Allopurinol Hypersensitivity: Strategies to Minimize the Risk of a Reaction

December 31, 2006

Allopurinol has been usedto treat gout for well over3 decades. In addition,this drug is prescribed toprevent urate nephropathyin patients who are receiving cancerchemotherapy.

Allopurinol has been usedto treat gout for well over3 decades. In addition,this drug is prescribed toprevent urate nephropathyin patients who are receiving cancerchemotherapy.

Although allopurinol is usuallywell tolerated, numerous reportshave documented a severe and sometimesfatal reaction to this drug.1-7The allopurinol hypersensitivity syndromeoccurred in more than 100 patientsbetween 1970 and 1990.6 Inmany cases, the morbidity and mortalityassociated with this syndromecould have been avoided.2 For example,allopurinol has been given to patientswho have only mild to moderateasymptomatic hyperuricemia.

Table 1 lists common clinical featuresof the allopurinol hypersensitivitysyndrome, such as drug-inducedtoxic epidermal necrolysis (Figure).Instruct patients to immediately stoptaking allopurinol at the first sign of arash. The onset of the syndrome isusually within the first few weeks ofthe initiation of therapy-most oftenat about 3 to 4 weeks. Mortality associatedwith allopurinol hypersensitivityis about 25%.3

 Table 1 - Allopurinol hypersensitivity syndrome: common clinical features
Eosinophilia

An early report suggested thatthiazide diuretics may be associatedwith allopurinol hypersensitivity syndromeand recommended caution, especiallyif the patient has concurrentrenal dysfunction.8 No mechanism forthis possible association has beenclearly established.

DOSINGRECOMMENDATIONS
When you prescribe allopurinol,base the dosage on the estimated creatinineclearance to minimize the risk ofa potentially devastating reaction.1,7,9The allopurinol metabolite, oxypurinol,is renally eliminated and accumulatesin patients with decreased creatinineclearance. Accumulation of oxypurinolis an important risk factor for the allopurinolhypersensitivity syndrome.1-4,6

 Table 2 - Allopurinol dosing recommendations
Estimated creatinine clearance Maintenance dosage

100 mL/min 300 mg/d

60 mL/min 200 mg/d

40 mL/min 150 mg/d
20 mL/min 100 mg/d
10 mL/min 100 mg q2d
0 mL/min 100 mg q3d

Data from Hande KR et al. Am J Med. 1984.



 Table 3 - Alternative allopurinol dosing recommendations
Estimated creatinine clearance Maintenance dosage

100 mL/min 300 mg/d

> 50 mL/min 75% of usual dose

10 - 50 mL/min 50% of usual dose
< 10 mL/min 25% of usual dose

Data from Aronoff GR et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. 1999.



 Table 4 - Intravenous allopurinol dosing recommendations
Estimated creatinine clearance Maintenance dosage

10 - 20 mL/min 200 mg/d

3 - 10 mL/min 100 mg/d

< 3 mL/min 100 mg/d at extended intervals

Data from Physicians' Desk Reference. 2002.

Tables 21 and 39 list 2 sets ofrecommendations for dosing allopurinolbased on estimated creatinineclearance. Table 4 provides the recommendeddosages of intravenousallopurinol.10

The only exception to these recommendationsis dosing during thefirst 2 or 3 days of prophylactic therapyfor urate nephropathy, before cancerchemotherapy is initiated.1 Higherdosages (eg, 600 to 800 mg daily for the first 2 to 3 days11) are giveninitially; the dosage is then adjustedbased on the estimated creatinineclearance if subsequent allopurinoltherapy is required.

DESENSITIZATION
It is possible to desensitize somepatients who have cutaneous reactionsto allopurinol.12-15 Obviously, attemptsto desensitize patients to allopurinolshould be made only if thedrug is absolutely necessary, andonly by clinicians who are experiencedin the procedure. Slow oraldesensitization involves starting withvery small oral doses (eg, 8 micrograms12),followed by gradual doseescalation, typically over 30 days. Theprocedure is not always successful,and it would not be appropriate forpatients who had experienced themore severe form of the allopurinolhypersensitivity reaction.

References:

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2. Singer JZ, Wallace SL. The allopurinol hypersensitivitysyndrome: unnecessary morbidity and mortality.Arthritis Rheum. 1986;29:82-87.
3. Elasy T, Kaminsky D, Tracy M, Mehler PS.Allopurinol hypersensitivity syndrome revisited.West J Med. 1995;162:360-361.
4. Hanger HC, Pillans PI. Death following allopurinolhypersensitivity syndrome. N Z Med J. 1994;107:229.
5. Roujeau JC, Kelly JP, Naldi L, et al. Medicationuse and risk of Stevens-Johnson syndrome ortoxic epidermal necrolysis. N Engl J Med. 1995;333:1600-1607.
6. Arellano F, Sacristan JA. Allopurinol hypersensitivitysyndrome: a review. Ann Pharmacother. 1993;27:337-343.
7. Hammer B, Link A, Wagner A, Bohm M. Hypersensitivitysyndrome during therapy with allopurinolin asymptomatic hyperuricemia with a fatal outcome.Dtsch Med Wochenschr. 2001;126:1331-1334.
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9. Aronoff GR, Berns JS, Brier ME, et al. Drug Prescribingin Renal Failure: Dosing Guidelines for Adults.4th ed. Philadelphia: American College of Physicians;1999:77.
10. Aloprim product literature. Physicians' Desk Reference.56th ed. Montvale, NJ: Medical EconomicsCo; 2002:2249.
11. Insel PA. Analgesics-antipyretics and antiinflammatoryagents and drugs employed in thetreatment of gout. In: Hardman JG, Linbird LE, eds.Goodman and Gilman's The Pharmacological Basis ofTherapeutics. 9th ed. New York: McGraw Hill; 1996:617-657.
12. Meyrier A. Desensitization in a patient withchronic renal disease and a severe allergy to allopurinol.Br Med J. 1976;2:458.
13. Fam AG, Paton TW, Chaiton A. Reinstitution ofallopurinol therapy for gouty arthitis after cutaneousreactions. Can Med Assoc J. 1980;123:128-129.
14. Fam AG, Dunne SM, Iazzetta J, Paton TW.Efficacy and safety of desensitization to allopurinolfollowing cutaneous reactions. Arthritis Rheum.2001;44:231-238.
15. Tanna SB, Barnes JF, Seth SK. Desensitizationto allopurinol in a patient with previous failed desensitization.Ann Pharmacother. 1999;33:1180-1183.