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Allopurinol Hypersensitivity: Strategies to Minimize the Risk of a Reaction

Allopurinol Hypersensitivity: Strategies to Minimize the Risk of a Reaction

Allopurinol has been used
to treat gout for well over
3 decades. In addition,
this drug is prescribed to
prevent urate nephropathy
in patients who are receiving cancer
chemotherapy.

Although allopurinol is usually
well tolerated, numerous reports
have documented a severe and sometimes
fatal reaction to this drug.1-7
The allopurinol hypersensitivity syndrome
occurred in more than 100 patients
between 1970 and 1990.6 In
many cases, the morbidity and mortality
associated with this syndrome
could have been avoided.2 For example,
allopurinol has been given to patients
who have only mild to moderate
asymptomatic hyperuricemia.

Figure

Table 1 lists common clinical features
of the allopurinol hypersensitivity
syndrome, such as drug-induced
toxic epidermal necrolysis (Figure).
Instruct patients to immediately stop
taking allopurinol at the first sign of a
rash. The onset of the syndrome is
usually within the first few weeks of
the initiation of therapy—most often
at about 3 to 4 weeks. Mortality associated
with allopurinol hypersensitivity
is about 25%.3

  Table 1 — Allopurinol
hypersensitivity syndrome: common clinical features
  • Eosinophilia
  • Erythematous, pruritic, maculopapular rash
  • Hepatitis
  • Toxic epidermal necrolysis
  • Worsening renal function

An early report suggested that
thiazide diuretics may be associated
with allopurinol hypersensitivity syndrome
and recommended caution, especially
if the patient has concurrent
renal dysfunction.8 No mechanism for
this possible association has been
clearly established.

DOSING
RECOMMENDATIONS

When you prescribe allopurinol,
base the dosage on the estimated creatinine
clearance to minimize the risk of
a potentially devastating reaction.1,7,9
The allopurinol metabolite, oxypurinol,
is renally eliminated and accumulates
in patients with decreased creatinine
clearance. Accumulation of oxypurinol
is an important risk factor for the allopurinol
hypersensitivity 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. 1984.1
  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. 1999.9
  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. 2002.10

Tables 21 and 39 list 2 sets of
recommendations for dosing allopurinol
based on estimated creatinine
clearance. Table 4 provides the recommended
dosages of intravenous
allopurinol.10

The only exception to these recommendations
is dosing during the
first 2 or 3 days of prophylactic therapy
for urate nephropathy, before cancer
chemotherapy is initiated.1 Higher
dosages (eg, 600 to 800 mg daily for the first 2 to 3 days11) are given
initially; the dosage is then adjusted
based on the estimated creatinine
clearance if subsequent allopurinol
therapy is required.

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