A SUGGESTED STARTING DOSE OF ALLOPURINOL IS 100 MG DAILY BY MOUTH, GRADUALLY INCREASED BY 100 MG FOR EXAMPLE AT WEEKLY INTERVALS UNTIL THE CONCENTRATION OF URATE IN PLASMA IS REDUCED TO 0.36 MMOL/LITRE (6 MG PER 100 ML) OR LESS. A DAILY DOSE RANGE OF 100 TO 300 MG MAY BE ADEQUATE FOR THOSE WITH MILD GOUT AND UP TO 600 MG FOR THOSE WITH MODERATELY SEVERE TOPHACEOUS GOUT. THE MAXIMUM RECOMMENDED DAILY DOSE IS 800 MG IN THE USA AND 900 MG IN THE UK. UP TO 300 MG MAY BE TAKEN AS A SINGLE DAILY DOSE; LARGER AMOUNTS SHOULD BE TAKEN IN DIVIDED DOSES TO REDUCE THE RISK OF GASTRIC IRRITATION. TAKING ALLOPURINOL AFTER FOOD WILL ALSO MINIMISE GASTRIC IRRITATION. PATIENTS SHOULD MAINTAIN AN ADEQUATE FLUID INTAKE TO PREVENT RENAL XANTHINE DEPOSITION.
DOSES OF ALLOPURINOL SHOULD BE REDUCED IN PATIENTS WITH RENAL IMPAIRMENT
WHEN USED FOR THE PREVENTION OF URIC ACID NEPHROPATHY ASSOCIATED WITH CANCER THERAPY 600 TO 800 MG MAY BE GIVEN DAILY GENERALLY FOR 2 OR 3 DAYS BEFORE STARTING THE CANCER TREATMENT. A HIGH FLUID INTAKE IS ESSENTIAL. IN HYPERURICAEMIA SECONDARY TO CANCER OR CANCER CHEMOTHERAPY, MAINTENANCE DOSES OF ALLOPURINOL ARE SIMILAR TO THOSE USED IN GOUT AND ARE GIVEN ACCORDING TO THE RESPONSE.
THE MAIN USE OF ALLOPURINOL IN CHILDREN IS FOR HYPERURICAEMIA ASSOCIATED WITH CANCER OR CANCER CHEMOTHERAPY OR WITH ENZYME DISORDERS. THE DOSAGE USED MAY VARY: IN THE UK A DOSE OF 10 TO 20 MG/KG DAILY UP TO A MAXIMUM OF 400 MG DAILY IS RECOMMENDED FOR CHILDREN UNDER 15 YEARS OF AGE, WHILE IN THE USA THE DOSE IS 150 MG DAILY FOR CHILDREN UNDER 6 YEARS OF AGE AND 300 MG DAILY FOR THOSE AGED 6 TO 10 YEARS, ADJUSTED IF NECESSARY AFTER 48 HOURS.
ALLOPURINOL SODIUM HAS BEEN GIVEN BY INTRAVENOUS INFUSION IN SODIUM CHLORIDE 0.9% OR GLUCOSE 5% TO PATIENTS (USUALLY CANCER PATIENTS) UNABLE TO TAKE ALLOPURINOL BY MOUTH. THE RECOMMENDED DOSE IN ADULTS IS THE EQUIVALENT OF ALLOPURINOL 200 TO 400 MG/M2 DAILY UP TO A MAXIMUM OF 600 MG DAILY. ALLOPURINOL SODIUM 116.2 MG IS EQUIVALENT TO 100 MG OF ALLOPURINOL.
ADMINISTRATION IN RENAL IMPAIRMENT.
EXCRETION OF ALLOPURINOL AND ITS ACTIVE METABOLITE OXIPURINOL IS PRIMARILY VIA THE KIDNEYS AND THEREFORE THE DOSAGE SHOULD BE REDUCED IN RENAL IMPAIRMENT ACCORDING TO CREATININE CLEARANCE (CC).
IN THE USA THE FOLLOWING DOSES ARE SUGGESTED FOR ORAL AND INTRAVENOUS USE:
CC 10 TO 20 ML/MINUTE: 200 MG DAILY
CC LESS THAN 10 ML/MINUTE: NO MORE THAN 100 MG DAILY
CC LESS THAN 3 ML/MINUTE: CONSIDER ALSO A LONGER DOSAGE INTERVAL
IN THE UK A MAXIMUM INITIAL ORAL DAILY DOSAGE OF 100 MG IS RECOMMENDED FOR THOSE WITH RENAL IMPAIRMENT, INCREASED ONLY IF THE RESPONSE IS INADEQUATE. DOSES LESS THAN 100 MG DAILY OR 100 MG AT INTERVALS LONGER THAN 1 DAY ARE RECOMMENDED FOR THOSE WITH SEVERE RENAL INSUFFICIENCY. BECAUSE OF THE IMPRECISION OF LOW CREATININE CLEARANCE VALUES, IT IS SUGGESTED THAT, IF FACILITIES ARE AVAILABLE FOR MONITORING, THE ALLOPURINOL DOSE SHOULD BE ADJUSTED TO MAINTAIN PLASMA-OXIPURINOL CONCENTRATIONS BELOW 100 MICROMOLES/LITRE (15.2 MICROGRAMS/ML). A SUGGESTED ALTERNATIVE DOSE FOR PATIENTS REQUIRING DIALYSIS TWO OR THREE TIMES WEEKLY IS 300 TO 400 MG ALLOPURINOL IMMEDIATELY AFTER DIALYSIS ONLY.
ORGAN AND TISSUE TRANSPLANTATION.
ALLOPURINOL 25 MG ON ALTERNATE DAYS HAS BEEN ADDED TO THE IMMUNOSUPPRESSIVE TREATMENT FOR RENAL TRANSPLANTATION, AND IS REPORTED TO REDUCE THE FREQUENCY OF ACUTE REJECTION. ONE POSSIBLE EXPLANATION FOR THIS EFFECT IS ALLOPURINOL'S ABILITY TO SUPPRESS THE PRODUCTION OF FREE RADICALS (SEE OXIDATIVE STRESS). ORGAN AND TISSUE TRANSPLANTATION, AND THE MORE USUAL DRUGS USED IN IMMUNOSUPPRESSIVE REGIMENS ARE DISCUSSE. IT SHOULD BE NOTED THAT ALLOPURINOL INTERACTS WITH AZATHIOPRINE (SEE IMMUNOSUPPRESSANTS, UNDER INTERACTION) AND CICLOSPORIN.
PROTOZOAL INFECTIONS.
ALLOPURINOL HAS BEEN WIDELY USED AS AN ADJUNCT TO PENTAVALENT ANTIMONIALS IN THE TREATMENT OF OLD WORLD VISCERAL LEISHMANIASIS , PARTICULARLY WHERE RESISTANCE TO ANTIMONY ALONE IS LIKELY, ALTHOUGH THE DEGREE OF BENEFIT HAS BEEN CALLED INTO QUESTION. IT HAS ALSO BEEN USED WITH OTHER DRUGS SUCH AS PENTAMIDINE OR AZOLE ANTIFUNGALS , INCLUDING IN TRANSPLANT PATIENTS OR THOSE WITH AIDS, OR IN WHOM ANTIMONIALS WERE OTHERWISE POORLY TOLERATED. ALLOPURINOL HAS ALSO BEEN TRIED ALONE OR WITH OTHER DRUGS IN BOTH OLD WORLD AND NEW WORLD CUTANEOUS OR MUCOCUTANEOUS LEISHMANIASIS; RESULTS, PARTICULARLY IN THE LATTER, HAVE BEEN VARIABLE.
THE SELECTIVE ANTIPARASITIC ACTION OF ALLOPURINOL IS BELIEVED TO BE DUE TO ITS INCORPORATION INTO THE PROTOZOAL, BUT NOT THE MAMMALIAN, PURINE SALVAGE PATHWAY. THIS LEADS TO THE FORMATION OF 4-AMINOPYRAZOLOPYRIMIDINE RIBONUCLEOTIDE TRIPHOSPHATE, A HIGHLY TOXIC ANALOGUE OF ADENOSINE TRIPHOSPHATE, THAT IS INCORPORATED INTO RIBONUCLEIC ACID. THIS ACTION OF ALLOPURINOL IS SHARED BY ALLOPURINOL RIBOSIDE, ONE OF THE MINOR METABOLITES IN MAN, BUT NOT BY OXIPURINOL, THE MAJOR HUMAN METABOLITE. THUS, SOME STUDIES HAVE BEEN CONDUCTED WITH ALLOPURINOL RIBOSIDE, RATHER THAN ALLOPURINOL, IN AN ATTEMPT TO ENHANCE ACTIVITY BY AVOIDING HOST-MEDIATED INACTIVATION.
WITH HYPERURICOSURIA. THE RECOMMENDED DOSE OF ALLOPURINOL IS 200 TO 300 MG DAILY BY MOUTH ADJUSTED ON THE BASIS OF SUBSEQUENT 24-HOUR URINARY URATE EXCRETION. ALLOPURINOL IS ALSO ADVOCATED FOR THE MANAGEMENT OF 2,8-DIHYDROXYADENINE (2,8-DHA) RENAL STONES ASSOCIATED WITH DEFICIENT ACTIVITY OF THE ENZYME ADENINE PHOSPHORIBOSYLTRANSFERASE.