Uloric Step Therapy Program

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1 Uloric Step Therapy Program Policy Number: Last Review: 7/2017 Origination: 7/2014 Next Review: 7/2018 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for brand name Uloric when the following criteria are met. The brand name Uloric affected are: Uloric (febuxostat tablets Takeda) When Policy Topic is covered Step therapy rules have been developed to encourage the use of allopurinol prior to Uloric. If the step therapy rule is not met for a Step 2 agent at the point of service, coverage will be determined by the step therapy criteria below. All approvals are provided for 1 year in duration. Automation: Patients with a history of one Step 1 drug within the 130-day look-back period are excluded from step therapy. Step 1: allopurinol (Zyloprim ) tablets Step 2: Uloric tablets CRITERIA Exceptions for Uloric can be made for those who have met one of the following criteria: 1. The patient has tried allopurinol (brand or generic) at any time in the past. 2. The patient has renal insufficiency or decreased renal function with an estimated creatinine clearance (CrCl) less than 50 ml/min. 3. The patient is receiving concomitant medications that have significant drug-drug interactions with allopurinol, which are not noted with Uloric (e.g., cyclosporine, chlorpropamide). 4. No other exceptions are recommended. When Policy Topic is not covered The use of Uloric is considered investigational for all other indications. Considerations Uloric requires prior authorization through the Clinical Pharmacy Department. This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers.

2 Description of Procedure or Service Uloric - Indications and Dosing Uloric is a xanthine oxidase inhibitor indicated for the chronic management of hyperuricemia in patients with gout. 1 The agent is not recommended for the treatment of asymptomatic hyperuricemia. Uloric achieves its therapeutic effect by decreasing serum uric acid. The recommended starting dose of Uloric is 40 mg once daily (QD). For patients who do not achieve a serum uric acid < 6.0 mg/dl after 2 weeks with 40 mg, Uloric 80 mg QD is recommended. No dosage adjustment is needed when administering Uloric to patients with mild to moderate renal or hepatic impairment. There are insufficient data in patients with severe renal impairment; use caution when administering to such patients. The prescribing information for Uloric notes that no studies have been conducted in patients with secondary hyperuricemia (including patients being treated for Lesch-Nyhan syndrome or malignant disease, or in organ transplant patients); use of Uloric in these patients is not recommended. 1 Zyloprim (allopurinol tablets; generics) is another xanthine oxidase inhibitor that is indicated for the management of patients with signs and symptoms of primary or secondary gout (e.g., acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy). 2 It is also indicated for the management of patients with leukemia, lymphoma, and malignancies who are receiving cancer therapy which causes elevations on serum and urinary uric acid levels. In addition, it is also indicated for the management of patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds > 800 mg/day for male patients and > 750 mg/day for female patients. Zyloprim is also not indicated for the treatment of asymptomatic hyperuricemia. Allopurinol has been available in the US for approximately 40 years. The average dose of allopurinol is 200 to 300 mg/day for patients with mild gout and 400 to 600 mg/day for patients with moderately severe tophaceous gout. The starting dosage of allopurinol should not be > 100 mg/day and the maximal recommended dosage is 800 mg daily. Patients with impaired renal function should be carefully observed during the early stages of administration of allopurinol. Since allopurinol and its metabolites are primarily eliminated by the kidney, accumulation of the agent can occur in renal failure, and the dose of allopurinol should consequently be reduced. With a creatinine clearance (CrCl) of 10 to 20 ml/min, a daily dosage of 200 mg of allopurinol is suitable. When the CrCl < 10 ml/min, the daily dosage should not exceed 100 mg. With extreme renal impairment (CrCl < 3 ml/min) the interval between doses may also need to be lengthened. Rationale Comparative trials Uloric vs. Allopurinol Three randomized, double-blind, controlled trials that were pivotal for Uloric approval by the Food and Drug Administration (FDA) have compared it to allopurinol. 1,3-5 The trials range from 6 to 12 months in duration and defined hyperuricemia as a baseline serum uric acid level 8.0 mg/dl. In these trials, Uloric 80 mg QD was superior to a fixed dose of allopurinol 300 mg QD in patients with hyperuricemia and gout. The proportion of patients with serum uric acid levels < 6.0 mg/dl at final visit in the three trials was 67%, 72%, and 74% with Uloric 80 mg and 42%, 39%, and 36% with allopurinol. Uloric 40 mg QD was not superior to allopurinol 300 mg QD but was efficacious at decreasing serum uric acid levels to < 6.0 mg/dl. Uloric 40 mg QD and 80 mg QD were superior to allopurinol 300 mg/day at reducing serum uric acid levels to < 6.0 mg/dl at final visit in patients with mild or moderate impairment (50%, 72% and 42%, respectively). Also of note, fewer patients with higher baseline serum urate levels ( 10.0 mg/dl) and/or tophi achieved the goal of lowering serum uric acid to less than 6.0 mg/dl at final visit. However, more patients given Uloric 80 mg QD achieved this goal compared with patients given Uloric 40 mg QD or allopurinol. Uloric may be used in patients with mild to moderate kidney disease without dose reduction. 1 The urate lowering ability of Uloric 80 mg QD was significantly greater than allopurinol (300, 200, or 100 mg doses) in female patients in the study (older patients with higher rates of obesity and other comorbidities). 6 Likewise, another posthoc analysis on one of the pivotal trials 5 showed that Uloric is superior to allopurinol (200 or 300 mg) in achieving the target serum uric acid level < 6.0 mg/dl in elderly patients 65 years of age with mild to moderate renal impairment. 7 Though the pivotal studies for Uloric demonstrated better efficacy than allopurinol, it is important to note that these studies used a fixed, lower dose of allopurinol. 14 Other clinical trials data have also compared Uloric and allopurinol. 8

3 A randomized, single-blind comparative study assessed the efficacy of allopurinol or Uloric in cardiac surgery patients. 13 Even after 1 month of treatment, the uric acid level was significantly lower in the Uloric group than the allopurinol group. The target uric acid level ( 6.0 mg/dl) was achieved in 71.8% of the Uloric group and in 30.4% of the allopurinol group. It was reached in 91.5% and 65.2% of the Uloric and allopurinol groups, respectively, after 3 months and in 95.8% and 69.6% of the groups, respectively, after 6 months. Uloric Long-Term Use A 5-year study 9 assessed the urate-lowering clinical efficacy and safety of long-term Uloric in patients with gout (Febuxostat Open-label Clinical trial of Urate-lowering efficacy and Safety [FOCUS]). A total of 116 patients were initially enrolled and the final doses, after adjustment, were as follows: Uloric 40 mg (n = 8/116), Uloric 80 mg (n = 79/116), and Uloric 120 mg (n = 29/116). At 5 years, 93% of the remaining patients (n = 54/58) had serum uric acid levels < 6.0 mg/dl; gout flares were rare. In patients with tophus at baseline, resolution was achieved in 69% (n = 18/26) of patients by the final visit. Guidelines for Gout The American College of Rheumatology (ACR) guidelines (2012) for the management of gout recommend xanthine oxidase inhibitors, either allopurinol or Uloric, as first-line pharmacologic uratelowering therapies (ULT). 12 The panel did not prefer either allopurinol or Uloric over the other agent. Serum urate level should be lowered sufficiently to improve the signs and symptoms of gout, with the target level < 6 mg/dl at a minimum. Probenacid is recommended as an alternative first-line pharmacologic therapy if the patient had intolerance or contraindications to either allopurinol or Uloric; however, it is not recommended as first-line monotherapy in patients with CrCl < 50 ml/min. Combination therapy with one xanthine oxidase inhibitor and one uricosuric agent is appropriate when the target serum urate levels have not been achieved by a xanthine oxidase inhibitor alone. Krystexxa (pegloticase injection, for intravenous infusion) is appropriate in patients with severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral ULTs. The European League Against Rheumatism (EULAR) [2011] recommends ULT in patients with recurrent acute attacks (> 1 attack/ year), arthropathy, tophi, nephrolithiasis, or radiographic changes of gout. 10 The guidelines state that xanthine oxidase inhibitors (allopurinol and Uloric) are the agents of choice for ULT (goal serum uric acid level < 6.0 mg/dl). If allopurinol toxicity occurs, it should be stopped immediately and other treatment options (Uloric or probenecid) can be considered. Allopurinol and Uloric should not be coadministered. Uloric may be a good therapeutic option in patients with gout who experience severe allopurinol hypersensitivity syndrome (AHS). A review article compared the currently available guidelines for management of gout, which are published by the various organizations (EULAR, ACR, British Society of Rheumatology, and the 3e initiative [Multinational Evidence, Exchange and Expertise group]). 15 It noted that a treat-to-target strategy to achieve serum urate of at least 6 mg/dl or lower is agreed upon across all guidelines. With regards to ULTs, all guidelines, except the ACR, recommends allopurinol as a first-line agent; ACR recommends allopurinol or Uloric. All guidelines also support the use of combination therapy (e.g., xanthine oxidase inhibitors and uricosuric agents) if monotherapy is not effective. International Position Paper on Uloric In 2010, an international position paper recommended that Uloric should not be considered as first-line ULT in patients with gout and associated hyperuricemia. Uloric may be considered under the following circumstances: 1) patients who are intolerant of allopurinol and have failed, or who have contraindications for available uricosuric ULT; and 2) patients who do not achieve the therapeutic target of allopurinol at the highest dosage recommended, or the highest dose that they can tolerate, or at the highest dose that is individually indicated. Contraindications to Uloric use, as well as recommended monitoring, are also provided. References 1. Uloric tablets [prescribing information]. Deerfield, IL: Takeda; November 2012.

4 2. Zyloprim tablets [prescribing information]. San Diego, CA: Prometheus Laboratories, Inc.; October Schumacher HR, 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): Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353: 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 [Epub 2010 Apr 6]. 6. Chohan S, Becker MA, MacDonald PA, et al. Women with gout: efficacy and safety of uratelowering with febuxostat and allopurinol. Arthritis Care Res. 2012;64: Jackson RL, Hunt B, MacDonald PA. The efficacy and safety of febuxostat for urate lowering in gout patients [greater than or equal to] 65 years of age. BMC Geriatr 2012;12:11 8. Becker MA, Schumacher HR, MacDonald PA, et al. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009;36(6): Schumacher HR, Becker MA, Lloyd E, et al. Febuxostat in the treatment of gout:5-year findings of the FOCUS efficacy and safety study. Rheumatol. 2009;48: Hamburger M, Baraf HSB, Adamson TC III, et al recommendations for the diagnosis and management of gout and hyperuricemia. Postgrad Med. 2011;123: Jansen TL, Richette P, Perez-Ruiz F, et al. International position paper on febuxostat. Clin Rheumatol. 2010;29: Khanna D, Fitzgerald JD, Khanna PP, et al American College of Rheumatology Guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64: Sezai A, Soma M, Nakata Ki, et al. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients (NU-FLASH Trial). Circ J. 2013;77: Burns CM, Wortmann RL. Latest evidence on gout management: What the clinician needs to know. Ther Adv Chronic Dis. 2012;3: Khanna PP, FitzGerald J. Evolution of management of gout: a comparison of recent guidelines. Curr Opin Rheumatol. 2015;27: Other References Utilized Burns CM, Wortmann RL. Gout therapeutics: new drugs for an old disease. Lancet. 2011;377: Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep. 2009;11: Ernst ME, Clark EC, Hawkins DW. Gout and hyperuricemia. In: Dipiro JT, Talbert RL, Yee GC, et al., (Eds). Pharmacotherapy a Pathophysiologic Approach. 7 th ed. New York NY: McGraw-Hill. 2008; Gray CL, Walters-Smith NE. Febuxostat for treatment of chronic gout. Am J Health-System Pharm. 2011;68: Love BL, Barrons R, Veverka A, Snider KM. Urate-lowering therapy for gout: focus on febuxostat. Pharmacother. 2010;30(6): Reinders MK, Jansen TLTA. Management of hyperuricemia in gout: focus on febuxostat. Clin Interv Aging. 2010;5:7-18. Billing Coding/Physician Documentation Information Pharmacy benefit

5 Additional Policy Key Words Policy Number: Policy Implementation/Update Information 07/ / / /2017 New Policy titled Uloric Step Therapy Program Annual review no changes made Annual review no changes made to policy statement Annual review no changes made to policy statement State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.