Commonly Used Gout, Kidney Stone Drug Too Dangerous for Unproven Uses

For most patients suffering from gout, allopurinol (LOPURIN, ZYLOPRIM) is a first-line therapy: By reducing high uric acid levels in the blood, the drug prevents sudden attacks of disabling joint pain and swelling, progressive joint damage, and other gout complications. The drug also is a cornerstone of treatment for patients with kidney stones caused by high levels of uric acid in the urine.

Although allopurinol has serious risks, these generally are outweighed by its benefits when used to treat these two disorders.

Over the past several years, physicians increasingly have prescribed the drug for a use not approved by the Food and Drug Administration (FDA): to reduce high blood uric acid levels in people without any signs or symptoms of gout or kidney stones but who have a condition known as asymptomatic hyperuricemia.[1] However, there is evidence that the risks of allopurinol for this “off-label” use outweigh the benefits. In fact, the FDA-approved label for allopurinol states:

This is not an innocuous drug. It is not recommended for the treatment of asymptomatic hyperuricemia.[2]

A September 2015 study in JAMA Internal Medicine reveals that use of allopurinol to lower high blood uric acid levels in people without symptoms clearly is associated with an alarming increase in the risk of life-threatening skin reactions, a known danger of the drug in gout and kidney stone patients. These findings reinforce the advice in the drug’s label warning against such use.

Uric-acid-related illness

Uric acid is a substance produced naturally in the body. It is filtered out of the blood by the kidneys and removed from the body through the urine. Too much uric acid in the blood, which can be measured by a routine blood test, may lead to deposits of uric acid crystals in joints and other tissues, resulting in gout attacks. Likewise, too much uric acid in the urine may cause crystal formation in the kidney, which can lead to kidney stones or renal failure.

Allopurinol blocks the body’s production of uric acid, thereby decreasing blood and urine levels of the substance. The goal of treatment for gout and kidney stone patients is to reduce uric acid concentrations in the blood and urine, respectively, to levels below those needed for crystal formation.

Importantly, about two-thirds of people with high blood levels of uric acid never go on to develop gout or uric-acid-related kidney stones.[3] Nevertheless, some doctors prescribe allopurinol to people who have asymptomatic hyperuricemia because the condition is associated with other diseases unrelated to uric acid crystal formation, including hypertension, heart disease and pre-diabetes.[4],[5] Such treatment is controversial because high uric acid has never been shown to cause these diseases,[6],[7] whereas allopurinol is known to cause dangerous hypersensitivity reactions.

Hypersensitivity reactions

These allergic-like reactions can develop within several weeks of starting allopurinol. The most prominent symptom of these adverse reactions is a severe rash. The rash often appears as large red blotches that can progress to cover large portions of the skin. In the most severe types of hypersensitivity reactions, patients develop blisters, and skin subsequently sloughs off. Such cases resemble severe burns.

The skin rash is often accompanied by similar lesions in the mouth, as well as symptoms of systemic illness, such as fever, fatigue, and muscle and joint pains. Damage to internal organs, such as the liver and lungs, also can occur.

The JAMA Internal Medicine study sheds new light on the frequency with which allopurinol is being used for asymptomatic hyperuricemia and the unacceptable risk this poses to patients.

The new study[8]

A team of researchers in Taiwan wanted to learn why doctors prescribe allopurinol to patients and how often these patients develop potentially fatal hypersensitivity reactions. To answer these questions, they examined medical records stored in a national database that covers 23 million people — nearly all of the country’s population — under Taiwan’s national health insurance program.

The researchers identified all patients who were started on allopurinol from 2005 through 2011 (about 496,000 people). Over the seven-year study period, 43 percent of these patients were prescribed the drug for high blood uric acid levels without having symptoms of illness. This percentage steadily rose from 37 percent in 2005 to 50 percent in 2011.

Over the entire study period, approximately one of every 200 allopurinol-treated patients developed hypersensitivity reactions within three months of starting the drug. Of these, more than 40 percent required hospitalization within one month of developing the reaction, and 8 percent died within two months. The investigators also found that the incidence of allopurinol-induced hypersensitivity reactions steadily increased from 2005 to 2011, due in part to the increased use of the drug for asymptomatic hyperuricemia.

Strikingly, the researchers found that treatment with allopurinol for asymptomatic hyperuricemia doubled the risk of having or dying from a hypersensitivity reaction, compared with patients who were taking the drug for gout or other symptomatic uric-acid-caused illnesses.

In the U.S., the incidence of allopurinol hypersensitivity reactions is about one-fourth that seen in Taiwan, which means about one of every 1,000 U.S. patients treated with allopurinol develop these reactions.[9] This difference is due in part to the fact that many people in Taiwan, because of their Chinese heritage, carry genes that make them more susceptible to such drug reactions.[10] Nevertheless, the new study results are important to patients in the U.S. because even a 1 in 1,000 chance of having a potentially fatal hypersensitivity reaction represents an unacceptable risk for patients prescribed — but deriving no proven benefit from — allopurinol for asymptomatic hyperuricemia.

What You Can Do

Do not take allopurinol for asymptomatic hyperuricemia. If you are taking the drug but have not been diagnosed with gout, uric-acid-related kidney stones or renal disease, talk to your doctor about stopping the drug. If you are taking allopurinol for an appropriate medical reason, be alert for skin symptoms and contact your doctor immediately if you develop a skin rash, hives or itching.

References

[1] Yang CY, Chen CH, Deng ST, et al. Allopurinol use and risk of fatal hypersensitivity reactions: A nationwide population-based study in Taiwan. JAMA Intern Med. 2015;175(9):1550-1557.

[2] DailyMed. Drug label for Zyloprim. Updated November 2009. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=342832b5-1a32-4bea-bc49-ab0fd152154e&audience=professional. Accessed November 6, 2015.

[3] Becker MA. Asymptomatic hyperuricemia. Last updated February 5, 2015. UpToDate. http://www.uptodate.com/contents/asymptomatic-hyperuricemia?source=search_result&search=asymptomatic+hyperuricemia&selectedTitle=1~24. Accessed November 6, 2015.

[4] Ibid.

[5] Yang CY, Chen CH, Deng ST, et al. Allopurinol use and risk of fatal hypersensitivity reactions: A nationwide population-based study in Taiwan. JAMA Intern Med. 2015;175(9):1550-1557.

[6] Ibid.

[7] Becker MA. Asymptomatic hyperuricemia. Last updated February 5, 2015. UpToDate. http://www.uptodate.com/contents/asymptomatic-hyperuricemia?source=search_result&search=asymptomatic+hyperuricemia&selectedTitle=1~24. Accessed November 6, 2015.

[8] Yang CY, Chen CH, Deng ST, et al. Allopurinol use and risk of fatal hypersensitivity reactions: A nationwide population-based study in Taiwan. JAMA Intern Med. 2015;175(9):1550-1557.

[9] Stern RJ. Editor’s note: Reducing life-threatening allopurinol hypersensitivity. JAMA Intern Med. 2015;175(9):1558.

[10] Ibid.