Gout Pharmacotherapy Ryan L. Crass, PharmD PGY1 Pharmacy Resident UK HealthCare ryan.crass@uky.edu

Learning Objectives Understand the pathophysiology of and risk factors for the development of gouty arthritis Recognize clinical and laboratory findings consistent with the diagnosis of gout and how they are modified by treatment Explain the different treatment modalities for acute gout attacks and long-term prophylaxis Discuss the mechanisms, major adverse effects, and key drug-drug interactions for the primary medications used in the treatment and prevention of gout

“The Disease of Kings”

Pathophysiology, Manifestations, and Diagnosis Characterizing the Disease Pathophysiology, Manifestations, and Diagnosis

Characterizing Gout Gout is a spectrum of clinical features related to an excess total body burden of uric acid One of the most common adulthood rheumatic diseases about 4% of U.S. adults (~ 8.3 million people) Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.

Pathophysiology Hyperuricemia Uric acid is byproduct of purine metabolism Hyperuricemia occurs when there is an imbalance in uric acid production and excretion Defined as serum uric acid > 7 mg/dL Does anyone remember back to biochemistry what purines are? Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Pathophysiology Hyperuricemia Overproduction Underexcretion Xanthine Oxidase Xanthine Oxidase Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Pathophysiology Gouty Arthritis Precipitation of monosodium urate (MSU) crystals and activation of inflammation Hyperuricemia (> 7 mg/dL) Overproduction Underexcretion Precipitation of MSU crystals Temperature pH Concentration Neutrophil infiltration and inflammation Redness Swelling Pain Warmth Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Risk Factors Hyperuricemia* Male sex High purine diet (red meats, shellfish) Beer and alcohol Obesity and the metabolic syndrome CKD Solid organ transplantation Hyperuricemia (incidence of acute gout males followed 15 years) < 7: 0.1% annual incidence 7 – 8.9: 0.5% annual incidence ≥9: 4.9% annual incidence Diet - Beer is rich in purines Organ meats (liver, kidney) and to lesser extent red meat and shellfish are rich in purines High Fructos corn syrup *Hyperuricemia ≠ gout Teng GG, et al. Drugs. 2006;66(12):1547-1563. Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.

Risk Factors Medications Diuretics (thiazides, loops) Calcineurin inhibitors Low-dose salicylates Niacin Teng GG, et al. Drugs. 2006;66(12):1547-1563. Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.

Clinical Manifestations Acute Gouty Arthritis (“Flare”) Chronic Gouty Arhritis Symptoms Warmth/swelling Severe Pain Fever, leukocytosis Location: Usually monoarticular Time course Onset: Rapid Peak: 8-12 hours Duration: 3-10 days Chronic Gout Polyarticular involvement Tophi = urate crystal aggregates Nephropathy Teng GG, et al. Drugs. 2006;66(12):1547-1563. Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.

Summary Disease Characteristics The pathophysiology of gout is a dysregulation of the production and/or excretion of uric acid Gout commonly manifests as an acutely painful monoarticular arthritis with or without tophi formation Modifiable risk factors include diet, lifestyle, medications, and hyperuricemia

Treatment Acute gouty arthritis

General Principles Maintenance ULT should be continued during attacks Timing Therapy should be initiated within 24 hours AND Continued until resolution of symptoms *ULT = Urate lowering therapy Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.

Pharmacotherapy Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.

NSAIDs NSAIDs (naproxen, indomethacin, sulindac) Mechanism Inhibition of cyclooxygenase (COX) enzymes reducing prostaglandin synthesis Dose Full antiinflammatory doses Naproxen: 750 mg x1, then 250 mg TID Indomethacin: 50 mg TID Sulindac: 200 mg BID Administration Take with food or dairy Adverse Events Common: dysepsia, hypetension, fluid retention Rare/Serious: GI bleeding, acute kidney injury Drug Interactions Antiplatelets/anticoagulants, antihypertensives, corticosteroids Pearls Generally not used in combination with systemic steroids Do not use salicylates as can disrupt uric acid levels Antiinflammatory doses of other NSAIDs may be effective Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461. Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Systemic Corticosteroids Corticosteroids (prednisone, prednisolone, methylprednisolone) Mechanism Broad range of effects leading to reduced neutrophil infiltration and cytokine release Dose 1. Pulse: 0.5 mg/kg/day x 5-10 days 2. Taper: 0.5 mg/kg/day x 2-5 days, then taper over 7-10 days 3. Methyprednisolone dose pack Administration Take with food and early in the day Adverse Events Common: hyperglycemia, hypertension, edema, insomnia Rare/Serious: delayed wound healing, osteoporosis Drug Interactions NSAIDS*, fluoroquinolones Pearls Generally not used in combination with NSAIDs May exacerbate underlying hypertension or diabetes Consider adding intraarticular steroids to any modality if 1-2 large joints affected Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461. Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Colchicine Colchicine (Colcrys®) Mechanism Inhibits beta-tubulin polymyerization leading to decreased neutrophil chemotaxis and inflammation Dose Acute Gout Attack: 1.2 mg, then 0.6 mg 1-hour later. Prophylaxis dosing starting 12 hours later Prophylaxis: 0.6 mg QD – BID Administration Take with a full class of water Adverse Events Common: GI distress (diarrhea, N&V) Rare/Serious: myelosuppression, myopathy Drug Interactions CYP3A4/P-gp substrate (Avoid strong inducers/inhibitors) Pearls Treatment generally titrated to diarrhea Do not repeat treatment courses within 14 days Contraindicated with renal or hepatic impairment AND a strong CYP3A4/P-gp inhibitor Cyclosporin – inhibition of PGP increases CSA levels Statins/Fibrates – increase risk of mylagias  rhabdo Contraindicated if organ dysfunction AND enzyme inhibitor Renal Impairment: Dose reduction indicated in CrCL < 30 mL/min; however, PK analysis says AUC increases 50% at 50 mL/min which may suggest higher range for dose reduction Colcrys®. [package insert]:Philadelphia, PA. AR Scientific, INC;2009.

Criteria for Inadequate Response Evaluating Response ULT should start 6-8 weeks after resolution of acute attack Criteria for Inadequate Response ↓ < 20% in pain score within 24 hours ↓ < 50% in pain score beyond 24 hours Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.

Summary: Acute Gouty Arthritis Pharmacotherapy is the mainstay of acute gout treatment NSAIDs, systemic cortiocosteroids, and colchcine are all first line options and choice of agent should be guided by patient- specific factors Combination therapy can be used for severe attacks

Maintenance Urate lowering therapy Treatment Maintenance Urate lowering therapy

Non-pharmacologic Therapy Dietary and lifestyle modifications Consume in moderation Alcohol, red meat, shellfish, sweets Weight loss Tobacco cessation Appropriate hydration Minimize non-essential medications that may induce hyperuricemia Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.

Who should receive ULT? Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.

Which agents are first line? Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.

Xanthine Oxidase Inhibitors Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Allopurinol Allopurinol (Zyloprim®) Mechanism Xanthine oxidase inhibitor (XOI) Dose Initial: 100 mg QD Titrate: q2-5 weeks until uric acid target achieved Max Dose: 800 mg/day divided Administration Take with or without meals Adverse Events Common: Rash, pruritis, transaminitis Rare/Serious: myelosuppression, hepatotoxicity, SJS/TEN Drug Interactions Purine antimetabolites (azathioprine, 6-mercaptopurine), theophylline, didanosine Pearls Dose is titrated up slowly to avoid acute gout flare Dose is reduced by 50% in renal impairment Hypersensitivity reaction more common with concurrent thiazides and in Asian populations (consider HLA-B*5801 screening) Cyclosporin – inhibition of PGP increases CSA levels Statins/Fibrates – increase risk of mylagias  rhabdo Contraindicated if organ dysfunction AND enzyme inhibitor Renal Impairment: Dose reduction indicated in CrCL < 30 mL/min; however, PK analysis says AUC increases 50% at 50 mL/min which may suggest higher range for dose reduction Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461. Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Febuxostat Febuxistat (Uloric®) Mechanism Xanthine oxidase inhibitor (XOI) Dose Initial: 40 mg QD Titrate: may incease to 80 mg if not at goal in 2 weeks Max Dose: 120 mg/day Administration Take with or without meals Adverse Events Common: Rash, gout flare, transaminitis Rare/Serious: hepatotoxicity, thrombotic events, SJS/TEN Drug Interactions Purine antimetabolites (azathioprine, 6-mercaptopurine), theophylline, didanosine Pearls Consider in patients who do not tolerate allopurinol or have inadequate response (BRAND only) Gout flares more common during initiation of therapy Not renally eliminated Cyclosporin – inhibition of PGP increases CSA levels Statins/Fibrates – increase risk of mylagias  rhabdo Contraindicated if organ dysfunction AND enzyme inhibitor Renal Impairment: Dose reduction indicated in CrCL < 30 mL/min; however, PK analysis says AUC increases 50% at 50 mL/min which may suggest higher range for dose reduction Uloric®. [package insert]:Deerfield, IL. Takeda Pharmaceuticals America, Inc;2013.

CONTRAINDICATION 6-MP Theophylline Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Uricosurics fenofibrate Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Probenecid Probenecid Mechanism Inhibits the uric acid – organic anion transport pathway Dose Initial: 250 mg BID x 1 week Titrate: 500 mg/day increments every 4 weeks Max Dose: 2 g/day Administration Take with food and plenty of fluids Adverse Events Common: GI intolerance (dyspepsia, reflux), rash, acute gout Rare/Serious: nephrolithiasis Drug Interactions Significant – inhibits secretory elimination of anionic drugs Pearls No benefit if CrCL < 30-50 mL/min Can be used therapeutically to boost beta-lactam levels Monitor urinary uric acid excretion before and during therapy Contraindicated: history of nephrolithiasis Cyclosporin – inhibition of PGP increases CSA levels Statins/Fibrates – increase risk of mylagias  rhabdo Contraindicated if organ dysfunction AND enzyme inhibitor Renal Impairment: Dose reduction indicated in CrCL < 30 mL/min; however, PK analysis says AUC increases 50% at 50 mL/min which may suggest higher range for dose reduction Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461. Teng GG, et al. Drugs. 2006;66(12):1547-1563.

Prophylaxis When Initiating ULT 6-8 weeks after acute attack resolution Khanna D, et al. Arthritis Care Res. 2012;64(10):1447-1461.

Treatment-Resistant Gout Referral to a rheumatologist Refractory signs and symptoms Difficulty reaching serum uric acid target, particularly with renal impairment and trial of XOI Multiple/serious adverse effects to treatment Khanna D, et al. Arthritis Care Res. 2012;64(10):1431-1446.

Uricase Enzyme Rasburicase (Elitek®) Medicinal Chemistry Rasburicase isolated from Aspergillus flavus Unfortunately it was highly immunogenic and caused severe immune reactions: anaphylaxis, hemolysis (G6PD), methemoglobinemia Intravenous administration Pegloticase Pegylated form is less immunogenic Dose: 8 mg IV q2 weeks (unclear optimal duration)  premedicate (antihstamines and steroids) Contraindicated: G6PD Antibody formation has been seen over time which may limit long term efficacy Rasburicase (Elitek®) Medicinal Chemistry Pegloticase (Krystexxa®) Teng GG, et al. Drugs. 2006;66(12):1547-1563.

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Lesinurad (Zurampic®) Probenecid Mechanism Selective inhibitor of URAT1 and OAT4 (diuretic-induced) Dose 200 mg QD with a XOI Administration Take with food and plenty of fluids (2L/day) at the same time as XOI Adverse Events Common: Headache, reflux, influenza Rare/Serious: Acute renal failure (monotherapy) Drug Interactions CYP2C9 inhibitors/inducers Pearls Contraindicated: monotherapy or with CrCL < 45 mL/min Limited experience and yet to define place in therapy Dose of XOI: allopurinol 300 mg QD or more (200 mg QD if CrCL < 60) Zurampic®. [package insert]:Wilmington, DE. AstraZeneca Pharmaceuticals LP;2015.

Summary: Urate Lowering Therapy Maintenance ULT is indicated in significant disease burden and renal comorbidities Xanthine oxidase inhibitors are the mainstay of therapy to target uric acid levels of at least < 6 mg/dL Uricosuric agents are alternatives to XOIs and useful adjuncts in resistant disease

Take Away Points Gout is a common rheumatic disease that can be largely “cured” with pharmacotherapy Medication selection during acute attacks should be guided by patient-specific factors Maintenance ULT is largely well tolerated by some significant drug-drug interactions exist and most medications should be adjusted for renal dysfunction

Patient Case Doran Martell is a 58 YOM with PMHx HTN, HLD, T2DM, DVT who presents with a chief complaint of swelling and excruciating pain in his right foot.

Patient Case Doran Martell supplies the following history Diet: Eats shellfish frequently due to proximity to the sea, red meat on weekends EtOH: Drinks 3-4 ales/day Exercise: Little physical activity

Medications ASA 325 mg q4-6 PRN pain Valsartan 160 mg QD HCTZ 25 mg QD Niacin OTC capsules QD Simvastatin 20 mg QHS Warfarin 5 mg QMWF & 2.5 mg QTuThSaSu

Patient Counseling What modifiable risk factors could you counsel this patient on? Which medications may exacerbate gout?

Physical Exam Findings Erythema, tenderness, and swelling in the right great toe

Patient Case Labs Vitals A1c 5.9% Scr: 1.4 (CrCL ~ 59 mL/min) LFTs: WNL Uric Acid: 9 mg/dL Vitals BP: 150/94 | HR: 87 | RR: 16

Medications ASA 325 mg q4-6 PRN pain Valsartan 160 mg QD HCTZ 25 mg QD Niacin OTC capsules QD Simvastatin 20 mg QHS Warfarin 5 mg QMWF & 2.5 mg QTuThSaSu

Patient Case With your neighbor discuss: Which laboratory/physical exam findings are consistent with acute gout? Which medication(s) you want initiate for Doran Martell’s acute gout attack? Why?

Patient Case One year later, Prince Doran returns to clinic for follow up (he was swept away in wars and intrigue and missed his other follow ups). This is his physical exam today:

Patient Case He is asymptomatic but has tophi on examination. He has made the dietary and lifestyle modifications you discussed previously. What therapy would you like to initiate?

Questions?