Allopurinol

See Also

Indications
Uric Acid Lowering Therapy In Gout

Gout Prophylaxis (first-line agent)
1. Uric Acid over-producers (Uric Acid > 750 mg/24h)
2. Used in Uric Acid under-excreters as well
Criteria
1. Recurrent episode of gout (>=2 attacks per year, and consider for 1 gout flare/year)
2. Tophaceous gout
3. Radiographic damage attributable to gout
4. Nephrolithiasis

Indications
Other

Tumor Lysis Syndrome Prevention
Calcium oxylate stone Prevention (in Calcium Nephrolithiasis)

Precautions

Avoid use with Azathioprine (causes toxic levels)
Avoid in Renal Failure (or use low dose)
Do not use for asymptomatic Hyperuricemia
Genetic Testing (HLA B5801)
1. Obtain prior to use if risk of severe Hypersensitivity skin reaction
2. Risks include southeast asian (esp. Hans Chinese, Thai, Korean) and African American
Avoid in acute gout attack (wait at least 4-6 weeks after acute attack)
1. However, more recent data suggests safety in starting during acute attack (per email, Dr. John Rasor)

Mechanism

Xanthine oxidase
1. Enzyme that converts oxypurines (including Nucleic Acids) to Uric Acid
Xanthine Oxidase Inhibitor
1. Allopurinol is an isomer of hypoxanthine and is metabolized to the active oxypurinol
2. Oxypurinol inhibits xanthine oxidase Enzyme Activity, thereby inhibiting Uric Acid formation
3. Oxypurinol is renally excreted
4. Allopurinol increases renal xanthine excretion (since it is not converted to Uric Acid)
  1. Renal xanthines may crystallize in the renal tubules resulting in obstructive uropathy

Medications

Allopurinol Tablets: 100 mg, 300 mg

Dosing
Gouty Arthritis

See Gouty Arthritis
Use concurrent antiinflammatory agent when starting to prevent triggering attack
1. Wait to start Allopurinol until at least 6-8 weeks symptom-free from last attack
  1. However, see precautions above for recent data suggesting safety in starting with acute attack
2. Antiinflammatory agent options to start concurrently with Allopurinol (continue for first 3-6 months)
  1. NSAIDS (avoid in Chronic Kidney Disease, heart disease or liver disease)
    1. Aleve 220 mg (OTC) orally twice daily or
    2. Naprosyn 250 mg orally twice daily or
    3. Indomethacin 25 mg orally twice daily
  2. Prednisone (if NSAIDs contraindicated)
    1. Maintenance: 10 mg orally daily, then 5 mg orally daily for 3-6 months
    2. Acute Exacerbation (start at first symptoms of gout recurrence): 40 mg orally for 1-3 days
      1. Have available as emergency prescription
  3. Colchicine
    1. Colchicine was a first line agent for Allopurinol initiation (but now too expensive)
      1. Generic preparations were removed from market
    2. Colchicine 0.6 mg PO daily to twice daily
Allopurinol 100-300 mg/day
1. Use lowest dose to keep Uric Acid <6 mg/dl (<5 mg/dl if symptomatic)
  1. Probenacid may be used with Allopurinol if GFR>50 ml/min and normal Urine Uric Acid normal
  2. Duzallo (Allopurinol with Lesinurad) is an expensive alternative to Probenacid and Allopurinol
2. Initiating dose
  1. Start: 100 mg daily for 2 weeks
  2. Next: 200 mg daily for 2 weeks
  3. Next: 300 mg daily (most effective dose for most patients)
  4. Some patients require higher doses
    1. Moderate to high dosing is 400 to 600 mg/day
    2. High doses may be needed up to 600 to 800 mg/day) to maintain Uric Acid <6 mg/dl
3. Adjust starting dose for Renal Function
  1. GFR >90 ml/min: 300 mg daily
  2. GFR 60-89 ml/min: 200 mg daily
  3. GFR 30-59 ml/min: 100 mg daily
  4. GFR 10-29 ml/min (or Cr >1.5): 50 mg daily (maximum dose 300 mg/day)
  5. GFR <10 ml/minute: Avoid or use with caution

Dosing
Tumor Lysis Syndrome Prevention

Start 24 to 48 hours before Chemotherapy
Adult
1. IV: 200 to 400 mg/m2/day (max 600 mg/day) IV in one infusion or divided every 6 to 12 hours
2. Oral: 600 mg orally daily (or in divided doses)
Child
1. IV: 200 mg/m2/day (max 600 mg/day) IV in one infusion or divided every 6 to 12 hours
2. Oral: 10 mg/kg/day (max: 800 mg/day) orally divided every 8 hours
  1. Age <6 years: 150 mg orally daily or divided every 8 hours
  2. Age 6 to 10 years: 300 orally daily or divided every 8 hoiurs

Dosing
Miscellaneous

Calcium Oxalate Stone prevention
1. Indicated in Calcium Oxalate Stones regardless of Uric Acid level
2. Start Allopurinol 100 mg orally daily
3. Advance to 2 to 3 times daily

Adverse Effects (more common with renal dysfunction)

May precipitate acute gout attack (never start during active gout attack)
1. See Dosing above for protocol using NSAIDs or Colchicine concurrently
Severe Hypersensitivity Syndrome (presents as dermatitis, Pruritus)
1. Varies from mild rash to Stevens Johnson Syndrome
2. Genetic Testing (HLA B5801) prior to use if Hans Chinese, Thai or if CKD 3, Korean
3. Stop Allopurinol if this occurs
4. Increased risk when concurrent use of Bendamustine, Thiazide Diuretics, Ampicillin or Amoxicillin
Toxic Hepatitis
Gastrointestinal (Nausea, Diarrhea)
Myelosuppression (Cytopenias)
Nephrotoxicity
1. Maximize hydration before dosing (esp. IV dosing)

Safety

Unknown safety in pregnancy
Considered safe in Lactation
Monitoring: Obtain 6 weeks after starting Allopurinol
1. Complete Blood Count (CBC)
2. Alanine Aminotransferase (ALT)
3. Serum Creatinine
4. Serum Uric Acid

Drug Interactions

Mercaptopurine
1. Reduce Mercaptopurine dose by 75% (Increased toxicity risk)
Azathioprine
1. Reduce Azathioprine dose by 75% (Increased toxicity risk)
Warfarin
1. Allopurinal increases INR
Capecitabine
1. Do not use with Allopurinol
Pegloticase
1. Do not use with Allopurinol

Resources

Allopurinol (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fbac3b4f-dc23-4359-ac3f-2b3fdde41af2

References

(2018) Presc Lett 25(9):50-1
Eggebeen (2007) Am Fam Physician 76:801-12 [PubMed]
Hainer (2014) Am Fam Physician 90(12): 831-6 [PubMed]