OBJECTIVE

The intent of the URAT1 Inhibitor Prior Authorization criteria is to promote appropriate selection of patients for treatment according to product labeling and/or clinical studies and/or guidelines. Doses above the set limit will be approved if the requested quantity is below the maximum FDA limit and cannot be dose optimized or when the requested quantity is above the maximum FDA limit and the prescriber has submitted documentation in support of therapy with a higher dose.

TARGET AGENT

Duzallo^® (lesinurad/allopurinol)

Zurampic^® (lesinurad)

Brand (generic)	GPI	Multisource Code	Quantity Limit Per Day
Duzallo (lesinurad/allopurinol)
200 mg/200 mg tablet	68990002500320	M, N, O, or Y	1 tablet
200 mg/300 mg tablet	68990002500330	M, N, O, or Y	1 tablet
Zurampic (lesinurad)
200 mg tablet	68000040000320	M, N, O, or Y	1 tablet

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL

Initial Evaluation

URAT1 Inhibitor will be approved when ALL of the following is met:

      1.  The patient has a diagnosis of gout

           AND

      2.  ONE of the following:

                a.  The patient has a baseline serum uric acid level that is >6.0 mg/dL

                      OR

2.  

                b.  The patient’s current serum uric acid level is ≤6.0 mg/dL and the prescriber has provided documentation supporting the further lowering of the serum uric acid level

           AND

      3.  ONE of the following:

                a.  The patient is currently taking at least allopurinol 300 mg OR at least febuxostat 80 mg

                     OR

1.  

                b.  BOTH of the following:

                             i.  The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to allopurinol

                                 AND

1. 1.  

                            ii.  The patient has a documented intolerance or expected intolerance to febuxostat 80 mg or higher

                    OR

1. 3. BOTH of the following:

                             i.  The patient has a documented intolerance FDA labeled contraindication, or hypersensitivity to febuxostat​​​​​​​

                                 AND

1. 1.  

                            ii.  The patient has a documented intolerance or expected intolerance to allopurinol 300 mg or higher ​​​​​​​

                    OR

1.  

               d.  The patient has a documented intolerance or expected intolerance to 300 mg or higher of allopurinol AND has a documented intolerance or expected intolerance to febuxostat 80 mg or higher

          AND

     4.  The patient will be taking a xanthine oxidase inhibitor (e.g. allopurinol or febuxostat) concurrently with the requested agent (Duzallo requests automatically qualify)

           AND

     5.  The patient does NOT have an FDA labeled contraindication to the requested agent

           AND

      6.  ONE of the following:

                 a.  The requested quantity (dose) does NOT exceed the program quantity limit

                      OR

1.  

                 b.  ALL of the following:

                             i.  The requested quantity (dose) is greater than the program quantity limit

                                 AND

1. 1.  

                            ii.  The requested quantity (dose) does NOT exceed the maximum FDA labeled dose

                                 AND

1. 1.  

                           iii.  The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit

                    OR

1.  

               c.  ALL of the following:

                           i.  The requested quantity (dose) is greater than the program quantity limit

                                AND

1. 1.  

                           ii.  The requested quantity (dose) is greater than the maximum FDA labeled dose

                                AND

1. 1.  

                          iii.  The prescriber has submitted documentation in support of therapy with a higher dose for the requested indication

 

Length of approval: 12 months

 

Renewal Evaluation

URAT1 Inhibitor will be approved when ALL of the following are met:

      1.  The patient has been previously approved for the requested agent through Prime Therapeutics’ Prior Authorization process

           AND

      2.  The patient will be taking a xanthine oxidase inhibitor (e.g. allopurinol or febuxostat) concurrently with the requested agent (Duzallo requests automatically qualify)

           AND

      3.  The patient does NOT have an FDA labeled contraindication to the requested agent

           AND

     4.  ONE of the following:

               a.  The requested quantity (dose) does NOT exceed the program quantity limit

                    OR

               b.  ALL of the following:

                           i.  The requested quantity (dose) is greater than the program quantity limit

                               AND

                          ii.  The requested quantity (dose) does NOT exceed the maximum FDA labeled dose

                               AND

                         iii.  The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit

                   OR

              c.  ALL of the following:

                          i.  The requested quantity (dose) is greater than the program quantity limit

                              AND

                         ii.  The requested quantity (dose) is greater than the maximum FDA labeled dose

                              AND

                        iii.  The prescriber has submitted documentation in support of therapy with a higher dose for the requested indication

 

Length of approval: 12 months

 

FDA APPROVED INDICATIONS AND DOSAGE^1,2

Agent	Indication	Dosage
Duzallo® (lesinurad/allopurinol) tablets	Treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a medically appropriate daily dose of allopurinol alone. Limitations of Use: Duzallo is not recommended for the treatment of asymptomatic hyperuricemia.	One tablet once daily by mouth
Zurampic® (lesinurad) tablets	Indicated in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. Limitations of Use: Zurampic is not recommended for the treatment of asymptomatic hyperuricemia. Zurampic should not be used as monotherapy.	200 mg once daily in combination with a xanthine oxidase inhibitor, including allopurinol or febuxostat The maximum daily dose of Zurampic is 200 mg.

CLINICAL RATIONALE

Gout is one of the most common forms of inflammatory arthritis and is caused by accumulation of excess urate crystals (monosodium urate) in joint fluid, cartilage, bones, tendons, bursas, and other sites. In absence of hyperuricemia, defined as serum urate levels >6.8 mg/dL (405 micromol/L) and of urate crystal deposition and inflammatory responses to crystal deposition, the signs and symptoms of gout do not occur. Typically, gout initially presents as acute episodic arthritis and can also manifest as chronic arthritis of 1 or more joints. Tophi, mainly found in articular, periarticular, bursal, bone, auricular, and cutaneous tissues, are pathognomonic features of gout. Risk factors for gout include hypertension, obesity, metabolic syndromes, chronic kidney disease, consuming alcoholic drinks, consuming red meats and some seafood, and diuretic use.^3-6

Goals of therapy are to treat acute gout episodes, prevent the recurrence of gout flares, and to reverse prior signs of the disease by achieving and maintaining subsaturating serum urate concentrations.^4,6 Management for the prevention of recurrent gout flares and damage to joints and other tissues from urate crystal deposition includes drug therapy as well as lifestyle modification and other strategies for risk reduction.⁶ The goal of urate lowering therapy is to achieve a serum urate level to <6 mg/dL. Additionally, guidelines recommend that the target serum urate level should be lowered sufficiently to durably improve the signs and symptoms of gout, including palpable and visible tophi detected, and this may involve therapeutic serum urate level lowering to below 5 mg/dL.³ Treatment includes both lifestyle modifications and pharmacological therapies. Lifestyle modifications include weight loss, reduction in high fructose corn syrup, reduction in alcohol intake, limit intake of purine rich animal proteins (e.g., organ meats, beef, lamb, pork, shellfish), control of diabetes, control of hypertensions, and/or control of other comorbidities.^3,4 Corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine are recommended to treat patients with acute gout.^3-5

Guidelines do not recommend urate lowering therapy for all patients. The main indications for pharmacologic urate-lowering therapy in patients with a diagnosis of gout are:⁶

• Frequent or disabling gout flares
• Clinical or radiographic signs of joint damage (e.g., gouty bone erosion or gouty arthropathy)
• Tophaceous deposits in soft tissues or subchondral bone
• Gout with renal insufficiency (creatinine clearance <60 mL/minute/1.73 m²)
• Recurrent uric acid nephrolithiasis despite treatment with hydration and urinary alkalization, even without another primary indication (such as frequent gout flares or the development of tophi) for urate-lowering pharmacotherapy; or in the presence of either recurrent uric acid or calcium oxalate nephrolithiasis in patients with hyperuricosuria (daily uric acid >800 mg per day in a man or 750 mg per day in a woman). The benefit of urate-lowering therapy in patients with calcium stones is less well-established
• Urinary uric acid excretion exceeding 1100 mg/day (6.5 mmol) when determined in men less than 25 years of age or in premenopausal women

Although evidence supports the benefit of using urate lowering therapy for shorter duration to reduce gout flares, long term use (≥12 months) in patients with a single or infrequent gout attacks (<2 attacks per year) have not been studied. Thus, the American College of Physicians (ACP) recommends against initiating urate therapy in most patients after a first gout attack or in patients with infrequent attacks.⁴ Urate lowering therapies include xanthine oxidase inhibitors (allopurinol, febuxostat), uricosuric agents (probenecid, benzbromarone, and lesinurad), and uricase (pegloticase and rasburicase).^3-6 There is strong consensus that allopurinol constitutes first line urate lowering therapy after consideration of its safety, efficacy and cost. Uricosurics and low to medium doses of febuxostat are considered alternatives in the presence of intolerance or nonresponsiveness to allopurinol.⁷

The American College of Rheumatology (ACR) recommend diet and lifestyle measures for majority of patients with gout. In addition, these pharmacologic therapies are recommended:³

• Xanthine oxidase inhibitors allopurinol and febuxostat are first line agents for pharmacologic urate lowering therapy. The ACR did not preferentially recommend either xanthine oxidase inhibitor, but they did note there was a lack of published safety data for febuxostat in the setting of severe chronic kidney disease (CKD).
• Probenecid was recommended as an alternative to a xanthine oxidase inhibitor in the setting of contraindication or intolerance to ≥ 1 xanthine oxidase inhibitor. Also, probenecid is not recommended for monotherapy in those with a creatinine clearance of < 50 mL/minute.
• For refractory gout, febuxostat can be substituted for allopurinol in the event of drug intolerance or adverse events.
• Effective therapeutic options include addition of a uricosuric agent such as probenecid to a xanthine oxidase inhibitor for refractory gout.
• Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, conventional and appropriately dosed urate lowering therapy. Pegloticase is not recommended as first line urate lowering therapy for any case scenarios.

Allopurinol is the first-line therapy for most patients and has been the mainstay of prophylactic treatment for gout and conditions associated with hyperuricemia for over 40 years. The ACR recommends initial dose of allopurinol should not exceed 100 mg/day and should be less for patients with moderate to severe chronic kidney disease (50mg/day). The rationale for starting the initial dose at ≤ 100 mg/day is that “a low dose could reduce early gout flares after urate lowering therapy initiation, and as a component risk management with respect to the potential for severe hypersensitivity reaction to allopurinol.”³ Allopurinol is effective in most patients with hyperuricemia if a sufficient dose is taken, but achieving normal serum urate levels may be difficult in patients with impaired renal function or in transplant recipients.⁹ Febuxostat is considered an alternative to allopurinol.⁴

Clinical data supporting the dose escalation of allopurinol from 300 mg daily to 300 mg twice daily measured the percentage of patients who achieved a serum uric acid level of ≤ 5 mg/dL. Dose escalation increased the response rate from 26% (for 300 mg daily) to 78% (for 300 mg twice daily).⁸ Two large observational studies (one in heart failure and one in hyperuricemic patients) have shown that allopurinol is associated with reduced total mortality.^8,9 Two small randomized controlled trials showed allopurinol reduced cardiovascular events markedly in both studies.^10,11

Efficacy¹

The efficacy of lesinurad 200 mg and 400 mg once daily was studied in 3 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with hyperuricemia and gout in combination with a xanthine oxidase inhibitor, allopurinol (at least 300 mg) or febuxostat (80 mg). All studies were of 12 months duration and patients received prophylaxis for gout flares with colchicine or non-steroidal anti-inflammatory drugs (NSAIDs) during the first 5 months of Zurampic treatment. Zurampic 200 mg in combination with allopurinol was superior to allopurinol alone in lowering serum uric acid to less than 6 mg/dL at Month 6. Zurampic in combination with febuxostat was statistically superior to febuxostat alone in lowering serum uric acid levels.¹ However, there was not statistical evidence of a difference in the proportion of patients treated with Zurampic 200 mg in combination with febuxostat achieving a serum uric acid < 5 mg/dL by month 6, compared with patients receiving febuxostat alone. 

There have been no phase 3 clinical trials with lesinurad/allopurinol. Bioequivalence of lesinurad/allopurinol to co-administered lesinurad and allopurinol was demonstrated.

Safety¹

Lesinurad is contraindicated in severe renal impairment, end stage renal disease, kidney transplant recipients, or patients on analysis.  It is also contraindicated in those with tumor lysis syndrome or Lesch-Nyhan syndrome.  Lesinurad carries black box warnings that acute renal failure has occurred with lesinurad and was more comment when lesinurad was given alone, and that Lesinurad should be used in combination with a xanthine oxidase inhibitor.¹

Lesinurad/allopurinol is contraindicated in severe renal impairment, end stage renal disease, kidney transplant recipients, or patients on dialysis.  It is also contraindicated in those with tumor lysis syndrome or Lesch-Nyhan syndrome.  A third contraindication is a known hypersensitivity to allopurinol, including previous occurrence of skin rash.  Lesinurad/allopurinol carries a black box warning that acute renal failure has occurred with lesinurad.

For additional clinical information see the Prime Therapeutics Formulary Chapter 10.5: Gout.

REFERENCES

1. Zurampic prescribing information. AstraZeneca Pharmaceuticals LP. January 2016.
2. Duzallo prescribing information. Ironwood Pharmaceuticals, Inc. August 2017.
3. Khanna, D., et al. 2012 American College of Rheumatology Guideline Management of Gout part 1. Arthritis Care & Research. October 2012. Vol 64(10):1431-1446.
4. Hainer, Barry L, MD, et al. Diagnosis, Treatment, and Prevention of Gout. American Family Physician. 2014;90(12):831-836.
5. Qaseem Amir, et al.  Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians.  Ann Intern Med. January 2017. 166(1):58-70.
6. Becker, Michael, et al. Pharmacologic Urate-Lowering Therapy and Treatment of Trophi in Patients with Gout. UpToDate. Last updated August 2018.
7. Sivera F, Andres 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. Ann Rheum Dis 2014;73:328-335
8. Luk AJ, Levin GP, Moore EE, Allopurinol and mortality in hyperuricaemic patients Rheumatology. 2009;48:804-806.
9. Thanassoulis G, Brophy JM, Hugues R, et al. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med 2010;170(15):1358-1364.
10. Rentoukas E, Tsarouhas K, Tsitsimpikou C, et al. The prognostic impact of allopurinol in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Int J Cardiol. 2010;145:257–258.
11. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388–1393.

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

The purpose of pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.

Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.