Subject: Krystexxa (pegloticase) Original Effective Date: 06/26/13. Policy Number: MCP-138. Revision Date(s):

Transcription

1 Subject: Krystexxa (pegloticase) Original Effective Date: 06/26/13 Policy Number: MCP-138 Revision Date(s): Review Date(s): 12/16/15; 6/15/2016; 3/21/2017 DISCLAIMER This Molina Clinical Policy (MCP) is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this Molina Clinical Policy (MCP) document and provide the directive for all Medicare members. SUMMARY OF EVIDENCE/POSITION This policy addresses the use of Krystexxa (pegloticase) for the treatment of long-term gout. The covered FDA-approved indications are conditions that are considered medically necessary; however it is not inclusive of all conditions which may be approved by the Medical Reviewer. At the discretion of the Medical Director and on a case-by-case basis, Molina Healthcare may consider authorization of the biologic therapies addressed in this POLICY for members with exceptional circumstances and for members with severe disease who may fall outside of the defined criteria. Molina Healthcare reserves the right to update this POLICY and revise coverage criteria to include or omit any offlabel condition(s) as necessary based on medical literature and clinical studies that may become available. Krystexxa (pegloticase) will not be authorized as first-line therapy. It is an alternative treatment to lower uric acid after other therapies and agents have been ineffective or have not been tolerated. The use of pegloticase for treatment of gout is considered as last-line therapy for the treatment of long-term gout due to concerns regarding adverse events and a lack of evidence on long-term safety and effectiveness. While demonstrating to be efficacious in two pivotal clinical trials [pegloticase administered every 2 weeks was superior to placebo in achieving plasma uric acid levels of less than 6mg/dL for at least 80% of the time during study months 3 and 6], pegloticase therapy was associated with significant adverse events including anaphylactic reactions which occurred in 6.5% of patients on the every 2 week regimen compared to 0% for placebo. Infusion site reactions occurred in 26% of patients on the every 2 week regimen compared to 5% for placebo. These reactions occurred despite premedication. Additionally, anti-pegloticase antibodies developed in over 90% of patients. High antibody titers were associated with a failure to maintain normalized uric acid levels and a higher incidence of infusion reactions. Page 1 of 20

2 Allopurinol, febuxostat (Uloric ), and pegloticase (Krystexxa ) are not recommended for the treatment of asymptomatic hyperuricemia. a Multisource colchicine has not demonstrated bioequivalence to an innovator product; therefore, multisource colchicine products are not considered generics nor have the multisource products received Food and Drug Administration (FDA) approval. On September 30, 2010, the FDA halted marketing of unapproved colchicine products. Interstate shipping of unapproved colchicine ceased the end of December e FDA INDICATIONS Gout: For the treatment of long-term gout in adult patients refractory to conventional therapy. a,b Gout refractory to conventional therapy 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 whom these drugs are contraindicated. Pegloticase is not recommended for the treatment of asymptomatic hyperuricemia. a Available as: 8mg/ml Solution for Injection Krystexxa concentrations are expressed as concentrations of uricase protein. Each ml of Krystexxa contains 8mg of uricase protein. Approved by the FDA: September 2010 RECOMMENDATIONS/COVERAGE CRITERIA Initiation of therapy with Krystexxa (pegloticase) may be authorized for members who meet ALL of the following criteria [ALL] 1. Prescriber specialty [ONE] Board-certified rheumatologist or nephrologist Consult with a Board-certified rheumatologist or nephrologist with experience in the treatment of gouty arthritis (submit consultation notes) 2. Diagnosis/Indication [ALL] Symptomatic gout flare when ALL of the following criteria are met: [ALL] Diagnosis established by ONE of the following criteria: A,D,F [ONE] o Crystal identification in the joint fluid o Classic presentation of podagra involving the first metatarsophalangeal (MTP) joint Any ONE of the following criteria: [ONE] o History of at least 3 gout flares in the previous 18 months 2,a,c o At least 1 gouty tophus 2,a,c Patients with gout experience recurrent attacks of painful inflamed joints, often involving the toes, knees and fingers. Sometimes urate crystals accumulate at joints along with red, painful tissue, referred to as tophi. Tophi can cause a lot of pain and limit the use of the affected joints. 1 o Chronic gouty arthritis 2,a,c (documented clinically or radiographically as joint damage due to gout) Baseline serum uric acid (SUA) level equal to or greater than 8.0mg/dL 2,a,c (baseline as measured by Step/Conservative Therapy/Other condition Requirements) Page 2 of 20

3 3. Age/Gender/Other restrictions [ONE] 18 years of age or older The safety and efficacy of Krystexxa (pegloticase) in children have not been established. a,b Completion of a G6PD screen before treatment initiation. Documentation of negative results required. Pegloticase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to generation of hydrogen peroxide in conversion of uric acid into allantoin and consequent risk of hemolytic anemia and met-hemoglobinemia G6PD deficient patients. G6PD deficiency is an X-linked recessive hereditary disease. 4. Step/Conservative Therapy/Other condition Requirements [ONE] Therapeutic trial and clinical failure of BOTH of the following for maintenance treatment of gout, at a maximum tolerated dose or an adequate therapeutic dose. Clinical failure is defined as the inability to maintain serum uric acid (SUA) level 6 mg/dl after reaching the maximum tolerated dose or an adequate therapeutic dose of three (3) months on each of the following treatment: 2,a,c [BOTH] allopurinol [Maximum Doses: Aloprim 600 mg/day; Zyloprim 800 mg/day] f AND febuxostat [Maximum Doses: Uloric 80 mg/day] g NOTE: If contraindication to allopurinol, probenecid is an alternative [dose: 500 mg twice daily] h *Refer to Appendix 1 regarding dosing and optimal duration of therapy. Inadequate clinical response in regard to ongoing gout-related symptoms such as arthritis, tophi or uric acid renal stones after an adherent trial at maximum tolerated dose or an adequate therapeutic dose of at least three (3) months for each of the following for maintenance treatment of gout: [BOTH] allopurinol [Maximum Doses: Aloprim 600 mg/day; Zyloprim 800 mg/day] f AND febuxostat [Maximum Doses: Uloric 80 mg/day] g NOTE: If contraindication to allopurinol, probenecid is an alternative [dose: 500 mg twice daily] h *Refer to Appendix 1 regarding dosing and optimal duration of therapy. Clinical intolerance or contraindication to xanthine oxidase inhibitors [allopurinol (Aloprim, Zyloprim ), febuxostat (Uloric )] documented by ONE of the following: [ONE] A severe allergic reaction Experienced toxicity Clinical intolerance Significant drug interaction Severe renal dysfunction (for allopurinol only) Page 3 of 20

4 5. Contraindications/Exclusions to Krystexxa (pegloticase) therapy [ANY] Authorization will not be granted if ANY of the following conditions apply [ANY] Non-FDA approved indications Hypersensitivity to Krystexxa (pegloticase) or any ingredient in the formulation a,b Concurrent use of other urate-lowering therapies including allopurinol, febuxostat, probenecid, etc. Combined use of pegloticase and other urate lowering drugs may mask a rise in uric acid concentrations attributable to loss of effectiveness of pegloticase, due to antibody development. Development of anti-pegloticase antibodies can lead to loss of efficacy and a higher risk for infusion reactions and anaphylaxis. Krystexxa has not been studied in patients with the following conditions. Authorization will not be authorized in members with the following conditions: Unstable angina Uncontrolled arrhythmia Non-compensated heart failure (CHF) Uncontrolled hypertension (e.g. > 150/95 mmhg) Dialysis Recipient of organ transplant Glucose-6-phosphate dehydrogenase(g6pd) deficiency a,b Patients at high risk for G6PD deficiency should be screened prior to initiating therapy with pegloticase. Higher risk patients include those of African or Mediterranean descent. 6. Labs/Reports/Documentation required [ALL] All documentation for determination of medical necessity must be submitted for review. Prescriber to submit documentation as indicated in the criteria above, including but not limited to chart notes, applicable lab values and/or tests, adverse outcomes, treatment failures, or any other additional clinical information or clinical notes from the member s medical records supporting the diagnosis. Letters of support and/or explanation are often useful, but are not sufficient documentation unless ALL specific information required by this MCP are included. NOTE: Additional documentation, rationale, and/or supporting evidence may be requested for review as deemed necessary or appropriate by Molina Medical/Pharmacy staff. ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD 7. Recommended Dosing Regimen 1 [ALL] Dosage prescribed for pegloticase is within the FDA-approved labeling based on member s confirmed diagnosis: 8mg given as an intravenous infusion every two weeks. The pegloticase admixture should only be administered by intravenous infusion over no less than 120 minutes via gravity feed, syringe-type pump, or infusion pump. Patients should be pre-medicated with antihistamines and corticosteroids. Monitor serum uric acid levels before each infusion. Pre-medicate with antihistamines and corticosteroids Premedication in clinical trials consisted of: fexofenadine 60mg PO the evening before and again before infusion; acetaminophen 1000mg the morning of infusion; and hydrocortisone 200mg IV immediately before infusion. Gout flare prophylaxis with an NSAID or colchicines should be started one week before initiation of Krystexxa therapy. Dose adjustment not necessary for renal impairment. Page 4 of 20

5 8. Authorization Limit 1 [ALL] May authorize up to 3 months of continuation of therapy NOTE: The optimal treatment duration has not been established. a,b Quantity limitation: maximum of six (6) infusions for three (3) months [Krystexxa 8mg IV every two (2) weeks. Dose not to exceed one 8mg infusion every 2 weeks] 9. Route of Administration [ALL] Medication will be authorized for provider administration in a physician office setting only. Richard Sanchez, MD NOTE: Hospital Outpatient Setting will not be authorized] Member will receive appropriate prophylactic treatment for anaphylaxis and infusion reactions in accordance with the recommendations from the FDA and the Krystexxa REMS program. Molina Healthcare supports administering injectable medications in various settings, as long as those services are furnished in the most appropriate and cost-effective setting that are supportive of the member s medical condition and unique needs. The decision on the most appropriate setting for administration is based on the member s current medical condition and any required monitoring or additional services that may coincide with the delivery of the specific medication. If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider; they must be dispensed through a participating pharmacy. Page 5 of 20

6 CONTINUATION OF THERAPY Continuation of therapy with Krystexxa (pegloticase) may be authorized for members who meet ALL of the following criteria [ALL] 1. Initial Coverage Criteria Member currently meets ALL initial coverage criteria 2. Compliance Compliance with therapy as verified by Prescriber and member s medication fill history (review Rx history for compliance) NOTE: Therapy may be discontinued due to compliance issues or poor adherence upon agreement among treating physician, member, and Medical Director. 3. Labs/Reports/Documentation required [ALL] Positive response to Krystexxa (pegloticase) treatment, including: Demonstrated efficacy as evidenced by an improvement in serum uric acid levels demonstrated by a reduction in serum uric acid levels compared to baseline, and that consecutive serum uric acids levels are less than 6mg/dL. NOTE: Members with documented serum uric acid concentrations (prior to their next infusion) of greater than 6 mg/dl on more than one occasion during treatment must discontinue treatment with pegloticase. The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dl, particularly when 2 consecutive levels above 6 mg/dl are observed. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dl despite treatment. a,c The accepted goal range of serum uric acid for maintenance in clinical studies and evidencebased guidelines is less than 6mg/dL. B,10 4. Discontinuation of Treatment Two (2) consecutive pre-infusion serum uric acid levels above 6 mg/dl are observed. Two consecutive uric acid levels greater than 6mg/dL indicate loss of therapeutic response with Krystexxa and increases the risk of anaphylaxis and infusion reactions due to development of antibodies against Krystexxa. Treatment should be discontinued OR the monitoring of serum uric acid levels prior to infusions is required. [MEDICAL/PHARMACY DIRECTOR REVIEW REQUIRED] The accepted goal range of serum uric acid for maintenance in clinical studies and evidence-based guidelines is less than 6 mg/dl. During treatment, the risk of anaphylaxis is higher in individuals when uric acid levels increase above 6 mg/dl, particularly when 2 consecutive levels above 6 mg/dl are observed. Therefore, the monitoring of serum uric acid levels prior to infusions is required. Page 6 of 20

7 Re-treatment/restarting treatment: Data are lacking for re-treatment/restarting treatment with pegloticase in patients stopping therapy with pegloticase for > 4 weeks. Due to the immunogenicity of pegloticase, the risk for anaphylaxis and infusion reactions may be increased and therefore these patients should be more closely monitored. In addition, the risk of anaphylaxis or infusion reactions may be increased if an infusion is missed or skipped. [MEDICAL/PHARMACY DIRECTOR REVIEW REQUIRED] Contraindications/Exclusions to Krystexxa (pegloticase) therapy [ANY] Authorization will not be granted if ANY of the following conditions apply: Non-FDA approved indications Hypersensitivity to Krystexxa (pegloticase) or any ingredient in the formulation a,b Concurrent use of other urate-lowering therapies including allopurinol, febuxostat, probenecid, etc. Combined use of pegloticase and other urate lowering drugs may mask a rise in uric acid concentrations attributable to loss of effectiveness of pegloticase, due to antibody development. Development of anti-pegloticase antibodies can lead to loss of efficacy and a higher risk for infusion reactions and anaphylaxis. Krystexxa has not been studied in patients with the following conditions. Authorization will not be authorized in members with the following conditions: o Unstable angina o Uncontrolled arrhythmia o Non-compensated heart failure (CHF) o Uncontrolled hypertension (e.g. > 150/95 mmhg) o Dialysis o Recipient of organ transplant o Glucose-6-phosphate dehydrogenase(g6pd) deficiency a,b Patients at high risk for G6PD deficiency should be screened prior to initiating therapy with pegloticase. Higher risk patients include those of African or Mediterranean descent. ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD 5. Recommended Dosing Regimen [ALL] Dosage prescribed is within the FDA-approved labeling based on member s confirmed diagnosis: Recommended dose of pegloticase is 8mg given as an intravenous infusion every two weeks. The pegloticase admixture should only be administered by intravenous infusion over no less than 120 minutes via gravity feed, syringe-type pump, or infusion pump. Patients should be pre-medicated with antihistamines and corticosteroids. Monitor serum uric acid levels before each infusion. Pre-medicate with antihistamines and corticosteroids Premedication in clinical trials consisted of: fexofenadine 60mg PO the evening before and again before infusion; acetaminophen 1000mg the morning of infusion; and hydrocortisone 200mg IV immediately before infusion. Gout flare prophylaxis with an NSAID or colchicines should be started one week before initiation of Krystexxa therapy. Dose adjustment not necessary for renal impairment. Page 7 of 20

8 6. Authorization Limit [ALL] May authorize up to 3 months of continuation of therapy NOTE: The optimal treatment duration has not been established. a,b Quantity limitation: maximum of six (6) infusions for three (3) months [Krystexxa 8mg IV every two (2) weeks. Dose not to exceed one 8mg infusion every 2 weeks] 7. Route of Administration [ALL] Medication is considered to be provider-administered in the physician office setting only [Hospital Outpatient Setting will not be authorized] Richard Sanchez, MD until information from the manufacturer, scientific literature, practice standards, or governing State or Federal agency indicates that self-administration by a patient or caregiver is safe and acceptable. Member will receive appropriate prophylactic treatment for anaphylaxis and infusion reactions in accordance with the recommendations from the FDA and the Krystexxa REMS program. Molina Healthcare supports administering injectable medications in various settings, as long as those services are furnished in the most appropriate and cost-effective setting that are supportive of the member s medical condition and unique needs. The decision on the most appropriate setting for administration is based on the member s current medical condition and any required monitoring or additional services that may coincide with the delivery of the specific medication. If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider; they must be dispensed through a participating pharmacy. Page 8 of 20

9 COVERAGE EXCLUSIONS All other uses of the mentioned drugs that are not an FDA-approved indication or included in Coverage Criteria section above are considered experimental/investigational and is not a covered benefit. The following list may not be all-inclusive and is subject to change based on research and medical literature: Hyperuricemia not associated with gout Asymptomatic hyperuricemia WARNINGS/ PRECAUTIONS A. Adverse Reactions Black Box Warnings Anaphylaxis AND Infusion Reactions Anaphylaxis and infusion reactions have been reported to occur during and after administration of Krystexxa. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported. Krystexxa should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. Patients should be pre-medicated with antihistamines and corticosteroids Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of Krystexxa. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dl, particularly when 2 consecutive levels above 6 mg/dl are observed. Contraindications a,b Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Pegloticase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to generation of hydrogen peroxide in conversion of uric acid into allantoin and consequent risk of hemolytic anemia and met-hemoglobinemia G6PD deficient patients. G6PD deficiency is an X-linked recessive hereditary disease. Common Adverse Effects The most common adverse reactions (occurring in at least 5% of pegloticase-treated patients) are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting. Updated Labeling Warning In April 2012, the FDA approved updated labeling warning against combining pegloticase with other uratelowering therapies because of the concern that other urate-lowering therapies may mask antibody development by blunting a rise in uric acid levels attributable to loss of effectiveness of pegloticase due to antibody development. The manufacturer recommends discontinuing other urate-lowering therapies prior to initiating pegloticase and not restarting them. REMS Program The FDA has required a Risk Evaluation and Mitigation Strategy (REMS), which includes a Medication Guide for patients and a communication plan to assist healthcare providers understand the risks associated with Krystexxa. Risk Evaluation and Mitigation Strategy (REMS) required and approved by FDA. d Page 9 of 20

10 Goal is to inform healthcare providers and patients about serious risks associated with pegloticase, including risk of anaphylaxis and infusion reactions and the contraindication to use in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. d Krystexxa has a Risk Evaluation and Mitigation Strategy (REMS) program that consists of a Medication Guide, a Dear Healthcare Professional Letter, and a Dear Infusion Site Medical Personnel (DISMP) Letter. Patient and physician enrollment in the manufacturer's REMS program is not required. B. Special Populations a Pregnancy: Category C. A complete evaluation of the reproductive and developmental toxicity of pegloticase has not been completed. Adequate animal reproduction studies have not been conducted with pegloticase. It is not known whether pegloticase can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled studies in pregnant women. Pegloticase should be used during pregnancy only if clearly needed. Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breast-feeding infants, it is not recommended to administer pegloticase to a breast-feeding mother. Pediatric use: The safety and efficacy of pegloticase have not been established in neonates, infants, children, or adolescents. Geriatric use: No overall differences in safety or effectiveness were observed between older and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is needed for patients 65 years of age and older. a,b C. Drug Interactions a No clinical studies have been conducted with pegloticase and other drugs to determine drug interactions a PEG products: There may be potential for binding with other PEGylated products since anti-pegloticase antibodies appear to bind to the PEG portion of the drug. a Allopurinol and febuxostat should not be used in combination with each other or with pegloticase. Page 10 of 20

11 SUMMARY Krystexxa (pegloticase) [Savient Pharmaceuticals] was approved by the U.S. Food and Drug Administration (FDA) on September 14, 2010 for the treatment of chronic gout in adults who cannot be adequately managed with conventional therapy. Gout refractory to conventional therapy 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 whom these drugs are contraindicated. Krystexxa was approved after two clinical trials demonstrated the drug lowered uric acid levels and reduced deposits of uric acid crystals in joints and soft tissue. The first pegylated uric acid specific enzyme approved for treatment of chronic gout in adults refractory to conventional therapy. It is not recommended in patients with asymptomatic hyperuricemia. Pegloticase (Krystexxa) is a pegylated uric acid specific enzyme that helps to metabolize uric acid and thus lowers uric acid levels in the body. Although most mammals possess uricase (uric acid oxidase), it is absent in humans. Pegloticase acts to reduce serum uric acid by catalyzing oxidation of uric acid to allantoin. Allantoin is an inert and water-soluble purine metabolite, which is rapidly eliminated, primarily by the kidneys. Oxidative byproducts from the metabolism of uric acid include hydrogen peroxide and carbon dioxide. To extend the circulating half-life of the uricase enzyme and to reduce the body s immune response to a foreign protein during prolonged use, the inert polymer polyethylene glycol (PEG) was attached to uricase. Pegloticase (Krystexxa ) achieves its therapeutic effect by increasing the conversion of uric acid to allantoin, which lowers the serum uric acid level. The allantoin is then excreted by the kidneys. Gout is a rheumatic disease that results from an excess body burden of uric acid, or hyperuricemia E (serum uric acid > 6.8 mg/dl) can occur due to either an overproduction of uric acid or an under excretion of uric acid or a combination of the two mechanisms. 9 This is an acute inflammatory and chronically destructive disorder resulting from the formation and deposition in tissues of urate crystals from extracellular fluid saturated for urate, the end product of human purine metabolism. Crystals are deposited in joints, tendons and surrounding tissues. Gout commonly manifests as recurrent episodes of acute joint pain and inflammation secondary to the deposition of monosodium urate (MSU) crystals (tophi) in the synovial fluid and lining. Furthermore, renal involvement of gout due to MSU deposition in the urinary tract can result in urolithiasis and urinary obstruction. 3,4 Hyperuricemia is caused by an increased production or a decreased excretion of uric acid, or both. Underexcretion, the most common cause, is thought to account for 80% to 90% of hyperuricemia. 5 Although the risk of developing gout increases with the chronicity and increased concentrations of uric acid (> 9 mg/dl), not all patients with hyperuricemia will develop gout. 3,4 Gout is the most common rheumatic disease of adulthood, with a self-reported prevalence of more than 8 million cases in the United States, affecting 3.9% of adults and a male predominance, male-to-female ratio of 3:1. 6 Gout is the most prevalent form of arthritis in men and is increasing in incidence and prevalence among older persons of both genders. 7 Diagnosis of gout is based on symptom presentation and confirmed by the presence of monosodium urate crystals upon aspiration of synovial joint fluid. The gold standard for diagnosing gout is aspiration and microscopic analysis for urate crystals in joint fluid or a tophus. H European League Against Rheumatism (EULAR) recommendations for the diagnosis of gout also highlight the value of synovial fluid crystal analysis. A Athough synovial fluid aspiration and analysis is the gold standard for making the diagnosis of gout but is not always performed when indicated in clinical practice. In clinical situations when joint aspiration simply cannot be performed, a presumptive (or clinical) diagnosis of gout may be made in consultation with published recommendations and criteria from expert societies. In clinical situations when joint aspiration cannot be performed, the EULAR recommendations A and the ACR criteria provide POLICY for making a clinical or presumptive diagnosis of gout. As noted in the EULAR recommendations, a comprehensive patient history and physical examination are critical in making a presumed diagnosis of gout. If the patient presents during an acute attack, serum urate measurement may be useful in making a clinical diagnosis if it reveals an elevated level. Measuring serum urate during the initial attack and then 2 weeks later yields two serum urate levels that can be compared to assist in considering a presumed diagnosis of gout. Serum urate levels are Page 11 of 20

12 likely to be elevated after an attack, at the 2-week follow-up, suggesting a clinical diagnosis of gout, per the EULAR recommendations, A if the attack occurred in the great toe. GOAL OF THERAPY The goals of treatment are to end the pain of acute flares, and to prevent future attacks and the formation of tophi and kidney stones. UPTODATE 10 The long-term management of gout is focused on lowering uric acid levels. According to a review in UpToDate, pharmacologic modalities employed in the treatment of gout can be categorized in three distinctive aims of treatment: 1) Anti-inflammatory therapy for prompt and safe termination of the acute arthritic attack 2) Anti-inflammatory prophylaxis for prevention of recurrences of acute gouty arthritis 3) Anti-hyperuricemic (urate-lowering) therapy for prevention and reversal of the consequences of urate crystal deposition in joints (gouty arthropathy), urinary tract (nephrolithiasis), renal interstitium (rarely producing renal failure due to urate nephropathy), and tissues and parenchymal organs (tophi) The general goal of antihyperuricemic therapy is to maintain a serum urate concentration of < 6 mg/dl (<357 micromol/l). TREATMENT OPTIONS Acute gouty arthritis can be treated with colchicine, NSAIDs, and intra-articular corticosteroid injections. After an initial gout attack, the choice of urate-lowering medications is probenecid, colchicine/probenecid combination, or xanthine oxidase inhibitors. Probenecid promotes uric acid excretion by inhibiting the tubular reabsorption of filtered and secreted urate thereby increasing urate excretion. Xanthine oxidase inhibitors, allopurinol, and febuxostat, inhibit uric acid production. Febuxostat (Uloric) reduced serum urate levels below 6 mg/dl in a significantly greater proportion of patients with gout and hyperuricemia compared to allopurinol; however the incidence of gout flares, a clinical outcome, does not appear lower with febuxostat compared to allopurinol. Colchicine (Colcrys) is the first FDA-approved colchicine product. Colchicine has significant drug interactions and frequent gastrointestinal adverse effects; however, Colcrys is approved at a lower dosage for the treatment and prevention of gout flares than previously described. Colcrys is approved as an orphan drug for the treatment of Familial Mediterranean Fever (FMF). Pegloticase (Krystexxa) provides an effective alternative therapy to conventional oral urate-lowering medications for those patients who cannot take oral urate-lowering medications. Page 12 of 20

13 PUBLISHED CLINICAL TRIALS The efficacy and safety of pegloticase was studied in adult patients with chronic gout refractory to conventional therapy in two similar, multicenter, randomized, double-blind, placebo controlled studies of six months duration. 2 Two replicate, double-blinded, randomized, placebo controlled trials were conducted for six months in 225 patients throughout 56 rheumatology clinics in the United States, Mexico, and Canada for the purposes of assessing the efficacy and tolerability of pegloticase in the management of refractory chronic gout. Patients were 18 years or older and had severe gout, allopurinol intolerance or refractoriness, serum uric acid concentrations of 8 mg per dl or more, and at least one of the following conditions: three or more self-reported gout flares within the last 18 months, at least one tophi, and gouty arthropathy. Patients who were receiving urate-lowering medications at the onset of screening were required to undergo a one week washout. Prophylactic gout therapy was started one week before the pegloticase infusion and continued throughout the study. Patients also received pretreatment with medications to protect against infusion reactions. Patients were randomized into three study groups in a 2:2:1 ratio: pegloticase biweekly, pegloticase monthly, or placebo, respectively. In the pooled analysis, the portion of uric acid (UA) responders (defined as plasma UA less than 6 mg per dl for greater than or equal to 80 percent of the time during months three and six) in the pegloticase groups were significantly greater than placebo (p <0.001). The primary endpoint in both trials was the proportion of patients who achieved PUA less than 6 mg/dl for at least 80 % of the time during month 3 and month 6. The data in both clinical studies demonstrated that a greater proportion of patients treated with pegloticase every 2 weeks achieved urate lowering to below 6 mg/dl than patients receiving placebo. During the first 6 months of treatment, 47 % (p < 0.001) and 38 % (p < 0.001) of patients in the pegloticase arms of the 2 clinical studies achieved the primary efficacy endpoint, compared with 0 % of patients in the placebo arm. The study also found that non-responder patients had UA levels below 6 mg per dl through week ten but then remained above the target level thereafter suggesting an emergence of decreased urate-lowering efficacy early in treatment. The study also found that 41 percent of the biweekly pegloticase, 21 percent of the monthly pegloticase, and seven percent of the placebo patients experienced a complete response to at least one tophi (p=0.002 and p=0.2, respectively). Immunogenicity occurred in 134 of the 150 patients treated with pegloticase indicated by the presence of pegloticase antibodies (95% CI). Overall the study concluded that pegloticase provided significant improvements in patient quality of life, physical function, and pain levels due to its ability to reduce uric acid levels compared to placebo. Pharmacological Treatment of Acute Gout: A Systematic Review 8 A systematic review looked at pharmacological treatments for acute gout. 8 The lack of published evidence in acute management strategies was demonstrated when only 26 suitable studies and three abstracts papers were identified. The review concluded non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are the most frequently used effective treatments, but steroid and anti-il-1 can be used in those who are treatment resistant. Page 13 of 20

14 AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) This is the first time that the ACR has offered POLICY on the management of gout since the ACR s founding 78 years ago. E,F Part 1 covers non-pharmacologic and pharmacologic treatment approaches to hyperuricemia, including detailed dietary measures, and part 2 addresses therapy and anti-inflammatory prophylaxis of acute gouty arthritis. In summary, the major recommendations of the ACR TFP include patient education, pharmacologic treatment to lower serum uric acid to <6 mg/dl, prompt pharmacologic treatment of acute gouty arthritis, and pharmacologic prophylaxis against gout attacks when ULT is initiated. According to the 2012 ACR guidelines, core therapy for management of gout and for hyperuricemia includes patient education about diet, lifestyle, treatment objectives, and management of comorbid conditions. E First-line pharmacological urate-lowering therapy (ULT) in gout is xanthine oxidase inhibitor (XOI) therapy with either allopurinol or febuxostat to achieve a target serum urate level of less than 6 mg/dl, and often less than 5 mg/dl. The ACR guidelines recommend treating patients with a xanthine oxidase inhibitor (XOI), such as allopurinol, as the first-line pharmacologic ULT approach. The recommended goal is to reduce serum urate to less than 6 mg/dl, and the initial allopurinol dosage should be no greater than 100 mg/day, the guidelines say. This should be followed by gradual increase of the maintenance dose, which can safely exceed 300 mg even in patients with CKD. E For chronic tophaceous gouty arthropathy (CTGA), the guidelines recommend: E Combination therapy with one (1) xanthine oxidase inhibitor [allopurinol or febuxostat] and one (1) uricosuric agent when target urate levels are not achieved. Use probenecid as an alternative first-line urate-lowering drug in the setting of contraindication or intolerance to at least 1 xanthine oxidase inhibitor (except in patients with creatinine clearance below 50 ml/minute). Pegloticase in patients with severe gout disease who do not respond to standard, appropriately dosed ULT. For an acute gouty arthritis attack, pharmacotherapy with NSAIDs, corticosteroids, or oral colchicine should be started within 24 hours of onset, and ULT should be continued without interruption. F All patients with gout starting ULT should receive pharmacologic anti-inflammatory prophylaxis with oral colchicine or low-dose NSAIDs (as long as there is no medical contraindication or lack of tolerance). Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or oral colchicine are the recommended first-line treatment for acute gout, and combinations of these medications can be used for severe or unresponsive cases. F EUROPEAN LEAGUE AGAINST RHEUMATISM (EULAR) In 2006, EULAR published the first international recommendations for the diagnosis and treatment of gout. A,B These evidence-based recommendations for the treatment of gout were developed that addressed the symptomatic control of acute gout, urate lowering therapy, and prophylaxis of acute attacks. B Recommended drugs for acute attacks were oral non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine, or joint aspiration and injection of corticosteroid. Urate lowering therapy is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol is effective long term urate lowering therapy. If allopurinol toxicity occurs, options include xanthine oxidase inhibitors, allopurinol desensitization, or a uricosuric agent. Febuxostat was not available at the time of guideline development, but in a 2008 review, febuxostat was noted only to be used in those patients intolerant of allopurinol. Nothing else changed in the guidelines. When gout is associated with the use of diuretics, the diuretic should be discontinued if possible. For prophylaxis against acute attacks, either colchicine mg daily or an NSAID, with gastroprotection if indicated, are recommended. Pegloticase (Krystexxa) was not available at the time the guidelines were developed or reviewed. Page 14 of 20

15 THE BRITISH SOCIETY FOR RHEUMATOLOGY (BSR) AND BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY D The British Society for Rheumatology and British Health Professionals in Rheumatology established guidelines for the management of gout in Pegloticase (Krystexxa) was not available at the time these guidelines were established. The guidelines recommended the following: For an acute attack, maximal doses of NSAIDs should begin immediately and continue for one to two weeks unless contraindicated. Prescribers should consider the value of gastroprotective agents (proton pump inhibitors) in patients with increased risk of peptic ulcers, bleeds or perforations. Colchicine is effective, but it works more slowly than NSAIDs. In order to reduce the risk of adverse effects, especially diarrhea, colchicine is used at a dose of mg once to twice daily. Xanthine oxidase inhibitor therapy should not be initiated during an acute attack, but four to six weeks after the acute episode; however, in patients already on allopurinol or febuxostat therapy should not be discontinued. Opiate analgesics may be used as adjuncts for pain. Corticosteroids, given orally, intramuscularly, intravenously, or intra-articularly, are an effective treatment in the management of acute gout in patients who cannot tolerate NSAIDs or are refractory to other treatments. Intra-articular corticosteroids are highly effective for acute gouty arthritis in one joint. If diuretics are being used for management of hypertension, an alternative treatment should be considered, except in patients with heart failure. NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE (NICE) The National Institute for Health and Care Excellence (NICE) as of February 2013 has opened a consultation on the use of Krystexxa (peglioticase) from Savient Pharma, in treating severe debilitating chronic tophaceous Gout in adults. The draft POLICY does not recommend the drug for this use. Considering the evidence presented, the Committee concluded that pegloticase effectively lowers the level of uric acid in the blood for a significant proportion of patients with severe gout. However the Committee noted the risk of serious adverse reactions, and concluded that there was considerable uncertainty about the long-term efficacy and safety of pegloticase. This is draft POLICY; NICE has not yet issued final POLICY to the NHS at the time of this writing in May HAYES DIRECTORY A Hayes Directory report was not available for Krystexxa at the time of this writing in May A Prognosis Overview was available for Krystexxa (to track new technologies up to 3 years before these agents enter the marketplace), however this report was archived on May 24, 2011 since the Technology is too mature for scope of product. COCHRANE DATABASE OF SYSTEMATIC REVIEWS A Cochrane review was available for Pegloticase for Chronic Gout at the time of this writing in May 2013; however this review may not be current as it was published in 2010 when only one open-label, phase-ii RCT (n=41) was published and met the selection criteria that compared various doses of pegloticase without comparison to placebo or another treatment. The review concluded that There are no published double-blind, placebo-controlled RCTs of pegloticase. More evidence is needed to assess risks/benefits of pegloticase in patients with chronic gout. Page 15 of 20

16 DEFINITIONS N/A APPENDIX APPENDIX 1 Recommended dose and duration of therapy and dose for step/conservative therapy requirement According to the rheumatologist peer reviewer (AMR Reviewer, 2013): Both allopurinol and febuxostat (Uloric) take approximately 2 weeks to lower the concentration of uric acid to stable extent after a dose adjustment. Hence, it may take 2-3 months for a patient to reach an adequate dose of allopurinol or Uloric that will control the uric acid to a level of 6.0 or less. Note that the "adequate" dose for a given patient may not be 600 to 800mg per day of allopurinol or Uloric 80mg per day. These would be the "maximum" doses. The adequate dose is the dose required to reach a uric acid concentration of < 6.0. Neither Becker in UpToDate or the ACR recommendations on Gout mention an optimal duration of time at the "adequate" dose of medication before an adherent trial is deemed a failure. If ongoing gout-related symptoms such as arthritis, tophi or uric acid renal stones continue to occur once the "adequate" dose is achieved, then the treatment would be considered inadequate and an alternative therapy (e.g. Krystexxa) would be indicated. As such, a trial of 3 months on each treatment (allopurinol and Uloric) to allow a patient to reach the adequate uric acid level would be appropriate. As many of these patients may not reach a uric acid of < 6.0 at "maximum" doses (e.g. allopurinol of 800 mg per day, Uloric 80mg per day), this should be another criteria for movement to Krystexxa treatment. Reference: AMR Peer Review Network. AMR Tracking Num: Board certified in Internal Medicine, Rheumatology. Date completed: 5/10/2013 References cited by AMR Reviewer: Becker, MA. Prevention of recurrent gout. In: UpToDate, Basow, DS (Ed). UpToDate, Waltham, MA, (Reference no. 1 in references section) Khanna D, Fitzgerald JD, Khanna PP, et al. American College of Rheumatology American College of Rheumatology guidelines for management of gout. Part 1: systematic non-pharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) Oct;64(10): doi: /acr PubMed PMID: (Reference no. E in references section) Page 16 of 20

17 CODING INFORMATION: THE CODES LISTED IN THIS POLICY ARE FOR REFERENCE PURPOSES ONLY. LISTING OF A SERVICE OR DEVICE CODE IN THIS POLICY DOES NOT IMPLY THAT THE SERVICE DESCRIBED BY THIS CODE IS A COVERED OR NON-COVERED. COVERAGE IS DETERMINED BY THE BENEFIT DOCUMENT. THIS LIST OF CODES MAY NOT BE ALL INCLUSIVE. CPT Description Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure) HCPCS J2507 Description Injection, pegloticase, 1 mg. Use this code for Krystexxa. ICD-9 Description [For dates of service prior to 10/01/2015] Gouty arthropathy, unspecified Chronic gouty arthropathy without mention of tophus (tophi) Chronic gouty arthropathy with tophus (tophi) ICD-10 Description [For dates of service on or after 10/01/2015] M10.00 Idiopathic gout, unspecified site (274.00) M Idiopathic gout, right shoulder (274.00) M Idiopathic gout, left shoulder (274.00) M Idiopathic gout, unspecified shoulder (274.00) M Idiopathic gout, right elbow (274.00) M Idiopathic gout, left elbow (274.00) M Idiopathic gout, unspecified elbow (274.00) M Idiopathic gout, right wrist (274.00) M Idiopathic gout, left wrist (274.00) M Idiopathic gout, unspecified wrist (274.00) M Idiopathic gout, right hand (274.00) M Idiopathic gout, left hand (274.00) M Idiopathic gout, unspecified hand (274.00) M Idiopathic gout, right hip (274.00) M Idiopathic gout, left hip (274.00) M Idiopathic gout, unspecified hip (274.00) M Idiopathic gout, right knee (274.00) M Idiopathic gout, left knee (274.00) M Idiopathic gout, unspecified knee (274.00) M Idiopathic gout, right ankle and foot (274.00) M Idiopathic gout, left ankle and foot (274.00) M Idiopathic gout, unspecified ankle and foot (274.00) M10.08 Idiopathic gout, vertebrae (274.00) M10.09 Idiopathic gout, multiple sites (274.00) M1A.00X0 Idiopathic chronic gout, unspecified site, without tophus (tophi) (274.02) M1A.0110 Idiopathic chronic gout, right shoulder, without tophus (tophi) (274.02) M1A.0120 Idiopathic chronic gout, left shoulder, without tophus (tophi)(274.02) M1A.0190 Idiopathic chronic gout, unspecified shoulder, without tophus (tophi) (274.02) M1A.0210 Idiopathic chronic gout, right elbow, without tophus (tophi)(274.02) M1A.0220 Idiopathic chronic gout, left elbow, without tophus (tophi) (274.02) (274.02) M1A.0290 Idiopathic chronic gout, unspecified elbow, without tophus (tophi) (274.02) M1A.0310 Idiopathic chronic gout, right wrist, without tophus (tophi) (274.02) Page 17 of 20

18 M1A.0320 Idiopathic chronic gout, left wrist, without tophus (tophi) (274.02) M1A.0390 Idiopathic chronic gout, unspecified wrist, without tophus (tophi) (274.02) M1A.0410 Idiopathic chronic gout, right hand, without tophus (tophi) (274.02) M1A.0420 Idiopathic chronic gout, left hand, without tophus (tophi) (274.02) M1A.0490 Idiopathic chronic gout, unspecified hand, without tophus (tophi) (274.02) M1A.0510 Idiopathic chronic gout, right hip, without tophus (tophi) (274.02) M1A.0520 Idiopathic chronic gout, left hip, without tophus (tophi) (274.02) M1A.0590 Idiopathic chronic gout, unspecified hip, without tophus (tophi) (274.02) M1A.0610 Idiopathic chronic gout, right knee, without tophus (tophi) (274.02) M1A.0620 Idiopathic chronic gout, left knee, without tophus (tophi) (274.02) M1A.0690 Idiopathic chronic gout, unspecified knee, without tophus (tophi) (274.02) M1A.0710 Idiopathic chronic gout, right ankle and foot, without tophus (tophi) (274.02) M1A.0720 Idiopathic chronic gout, left ankle and foot, without tophus (tophi) (274.02) M1A.0790 Idiopathic chronic gout, unspecified ankle and foot, without tophus (tophi) (274.02) M1A.08X0 Idiopathic chronic gout, vertebrae, without tophus (tophi) (274.02) M1A.09X0 Idiopathic chronic gout, multiple sites, without tophus (tophi) (274.02) M1A.00X1 Idiopathic chronic gout, unspecified site, with tophus (tophi) (274.03) M1A.0111 Idiopathic chronic gout, right shoulder, with tophus (tophi) (274.03) M1A.0121 Idiopathic chronic gout, left shoulder, with tophus (tophi) (274.03) M1A.0191 Idiopathic chronic gout, unspecified shoulder, with tophus (tophi) (274.03) M1A.0211 Idiopathic chronic gout, right elbow, with tophus (tophi) (274.03) M1A.0221 Idiopathic chronic gout, left elbow, with tophus (tophi) (274.03) M1A.0291 Idiopathic chronic gout, unspecified elbow, with tophus (tophi) (274.03) M1A.0311 Idiopathic chronic gout, right wrist, with tophus (tophi) (274.03) M1A.0321 Idiopathic chronic gout, left wrist, with tophus (tophi) (274.03) M1A.0391 Idiopathic chronic gout, unspecified wrist, with tophus (tophi) (274.03) M1A.0411 Idiopathic chronic gout, right hand, with tophus (tophi) (274.03) M1A.0421 Idiopathic chronic gout, left hand, with tophus (tophi) (274.03) M1A.0491 Idiopathic chronic gout, unspecified hand, with tophus (tophi) (274.03) M1A.0511 Idiopathic chronic gout, right hip, with tophus (tophi) (274.03) M1A.0521 Idiopathic chronic gout, left hip, with tophus (tophi) (274.03) M1A.0591 Idiopathic chronic gout, unspecified hip, with tophus (tophi) (274.03) M1A.0611 Idiopathic chronic gout, right knee, with tophus (tophi) (274.03) M1A.0621 Idiopathic chronic gout, leftt knee, with tophus (tophi) (274.03) M1A Idiopathic chronic gout, unspecified knee, with tophus (tophi) (274.03) M1A.0711 Idiopathic chronic gout, right ankle and foot, with tophus (tophi) (274.03) M1A.0721 Idiopathic chronic gout, left ankle and foot, with tophus (tophi) (274.03) M1A.0791 Idiopathic chronic gout, unspecified ankle and foot, with tophus (tophi) (274.03) M1A.08X1 Idiopathic chronic gout, vertebrae, with tophus (tophi)(274.03) M1A. 09X1 Idiopathic chronic gout, multiple sites, with tophus (tophi) (274.03) REFERENCES Package Insert and FDA a. Krystexxa [package insert]. East Brunswick, NJ: Savient Pharmaceuticals, Inc.; September b. Facts & Comparisons. Krystexxa. [Facts & Comparisons Web site]. Available at: [via subscription only]. Accessed May 2013 c. Food and Drug Administration; Center for Drug Evaluation and Research; Medical Review for BLA , Krystexxa (Pegloticase) August 20, Available from: Accessed May 2013 Page 18 of 20