Allopurinol

Article Author:
Ahmad Qurie
Article Editor:
Rina Musa
Updated:
4/19/2018 10:19:44 PM
PubMed Link:
Allopurinol

Indications

Allopurinol is a urate-lowering medication.

Allopurinol is FDA approved for the following indications:

  1. Gout: Allopurinol is used in recurrent gout flares or if gout arthropathy is seen on imaging. 
  2. Cancer therapy-induced hyperuricemia or tumor lysis syndrome
  3. Calcium oxalate stones

Other non-FDA approved indications include Lesch-Nyhan syndrome-associated hyperuricemia. 

Allopurinol, as part of the different urate-lowering agents, is recommended to be started in the setting of gout in the following situations:

  1. Frequent gout attacks, defined as equal or more than 2 per year
  2. Overproduction of uric acid, with serum uric acid level more than 8 
  3. Uric acid urolithiasis. Allopurinol is used if there are recurrent stones despite adequate hydration and urinary alkalization. It is used to decrease the amount of uric acid excreted in the urine. 
  4. Tophaceous gout 
  5. Chronic persistent gout arthritis

One important point to add is that allopurinol is not recommended for use in asymptomatic hyperuricemia.

Mechanism of Action

Allopurinol is processed in the liver where it is converted into its pharmacologically active metabolite, oxypurinol. Oxypurinol has a long half-life of 24 hours and is renally cleared. Lower dosages are used in renal insufficiency due to renal clearance of allopurinol. Allopurinol and oxypurinol both competitively inhibit xanthine oxidase. This decreases the conversion of hypoxanthine and xanthine into uric acid. As a result, there is an increase in serum hypoxanthine and xanthine which affect pyrimidine metabolism.

Administration

Allopurinol can be administered in 2 forms, either intravenous (IV) or oral. While oral is the standard route of administration for gout and calcium oxalate stones, IV is reserved for cancer therapy-induced hyperuricemia.

For long-term gout treatment, allopurinol is usually started at a dosage of 100 mg per day for one week. This dose is increased every 2 to 4 weeks until the serum uric acid level is within goal range. The goal serum uric acid range is 6.0 mg/dL and less. Serum uric acid levels start to decrease within two days after starting allopurinol.

The usual daily dose prescribed for allopurinol is 300 mg daily. The maximum dose is 800 mg.

For renal insufficiency (chronic kidney disease stage 3 and greater), the dosage of allopurinol must be reduced. Oxypurinol's half-life in renal insufficiency is prolonged and may result in increased circulation of allopurinol and oxypurinol. If the creatinine clearance (CrCl) is 10 to 20 mL per minute, allopurinol should be prescribed as 200 mg daily. If the CrCl is 3 to 10 mL per minute, then the allopurinol dose is lowered to 100 mg daily. If the patient has the end-stage renal disease and is on hemodialysis or peritoneal dialysis, the patient may take daily allopurinol since allopurinol and oxypurinol are dialyzable.

For cancer-treatment induced hyperuricemia, oral doses of allopurinol are usually 600 to 800 mg daily for 2 to 3 days. Intravenous doses may also be given as 200 to 400 mg/m2 daily prior to initiating chemotherapy. Doses may be divided instead of being administered as a single infusion.

For recurrent calcium oxalate nephrolithiasis, allopurinol is administered as an oral dose, 200 to 300 mg daily.

Adverse Effects

Most common side effects of allopurinol are listed below:

A rash may occur. The rash may appear as maculopapular or be pruritic. This may occur more frequently in at least 20% of a patient taking amoxicillin or ampicillin.

Gout flares or worsening of a current flare may be precipitated after starting allopurinol treatment to acutely lower serum uric acid This adverse effect may be avoided by starting a low dose urate-lowering treatment, such as colchicine. An alternative to colchicine in this instance is a nonsteroidal anti-inflammatory drug (NSAID).

Gastrointestinal (GI) side effects are seen. Diarrhea and nausea are most commonly experienced.

Hepatic side effects are seen in about 3% to 5% of patients. These include transaminitis and elevated serum alkaline phosphatase. This may occur since the liver metabolizes the medication. Rare but more serious gastrointestinal side effects that may occur are liver necrosis, granulomatous hepatitis or cholestatic jaundice.

Hematologic abnormalities such as leukopenia and thrombocytopenia may also be seen. Evidence of bone marrow suppression is seen more frequently with higher doses of allopurinol.

Several drug interactions exist with allopurinol. Xanthine oxidase also metabolizes both 6-mercaptopurine and azathioprine. Serious agranulocytosis may occur when allopurinol is combined with azathioprine.

Drowsiness may occur. Patients should be educated to avoid driving or operating machinery if this adverse effect occurs.

Other less common adverse effects include interstitial nephritis or vasculitis.

Allopurinol hypersensitivity syndrome (AHS) may occur and is a serious adverse effect. This has a high mortality rate of about 25%. The first 60 days after the start of allopurinol therapy has the most risk for the development of AHS. Major risks factors of AHS include renal insufficiency, thiazide use, HLA-B*5801 genotype, and initiation of allopurinol at higher dosages. Older patients with renal insufficiency and on diuretic medications are prone to allopurinol sensitivity. The mechanism of AHS is due to T-cell activation in response to increase in serum allopurinol and its active metabolite, oxypurinol.

In order to diagnose ASH, there must be at least two major criteria, one major and at least one minor criteria, or rash only and/or additional minor criteria. 

  • Major criteria: acute hepatocellular injury, worsening renal function, rash. Different rashes of ASH include toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, maculopapular rash.
  • Minor criteria: Fever, elevated white blood cell count, eosinophilia

In order to lower the possibility of developing, allopurinol is started at lower doses, such as 100 mg daily.

Contraindications

The HLA-B*5801 genotype is more susceptible to developing allopurinol hypersensitivity syndrome. This genotype is found to occur more in Koreans with chronic kidney disease, Han Chinese, or Thai descent. It is particularly seen in populations of East and Southeast Asia and may also be seen in those of African descent. Susceptible populations should be screened for HLA-B*5801 genotype through polymerase chain reaction (PCR) testing. It is recommended to avoid treating patients with HLA-B*5801 genotype with allopurinol due to the high risk of developing AHS.

Monitoring

Monitoring parameters for allopurinol include measuring serum uric acid levels every 2 to 5 weeks during dose titration until desired levels are achieved, hydration status, response to therapy, and CBC. Measure serum uric acid level before and after allopurinol therapy is started. 

If there is suspicion of noncompliance with allopurinol therapy, oxypurinol levels may be measured.