Febuxostat

[Admin]

[Admin]

Clinical Efficacy and Safety of Successful Longterm Urate Lowering with Febuxostat or Allopurinol in Subjects with Gout.
Becker MA, Schumacher HR, Macdonald PA, Lloyd E, Lademacher C.
J Rheumatol. 2009 Mar 13. [Epub ahead of print]

OBJECTIVE: To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with febuxostat or allopurinol in subjects with gout.

METHODS: Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and < 6.0 mg/dl. Flares requiring treatment, tophus size, safety, and SUA levels were monitored during up to 40 months of ULT maintenance.

RESULTS: After 1 month initial treatment, > 80% of subjects receiving either febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA < 6.0 mg/dl. After ULT reassignment, > 80% of all remaining subjects maintained the primary efficacy endpoint of SUA < 6.0 mg/dl at each visit. More subjects initially randomized to allopurinol required ULT reassignment to achieve SUA < 6.0 mg/dl compared with subjects receiving febuxostat. Maintenance of SUA < 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment. Baseline tophus resolution was achieved by 46%, 36%, and 29% of subjects maintained on febuxostat 80 mg, febuxostat 120 mg, and allopurinol, respectively. Overall adverse event rates (including cardiovascular adverse event rates), adjusted for 10-fold greater febuxostat than allopurinol exposure, did not differ significantly among treatment groups.

CONCLUSION: Durable maintenance of goal range SUA level with either dose of febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time

[Admin]

Press Releases:
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE SUMMARY OF POSITIVE OPINION*
for ADENURIC
International Nonproprietary Name (INN): febuxostat
European Medicines Agency
Pre-Authorisation Evaluation of Medicines for Human Use

On 21 February 2008 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion,** recommending to grant a marketing authorisation for the medicinal product Adenuric, 80 mg and 120 mg, film-coated tablets intended for treatment of chronic hyperuricaemia in gout patients. The applicant for this medicinal product is Ipsen Manufacturing Ireland Limited.
The active substance of Adenuric is febuxostat, a medicinal product against gout and inhibits uric acid production (ATC Code MO4AA03); febuxostat is a non-purine selective inhibitor of xanthine oxidase.
The benefits with Adenuric are its potency to reduce serum urate. The most common side effects are liver function abnormalities, diarrhoea, headache, nausea and rash. In the clinical trials serious cardiovascular adverse events were the main safety concern.
A pharmacovigilance plan for Adenuric, as for all medicinal products, will be implemented as part of the marketing authorisation.
The approved indication is: “treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history or presence of, tophus and/or gouty arthritis)”.
Detailed recommendations for the use of this product will be described in the Summary of Product Characteristics (SPC) which will be published in the European Public Assessment Report (EPAR) and will be available in all official European Union languages after the marketing authorisation has been granted by the European Commission.
The CHMP, on the basis of quality, safety and efficacy data submitted, considers that there is a favourable benefit to risk balance for Adenuric and therefore recommends the granting of the marketing authorisation.

Press release
EMEA recommends marketing authorisation of Ipsen’s Adenuric® (febuxostat) for the treatment of chronic hyperuricaemia in gout
Adenuric® represents the first major treatment of gout for more than forty years

Paris (France), 21 February 2008 - Ipsen (Euronext: FR0010259150; IPN) announced today
that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines
Agency (EMEA) provided a positive opinion for Adenuric® (febuxostat) 80 mg and 120 mg
tablets for the treatment of chronic hyperuricaemia in gout and recommended it for marketing
authorisation. The CHMP recommendation will now be forwarded to the European Commission
for final marketing approval, which typically occurs within 60 to 90 days. Following marketing
approval, Adenuric® will become, since 1964, the first significant treatment alternative for chronic
hyperuricaemia available to gout patients.
Adenuric® is to be indicated for the treatment of chronic hyperuricaemia for conditions in which
urate deposition has already occurred (including a history, or presence of, tophus and/or gouty
arthritis). The detailed recommendations for the use of this product will be described in the
Summary of Product Characteristics (SPC), to be made available after the medication receives
marketing authorisation from the European Commission.
Once the product receives its marketing authorisation and its price is agreed, Febuxostat will be
marketed by Ipsen in France under the brand name Adenuric®. Outside France, the
commercialisation of the product will be partnered.
Jean-Luc Bélingard, Chairman and Chief Executive Officer of Ipsen, said, “We are very proud to
receive this positive opinion for Adenuric® from the EMEA, and look forward to bringing this new
molecule to market, pending European Commission approval. This innovative drug pioneers the
first major treatment of gout for more than 40 years. It confirms Ipsen’s ability to continue to
bring to the market important new treatment options for severely debilitating diseases.”

About Adenuric® (febuxostat)
Gout, a particularly painful type of arthritis, is the most frequent arthritis in men. It is caused by elevated
levels of uric acid in the body: hyperuricaemia. Febuxostat, an oral, once-daily medication, is a novel nonpurine,
selective inhibitor of xanthine oxidase studied for its effects on lowering levels of serum uric acid
(sUA) in patients with gout. Febuxostat is licensed to Ipsen for Europe from Teijin Pharma Limited, Tokyo.
The EU submission includes two of the largest industry sponsored studies to date studying treatment of
chronic gout patients. The goal of chronic gout treatment is per EULAR guidelines (European League
Against Rheumatism) to reduce and maintain sUA levels below 6 mg/dL. Febuxostat demonstrated
superior ability to lower and maintain in patients, serum uric acid at a level inferior to 6 mg/dl compared to
conventionally used doses of allopurinol (febuxostat 80 and 120 mg: 51 & 63 % resp. vs. allopurinol: 22%).
In addition, one phase III study showed that gout patients with mild to moderate renal impairment (serum
2/2
creatinine >1.5 - ≤2.0 mg/dl) had response rate of 44 and 45 % respectively with febuxostat 80 and 120
mg.

In 2003, Ipsen entered into a Research and Development partnership with Teijin Pharma Limited, the core
company of Teijin Group’s pharmaceutical and home healthcare business. The Teijin group is a Japanese
industrial conglomerate specialising in the businesses of fibres, films, plastics and information technology
(IT) as well as pharmaceuticals and home healthcare. This partnership covers the development and
subsequent commercialisation of four of Ipsen’s products by Teijin Pharma in Japan and the development
and marketing by Ipsen in Europe (i.e. European Union and Russia) of febuxostat, a product owned by
Teijin Pharma and known as TMX-67.

[Admin]

Press Release:
Arthritis Advisory Committee Recommends FDA Approval Of Febuxostat For The Treatment Of Hyperuricemia In Patients With Gout
25 Nov 2008

Takeda Pharmaceutical Company Limited and its wholly-owned subsidiary, Takeda Global Research & Development Center, Inc., U.S., announced today that the Arthritis Advisory Committee of the U.S. Food and Drug Administration (FDA) recommended that the FDA approve febuxostat for the treatment of hyperuricemia in patients with gout. The vote was 12 to zero in favor of approval, with one panel member abstaining. The vote followed presentations by Takeda Global Research & Development Center, Inc., the FDA, and invited guest speakers. If approved in the United States by the FDA, febuxostat will be the first new treatment for the management of hyperuricemia associated with gout in more than 40 years.

The FDA will review the current new drug application for febuxostat and make its approval decision. The FDA's decision may or may not follow the Committee's recommendation.

"Today's vote by the Arthritis Advisory Committee, recommending approval of febuxostat for the treatment of hyperuricemia in patients with gout, is a positive step in bringing this new treatment to market," said Nancy Joseph-Ridge, MD, president, Takeda Global Research & Development, Inc., U.S. "Takeda is committed to developing innovative therapies that fulfill unmet treatment needs, and we believe febuxostat will represent an important new option for patients who suffer the debilitating effects of gout. In the coming months, we will work with the FDA to complete their review, including the design of post-marketing studies."

Febuxostat is a potent non-purine, selective inhibitor of xanthine oxidase, which was studied for its ability to lower levels of serum uric acid in patients with hyperuricemia associated with gout. Hyperuricemia, elevated uric acid levels in the body, is associated with gout, a painful type of arthritis. In clinical trials, febuxostat 40 mg and 80 mg were shown to be effective treatments for the management of hyperuricemia associated with gout. Both doses were well tolerated and required no dose adjustments in patients with renal impairment. The most commonly reported adverse events were upper respiratory tract infections, musculoskeletal and connective tissue signs and symptoms, and diarrhea.

[Admin]

Febuxostat: A selective xanthine-oxidase/xanthine-dehydrogenase inhibitor for the management of hyperuricemia in adults with gout.
Ernst ME, Fravel MA.
Clin Ther. 2009 Nov;31(11):2503-2518.

Background: Febuxostat, a nonpurine selective inhibitor of both the oxidized and reduced forms of xanthine oxidase, was approved in February 2009 by the US Food and Drug Administration for the management of hyperuricemia in adults with gout.

Objective: The purpose of this review was to summarize available information about the clinical use of febuxostat, including its chemistry, pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety profile.

Methods: A search of the medical literature using PubMed (1949-August 2009) and the Iowa Drug Information Service (1966-August 2009) was performed to identify all published articles about febuxostat. Key search terms included febuxostat, hyperuricemia, gout, TMX-67, and TEI-6720. Articles were limited to those published in English. Reference lists of the primary set of articles identified were reviewed for pertinent articles and scientific meeting abstracts not identified in the original search.

Results: A total of 88 published articles (including 14 human studies) were identified in the original search. Review of the references of these 88 articles yielded 7 additional trials published in abstract form. Clinical trial data from this review were obtained from these 21 studies. Dose-dependent reductions from baseline in serum urate occur with febuxostat. Clinical trials found that 40 mg/d of febuxostat was noninferior to conventionally dosed allopurinol (300 mg/d) in the percentage of subjects achieving the primary end point of serum urate <6.0 mg/dL (45% for febuxostat vs 42% for allopurinol), whereas 80 mg/d of febuxostat was reported to be superior (67% vs 42%; P < 0.001). Febuxostat 40 and 80 mg/d appeared to be well tolerated in the populations studied, with adverse events mostly limited to liver enzyme elevations (6.6% and 4.6%, respectively), nausea (1.1% and 1.3%), arthralgias (1.1% and 0.7%), and rash (0.5% and 1.6%). Febuxostat does not require dosage adjustment in patients with mild to moderate renal impairment (creatinine clearance, 30-89 mL/min). Because of the risk of acute gout flares occurring when febuxostat treatment is initiated, concomitant therapy with colchicine or an NSAID for >/=8 weeks is recommended.

Conclusions: Febuxostat is the first agent marketed in the United States to treat hyperuricemia of gout since allopurinol was approved in 1964. In English-language published clinical trials, it was found to be noninferior to allopurinol and generally well tolerated.

[Admin]

The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.
Becker MA, Schumacher HR, Espinoza LR, Wells AF, Macdonald P, Lloyd E, Lademacher C.
Arthritis Res Ther. 2010 Apr 6;12(2):R63. [Epub ahead of print]

INTRODUCTION: Compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) [greater than or equal to]8.0 mg/dL in a 6-month trial.

METHODS: Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death.

RESULTS: Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and 3 in the allopurinol group.

CONCLUSIONS: Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable

[Admin]

Urate-lowering therapy for gout: focus on febuxostat.
Love BL, Barrons R, Veverka A, Snider KM.
Pharmacotherapy. 2010 Jun;30(6):594-608.

Gout is a common, painful, and often debilitating rheumatologic disorder that remains one of the few arthritic conditions that can be diagnosed with certainty and cured with appropriate therapy. Allopurinol is the most frequently prescribed agent for gout in the United States. Unfortunately, most patients treated with allopurinol do not achieve target serum uric acid (sUA) levels, possibly due to a perceived intolerability to allopurinol in doses above 300 mg and the need for reduced doses in patients with renal insufficiency. Febuxostat, an orally administered, nonpurine inhibitor of xanthine oxidase, was recently approved by the U.S. Food and Drug administration for chronic management of hyperuricemia in patients with gout. Patients treated with febuxostat achieve rapid and substantial reductions in sUA levels. Compared with allopurinol-treated patients, patients receiving febuxostat 80 mg/day were more likely to achieve sUA concentrations less than 6 mg/dl. In long-term studies (up to 5 yrs), febuxostat demonstrated sustained reductions in sUA levels, nearly complete elimination of gout flares, and a frequency of adverse effects comparable to allopurinol. The most commonly reported adverse effects were liver function abnormalities, rash, nausea, and arthralgias. The recommended starting dose of febuxostat is 40 mg/day, which may be increased to 80 mg/day after 2 weeks if patients do not achieve sUA levels less than 6 mg/dl. Dosage adjustment in mild-to-moderate renal insufficiency is unnecessary; however, data are lacking on the safety of febuxostat in patients with severe renal impairment. Although more costly than allopurinol, febuxostat appears to be an acceptable alternative for the treatment of gout and hyperuricemia, and may be advantageous in patients with renal impairment, intolerance to allopurinol, or the inability to attain sUA levels less than 6 mg/dl despite adequate therapy with available agents.

[Admin]

Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non-purine selective inhibitor of xanthine oxidase.
Grabowski B, Khosravan R, Wu JT, Vernillet L, Lademacher C.
Br J Clin Pharmacol. 2010 Jul;70(1):57-64.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Hyperuricaemia and gout frequently coexist with cardiovascular disorders such as hypertension and heart failure. The use of diuretics has been re-established as a first-line treatment for patients with hypertension and the effects of diuretics on serum uric acid may diminish the urate-lowering effects of febuxostat, a novel, potent, non-purine selective inhibitor of xanthine oxidase.

WHAT THIS STUDY ADDS * Co-administration of febuxostat 80 mg and hydrochlorothiazide 50 mg had no effect on the pharmacokinetics and did not have a clinically significant effect on the pharmacodynamics of febuxostat. Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide. AIM This study examined the effect of co-administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat.

METHODS Healthy subjects (36 healthy men and women) received single doses of febuxostat 80 mg alone and febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open-label, randomized, crossover fashion. Plasma concentrations of febuxostat and urinary and serum concentrations of uric acid were assessed.

RESULTS Mean febuxostat C(max), AUC((0-t)), AUC((0-infinity)), t(1/2,z), CL/F and V(ss)/F values for regimens co-administration/febuxostat alone were 2.9/2.9 microg ml(-1), 9.3/9.1 microg ml(-1) h, 9.6/9.3 microg ml(-1) h, 6.5/6.1 h, 8.8/9.3 l h(-1) and 45/44 l, respectively. Geometric mean ratios (co-administration : febuxostat alone) and their 90% confidence intervals for febuxostat plasma C(max), AUC((0-t)), and AUC((0-infinity)) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid C(mean,24h), C(mean,48h) and CL(R) for both regimens co-administration/febuxostat alone were 216/203 micromol l(-1), 218/202 micromol l(-1) and 9.1/10.1 ml min(-1), respectively. Although serum uric acid C(mean,24h) and C(mean,48h) values were higher and CL(R) values lower after co-administration compared with dosing of febuxostat alone, with the differences being statistically significant (P < 0.003), none of the differences (6.5%-9.5%) was considered clinically significant.

CONCLUSION Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.