Chemical formula: C₉H₇N₇O₂S Molecular mass: 277.263 g/mol PubChem compound: 2265
Azathioprine interacts in the following cases:
Xanthine 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 given concomitantly with 6-mercaptopurine or azathioprine, the dose of 6-mercaptopurine and azathioprine should be reduced to 25% of the original dose.
Caution is advised during the administration of azathioprine in patients with hepatic impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored.
Caution is advised during the administration of azathioprine in patients with renal impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored.
There have been case reports suggesting that haematological abnormalities may develop due to the concomitant administration of azathioprine and ACE Inhibitors.
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
It has been suggested that cimetidine and indomethacin may have myelosuppressive effects which may be enhanced by concomitant administration of azathioprine.
There is in vitro and in vivo evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfasalazine) inhibit the thiopurine S-methyltransferase enzyme. Therefore, lower doses of azathioprine may need to be considered when administered concomitantly with aminosalicylate derivatives.
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 white blood cell count.
Where possible, concomitant administration of cytostatic drugs, or drugs which may have a myelosuppressive effect, such as penicillamine, should be avoided.
Co-administration of ribavirin and azathioprine is not advised. Ribavirin may reduce efficacy and increase toxicity of azathioprine. Ribavirin inhibits the enzyme, inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of azathioprine and ribavirin; therefore co-administration is not advised.
Azathioprine can potentiate the neuromuscular blockade produced by depolarising agents such as succinylcholine. There is considerable variation in the potency of this interaction.
There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between azathioprine and co-trimoxazole.
Azathioprine can reduce the blockade produced by non-depolarising agents such as tubocurarine. There is considerable variation in the potency of this interaction.
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with azathioprine; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with azathioprine.
Limited evidence suggests that azathioprine is not beneficial to patients with hypoxanthine-guaninephosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore, given the abnormal metabolism in these patients, it is not prudent to recommend that these patients should receive azathioprine.
Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe azathioprine toxicity from conventional doses of azathioprine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established. Most patients with heterozygous TPMT deficiency can tolerate recommended azathioprine doses, but some may require dose reduction. Genotypic and phenotypic tests of TPMT are available.
Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine toxicity. These patients generally require dose reduction; particularly those being NUDT15 variant homozygotes. Genotypic testing of NUDT15 variants may be considered before initiating 6-mercaptopurine therapy. In any case, close monitoring of blood counts is necessary.
Substantial transplacental and transamniotic transmission of azathioprine and its metabolites from the mother to the foetus have been shown to occur.
Azathioprine should not be given to patients who are pregnant or likely to become pregnant in the near future without careful assessment of risk versus benefit. Evidence of the teratogenicity of azathioprine in man is equivocal. As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Azathioprine.
There have been reports of premature birth and low birth weight following maternal exposure to azathioprine, particularly in combination with corticosteroids. There have also been reports of spontaneous abortion following either maternal or paternal exposure.
Leucopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took azathioprine throughout their pregnancies.
6-mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment. Available data has shown that the excreted levels in breast-milk are low. From the limited available data, the risk to newborns/infants is considered to be unlikely but cannot be excluded.
It is recommended that women receiving azathioprine should avoid breastfeeding unless the benefits outweighs the potential risks.
If a decision is made to breastfeed, because 6-mercaptopurine is a strong immunosuppressant, the breastfed infant should be closely monitored for signs of immunosuppression, leukopenia, thrombocytopenia, hepatotoxicity, pancreatitis or other symptoms of 6-mercaptopurine exposure.
The specific effect of azathioprine therapy on human fertility is unknown.
There are no data on the effect of azathioprine on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of azathioprine.
For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the indication. The following convention has been utilised for the classification of 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)
Very common: viral, fungal and bacterial infections in transplant patients receiving azathioprine in combination with other immunosuppressants
Uncommon: viral, fungal and bacterial infections in other patient populations, bacterial and viral infections, infections associated with neutropenia
Patients receiving azathioprine alone, or in combination with other immunosupressants, particularly corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection with varicella, herpes zoster and other infectious agents.
Very rare: cases of JC virus associated PML have been reported following the use of azathioprine in combination with other immunosuppressants.
Rare: neoplasms including lymphoproliferative disorders, skin cancers (melanomas and non-melanomas), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ, myelodysplasia.
The risk of developing non-Hodgkin’s lymphomas and other malignancies, notably skin cancers (melanomas 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).
Very common: depression of bone marrow function; leucopenia
Common: thrombocytopenia
Uncommon: anaemia
Rare: agranulocytosis, pancytopenia, aplastic anaemia, megaloblastic anaemia, erythroid hypoplasia
Azathioprine may be associated with a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leucopenia, but also sometimes as anaemia and thrombocytopenia and rarely as agranulocytosis, pancytopenia and aplastic anaemia. These occur particularly in patients predisposed to myelotoxicity, such as those with TPMT deficiency and renal or hepatic insufficiency 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.
Uncommon: hypersensitivity reactions
Very rare: Stevens-Johnson syndrome and toxic epidermal necrolysis
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, rash, vasculitis, myalgia, arthralgia, hypotension, renal dysfunction, hepatic dysfunction and cholestasis (see Hepato-biliary disorders).
In many cases, rechallenge has confirmed an association with azathioprine.
Immediate withdrawal of azathioprine and institution of circulatory support where appropriate have led to recovery in the majority of cases.
Other marked underlying pathology has contributed to the very rare deaths reported.
Following a hypersensitivity reaction to azathioprine, the necessity for continued administration of azathioprine should be carefully considered on an individual basis.
Very rare: reversible pneumonitis
Common: nausea
A minority of patients experience nausea when first given azathioprine. This appears to be relieved by administering the tablets after meals.
Uncommon: pancreatitis
Very rare: colitis, diverticulitis and bowel perforation reported in transplant population, severe diarrhoea in inflammatory bowel disease population
Serious 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. Severe diarrhoea, recurring on rechallenge, 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.
Pancreatitis has been reported in a small percentage of patients on 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 rechallenge has confirmed an association with azathioprine on occasions.
Uncommon: cholestasis and deterioration of liver function tests
Rare: life-threatening hepatic damage
Cholestasis and deterioration of liver function have occasionally been reported in association with azathioprine therapy and are usually reversible on withdrawal of therapy. This may be associated with symptoms of a hypersensitivity reaction (see Immune system disorders).
Rare, but life-threatening hepatic damage associated with chronic administration of azathioprine has been described primarily in transplant patients. Histological findings include sinusoidal dilatation, peliosis hepatis, veno-occlusive disease and nodular regenerative hyperplasia. In some cases withdrawal of azathioprine has resulted in either a temporary or permanent improvement in liver histology and symptoms.
Rare: alopecia
Hair loss has been described on a number of occasions in patients receiving azathioprine and other immunosuppressive agents. In many instances the condition resolved spontaneously despite continuing therapy. The relationship between alopecia and azathioprine treatment is uncertain.
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