cirrhosis) and those with hepatic impairment and cirrhosis. The study demonstrated that 6-mercaptopurine exposure was 1.6 times higher in patients with hepatic impairment (but no cirrhosis) and 6 times higher in patients with hepatic impairment and cirrhosis, compared to patients without liver disease. Therefore, consideration should be given to reducing the dosage in patients with impaired hepatic function (see sections 4.2).

5.3. Preclinical Safety Data Teratogenicity: Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5-15 mg/kg bodyweight/day over the period of organogenesis have shown varying degrees of foetal abnormalities.

Teratogenicity was evident in rabbits at 10 mg/kg bodyweight/day.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients Microcrystalline cellulose. Mannitol. Maize starch. Povidone. Croscarmellose . Sodium stearyl fumarate. Opadry Clear OY-7240.: Hypromellose Macrogol 4000

6.2 Incompatibilities Not applicable

6.3 Shelf life 3 years

6.4 Special precautions for storage Store in the original package in order to protect from light.

6.5 Nature and contents of container PVC/PVDC/aluminium blister packaging.

Pack sizes: 14, 20, 28, 30, 50, 56, 98, 100 in blisters.

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling Surplus medical products as well as contaminated appliances should be temporarily stored in clearly labelled containers and then discarded safely. High-temperature incineration is recommended.

7. MARKETING AUTHORISATION HOLDER

Orifarm Generics A/S Energivej 15 DK-5260 Odense S Denmark E-mail: [email protected]

8. MARKETING AUTHORISATION NUMBER

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT 12.12.2017