Dosage azathioprine

Allopurinol inhibits the enzymatic inactivation of mercaptopurine and its derivative azathio-prine by xanthine oxidase. Thus, when allopurinol is used concomitantly with oral mercaptopurine or azathioprine, dosage of the antineoplastic agent must be reduced by 25-33% (see Chapters 38 and 51). This is of importance when treating gout in the transplant recipient. The risk of bone marrow suppression also is increased when allopurinol is administered with cytotoxic agents that are not metabolized by xanthine oxidase, particularly cyclophosphamide. 

Azathioprine was originally approved by the FDA in 1968 as an adjunct immunosuppressant for use in renal transplant recipients. It is available in oral and IV dosage forms.11 Prior to the advent of cyclosporine, the combination of azathioprine and corticosteroids was the mainstay of immunosuppressive therapy. Over the past 10 years, the use of azathioprine has declined markedly due in large part to the success of the MPA derivatives, which are more specific inhibitors of T cell proliferation. 

Patients deficient in thiopurine S-methyltransferase (TPMT) are at greater risk of bone marrow suppression from azathioprine and mercaptopurine. Determination of TPMT or TPMT genotype is recommended to guide dosage. 

HI. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclophosphamide (p. 298). The antiproliferative effect is not specific for lymphocytes and involves both T- and B-cells. 

Absorption of thioguanine is incomplete and erratic. It is eliminated mainly by S-methylation. Thioguanine can be administered concurrently with allopurinol without reduction in dosage, unlike mercaptopurine and azathioprine. 

Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 1989 7 1816-1823. Erratum itv.JClin Oncol 1990 8 567. Lennard L, Lewis IJ, Michelagnoli M et al. Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia 6-mercaptopurine dosage strategies. MedPediatr Oncol 1997 29 252-255. Lennard L, Van Loon JA, Weinshilboum RM. Pharmaeogenetics of acute azathioprine toxicity relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989 46 149-154. 

The metabolism of azathioprine is bimodal in humans, with rapid metabolizers clearing the drug four times faster than slow metabolizers. Production of 6-thioguanine is dependent on thiopurine methyltransferase (TPMT), and patients with low or absent TPMT activity (0.3% of the population) are at particularly high risk of myelosuppression by excess concentrations of the parent drug if dosage is not adjusted. 

Azathioprine is approved for use in rheumatoid arthritis and is used at a dosage of 2 mg/kg/d. Controlled trials show efficacy in psoriatic arthritis, reactive arthritis, polymyositis, systemic lupus erythematosus, and Behget s disease. 

When chemotherapeutic mercaptopurines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%. Allopurinol may also increase the effect of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants... 

The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression, usually manifested as leukopenia, although anemia and thrombocytopenia may occur. Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur, with the gastrointestinal symptoms seen mainly at higher dosages. Flepatic dysfunction, manifested by very high serum alkaline phosphatase levels and mild jaundice, occurs occasionally, particularly in patients with preexisting hepatic dysfunction. 

A 33-year-old woman took immunosuppressive therapy after renal transplantation ciclosporin (dosage adjusted to achieve blood concentrations of 120-160 ng/ml), azathioprine 1 mg/kg (frequency of administration not stated), and methylprednisolone 40 mg/ day from day 1 after transplantation, tapered weekly by 4—8 mg/day. Because of rejection symptoms at weeks 1, 4, and 7, she received three cycles of intravenous methylprednisolone 250 mg/day, each cycle lasting 5-7 days she also received a bolus dose of methylprednisolone 500 mg on day 0. Pregnancy was diagnosed on day 12 after transplantation (9 weeks after conception). At week 6 after transplantation she had a missed abortion. Curettage was performed and a partial hydatidiform mole was detected. She was discharged at week 10 and immunosuppressive therapy was tapered. 

The special risk is observed in patients with hepatic or renal impairment. It is not advised to use allopurinol in acute attacks of gout, but it is useful in chronic gout. Excretion of allopurinol and its active metabolite oxypurinol is primarily via the kidneys and therefore the dosage should be reduced if renal function is impaired. The adverse effects have been reported in patients receiving allopurinol with thiazide diuretics, particularly in patients with impaired renal function. The metabolism of azathioprine and mercaptopurine is inhibited by allopurinol and their doses should be reduced to one-quarter to one-third of the usual dose when either of them is given with allopurinol to avoid potentially life-threatening toxicity.27-29... 

UDCA + prednisone -F azathioprine More recent results presented by F.H.J. Wolfhagen et al. on the first implementation of this triple therapy showed an impressive improvement in clinical, biochemical and histological findings. Dosage was as follows UDCA (usual dose), prednisone (30 mg/day, gradually reduced to 10 mg/day) and azathioprine (50 mg/day). (291)... 

At an advanced stage (II, III) with AMA profile B, the combination of UDCA -I- prednisolone (maintenance dose 4-8 mg/day in the morning) should generally be administered as first medication. In the case of unsatisfactory therapeutic results or with AMA profiles C or D (= stages III or IV), we would recommend the additional administration of azathloprine as a triple therapy. A dosage of 1 x 50 mg (up to 2 x 50 mg) per day is well-tolerated and, like prednisolone at this dosage, has relatively few side effects. A maintenance dose of 50 mg every second day may be sufficient. (170) The immunomodulatory action of UDCA is thus combined with the immunosuppressive effect of azathioprine, while the antiinflammatory characteristics of the steroids are also included, i.e. the two-substance combination is extended to a triple combination if necessary, especially in profiles Cor D. 

Azathioprine should not be used initially as monotherapy. However, remission attained with prednisolone and azathioprine can be maintained by azathioprine on its own (some 100-200 mg/day). (42, 85) The combination of prednisolone with azathioprine (I.R. MacKay, 1968) is just as effective as monotherapy with prednisolone. Moreover, with the above-mentioned initial dose of prednisolone (together with azathioprine), any subsequent dosage of prednisolone can be reduced more rapidly to a maintenance dose of 4-6 (-8) mg/day. 

Dosage An initial dose of azathioprine of 1—2 mg/kg BW/day (rounded off to the nearest 25 mg or 50 mg tablet) is recommended. A maintenance dose of 50-75 (—100) mg/day is sufficient. We always administered the combination therapy from the outset and thereby did not observe any side effects from azathioprine — minor fluctuations in bone-marrow depression reverted to normal values spontaneously or after a short period of reduced dosage (25 mg). With this maintenance dose, we retained a... 

Hematological toxicity is the most commonly reported severe adverse effect of azathioprine, and is marked by predominant leukopenia, thrombocytopenia, and pancytopenia (SED-13, 1120). In a 27-year survey of 739 patients treated with azathioprine 2 mg/kg for inflammatory bowel disease, dosage reduction or withdrawal of the drug because of bone marrow toxicity was necessary in 37 patients (5%) (11). There was moderate or severe leukopenia in 3.8% of patients in three patients pancytopenia resulted in severe sepsis or death. 

Azathioprine or mercaptopurine have been sometimes involved in reduced warfarin and acenocoumarol activity, and increased warfarin dosages may be necessary (103). Similar findings were found in a patient taking maintenance phenprocoumon (SEDA-21, 382). 

Two patients required an approximate three-fold increase in the weekly anticoagulant dosage while taking azathioprine or mercaptopurine (104,105). 

A 57-year-old man took prednisone 20-30 mg/day for 13 years for rheumatoid arthritis (45). He had been treated unsuccessfully with gold, azathioprine, hydroxychloroquine, and sulfasalazine tapering his glucocorticoid dosage had been unsuccessful. He developed worsening back pain in his thoracic spine and lateral... 

Shafaati, A. and Clark, B. J. Determination of azathioprine and its related substances by capillary zone electrophoresis and its application to pharmaceutical dosage forms assay. Drug Dev. Ind. Pharm. 26 267-273, 2000. 

Certain drugs inhibit non-microsomal metabolic pathways. Metronidazole, like disulfiram, inhibits aldehyde dehydrogenase, the enzyme that normally oxidizes acetaldehyde to acetic acid in the metabolic pathway for ethanol. Allopurinol inhibits xanthine oxidase, the enzyme that catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Because azathioprine and 6-mercaptopurine are metabolized by xanthine oxidase, the dosage of these drugs (synthetic xanthine analogues), when used concomitantly with... 

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