A DIFFERENT WAY TO REMOVE URATE

KRYSTEXXA has a unique MOA for patients with chronic gout uncontrolled by conventional therapy.

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Image used with permission from nephrotox.com.

THE BURDEN OF URATE REMOVAL FALLS ON THE KIDNEYS

Only 10% of uric acid filtered through the kidney is excreted1

Artist’s rendition.

Urate reabsorbed

Urate excreted

Generally, the kidneys tend to retain uric acid, making uric acid elimination highly inefficient even in healthy kidneys2

o90% of hyperuricemia is a result of underexcretion of uric acid by the kidneys1

EVEN WITH HIGH DOSES OF ORAL ULTs MANY PATIENTS STRUGGLE TO SUFFICIENTLY LOWER THEIR sUA LEVEL3-5

Percentage of patients treated with febuxostat and allopurinol who reached target sUA level5,6

FEBUXOSTAT 80 mg VS ALLOPURINOL 300 mg CLINICAL TRIAL (STUDY 3)5,6*
Target sUA (mg/dL)
FEB 80 mg (n=256)
ALLO 300 mg (n=253)
Primary endpoint: <6.0
Last 3 monthly measurements
53% 21%
<5.0*
At final visit
47% 13%
<4.0*
At final visit
20% 2%

*Post hoc analysis.

ULT=urate-lowering therapy.

The pooled phase 3 results for the percentage of patients with an sUA level <6 mg/dL at final visit for febuxostat 80 mg was 70%6,7

A DIFFERENT APPROACH: KRYSTEXXA IS A PEGylated, RECOMBINANT URICASE ENZYME THAT CONVERTS URATE INTO ALLANTOIN14

Artist’s rendition.

URATE

KRYSTEXXA

ALLANTOIN

KRYSTEXXA is indicated for the treatment of chronic gout in adult 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.

IMPORTANT LIMITATIONS OF USE

KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia

RENAL EXCRETION OF ALLANTOIN IS UP TO 10 TIMES MORE EFFICIENT THAN EXCRETION OF URIC ACID18

Nearly all of allantoin filtered through the kidney is excreted1,18

Artist’s rendition.

Allantoin reabsorbed

Allantoin excreted

SELECT IMPORTANT SAFETY INFORMATION

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients

Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion

KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions

IMPORTANT RENAL CONSIDERATIONS REGARDING ORAL URATE-LOWERING THERAPIES

Xanthine oxidase inhibitors
(XOIs) (eg, allopurinol and febuxostat) reduce the production of uric acid.

HOR_KRY_aggNET_assets_00a The kidneys are still primarily responsible for removing years' worth of urate buildup.8-10

Uricosurics
(eg, lesinurad and probenecid) induce the kidneys to eliminate more uric acid than normal, causing an increase in the concentration of uric acid in the urine.

These drugs may contribute to acute kidney failure and nephrolithiasis.11-13

ALLANTOIN IS A NON-TOXIC, WATER-SOLUBLE PRODUCT OF URIC ACID OXIDATION15,16

Allantoin is readily excreted in the urine regardless of renal function. When there is little to no renal output, allantoin is also readily removed via dialysis.16,17*

*KRYSTEXXA was studied in uncontrolled gout patients in stages 1-4 but has not been studied in gout patients requiring dialysis.

IMPORTANT LIMITATIONS OF USE

KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia

KRYSTEXXA IS SAFE AND EFFECTIVE FOR PATIENTS WITH UNCONTROLLED GOUT AND CKD14,19

Pivotal clinical trials
32% of patients in the pivotal clinical trials had creatinine clearance <62.5 mL/min14

Estimation of glomerular filtration rate (eGFR) from serum creatinine remains the clinical standard worldwide to determine renal function20-23

Post hoc analysis
38% of patients had stage 3 CKD and
11% had stage 4 CKD, as determined by eGFR19

Patients with CKD can be effectively treated with KRYSTEXXA without dose adjustment14

CKD patients experienced similar reductions in sUA levels compared with patients without CKD14,19

oThere was no observed difference in efficacy of KRYSTEXXA across CKD stages 1, 2, 3, and 4

The safety profile of KRYSTEXXA was demonstrated to be the same in patients with or without CKD, and across all CKD stages14,19

KRYSTEXXA did not affect the eGFR during the 25-week treatment period19

SELECT IMPORTANT SAFETY INFORMATION

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients

Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion

KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions

References
  1. Terkeltaub R, et al. Arthritis Res Ther. 2006;8(suppl 1):S4.
  2. Kang DH, et al. Semin Nephrol. 2005;25(1):43-49.
  3. Schumacher HR, et al. Arthritis Rheum. 2008;59(11):1540-1548.
  4. Becker MA, et al. Semin Arthritis Rheum. 2015;45(2):174-183.
  5. Becker MA, et al. N Engl J Med. 2005;353(23):2450-2461.
  6. Uloric [prescribing information]. Takeda Pharmaceuticals America, Inc. August 2017.
  7. Uloric efficacy and safety profile. Uloric website. http://www.goutrx.com/urx/efficacy-safety. Accessed August 21, 2017.
  8. Schett G, et al. RMD Open. 2015;1(suppl 1):e000046.
  9. Edwards NL. Primer on the Rheumatic Diseases. 13th ed. New York, NY: Springer; 2008:241-249.
  10. Krishnan E. PLoS ONE. 2012;7(11):e50046.
  11. Rees F, et al. Nat Rev Rheumatol. 2014;10(5):271-283.
  12. Emmerson BT. N Engl J Med. 1996;334(7):445-451.
  13. Zurampic [prescribing information]. Ironwood Pharmaceuticals, Inc. July 2017.
  14. KRYSTEXXA [prescribing information]. Horizon Pharma Rheumatology LLC.
  15. Becker LC, et al. Int J Toxicol. 2010;29(suppl 3):84S-97S.
  16. Friedman M, et al. Am J Physiol. 1948;155(2):278-281.
  17. Caussé E, et al. Clin Nephrol. 2010;73(1):51-57.
  18. McDonagh EM, et al. Pharmacogenet Genomics. 2014;24(9):464-476.
  19. Yood RA, et al. BMC Res Notes. 2014;7:54.
  20. Levey AS, et al. Ann Intern Med. 1999;130(6):461-470.
  21. Levey AS, et al. Ann Intern Med. 2009;150(9):604-612.
  22. Michels WM, et al. Clin J Am Soc Nephrol. 2010;5(6):1003-1009.
  23. Poggio ED, et al. J Am Soc Nephrol. 2005;16(2):459-466.
  24. Thiele RG, et al. Rheumatology (Oxford). 2007;46(7):1116-1121.
  25. Naredo E, et al. Ann Rheum Dis. 2014;73(8):1522-1528.
  26. Dalbeth N, et al. BMC Musculoskelet Disord. 2013;14:363.
  27. Dalbeth N, et al. Arthritis Rheum. 2010;62(5):1549-1556.
  28. Doghramji PP, et al. Postgrad Med. 2012;124(6):98-109.
  29. Bongartz T, et al. Ann Rheum Dis. 2015;74(6):1072-1077.
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Indications and Usage

KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult 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.

Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

Important Safety Information

WARNING: 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 premedicated 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: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.

INDICATIONS AND USAGE

KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult 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.

Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

IMPORTANT SAFETY INFORMATION

WARNING: 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 premedicated 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.

The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response.

Concomitant use of KRYSTEXXA and oral urate-lowering agents may blunt the rise of sUA levels. Patients should discontinue oral urate-lowering agents and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

In the event of anaphylaxis or infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

Inform patients of the symptoms and signs of anaphylaxis, and instruct them to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.

GOUT FLARES

An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with KRYSTEXXA. If a gout flare occurs during treatment, KRYSTEXXA need not be discontinued. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated.

CONGESTIVE HEART FAILURE

KRYSTEXXA has not been studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion.

ADVERSE REACTIONS

The most commonly reported adverse reactions in clinical trials with KRYSTEXXA are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.

Please see Full Prescribing Information and Medication Guide for more information.

INDICATIONS AND USAGE

KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult 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.

Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

IMPORTANT SAFETY INFORMATION

WARNING: 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 premedicated 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.

The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response.

Concomitant use of KRYSTEXXA and oral urate-lowering agents may blunt the rise of sUA levels. Patients should discontinue oral urate-lowering agents and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

In the event of anaphylaxis or infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

Inform patients of the symptoms and signs of anaphylaxis, and instruct them to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.

GOUT FLARES

An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with KRYSTEXXA. If a gout flare occurs during treatment, KRYSTEXXA need not be discontinued. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated.

CONGESTIVE HEART FAILURE

KRYSTEXXA has not been studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion.

ADVERSE REACTIONS

The most commonly reported adverse reactions in clinical trials with KRYSTEXXA are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.

Please see Full Prescribing Information and Medication Guide for more information.