AZATHIOPRINE

Posology Transplantation Depending on the immunosuppressive regime selected, a dosage of up to 5 mg/kg/body weight/day may be given on the first day of therapy. The maintenance dose can range from 1-4 mg/kg/body weight/day and must be adjusted according to the clinical requirements and haematological tolerance.

Other conditions In general, the starting dosage is 1-3 mg/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. 5 mg/kg/body weight/day.

When the therapeutic response is evident consideration should be given to reducing the maintenance dosage to the lowest level compatible with maintenance of the response. If no improvement occurs in the patient’s condition within three to six months, consideration should be given to withdrawing the medicinal product.

The maintenance dosage required may range from less than 1 mg/kg body weight/day to 3 mg/kg/body weight/day depending on the clinical condition being treated and the individual patient response including haematological tolerance. 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 contra-indicated in severe hepatic impairment. 3). 4). 4). Genotypic testing of NUDT15 variants may be considered before initiating 6- mercaptopurine therapy. In any case, close monitoring of blood counts is necessary. Paediatric population There are insufficient data to recommend the use of azathioprine for the treatment of juvenile chronic arthritis, systemic lupus erythematosus, dermatomyositis, and polyarteritis nodosa.

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. 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. In cases, such as rheumatoid arthritis and certain haematological conditions, the treatment can be stopped after a certain period without problems.

Withdrawal of azathioprine should always be a gradual process performed under close monitoring. 6). For appropriate long-term dosing other medicinal products containing 25 mg should be used, if necessary. Method of administration For oral use.

The tablet should be taken with at least a glass of liquid (200 ml). The tablets should be taken during meals.

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 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).

8% of RH patients (in order of falling frequency): squamous cell skin carcinoma, non- Hodgkin’s lymphoma, cervical cancer, Kaposi’s sarcoma, Post- transplantati on lymphoprolif erative disorder. Neoplasms including lymphoprolif erative disorders, skin cancers (melanomas and non- melanomas), sarcomas (Kaposi's and non- Kaposi's) and uterine cervical cancer in situ Acute myeloid leukaemia and myelodyspla stic syndrome.

vulval cancer. 4). Blood and lymphatic system disorders Leucopenia - in >50% with RH (significant in 16%), - in 28% with RA, - in 15% with Crohn’s disease. Thrombocyt openia, anaemia. 3% of RA patients. Granulocyto penia, pancytopenia and aplastic anaemia, megaloblasti c anaemia, erythrohypo plasia, Agranulocyt osis Immune system disorders Hypersensiti vity reaction including general malaise, hypotension, dizziness, leukocytosis, exanthema, excessive nausea and vomiting, diarrhoea, fever, shivering, chill, rash, erythema nodosum, myalgia, arthralgia, vasculitis, renal impairment, elevated hepatic enzymes.

Hypersensiti vity reaction with fatal outcome. Stevens- Johnson syndrome and toxic epidermal necrolysis Metabolism and nutrition disorders Pellagra Nervous system disorders Posterior reversible encephalopath y syndrome (PRES) Tremor Respiratory, thoracic and mediastinal disorders Interstitial pneumonia (reversible).

2-8% Steatorrhoea. Diarrhoea. Gastroduode nal Sialoadenitis with isolated reports of vomiting (12% with RA). most commonly in organ recipients and patients with Crohn’s disease). ulceration, haemorrhage , necrosis or perforation. Colitis, diverticulitis.

These complication s only occur after transplantati on. The aetiology is not clearly established. Steroid therapy may be implicated. Hepatobiliar y disorders Hepatic impairment. Various pathologies, including cholestasis, destructive cholangitis, peliosis hepatitis, perisinusoida l fibrosis and nodular regenerative hyperplasia in 3-10% with RH.

Hepatic toxicity occurs in < 1% of RA patients. Life- threatening endophlebiti s hepatica obliterans. Non-cirrhotic portal hypertension, portosinusoidal vascular disease Skin and subcutaneou s tissue disorders Alopecia. Photosensiti vity Acute febrile neutrophilic dermatosis (Sweet’s syndrome) Immune system disorders Several different clinical syndromes, which appear to be idiosyncratic manifestations of hypersensitivity, have been described occasionally following administration of azathioprine.

Clinical features include general malaise, dizziness, nausea, vomiting, diarrhoea, fever, rigors, exanthema, erythema nodosum, vasculitis, myalgia, arthralgia, hypotension, cardiac dysfunction, renal dysfunction, hepatic dysfunction and cholestasis.

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 Azathioprine may be associated with a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leukopenia, but also sometimes as anaemia and thrombocytopenia and rarely as agranulocytosis, pancytopenia and aplastic anaemia.

5). Even though haemopoiesis is most likely to occur at the start of azathioprine treatment, cases with late onset have been rarely reported. 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. Rare, but life-threatening hepatic damage associated with chronic administration of azathioprine has been described.

Histological findings include sinusoidal dilatation, peliosis hepatis, veno-occlusive disease and nodular regenerative hyperplasia. In some cases, withdrawal of azathioprine has resulted in either temporary or permanent improvement in liver histology and the symptoms.

Cholestasis and deterioration of liver function are usually reversible on withdrawal of […]

There are potential dangers in the use of azathioprine film-coated tablets; they should therefore not be prescribed unless the patient can be adequately monitored for toxic effects throughout the duration of therapy. During the first eight weeks of treatment, a complete blood count, including platelet count must be performed at least once weekly.

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. Patients must be advised to inform their doctor immediately about ulcerations of the throat, fever, infections, bruising, bleeding or other signs of myelosuppression.

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.

Cases of non- cirrhotic portal hypertension/portosinusoidal vascular disease have been reported. 8). The patient should be informed about the symptoms of liver injury and advised to contact their doctor immediately if these occur. 5) About 10% of patients have thiopurine methyltransferase (TPMT) deficiency due to genetic polymorphism.

They may therefore be unable to metabolise azathioprine completely. Consequently, they may be exposed to an increased myelotoxic effect. Special care should therefore be taken during co-administration of aminosalicylate derivatives, including sulphasalazine, which are inhibitors of the TPMT enzyme.

Phenotyping or genotyping the patient is desirable, before administration of the medicinal product in order to investigate a possible thiopurine transferase deficiency. Limited data indicate that azathioprine is not effective in patients with hereditary hypoxanthineguanine- phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome).

Therefore azathioprine should not be used in these patients. 5). Metabolic and nutritional disorders Purine analogues (azathioprine and mercaptopurine) may interfere with the niacin pathway, potentially leading to nicotinic acid deficiency (pellagra).

Cases of pellagra have been reported with the use of azathioprine, particularly in patients with chronic inflammatory bowel disease. The diagnosis of pellagra should be considered in patients with a localised pigmented rash, gastroenteritis, and extensive neurological deficits including cognitive deterioration.

Appropriate medical care with niacin/nicotinamide supplementation must be initiated, and dose reduction or discontinuation of azathioprine must be considered. Posterior reversible encephalopathy syndrome (PRES) Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients using azathioprine.

If patients taking azathioprine present with symptoms indicating PRES such as headache, altered mental status, seizures, hypertension, and visual disturbances, a diagnostic imaging should be performed. If PRES is diagnosed, adequate blood pressure and seizure control and immediate discontinuation of azathioprine is advised.

Most cases reported resolved following discontinuation of azathioprine and appropriate treatment. 5). Anesthesiologists should check whether their patients are administered azathioprine prior to surgery. 5). g. in systemic lupus erythematosus with nephritis, Crohn’s disease, ulcerative colitis or autoimmune hepatitis.

Withdrawal of azathioprine should always be a gradual process performed under close monitoring. If inactivated or toxoid vaccines are applied together with azathioprine, immune response should always be controlled by means of titre determination.

An increased number of skin tumours have occurred in patients during treatment with azathioprine. They have been mainly on areas of skin exposed to the sun. 8). 3). Patients with concomitant cytotoxic therapy may 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 […]

1. - Severe infections - Seriously impaired hepatic or bone marrow function - Pancreatitis - Any live vaccine, especially BCG, smallpox, yellow fever. 6)