24 October 2012

SUMMARY OF PRODUCT CHARACTERISTICS

for

Azathioprine ”Actavis”, film-coated tablets

1. NAME OF THE MEDICINAL PRODUCT Azathioprine ”Actavis”

2. QUALITATIVE AND QUANTITATIVE COMPOSITION Azathioprine 50 mg

3. PHARMACEUTICAL FORM Film-coated tablets.

Pale yellow, film-coated, circular, biconvex tablet marked "AZA" and "50", separated by a 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 to prevent rejection of transplanted organs in patients who have received a kidney, liver, heart, lung or pancreas allograft. Azathioprine is usually indicated as part of an immunosuppressive regimen as a supplement to immunosuppressive agents, which form the cornerstone of the treatment (basic immune suppression).

Azathioprine is indicated in severe cases of systemic lupus erythematosus in patients who do not tolerate steroids or who are dependent on steroids and whose treatment response is inadequate despite their receiving high doses of steroids.

4.2 Posology and method of administration Azathioprine ”Actavis” is for oral administration. The tablet should be taken with at least one glass of fluid (200ml). Azathioprine ”Actavis” should be taken during a meal. The film-coated tablet should not be divided into halves, unless this is necessary to facilitate gradual discontinuation. If the tablet is to be divided into halves, tablet dust or the fractured surface should not get into contact with the skin and inhalation of the tablet dust should be avoided.

Transplantation

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Depending on the immunosuppressive regimen employed, usually an initial dosage of up to 5mg/kg body weight/day may be given orally. Maintenance dosage should range from 1 to 4 mg/kg body weight/day and must be adjusted according to clinical response and haematological tolerance. Azathioprine is often given in combination with corticosteroids to enhance the survival and performance of the transplanted organ. The discontinuation of azathioprine after several years of treatment involves a high risk of organ rejection.

Systemic lupus erythematosus In general, starting dosage is from 1 to 3 mg/kg body weight/day and should be adjusted depending on the clinical response (which may not be evident for weeks or months) including haematological tolerance. Maintenance dosage should range from 2 to 2.5 mg/kg body weight/day and must be adjusted according to clinical response and haematological tolerance. The clinical response should set in within a few days or weeks after the initial treatment with azathioprine. If no clinical effect occurs within 3 months, consideration should be given to discontinuation of therapy. Otherwise, if well tolerated, azathioprine may be continued as long-term treatment. The effect of treatment may be delayed, and it is important to adjust dosage promptly in case of an abrupt drop in white blood count values or any other signs of bone marrow depression.

Patients with renal and/or hepatic impairment: In patients with renal impairment and/or mild to moderate hepatic impairment, dosages must be at the lower end of the normal range. Azathioprine is contra-indicated in severe hepatic impairment. (See section 4.3).

Children and adolescents: Azathioprine is not recommended for the treatment of systemic lupus erythematosus (in children below 18 years of age) due to insufficient data.

Regarding the other indication, the recommended doses apply to children, adolescents and adults alike.

Elderly patients: There is no special information on how azathioprine is tolerated by elderly patients. It is recommended that the dosages used should be at the lower end of the normal range (monitoring of blood counts, see section 4.4).

When allopurinol, oxipurinol or thiopurinol is combined with azathioprine, the dosage of azathioprine should be lowered by one fourth of the original dosage (see sections 4.4 and 4.5).

The treatment effect may take weeks or months to become evident.

The product can be given for a prolonged period, unless the patient does not tolerate azathioprine.

Azathioprine must be discontinued gradually and under close supervision.

Treatment with azathioprine must be initiated or supervised by a doctor with extensive experience in immunosuppressive therapy. Azathioprine should be prescribed only when

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the treatment is accompanied by monitoring of toxic effects throughout the treatment period.

4.3 Contraindications - Hypersensitivity to azathioprine, 6-mercaptopurine (metabolite of azathioprine) or to any of the excipients - Severe infections - Severe hepatic impairment or bone marrow depression - Pancreatitis - Any form of live vaccine, particularly tuberculosis (BCG), smallpox and yellow fever vaccines - Pregnancy, unless the benefits outweigh the risks (see section 4.6) - Lactation (See section 4.6).

4.4 Special warnings and precautions for use There are potential hazards in the use of azathioprine film-coated tablets, and the product should be prescribed only if the patient can be adequately monitored for toxic effects throughout the duration of treatment. During the first eight weeks of treatment, full blood counts should be performed at least once weekly. The blood count frequency must be increased: - if high doses are used - in elderly patients - in renal impairment - in the presence of mild to moderate hepatic impairment (see also sections 4.2 and 5.2) - in the presence of mild to moderate bone marrow depression (see also section 4.2) - in patients with hypersplenism

The blood count frequency may be reduced after eight weeks. It is suggested that full blood counts are repeated monthly or at least at intervals of not longer than 3 months.

The patients should be instructed immediately to report to their own doctor any evidence of ulceration of the throat, fever, infections, bruising or bleeding or other manifestations of bone marrow depression.

In particular patients with hepatic impairment should be monitored periodically.

Close monitoring of blood counts is required when azathioprine is given concurrently with: - allopurinol, oxipurinol or thiopurinol (see section 4.2 and 4.5) - aminosalicylic acid derivatives such as mesalazine, olsalazine or sulfasalazine (see section 4.5) - ACE inhibitors, trimethoprime/sulfamethoxazole, cimetidine or indomethacin (see section 4.5) - cytoxic and/or bone marrow suppressive agents (see section 4.5)

About 10% of the patients have deficiency of thiopurine methyltransferase (TPMT) due to genetic polymorphism. This may render them unable to break down azathioprine completely. Consequently they may be exposed to increased myelotoxic effects. Special caution should be exercised at co-administration of aminosalicylate derivatives such as sulfasalazine, which is known to inhibit the TPMT enzyme. The patient's phenotype or

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genotype should be determined before administration of the product to establish whether thiopurine methyltransferase deficiency is involved.

The limited data indicate that azathioprine is not beneficial to patients with the hereditary hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore azathioprine is not recommended for use in these patients.

When allopurinol, oxipurinol and/or thiopurinol are combined with azathioprine, the dosage of azathioprine should be lowered to one fourth of the original dosage (see sections 4.2 and 4.5).

Special caution is required when azathioprine is co-administered with agents that have a neuromuscular effect, such as tubocurarine or succinylcholine (see section 4.5). It may also potentiate the neuromuscular blockade produced by depolarising agents such as succinylcholine (see section 4.5). Patients should be instructed to inform their anaesthesiologist before any surgical intervention that they are treated with azathioprine.

Patients receiving anticoagulants of the coumarin type concomitantly with azathioprine should be monitored closely for coagulation (see section 4.5).

Discontinuation of azathioprine may seriously complicate the condition, for instance in patients with systemic lupus erythematosus by nephritis.

Azathioprine must always be withdrawn gradually and under close supervision.

When inactivated or toxoid vaccines are co-administered with azathioprine, the immune response should be checked by titration.

An increased number of skin tumours have been observed in patients treated with azathioprine. They were mainly in areas of the skin which had been exposed to the sun. Patients should be warned against excessive exposure to sunlight or ultraviolet irradiation, and their skin should be examined periodically (see also section 4.8).

Special caution is required with patients with untreated acute infections (see also section 4.3).

Patients in concomitant cytoxic treatment should only be given azathioprine under supervision.

Mutagenicity and carcinogenicity/Carcinogenicity 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

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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.

Handling of the product: Azathioprine is mutagenic and potentially carcinogenic. The substance should only be handled while taking appropriate precautions. This applies in particular to pregnant nurses (see section 6.6).

If it is necessary to divide the film-coated tablet, the skin must not be exposed to tablet dust or broken surfaces (see sections 4.2 and 6.6).

4.5 Interaction with other medicinal products and other forms of interaction Allopurinol, oxipurinol and thiopurinol inhibit the degradation of azathioprine through blockade of the xanthinoxidase enzyme. When allopurinol, oxipurinol and/or thiopurinol are combined with azathioprine, the dosage of azathioprine should be lowered to one fourth of the original dosage (see sections 4.2 and 4.4).

Clinical experience shows that azathioprine counteracts the effects of non-depolarising muscle relaxants such as curare, d-tubocurarine and pancuronium. Experimental data confirm that azathioprine counteracts the neuromuscular blockade induced by d- tubocurarine and it shows that azathioprine potentiates the neuromuscular blockade induced by succinylcholine (see section 4.4).

When azathioprine is combined with other immunosuppressants such as cyclosporin or tacrolimus, it is important to be aware of the increased risk of unusually high immunosuppression.

When azathioprine is given concomitantly with aminosalicylate derivatives such as olsalazine, mesalazine and sulfasalazine, it may involve a risk of increased myelo- suppressive action as a result of inhibited degradation in the liver

Inhibition of the anticoagulant effects of warfarin or phenprocoumon, when administered with azathioprine, has been reported (see section 4.4).

Co-administration of azathioprine and ACE inhibitors, trimethoprime/sulfamethoxazole, cimetidine or indomethacin increases the risk of bone marrow depression (see section 4.4).

Concomitant treatment of azathioprine and agents with myelosuppressive/cytotoxic properties may potentiate the myelotoxic effect. This applies also to myelosuppressive therapies which are discontinued shortly before the initiation of treatment with azathioprine (see section 4.4).

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There is in vitro evidence that furosemide reduces the degradation of azathioprine in human hepatic tissues. The clinical relevance of this is not known.

The immunosuppressive activity of azathioprine could result in an atypical and potentially deleterious response to live vaccines, and so the administration of live vaccines to patients receiving azathioprine therapy is contra-indicated on theoretical grounds (see section 4.3).

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 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 antibody concentration (see section 4.4).

In a small clinical study of patients with Crohn's disease receiving azathioprine, infusion of infliximab was shown to increase reversibly the concentration of 6-thioguanine in red blood cells by a factor of 1.5 one to three weeks after the administration. This may be accompanied by a reduction in white blood counts.

4.6 Pregnancy and lactation

Pregnancy Azathioprine should not be given to pregnant women without careful assessment of risk versus benefit. Azathioprine and its metabolites have been found in low concentrations in foetal blood and amniotic fluid after maternal administration. Leucopenia and/or thrombocytopenia have been reported in a proportion of newborn children whose mothers took azathioprine during their pregnancies. Extra care in haematological monitoring is advised during pregnancy. Women of childbearing potential and men receiving azathioprine should be advised to use contraception during and for at least three months after the end of therapy. This also applies to patients with impaired reproduction due to chronic uraemia, since reproduction is usually normalised following transplantation. Azathioprine has been reported to inhibit the efficacy of intrauterine contraceptive devices.

Following intrauterine exposure to azathioprine combined with prednisone, transient decreases in immune response have been observed. There have been reports of intrauterine growth retardation (IUGR) and premature birth following treatment with azathioprine in combination with prednisolone. The long-term consequences of these effects of azathioprine are not known; however, many children who had been exposed to the agent in the womb have now reached the age of 10 years without any reports of adverse effects.

Lactation Mercaptopurine has been detected in the colostrum and breast milk of women receiving azathioprine. Lactation and concurrent azathioprine therapy is contraindicated (see section 4.3).

4.7 Effects on ability to drive and use machines No warning symbol. No studies on the effects on the ability to drive and use machines have been performed.

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4.8 Undesirable effects Undesirable effects are expected to affect about 15% of the patients. The type, frequency and severity of the undesirable effects may depend on the azathioprine dosage, duration of treatment, the patient's underlying condition or any concurrent treatment.

The most important adverse reaction is a dose-related, generally reversible, bone marrow depression, most frequently expressed as leucopenia, thrombocytopenia or anaemia. Leucopenia may occur in over 50% of all patients treated with azathioprine in conventional doses. Other signs of bone marrow depression such as thrombocytopenia, anaemia, macrocytosis or megaloblastic bone marrow changes are less frequent.

The adverse reactions are listed below as MedDRA preferred term by system organ class and absolute frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

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Very rare Very common Common Uncommon Rare (<1/10,000), (1/10) (1/100 to <1/10) (1/1,000 to <1/100) (1/10,000 to <1/1,000) including isolated cases Infections and In 20% of patients Increased sensitivity In <1% of patients with infestations with renal homograft to infection in rheumatoid arthritis (RA) (RH) patients with inflammatory bowel disease Neoplasms, In up to 2.8% of RH Post-transplantation Neoplasms including Acute myeloid benign and patients (in order of lymphoproliferative lymphoproliferative leukaemia and malignant falling frequency): disorder. disorders, skin cancers myelodysplastic (including cysts squamous cell skin (melanomas and non- syndrome. and polyps) carcinoma, non- melanomas), sarcomas Hodgkin's (Kaposi's and non- lymphoma, cervical Kaposi's) and uterine cancer, Kaposi's cervical cancer in situ sarcoma, vulval (see section 4.4). cancer. Blood and Leucopenia Thrombocytopenia, Granulocytopenia, lymphatic system - in >50% with RH anaemia. Significant pancytopenia and disorders (significant in 16%), leucopenia in 5.3% aplastic anaemia, - in 28% with RA, of RA patients. megaloblastic anaemia, - in 15% with erythrohypoplasia, Crohn's disease. Agranulocytosis

Immune system Hypersensitivity Hypersensitivity disorders reaction, including reaction with general malaise, fatal outcome. hypotension, dizziness, leukocytosis, exanthema, Stevens-Johnson excessive nausea and syndrome and vomiting, diarrhoea, toxic epidermal fever, shivering, chill, necrolysis. rash, myalgia, arthralgia, vasculitis, renal impairment, elevated hepatic enzymes. Respiratory, Interstitial pneumonia thoracic and (reversible) mediastinal disorders Gastrointestinal Nausea and anorexia Pancreatitis Steatorrhoea. Diarrhoea. Gastroduodenal disorders with isolated reports (0.2-0.8%, most ulceration, of vomiting (12% frequently in organ haemorrhage, necrosis with RA). recipients and or perforation. Colitis, patients with Crohn's diverticulitis. These disease). complications only occur after transplantation. The aetiology is not clearly established. Steroid therapy may be implicated. Hepato-biliary Hepatic impairment. Hepatic toxicity occurs Life-threatening disorders Various pathologies, in <1% of RA patients. endophlebitis hepatica including cholestasis, obliterans. destructive chol- angitis, peliosis hepatitis, perisinusoidal fibrosis and nodular regenerative hyperplasia in 3-10% with RH.

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Skin and Alopecia Photosensitivity subcutaneous tissue disorders

Immune system disorders In cases of hypersensitivity reactions, immediate withdrawal of azathioprine and institution of circulatory support where appropriate have led to recovery in the majority of cases. Following a hypersensitivity reaction to azathioprine, the patient must not continue the therapy.

Blood and lymphatic system disorders TPMT deficiency and impaired hepatic or renal function increase the predisposition for azathioprine-induced bone marrow toxicity.

Even though haemopoiesis is most likely to occur at the start of azathioprine treatment, cases with late onset have been rarely reported. Careful monitoring of the blood counts is recommended, even in patients stabilised on long-term therapy (see section 4.4).

Gastrointestinal disorders Gastrointestinal disorders can be reduced by giving azathioprine in divided doses and/or with meals.

The possibility that exacerbation of diarrhoea might be associated with azathioprine therapy in patients with IBD should be borne in mind.

Hepato-biliary disorders Endophlebitis obliterans, a rare, but life-threatening disease, has been reported in association with prolonged administration of azathioprine, mainly in transplant recipients. In some cases, the withdrawal of azathioprine resulted in either a temporary or permanent improvement in liver histology and symptoms.

Cholestasis and deterioration of liver function are usually reversible on withdrawal of therapy.

Neoplasms, benign and malignant (including cysts and polyps) The risk of developing tumours is increased by use of azathioprine both following trans- plantation and in connection with other indications. The dosage is usually higher for this indication in connection with transplantation. Therefore, the risk of developing tumours is higher when the agent is used in connection with transplantation than with the other indications. The tumour type does not change according to the indication. Typically the tumours occur in connection with immunosuppression (induced by oncovirus or natural irradiation).

Skin and subcutaneous tissue disorders Hair loss has been described on a number of occasions in patients receiving azathioprine alone or combined with other immunosuppressive agents. In many instances the symptom resolved spontaneously despite continuing therapy.

4.9 Overdose

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The most probable effect of an overdose is bone marrow depression, which usually peaks within 9 to 19 days following dosing. The most important signs of bone marrow depression are ulceration of the throat, fever and infections. Bruising, bleeding and fatigue may also occur. A high single dose of azathioprine would probably be less toxic than prolonged overdosing with low doses (e.g., on prescription). Recovery may take long, but it usually sets in from day 12 following an overdose provided that the patient did not take a high dose in the meantime.

There is no specific antidote for azathioprine. In case of an overdose, monitoring the patient's blood counts liver function is particularly important. Azathioprine is known to be dialysable, and dialysis can be used in severe cases.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutical group: Other immunosuppressive agents. ATC code: L 04 AX 01.

Azathioprine is used as an immunosuppressive antimetabolite either alone or, more often, in combination with other agents (usually corticosteroids) affecting the immune response.

Azathioprine is an imidazole derivate of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and 1-methyl-4-nitro-5-thioimidazole.

The 6-MP crosses cell membranes and is converted intracellularly into a number of purine thioanalogues, which include the main active nucleotide, thioinosinic acid. The activity of the methylnitroimidazole moiety has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP.

Azathioprine affects both the immune reaction and tumour growth. The agent's main role is suppression of the immune response. Its precise modes of action are not known, Dog er følgende virkningsmekanismer blevet foreslået:

i. The released 6-MP acts as a purine antimetabolite.

ii. The possible blockade of –SH groups by alkylation.

iii. The inhibition of many pathways in nucleic acid biosynthesis, preventing the proliferation and activity of immunocompetent cells (B- and T-lymphocytes).

iv. Damage to deoxyribonucleic acid (DNA) through incorporation of purine thioanalogues.

5.2 Pharmacokinetic properties Azathioprine is well absorbed following oral administration. Peak plasma concentration occurs at 1-2 hours following administration. Azathioprine is readily distributed in the body. The plasma half-life is seven hours. Only 30% of the product binds to plasma proteins, while 12.5% crosses into the cerebrospinal fluid.

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Azathioprine is extensively metabolised into 6-thioinosinic acid and methyl mercaptopurine ribonucleotide, which are partly responsible for the activity of the medicinal product.

In vivo, the activity is complicated by the presence of methylnitroimidazole.

Up to 50% of a dose is excreted in the urine during the first 24 hours following administration, of which approximately 10% is unconverted. Only 12.6% of the dose is excreted within 48 hours with the faeces. There is no evidence of enterohepatic circulation.

Patients with renal impairment may require a lower dose, presumably because of reduced elimination of the active metabolites of azathioprine.

The metabolism of azathioprine is also affected in patients with hepatic impairment. The conversion to the active metabolite is lowered, and in particular the breaking down into metabolites that can be eliminated is reduced (see sections 4.2 and 4.4).

Mercaptopurine, an azathioprine metabolite, has been identified in the colostrum and breast-milk in women receiving azathioprine.

5.3 Preclinical safety data Toxicology studies in animals have shown that the haemopoiesis is most affected by a lowering of the granulopoiesis and relatively little by megacaryocytes and thus by platelet formation.

In dogs, following administration of 10 mg/kg body weight for 10 days, azathioprine proved fatal because of agranulocytosis. Its effect on the haematopoiesis is associated with its effect on the lymphatic system with atrophy of lymphatic tissues as observed in Rhesus monkeys at a dose of 1 mg/kg bodyweight/day.

Similar to 6-mercaptopurine, azathioprine may damage the liver. Reversible hepatic toxicity was observed in dogs. Dogs are highly sensitive to this reaction, and a dose as low as 5 mg/kg body weight/day induces hepatic toxicity.

Teratogenicity was seen in several animal species at different degrees of susceptibility.

In rabbits, a dose of 5-15 mg/kg body weight/day caused skeletal malformations on the 6th to 14th days of pregnancy. In mice and rats, doses of 1-2 mg/kg body weight/day proved fatal for the fetus on the 3rd to 12th days of pregnancy.

Azathioprine given in a dose of 50 µg/ml caused cytogenetic damage in human lymphocytes in vitro, and cytogenetic changes were observed in the lymphocytes of rabbits receiving 5-20 mg/kg body weight/day. Azathioprine also proved mutagenic in the Ames test. The Wellcome research laboratories have carried out carcinogenicity studies in 100 male mice and 100 female mice (CDI mice), which were given 0, 0.3 or 10 mg of azathioprine per kg body weight per day for 18 months. The mice treated with high doses did not receive azathioprine during weeks 21-38. A dose-related elevation in the number of lymph sarcomas occurred in both male and female mice. A similar study in rats produced carcinomas in the treated animals, but the finding was not dose-related.

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6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients Microcrystalline cellulose Mannitol Maize starch Povidone Croscarmellose sodium Sodium stearyl fumarate Opadry Clear OY-7240: Hypromellose Macrogol 400

6.2 Incompatibilities Not relevant.

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.

Pack sizes: 14, 20, 28, 30, 50, 56, 98 or 100 in a blister.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and handling There is no risk involved in handling these tablets when the coating is intact, and provided that this is so, no precautions are required

However, once tablets containing cytotoxic agents have been divided into halves, they must be handled strictly in accordance to the guidelines (see sections 4.2 and 4.4).

Any unused product or contaminated tools must be stored temporarily in duly labelled containers, which must be safely disposed of. High-temperature incineration is recommended.

7. MARKETING AUTHORISATION HOLDER Actavis Nordic A/S Ørnegårdsvej 16 DK-2820 Gentofte Denmark

8. MARKETING AUTHORISATION NUMBER

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9. DATE OF FIRST AUTHORISATION 3 October 2003

10. DATE OF REVISION OF THE TEXT 25 November 2013

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