Allopurinol dosage

Allopurinol is an xanthine oxidase inhibitor. It reduces urate production and is used in primary and secondary urate overproduction. Therapy of hyperuricemia prevents recurring attacks of acute gouty arthritis. Allopurinol dosages are 300 mg/day for serum creatinine < 1.5 mg/dl and 100 mg/day for serum creatinine between 1.6-2.0 mg/dl. Reduction of tophi is slow with allopurinol, particularly in patients with giant tophi and renal insufficiency where drug dosage is limited. 

Allopurinol Starting dose CrCI greater than 90 mL/minute = 300 mg/day CrCI 60-90 mL/minute = 200 mg/day CrCI 30-60 mL/minute = 100 mg/day CrCI less than 30 mL/minute = 50 mg/day Adjust dosage based on follow-up uric acid levels maximum 800 mg/day... 

Most patients in the United States are treated with allopurinol, which usually is effective if the dosage is titrated appropriately. The drug and its primary active metabolite, oxypurinol, reduce serum uric acid concentrations by inhibiting the enzyme xanthine oxidase, thereby blocking the oxidation of hypoxanthine and xanthine to uric acid. 

Renai function impairment Some patients with preexisting renal disease or poor urate clearance have increased BUN during allopurinol administration. Patients with impaired renal function require less drug and careful observation during the early stages of treatment reduce dosage or discontinue therapy if increased abnormalities in renal function appear and persist. 

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. 

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 initial dosage of allopurinol is 100 mg/d. It may be titrated upward until serum uric acid is below 6 mg/dL this level is commonly achieved at 300 mg/d but is not restricted to this dose. 

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... 

Pharmacokinetics Allopurinol is completely absorbed after oral administration. The primary metabolite is alloxanthine (oxypurinol) which is also a xanthine oxidase inhibitor. The pharmacologic effect of administered allopurinol results from the combined activity of these two compounds. The plasma half-life of allopurinol is short (2 hours), whereas the half-life of oxypurinol is long (15 hours). Thus, effective inhibition of xanthine oxidase can be maintained with once daily dosage. The drug and its metabolite are excreted in the feces and urine. 

Allopurinol Potentiation (109) Inhibition of microsomal enzymes (110) Adjust dosage... 

The usual initial dose is 2 mg/kg daily hy the oral route. If there is no clinical improvement or leukopenia after 4 weeks the dosage is increased to 3 mg/kg daily. In contrast to mercaptopurine, thioguanine may be continued in the usual dose when allopurinol is used to inhibit uric acid formation. 

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... 

Immunosuppressants such as azathioprine and mercaptopurine have a significant potential for adverse reactions. Azathioprine causes bone marrow suppression and has been associated with lymphomas (in renal transplant patients), skin cancer, and pancreatitis (about 3% of patients). Some investigators believe that induction of leukopenia may be necessary for therapeutic effect. Mercaptopurine causes adverse reactions similarly to azathioprine however, there are fewer reports of lymphomas with this agent. In one cohort of IBD patients, adverse effects from mercaptopurine were as follows pancreatitis, 1.2% allergic reactions, 3.9%, significant leukopenia, 11.5% and infectious complications, 14%. Ten percent of patients who received azathioprine or mercaptopurine required discontinuation of treatment because of adverse effects. Allopurinol inhibits the metabolism of mercaptopurine, and a dosage reduction of the latter is required when the two are used in combination. 

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. 

If allopurinol is used adjunctively in cancer chemotherapy to offset hyperuricemia, the dosage of this drug should be reduced to 25% of normal. 

Information is limited to these studies, but be alert for the need to reduce the dosage of carbamazepine if high doses of allopurinol are used longterm. This interaction apparently takes several weeks or even months to develop fully. More study is needed. 

In a study of add-on therapy, allopurinol (150 mg daily in those less than 20 kg, and 300 mg daily for other patients) for 4 months, had no effeet on phenobarbital levels in 46 patients taking antiepileptics including phenobarbital. In another similar study, allopurinol 10 mg/kg increased to 15 mg/kg daily for 12 weeks had no effect on serum phenobarbital levels in 11 patients taking primidone or phenobarbital with or without other an-tiepileptics. Therefore phenobarbital or primidone dosage alterations are unlikely to be required if allopurinol is used. 

Profound pancytopenia developed in the first 3 of 13 children given maintenance treatment with meicaptopurine 2.5 mg/kg daily and allopuri-nol 10 mg/kg daily, but when the meieaptopurine dosage was halved, toxicity was manageable in the remaining 9 children. Severe leucopenia and thrombocytopenia occurred in another patient given allopurinol with standard dose mercaptopurine. ... 

Buffered didanosine 400 mg was given to 14 healthy subjeets, with and without allopurinol 300 mg daily for 7 days. The allopurinol signifieantly inereased didanosine absorption, shown by a twofold inerease in the AUC and a 69% rise in its maximum serum levels. Similar findings were seen in HIV-positive subjects. Moreover, the addition of allopurinol 300 mg daily allowed the dosage of didanosine to be halved from 400 mg to 200 mg daily in 4 patients taking buffered didanosine, hydroxyearbamide and chloroquine. Didanosine plasma levels and antiviral effieaey were unchanged. ... 

Boelaert JR, Dorn GM, Huitema ADR, Beijnen JH, Lange JMA. The boosting of didanosine by allopurinol permits a halving of the didanosine dosage. AIDS (2002) 16, 2221-3. 

The median dose of mercaptopurine in adults fell four- to fivefold after the addition of allopurinol lOOmg/day in 20 adults and children, with preferential metabolism of 6-mercaptopurine to 6-methylmercaptopurine [174 ]. Before the addition of allopurinol, six patients had mild rises in aminotransferase activities associated with high concentrations of methylmercaptopurine all subsequently had normalization with mercaptopurine dosage reduction. There were no adverse reactions, such as rash, renal failure, or pancreatitis, attributable to the combination of allopurinol and mercaptopurine. Three patients developed mild leukopenia after starting allopurinol. 

Treatment in both children involved the use of allopurinol - but at a lesser dosage (5 mg/kg/2hh) because of the retention of the principal metabolite oxipurinol in severe renal failure Careftil monitoring of plasma oxipurinol levels is desirable For the HGPRT deficient child alkali was also given to enhance uric acid solubility It was not prescribed in the APRT deficient child since 2 8-dihyroxy adenine solubility is unaffected by alkali and its use may even be contraindicated ... 

The lack of effect of allopurinol in this patient and the poor recovery suggested the drug had not been taken, despite careful surveillance. However plasma oxipurinol levels were comparable to patients on similar doses and doubled when the dosage doubled. These results argue against poor compliance and suggest plasma oxipurinol levels should be investigated where this is suspected. 

In the pig on a purine free diet allopurinol had little effect on total urinary purine excretion, even at dosages of 300 mg/kg/day. 

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