Utah Medicaid Pharmacy and Therapeutics Committee Drug ... · unapproved drugs in order to continue...

1

Utah Medicaid Pharmacy and Therapeutics Committee

Drug Class Review

Antigout Agents

AFHS classifications: Antigout Agents 92:16, Uricosuric Agents 40:40

Allopurinol (Zyloprim, Alloprim, generic) Colchicine (Colcrys, Mitigare, generic)

Colchicine and probenecid (Col-Probenecid, generic) Febuxostat (Uloric)

Lesinurad (Zurampic) Pegloticase (Krystexxa)

Probenecid (Probalan, generic)

Final Report May 2017

Review prepared by: Elena Martinez Alonso, B.Pharm., Medical Writer Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Valerie Gonzales, Pharm.D., Clinical Pharmacist Joanita Lake, B.Pharm., MSc EBHC (Oxon), Clinical Pharmacist Michelle Fiander, MA, MLIS, Systematic Review/Evidence Synthesis Librarian Joanne LaFleur, PharmD, MSPH, Associate Professor University of Utah College of Pharmacy University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2017 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

2

Table of Contents Executive Summary ........................................................................................................................ 3 Introduction ..................................................................................................................................... 6

Table 1. FDA Approved Antigout Agents .......................................................................... 8

Table 2. Dosing Recommendations for Antigout Agents ................................................. 10

Disease Overview 11

Table 3. Guidelines for the Management of Gout ............................................................. 14

Pharmacology ............................................................................................................................... 19

Table 4. Pharmacokinetics of Antigout Agents ................................................................ 20

Special Populations ....................................................................................................................... 21

Table 5. Recommendations for Special Populations of Antigout Agents ......................... 22

Methods......................................................................................................................................... 24

Clinical Efficacy and Safety ......................................................................................................... 26

Safety ............................................................................................................................................ 34

Table 6. Adverse Reactions and Warnings of Antigout Agents ....................................... 36

Summary ....................................................................................................................................... 38

References ..................................................................................................................................... 41

Appendix A. MEDLINE & EMBASE Literature Search Strategies for Antigout Agents ........... 45

Appendix B. Key Evidence: Cochrane Systematic Reviews Including Agents for Acute and Chronic Gout .............................................................................................................................. 49

Appendix C. Key Evidence: Other Systematic Reviews Including Agents for Acute and Chronic Gout ............................................................................................................................................ 54

Appendix D. Additional Evidence: Systematic Reviews and Meta-Analysis Including Agents for Acute and Chronic Gout ............................................................................................................. 56

Appendix E. Randomized Controlled Trial of Lesinurad (Not Included in the Previous Systematic Reviews) .................................................................................................................. 59

Appendix F. Randomized Controlled Trials Included in Systematic Reviews and Meta-analyses for Chronic Gout ......................................................................................................................... 60

Appendix G. List of Excluded References ................................................................................... 61

3

Executive Summary Introduction: Gout is a painful and debilitating inflammatory arthritis associated with high serum uric acid (SUA) levels and triggered by the deposition of monosodium urate crystals in joints and other tissues. The number of people with gout has increased worldwide in recent years due to the increase of the aging population, dietary and lifestyle changes, higher use of gout-inducing medicines such as diuretics, and comorbidities including hypertension, obesity, diabetes, renal impairment and cardiovascular disease.

The primary goals of gout treatment include relieving the pain associated with acute gout attacks, and reducing serum uric acid concentrations below 6 mg/dL in order to prevent recurrent gout flares and the development of complications. Gout therapy includes non-pharmacological and pharmacological approaches. In the United States, pharmacological options for the treatment of acute gout attacks include non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids and adrenocorticotropic hormone (ACTH). Chronic management of gout includes xanthine oxidase inhibitors (allopurinol and febuxostat), uricosuric medications (probenecid and lesinurad), a pegylated recombinant uricase product (pegloticase) and a combination of probenecid plus colchicine. Non-pharmacological approaches include lifestyle and dietary changes.

This report evaluates the comparative efficacy and safety of the antigout drug class based on systematic reviews, meta-analyses and randomized controlled trials (RCT) assessing intra-class comparisons. Currently, seven products for the treatment of gout are available for use in the US: allopurinol, colchicine, colchicine/probenecid, febuxostat, lesinurad, pegloticase and probenecid.

Clinical efficacy and safety: Intra-class head-to-head comparisons were identified for allopurinol, febuxostat and probenecid, all indicated for the management of chronic gout. No head-to-head intra-class comparisons for lesinurad, colchicine and colchicine/probenecid were found. Pegloticase is an intravenous injection for the treatment of chronic gout in adult patients refractory to conventional therapy. It is not prescribed in the primary care setting and therefore, is outside the scope of this report.

For the treatment of acute gout, no head-to-head intra-class comparisons involving colchicine were found. Moreover, colchicine was not directly compared to agents outside this class, such as NSAIDs and corticosteroids. High-quality evidence from guidelines and systematic reviews concluded that NSAIDs, colchicine and corticosteroids are similarly effective for the reduction of pain caused by acute gout flares. Evidence indicated that low-dose colchicine (1.2 mg followed by 0.6 mg 1 hour later) was as effective as high-dose colchicine but presented a more favorable safety profile.

4

For the management of chronic gout, a large amount of comparative evidence assessing allopurinol versus febuxostat indicated that both antigout agents are efficacious in reducing SUA levels below 6 mg/dL and decreasing the incidence of gout flares over time. Febuxostat 40 mg showed similar urate lowering efficacy to allopurinol, with febuxostat 80 mg being superior compared to allopurinol. The incidence of gout flares was similar between both agents, with a non-significant trend towards a higher incidence of gout attacks with febuxostat compared to allopurinol. Safety profile was similar between groups. Several studies in patients with renal impairment and advanced chronic kidney disease revealed better efficacy in terms of SUA reduction below 6 mg/dL with febuxostat compared to allopurinol.

Limited comparative evidence for probenecid is available. Two systematic reviews including one RCT were identified. Results indicated that probenecid is effective as uric acid lowering agent. However, the small study size and the low-quality evidence extracted from the RCT raised uncertainties on the results found. No evidence was identified comparing colchicine plus probenecid with other antigout agents for the management of chronic gout.

Lesinurad was approved in 2015. One trial evaluating the efficacy and safety of lesinurad in combination with allopurinol compared to allopurinol alone was found. This trial supported the approval of Lesinurad 200 mg in combination with a XOI for the treatment of hyperuricemia associated with gout in patients who have not achieved target SUA levels with a XOI alone.

Adverse drug reactions: In general, XOIs are safe and well-tolerated. Allopurinol use is associated with diarrhea, stomach pain, skin rash, headache, and liver abnormalities. Rare but life-threatening cases of allopurinol hypersensitivity syndrome (AHS) have been reported, especially in the Asian population, a group with a higher prevalence of the HLA-B*5801 allele than other populations. Febuxostat may cause increased levels of liver transaminases, gastrointestinal disorders, musculoskeletal pain and skin rash. Probenecid is associated with gastrointestinal intolerance, rash, hepatotoxicity, acute gout attack, nephrolithiasis and nephrotic syndrome. Due to these potential renal adverse events, this agent is contraindicated in patients with severe renal impairment. Lesinurad is associated with increases in serum creatinine and risk of renal failure. Therefore, it is not recommended in patients with a creatinine clearance below 45 mL/min. Colchicine has a narrow therapeutic index with a significant risk of toxicity and death if used inappropriately. The most common adverse events reported with oral colchicine are gastrointestinal disorders, particularly diarrhea.

Summary: Based on the evidence identified, febuxostat and allopurinol are similarly safe and efficacious for the management of chronic gout, with febuxostat 80 mg showing superior urate lowering efficacy compared to allopurinol. For the treatment of acute gout, guidelines and high-quality systematic reviews reported that low-dose colchicine is as effective as NSAIDs and corticosteroids in the reduction of pain caused by acute gout flares. No conclusions are possible for the other antigout agents (i.e. probenecid, lesinurad or colchicine/probenecid) due to limited

5

evidence available. Treatment decisions should be based on individual patient characteristics, comorbidities, drug safety profiles and contraindications.

Current guidelines from the American College of Physicians (ACP) and the American College of Rheumatology (ACR) recommend the use of colchicine, NSAIDs or corticosteroids as first-line treatments for acute gout attacks, without any specific preference of one agent over another. Low-dose colchicine is preferred over high-dose colchicine due to the lower incidence of adverse events. For the management of chronic gout, guidelines consider either allopurinol or febuxostat as first-line urate lowering therapies (ULT). Uricosuric agents including probenecid are classified as second-line options when patients do not achieve SUA target levels with XOIs or if first line treatments are contraindicated. Lesinurad is a new agent approved in 2015 for chronic gout that has not yet been included in current guidelines. Pegloticase is an intravenous injection recommended by the ACR in patients with severe gout disease and refractory to conventional therapy. Neither the ACP nor ACR guidelines offer recommendations concerning colchicine-probenecid combination therapy.

6

Introduction

Gout is a major and increasing public health concern affecting 3.9% of adults in the United States,1 especially middle-aged to elderly men and postmenopausal women.2-4 This extremely painful and debilitating form of inflammatory arthritis5 is associated with high serum uric acid (SUA) levels and is triggered by deposition of monosodium urate crystals in joints, tendons, bursas and other tissues.6 The number of people with gout has increased in recent years in many regions,1,7 especially in the developed countries,5 due to growing aging population, dietary and lifestyle changes (e.g. high consumption of purine and fructose containing food and beverages, seafood, and alcohol), higher use of gout-inducing medications (e.g. diuretics), and comorbidities including hypertension, obesity, diabetes, renal impairment and cardiovascular disease.5,8

The primary goals of gout treatment are to relieve pain associated with acute gout attacks, and to reduce SUA concentration to less than 6 mg/dL (360 µmol/L)9,10 in order to prevent recurrent flares and the development of complications.6 Gout therapy include both non-pharmacological and pharmacological approaches. In the United States, pharmacologic approaches for acute gout attacks are NSAIDs, colchicine, corticosteroids and ACTH.2,11-13 Maintenance therapy for chronic gout includes xanthine oxidase inhibitors (i.e. allopurinol and febuxostat), uricosuric medications (i.e. probenecid and lesinurad), uricases (i.e. pegloticase) and a combination of probenecid plus colchicine.10,13 Non-pharmacological approaches include lifestyle and dietary changes.9,10,13 Antigout medications available in Europe but not approved in the United States, include canakinumab.14

This report evaluates the clinical efficacy and safety of the antigout drug class based on systematic reviews, meta-analyses and randomized controlled trials (RCTs) assessing intra-class head-to-head comparisons. Currently, seven products are available for use in the U.S. for the treatment of acute and chronic gout: allopurinol,15 colchicine,16 colchicine/probenecid,17 febuxostat,18 lesinurad,19 pegloticase20 and probenecid.21 Table 1 contains comparative information for the antigout products included in this review. Colchicine is the only antigout agent approved for the treatment of acute gout attacks. Other agents are indicated for the management of chronic gout. Products are administered orally, with the exception of pegloticase that is administered as an intravenous injection. The antigout agents are typically used as monotherapy, except lesinurad that was approved for use in combination with a xanthine oxidase inhibitor (XOI). Dosing recommendations for the antigout agents are outlined in Table 2.

Colchicine is an old drug that has been used to treat gout over centuries.22 Oral colchicine was prescribed in the U.S. as an unapproved drug (i.e. it lacked formal FDA approval) for the treatment of gout from the late 19th century until 2009, at which time the brand-name colchicine (Colcrys) was approved by the FDA. In 1938, new drugs were required to be approved based only upon safety evidence. In 1962, a policy amendment introduced that companies should

7

demonstrate both drug efficacy and safety. Drugs sold in the U.S. between 1938 and 1962 (e.g. colchicine), that were approved based on safety considerations, became Drug Efficacy Study Implementation (DESI) drugs.23 These drugs were retrospectively evaluated to confirm efficacy. In order to assure patient protection and promote public health, the FDA implemented an initiative in 2006 that required companies to submit efficacy and safety data for FDA-unapproved drugs in order to continue on the market. This enforcement was especially critical for those drugs with potential safety risks such as colchicine.23 A small clinical study was presented to the FDA proving the efficacy and safety of colchicine in the treatment of acute gout. Colcrys, with updated prescribing information including dosing recommendations and warnings (e.g. potential fatal interaction between colchicine and clarithromycin or cyclosporin), was approved by the FDA in 2009 and obtained market exclusivity for 3 years.24 The average price per tablet for the unapproved colchicine was nine cents compared to five dollars for Colcrys. A retrospective cohort study was conducted to evaluate the impact of Colcrys authorization in the prescription patterns, cost for patients and co-prescription rates of colchicine and clarithromycin or cyclosporin. Results indicated a decrease in the odds of receiving colchicine within 30 days for acute gout by 0.5% after FDA enforcement compared to 1.4% increase in the odds per month before Colcrys’ market exclusivity. Higher drug expenditures by patient (from $418 to $651 per month) were also reported. Troublesome prescribing patterns with respect to the coadministration of colchicine with clarithromycin or cyclosporine did not improve.24

According to Utah Medicaid fee-for-service (FFS) data, the most commonly prescribed antigout agent during 2016 was allopurinol (oral formulation, 968 claims, 237 unique patients), followed by probenecid (27 claims, 8 unique patients), febuxostat (25 claims, 7 unique patients), colchicine/probenecid (24 claims, 9 unique patients) and generic colchicine (17 claims, 12 unique patients). The overall number of patients on antigout treatment for 2013-2017 period was 851 unique patients.

8

Table 1. FDA Approved Antigout Agents15-21,25-28 Active Substance (Brand Name)

Mechanism of Action Dosage Form and Strengths (Generic availability)

FDA Approved Indication/Unlabeled indications Approval Date

Allopurinol (Zyloprim, Alloprim)

Xanthine oxidase inhibitor

Tablets: 100 mg and 300 mg (Generic available) IV infusion EQ 500 mg base/vial (only for cancer patients) (Generic available)

1. Management of patients with signs and symptoms of primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy)

2. Management of patients with leukemia, lymphoma and malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels. Treatment with allopurinol tablets should be discontinued when the potential for overproduction of uric acid is no longer present

3. Management of patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in male patients and 750 mg/day in female patients. Therapy in such patients should be carefully assessed initially and reassessed periodically to determine in each case that treatment is beneficial and that the benefits outweigh the risks

Unlabeled indications Disorder of hematopoietic structure (hyperuricemia), hyperuricemia thiazide-induced, Lesch-Nylan syndrome-associated hyperuricemia (pediatrics), leishmaniasis, malaria, schizophrenia (adjunct)

08/19/1966 (Zyloprim, tablets) 05/17/1996 (Alloprim, IV infusion)

Colchicine (Colcrys, Mitigare)

Disrupts microtubule polymerization preventing activation, degranulation, and migration of neutrophils

Tablets: 0.6 mg (Colcrys) (Generic available) Capsules: 0.6 mg (Mitigare)

1. Gout flares in adults: • Prophylaxis of gout flares • Treatment of acute gout flares when tablets are taken at the first sign of a flare 2. Familial Mediterranean fever (FMF) in adults and children 4 years or older Colchicine is not an analgesic medication and should not be used to treat pain from other causes Note: Colcrys is approved for prophylaxis and flare treatment. Mitigare is only approved for prophylaxis Unlabeled indications Actinic keratosis, amyloidosis, aphthous ulcer of mouth, behcet's syndrome, acute pericarditis, prophylaxis of recurrent pericarditis, pericarditis with multiple recurrences, fibrosis and/or non-suppurative inflammation in peyronie's disease, prophylaxis of post-pericardiotomy syndrome, and psoriasis

1961 (initial U.S. Approval of colchicine) 07/30/2009 (Colcrys) 09/26/2014 (Mitigare)

Colchicine/ Probenecid (Col-Probenecid)

Colchicine: inhibits β-tubulin polymerization into microtubules Probenecid: uricosuric agent, URAT 1 inhibitor

Tablets: probenecid 500 mg & colchicine 0.5 mg

(Generic available)

For the treatment of chronic gouty arthritis when complicated by frequent, recurrent acute attacks of gout

11/23/1976 (Col-Probenecid)

9

Active Substance (Brand Name)

Mechanism of Action Dosage Form and Strengths (Generic availability)

FDA Approved Indication/Unlabeled indications Approval Date

Febuxostat (Uloric)

Xanthine oxidase inhibitor

Tablets: 40 mg, 80 mg Chronic management of hyperuricemia in patients with gout. Febuxostat is not recommended for the treatment of asymptomatic hyperuricemia Unlabeled indication: prophylaxis of increased uric acid level, in patients receiving chemotherapy and at intermediate to high risk of tumor lysis syndrome;

02/13/2009 (Uloric)

Lesinurad (Zurampic)

Uric Acid Transporter 1 (URAT1) inhibitor

Tablets: 200 mg In combination with a XOI for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a XOI alone Limitations of Use: Lesinurad is not recommended for the treatment of asymptomatic hyperuricemia and should not be used as monotherapy

12/22/2015 (Zurampic)

Probenecid (Probalan)

Uricosuric agent and renal tubular blocking agent

Tablets: 500 mg (Generic available)

1. Treatment of hyperuricemia associated with gout or gouty arthritis 2. As an adjuvant to antibiotic therapy for prolongation and elevation of beta-lactam plasma

levels

Unlabeled indications: Neurosyphilis, including ocular syphilis, pelvic inflammatory disease and calcinosis (pediatric)

07/29/1976 (Probalan)

Pegloticase* (Krystexxa)

PEGylated uric acid specific enzyme

Injection, for IV infusion

Indicated for the treatment of chronic gout in adult patients refractory to conventional therapy Limitations of Use: Pegloticase is not recommended for the treatment of asymptomatic hyperuricemia

09/14/2010

*Data included for informational purposes to provide a better overview of gout management Abbreviation: IV, intravenous

10

Table 2. Dosing Recommendations for Antigout Agents15-21,25,26 Active Substance

Dosing Recommendations/Off-label dosing

Allopurinol • Initial dosage: 100 mg/day; titration: increase by 100 mg/day at weekly intervals until SUA levels ≤6 mg/dL (0.36 mmol/L); maximum daily dose: 800 mg • Mild gout: 200 mg to 300 mg orally daily • Moderately severe tophaceous gout: 400 mg to 600 mg orally daily; doses >300 mg should be administered in divided doses Off-label Dosing: Initial dosage: 100 mg/day, increasing the dose gradually in increments of 100 mg/day every 2 to 5 weeks as needed to achieve desired SUA level of ≤6 mg/dL. Some patients may require therapy targeted at a serum uric acid level <5 mg/dL to control symptoms. Allopurinol may be initiated during an acute gout attack so long as anti-inflammatory therapy has been initiated as well10,29 Pediatric: Allopurinol is rarely indicated for use in children with the exception of those with hyperuricemia secondary to malignancy or to certain rare inborn errors of purine metabolism

Colchicine • Flare treatment: 1.2 mg orally at the first sign of a flare followed by 0.6 mg one hour later; maximum 1.8 mg over 1 hour (Doses larger than the currently recommended dosage for gout flare have not been proven to be more effective)30

• Prophylaxis: 0.6 mg orally QD or BID, maximum 1.2 mg/day11 Pediatric: adolescents >16 years: adult dosing

Colchicine/Probenecid

• One tablet orally QD for 7 days, then 1 tablet orally BID • Maintenance: Continue at dosage that maintains normal SUA levels Pediatrics: contraindicated in children <2 years

Febuxostat • 40 mg orally QD; may be increased to 80 mg orally QD if SUA levels of <6 mg/dL are not achieved after 2 weeks • Gout flare prophylaxis with an NSAID or colchicine is recommended when initiating therapy with febuxostat10,12 Pediatric: Safety and efficacy have not been established in pediatric patients

Lesinurad • 200 mg orally QD in the morning with food and water; maximum 200 mg/day; give at the same time of the day with a XOI including allopurinol (at least 300 mg/day or 200 mg/day if CrCl is <60 mL/min) or febuxostat

• Prophylaxis of gout flare is suggested when initiating therapy Pediatric: Safety and efficacy have not been established in pediatric patients Note: evaluate renal function prior to and during treatment with lesinurad. Do not initiate therapy if estimated CrCl is <45 mL/min

Probenecid • 250 mg orally BID for 1 week; may increase to 500 mg BID; if needed, may increase to a maximum of 2 g/day (increase dosage in 500 mg increments every 4 weeks). If SUA levels are within normal limits and gout attacks have been absent for 6 months, daily dosage may be reduced by 500 mg every 6 months

Pediatrics: contraindicated in children <2 years

Pegloticase* • 8 mg IV every 2 weeks (discontinue oral urate-lowering medications and give an antihistamine and corticosteroid) Off-label dosing: • 8 mg IV infusion every 3 to 4 weeks Pediatric: Safety and efficacy have not been established in pediatric patients

*Data included for informational purposes to provide a better overview of gout management Abbreviation: BID, twice daily; CrCl, creatinine clearance; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; QD, once daily; SUA, serum uric acid; XOI, xanthine oxidase inhibitor

11

Disease Overview

Gout is a painful and debilitating inflammatory arthritis associated with high SUA levels and triggered by the deposition of monosodium urate crystal in joints and other tissues.6 Hyperuricemia is defined as a serum urate concentration greater than 6.8 mg/dL, at which point uric acid is not soluble and may precipitate out as crystals in tissues. Hyperuricemia is the hallmark of gout, however, the majority of people with hyperuricemia do not progress to develop gout.6,12 Several studies have indicated that SUA level reduction is associated with fewer gout flares and tophi disappearance.31,32 The current American and European guidelines recommend that SUA levels should be maintained below 6 mg/dL,9,10 or below 5 mg/dL for patients with severe gout (tophi, chronic arthropathy, frequent attacks).9 Nonetheless, SUA levels may be normal or below the target level of 6 mg/dL at the time of an acute attack,12 which reduces the value of measuring SUA to diagnose gout.2 The gold standard for the diagnosis of gout is the identification of monosodium urate crystals in synovial fluid aspirated from a joint or tissue.5,6

Three stages of gout have been described: 1) acute gouty arthritis, 2) intercritical or the asymptomatic period between flares, and 3) chronic tophaceous gout. Acute gout is characterized by gout flares or episodic severe pain, redness, warmth, swelling and disability at the lower extremities. This generally occurs in one single joint involving the great toe or knee with peak severity typically within 12-24 hours, and commonly at night. Untreated gout flares can last a few days to several weeks producing work limitations. Tophaceous gout is typified by longstanding accumulation of monosodium urate crystals (i.e. tophi) in tissues, which causes chronic inflammation, soft tissue destruction, joint deformities and impaired quality of life.6,33,34 Nephrolithiasis and chronic nephropathy are the two major renal complications of hyperuricemia and gout.6

Authors of a study performed to assess the health-related quality of life (HRQoL) in adult patients with gout, found that those who were overweight and had additional comorbidities demonstrated a lower HRQoL, especially in patients with repeat attacks and a larger number of affected joints.35 In relation to the economic impact of gout, evidence suggested that gout can lead to reduction in productivity, increase in hospitalizations and higher annual healthcare costs.36

The number of people with gout and hyperuricemia has increased in many parts of the world over the last 50 years.1,7 The incidence continues to rise3,5 due to the growing aging population, the greater use of gout-inducing medicines such as diuretics, and comorbidities including hypertension, metabolic syndrome, obesity, diabetes mellitus, renal impairment and cardiovascular disease.5,8 Studies suggest that gouty tophi and elevated SUA levels are linked to a higher risk of cardiovascular mortality.8,37 Moreover, dietary and lifestyle changes play an important role in the development of gout. Purine catabolism results in uric acid metabolites. High dietary consumption of purine containing food and beverages such as meat, seafood and

12

alcohol may increase the risk of developing gout. Soft drinks and fructose are also associated with an increase occurrences of gout.2,3,5,6

Epidemiological evidence reported a worldwide prevalence of gout between 0.1% and 10%, and an incidence between 0.3 and 6 cases per 1,000 person-years, with both the prevalence and incidence higher in developed countries than in developing countries.5 According to the U.S. National Health and Nutrition Examination Survey of 2007-2008 (NHANES),1 3.9% of adults (8.3 million) self-reported gout during this time period, of which 73% were men and 27% were women. Age, gender, race and ethnicity are risk factors associated with hyperuricemia and gout.6 Postmenopausal women and men over 40 years of age are at higher risk of developing gout. Gout is rare in children. Among the U.S. adult population, a study that followed U.S. adult patients from 1987 to 2012 reported an incidence of gout of 0.84 cases per 1,000 person-years. Data also suggested an increasing incidence of gout over time.5

Gout therapy includes agents for the treatment of acute gout (NSAIDs, colchicine, corticosteroids and ACTH)2,11-13 and agents for the management of chronic gout (allopurinol, febuxostat, lesinurad, probenecid, pegloticase or colchicine in combination with probenecid).10,13 Treatment of an acute gout flare with pain relievers and anti-inflammatories should be initiated as soon as possible for faster resolution of symptoms.12 Allopurinol and febuxostat act as XOIs, which block the synthesis of uric acid. Both are recommended for long-term gout management in clinical practice, however, their place in therapy differs according to the currently available guidelines.9,12 Probenecid and the recently approved lesinurad are uric acid transporter inhibitors (URATI) that increase the urinary excretion of uric acid by modifying renal tubular reabsorption.8,19,21 Probenecid is classified by current guidelines as second-line treatment in patients that do not respond or are intolerant to XOIs.9,10,38 Lesinurad is not yet included in treatment guidelines for gout. Pegloticase, a pegylated recombinant form of urate-oxidase enzyme that activates uric acid metabolism, is a treatment option for those patients not responding to conventional first- or second-line therapies.8,20 Pegloticase is an intravenous injection not prescribed in the primary care setting and only general information to provide a complete overview of the disease will be included in this report.

Gout treatment should be individually tailored. Patient´s potential comorbidities, cardiovascular risk factors, contraindications to treatment alternatives for gout9 and adherence barriers should be considered prior to the initiation of gout therapy. Some recent studies have reported non-adherence to ULT in patients suffering from acute gout flares when initiating ULT.11 A systematic review evaluating adherence in gout39 suggested that adherence rates were low (below 80%), especially in younger patients, with only 10 to 46% patients demonstrating adherence to therapy. Hence, patient education and counseling by health care providers are key components in gout therapy. Information about the clinical features associated with gout,

13

effective antigout treatments, initiation of therapy, and the importance of adherence should be provided to patients, together with lifestyle and dietary recommendations.9

Diverse guidelines for the management of acute and chronic gout have been developed by the American College of Physicians (ACP),12 the European League Against Rheumatism (EULAR),9 the 3e (Evidence, Expertise, Exchange) Initiative,31 the American College of Rheumatology (ACR),10,11 and the British Society for Rheumatology (BSR).40 ACP and ACR include similar recommendations. Conversely, some differences in recommendations are noted. For the management of acute gout, all guidelines except BSR recommend the use of colchicine, NSAIDs or corticosteroids as first-line treatment for acute gout attacks, without any specific preferences of one particular agent over another. All guidelines recommend the use of low-dose colchicine; however, the daily oral colchicine dose varies between guidelines, ranging from 1 to 2 mg daily. The most recent guideline (i.e. ACP)12 recommends an initial colchicine dose of 1.2 mg, followed by 0.6 mg 1 hour later. For the management of chronic gout, the following differences are noted:

1. ACP and ACR consider allopurinol and febuxostat as first-line ULT for chronic gout. EULAR, 3e Initiative and BSR give first-line treatment status to allopurinol based on cost-effectiveness analyses of both XOIs. If patients do not respond to, or are intolerant to allopurinol, then febuxostat, a uricosuric agent (e.g. probenecid), or a combination of XOI with a uricosuric agent are promoted as second-line therapies. BSR recommendations do not include febuxostat because it was approved after the development of the guideline.

2. EULAR recommends allopurinol dose-titration according to creatinine clearance estimates in patients with renal failure. ACP and ACR recommend that the initiation dose of allopurinol should be 50 mg/day in chronic kidney disease ≥ stage 4.

3. ACP, ACR, 3e Initiative and BSR address initiation of ULT during gout flares only if colchicine or an NSAID are administered, whereas EULAR indicates that ULT can be started early in an acute gout flare without requiring an anti-inflammatory drug.

4. EULAR does not include a recommendation concerning routine HLA-B*5801 screening test before initiation of allopurinol therapy, due to the low allele frequency in European patients. The risk of severe allergic reactions related to the presence of HLA-B*5801 allele is high in Han Chinese, Thai and Korean patients. ACR includes the consideration of performing HLA-B*5801 screening test prior to initiation of allopurinol, particularly in Asian populations.

Pharmacologic recommendations from guidelines are included in Table 3.

14

Table 3. Guidelines for the Management of Gout Evidence of Comparative Effectiveness (SR/RCTs) Recommendations

1. American College of Physicians (ACP) Qaseem et al 201712: Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians Information based on:

• 1 SR (Shekelle 2017)29

• 1 systematic evidence review sponsored by AHRQ (Shekelle 2016)13

Acute gout: • NSAIDs vs NSAIDs (16 RCTs): No clinically relevant

differences • CS vs ACTH (1 RCT): No differences in gout flares duration

and joints affected • CS vs NSAIDs (6 RCTs): No difference in efficacy outcomes

(time to resolution of symptoms, clinical joint status and pain reduction). More GI, non-GI and serious AEs with NSAIDs than with CS.

• NSAIDs vs COXIBs (4 RCTs): No difference in pain, joint swelling, global improvement and HRQoL. COXIBs presented less total AEs and less withdrawals than NSAIDs.

• NSAIDs vs parenteral ACTH (1 RCT): time to pain relief was shorter with ACTH than with indomethacin. No AEs reported with ACTH. NSAIDs associated with GI AEs and headache.

• No head-to head comparative trials of colchicine compared to NSAIDs, CS or ACTH were identified.

Chronic gout: Febuxostat vs allopurinol (4 SR and 1 RCT: CONFIRMS trial): • SUA level reduction: Statistically significant higher

reduction in SUA levels with febuxostat 80 mg/day versus allopurinol 300 mg/day, but no differences between febuxostat 40 mg/day and allopurinol 300 mg/day

• Gout flares: higher incidence with 120 and 240 mg/day and no differences between 40 and 80 mg/day compared to allopurinol (100-300 md/day)

• Safety was unconvincing. Limited data with febuxostat use • Duration of ULT is uncertain. Evidence suggests that ULT

does not decrease the risk of gout flares after 6 months, but some observational data indicate a reduction after 1 year treatment

• Both allopurinol and febuxostat are efficacious for the long-term reduction of gout flares. The cost of febuxostat is higher than that of allopurinol.

Acute gout: 1. CS (e.g. triamcinolone, prednisolone), NSAIDs (e.g. indomethacin, naproxen, and

ibuprofen) and colchicine are effective for pain reduction and should be used to treat acute gout (HQE). • CS should be used as first-line in patients without contraindications due to

better safety profile and lower cost than the other alternative treatments (i.e. NSAIDs and colchicine).

• NSAIDs are contraindicated in patients with renal disease, heart failure, or cirrhosis.

• Colchicine is contraindicated in patients with renal or hepatic impairment 2. Low-dose colchicine (1.2 mg followed by 0.6 mg 1 hour later) is preferred over

high-dose colchicine to treat acute gout attacks (MQE) since it is linked with less GI AEs.

Chronic gout: 3. Long-term ULT should not be initiated in most patients after a first gout attack

or with infrequent attacks (MQE). 4. Clinicians should discuss benefits, harms, costs, and individual preferences with

patients before initiating ULT, including concomitant prophylaxis, in patients with recurrent gout attacks (MQE). Low doses of colchicine or low dose NSAIDs during more than 8 weeks prevents the risk of gout flares in patients initiating ULT

Note: Lesinurad and pegloticase were excluded from the systematic review since it is improbable that primary care physicians prescribe these agents

15

Evidence of Comparative Effectiveness (SR/RCTs) Recommendations

2. European League Against Rheumatism (EULAR): Richette et al 20179: 2016 updated EULAR evidence-based recommendations for the management of gout

• Systematic literature review from January 2005 to May 2016

New evidence found from EULAR 2006 guideline: 1. No direct comparative evidence of colchicine versus NSAIDs

or CS. EULAR does not prioritize one alternative over another 2. One RCT demonstrated similar efficacy between naproxen

(500 mg BID) and prednisolone (35 mg QD) 3. One RCT showed similar efficacy between prednisolone (30

mg/day) and indomethacin 4. One RCT demonstrated that low-dose colchicine is equally

effective as high-dose colchicine but presents a more favorable safety profile (AGREE study)

5. The use of combination therapy and intraarticular CS is based on expert opinion and need further evidence

6. Allopurinol is considered the first line option in patients with normal kidney function based on its efficacy and safety versus placebo (2 RCTs) and its low cost. SCARs have been reported with allopurinol

7. Febuxostat 80 mg or 120 mg showed superior urate lowering efficacy versus allopurinol 300 mg in three RCTs. SCARs have been reported with febuxostat. Febuxostat can be used in patients with mild to moderate renal failure

8. Uricosurics are recommended alone or in combination with allopurinol in patients not responding to allopurinol. The combination strategy is based on uncontrolled studies and expert opinion. Lesinurad is a promising agent (only data from a phase II study)

9. Pegloticase 8 mg biweekly was more efficacious in the reduction of SUA versus placebo in 2 RCTs. Due to its safety profile, EULAR recommends it use only in patients with severe gout refractory to conventional treatment or a combination of XOI and a uricosuric agent.

Acute gout 1. Acute flares should be treated as soon as possible. Patients should receive

education and counseling to encourage a “pill-in-the-pocket” approach 2. First line treatment options for acute gout: Colchicine, NSAIDs or CS

• Colchicine: alone or in combination with an NSAID or CS - Start within 12 hours of flare onset - Dose/day: 1 mg followed by 0.5 mg after 1 hour - Contraindications: in patients with severe renal impairment (GFR<30

mL/min) and in combination with p-glycoprotein and/or CYP3A4 inhibitors (e.g. cyclosporine and clarithromycin)

• NSAIDs: avoided with severe renal impairment • Oral CS: 30-35 mg/day prednisolone for 3-5 days • Intra-articular CS

3. IL-1 blockers should be considered in patients with contraindications to colchicine, NSAIDs and CS

4. Prophylaxis of flares: • Recommended during the first 6 months of ULT • Colchicine 0.5-1 mg/day. If contraindicated, use NSAIDs

Chronic gout 5. ULT is recommended in patients with recurrent flares, tophi, urate arthropathy

and/or renal stones. It should be initiated close to the first presentation 6. SUA levels should be monitored and maintained < 6 mg/dL. SUA levels <5 mg/dL

are recommended for severe gout 7. ULT should start at a low dose and then titrate until SUA <6 mg/dL 8. Allopurinol is the first-line ULT in patients with normal kidney function. Start

dose: 100 mg and increase by 100 mg increments until SUA levels are reached. If SUA target is not reached, switch to febuxostat or a uricosuric, or combine XOI with a uricosuric

9. If renal impairment, allopurinol should be adjusted to CrCl. If SUA levels are not reached, switch to febuxostat or benzbromarone

10. In patients with advanced gout not responding to the conventional therapy, pegloticase is recommended

11. When gout occurs in a patient receiving loop or thiazide diuretics, substitute diuretic if possible

16


3. 3e (Evidence, Expertise, Exchange) initiative Sivera et al 201431: Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative

• Systematic literature search from 2010 to 2011

• Panel of 78 international rheumatologists from 14 countries

3e initiative classifies evidence into levels according to the Oxford Center for Evidence-based Medicine 1. First-line therapy for acute gout: decision based on 25 trials

(21 for NSAIDs, 5 for CS and one for colchicine) 2. ULT: 40 studies evaluating efficacy, safety and cost-

effectiveness of allopurinol, febuxostat and pegloticase were included

3. Gout attack prophylaxis recommendations supported by 4 studies

Acute gout: 1. First-line therapy: low-dose colchicine (up to 2 mg/day), NSAIDs or CS (oral,

intraarticular or IM) Chronic gout: 2. First-line therapy for chronic gout: allopurinol (based on its efficacy, safety and

cost). Start with low doses and progressively increase until target SUA level of 6 mg/dL is reached

3. Second-line therapy: febuxostat (40-120 mg) or uricosuric agents if patients do not respond to allopurinol

4. Third-line therapy: peglotiase 5. Prophylaxis of gout flares when ULT is initiated: colchicine up to 1.2 mg/day,

followed by NSAIDs or CS 6. Patients with renal impairment: adjust dose of allopurinol. Febuxostat is an

alternative treatment with no need of dose adjustment

4. American College of Rheumatology (ACR): Khanna et al 201210: 2012: American College of Rheumatology Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic

ACR classifies evidence into level A (high-quality evidence), B (moderate quality evidence) and C (low quality evidence). Mainly level A or B of evidence is outlined in the “recommendation” column

Chronic gout: 1. Patient education on diet, lifestyle, treatment objectives, and management of

comorbidities is a recommended core therapeutic measure in gout. 2. XOI therapy with either allopurinol or febuxostat is recommended as the first-

line pharmacologic ULT approach in gout (level A) 3. Target SUA <6 mg/dL (level A). In some patients <5 mg/dL (level B) 4. Allopurinol:

• Starting dose <100 mg/day for any patient (<50 mg/day in patients with stage 4 or worse CKD) (level B). Gradually titrate with allopurinol increments every 2-5 weeks. Doses can exceed 300 mg/day

• Prior to initiation, consider HLA-B*5801 screening, particularly in special Asian populations (level A)

17


and Pharmacologic Therapeutic Approaches to Hyperuricemia

• Systematic literature search from 1950 to 2012

5. Uricosuric therapy: • Probenecid is the first option among uricosuric agents (level B) • Probenecid is indicated alone or in combination with XOI when SUA target

has not been achieved or first line alternatives are contraindicated (level B) • If CrCl <50 ml/min, probenecid is not recommended as first line

6. Pegloticase: • It is recommended in patients with severe gout disease and refractory to

conventional therapy

5. American College of Rheumatology (ACR) Khanna et al 201211: 2012 American College of Rheumatology Guidelines for Management of Gout Part II: Therapy and Anti-inflammatory Prophylaxis of Acute Gouty Arthritis

• Systematic literature search from 1950 to March 2011

ACR classifies evidence into level A (high-quality evidence), B (moderate quality evidence) and C (low quality evidence). Mainly level A or B of evidence is outlined in the “recommendation” column

Acute gout: 1. Initiate pharmacologic therapy within 24 hours of flare onset 2. ULT should be continued during the gout flare 3. First line options for acute flare treatment include NSAIDs, colchicine and CS.

Combinations can be used for severe or refractory attacks • No preference between NSAIDs, although naproxen and indomethacin are

approved by FDA for acute gout (level A) • COX-2: celecoxib is an option when NSAIDs are contraindicated (level B) • Colchicine: 1.2 mg followed by 0.6 mg 1 hour later (level B) • CS: oral CS are recommended when 1 or 2 joints are affected and

intraarticular CS can be used when 1 or 2 large joints are involved (level B) • Oral prednisone 0.5 mg/kg/day for 5-10 days , then stop (level A) • ACTH: 25-40 IU SC for patients unable to swallow (level A) • Topical ice may be an adjunctive therapy (level B)

4. Prophylaxis of acute flares: administer anti-inflammatories such as low-dose oral colchicine (level A) or a low-dose NSAID (level C) when ULT is started. Contraindications and tolerance should be considered prior to treatment

6. British Society for Rheumatology (BSR): Jordan et al 200740: British Society for Rheumatology and British Health Professionals in Rheumatology

BSR classifies evidence into level A (high-quality evidence), B (moderate quality evidence) and C (low quality evidence). Mainly level A or B of evidence is outlined in the “recommendation” column

Acute gout: 1. Start anti-inflammatory therapy immediately and during 1-2 wks (level A) 2. NSAIDs at maximum doses are the first-line therapy for acute gout (level A),

followed by colchicine (level A) (0.5 mg 2-4 times/day) 3. Oral and intraarticular CS are treatment options if NSAIDs are contraindicated

(level B) Chronic gout: 1. Allopurinol 50 mg-100 mg/day, with increments of 50-100 mg every few wks

until SUA levels <300 µmol/L are achieved (level B)

18


Guideline for the Management

• This guideline is currently being revised

2. Uricosurc agents are second-line agents in patients not responding to allopurinol (level B)

3. Colchicine 0.5 mg BID for a 6 month period should be administered when allopurinol or uricosuric agents are initiated (level A)

7. National Institute for Health and Care Excellence (NICE). Appraisal consultation document in development (July 2016). Lesinurad for treating chronic hyperuricaemia in people with gout41

• Status: In development, not NICE’s final guideline. Expected publication date: July 2017

Committee preliminary decisions based on clinical data provided form the Company: • 2 RCTs comparing lesinurad plus allopurinol versus

allopurinol plus placebo • Limitations of these two RCTs: outcomes that impact the

patient’s quality of life including the reduction of gout flares and the regression of tophi are not sufficiently supported

Preliminary recommendations: • Lesinurad in combination with a XOI is not recommended within its marketing

authorization (i.e. to treat hyperuricaemia in adults with gout whose serum uric acid is above the target level despite an adequate dose of a XOI alone).

• Lesinurad would be a treatment choice only if patients do not achieve the SUA target levels with:

o the maximum tolerated dose of allopurinol (900 mg/day) or o the maximum tolerated dose of febuxostat (120 mg) when allopurinol

is not tolerable or contraindicated

Abbreviation: ACTH, adrenocorticotropic hormone; AE, adverse event; BID, twice daily; CKD, chronic kidney disease; CONFIRMS, Confirmation of Febuxostat in Reducing and Maintaining Serum Urate; CrCl, creatinine clearance; CS, corticosteroids; COXIBs, selective COX-2 inhibitors; GFR, glomerular filtration rate; GI, gastrointestinal; non-GI, non-gastrointestinal; HQE, high-quality evidence; IL, interleukin; MQE, moderate quality evidence; NA, not available; NSAIDs, non-steroidal anti-inflammatory drug; QD, once daily; RCT, randomized controlled trial; SR, systematic review; ULT, urate-lowering therapy; XOI, xanthine oxidase inhibitor

19

Pharmacology

Allopurinol and febuxostat are xanthine oxidase inhibitors, which block the synthesis of uric acid.15,18 Probenecid and the recently approved lesinurad are uric acid transporter inhibitors that increase the urinary excretion of uric acid by modifying renal tubular reabsorption.8,19-21 Pegloticase is a pegylated recombinant form of urate-oxidase enzyme that activates uric acid metabolism. Colchicine, a natural alkaloid, is an ancient drug used for centuries for treatment of acute gout.22 The mechanism of action of colchicine is poorly defined.22 It is believed that colchicine acts via disruption of microtubule polymerization causing a change in the neutrophil response and triggering the anti-inflammatory effect.22

Pharmacokinetic properties vary among the seven FDA approved antigout agents. Generally, antigout agents undergo extensive hepatic metabolism and are primarily eliminated by the kidneys with a wide range of elimination half-lives, from 1 hour for allopurinol to 31.2 hours with colchicine. Additionally, fecal elimination occurs with allopurinol, febuxostat and lesinurad. Table 4 summarizes the pharmacokinetic properties of the antigout agents.

Antigout agents are involved in multiple drug interactions, especially allopurinol, febuxostat, colchicine and probenecid. Allopurinol and febuxostat are XOIs that modify the metabolism of xanthine oxidase substrates such as theophylline, mercaptopurine or azathioprine. Doses of these concomitant agents should be reduced when administered with XOIs since an increase of plasma drug levels and toxicity is common.18,42 Febuxostat should not be administered with azathioprine or mercaptopurine due to the high risk of myelosuppression.13,43 Colchicine is metabolized by liver enzymes including CYP3A4 and P-glycoprotein.22,30 Interactions with CYP3A4 inhibitors (e.g. clarithromycin, erythromycin, ketoconazole, ritonavir, verapamil, and diltiazem) and P-glycoprotein inhibitors (e.g. cyclosporine) may lead to elevated colchicine concentrations that may be life-threatening. The administration of low-dose colchicine may reduce potential drug interactions.30 Probenecid may interact with azathioprine, rifampin, salicylated, penicillins, indomethacin and heparin.42 Lesinurad is metabolized via CYP2C9 and caution should be taken when lesinurad is administered with CYP2C9 inhibitors. Moreover, it is a mild to moderate CYP3A inducer and may affect the activity of other medications.44

20

Table 4. Pharmacokinetics of Antigout Agents15-21,25,26 Active Substance Onset of action Absorption Distribution Metabolism

Active Metabolite(s) Excretion Elimination Half-life,

Adults Allopurinol ↓SUA: 2 to 3 days

Peak effect: ≥1 wk Normal SUA levels:

1-3 wks

BA (oral): 80 to 90% Tmax: 1.5 hr

(allopurinol), 3.5 hr (oxypurinol)

Vd: 1.6 L/kg Liver: 70% Rapidly oxidized to oxypurinol (active

metabolite)

Renal: 80% (76% as oxypurinol, 12% as unchanged drug)

Fecal: 20%

1 to 2 hr (allopurinol) 15 hr (oxypurinol)

Colchicine Oral: Pain relief: 18 to 24 hr

BA (oral): 45% Tmax (oral): 0.5 to 3 hr: • Young: 1.3 hr • Elderly: 1.25 hr • Hepatic impairment:

2.16 hr

PB: 39% Vd: 5 to

8L/kg

Hepatic: via CYP3A4 and glucuronidation Metabolites: 2-O-demethylcolchicine, 3-O-

demethylcolchicine

Renal: 40 to 65% (unchanged)

Fecal: extensive Bile: some

26.6 to 31.2 hr: • Young: 24.92 hr • Elderly: 30.06 hr

(women: 34 hr, men: 30 hr)

• Renal impairment: 18.8 hr

Colchicine/Probenecid See individual agents Febuxostat N/A BA (oral): ≥49%

Tmax: 1 to 2.1 hr Take without food (Effect

of food: Cmax ↓ 49%, AUC ↓ 19%)

PB: 99% Vd: 47.1 to

50 L

Hepatic: conjugation via UGT and oxidation via CYP450 and other enzymes

Active metabolites: hydroxy febuxostat metabolites

Renal: 49% as metabolites (3% as unchanged drug)

Fecal: 45% as metabolites (12% as

unchanged drug)

5 to 8 hr

Lesinurad N/A BA (oral): 100% Tmax: 1 to 4 hr

Effect of food: Cmax ↓ up to 18%, AUC

unchanged with high-fat meal

PB: >98% Vd: 20 L

Hepatic: Extensive via CYP2C9 Renal: 63% (30% as unchanged drug)

Fecal: 32%

5 hr

Probenecid N/A BA: >90%

Tmax:

• Adults: 1 to 5 hr • Children: 3 to 9 hr

PB: 80 to 99%

Vd: 11 L

Liver: extensive. Oxidation of alkyl side chain (70%) and glucuronide conjugation (20%)

Metabolites: Hydroxylated metabolites, N-despropyl metabolite and Probenecid

acylglucuronide

Renal: 75 to 88% Unchanged drug in

urine: 5 to 11%

3 to 17 hr

Pegloticase* 24 hr after first dose

Tmax (IV): 18.25 hr Renal: as allantoin 14 days

*Data included for informational purposes to provide a better overview of gout management Abbreviation: BA, bioavailability; CYP, cytochrome; hr, hour; IV, intravenous; N/A, not available; PB, protein binding; SUA, serum uric acid; Tmax, time to maximum serum concentration; UGT, uridine diphosphate glucuronosyltransferase; Vd, volume of distribution; Wk, week

21

Special Populations

Table 5 describes the recommendations for antigout agent use in special populations.

In patients with severe renal impairment (creatinine clearance less than 30 mL/min), dosage adjustments are required for allopurinol and colchicine.15,16,45 Probenecid is contraindicated in patients with creatinine clearance less than 30 mL/min21,45 and lesinurad should not be initiated or discontinue if creatinine clearance is less than 45 mL/min.19 Colchicine is contraindicated in patients with both renal and hepatic impairment.16 Febuxostat does not require dosage adjustments18 and may be a preferred treatment option for chronic gout in patients with renal impairment. Two systematic reviews (van Echteld et al 201446 and Fravel et al 201147) and two RCTs (APEX48 and CONFIRMS49) found that febuxostat had better efficacy, in terms of SUA reduction below 6 mg/dL, compared to allopurinol in patients with mild to moderate renal impairment. A small RCT performed by Tanaka et al50 (2015) in patients with advanced chronic kidney disease demonstrated that febuxostat produced a significantly higher reduction in SUA levels than allopurinol (SUA reduction: -2.2 mg/dL in febuxostat group vs -0.3 mg/dL in allopurinol group; P<0.001).

In patients with severe hepatic impairment, antigout agents generally do not require dose adjustment, with the exception of colchicine.16 Lesinurad is not recommended in these type of patients and caution should be exercised with febuxostat.16

Antigout agents may be used with caution during pregnancy and breast-feeding only if the benefits outweigh the risks.20

The incidence of gout is very rare in pediatric patients. Colchicine may be used in children older than 16 years old and probenecid in those older than 2 years old.16,21 Safety and efficacy have not been established in pediatric patients for febuxostat, lesinurad and pegloticase.18-20 In elderly patients, colchicine doses may be reduced. Due to the narrow therapeutic index of colchicine and the common presence of comorbidities and polypharmacy in older patients, higher toxicity with colchicine therapy is common.16,22 Dosage adjustments may be necessary, especially in patients with renal insufficiency, hepatic impairment and concomitant use with P-glycoprotein or CYP3A4 inhibitors.47 Concerning XOIs, a secondary analysis of the CONFIRMS study was conducted by Becker et al (2011)51 to evaluate the efficacy and safety of allopurinol versus febuxostat in patients >65 years old compared to <65 years old. No significant differences in efficacy (SUA reduction) or safety were reported between treatment groups or by age group. In patients with mild renal impairment, the efficacy results were better in older patients than in younger patients.

A small retrospective study52 in female patients diagnosed with gout reported better efficacy (SUA reduction below 6 mg/dL) in the febuxostat group (all doses) compared to allopurinol group.

22

Table 5. Recommendations for Special Populations of Antigout Agents15-21,25,26 Renal Impairment Hepatic Impairment Pregnancy and lactation Pediatric Geriatric

Allopurinol Dosage adjustment required: • CrCl 10 to 20 mL/min: 200 mg

orally daily • CrCl 3 to 10 mL/min: <100 mg

orally daily • CrCl <3 mL/min: 100 mg orally at

extended intervals

No dosage adjustment required Pregnancy Category: C Crosses placenta Excreted into breast milk (allopurinol and metabolite). Use with caution to breast-feeding women

Rarely indicated for gout in children. Dosage adjustment for cancer therapy-induced hyperuricemia

Adult dosing

Colchicine Always monitor for AEs. Contraindicated in patients with both renal and hepatic impairment. For severe renal impairment (CrCl <30 mL/min): • Gout prophylaxis: 0.3 mg/day

orally initially; increase dose with adequate monitoring.

• Gout flares: Do not repeat treatment course more than once every 2 weeks

Always monitor for AEs. Contraindicated in patients with both renal and hepatic impairment. Contraindicated use of colchicine and P-glycoprotein or strong CYP3A4 inhibitors in hepatic impairment. Treatment of gout flare with colchicine is not recommended in patients with hepatic impairment receiving prophylactic colchicine For severe hepatic impairment: • Gout prophylaxis: consider

dose reduction • Gout flares: Do not repeat

treatment course more than once every 2 weeks

Pregnancy Category: C Crosses placenta Excreted into breast milk. Use with caution to breast-feeding women

Adolescents >16 years: adult dosing

More toxic in older adults, particularly in the presence of renal, gastrointestinal, or cardiac disease. Dosage adjustments based on renal function. Reduce dose by 50% in patients >70 years

Colchicine/Probenecid See individual components Febuxostat No dosage adjustment required for

mild to moderate renal impairment Use with caution in patients with severe impairment

No dosage adjustment required for mild to moderate hepatic impairment. Use with caution in patients with severe impairment

Pregnancy Category: C Unknown if febuxostat is excreted into breast milk. Use with caution to breast-feeding women

Safety and efficacy have not been established in pediatric patients

No dosage adjustment required

Lesinurad Do not initiate or discontinue therapy if estimated CrCl is <45 mL/min. Evaluate renal function prior to and during treatment with lesinurad.

Not recommended for patients with severe hepatic impairment

Pregnancy: Adverse events were not observed in animal reproduction studies. Fetal risk cannot be ruled out since available data is inconclusive Unknown if lesinurad is excreted into breast milk. Use with caution to breast-feeding women



23

Renal Impairment Hepatic Impairment Pregnancy and lactation Pediatric Geriatric Probenecid Do not use with CrCl <30 mL/minute No dosage adjustment required Pregnancy Category: B

Crosses placenta Breast-feeding: Fetal risk cannot be ruled out since available data is inconclusive

Contraindicated in children <2 years

Adult dosing

Pegloticase* No studies available No dosage adjustment required Pregnancy Category: C Unknown if pegloticase is excreted into breast milk. Breast-feeding is not recommend unless the potential benefit to the mother is greater than the possible risk to the infant



*Data included for informational purposes to provide a better overview of gout management Abbreviation: AE, adverse effect; CrCl, creatinine clearance

24

Methods

Literature Search

Search strategies were developed by an Informational Scientist for OVID Medline and EMBASE. Strategies consisted of controlled vocabulary, such as MeSH, and keyword phrases. Two methodological filters were used, one for systematic reviews, another for randomized controlled trials. Results were limited to English language. Databases were searched from date of inception forward. Searches were conducted in April 2017. The complete search strategies and terms are available in Appendix A.

We screened the reference lists of related systematic reviews. Moreover, we also searched:

1. American College of Physicians (ACP), American College of Rheumatism (ACR), European League against Rheumatism (EULAR) and Agency for Healthcare Research and Quality (AHRQ) web-sites for the most recent treatment guidelines for acute and chronic gout

2. Food and Drug Administration (Drugs@FDA: FDA Approved Drug Products: https://www.accessdata.fda.gov/scripts/cder/daf/ for prescribing information package inserts

3. Evidence based drug information databases (Micromedex, Lexicomp, and UpToDate)

Screening

At least two review authors screened titles and abstracts. The full text for all citations receiving two inclusion votes was retrieved; screening and inclusion were determined by the lead author. Conflicts were resolved via discussion between reviewers or a third person. The PRISMA flow chart53 for the review process is shown in Figure 1.

Inclusion and Exclusion Criteria

Systematic reviews and randomized controlled trials providing head-to-head efficacy comparisons between antigout agents within the drug class review were included. Cochrane systematic reviews were preferred to non-Cochrane reviews due to their high methodological quality and stringent editorial processes. Non-Cochrane reviews were limited to publication between 2013 and 2017. Cochrane and other systematic reviews included comprehensive search strategies for the agents included in this review, with the exception of lesinurad, which is a new agent and a specific search was therefore conducted for recently published studies including lesinurad. For drug comparisons where a systematic review (or reviews) provided robust data, we examined only those trials or systematic reviews published after the search date of the robust systematic reviews.

Systematic reviews and RCTs were included in the analysis if they met the following eligibility criteria according to PICOS (Population, Intervention, Comparison, Outcome and Setting):

25

• They had to include adult patients diagnosed with acute or chronic gout • They had to evaluate intra-class, head-to-head efficacy drug comparisons among the

antigout drug class review • The primary endpoints related to clinical efficacy were reduction in pain or joint

inflammation at ≥ 24 hours for acute gout, and incidence of gout flares or proportion of subjects with SUA levels <6 mg/dL for chronic gout

• Trials occurred in the primary care setting (Pegloticase is an intravenous injection not prescribed in primary care setting. Only general information was considered for this review)

Studies were excluded if they met the following exclusion criteria:

• Studies evaluating non-FDA-approved doses • Studies assessing the prevention of gout flares • Studies measuring safety as primary outcome • Other types of studies (e.g. non-comparative or non-randomized trials, placebo-controlled

studies, phase 2 studies, observational studies, in vitro studies, animal studies, cost-effectiveness studies, etc.)

Figure 1. PRISMA Flow Diagram of the selection process

Records identified through database searching

(n = 1100)

Scre

enin

g In

clud

ed

Elig

ibili

ty

Iden

tifi

cati

on

Additional records identified through other sources

(n = 2)

Records screened (n = 1102)

Records excluded (n = 1010)

Full-text articles assessed for eligibility

(n = 92)

Full-text articles excluded for one or more of the following reasons: (n = 65)

• Duplicates (5) • Full text not available (2) • Guidelines not relevant for this report (2) • RCTs already included in systematic reviews and guidelines (9) • References published in 2012 and earlier, except relevant guidelines

and Cochrane reviews (35) • Wrong outcome (5) • Wrong study design (4) • Methodological limitations (3)

Studies included in qualitative synthesis for this report

(n = 27)

Systematic Reviews (n=12)

Guidelines (n=6)

RCTs (n=1) Additional references (n=3; 1 related to safety, 2 related to

special populations)

Meta-Analyses (n=5)

26

Clinical Efficacy and Safety

Clinical evidence involving head-to-head comparisons among antigout agents is presented for the products currently available in the United States. Figure 1 shows the study selection process. From a total of 92 records identified using the developed search strategy, we included 27 references in this report, of which 12 were systematic reviews (including 7 Cochrane systematic reviews), 6 treatment guidelines based on systematic reviews, 5 meta-analyses (including 1 network meta-analysis) and 1 randomized controlled trial (RCT). Three additional studies pertaining to safety and special populations were reviewed but not included under the tables of evidence. Appendixes B to E outline the main efficacy and safety findings from the systematic reviews, meta-analyses and RCTs considered for this evaluation. Evidence for pegloticase, NSAIDs and corticosteroids for the treatment of gout was not systematically searched since these agents are outside the scope of this report; however, some information from Cochrane systematic reviews and relevant guidelines was extracted for informational purposes. Appendix F describes the intra-class head-to-head RCTs included in the 8 systematic reviews (3 Cochrane reviews, 3 systematic reviews that informed guidelines and 2 additional systematic reviews) and 5 meta-analysis regarding chronic gout. A list containing the excluded references is provided in Appendix G.

The comparative effectiveness discussion and conclusions included in this report are predominantly based on high-quality evidence from Cochrane systematic reviews and systematic reviews performed by the American College of Physicians (ACP), the American College of Rheumatology (ACR), the European League against Rheumatism (EULAR) and the Agency for Healthcare Research and Quality (AHRQ).

Overall, studies performed in patients with acute and/or chronic gout evaluated benefits by the Outcome Measures in Rheumatology Meeting (OMERACT) domains.54 The most common primary endpoint measured throughout the studies of acute gout was pain, defined as the proportion of patients achieving a 50% or greater reduction in pain. Joint inflammation was measured in some trials.55 For those studies evaluating therapies for chronic gout management, the primary endpoints were the incidence of gout flares and the proportion of subjects with SUA levels below 6 mg/dL.4,56 Secondary endpoints included number of tophi and safety outcomes.

A large quantity of head-to-head clinical evidence comparing allopurinol versus febuxostat in patients with chronic gout was identified. However, absent or limited head-to-head comparative evidence was found for probenecid, colchicine, colchicine plus probenecid or the most recently approved lesinurad. Pegloticase is an intravenous injection not prescribed in primary care setting and data from a single Cochrane systematic review is included to provide a better overview of gout management. Evidence from two Cochrane systematic reviews including NSAIDs and corticosteroids indicated for acute gout were briefly described since these agents do not belong to this drug class review.

27

EVIDENCE SUPPORTING TREATMENT OF ACUTE GOUT

No head-to head comparisons of colchicine versus other antigout agents were identified. For informational purposes, an overview of evidence supporting the use of colchicine or other anti-inflammatories indicated for acute gout (i.e. NSAIDs and corticosteroids) will be provided in lieu of lacking intra-class head-to-head comparison data.

Colchicine

Colchicine reduces pain and is the only medication indicated for the treatment of acute gout within this drug class review, with NSAIDs and corticosteroids as direct competitors in clinical practice. Other antigout agents such as XOIs, uricosuric agents and uricase, reduce SUA levels and are indicated for the management of chronic gout. Therefore, head-to-head comparisons between colchicine and any other antigout product included in this drug class review were not identified.

One Cochrane systematic review (van Echteld et al57) including 2 RCTs30,58 with low risk of bias evaluated the efficacy and safety of colchicine for acute gout. The two studies provided low quality evidence and assessed colchicine (low and high doses) versus placebo or high-dose versus low-dose colchicine. One study58 including 43 patients, demonstrated superior efficacy in pain reduction with high-dose colchicine versus placebo, while the incidence of adverse events was shown to be greater in the high-dose colchicine compared to placebo. Results from the second trial (i.e. AGREE study)30 including 126 patients demonstrated similar proportion of patients with ≥50% decrease in pain score for those receiving low-dose colchicine compared to those on high-dose colchicine. However, a statistically significant greater incidence of adverse events including diarrhea, vomiting and nausea was reported in the high-dose colchicine group compared to low-dose colchicine group (77% versus 26%; RR 3.00; 95% CI: 1.98 to 4.54). The authors considered colchicine effective for the treatment of acute gout attacks, with low-dose colchicine the preferred treatment option due to the more favorable gastrointestinal safety profile and the lower incidence of drug interactions compared to high-dose colchicine. Since the publication of the study comparing colchicine versus placebo58 in 1987, no further evidence was identified for colchicine therapy. The AGREE study published in 2010 was the first trial analyzing the use of low-dose colchicine in the treatment of acute gout attacks, which led to include the low-dose colchicine instead of high-dose colchicine as recommended therapy in treatment guidelines for acute gout flares. Given that no head-to-head comparisons of colchicine over NSAIDs or glucocorticoids are available, the place in therapy of colchicine should be determined according to patient characteristics, comorbidities and drug safety profiles.

Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids

High-quality evidence from Cochrane systematic reviews and treatment guidelines reported that NSAIDs, corticosteroids and colchicine are effective for the treatment of acute gout. Two

28

Cochrane systematic reviews were identified, one for non-steroidal anti-inflammatory drugs,55 and one for systemic corticosteroids for acute gout.59 Overall, results from van Durme et al55 demonstrated that all NSAIDs are equally effective for the treatment of acute gout. Selective cyclooxigenase-2 inhibitors (COXIBs) demonstrated similar efficacy in pain reduction but better safety profile compared to NSAIDs. Similarly, Janssen et al59 reported that corticosteroids (oral or intramuscular) seemed to have similar efficacy but a better safety profile than NSAIDs. Statistical analysis for the pooled results was not possible. Gastrointestinal and non-gastrointestinal adverse events were more frequently reported with NSAIDs than with corticosteroids. The authors concluded that further evidence is required concerning the efficacy of corticosteroids and the comparative efficacy of systemic corticosteroid and NSAIDs for the management of acute gout.

Current guidelines consider NSAIDs, colchicine and corticosteroids equally effective in the reduction of pain caused by acute gout flares. Each of the therapies are recommended as first-line options, and treatment choices should be based on patient characteristics, comorbidities, drug safety profiles and contraindications.

EVIDENCE SUPPORTING MANAGEMENT OF CHRONIC GOUT

Head-to-head comparisons:

Allopurinol compared to febuxostat

Two Cochrane systematic reviews conducted by Seth et al4 and Tayar et al56 were identified (see Appendix B). Moreover, key evidence from three systematic reviews (Shekelle et al 2017, Shekelle et al 201613,29, and Richette et al9) and additional evidence from 2 systematic reviews60,61 and 5 meta-analyses62-66 were found (see Appendixes C and D). The main RCTs included in the systematic reviews assessing allopurinol versus febuxostat were APEX67 (8-week results), CONFIRMS49 (26-week results), FACT48 (52-week data) and EXCEL32 (long-term results) (See Appendix F).

Seth et al4 (2014) performed a Cochrane systematic review evaluating the efficacy and safety of allopurinol versus placebo and allopurinol versus other ULTs for chronic gout management. The evaluation of allopurinol 100 mg to 300 mg versus febuxostat was considered the main comparison for this report. Different doses of febuxostat (40 mg to 240 mg daily) were investigated; however, only data from FDA approved doses (40 and 80 mg) were extracted in this report. Comparing allopurinol with febuxostat, four RCTs (FACT trial by Becker et al 2005, APEX trial by Schumacher et al 2008, CONFIRMS study by Becker et al 2010 and a non-randomized trial by Singal 2011) contributed to the systematic review. No significant differences in acute gout attack rates were reported between allopurinol and febuxostat 80 mg over 8 to 24 weeks. The relative risk (RR) was 0.89 (95% confidence interval (CI), 0.71 to 1.1), although a slight increase in gout flare rates was observed in the febuxostat group compared to allopurinol

29

group. The percentage of patients achieving target SUA levels was similar between allopurinol and febuxostat 40 mg, while a significantly higher percentage of patients achieved the endpoint with febuxostat 80 mg when compared to allopurinol 300 mg (RR 0.55, 95% CI 0.48 to 0.65). FACT study reported no differences between groups in the number of tophi and the percentage reduction in tophus area at week 52. The number of withdrawals due to adverse events and the incidence of serious adverse events were similar between allopurinol and febuxostat 40 mg or 80 mg at 24 and 52 weeks. Overall, the total number of adverse events was higher in the allopurinol group compared to febuxostat 80 mg group.

Tayar et al56 (2012) performed a systematic review to analyze febuxostat versus placebo and febuxostat versus allopurinol. A total of 2619 patients were treated with febuxostat and 1187 patients with allopurinol. When febuxostat was compared to placebo, no significant differences on gout flare incidence were reported. However, statistically significant reduction in SUA levels were confirmed in the febuxostat group compared to placebo. For the comparison of febuxostat versus allopurinol, three RCTs (APEX, CONFIRMS and FACT) contributed to this systematic review. Results reported no differences between groups with respect to the incidence of gout flares when febuxostat 40 mg, 80 mg or 120 mg (dose approved in Europe) were compared to allopurinol. For febuxostat 240 mg, the incidence of gout flares was 2.3 times higher compared to allopurinol at week 28. A statistically significantly greater reduction in SUA levels below 6 mg/dL was reported with febuxostat 80 mg or 120 mg in comparison to allopurinol (RR 1.8, 95% CI 1.6 to 2.1 and RR 2.16, 95% CI 1.91 to 2.45, respectively). With febuxostat 40 mg, no urate lowering differences were observed compared to allopurinol. One study demonstrated no differences between groups in the percentage of patients with a reduction in tophus area. Nevertheless, a higher median percentage reduction in tophus area at week 52 was reported with febuxostat 80 mg (83%) or 120 mg (66%) compared to allopurinol (50%). A lower incidence of total adverse events but greater number of total discontinuations were reported with febuxostat 80 and 120 mg compared to allopurinol. Concerning serious adverse events and discontinuations due to adverse events, similar safety results were reported between febuxostat 40, 80 or 120 mg daily group and allopurinol.

Findings from three recent systematic reviews conducted by ACP29, AHRQ13 and EULAR9 (see Appendix C) were consistent with those found by the two Cochrane systematic reviews identified. ACP and EULAR recommend the use of allopurinol and febuxostat prior to uricosuric agents and pegloticase for chronic gout. However, ACP recommends both allopurinol and febuxostat as first-line treatments for chronic gout management, whereas EULAR considers allopurinol as first line therapy and febuxostat as second line treatment option when SUA target levels cannot be reached with allopurinol or in patients intolerant to allopurinol.

Additional evidence from 2 systematic reviews and 5 meta-analyses is described below. The main RCTs included in the Cochrane systematic reviews described above were also included

30

in the additional systematic reviews and meta-analyses. The rest of the RCTs included in the reviews varied between systematic reviews, with differences in study methodologies and level of bias. This may lead to differences in results (see Appendix F for further reference about the RCTs included in each systematic review and meta-analysis for chronic gout).

Systematic reviews from Underwood 201560 and Kydd et al61 (2014) agreed that febuxostat and allopurinol are effective for the management of chronic gout.

Borghi et al62 (2016) performed a meta-analysis to evaluate the efficacy and safety of febuxostat versus allopurinol. Eight studies including both allopurinol and febuxostat were pooled in the meta-analysis. The majority of these studies evaluated febuxostat at doses ≤120 mg/day and allopurinol at doses ≤300 mg/day. Results demonstrated a superior efficacy in terms of proportion of patients achieving SUA below 6 mg/dL of febuxostat versus allopurinol in all patients with gout, with an odds ratio (OR) of 2.64 (95% CI, 1.35 to 1.97). Similar results were observed in patients with renal impairment. The rate of adverse events was significantly lower with febuxostat use compared to allopurinol use. The OR was 0.85 (95% CI, 0.75 to 0.97).

Li et al 201663 (2016) conducted a network meta-analysis including fifteen RCTs to evaluate the comparative effectiveness and safety of ULTs (i.e. allopurinol, benzbromarone, febuxostat, pegloticase and probenecid). Eight RCTs assessed febuxostat versus allopurinol. Results revealed a superior efficacy and safety of febuxostat (40, 80 and 120 mg) compared to other ULTs in terms of SUA reduction to target levels and incidence of adverse events. Of note, the efficacy seemed to increase with higher doses of febuxostat. The greatest efficacy and safety results were reported with the 120 mg dose (OR for SUA reduction=5.95, 95% CI: 4.15–8.52; OR for safety=0.72, 95% CI: 0.56-0.91) in comparison to allopurinol. In addition, the study showed that the incidence of adverse events was higher with probenecid than with alloprurinol or febuxostat. The authors cite the need for further clinical exploration of pegloticase.

Villazor-Isidro et al64 (2014) developed a meta-analysis involving three RCTs. Clinical outcomes demonstrated that reductions in SUA below target levels were higher with febuxostat than allopurinol treatment. These results were also observed in the subgroup of patients with renal impairment. The incidence of adverse events was higher in the allopurinol group, although there was a tendency for greater risk of abnormal liver enzymes with febuxostat.

Faruque et al66 (2013) conducted a meta-analysis involving 5 studies. A slightly lower risk of gout flares and gouty arthritis was reported with allopurinol. However, urate lowering effect and incidence of adverse events was more favorable for febuxostat than allopurinol.

Ye et al65 (2013) performed a meta-analysis including 10 trials. Results indicated that febuxostat (40–120 mg/d) was more efficacious with respect to SUA lowering than allopurinol (100–300 mg daily). The clinical efficacy increased with higher doses of febuxostat. Safety profile was similar between groups.

31

In summary, a large volume of evidence showed that febuxostat and allopurinol decrease SUA concentration to target levels and reduce the incidence of gout flares over time (≥1 year of treatment).13,29,32,48,49,67 The most relevant evidence reported similar incidence of gout flares between febuxostat 40 or 80 mg/day and allopurinol (100-300 mg/day). A trend towards higher incidence of acute gout flares was observed in the febuxostat 80 mg/day group compared to allopurinol. In relation to SUA reduction to target levels (less than 6 mg/dL), allopurinol and febuxostat were effective in lowering SUA levels, with febuxostat 80 mg being significantly more efficacious than allopurinol. Safety profiles in terms of serious adverse events and discontinuations due to adverse events were similar between allopurinol and febuxostat. Key evidence from three systematic reviews conducted by ACP, AHRQ and EULAR were consistent with the findings described by the two Cochrane systematic reviews identified. ACP and EULAR recommend the use of allopurinol and febuxostat prior to uricosuric agents and pegloticase. ACP recommends either allopurinol or febuxostat as first-line treatments for chronic gout management, whereas EULAR considers allopurinol as first-line therapy and febuxostat as second-line treatment choice when SUA target levels are not achieved with allopurinol or in patients intolerant to allopurinol. Results from most of the meta-analyses identified indicated that urate lowering effect and incidence of adverse events were more favorable for febuxostat than allopurinol.

Probenecid compared to allopurinol

Seth et al4 (2014) and Kydd et al38 (2014) evaluated the efficacy and safety of allopurinol versus probenecid for chronic gout management. Only one single quasi-randomized controlled trial68 with high risk of bias including 37 patients compared allopurinol 300 to 600 mg daily versus probenecid 1 to 2 g daily. Results indicated no differences between groups with respect to the number of gout attacks (11/20 and 9/17 in allopurinol and probenecid groups, respectively). SUA levels decreased in both treatment groups from 9.3 at baseline to 4.7 mg/dL and from 8.5 to 5.2 mg/dL in the allopurinol and probenecid groups, respectively. Tophi deposits disappeared in 2 of 3 patients in the allopurinol arm versus 1 of 2 patients in the probenecid arm. The incidence of adverse events was similar between groups and no serious adverse events were reported. Kydd et al38 deemed that probenecid acts as a uric acid lowering agent, however, the small study size and the low-quality evidence extracted from this study raised uncertainties about the reported results. Further literature evidence comparing uricosuric agents to urate lowering drugs such as XOIs (allopurinol or febuxostat) is lacking. The insufficient data available for uricosuric agents together with the large high-quality clinical evidence related to XOIs tended authors to consider uricosuric products as second line therapy for the management of chronic gout.

32

Other comparisons:

Allopurinol plus colchicine versus colchicine

Seth et al4 (2014) evaluated the efficacy and safety of allopurinol plus colchicine versus colchicine for chronic gout management. One trial69 with high risk of bias, including 59 patients compared a combination of allopurinol 200 mg daily plus colchicine 0.5 mg twice daily versus colchicine 0.5 mg twice daily. Results demonstrated similar efficacy between groups in terms of gout attack incidence over 1 year of treatment (RR 0.63, 95% CI 0.25 to 1.63). A significantly lower SUA level was observed in the allopurinol plus colchicine group compared to colchicine alone. The authors reported that the available evidence was supported by a small single trial with high risk of bias, restricting conclusions.

Lesinurad

Saag et al70 (2017) performed a randomized controlled trial (CLEAR study) to evaluate the efficacy and safety of lesinurad 200 mg or 400 mg plus allopurinol compared to allopurinol alone (mean dosage: 306.6 mg/day) in patients who did not achieve the target SUA levels with allopurinol (see Appendix E). This trial demonstrated statistically significant differences for the primary endpoint, defined as the proportion of patients with SUA levels of <6 mg/dL at month 6, in the lesinurad 200 or 400 mg group compared to allopurinol group. No statistically significant differences between groups were observed for the key secondary endpoints of gout flares and complete resolution of tophi. The incidence of total adverse events, serious adverse events, renal events and serum creatinine increase were higher in patients receiving lesinurad 400 mg compared to those receiving lesinurad 200 mg or allopurinol alone. Overall, the safety profile for the lesinurad 200 mg groups and allopurinol alone was similar. Lesinurad 200 mg was approved by the FDA in 2015 including a recommendation to assess the renal function prior to initiation and during lesinurad therapy.

Colchicine and probenecid

The combination of colchicine and probenecid is approved for the treatment of chronic gouty arthritis when gout flares are frequent and recurrent.17 No head-to-head comparisons involving colchicine in combination with probenecid and other antigout agents were identified.

Pegloticase

One Cochrane systematic review by Sriranganathan et al71 (2014) and two RCTs described the efficacy and safety of biweekly and monthly pegloticase 8 mg intravenous infusion versus placebo in patients with chronic gout refractory to allopurinol. Pooled results demonstrated a beneficial effect of pegloticase (both biweekly and monthly) compared to placebo for the primary endpoint, defined as the reduction of SUA levels to less than 6 mg/dL at month 3 and 6. In the subgroup of patients with tophi, regression of tophi was significantly higher with the

33

biweekly pegloticase infusion compared to placebo (RR 5.45; 95% CI 1.38 to 21.54), while the monthly pegloticase arm did not differ from placebo. Discontinuation rates due to adverse events (generally infusion reactions) and total adverse events were significantly greater for both pegloticase groups compared to placebo. Overall, biweekly and monthly pegloticase may regress tophi in refractory gout patients, but there is an extremely high risk of withdrawals due to infusion reactions. The authors concluded that further clinical investigation is needed to evaluate the place in therapy of pegloticase over other pharmacological and non-pharmacological therapeutic alternatives for the treatment of tophi.

34

Safety

Overall, xanthine oxidase inhibitors including allopurinol and febuxostat, are safe and well-tolerated.8 However, some adverse events can be serious. The most frequently reported adverse events with allopurinol use are diarrhea, stomach pain, skin rash, headache, and liver abnormalities.8,15 Allopurinol is rarely associated with allopurinol hypersensitivity syndrome (AHS), which occurs in 2 to 5%13,43 of patients and may be life-threatening in approximately 0.1% of patients.43,72 The majority of cases occur during the first 6 months of therapy at high starting doses. Serious cutaneous adverse reactions (SCARs) including Toxic Epidermal Necrolysis and Stevens Johnson Syndrome have been reported with allopurinol use. Incidence of AHS and SCARs is more prominent in patients with the presence of HLA-B*5801 allele, particularly in the Asian populations. A screening test for HLA-B*5801 may be performed in Asian patients (and others at risk) before initiating allopurinol.10,12,43 In addition, renal impairment is a risk factor for AHS. Dosage adjustment of allopurinol in patients with renal impairment is required to reduce the risk of AHS. Some studies have suggested that allopurinol has a protective effect on the cardiovascular system (e.g. blood pressure improvement) due to the lowering effect in SUA and antioxidant activity as a XOI.8

The most frequent adverse events reported in clinical trials with febuxostast are increased levels of liver transaminases, gastrointestinal disorders, musculoskeletal pain and skin rash.8 Skin rashes were more common at higher doses72 and the elevation of liver enzymes led to treatment discontinuation in some studies. Three placebo-controlled trials suggested no differences in the incidence of adverse events between febuxostat and placebo. Randomized controlled trials and systematic reviews indicated that febuxostat and allopurinol are equally safe in terms of serious adverse events and discontinuation rates due to adverse events.4,49,56 In contrast to allopurinol, no dosage adjustments of febuxostat are needed in patients with renal impairment,18 which makes febuxostat an attractive option in this subgroup of patients. In relation to cardiovascular events, long-term studies and post-marketing data suggested that febuxostat may increase cardiovascular risk compared to allopurinol. However, this association was not statistically significant in another phase III study and requires further investigation.18,73,74 Febuxostat should not be administered with azathioprine or mercaptopruine due to the high risk of myelosuppression.13,43 Fatal and non-fatal hepatic failure have been reported post-marketing, although causal relationship with febuxostat is not well-established due to limited information available.13,18

Among uricosuric agents, probenecid and lesinurad are currently authorized in the U.S. Benzbromarone was withdrawn by the FDA due to serious hepatic toxicity.42,75 Probenecid is associated with gastrointestinal intolerance, rash, hepatotoxicity, acute gout attack, nephrolithiasis and nephrotic syndrome. Its use is contraindicated in patients with a history of renal calculi due to the increased risk of nephrolithiasis. Given the numerous drug interactions, probenecid is not recommended in elderly patients.42 A meta-analysis evaluating allopurinol

35

versus other ULTs demonstrated a better safety profile in terms of discontinuation rates for allopurinol compared to probenecid (11% vs 26%). Lesinurad is indicated in combination with an XOI and is usually well-tolerated. Adverse events reported during clinical trials were generally mild or moderate and included headache, upper respiratory tract infection, increased serum creatinine, sinusitis and gastroesophageal reflux disease.70 A warning about the increased risk of acute renal failure, especially when lesinurad is administered without a XOI, is included in the package insert.19 This product is not recommended in patients with creatinine clearance lower than 45 mL/min.19

Pegloticase is administered as an intravenous injection and studies reported a high incidence of infusion reaction and a high withdrawal rate due to adverse events.71

Colchicine has a narrow therapeutic index22,23 with a significant risk of toxicity if used incorrectly.43 Fatalities have been reported at colchicine doses of 7 mg.22 The risk of drug accumulation and resultant toxicity is much higher when colchicine is administered by intravenous injection. The FDA withdrew this formulation in 200976 due to the incidence of deaths reported.22 The most common adverse events with oral colchicine are gastrointestinal disorders, particularly diarrhea, which was reported in 77% or 23% of patients receiving high-dose colchicine or low-dose colchicine, respectively.16,30 Myotoxicity is rare but serious, especially in men older than 50 years with renal impairment. Dosage adjustments in hepatic or renal impairment are necessary.16 Colchicine interacts with P-glycoprotein and CYP3A4 inhibitors resulting in high serum concentrations of colchicine that may be life-threatening. By contrast, studies have suggested that colchicine has a protective effect in the cardiovascular system.43

NSAIDs are mainly associated with mild gastrointestinal symptoms such as dyspepsia and abdominal pain (more than 10%) or severe gastrointestinal disorders such as bleeding or ulcers (less than 1%). Short term use of corticosteroids are associated with dysphoria, elevation in blood glucose, immune suppression, and fluid retention, being more serious during long-term use.13

Table 5 outlines the most common adverse events and warnings pertaining to antigout agents.

36

Table 6. Adverse Reactions and Warnings of Antigout Agents15-21,25,26 Adverse Reactions Warning and Precautions

Allopurinol Most commonly reported: • Derm: Skin rash • Endo: acute gout attacks • GI: Diarrhea, nausea • Hepatic: Increased liver enzymes, increased serum alkaline phosphatase

• HSR: Discontinue if skin rash or other signs indicating an allergic reaction. HSR increased in patients with decreased renal function receiving thiazides and allopurinol concomitantly. Consider HLA-B*5801 testing

• Doses of mercaptopurine or azathioprine should be reduced when administered with allopurinol

• Hepatotoxicity • Drowsiness, • Increase in gout flares during initiation of

anti-hyperuricemic agents • Bone marrow suppression • Dosage adjustment required with renal

impairment • Hydration: increase fluid intake during

therapy to prevent renal stones Colchicine Data from clinical trials:

Low dose (1.8 mg/1 hr)-recommended

High dose (4.8 mg/6 hr)

GI GI disease 26% 77% Diarrhea 23% 77% Vomiting 0% 17% Nausea 4% 17% CNS Fatigue 1% 4% Headache 1% 2% Endo Gout 4% 0% Resp Pharyngolaryngeal pain 3% 2%

Note: At toxic doses, colchicine may cause severe diarrhea, generalized vascular damage, and renal damage with hematuria and oliguria.

• Fatal overdoses have been reported with colchicine in adults and children

• Blood discrasias • Monitor for toxicity and if present consider

temporary interruption or discontinuation of colchicine

• Drug interaction P-gp and/or CYP3A4 inhibitors: Coadministration of colchicine with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death

• Neuromuscular toxicity

Colchicine& Probenecid

See individual components

37

Adverse Reactions Warning and Precautions Febuxostat 1% to 10%:

Derm: Rash (1% to 2%) GI: Nausea (1%) Hepatic: Liver function abnormalities (5% to 7%) NMS: Arthralgia (1%)

• Increase in gout flares during initiation of anti-hyperuricemic agents. If gout flare occurs, discontinue febuxostat

• CV Events: higher incidence of CV events in febuxostat than allopurinol

• Hepatic Effects: hepatic failure Lesinurad 1% to 10%:

CNS: Headache (5%) GI: Gastroesophageal reflux disease (3%) Infection: Influenza (5%) Renal: Increased serum creatinine (≤6%; 1.5 x to <2.0 x baseline: 4%; ≥2.0 x baseline: 2%; most elevations were transient and resolved without therapy interruption), renal failure (2%) Frequency not defined: CV: Cerebrovascular accident, myocardial infarction Renal: Acute renal failure

• Renal events: RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR. Monitor renal function at initiation and during therapy with lesinurad

• CV events

Pegloticase >10%: Derm: Urticaria (11%) Endo: Gout (flare: 74%; within the first 3 months) GI: Nausea (12%) Hema: Bruise (11%) Immuno: Antibody development (antipegloticase antibodies: 92%; anti-PEG antibodies: 42%) Misc: Infusion-related reaction (26%) 1% to 10%: CV: Chest pain (6% to 10%) Derma: Erythema (10%), pruritus (10%) GI: Constipation (6%), vomiting (5%) HS: Anaphylaxis (≤7%) Resp: Dyspnea (7%), nasopharyngitis (7%)

• Anaphylaxis, generally manifested within 2 hours of the infusion, and infusion reactions. Patients should be pre-medicated with antihistamines and corticosteroids.

• G6PD deficiency associated hemolysis and methemoglobinemia (screen patients for G6PD deficiency prior to initiate pegloticase)

• Gout flares • Congestive heart failure exacerbation

Probenecid Frequencies not defined CNS: headache, dizziness. Metabolic: precipitation of acute gouty arthritis. GI: hepatic necrosis, vomiting, nausea, anorexia, sore gums. GU: nephrotic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequency. HS: anaphylaxis, fever, urticaria, pruritus. Hema: aplastic anemia, leukopenia, hemolytic anemia which in some patients could be related to genetic deficiency of glucose -6- phosphate dehydrogenase in red blood cells, anemia. Integumentary: dermatitis, alopecia, flushing.

• Exacerbation of gout following therapy with probenecid

• If probenecid is given with methotrexate, the dosage of methotrexate should be reduced

• Use of salicylates and probenecid is contraindicated to avoid “paradoxical effect” of uricosuric agents

• Severe allergic reactions and anaphylaxis (rarely)

Abbreviation: CNS, central nervous system; CV, cardiovascular; Derm, dermatologic; Endo, Endocrine; GI, gastrointestinal; GU, genitourinary; Hema, hematologic; HS, hypersensitivity; Misc, miscellaneous; NMS, neuromuscular system; Resp, respiratory

38

Summary

Gout is a painful and debilitating inflammatory arthritis associated with high serum uric acid levels and triggered by the deposition of monosodium urate crystal in joints and other tissues. The primary goals of gout treatment are relieving the pain associated with acute gout attacks and reducing serum uric acid concentration below 6 mg/dL (360 µmol/L). Gout therapy includes agents for the treatment of acute gout (NSAIDs, colchicine, corticosteroids and ACTH) and agents for the management of chronic gout (allopurinol, febuxostat, lesinurad, probenecid, pegloticase and colchicine in combination with probenecid). Gout treatment should be tailored considering individual patient comorbidities, cardiovascular risk factors and drug contraindications.

For the treatment of acute gout, no head-to head comparisons of colchicine versus other antigout agents were identified. For informational purposes, an overview of evidence supporting the use of colchicine or other anti-inflammatories indicated for acute gout (i.e. NSAIDs and corticosteroids) was provided. Evidence from guidelines and systematic reviews reported that NSAIDs, colchicine and corticosteroids are equally effective in the reduction of pain caused by acute gout flares. Current guidelines recommend all of these options as first-line therapy, with treatment decisions based on individual patient characteristics, comorbidities, drug safety profiles and contraindications. Available evidence for colchicine in acute gout came from one Cochrane systematic review including 2 RCTs. Results demonstrated superior efficacy in pain reduction of high-dose colchicine versus placebo, but a greater incidence of adverse events in the high dose colchicine group. When low-dose colchicine was compared to high-dose colchicine, similar efficacy was shown. However, a more favorable gastrointestinal safety profile was reported with low-dose colchicine. Current guidelines recommend the use of low-dose for the treatment of gout flares. High-dose colchicine is not recommended.

With respect to NSAIDs and corticosteroids, two Cochrane systematic reviews were summarized in this report for informational purposes. Overall, results from one systematic review demonstrated that all NSAIDs are equally efficacious for the treatment of acute gout. COXIBs demonstrated similar efficacy in pain reduction but better safety profile compared to NSAIDs. Similarly, the other systematic review reported that corticosteroids (oral or intramuscular) afford similar efficacy with a better safety profile than NSAIDs. However, further comparative investigations are necessary.

For the management of chronic gout, a large amount of moderate to high-quality evidence (2 Cochrane systematic reviews, 3 relevant systematic reviews and 7 additional references) evaluating the efficacy and safety of allopurinol versus febuxostat was identified. Findings showed that febuxostat and allopurinol are both effective for chronic gout management. Similar incidence of gout flares were reported between febuxostat 40 or 80 mg/day and allopurinol (100-

39

300 mg/day), although a trend towards higher incidence of acute gout flares was observed in the febuxostat 80 mg/day group compared to allopurinol. Allopurinol and febuxostat were efficacious in lowering SUA levels below 6 mg/dL, with febuxostat 80 mg being significantly more efficacious than allopurinol. Safety were similar between allopurinol and febuxostat. Key evidence from three systematic reviews conducted by ACP, AHQR and EULAR were consistent with the findings described by the two Cochrane systematic reviews. Results from most of the meta-analyses identified, indicated that the urate lowering effect and incidence of adverse events were more favorable for febuxostat (doses ≤120 mg) than allopurinol (doses ≤300 mg/day). Several studies in patients with mild to moderate renal impairment and one small RCT in patients with advanced chronic kidney disease revealed a better efficacy in terms of SUA reduction below 6 mg/dL with febuxostat compared to allopurinol.

Limited comparative evidence for probenecid is available. Two systematic reviews including one RCT were identified. Results indicated that probenecid is efficacious as an uric acid lowering agent. However, the small study size and the low-quality evidence extracted from the RCT raised uncertainties about the reported results.

Lesinurad was recently approved in 2015 and only one RCT evaluating the efficacy and safety of lesinurad in combination with allopurinol compared to allopurinol alone was found. This trial supported the approval of Lesinurad 200 mg in combination with an XOI for the treatment of hyperuricemia associated with gout in patients who have not achieved target SUA levels with an XOI alone.

Pegloticase is an intravenous injection for the treatment of chronic gout in adult patients refractory to conventional therapy. Biweekly and monthly pegloticase may regress tophi in refractory gout patients, but there is an extremely high risk of withdrawal due to infusion reactions. Pegloticase is not prescribed in primary care setting and therefore, is out of the scope of this report.

Evidence comparing colchicine plus probenecid versus other antigout agents for the management of chronic gout was not found.

In relation to safety, XOIs are generally safe and well-tolerated. Allopurinol use is associated with diarrhea, stomach pain, skin rash, headache, and liver abnormalities. Rare and life-threatening cases of allopurinol hypersensitivity syndrome have been reported, especially in Asian population where the presence of HLA-B*5801 allele is more common. Therefore, a screening test for HLA-B*5801 may be performed before initiating allopurinol in patients at increased risk. Febuxostat may cause increased levels of liver transaminases, gastrointestinal disorders, musculoskeletal pain and skin rash. Probenecid is associated with gastrointestinal intolerance, rash, hepatotoxicity, acute gout attack, nephrolithiasis and nephrotic syndrome. Due to the potential adverse renal events, this agent is contraindicated in patients with severe renal

40

impairment. Lesinurad may increase serum creatinine and therefore is not recommended in patients with creatinine clearance lower than 45 mL/min. Colchicine has a narrow therapeutic index with a significant risk of toxicity and death if used inappropriately. The most common adverse events with oral colchicine are gastrointestinal disorders, particularly diarrhea.

Guidelines for the management of acute and chronic gout have been developed by the American College of Physicians (ACP), the European League Against Rheumatism (EULAR), the 3e (Evidence, Expertise, Exchange) Initiative and the American College of Rheumatology (ACR), among others. American guidelines (ACP and ACR) recommend the use of colchicine, NSAIDs or corticosteroids as first-line treatments for acute gout attacks, without any specific preferences of one agent over another. Low-dose colchicine is preferred over high-dose colchicine due to the lower incidence of adverse events. For the management of chronic gout, these guidelines consider either allopurinol or febuxostat as first-line urate lowering therapies. Uricosuric agents including probenecid are classified as second-line options when patients do not achieve SUA target levels with xanthine oxidase inhibitors, or first line treatments are contraindicated. Lesinurad is a new agent approved in 2015 for chronic gout that has not yet been included in current guidelines. Pegloticase is an intravenous injection recommended by ACR in patients with severe gout disease and refractory to conventional therapy. Neither the ACP nor ACR guidelines offer recommendations concerning colchicine-probenecid combination therapy.

Based on the evidence identified, febuxostat and allopurinol are similarly safe and efficacious, with febuxostat 80 mg showing superior urate lowering efficacy compared to allopurinol. According to guidelines and high-quality systematic reviews, low-dose colchicine is as effective as NSAIDs and corticosteroids for the treatment of acute gout. No conclusions are possible for the other antigout agents (i.e. probenecid, lesinurad or colchicine/probenecid) due to limited evidence available.

41

References 1. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the

National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63(10):3136-3141. 2. Schumacher HR, Chen LX. Chapter 333. Gout and Other Crystal-Associated Arthropathies. In: Longo DL,

Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: The McGraw-Hill Companies; 2012.

3. Roddy E, Choi HK. Epidemiology of gout. Rheumatic diseases clinics of North America. 2014;40(2):155-175.

4. Seth R, Kydd AS, Buchbinder R, Bombardier C, Edwards CJ. Allopurinol for chronic gout. Cochrane Database Syst Rev. 2014(10):CD006077.

5. Kuo CF, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nature reviews Rheumatology. 2015;11(11):649-662.

6. UpToDate, Inc. Wolters Kluwer; 2017. https://www.uptodate.com/. Accessed April 19, 2017. 7. Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Ther. 2010;12(6):223. 8. Bove M, Cicero AF, Veronesi M, Borghi C. An evidence-based review on urate-lowering treatments:

implications for optimal treatment of chronic hyperuricemia. Vasc Health Risk Manag. 2017;13:23-28. 9. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the

management of gout. Ann Rheum Dis. 2017;76(1):29-42. 10. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American college of rheumatology guidelines for

management of gout. part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care and Research. 2012;64(10):1431-1446.

11. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64(10):1447-1461.

12. Qaseem A, Harris RP, Forciea MA, Clinical Guidelines Committee of the American College of P. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2017;166(1):58-68.

13. Shekelle PG, FitzGerald J, Newberry SJ, et al. AHRQ Comparative Effectiveness Reviews. Management of Gout. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016.

14. Ilaris® (canakinumab) 150 mg powder for solution for injection [package insert]. Camberley, United Kingdom: Novartis Europharm Limited; revised June 2014.

15. Allopurinol oral tablets [package insert]. Durham, NC: Accord Healthcare, Inc., 2015; revised January 2017.

16. COLCRYS® oral tablets, colchicine oral tablets [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; revised December 2015.

17. Colchicine and probenecid oral tablets [package insert]. Fairfield, NJ: Ingenus Pharmaceuticals NJ, LLC; revised September 2016.

18. ULORIC® oral tablets, febuxostat oral tablets [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; revised November 2013.

19. ZURAMPIC® oral tablets, lesinurad oral tablets [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; revised January 2016.

20. KRYSTEXXA® intravenous injection, pegloticase intravenous injection [package insert]. Glendale, WI: Crealta Pharmaceuticals LLC; revised September 2016.

21. Probenecid oral tablets [package insert]. Olive Branch, MS: Wes tmins ter Pharmaceuticals , LLC; revised July 2016. .

22. Stack J, Ryan J, McCarthy G. Colchicine: New Insights to an Old Drug. American journal of therapeutics. 2015;22(5):e151-157.

23. Nasr A, Lauterio TJ, Davis MW. Unapproved drugs in the United States and the Food and Drug Administration. Advances in therapy. 2011;28(10):842-856.

24. Kesselheim AS, Franklin JM, Kim SC, Seeger JD, Solomon DH. Reductions in Use of Colchicine after FDA Enforcement of Market Exclusivity in a Commercially Insured Population. Journal of general internal medicine. 2015;30(11):1633-1638.

25. Micromedex (electronic version). Truven Health Analytics; 2017. http://www.micromedexsolutions.com/. Accessed April 11, 2017.

26. Lexicomp. Wolters Kluwer; 2017. http://online.lexi.com/action/home. Accessed April 13, 2017.

https://www.uptodate.com/

http://www.micromedexsolutions.com/

http://online.lexi.com/action/home

42

27. Aloprim®, allopurinol intravenous injection [package insert]. Rockford, IL: Mylan Institutional LLC; revised June 2014.

28. MITIGARE® capsules, colchicine capsules [package insert]. Memphis, TN: Hikma Americas, Inc.; revised November 2015.

29. Shekelle PG, Newberry SJ, FitzGerald JD, et al. Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2017;166(1):37-51.

30. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010;62(4):1060-1068.

31. Sivera F, Andrés M, Carmona L, et al. Multinational evidence-based recommendations for the diagnosis and management of gout: Integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Annals of the Rheumatic Diseases. 2014;73(2):328-335.

32. Becker MA, Schumacher HR, MacDonald PA, Lloyd E, Lademacher C. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009;36(6):1273-1282.

33. Singh JA. Quality of life and quality of care for patients with gout. Curr Rheumatol Rep. 2009;11(2):154-160.

34. Roddy E, Zhang W, Doherty M. Is gout associated with reduced quality of life? A case-control study. Rheumatology (Oxford, England). 2007;46(9):1441-1444.

35. Lee SJ, Hirsch JD, Terkeltaub R, et al. Perceptions of disease and health-related quality of life among patients with gout. Rheumatology (Oxford, England). 2009;48(5):582-586.

36. Trieste L, Palla I, Fusco F, et al. The economic impact of gout: a systematic literature review. Clinical and experimental rheumatology. 2012;30(4 Suppl 73):S145-148.

37. Perez-Ruiz F, Martinez-Indart L, Carmona L, Herrero-Beites AM, Pijoan JI, Krishnan E. Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout. Ann Rheum Dis. 2014;73(1):177-182.

38. Kydd AS, Seth R, Buchbinder R, Edwards CJ, Bombardier C. Uricosuric medications for chronic gout. Cochrane Database Syst Rev. 2014(11):CD010457.

39. De Vera MA, Marcotte G, Rai S, et al. Medication adherence in gout: A systematic review. Arthritis Care and Research. 2014;66(10):1551-1559.

40. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford, England). 2007;46(8):1372-1374.

41. National Institute for Health and Care Excellence. Appraisal consultation document – lesinurad for treating chronic hyperuricaemia in people with gout. July 2016.

42. Gaffo AL, Saag KG. Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Core Evid. 2010;4:25-36.

43. Stamp LK. Safety profile of anti-gout agents: an update. Current opinion in rheumatology. 2014;26(2):162-168.

44. Deeks ED. Lesinurad: A Review in Hyperuricaemia of Gout. Drugs & Aging. 2017:1-10. 45. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in

Older Adults. Journal of the American Geriatrics Society. 2015;63(11):2227-2246. 46. Van Echteld IA, Van Durme C, Falzon L, et al. Treatment of gout patients with impairment of renal

function: A systematic literature review. Journal of Rheumatology. 2014;41(SUPPL. 92):48-54. 47. Fravel MA, Ernst ME. Management of gout in the older adult. Am J Geriatr Pharmacother. 2011;9(5):271-

285. 48. Becker MA, Schumacher HR, Jr., Wortmann RL, et al. Febuxostat compared with allopurinol in patients

with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450-2461. 49. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in

the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63. 50. Tanaka K, Nakayama M, Kanno M, et al. Renoprotective effects of febuxostat in hyperuricemic patients

with chronic kidney disease: a parallel-group, randomized, controlled trial. Clin Exp Nephrol. 2015;19(6):1044-1053.

43

51. Becker MA, MacDonald PA, Hunt B, Gunawardhana L. Treating hyperuricemia of gout: safety and efficacy of febuxostat and allopurinol in older versus younger subjects. Nucleosides Nucleotides Nucleic Acids. 2011;30(12):1011-1017.

52. Chohan S, Becker MA, MacDonald PA, Chefo S, Jackson RL. Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol. Arthritis Care Res (Hoboken). 2012;64(2):256-261.

53. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS medicine. 2009;6(7):e1000097.

54. Araujo F, Cordeiro I, Ramiro S, Falzon L, Branco JC, Buchbinder R. Outcomes assessed in trials of gout and accordance with OMERACT-proposed domains: a systematic literature review. Rheumatology (Oxford, England). 2015;54(6):981-993.

55. van Durme CM, Wechalekar MD, Buchbinder R, Schlesinger N, van der Heijde D, Landewe RB. Non-steroidal anti-inflammatory drugs for acute gout. Cochrane Database Syst Rev. 2014(9):Cd010120.

56. Tayar JH, Lopez-Olivo MA, Suarez-Almazor ME, et al. Febuxostat for treating chronic gout. Cochrane database of systematic reviews.(2012) 11:CD008653.

57. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database Syst Rev. 2014(8):CD006190.

58. Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med. 1987;17(3):301-304.

59. Janssens HJ, Lucassen PL, Van de Laar FA, Janssen M, Van de Lisdonk EH. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev. 2008(2):CD005521.

60. Underwood M. Gout. Clin Evid (Online). 2015:19. 61. Kydd AS, Seth R, Buchbinder R, et al. Urate-lowering therapy for the management of gout: a summary of

2 Cochrane reviews. J Rheumatol Suppl. 2014;92:33-41. 62. Borghi C, Perez-Ruiz F. Urate lowering therapies in the treatment of gout: a systematic review and meta-

analysis. Eur Rev Med Pharmacol Sci. 2016;20(5):983-992. 63. Li S, Yang H, Guo Y, et al. Comparative efficacy and safety of urate-lowering therapy for the treatment of

hyperuricemia: a systematic review and network meta-analysis. Sci. 2016;6:33082. 64. Villazor-Isidro EBS, Brojan JCG, Pega-Flores CJR, et al. Urate lowering efficacy of febuxostat versus

allopurinol in hyperuricemic patients with gout. Phillippine Journal of Internal Medicine. 2014;52:1. 65. Ye P, Yang S, Zhang W, et al. Efficacy and Tolerability of Febuxostat in Hyperuricemic Patients With or

Without Gout: A Systematic Review and Meta-Analysis. Clinical Therapeutics. 2013;35(2):180-189. 66. Faruque LI, Ehteshami-Afshar A, Wiebe N, et al. A systematic review and meta-analysis on the safety and

efficacy of febuxostat versus allopurinol in chronic gout. Seminars in Arthritis and Rheumatism. 2013;43(3):367-375.

67. Schumacher HR, Jr., Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59(11):1540-1548.

68. Scott JT. Comparison of allopurinol and probenecid. Ann Rheum Dis. 1966;25(6 Suppl):623-626. 69. Gibson T, Rodgers V, Potter C, Simmonds HA. Allopurinol treatment and its effect on renal function in

gout: a controlled study. Ann Rheum Dis. 1982;41(1):59-65. 70. Saag KG, Fitz-Patrick D, Kopicko J, et al. Lesinurad Combined With Allopurinol: A Randomized, Double-

Blind, Placebo-Controlled Study in Gout Patients With an Inadequate Response to Standard-of-Care Allopurinol (a US-Based Study). Arthritis rheumatol. 2017;69(1):203-212.

71. Sriranganathan MK, Vinik O, Falzon L, et al. Interventions for Tophi in Gout: A cochrane systematic literature review. Journal of Rheumatology. 2014;41(SUPPL. 92):63-69.

72. Bridgeman MB, Chavez B, Author A, et al. Febuxostat for the treatment of gout. Expert Opinion on Pharmacotherapy. 2015;16(3):395-398.

73. Gandhi PK, Gentry WM, Bottorff MB. Cardiovascular thromboembolic events associated with febuxostat: investigation of cases from the FDA adverse event reporting system database. Semin Arthritis Rheum. 2013;42(6):562-566.

74. Waller A, Jordan KM. Use of febuxostat in the management of gout in the United Kingdom. Therapeutic advances in musculoskeletal disease. 2017;9(2):55-64.

75. Lee MH, Graham GG, Williams KM, Day RO. A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients? Drug safety. 2008;31(8):643-665.

44

76. U.S. Food and Drug Administration. Questions and Answers About FDA's Enforcement Action Against Unapproved Injectable Colchicine Products. May 2009.

77. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. Jama. 2011;306(7):711-720.

78. Khanna PP, Gladue HS, Singh MK, et al. Treatment of acute gout: A systematic review. Seminars in Arthritis and Rheumatism. 2014;44(1):31-38.

79. Singal KK, Goyal S, Gupta P, et al. Comparison between Allopurinol and Febuxostat in management of gout patients - A prospective study. Bangladesh Journal of Medical Science. 2011;10(4):257-259.

80. Kamatani N, Fujimori S, Hada T, et al. An allopurinol-controlled, randomized, double-dummy, double-blind, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J. 2011;17(4 Suppl 2):S13-18.

81. Kamatani N, Fujimori S, Hada T, et al. An allopurinol-controlled, multicenter, randomized, open-label, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 2 exploratory clinical study. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2011;17(4 Suppl 2):S44-49.

82. Hatoum, Hind, Khanna, Dinesh, Shiozawa, Aki, Lin, Swu-Jane, Akhras, Kasem, Khanna, Puja; Outcome Of Gout Patients Placed On Febuxostat After Failing To Reach Serum Urate Target With Allopurinol. [abstract]. Arthritis Rheum 2013;65 Suppl 10 :2003. DOI: 10.1002/art.2013.65.issue-s10.

83. Huang X, Du H, Gu J, et al. An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia. Int J Rheum Dis. 2014;17(6):679-686.

84. Singh JA, Akhras KS, Shiozawa A. Comparative effectiveness of urate lowering with febuxostat versus allopurinol in gout: analyses from large U.S. managed care cohort. Arthritis Res Ther. 2015;17:120.

85. Xu S, Liu X, Ming J, et al. A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and efficacy of oral febuxostat in Chinese gout patients with hyperuricemia. Int J Rheum Dis. 2015;18(6):669-678.

86. Yu KH, Lai JH, Hsu PN, et al. Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study. Scandinavian Journal of Rheumatology. 2016;45(4):304-311.

45

Appendix A. MEDLINE & EMBASE Literature Search Strategies for Antigout Agents Ovid MEDLINE

Database: Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Versions(R) Systematic Review and Randomized Controlled Trials Search Strategy (April-03-2017)

2 gout suppressants/ (1947) 3 allopurinol/ or colchicine/ or febuxostat/ (20573) 4 Probenecid/ (3424) 5 pegloticas$.ti,ab,kw,kf,rn. (118) 6 (allohexan or alloprin or allopurin or allopurinol or allorin or allpargin or allural or apulonga or apurin or atisuril or bleminol or caplenal or capurate or cellidrin or embarin or foligan or hamarin or jenapurinol or lopurin or lysuron or milurit or milurite or novopurol or pan quimica or progout or pureduct or purinol or remid or rimapurinol or roucol or suspendol or tipuric or uribenz or uridocid or uripurinol or urosin or urtias or xanthomax or xanturic or zygout or zyloprim).ti,ab,kw,kf,rn. [MeSH synonyms] (9853) 7 (febuxostat or tei 6720 or tei-6720 or tei6720 or uloric or benecid or benemid or benuryl or procid or probecid or probenecid or probenecid weimer).ti,ab,kw,kf,rn. [MeSH Synonyms] (5335) 8 (Allopurinol$ or colchicine$ or febuxostat$ or antigout agent? or antigout drug? or anti-gout agent? or anti-gout drug? or gout suppressant?).ti,ab,kw,kf,rn. (28937) 9 (aloprim* or loupurin* or zyloprim*).ti,ab,kw,kf,rn. (5) 10 zyloprim$.ti,ab,kw,kf,rn. (5) 11 (adenock or alinol or allnol or allo 300 or allo puren or allo purinol or allo-basan or allo-puren or allohexal or allopin or allopur or allopuren or allopurinol 300 or allopurinol sodium or alloril or allorin or allosig or allozym or allural or allurase or allurit or aloprim or alopron or alopurin or alositol or alpurase or alpurin or aluline or alunlan or alurin or aluron or anoprolin or anzief or apo allopurinol or apo-allopurinol or aprinol or apulonga or apurin or apurol or atisuril or bleminal or burmadon or bw 56 158 or bw 56-158 or bw 56158 or bw56-158 or bw56158 or caplenal or capurate or cellidrin or clint or cosuric or dabrosan or dabroson or epidropal or epuric or erloric or etindrax or foligan or gichtex or hamarin or isoric or kemorinol or ketanrift or ketobun-a or litinol or llanol or lo-uric or lopurin or lopurine or lysuron 300 or masaton or medoric or mefanol or mephanol or milurit or milurit 100 or milurit 300 or miniplanor or mylurit or nektrohan or neufan or nipurol or no-uric or progout or proxuric or puricemia or puricos or purinase or purinol or purinox or puristen or ranpuric or remid or riball or rinolic or salterprim or sigapurol or takanarumin or tonsaric or trianol or unizuric 300 or uricad or uriconorm or urinol or uripurinol or urogquad or uroquad or urosin or valeric or vitralgin or xanturat or xanturic or xylonol or zylapour or zylol or zyloprim or zyloric or zyroric).ti,ab,kw,kf,rn. [EMBASE] (8611) 12 (benacid or bencid or benecid or benemid or benemide or benemin or benuryl or procid or probalan or probecid or probe?icid or probenemid or probenicid or probenid or procid or prolongine or uricosid or urocid or pegloticase or krystexxa or peguricase or puricase).ti,ab,kw,kf,rn. (268) 13 (adenuric or tei 6720 or tei6720 or tmx 67 or tmx67 or uloric).ti,ab,kw,kf,rn. (34) 14 (aqua colchin or colchichine or colchicin or colchicine capsules or colchicine houde or colchicine sodium or colchicum-dispert or colchily or colchimedio or colchiquim or colchisol or colchysat or colcine or colcrys or colgout or goutichine or goutnil or kolkicin or mitigare or nsc 757 or tolchicine).ti,ab,kw,kf,rn. (13609) 15 (adenuric or tei 6720 or tei6720 or tmx 67 or tmx67 or uloric).ti,ab,kw,kf,rn. (34) 16 (64-86-8 or 144060-53-7 or "315 30 0" or 885051-90-1 or 57-66-9).rn. (0) 17 or/3-16 [Antigout agents] (35025) 18 gout/ or arthritis, gouty/ (10932) 19 Hyperuricemia/ (2559) 20 gout?.ti,ab,kw,kf. (11766) 21 (arthragra or cheiragra or chiragra or urate inflammation or uric arthritis).ti,ab,kw,kf. (43) 22 recurr$ acute arthritis.ti,ab,kw,kf. (2)

46

23 (hyperuric?emi$ or uric acid calculi$ or hyperuricacid?emi$ or uricacid?emia$ or uric?em$ or hyperuric?eciduria$ or hyperuricosuri$).ti,ab,kw,kf. (7755) 24 (disorder? adj2 purine metaboli$).ti,ab,kw,kf. (157) 25 ((tophaceous or monosodium urate or msu) adj2 (deposit or deposits or crystal or crystals) adj10 (joint or joints or bone or bones or tissue or tissues)).ti,ab,kw,kf. (316) 26 (urate lowering or uric acid nephrolithias$).ti,ab,kw,kf. (650) 27 (uric acid adj2 (disease? or stone or stones)).ti,ab,kw,kf. (672) 28 ((monosodium urate or msu) adj2 (crystal induced or inflammation)).ti,ab,kw,kf. (168) 29 Uric Acid/ (22022) 30 or/18-29 [Gout] (35314) 31 2 or (and/17,30) [Gout Suppressants OR Drugs & Gout] (5404) 32 (systematic adj2 review).ti,kw,kf. (71024) 33 meta-analysis.pt. (77267) 34 (meta-analy* or metaanaly*).ti,ab,kw,kf. (112474) 35 (meta regression* or metaregression* or mega regression*).ti,ab,kw,kf. (5174) 36 ((systematic* or methodologic$) adj3 (review* or overview*)).ti,ab,kw,kf. (113504) 37 (quantitative adj3 (review* or overview* or synthes*)).ti,ab,kw,kf. (3732) 38 (research adj3 (integrati* or overview*)).ti,ab,kw,kf. (4224) 39 ((integrative or INTEGRATED) adj3 (review* or overview*)).ti,ab,kw,kf. (3143) 40 (collaborative adj3 review).ti,ab,kw,kf. (314) 41 "our review".ab. (7476) 42 (data synthes* or data extraction* or data abstraction*).ti,ab. (19511) 43 (pool$ adj3 analys$).ti,ab. (13936) 44 (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab. (19794) 45 (medline or cochrane or pubmed or PSYCHINFO or CINAHL or medlars).ti,ab,hw,jn,jw. (146992) 46 (evidence adj3 (review? or appraisal? or overview* or synthesis)).ti,ab,kw,kf. (39621) 47 (critical adj3 (review? or appraisal? or overview?)).ti,ab,kw,kf. (23539) 48 ((synthes$ or evaluat$) adj2 evidence$).ti,ab,kw,kf. (11028) 49 or/32-48 [SR Filter 1.1 A] (345304) 50 and/31,49 [SR Results] (156) 51 limit 50 to english language (149) MARCH-31-2017 52 (randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti. (1122555) 53 exp animals/ not humans.sh. (4366043) 54 52 not 53 [Cochrane RCT Filter 6.4.d Sens/Precision Maximizing] (1036175) 55 (31 and 54) not 51 [RCT REsults] (480) 56 limit 55 to english language (430) [APRIL -03-2017]

EMBASE (via EMBASE.com) Systematic Review and Randomized Controlled Trials Search Strategy (April-03-2017)

#1 'antigout agent'/de 780 #2 'allopurinol'/de OR 'colchicine'/de OR 'febuxostat'/de OR 'probenecid'/mj OR 'pegloticase'/de 51660 #3 aloprim*:ti,ab,tn OR loupurin*:ti,ab,tn OR zyloprim*:ti,ab,tn OR allopurinol*:ti,ab,tn OR colchicin*:ti,ab,tn OR febuxostat*:ti,ab,tn OR 'antigout agent':ti,ab,tn OR 'antigout agents':ti,ab,tn OR 'gout suppressant':ti,ab,tn OR 'gout suppressants':ti,ab,tn 25988

47

#4 'adenock':ti,ab OR 'alinol':ti,ab OR 'allnol':ti,ab OR 'allo 300':ti,ab OR 'allo puren':ti,ab OR 'allo purinol':ti,ab OR 'allo-basan':ti,ab OR 'allo-puren':ti,ab OR 'allohexal':ti,ab OR 'allopin':ti,ab OR 'allopur':ti,ab OR 'allopuren':ti,ab OR 'allopurinol 300':ti,ab OR 'allopurinol sodium':ti,ab OR 'alloril':ti,ab OR 'allorin':ti,ab OR 'allosig':ti,ab OR 'allozym':ti,ab OR 'allural':ti,ab OR 'allurase':ti,ab OR 'allurit':ti,ab OR 'aloprim':ti,ab OR 'alopron':ti,ab OR 'alopurin':ti,ab OR 'alositol':ti,ab OR 'alpurase':ti,ab OR 'alpurin':ti,ab OR 'aluline':ti,ab OR 'alunlan':ti,ab OR 'alurin':ti,ab OR 'aluron':ti,ab OR 'anoprolin':ti,ab OR 'anzief':ti,ab OR 'apo allopurinol':ti,ab OR 'apo-allopurinol':ti,ab OR 'aprinol':ti,ab OR 'apulonga':ti,ab OR 'apurin':ti,ab OR 'apurol':ti,ab OR 'atisuril':ti,ab OR 'bleminal':ti,ab OR 'burmadon':ti,ab OR 'bw 56 158':ti,ab OR 'bw 56-158':ti,ab OR 'bw 56158':ti,ab OR 'bw56-158':ti,ab OR 'bw56158':ti,ab OR 'caplenal':ti,ab OR 'capurate':ti,ab OR 'cellidrin':ti,ab OR 'clint':ti,ab OR 'cosuric':ti,ab OR 'dabrosan':ti,ab OR 'dabroson':ti,ab OR 'epidropal':ti,ab OR 'epuric':ti,ab OR 'erloric':ti,ab OR 'etindrax':ti,ab OR 'foligan':ti,ab OR 'gichtex':ti,ab OR 'hamarin':ti,ab OR 'isoric':ti,ab OR 'kemorinol':ti,ab OR 'ketanrift':ti,ab OR 'ketobun-a':ti,ab OR 'litinol':ti,ab OR 'llanol':ti,ab OR 'lo-uric':ti,ab OR 'lopurin':ti,ab OR 'lopurine':ti,ab OR 'lysuron 300':ti,ab OR 'masaton':ti,ab OR 'medoric':ti,ab OR 'mefanol':ti,ab OR 'mephanol':ti,ab OR 'milurit':ti,ab OR 'milurit 100':ti,ab OR 'milurit 300':ti,ab OR 'miniplanor':ti,ab OR 'mylurit':ti,ab OR 'nektrohan':ti,ab OR 'neufan':ti,ab OR 'nipurol':ti,ab OR 'no-uric':ti,ab OR 'progout':ti,ab OR 'proxuric':ti,ab OR 'puricemia':ti,ab OR 'puricos':ti,ab OR 'purinase':ti,ab OR 'purinol':ti,ab OR 'purinox':ti,ab OR 'puristen':ti,ab OR 'ranpuric':ti,ab OR 'remid':ti,ab OR 'riball':ti,ab OR 'rinolic':ti,ab OR 'salterprim':ti,ab OR 'sigapurol':ti,ab OR 'takanarumin':ti,ab OR 'tonsaric':ti,ab OR 'trianol':ti,ab OR 'unizuric 300':ti,ab OR 'uricad':ti,ab OR 'uriconorm':ti,ab OR 'urinol':ti,ab OR 'uripurinol':ti,ab OR 'urogquad':ti,ab OR 'uroquad':ti,ab OR 'urosin':ti,ab OR 'valeric':ti,ab OR 'vitralgin':ti,ab OR 'xanturat':ti,ab OR 'xanturic':ti,ab OR 'xylonol':ti,ab OR 'zylapour':ti,ab OR 'zylol':ti,ab OR 'zyloprim':ti,ab OR 'zyloric':ti,ab OR zyroric:ti,ab,tn 1482 #5 '4 dipropylsulfamoyl) benzoic acid':ti,ab OR 'benacid':ti,ab OR 'bencid':ti,ab OR 'benecid':ti,ab OR 'benemid':ti,ab OR 'benemide':ti,ab OR 'benemin':ti,ab OR 'benuryl':ti,ab OR 'para (dipropylsulfamoyl) benzoic acid':ti,ab OR 'para (dipropylsulfamyl) benzoic acid':ti,ab OR 'pro-cid':ti,ab OR 'probalan':ti,ab OR 'probecid':ti,ab OR 'probemicid':ti,ab OR 'probenecid metabolite':ti,ab OR 'probenecide':ti,ab OR 'probenemid':ti,ab OR 'probenicid':ti,ab OR 'probenid':ti,ab OR 'procid':ti,ab OR 'prolongine':ti,ab OR 'uricosid':ti,ab OR 'urocid':ti,ab OR 'pegloticase':ti,ab OR 'krystexxa':ti,ab OR 'peguricase':ti,ab OR 'puricase':ti,ab 367 #6 '2 (3 cyano 4 isobutoxyphenyl) 4 methyl 5 thiazolecarboxylic acid; 2 [3 cyano 4 (2 methylpropoxy) phenyl] 4 methyl 5 thiazolecarboxylic acid':ti,ab OR adenuric:ti,ab OR 'tei 6720':ti,ab OR tei6720:ti,ab OR 'tmx 67':ti,ab OR 'tmx67':ti,ab OR uloric:ti,ab 57 #7'aqua colchin':ti,ab OR 'colchichine':ti,ab OR 'colchicin':ti,ab OR 'colchicine capsules':ti,ab OR 'colchicine houde':ti,ab OR 'colchicine sodium':ti,ab OR 'colchicum-dispert':ti,ab OR 'colchily':ti,ab OR 'colchimedio':ti,ab OR 'colchiquim':ti,ab OR 'colchisol':ti,ab OR 'colchysat':ti,ab OR 'colcine':ti,ab OR 'colcrys':ti,ab OR 'colgout':ti,ab OR 'goutichine':ti,ab OR 'goutnil':ti,ab OR 'kolkicin':ti,ab OR 'mitigare':ti,ab OR 'n (5, 6, 7, 9 tetrahydro 1, 2, 3, 10 tetramethoxy 9 oxobenzo [a] heptalen 7 yl) acetamide':ti,ab OR 'nsc 757':ti,ab OR 'tolchicine':ti,ab 276 #8 adenuric:ti,ab OR 'tei 6720':ti,ab OR tei6720:ti,ab OR 'tmx 67':ti,ab OR 'tmx67':ti,ab OR uloric:ti,ab 57 #9 '64-86-8':rn OR '144060-53-7':rn OR '315 30 0':rn OR '885051-90-1':rn OR '57-66-9':rn 52625 #10 'gout'/de 19554 #11 'arthragra':ti,ab OR 'cheiragra':ti,ab OR 'chiragra':ti,ab OR 'urate inflammation':ti,ab OR 'uric arthritis':ti,ab 47 #12 gout*:ti,ab 16621 #13 hyperuricemi*:ti,ab OR hyperuricaemi*or:ti,ab OR 'uric acid calculi':ti,ab OR hyperuricacidaemia*:ti,ab OR hyperuricacidemi*:ti,ab OR hyperuricaemia*:ti,ab OR uricacidemia*:ti,ab OR uricem*:ti,ab OR hyperuricaciduria*:ti,ab OR hyperuricosuria*:ti,ab 10772 #14 (disorder* NEAR/2 'purine metabolism'):ti,ab 187 #15 ((tophaceous OR 'monosodium urate' OR msu) NEAR/2 (deposit OR deposits OR crystal OR crystals) NEAR/10 (joint OR joints OR bone OR bones OR tissue OR tissues)):ti,ab 464 #16 'urate lowering':ti,ab OR 'uric acid nephrolithiasis':ti,ab OR 'uric acid nephrolithiases':ti,ab 1065 #17 ('uric acid' NEAR/2 (disease* OR stone OR stones)):ti,ab 1004 #18 (('monosodium urate' OR msu) NEAR/2 ('crystal induced' OR inflammation)):ti,ab 219 #19 'hyperuricemia'/mj 4474 #20 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 28484 #21 'meta analysis'/mj OR 'systematic review'/de 139048 #22 ((systematic OR integrative OR drug OR therapeutic*) NEAR/2 review):ti OR 'meta analys*':ti,ab OR metaanaly*:ti,ab 181051 #23 #21 OR #22 229368

48

#24 #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 61676 #25 'animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de NOT ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de AND ('human'/exp OR 'human cell'/de)) 6159163 #26'clinical study'/mj OR 'clinical trial'/mj OR 'controlled clinical trial'/mj OR 'controlled study'/mj OR 'major clinical study'/mj OR 'randomized controlled trial'/mj OR 'control group'/mj OR ((clinical OR comparative OR efficacy OR effectiveness OR randomi* OR controlled OR multicentre OR multicenter OR 'multi centre' OR 'multi center') NEAR/3 (study OR trial)):ab OR placebo:ab,ti OR controlled:ti OR trial:ti OR multicent*:ti OR 'multi cent*':ti OR study:ti OR randomly:ab OR 'head to head':ti,ab 2457120 #27 #26 NOT #25 2150906 #28 'conference abstract'/it 2489707 #29 #1 AND #27 95 #30 #24 AND #20 AND #27 868 #31 #29 OR #30 NOT #28 [RCT Results] = 657 #32 #1 OR (#24 AND #20) AND #23 NOT #25 [systematic review results] = 144

49

Appendix B. Key Evidence: Cochrane Systematic Reviews Including Agents for Acute and Chronic Gout* Study Reference and Search Date

Objective(s) Treatment Interventions

Clinical Efficacy Clinical Safety

1. Seth et al 2014: Allopurinol for chronic gout (Review)4 (Cochrane Database of Systematic Reviews 2014) • 11 trials (4 studies of

allopurinol versus febuxostat, 1 trial of allopurinol versus probenecid) included up to January 14, 2014 (Only data of interest for this report was extracted)

To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout

• Allopurinol (100 to 300 mg) vs placebo (2 trials)

• Allopurinol vs febuxostat (4 trials)

• Allopurinol+colchicine vs colchicine (1 trials)

• Allopurinol vs probenecid (1 trial)

Allopurinol (100-300 mg) vs placebo • Acute gout attacks (1-30 days): RR 0.64

(0.12 to 3.52) • Proportion achieving target SUA level (1-30

days): RR 49.11 (3.15 to 765.58)

Allopurinol 100-300 mg vs febuxostat 40mg/daily (Becker 2010 or CONFIRMS study) • Proportion achieving target serum urate

level <6 mg/dL at 6-12 months: RR 0.93 (0.83, 1.05)

(No differences between groups) Allopurinol 100-300 mg vs febuxostat 80mg/daily • Acute gout attacks (up to 24 wks): 21%

allopurinol vs 23% febuxostat; RR 0.89 (0.71 to 1.1) (3 studies: Becker 2005 or FACT study, Schumacher 2008 or APEX trial and Singal 2011) The exclusion of Signal 2011 (non-randomized trial) did not alter the results

(No differences between groups) • Proportion achieving target SUA level of

less than 6 mg/dL (24-52 weeks): 38% allopurinol vs 70% febuxostat; RR 0.56 (0.48 to 0.65) (4 studies: FACT, CONFIRMS, APEX and Signal 2011) The exclusion of Signal 2011 (non-randomized trial) did not alter the results

(Favors febuxostat) • Tophus regression: no between group

difference in the percentage reduction in tophus area at 52 weeks with 50% for

Allopurinol (100 mg and 300 mg/daily) vs placebo (2 trials) • Withdrawal due to adverse events

(0-28 wks): RR 1.36 (0.61 to 3.08) (3 studies)

• SAEs (0-28 wks): RR 1.93 (0.48 to 7.80)

Allopurinol 100-300 mg vs febuxostat 40mg/daily (1 trial) • Withdrawal due to AEs: RR 1.31

(0.92, 1.87) • Total AEs: 1.01 (0.93, 1.10) • SAEs: 1.63 (0.93, 2.87)

(No differences between groups) Allopurinol 100-300 mg vs febuxostat 80mg/daily (3 trials) • Withdrawal due to AEs (24-52

weeks): 7% allopurinol vs 8% febuxostat; RR 0.89 (0.62 to 1.26)

• Total AEs: 1.06 (1.01, 1.12) • SAEs (24-52 weeks): 4% in both

groups; RR 1.13 (0.71 to 1.82) (No differences between groups

except for total number of AEs that was higher in the allopurinol group)

Allopurinol vs probenecid (1 trial): • Number of AEs: No difference

between groups • No SAEs reported

50

Study Reference and Search Date



participants taking allopurinol 200 or 300 mg daily and 83% for participants taking febuxostat 80 mg daily. No differences in the number of tophi (1 trial: FACT)

Allopurinol plus colchicine vs colchicine (1 trial: Gibson 1982) • Acute gout attack frequency: RR 0.63, 95%

CI 0.25 to 1.63 (No differences between groups)

Allopurinol vs probenecid (1 trial: Scott 1966): • Acute gout attack frequency (mean follow-

up: 19.1 months): 11/20 (55%) in allopurinol vs 9/17 (53%) in probenecid; RR 0.96 (0.53 to 1.75)

(Analysis performed by authors) • Mean SUA decrease:

- From 9.3 at baseline to 4.7 mg/dL in allopurinol group

- From 8.5 to 5.2 mg/dL in probenecid group

• Tophus regression disappearance: - 2 of 3 in allopurinol group - 1 of 2 in probenecid group

(No statistical analysis was provided in this study)

2. Kydd et al 2014: Uricosuric medications for chronic gout (Review)38 (Cochrane Database of Systematic Reviews 2014) • 4 RCTs and 1 controlled

trial included up to May 13, 2013 (Only data from 1 trial68 comparing

To assess the benefits and harms of uricosuric medications in the treatment of chronic gout.

• Allopurinol 300-600 mg/day vs probenecid 1-2 g/day (37 patients)

Allopurinol vs probenecid: • Acute gout attack frequency (mean follow-

up: 19.1 months): 11/20 (55%) in allopurinol vs 9/17 (53%) in probenecid; RR 0.96 (0.53 to 1.75) (analysis performed by authors)

• Mean SUA decrease: - From 9.3 at baseline to 4.7 mg/dL in

allopurinol group

Number of AEs: No difference between groups No SAEs reported

51




probenecid and allopurinol was extracted)

- From 8.5 to 5.2 mg/dL in probenecid group

• Tophus regression disappearance: - 2 of 3 in allopurinol group - 1 of 2 in probenecid group (No statistical analysis was provided in this study)

3. Van Echteld et al 2014: Colchicine for acute gout (Review)57 (Cochrane Database of Systematic Reviews 2014) • 2 RCTs30,58 included up

to April 2014

To evaluate the benefits and harms of colchicine for the treatment of acute gout

• High dose colchicine vs placebo (2 studies)

• Low dose colchicine vs placebo (1 study, 103 participants)

• High dose (4.8 mg/6 hours) versus low dose (1.8 mg/1 hour) colchicine versus placebo (126 participants)

High dose colchicine placebo Dose of colchicine: 1 mg oral, then 0.5 mg every 2 hours. Mean dose: 6.7 mg • Proportion with ≥50% decrease in pain score

from baseline (32 to 36 hours): RR 2.16 (1.28 to 3.65) (2 studies)

• Proportion with ≥50% decrease in inflammation score from baseline (32 to 36 hours): RR 10.50 (1.48 to 74.38) (1 study)

Low dose colchicine vs placebo • Proportion with ≥50% decrease in pain score

from baseline (32 to 36 hours): RR 2.43 (1.05 to 5.64) (1 study)

High dose vs low dose colchicine • Proportion with ≥50% decrease in pain score

from baseline (24 hours): RR 0.86 (0.53 to 1.41) (1 study: AGREE study)

• Proportion with ≥50% decrease in pain score from baseline (32 to 36 hours): 37% in high-dose vs 42% in low-dose; RR 0.87 (0.56 to 1.36) (1 study: AGREE study)

(Better efficacy results with colchicine than placebo and similar between the two doses of

colchicine)

High dose colchicine vs placebo Total AEs (diarrhoea, vomiting or nausea): RR 3.81 (2.28 to 6.38) (2 studies) (More AEs with high dose colchicine than

placebo) Low dose colchicine vs placebo Total AEs (diarrhoea, vomiting or nausea): RR 1.24 (0.55 to 2.79) High dose vs low dose colchicine Total AEs (diarrhoea, vomiting or nausea): 77% in high-dose vs 26% in low-dose; RR 3.00 (1.98 to 4.54) (More AEs with high-dose colchicine than

with low-dose)

4. Sriranganathan et al 2014: Interventions for tophi in gout (Review)71 (Cochrane

To assess the benefits and harms of non-surgical and surgical treatments

• Pregloticase 8 mg infusion every 2 wks vs pegloticase

Pooled results from 2 RCTs: • Resolution of tophi after 6 months: Biweekly pegloticase: 40.3% pegloticase vs 7.4% placebo; RR 5.45 (1.38 to 21.54)

Pooled results from 2 RCTs: • Withdrawals due to AEs: Biweekly pegloticase: 17.6% pegloticase vs 2.3% placebo; RR 7.59 (1.04 to 55.55)

52




Database of Systematic Reviews 2014) • 2 RCT77 (225

participants, 145 with tophi at baseline) included up to May 20, 2013

for the management of tophi in gout.

infusion monthly vs placebo

Monthly pegloticase: 21.2% pegloticase vs 7.4% placebo; RR 2.86, 95% CI 0.68 to 11.97

Monthly pegloticase: 19% pegloticase vs 2.3% placebo; RR 8.19, 95% CI 1.12 to 59.71 • Total AEs: Biweekly pegloticase: 94% pegloticase vs 95% placebo (80% due to gout flares); RR 0.99, 95% CI 0.91 to 1.07 Monthly pegloticase: 100% pegloticase vs 95% placebo (80% due to gout flares); RR 1.05, 95% CI 0.98 to 1.14

5. Van Durme 2014: Non-steroidal anti-inflammatory drugs for acute gout (Review)55 (Cochrane Database of Systematic Reviews 2014) • 23 RCTs (2200

participants) included up to October 7, 2013. Results for 18 trials are reported (Only data of interest was extracted)

To assess the benefit and safety of NSAIDs (including COXIBs) for acute gout

• NSAID vs placebo (1 trial)

• NSAIDs vs NSAIDs (13 trials. Data shown for 2 trials)

• NSAIDs vs COXIBs (4 trials)

Tenoxicam vs placebo: • Pain improvement by 50% after 24 hours: RR

2.75 (1.13 to 6.72) • Inflammation-joint swelling improvement by

50% after 24 hours: RR 1.08 (0.79 to 1.49)

NSAIDs compared with COXIBs: Pain reduction (scale 0 to 10 points): 0.03 points lower with NSAIDs compared to COXIBs (MD: -0.03, 95% CI -0.19 to 0.13). Joint swelling (scale 0 to 3 points): 0.13 points higher with NSAIDs (MD 0.13, 95% CI -0.08 to 0.34) NSAID vs NSAID (i.e. etodolac vs naproxen): Patient’s Global Assessment of treatment success: 88% etodolac vs 87% naproxen (RR 1.03; 95% CI: 0.93 to 1.14)

Tenoxicam vs placebo: • AEs (follow-up: 11 days): RR 0.2 (0.01 to

3.85)

NSAIDs compared with COXIBs for acute gout • Withdrawals due to AE: fewer with

COXIBs (RR 2.39, 95% CI 1.34 to 4.28) • Number of total AEs: lower with

COXIBs (38%) compared to NSAIDs (60%) (RR 1.56, 95% CI 1.30 to 1.86).

NSAID vs NSAID (i.e. etorolac vs naproxen): Total AEs: 1.74 (0.38, 7.86)

6. Tayar et al 2012: Febuxostat for treating chronic gout (Review)56 (Cochrane Database of Systematic Reviews 2012) • 4 RCTs and 2 open label

trials (3978 patients) included up to July 2011

To evaluate the benefits and harms of febuxostat for chronic gout.

• Febuxostat (40mg, 80mg, 120 mg and 240 mg daily).vs placebo (3 studies)

• Febuxostat (40mg, 80mg, 120 mg and 240 mg daily) vs allopurinol

Febuxostat 40 mg/day vs placebo (1 trial) • Incidence of gout flares (up to 28 days): RR

0.95 (0.52 to 1.7) • SUA <6 mg/dL (up to 28 days): RR 40.1 (2.5

to 639.1) Febuxostat 80 mg/day vs placebo (2 trials) • Incidence of gout flares: RR of 1.3 (95% CI

0.96 to 1.8) • SUA <6 mg/dL: RR 68.9 (95% CI 13.8 to

343.9)

Febuxostat 40 mg/day vs placebo (28 days) • SAE: RR 1.0 (0 to 0) • Discontinuations due to AEs: RR 1.0

(0.07 to 15.8) Febuxostat 80 mg/day vs placebo (4-28 wks) • SAE: RR 2.8 (0.72 to 10.7) • Discontinuations due to AEs: RR 1.8

(0.74 to 4.5)

53




(Only data of interest for this report was extracted)

(No differences on gout flare incidence but statistically significant reduction in SUA

levels with febuxostat) Febuxostat 40 mg/day vs allopurinol 200-300 mg/day (1 study: CONFIRMS) • Incidence of gout flares at week 24: RR

0.97; 95% CI 0.57 to 1.7 • SUA <6 mg/dL at week 24: RR 1.1; 95% CI

0.94 to 1.2 (No differences between groups)

Febuxostat 80 mg/day vs allopurinol 200-300 mg/day (3 studies: APEX, FACT and CONFIRMS) • Incidence of gout flares at 8, 26, 52 weeks:

RR 1.1 (95% CI 0.98 to 1.3) (No differences between groups)

• SUA <6 mg/dL at 8, 26, 52 weeks: RR 1.8 (95% CI 1.6 to 2.1)

(Statistically significant higher reduction in SUA levels with febuxostat)

Febuxostat 40 mg/day vs allopurinol (24 wks) • SAE: RR 0.61 (0.35 to 1.07) • Discontinuations due to AEs: RR 1.2

(0.90 to 1.7) (No differences between groups)

Febuxostat 80 mg/day vs allopurinol (24, 28 and 52 wks) • SAE: RR 0.91 (0.34 to 2.4) • Discontinuations due to AEs: RR 1.3

(0.79 to 2.1) (No differences between groups)

7. Janssens et al 2008: Systemic corticosteroids for acute gout (Review) (Cochrane Database of Systematic Reviews 2008) • 3 RCTs included up to

April 2007 (Alloway 1993; Siegel 1994 and Man 2007)

To assess the efficacy and safety of systemic corticosteroids in the treatment of acute gout in comparison with placebo, NSAIDs, colchicine, other active drugs, other therapies, or no therapy

• Triamcinolone IM injection vs oral indomethacine

• Triamcinolone IM injection vs ACTH IM injection

• Oral prednisolone vs diclophenac IM injection plus oral indomethacine

• No clinically relevant differences in the reduction of pain and other outcomes between groups in each comparison

(Statistical pooling of the results was not feasible. Inconclusive evidence)

• Alloway 1993 : 20% patients reported dyspepsia in the indomethacine group

• Man 2007: more AEs (mostly gastrointestinal AEs) reported in the diclophenac plus indomethacine group than with prednisolone group

(Statistical pooling of the results was not feasible. Inconclusive evidence)

* Data have been extracted from studies comparing FDA approved products and doses. Treatment interventions of interest for this report are highlighted in blue. Abbreviation: ACTH, adrenocorticotropic hormone; AE, adverse event; COX-2, selective cyclooxigenase-2; COXIB, COX-2 selective inhibitor; IM, intramuscular; MD, mean difference; NSAIDs, non-steroidal anti-inflammatory drugs; RCT, randomized controlled trial; RR, relative risk (95% confidence interval); SR, systematic review; SUA, serum uric acid; ULT, urate lowering therapy; wk, week

54

Appendix C. Key Evidence: Other Systematic Reviews Including Agents for Acute and Chronic Gout Study Reference and Search Date

Objective(s) Source of Evidence Evidence found: Clinical Efficacy and Safety

1. Shekelle et al 201729: Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline • Literature search

from January 2010 to March 2016

To review evidence about treatment of acute gout attacks, management of hyperuricemia to prevent attacks, and discontinuation of medications for chronic gout in adults.

28 trials (3 placebo-controlled)

See also American College of Physicians guideline in table 3 for further details Main conclusions: • Effective treatments to reduce pain in adults with acute gout attacks include

colchicine, NSAIDs, and CS. • Low-dose colchicine is equally effective as high-dose colchicine but presents a

more favorable safety profile. • ULT reduces SUA levels and decreases the risk of acute gout attacks after long-

term use (≥ 1 year).

2. Shekelle et al 201613: Management of Gout (AHRQ) • Literature search up

to October 2016

15 studies supporting acute gout (10 SR, 3 new RCTs and 2 safety studies) 45 studies supporting chronic gout management (11 SR, 1 MA, 7 new RCTs, 1 abstract, 5 secondary analysis and 20 safety studies)

See also American College of Physicians guideline in table 3 Main findings: Acute gout: • Colchicine, NSAIDs and systemic CS are effective in reducing pain associated with

gout flares (HQE) • Low-dose colchicine and high-dose colchicine have similar efficacy to treat acute

gout attacks but low dose is linked with less GI AEs (MQE) • NSAIDs are equally effective for acute gout (MQE) • ACTH is effective for acute gout (MQE) • Insufficient evidence about the effect on other outcomes (joint swelling, patient

global assessment, etc) or the effect in different subgroup of patients Chronic gout: • During the first 6 months, the risk of gout flares is not reduced by ULT (HQE) • After 1 year on ULT, the risk of gout flares is lower (MQE) • ULT is effective in reducing SUA levels (HQE) • Febuxostat 40 mg and allopurinol 300 mg are equally effective in SUA reduction

(HQE) • Administration of low dose colchicine or low dose NSAIDs when ULT is initiated

prevents from acute gout flares (HQE). Periods of colchicine or NSAID prophylaxis longer than 8 weeks are more effective (MQE)

3. Richette et al 20179: 2016 updated EULAR evidence-based recommendations

See evidence summary from EULAR under table 3

55



for the management of gout • Systematic literature

review from January 2005 to May 2016

Abbreviation: ACTH, adrenocorticotropic hormone; AE, adverse event; CI, confidence interval; COX-2, selective cyclooxigenase-2; COXIB, COX-2 selective inhibitor; GI, gastrointestinal; HQE, high quality evidence; IL, interleukin; IM, intramuscular; MD, mean difference; MQE, moderate quality evidence; NSAIDs, non-steroidal anti-inflammatory drugs; OD, odds ratio; QD, once daily; RCT, randomized controlled trial; RR, relative risk (95% confidence interval); SR, systematic review; SUA, serum uric acid; ULT, urate lowering therapy; wk, week;

56

Appendix D. Additional Evidence: Systematic Reviews and Meta-Analysis Including Agents for Acute and Chronic Gout



1. Borghi et al 201662: Urate lowering therapies in the treatment of gout: a systematic review and meta-analysis • Literature search up

to March 2015

To retrieve evidence on the clinical trials on ULT in the treatment of gout.

16 RCTs and observational studies including febuxostat (febuxostat dose ≤120 mg/day) 14 RCTs and observational studies including allopurinol (10 studies with allopurinol dose ≤300 mg/day)

Meta-analysis results: Pooled analysis: • % patients who achieved target SUA level (≤6 mg/dL): 70.7% in febuxostat group vs

44.4% in allopurinol group (based on 16 studies for febuxostat and 14 trials for allopurinol)

• % reduction of SUA levels compared with baseline: 45.3% in febuxostat group vs 33.8% in allopurinol group (based on 8 studies for febuxostat and 8 trials for allopurinol)

Comparison of febuxostat vs allopurinol in terms of OR: • % patients who achieved target SUA level (≤6 mg/dL): OR 2.64 (95% CI 1.35 to 1.97)

(based on 8 comparative trials; results favor febuxostat) • % reduction of SUA levels compared with baseline: OR 12.97 (95% CI 7.66 to 18.28)

(based on 4 comparative trials; results favor febuxostat) • % patients with renal dysfunction who achieved the target level of SUA: OR 2.15

(95% CI, 1.73 to 2.67) (based on 2 comparative trials; results favor febuxostat) • Rate of AEs: OR 0.85 (95% CI 0.75 to 0.97) (based on 6 comparative trials; results

favor febuxostat)

2. Li et al 201663: Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: a systematic review and network meta-analysis • Literature search up

to January 2016

To compare the effectiveness and safety of different treatments for hyperuricemia using network meta-analysis methodology

15 RCT (7,246 patients) including ULT (allopurinol, benzbromarone, febuxostat, pegloticase and probenecid). 8 RCTs assessed allopurinol vs febuxostat

Network Meta-analysis results: Efficacy in achieving target SUA levels: • Allopurinol vs. febuxostat 40 mg QD: OR 1.52, 95% CI: 1.15-1.99 • Allopurinol vs. febuxostat 80 mg QD: OR 3.54, 95% CI: 2.80–4.4 • Allopurinol vs. febuxostat 120 mg QD: OR 5.95, 95% CI: 4.15–8.52 Safety: incidence of AEs: • Febuxostat 120 mg QD vs allopurinol: OR 0.72, 95% CI: 0.56-0.91 • Febuxostat 120 mg QD vs febuxostat 40 mg QD: OR 0.73, 95% CI: 0.56-0.95 • Probenecid vs. allopurinol: OR 8.40, 95% CI: 1.00–70.21 • Probenecid vs. febuxostat 40 mg QD: 8.56, 95% CI: 1.02–72.01 • Probenecid vs. febuxostat 80 mg QD: 9.62, 95% CI: 1.15–80.86 • Probenecid vs. febuxostat 120 mg QD: 11.71, 95% CI: 1.38–99.29

3. Underwood 201560: Gout

To systematically review treatments for

SR and RCTs • NSAIDs are used in clinical practice for acute gout, but there is a lack of evidence from RCTs.

57



• Literature search up to September 2013

acute and chronic gout

• Low-dose of colchicine may be effective and produce less adverse events. • Oral corticosteroids are effective compared to NSAIDs, but less adverse events are

reported. • Febuxostat seems to be effective in SUA reduction compared to allopurinol;

however, gout flares recurrences do not decrease in the first year of treatment. Febuxostat may be a second line treatment in patients not responding or intolerant to allopurinol.

4. Kydd et al 201461: Urate-lowering therapy for the management of gout: a summary of 2 Cochrane reviews • Literature search

from October 2011 to January 2014

To systematically review the evidence on the efficacy, safety, and cost-effectiveness of ULT for gout (as part of the 3e Initiative)

17 efficacy trials 31 safety trials 3 cost-effectiveness analysis

• Allopurinol, febuxostat, and pegloticase are effective in reducing SUA levels versus placebo

• Febuxostat (≥80 mg) was more effective than allopurinol • Pegloticase and febuxostat (≥120 mg) reported more acute flares than placebo • Pegloticase reported higher withdrawals due to AEs and infusion reactions than

placebo

5. Khanna et al 201478: Treatment of acute gout: A systematic review • Literature search up

to May 2013

To review the published data on the pharmacologic and non-pharmacologic agents used for the treatment of acute gouty arthritis

NSAIDs: 23 active comparator trials (15 studies evaluating indomethacin. Studies analyzing other NSAIDs, COXIBs, CS, ACTH, IL-inhibitor and Chinese herbs were also identified

Main findings: NSAIDs, COXIBs, CS, colchicine and ACTH were effective for gout flares • Indomethacin improve pain • Naproxen vs etodolac: no differences between groups • Naproxen vs prednisolone: no differences between groups • Indomethacin vs COXIBs: no differences between groups, except for low dose

celecoxib that was less effective • CS vs NSAIDs and IM triamcinolone vs active comparator: CS are effective in

reducing pain compared to NSAIDs, IL-1 and ACTH • IM ACTH vs indomethacin: better efficacy with ACTH • IM ACTH vs IM triamcinolone: similar efficacy • Oral colchicine vs placebo: pain reduction within 24-48 hours. Low dose colchicine

is as effective as high dose colchicine but reported less gastrointestinal AEs.

6. Villazor-Isidro et al 201464: Urate lowering efficacy of febuxostat versus allopurinol in hyperuricemic patients with gout

To determine the efficacy and safety of febuxostat compared with allopurinol in lowering sUA level in patients with

3 RCTs included in the meta-analysis (FACT, CONFIRMS and APEX)

Meta-analysis results: Urate lowering efficacy: • OR 0.31 (95%CI, 0.24 to 0.39): Less patients with elevated SUA in the febuxostat

80 mg group compared to allopurinol group (40% vs 66%, respectively) • Subgroup of patients with renal normal renal function: OR 0.34 (95% CI 0.22 to

0.54). Favors febuxostat 80 mg

58



• Literature search date not reported

hyperuricemia in gout with a baseline sUA ≥ 8 mg/ dl

• Subgroup of patients with renal impaired renal function: OR 0.28 (95%CI 0.18 to 0.45) Favors febuxostat 80 mg

Adverse events: Incidence of AEs: • Allopurinol vs febuxostat 120 mg: OR 0.90 (95% CI 0.84 to 0.96) • Allopurinol vs febuxostat 80 mg: OR 0.90 (95% CI 0.85 to 0.96)

(More AEs with allopurinol vs febuxostat 80 or 120 mg) Risk of abnormal liver function: • Allopurinol vs febuxostat 120 mg: OR 1.14 (95% CI 0.95 to 1.37) • Allopurinol vs febuxostat 80 mg: OR 1.21 (95% CI 0.89 to 1.64)

(No significant difference between groups, although there is a tendency of higher risk of abnormal liver enzymes with febuxostat 80 and 120 mg

7. Ye et al 201365: Efficacy and Tolerability of Febuxostat in Hyperuricemic Patients With or Without Gout: A Systematic Review and Meta-Analysis • Literature search up

to February 2012

To assess the efficacy and tolerability of febuxostat in hyperuricemic patients with/without gout

10 trials Meta-analysis results: • Proportion of patients achieved the target serum urate level (sUA 6.0 mg/dL) at

the final visit: Febuxostat vs allopurinol (100-300 mg/day): OR 3.14; 95 CI 1.82 to 5.44; P <0.01

Subgroup analysis: • Febuxostat 40 mg vs allopurinol: 50.9% vs 45.6%; OR 1.25; 95% CI, 1.05 to 1.49; P<

0.01 • Febuxostat 80 mg vs allopurinol: 71.5% vs 45.6% • Febuxostat 120 mg vs allopurinol: 82% vs 45.6% Safety: No differences in the safety profile

8. Faruque 201366: A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout • Literature search up

to February 2012

To compare febuxostat to allopurinol for treatment of chronic gout.

5 studies Meta-analysis results: • Gout flares and gouty arthritis: - Febuxostat vs allopurinol: RR 1.16, 95% CI 1.03 to 1.30 (a slightly lower risk with

allopurinol) • Incidence of AEs: - Febuxostat vs allopurinol: RR 0.94, 95%CI 0.90 to 0.99 (lower incidence with

febuxostat) • SUA reduction to target levels: - Febuxostat vs allopurinol: RR 1.56,95% CI 1.22 to 2.00 (better efficacy with

febuxostat)

Abbreviation: ACTH, adrenocorticotropic hormone; AE, adverse event; CI, confidence interval; COX-2, selective cyclooxigenase-2; COXIB, COX-2 selective inhibitor; GI, gastrointestinal; HQE, high quality evidence; IL, interleukin; IM, intramuscular; MD, mean difference; MQE, moderate quality evidence; NSAIDs, non-steroidal anti-inflammatory drugs; OR, odds ratio; QD, once daily; RCT, randomized controlled trial; RR, relative risk (95% confidence interval); SR, systematic review; SUA, serum uric acid; ULT, urate lowering therapy; wk, week

59

Appendix E. Randomized Controlled Trial of Lesinurad (Not Included in the Previous Systematic Reviews) Study Reference and Design Objective(s) Treatment Interventions Clinical Efficacy Clinical Safety 1. Saag 2017 [CLEAR 1]70

RCT: 12-month, multicenter, randomized, double-blind, placebo-controlled phase III trial

To investigate daily lesinurad (200 mg or 400 mg orally) added to allopurinol versus placebo plus allopurinol in patients with suboptimal response to allopurinol

Lesinurad 200 mg or 400 mg + allopurinol 200-600 mg vs allopurinol 200-600 mg + placebo (n=603)

Primary endpoint: % of patients with SUA level of <6.0mg/dl by month 6: • 27.9% allopurinol alone • 54.2% lesinurad 200 mg + allopurinol • 59.2% lesinurad 400 mg + allopurinol

(p<0.0001 for each comparison) Secondary endpoints: • Gout flare rate and complete resolution of

tophi: No statistically significant differences between groups

Safety outcomes: allopurinol alone vs lesinurad 200 mg + allopurinol vs lesinurad 400 mg + allopurinol • TEAEs: 68.7%, 73.1%, 77.6% (most

common AEs were mild to moderate: upper respiratory tract infection, increased blood creatinine phosphokinase levels, sinusitis, increased blood creatinine levels and headache)

• Discontinuations due to TEAEs: 4.0%, 8.0% and 7.0%

• Serious TEAEs: 5.5%, 4.5%, and 8.0% (mostly CV events)

• Renal TEAEs: 3.5%, 4.0%, and 10.0%. One renal failure in lesinurad 400 mg group

• Serum creatinine elevations ≥1.5 times the baseline levels: 1.0%, 6.0% and 15.9%

• CV events: 3.5%, 4.5%, and 4.0%

Abbreviations: CV, cardiovascular; TEAE, treatment-emergent adverse events

60

Appendix F. Randomized Controlled Trials Included in Systematic Reviews and Meta-analyses for Chronic Gout*

RCTs

SYSTEMATIC REVIEWS Cochrane Systematic Reviews Meta-analyses Other Systematic Reviews

Seth et al 20144 (A vs F; A vs P)

Kydd et al 201438 (A vs P)

Tayar et al 201256 (F vs A)

Borghi et al 201662 (A vs F)

Li et al 201663** (A vs F or other ULT)

Villazor-Isidro et al 201464 (A vs F)

Ye et al 201365*** (A vs F)

Faruque 201366 (A vs F)

Shekelle 201729 (ACP)

Shekelle 201613 (AHRQ)

Richette et al 20179 (EULAR)

Kydd et al 201461 (A vs F; A vs P)

Underwood 201560 (A vs F)

Allopurinol versus febuxostat Becker et al 201049 (CONFIRMS)

√ √ √ √ √ √ √ √ √ √ √

Becker et al 200932 (EXCEL) √ √ √

Schumacher et al 200867 (APEX) √ √ √ √ √ √ √ √ √ √ √ √

Becker et al 200548 (FACT) √ √ √ √ √ √ √ √ √ √ √ √

Singal et al 201179 Bangladesh (non- randomized trial)

√ √

Kamatani et al 201180 Japan √ √ √ √ √

Kamatani et al, 201181 Japan (phase II trial)

√ √ √ √ √

Hatoum 201382 (Abstract only) √

Huang 201483 China √ √ √

Singh 2015,84 U.S. (cohort study)

√

Xu 201585 China √ √ Yu 201686 Taiwan and China

√ √

Allopurinol versus probenecid Scott et al 196668 √ √ √ √ √

* Only intra-class head-to-head trials were included in this table. ** Also includes placebo-controlled studies and RCTs including ULT products not approved in the U.S. (not extracted in this table); *** Also includes placebo-controlled studies (not extracted in this table) Abbreviation: A, allopurinol; ACP; American College of Physicians; AHRQ, Agency of Healthcare Research and Quality; EULAR, European League Against Rheumatism; F, febuxostat; P, probenecid; RCT, randomized controlled trials; ULT, urate lowering therapy

61

Appendix G. List of Excluded References 1. Bove M, Cicero AF, Veronesi M, Borghi C. An evidence-based review on urate-lowering treatments: implications for

optimal treatment of chronic hyperuricemia. Vasc Health Risk Manag. 2017;13:23-28. 2. Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first

controlled study in acute gout. Aust N Z J Med. 1987;17(3):301-304. 3. Altan A, Shiozawa A, Bancroft T, et al. A real-world study of switching from allopurinol to febuxostat in a health plan

database. Journal of Clinical Rheumatology. 2015;21(8):411-418. 4. Becker MA, MacDonald PA, Hunt B, Gunawardhana L. Treating hyperuricemia of gout: safety and efficacy of

febuxostat and allopurinol in older versus younger subjects. Nucleosides Nucleotides Nucleic Acids. 2011;30(12):1011-1017.

5. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63.

6. Becker MA, Schumacher HR, Jr., Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450-2461.

7. Becker MA, Schumacher HR, MacDonald PA, Lloyd E, Lademacher C. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009;36(6):1273-1282.

8. Bridgeman MB, Chavez B, Author A, et al. Febuxostat for the treatment of gout. Expert Opinion on Pharmacotherapy. 2015;16(3):395-398.

9. Castrejon I, Toledano E, Rosario MP, et al. Safety of allopurinol compared with other urate-lowering drugs in patients with gout: A systematic literature review and meta-analysis. Annals of the Rheumatic Diseases. 2013;72 SUPPL. 3.

10. Chohan S, Becker MA, MacDonald PA, Chefo S, Jackson RL. Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol. Arthritis Care Res (Hoboken). 2012;64(2):256-261.

11. Curiel RV, Guzman NJ, Author A, et al. Challenges Associated with the Management of Gouty Arthritis in Patients with Chronic Kidney Disease: A Systematic Review. Seminars in Arthritis and Rheumatism. 2012;42(2):166-178.

12. De Vera MA, Marcotte G, Rai S, et al. Medication adherence in gout: A systematic review. Arthritis Care and Research. 2014;66(10):1551-1559.

13. Eminaga F, Le-Carratt J, Jones A, et al. Does the initiation of urate-lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature review. Rheumatology International. 2016;36(12):1747-1752.

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

15. Fan M, Liu J, Zhao B, et al. Indirect comparison of urate-lowering therapies for hyperuricemic patients with or without gout: Meta-analysis of randomized, controlled trials. International Journal of Rheumatic Diseases. 2016;19 Supplement 2:4.

16. Febuxostat: Hyperuricaemia: Risk of gout attacks AUTHOR ADDRESSES SOURCE Prescrire International (2009) 18:100 (63-65). Date of Publication: April 2009. 2009.

17. Fravel MA, Ernst ME. Management of gout in the older adult. Am J Geriatr Pharmacother. 2011;9(5):271-285. 18. Graf SW, Whittle SL, Wechalekar MD, et al. Australian and New Zealand recommendations for the diagnosis and

management of gout: Integrating systematic literature review and expert opinion in the 3e Initiative. International Journal of Rheumatic Diseases. 2015;18(3):341-351.

19. Gaffo AL, Saag KG. Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Core Evid. 2010;4:25-36.

20. Garay RP, El-Gewely MR, Labaune JP, et al. Therapeutic perspectives on uricases for gout. Joint Bone Spine. 2012;79(3):237-242.

21. Gulli G, De Filippis L, Author A, et al. [Febuxostat: A new drug for an old disease. Do we really need it? ORIGINAL (NON-ENGLISH) TITLE Febuxostat: Un nuovo farmaco per una vecchia malattia. Ne abbiamo davvero bisogno?]. Italian Journal of Medicine. 2009;3(2):103-106.

62

22. Huang X, Du H, Gu J, et al. An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia. Int J Rheum Dis. 2014;17(6):679-686.

23. Jackson RL, Hunt B, MacDonald PA, et al. The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age. BMC geriatrics. 2012;12:11.

24. Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL, van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet. 2008;371(9627):1854-1860.

25. Janssens HJEM, Janssen M, Van De Lisdonk EH, et al. [Prednisolone, a suitable first-choice treatment for gout pain: A randomized, double-blind, equivalent trial with naproxen as reference ORIGINAL (NON-ENGLISH) TITLE Prednisolon, een geschikte eerste keus voor pijnbehandeling bij jicht: Een gerandomiseerde dubbelblinde equivalentietrial met naproxen als referentie]. Nederlands Tijdschrift voor Geneeskunde. 2009;153(23):1108-1116.

26. Kamatani N, Fujimori S, Hada T, et al. An allopurinol-controlled, randomized, double-dummy, double-blind, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J. 2011;17(4 Suppl 2):S13-18.

27. Khanna P, Singh MK, Bae S, et al. Oral urate lowering therapies in chronic gout: A systematic review and meta-analysis. Arthritis and Rheumatism. 2011;63:10 SUPPL. 1.

28. Khanna P, Singh MK, FitzGerald JD, et al. Pharmacological treatment of acute gout: A systematic review. Arthritis and Rheumatism. 2011;63:10 SUPPL. 1.

29. Kim KY, Wigle PR, Author A, et al. Febuxostat: A novel, non-purine xanthine oxidase inhibitor. Journal of Pharmacy Technology. 2006;22(6):342-348.

30. Kumar B, Agarwal PK, Author A, et al. Comparative evaluation of efficacy and safety profile of febuxostat with allopurinol in patients with hyperuricemia and gout. International Journal of Pharma Medicine and Biological Sciences. 2013;2(4):52-56.

31. Lioté F, Ea HK, Author A, et al. Recent developments in crystal-induced inflammation pathogenesis and management. Current Rheumatology Reports. 2007;9(3):243-250.

32. Maistreli S, Kourlaba G, Tzanetakos C, et al. The clinical and pharmac oeconomic value of febuxostat for the treatment of persistent hyperuricaemia: A systematic literature review. Value in Health. 2016;19(7):A538

33. Manara M, Bortoluzzi A, Favero M, et al. Italian Society of Rheumatology recommendations for the management of gout. Reumatismo. 2013;65(1):4-21.

34. Pohar S, Murphy G. Febuxostat for prevention of gout attacks. Issues Emerg Health Technol. 2006(87):1-4. 35. Schumacher HR, Jr., Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing

serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59(11):1540-1548.

36. Scott JT. Comparison of allopurinol and probenecid. Ann Rheum Dis. 1966;25(6 Suppl):623-626. 37. Seth R, Kydd ASR, Falzon L, et al. Preventing attacks of acute gout when introducing urate-lowering therapy: A

systematic literature review. Journal of Rheumatology. 2014;41(SUPPL. 92):42-47. 38. Sezai A, Soma M, Nakata K, et al. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery

patients (NU-FLASH Trial). Circ J. 2013;77(8):2043-2049. 39. Sezai A, Soma M, Nakata K, et al. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery

patients with chronic kidney disease (NU-FLASH trial for CKD). J Cardiol. 2015;66(4):298-303. 40. Shannon JA, Cole SW. Pegloticase: a novel agent for treatment-refractory gout. Ann Pharmacother. 2012;46(3):368-

376. 41. Singal KK, Goyal S, Gupta P, et al. Comparison between Allopurinol and Febuxostat in management of gout patients -

A prospective study. Bangladesh Journal of Medical Science. 2011;10(4):257-259. 42. Singh JA, Author A, Medicine Service BVAM, et al. Advances in gout: Some answers, more questions. Arthritis

Research and Therapy. 2010;12:5 Article Number: 136. 43. Stevenson M, Pandor A. Febuxostat for the management of hyperuricaemia in patients with gout: a NICE single

technology appraisal. Pharmacoeconomics. 2011;29(2):133-140.

63

44. Stevenson M, Pandor A. Febuxostat for the treatment of hyperuricaemia in people with gout: a single technology appraisal. Health Technol Assess. 2009;13 Suppl 3:37-42.

45. Sun Y, Li L, Zhou TY, et al. A model-based meta-analysis to compare urate-lowering response rate of febuxostat and allopurinol in gout patient. Yaoxue Xuebao. 2014;49(12):1674-1683.

46. Sutaria S, Katbamna R, Underwood M, et al. Effectiveness of interventions for the treatment of acute and prevention of recurrent gout - A systematic review. Rheumatology. 2006;45(11):1422-1431.

47. Tausche AK, Christoph M, Forkmann M, et al. As compared to allopurinol, urate-lowering therapy with febuxostat has superior effects on oxidative stress and pulse wave velocity in patients with severe chronic tophaceous gout. Rheumatol Int. 2014;34(1):101-109.

48. Underwood M. Gout. Clin Evid (Online). 2008:17. 49. Underwood M. Gout. Clin Evid (Online). 2011:17. 50. Whelton A, MacDonald PA, Chefo S, Gunawardhana L. Preservation of renal function during gout treatment with

febuxostat: a quantitative study. Postgrad Med. 2013;125(1):106-114. 51. White WB, Chohan S, Dabholkar A, Hunt B, Jackson R. Cardiovascular safety of febuxostat and allopurinol in patients

with gout and cardiovascular comorbidities. Am Heart J. 2012;164(1):14-20. 52. Winzenberg T, Zochling J. Colchicine--what is its place in the management of acute gout? Aust Fam Physician.

2007;36(7):529-530. 53. Xu S, Liu X, Ming J, et al. A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and

efficacy of oral febuxostat in Chinese gout patients with hyperuricemia. Int J Rheum Dis. 2015;18(6):669-678. 54. Yim BT, Sims-McCallum RP, Chong PH. Rasburicase for the treatment and prevention of hyperuricemia. Ann

Pharmacother. 2003;37(7-8):1047-1054. 55. Yu KH, Lai JH, Hsu PN, et al. Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a

randomized, open-label, multicentre, allopurinol-controlled study. Scandinavian Journal of Rheumatology. 2016;45(4):304-311.

56. Yu KH. Febuxostat: a novel non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in gout. Recent Pat Inflamm Allergy Drug Discov. 2007;1(1):69-75.

57. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65(10):1312-1324.

Note: Duplicated references (n=8) were not included in this list

Utah Medicaid Pharmacy and Therapeutics Committee Drug ... · unapproved drugs in order to continue...

Documents

Transcript of Utah Medicaid Pharmacy and Therapeutics Committee Drug ... · unapproved drugs in order to continue...