allopurinol (Zyloprim, Lopurin, Zurinol)

Introduction

Tradenames: Zyloprim, Lopurin, Zurinol.

Indications

• hyperuricemia
• gout maintenance therapy:
  • do not use as lone therapy during an acute attack of gout
  • allopurinol may precipitate an attack of gout
  • drug of choice if patient has history of renal stones or renal insufficiency
  • improves clinical outcomes (reduction in flares, tophi, joint damage)
  • improves mortality in patients with chronic renal failure
  • 200-300 mg PO QD/BID*
  • maximum dose 800 mg QD
• prevention of chemotherapy-induced acute tumor lysis syndrome
• improves exercise tolerance in patients with chronic stable angina pectoris
• may improve outcomes in patients with heart failure & gout
• APRT deficiency
• phosphoribosyl pyrophosphate synthetase deficiency
• phosphoribosyl pyrophosphate synthetase superactivity
• may reduce recurrence of hepatic cirrhosis-related complications

Contraindications

• concurrent use of purine analogs (theophylline, mercaptopurine, azathioprine)
• HLA-B*5801 allele-positive Hans Chinese or Thai persons
• does not provide renal protection for patients with diabetes mellitus

pregnancy category = c

safety in lactation = ?

Dosage

• gout:
  • start: 100 mg PO QD; 50 mg PO QD if eGFR < 60 mL/min
    • start: 1.5 X GFR in mL/min/1.73 m2 QD
    • maximum: 800 mg QD
  • do not initiate during acute exacerbation of gout
  • titrate to achieve serum urate level of < 6.0 mg/dL
    • mean daily dose required = 460 mg QD
• tumor lysis syndrome
  • 600-800 mg QD with maintenance of high fluid intake
• chronic stable angina pectoris
  • 600 mg PO QD
• hepatic cirrhosis
  • 300 mg/day

* use in combination with colchicine 0.6 mg QD# during 1st 3-6 months of therapy

# dose reduction with renal failure

Tabs: 100 & 300 mg.

Injection:

Dosage adjustment in renal failure

• some controversy here (see below)*

creatinine clearance	dosage
60 mL/min	200 mg QD
40 mL/min	150 mg QD
20 mL/min	100 mg QD
10 mL/min	100 mg QOD
< 10 mL/min	100 mg 3 x/week

* some controversy here

* limiting allopurinol dosing to <= 300 mg/day suboptimally controls hyperuricemia & fails to adequately prevent hypersensitivity reactions.

* using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment.

• monitor for drug toxicity (pruritus, rash, increased ALT)
• dosage of 400 mg/day with creatinine clearance of 35 mL/min recommended in
• doses higher than those based on creatinine clearance well tolerated in patients with mild renal insufficiency

Pharmacokinetics

• bioavailability following oral administration is 80-90%
• peak plasma levels occur 2-6 hours after oral administration
• peak plasma leves 30 minutes after IV administration
• serum urate levels
  • generally decrease within 24-48 hours
    • delay may occur due to dissolution of urate crystals
  • normal serum urate levels generally within 1-3 weeks
• widely distributed to body tissues, including breast milk)
• metabolized in liver to active metabolite oxypurinol
• 1/2life of allopurinol is 1-3 hours
• 1/2life of oxypurinol is 18-30 hours
• allopurinol (12%) & oxypurinol excreted in the urine

elimination via kidney

Monitor

• serum creatinine every 6 months
• serum ALT renal insufficiency

Adverse effects

• common (> 10%)
  • rash*, generally maculopapular (not itchy)
  • exfoliative, urticarial or purpuric lesions
• less common (1-10%)#
  • drowsiness, fever/chills, nausea/vomiting, diarrhea, abdominal pain, gastritis, dyspepsia, alopecia, increased LFTs (ALP, AST, ALT, bilirubin), jaundice, hepatomegaly
• uncommon (< 1%)
  • hepatic necrosis, vasculitis, headache, somnolence, toxic epidermal necrolysis, Stevens-Johnson syndrome, bone marrow suppression, idiosyncratic reaction (fever/ chills, nausea/vomiting, eosinophilia, arthralgias), thrombophlebitis, peripheral neuropathy, paresthesias, neuritis, cataracts, renal impairment, epistaxis
  • allopurinol is associated with less chronic renal failure than febuxostat
• can worsen acute attack of gout with initiation of therapy
• drug reaction with eosinophilia & systemic symptoms (DRESS)
  • late reactions begin 2-8 weeks after starting medication
  • low SaO2, pulmonary crackles
  • bilateral interstitial infiltrates & lower lobe atelectasis
  • maculopapular eruptions, burning skin pain, morbilliform exanthem
• potentially fatal hypersensitivity reaction
  • severe dermatitis, fever, eosinophilia, hepatic necrosis, acute nephritis
  • not clear how this is distinguished from DRESS or idiosyncratic reaction described above

* discontinue allopurinol immediately if rash develops;

* increased incidence of cutaneous & generalized hypersensitivity reactions in the elderly & in patients with renal failure or cardiovascular disease

# risk of adverse effects is greater with renal failure

Drug interactions

• ampicillin & amoxicillin: increase in incidence of rash
• cyclophosphamide: increase in myelosuppression
• avoid use in combination with theophylline, mercaptopurine, or azathioprine; these drugs are metabolized by xanthine oxidase, thus may accumulate to toxic levels
• thiazide diuretics: increase in incidence of skin reactions

• drug interaction(s) of mercaptopurine in combination with allopurinol

Laboratory

• HLA-B*5801 allele testing
  • increased risk of allopurinol-induced SCAR* in individuals with the HLA-B*5801 allele
  • screening for HLA-B*5801 prior to starting allopurinol may be cost-effective in blacks & Asians, but not in whites or Hispanics
• allopurinol in CSF
• allopurinol in serum/plasma
• allopurinol/creatinine in urine

* SCAR = severe cutaneous skin reaction

• Stevens-Johnson syndrome
• toxic epidermal necrolysis

Mechanism of action

• structural analog of hypoxanthine
• reversibly inhibits xanthine dehydrogenase & xanthine oxidase
• diminishes formation of uric acid*
• diminished renal tubular resorption of uric acid
  • increased renal tubular resorption of Ca+2
  • reduced hypercalciuria
  • attenuation of hypocalcemia
• xanthine oxidase inhibitors can reduce myocardial oxygen consumption for a particular stroke volume
• may reduce bacterial translocation & inflammation

* clearance of hypoxanthine & xanthine at least 10 times that of uric acid

More general terms

• enzyme inhibitor
• anti-inflammatory agent
• metabolic agent (metabolic modifier)
• hypouricemic agent

Component of

• allopurinol/lesinurad (Duzallo)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2094
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5281000
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5270529