Coverage Policy Manual
Policy #: 2018027
Category: Pharmacy
Initiated: November 2018
Last Review: April 2022
  Pegloticase (e.g., Krystexxa®)

Description:
Pegloticase is a porcine uricase linked to methoxy polyethylene glycol form of uricase (urate oxidase) manufactured by Horizon Pharma as a treatment for adults with chronic, refractory tophaceous gout.  Refractory gout occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for those whom conventional treatment is contraindicated.
 
Regulatory status
 
In 2010, Pegloticase (e.g., Krystexxa) was approved for the treatment of chronic gout in adult patients refractory to conventional therapy.
 
The FDA PI label for pegloticase (Krystexxa PI label, 2016) includes a black box warning for anaphylaxis and infusion reactions; G6PD deficiency associated hemolysis and Methemoglobinemia.
 

Policy/
Coverage:
Effective 12/1/18 Prior Approval will be required for Pegloticase (e.g., Krystexxa)
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective January 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The initiation of pegloticase meets member benefit certificate primary coverage criteria for the treatment of refractory chronic gout when ALL the following guidelines are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
  1. Member is > 18 years of age AND
  2. Member has ALL three of the following (Sundy 2011, ACR 2020)
a.  Member must have had two (2) or more gouty flares in 12 months AND
b.  Presence of one or more tophi AND
c.  History of chronic gouty arthropathy, defined clinically or radiographically as joint damage due to gout. AND
3.  Baseline serum uric acid > 8 mg/dL prior to initiation of pegloticase (Sundy, 2011) AND
4.  Member has failed a trial of:
a.  *Allopurinol over at least 3 months with failure to achieve uric acid < 6mg/dL up to an FDA labeled maximum dose of 800mg orally per day OR intolerance or contraindication to allopurinol (the exact reason for contraindication or intolerance must be cited in clinical records) (Sundy, 2011, Gold Standard, Allopurinol, ACR 2020)
*Preferred as first-line over all other ULT, when dosed appropriately (often requiring doses >300 mg/day up to the maximum FDA approved dose of 800 mg/day).
b. *Febuxostat over at least 3 months with failure to achieve uric acid < 6mg/dL up to an FDA labeled maximum dose of 80mg orally per day OR intolerance or contraindication to febuxostat (the exact reason for contraindication or intolerance must be cited in clinical records). (Sundy, 2011, Uloric, 2021, ACR 2020)
*Start at low dose with subsequent dose titration to starting at a higher dose (e.g., <40mg/day, and lower in patients with CKD.  Strong recommendation. (ACR 2020).
c. Combination of 1 ^^xanthine oxidase inhibitor with **probenecid over at least 3 months with failure to achieve uric acid < 6mg/dL OR intolerance or contraindication to combination of xanthine oxidase inhibitor with probenecid. (Sundy, 2011, ACR 2020)
^^ ACR 2020 Strongly recommends a xanthine oxidase inhibitor over probenecid for those with CKD stage > 3.
** ACR 2020 conditionally recommends starting at a low dose (500 mg once or twice daily) with dose titration over starting at a high dose.  
AND
5. Continue to have frequent gout flares (> 2 flares/year) OR have non-resolving subcutaneous tophi (ACR 2020); AND  
6. Individual at higher risk for glucose-6-phosphate dehydrogenase (G6PD) deficiency should be screened and found negative for G6PD before starting pegloticase (FDA 2021 label); AND
7. For those members with CKD (stage >3) ACR 2020 Gout guidelines strongly recommends treatment with allopurinol as the preferred first-line agent, over all other ULTs, starting at a low dose with subsequent dose titration to target over starting at a higher dose, [e.g., <100 mg/day and lower in patients with moderate-to-severe CKD (stage 3)].
 
CONTINUED APPROVAL for 1 year:
Continued use and dosing of pegloticase meets member benefit certificate primary coverage criteria for the treatment of refractory chronic gout when ALL of the following guidelines are met:
  1. Dosing is limited to 8 mg IV infusion every 2 wks (FDA 2021 Label); AND
  2. There is documentation of improvement in gout flares and/or tophi in the medical record; AND
  3. Uric acid (UA) levels should be monitored prior to infusion with consideration of discontinuing pegloticase if UA levels increase above 6mg/dL, particularly if 2 consecutive levels >6mg/dL are observed. (FDA 2021 label).
 
*Pegloticase should be administered in a healthcare setting and by healthcare providers prepared to manage anaphylaxis and infusion reactions.  
 
Please refer to as separate policy on Site of Care or Site Service Review (policy #2018030) for pharmacologic/biologic medications.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Pegloticase does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication not described above, including but not limited to:
    • Asymptomatic hyperuricemia (FDA 2021 label)
    • Individual has known glucose-6-phosphate dehydrogenase (G6PD) deficiency (FDA 2021 label)
 
For members with contracts without primary coverage criteria, Pegloticase is considered investigational for any indication not described above, including but not limited to:
    • Asymptomatic hyperuricemia (FDA 2021 label)
    • Individual has known glucose-6-phosphate dehydrogenase (G6PD) deficiency (FDA 2021 label)
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective April 2020 through December 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The initiation of pegloticase meets member benefit certificate primary coverage criteria for the treatment of refractory chronic gout when ALL of the following guidelines are met:
 
    • Member is > 18 years of age
    • Baseline serum uric acid > 8 mg/dL prior to initiation of pegloticase
    • Conservative therapy of low purine diet, weight loss if obese, and limiting/avoiding alcohol has been instituted
    • Member has failed a trial of:
a) Allopurinol over at least 3 months with failure to achieve uric acid < 6mg/dL OR intolerance or contraindication to allopurinol.
b) Febuxostat over at least 3 months with failure to achieve uric acid < 6mg/dL OR intolerance or contraindication to febuxostat.
c) Combination of 1 xanthine oxidase inhibitor with probenecid over at least 3 months with failure to achieve uric acid  < 6mg/dL OR intolerance or contraindication to combination of xanthine oxidase inhibitor with probenecid.
    •  Individual at higher risk for glucose-6-phosphate dehydrogenase (G6PD) deficiency should be screened and found negative for G6PD before starting pegloticase
    • Member must have had three (3) gouty flares or more in previous 18 months
    • Presence of one or more tophi
 
Continued use and dosing of pegloticase meets primary coverage criteria when:
 
    • Dosing is limited to 8 mg IV infusion every 2 wks
    • There is documentation of improvement in gout flares and/or tophi in the medical record
    • Uric acid (UA) levels should be monitored prior to infusion with consideration of discontinuing pegloticase if UA levels increase above 6mg/dL, particularly if 2 consecutive levels >6mg/dL are observed.
 
*Pegloticase should be administered in a healthcare setting and by healthcare providers prepared to manage anaphylaxis and infusion reactions.  
 
Please refer to as separate policy on Site of Care or Site Service Review (policy #2018030) for pharmacologic/biologic medications.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Pegloticase does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than refractory chronic gout.
 
For members with contracts without primary coverage criteria, Pegloticase is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective November 2019 to March 2020
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The initiation of pegloticase meets member benefit certificate primary coverage criteria for the treatment of refractory chronic gout when ALL of the following guidelines are met:
  • Member > 18 years of age
  • Baseline serum uric acid > 8 mg/dL prior to initiation of pegloticase
  • Conservative therapy of low purine diet, weight loss if obese, and limiting/avoiding alcohol has been instituted
  • Member has failed a trial of:
a) Allopurinol,
b) Febuxostat, and
c) Combination of 1 xanthine oxidase inhibitor with probenecid [or member has intolerance of one of these drugs] over at least 3 months with failure to achieve uric acid < 6 mg/dL
    •  Allopurinol over at least 3 months with failure to achieve uric acid < 6mg/dL OR intolerance or contraindication to allopurinol
 
    • Febuxostat over at least 3 months with failure to achieve uric acid < 6mg/dL OR intolerance or contraindication to febuxostat
 
    • Combination of 1 xanthine oxidase inhibitor with probenecid over at least 3 months with failure to achieve uric acid < 6mg/dL OR intolerance or contraindication to combination of xanthine oxidase inhibitor with probenecid
 
  • Individual at higher risk for glucose-6-phosphate dehydrogenase (G6PD) deficiency should be screened and found negative for G6PD before starting pegloticase
  • Member must have had three (3) gouty flares or more in previous 18 months
  • Presence of one or more tophi
 
Continued use and dosing of pegloticase meets primary coverage criteria when:
    • Dosing is limited to 8 mg IV infusion every 2 wks
    • There is documentation of improvement in gout flares and/or tophi in the medical record
    • Uric acid (UA) levels should be monitored prior to infusion with consideration of discontinuing pegloticase if UA levels increase above 6mg/dL, particularly if 2 consecutive levels >6mg/dL are observed.
 
*Pegloticase should be administered in a healthcare setting and by healthcare providers prepared to manage anaphylaxis and infusion reactions.  
 
Pegloticase was approved with a Risk Evaluation and Mitigation Strategy (REMS) program intended to inform healthcare providers about anaphylaxis, infusion reactions, and contraindications of use. The REMS program is also intended to inform patients about the serious risks associated with pegloticase.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Pegloticase does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than refractory chronic gout.
 
For members with contracts without primary coverage criteria, Pegloticase is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective November 2018 to October 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The initiation of pegloticase meets member benefit certificate primary coverage criteria for the treatment of refractory chronic gout when ALL of the following guidelines are met:
    • Member > 18 years of age
    • Baseline serum uric acid > 8 mg/dL prior to initiation of pegloticase
    • Conservative therapy of low purine diet, weight loss if obese, and limiting/avoiding alcohol has been instituted
    • Member has failed a trial of:
a) Allopurinol,
b) Febuxostat, and
c) Combination of 1 xanthine oxidase inhibitor with probenecid [or member has intolerance of one of these drugs] over at least 3 months with failure to achieve uric acid < 6 mg/dL
    • Individual at higher risk for glucose-6-phosphate dehydrogenase (G6PD) deficiency should be screened and found negative for G6PD before starting pegloticase
    • Member must have had three (3) gouty flares or more in previous 18 months
    • Presence of one or more tophi
 
Continued use and dosing of pegloticase meets primary coverage criteria when:
    • Dosing is limited to 8 mg IV infusion every 2 wks
    • There is documentation of improvement in gout flares and/or tophi in the medical record
    • Uric acid (UA) levels should be monitored prior to infusion with consideration of discontinuing pegloticase if UA levels increase above 6mg/dL, particularly if 2 consecutive levels >6mg/dL are observed.
*Pegloticase should be administered in a healthcare setting and by healthcare providers prepared to manage anaphylaxis and infusion reactions.  
Pegloticase was approved with a Risk Evaluation and Mitigation Strategy (REMS) program intended to inform healthcare providers about anaphylaxis, infusion reactions, and contraindications of use. The REMS program is also intended to inform patients about the serious risks associated with pegloticase.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Pegloticase does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than refractory chronic gout.
 
For members with contracts without primary coverage criteria, Pegloticase is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
Regulatory approval in the United States was based upon the results of two replicate randomized trials, which showed efficacy for patients with gout reported to be refractory to conventional treatment. The two phase III trials enrolled a total of 225 patients with treatment-resistant gout and serum urate levels ≥8 mg/dL who were randomly assigned (in a 2:2:1 ratio) to receive infusions of pegloticase (8 mg every two weeks or 8 mg every four weeks) or placebo for six months. Persistent lowering of plasma urate to less than 6 mg/dL was achieved in 42, 35, and 0 percent, in the two-week, four-week, and placebo groups, respectively. Complete resolution of at least one tophus by the final visit was more frequent in those receiving pegloticase every two weeks than placebo (40 versus 7 percent).
 
Of note, the urate-lowering effect of pegloticase infusions was attenuated or lost in some patients, usually in conjunction with the development of high-titer pegloticase-antibody. Treatment should be discontinued if there is loss of urate-lowering effectiveness as indicated (during monitoring of each pre-infusion serum urate concentration) by serum urate values >6 mg/dL on one occasion accompanied by an infusion reaction or on two successive occasions. Other urate-lowering therapies should not be given to patients receiving pegloticase because they may mask recognition of the increasing serum urate levels associated with an increased risk for infusion-related reactions and loss of effectiveness resulting from the effects of high-titer pegloticase antibodies.
 
Five patients on pegloticase, but none on placebo, had mild to moderately severe infusion reactions consistent with anaphylaxis, although three of these patients continued in the trial without further incident.
 
Gout flares and infusion reactions were the most common causes for patient withdrawal from the trials, despite prophylaxis for gout flares and infusion reactions; withdrawals due to adverse events were more frequent in the two- and four-week pegloticase groups than in the placebo group (18 and 19 versus 2 percent, respectively).
 
2019 Update
A literature search conducted through November 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2021. The key literature identified is summarized below.
 
In 2020 Mackenzie IS, et al published a multicenter prospective trial of febuxostat versus allopurinol of patients with gout in Europe that occurred between Dec. 20, 2011, and Jan. 26, 2018.  The eligible patients were 60 and older, already receiving allopurinol and had at least one other cardiovascular risk factory.  Those who had an MI in the previous 6 months or had severe congestive heart failure or severe renal impairment were excluded.  Patients were randomly assigned to continue allopurinol (at the optimized dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration (<6mg/dL). In the allopurinol group, it was titrated up, by increasing the allopurinol dose 100mg every 2 weeks until the target or maximum recommended dose was reached to achieve a serum uric acid level of <6mg/dL.  
 
There were 6,128 patients (5,225 men and 903 women) were enrolled and randomly allocated to receive allopurinol (n=3063) or febuxostat (n=3063).  In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. This showed that Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol.
 
In Japan, a multicenter, prospective study was done in 141 hospitals in Japan.  There were 1,071 patients included in this study.  Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat (n = 537) and non-febuxostat groups (n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively (P < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592-0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562-0.987; P = 0.041). In conclusion Febuxostat lowers uric acid and delays the progression of renal dysfunction.  Febuxostat was also reported to be more suitable than allopurinol for patients with moderate to severe renal dysfunction.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J2507Injection, pegloticase, 1 mg

References: Becker MA, Schumacher HR, MacDonald PA et al. [abstract](2009) Clinical efficacy and safety of successful long-term urate lowering with febuxostat or allopurinol in subjects with gout. J Rheum 2009 Jun; 36 (6): 1273-82.

Chao J, Terkeltaub R. [abstract](2009) A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheum Rep 2009 Apr; 11(2): 135-40.

Edwards NL.(2008) Treatment-failure gout: A moving target. Arthritis Rheum. 2008 Sep;58(9):2587-90. doi: 10.1002/art.23803. PMID: 18759307

FitzGerald JD, Dalbeth N, Mikuls T, et al.(2020) 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Rheumatol. 2020;72(6):879-895. Available at: https://onlinelibrary.wiley.com/doi/epdf/10.1002/art.41247.

Gold Standard, Inc. Allopurinol. Clinical Pharmacology [database online]. Available at: http//www.clinicalpharmacology.com. Accessed 08/27/2021.

Gold Standard, Inc. Febuxostat. Clinical Pharmacology [database online]. Available at: http//www.clinicalpharmacology.com. Accessed 08/27/2021.

Kojima S, Matsui K, Hiramitsu S, et al.(2019) Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy. Eur Heart J. 2019 Jun 7;40(22):1778-1786. doi: 10.1093/eurheartj/ehz119. PMID: 30844048; PMCID: PMC6554652.

Mackenzie IS, Ford I, Nuki G, et al.(2020) Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020 Nov 28;396(10264):1745-1757. doi: 10.1016/S0140-6736(20)32234-0. Epub 2020 Nov 9. PMID: 33181081.

Reinders M, Jansen TL.(2010) New advances in the treatment of gout: review of pegloticase. Ther and Clin Risk Mgt 2010; 6: 543-550.

Savient Pharmaceuticals.(2016) Krystexxa® (pegloticase) Package Insert. September 2016.

Sundy J, Baraf H, Yood R et al.(2011) Efficacy and tolerability of pegloticase for the treatment of chronic gout in patient’s refractory to conventional treatment. JAMA 2011; 306 (7): 711-720.

Uloric [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; February 2019


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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