Nov. 24, 2008 -- Uloric should be the first new gout drug to be approved in over 40 years, an FDA expert panel recommends.
Currently, allopurinol (trade name, Zyloprim) is the only FDA-approved drug that prevents formation of the uric acid crystals that cause gout. However, side effects -- including potentially fatal reactions -- limit the amount of allopurinol that can be tolerated. Most gout patients do not receive fully effective doses of allopurinol.
In clinical trials sponsored by Takeda, Uloric's manufacturer, an 80-milligram dose of Uloric worked better than allopurinol; a 40-milligram dose worked at least as well as allopurinol.
Unlike allopurinol, very little Uloric is excreted through the urine, making Uloric safe for patients with kidney problems. Gout patients with impaired kidney function have to take very low doses of allopurinol, making the drug even less effective for these patients.
In 2005, the FDA refused to approve Uloric because there were slightly more deaths and heart problems in patients taking the drug than in patients taking allopurinol. As people with gout problems already are at higher risk of heart disease, the FDA issued an "approvable" letter, noting that Uloric could be approved if this safety question were addressed.
Takeda then performed a large new phase 3 clinical trial that enrolled more gout patients than the two previous phase 3 trials combined. The new study found no more deaths and no more heart problems in patients taking Uloric than in patients taking allopurinol.
Based on the safety and efficacy data, the FDA panel recommended by a 12-0 vote that the FDA approve Uloric at both the 40-milligram and 80-milligram doses. Takeda suggests the higher dose is more effective in subjects with more severe gout.
Takeda has offered to continue studying Uloric after FDA approval. A phase 4 clinical trial would compare Uloric to allopurinol for the reduction of gout flare-ups.
And because drugs with the same mechanism of action as Uloric and allopurinol may affect theophylline bronchodilators, Takeda has agreed to conduct a postmarketing phase 1 study of Uloric's interactions with theophylline.
Gout occurs when blood levels of uric acid rise. At blood levels above 7 mg/dL -- and above 6 mg/dL in the extremities -- crystals can form that lodge in the joints and other body tissues. These crystal deposits provoke an immune response that results in extremely painful swelling and in inflammatory arthritis that can permanently destroy the joints.
(For more on the causes, symptoms, and treatment of gout, see WebMD's Gout Pictures Slideshow.)
About 1.4% of men and 0.6% of women have gout. But prevalence rises with age. After age 80, about 9% of men and 6% of women develop gout.
The body converts a chemical called xanthine into uric acid via an enzyme called xanthine oxidase or XO. Allopurinol and Uloric each inhibit XO and prevent the formation of uric acid.
Allopurinol is approved in doses up to 800 milligrams. However, it's rarely dosed above 300 milligrams per day and is often ineffective. Allopurinol side effects include upset stomach, headache, diarrhea, and rash. Although rare, allopurinol hypersensitivity syndrome can develop. It's fatal 20% to 30% of the time.
The most common side effects seen in patients taking Uloric during clinical trials were upper respiratory tract infections, muscle and connective-tissue symptoms, and diarrhea. The drug was well tolerated, and these side effects did not increase over long-term use.