Allopurinol

Article Author:
Ahmad Qurie
Article Editor:
Rina Musa
Updated:
10/11/2019 8:17:49 PM
PubMed Link:
Allopurinol

Indications

Allopurinol is a urate-lowering medication.[1][2][3]

Allopurinol is FDA approved for the following indications:

  1. Gout: Allopurinol is used in recurrent gout flares or if gout arthropathy is visible 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 to 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 useful 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 recommendations for allopurinol do not include use in asymptomatic hyperuricemia.

Mechanism of Action

Allopurinol gets processed in the liver, where it converts into its pharmacologically active metabolite, oxypurinol. Oxypurinol has a long half-life of 24 hours and is renally cleared. Lower dosages are necessary for cases of 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.[4][5]

Administration

Allopurinol administration can be in two 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 usually starts 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.

Renal insufficiency (chronic kidney disease stage 3 and greater) requires allopurinol dose reduction. 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 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 before initiating chemotherapy. Doses may be divided instead of being administered as a single infusion.

Allopurinol oral dosing is 200 to 300 mg daily for recurrent calcium oxalate nephrolithiasis.

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 rash may occur more frequently in at least 20% of patients taking amoxicillin or ampicillin.

Starting allopurinol treatment to acutely lower serum uric acid may lead to gout flares or worsening of a current flare. To avoid this adverse effect, start with a low dose of urate-lowering treatment, such as colchicine. An alternative to colchicine in this instance is a nonsteroidal anti-inflammatory drug (NSAID).

Gastrointestinal (GI) side effects may result from treatment. Diarrhea and nausea are the most common.

Hepatic side effects occur in about 3% to 5% of patients. These include transaminitis and elevated serum alkaline phosphatase, which 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 occur. 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 combining allopurinol 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 severe adverse effect with 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 risk 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 diuretic medications are prone to allopurinol sensitivity. The mechanism of AHS is due to T-cell activation in response to an increase in serum allopurinol and its active metabolite, oxypurinol.

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: includes 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

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 present in those of African descent. Susceptible populations should receive screening for the 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 achieving desired levels, hydration status, response to therapy, and CBC. Measure serum uric acid level before and after starting allopurinol therapy.

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

Enhancing Healthcare Team Outcomes

Allopurinol is a relatively safe drug and has been in use for more than half a century. Still, healthcare workers, including nurse practitioners who prescribe this agent, should measure uric acid levels regularly to determine drug compliance and effectiveness. The rare patient may develop mild transaminitis, and thus follow up on liver function is necessary.

Allopurinol, as part of a hyperuricemia/gout regimen, requires management by an interprofessional team. Clinicians initiating allopurinol therapy should consult a pharmacist to ensure that there are no drug interactions and that xanthine oxidase inhibitor therapy is the optimal choice. Nursing will be able to assist with verifying patient compliance and helping to monitor for adverse events and therapeutic effectiveness. The best chance for allopurinol to have therapeutic success with minimal adverse events is via an interprofessional team approach. [Level V]


References

[1] Mikuls TR,Cheetham TC,Levy GD,Rashid N,Kerimian A,Low KJ,Coburn BW,Redden DT,Saag KG,Foster PJ,Chen L, A Pharmacist-Led Intervention to Improve Gout Medication Adherence and Outcomes with Urate Lowering Therapy: A Site Randomized Trial. The American journal of medicine. 2018 Nov 29     [PubMed PMID: 30503879]
[2] Shim JS,Yun J,Kim MY,Chung SJ,Oh JH,Kang DY,Jung JW,Cho SH,Kang HR, The presence of HLA-B75, DR13 homozygosity or DR14 additionally increases the risk of allopurinol induced severe cutaneous adverse reactions in HLA-B*58:01 carriers. The journal of allergy and clinical immunology. In practice. 2018 Dec 6     [PubMed PMID: 30529060]
[3] Hill-McManus D,Marshall S,Soto E,Lane S,Hughes D, Impact of Non-Adherence and Flare Resolution on the Cost-Effectiveness of Treatments for Gout: Application of a Linked Pharmacometric/Pharmacoeconomic Model. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2018 Dec     [PubMed PMID: 30502780]
[4] Alušík Š,Paluch Z, Controversies in the treatment of gout. Vnitrni lekarstvi. 2018 Fall     [PubMed PMID: 30441983]
[5] Robinson PC, Gout - An update of aetiology, genetics, co-morbidities and management. Maturitas. 2018 Dec     [PubMed PMID: 30415758]