Krystexxa

Generic Name: Pegloticase
Class: Antigout Agents
VA Class: MS400
Chemical Name: Amide with α-carboxy-ω-methoxypoly(oxy-1,2-ethanediyl), urate (synthetic Sus scrofa variant pigKS-DN subunit), oxidase, homotetramer
Molecular Formula: C1549H2430N408O448S8
CAS Number: 885051-90-1

Warning(s)

  • Anaphylaxis and Infusion Reactions
  • Anaphylaxis and infusion reactions reported during and after administration.1 (See Sensitivity Reactions under Cautions.)

  • Anaphylaxis may occur with any infusion; generally manifests within 2 hours of infusion.1 Delayed-type hypersensitivity also reported.1

  • Administer in a healthcare setting by healthcare providers prepared to manage anaphylaxis and infusion reactions.1

  • Premedicate patients with antihistamines and corticosteroids.1

  • Closely monitor for anaphylaxis for an appropriate period of time after administration.1

  • Determine serum uric acid concentration prior to each infusion and consider discontinuing treatment if concentrations rise above 6 mg/dL, particularly if 2 consecutive measurements exceed 6 mg/dL.1

REMS:

FDA approved a REMS for pegloticase to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of pegloticase and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Pegylated biosynthetic (recombinant DNA origin) modified mammalian urate oxidase (uricase) enzyme.1 7 8 11

Uses for Krystexxa

Gout

Management of chronic gout that is refractory to conventional therapy (i.e., chronic gout in patients in whom maximum recommended dosages of xanthine oxidase inhibitors have failed to normalize serum uric acid concentrations and to adequately control clinical manifestations of the disease or in whom these drugs are contraindicated).1 3 4 7 8 11 12 15 16 Designated an orphan drug by FDA for this use.14

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Not recommended for treatment of asymptomatic hyperuricemia.1

Krystexxa Dosage and Administration

General

Premedication for Sensitivity Reactions

  • Administer antihistamines and corticosteroids before each infusion to minimize risk of anaphylaxis and infusion reactions.1 Closely monitor patient for an appropriate period of time after administration.1 (See Sensitivity Reactions under Cautions.)

  • Measure uric acid concentration before each infusion; risk of anaphylaxis or infusion reactions is higher in patients who have lost therapeutic response to the drug.1

Gout Flare Prophylaxis

  • Initiate gout flare prophylaxis with an NSAIA or colchicine at least 1 week prior to initiation of pegloticase and continue for ≥6 months unless contraindicated or not tolerated.1 (See Gout Flares under Cautions.)

REMS Program

  • Risk Evaluation and Mitigation Strategy (REMS) required and approved by FDA.5

  • 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.5 (See Cautions.)

  • Program consists of a medication guide that must be dispensed with every prescription and a communication plan that includes initial and periodic communications targeting selected groups of healthcare providers.5

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

May administer via gravity feed, syringe pump, or infusion pump.1

Dilution

Pegloticase injection concentrate must be diluted prior to IV administration.1

Withdraw 1 mL of pegloticase injection concentrate from a vial containing 8 mg/mL of uricase protein.1 Inject into 250-mL bag containing 0.45 or 0.9% sodium chloride injection.1 Discard any unused portion.1 Invert the infusion bag a number of times to mix thoroughly; do not shake.1

Do not mix or dilute with any other drugs.1

Refrigerate diluted solution, protect from light, and use within 4 hours of dilution.1 Allow diluted solution to reach room temperature before administration,1 but do not subject to heating (e.g., hot water, microwave).1

Rate of Administration

Infuse over at least 120 minutes.1

If infusion reaction occurs, slow rate of infusion, temporarily stop and then restart infusion at a slower rate, or discontinue infusion, depending on severity of reaction.1

Dosage

Dosage expressed in terms of the amount of uricase protein.1

Adults

Gout
IV

8 mg (of uricase protein) every 2 weeks.1 12 Optimum duration of therapy not established.1 13

8 mg (of uricase protein) every 4 weeks also effective in controlling plasma uric acid concentrations, but associated with increased frequency of anaphylaxis and infusion reactions and reduced efficacy in resolving tophi.1

Consider discontinuing therapy if uric acid concentration rises above 6 mg/dL, particularly if 2 consecutive measurements exceed 6 mg/dL.1 (See Sensitivity Reactions under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations; not specifically studied in hepatic impairment.1

Renal Impairment

No dosage adjustment required in renal impairment.1

Geriatric Patients

No dosage adjustment required based on age.1

Cautions for Krystexxa

Contraindications

  • G-6-PD deficiency.1 Screen higher-risk patients (e.g., patients of African or Mediterranean ancestry) for G-6-PD deficiency before initiating pegloticase therapy.1

Warnings/Precautions

Sensitivity Reactions

Anaphylaxis

Anaphylaxis reported despite pretreatment with oral antihistamine, IV corticosteroid, and/or acetaminophen in 6.5% of patients receiving recommended pegloticase dosage.1 (See Boxed Warning.) Manifestations included wheezing, perioral or lingual edema, or hemodynamic instability, with or without rash or urticaria.1 Pretreatment may have blunted symptoms or signs of anaphylaxis; therefore, reported frequency may underestimate drug's potential to cause such reactions.1

Administer in a healthcare setting by healthcare providers prepared to manage anaphylaxis.1 Pretreat patients with antihistamines and corticosteroids.1 Monitor closely for an appropriate period of time after administration.1

Risk of anaphylaxis is higher in patients whose uric acid concentration rises above 6 mg/dL, particularly when 2 consecutive concentrations exceed 6 mg/dL.1 Determine serum uric acid prior to each infusion and consider discontinuing treatment if concentrations rise above 6 mg/dL.1

Infusion Reactions

Infusion reactions (e.g., urticaria, dyspnea, chest discomfort or pain, erythema, pruritus) reported despite pretreatment with oral antihistamine, IV corticosteroid, and/or acetaminophen in 26% of patients receiving recommended pegloticase dosage.1 (See Boxed Warning.) Pretreatment may have blunted symptoms or signs of infusion reactions; therefore, reported frequency may underestimate drug's potential to cause such reactions.1

Administer in a healthcare setting by healthcare providers prepared to manage infusion reactions.1 Pretreat patients with antihistamines and corticosteroids.1 Monitor for approximately 1 hour after administration.1 Infuse slowly over at least 120 minutes.1

If infusion reaction occurs, slow infusion, or stop and then restart the infusion at a slower rate.1 If reaction is severe, discontinue infusion and institute appropriate treatment as needed.1

Higher risk of infusion reaction in patients whose uric acid concentration rises above 6 mg/dL, particularly when 2 consecutive concentrations exceed 6 mg/dL.1 Determine serum uric acid prior to each infusion and consider discontinuing treatment if concentration rises above 6 mg/dL.1

Gout Flares

Increase in gout flares frequently observed upon initiation of antihyperuricemic therapy.1 Gout flares reported during first 3 months of therapy despite prophylaxis in 74% of patients receiving recommended pegloticase dosage.1

Initiate prophylaxis with an NSAIA or colchicine 1 week before initiation of pegloticase and continue for 6 months unless contraindicated or not tolerated.1

Discontinuance of pegloticase due to gout flare unnecessary.1

Congestive Heart Failure

Not formally studied in patients with CHF; exacerbation of heart failure has been reported.1 Exercise caution in patients with CHF; monitor closely following infusion.1

Retreatment with Pegloticase

Safety and efficacy of resuming pegloticase after treatment interruption of >4 weeks not established in controlled clinical trials.1 Possible increased risk of anaphylaxis and infusion reactions; closely monitor patients reinitiating treatment after a drug-free interval.1

Immunogenicity

Antipegloticase antibodies detected in 92% of patients receiving pegloticase every 2 weeks.1 Antibodies appear to bind to PEG portion of drug.1 17 (See Interactions.)

High antibody titer associated with reduced serum concentrations of the drug and failure to maintain pegloticase-induced normalization of serum uric acid.1 10 Higher incidence of infusion reactions in patients with high antipegloticase antibody titer.1 10

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether pegloticase is distributed into milk; do not use in nursing women.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1

Renal Impairment

About 32% of patients in clinical trials receiving recommended dosage (8 mg every 2 weeks) had Clcr ≤62.5 mL/minute.1 No substantial differences in efficacy were observed.1

Common Adverse Effects

Gout flares,1 3 infusion reactions,1 3 nausea,1 contusion or ecchymosis,1 nasopharyngitis,1 constipation,1 chest pain,1 anaphylaxis,1 vomiting.1

Interactions for Krystexxa

No formal drug interaction studies to date.1

PEG-containing Drugs

Antipegloticase antibodies appear to bind to the PEG portion of pegloticase; potential for binding with other pegylated drugs.1 Effect of antibodies on efficacy of other PEG-containing drugs is not known.1

Krystexxa Pharmacokinetics

Absorption

Onset

Rapidly reduces plasma uric acid.1 6 11 Minimum plasma urate concentration occurred 48–72 hours postinfusion in patients receiving doses of 1–8 mg.6

Duration

Single dose generally maintains plasma uric acid concentrations below 6 mg/dL for >12 days.1 6 11

Elimination

Half-life

Highly variable, 6.8–16.8 days.6 11

Special Populations

Pharmacokinetics in adults not affected by age, sex, weight, or Clcr.1

Stability

Storage

Parenteral

Injection

2–8°C.1 Protect from light; do not freeze.1

Diluted solution: Stable at 2–8 or 20–25°C for up to 4 hours; however, manufacturer recommends refrigeration.1 Do not freeze.1 Protect from light.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.45 or 0.9%1

Actions

  • Biosynthetic (recombinant DNA origin) modified mammalian (porcine-like) urate oxidase (uricase, urate hydroxylase) enzyme that is covalently bound to monoethoxypolyethylene glycol (PEG).1 8 11 13

  • Catalyzes the oxidation of uric acid to allantoin, thereby lowering serum uric acid concentrations.1 8 11 Allantoin is readily eliminated, primarily by renal excretion.1 11

  • Maintaining serum urate concentration below the saturation point for monosodium urate (e.g., maintaining concentrations at ≤6 mg/dL) may prevent crystal formation and promote resolution of tophaceous crystal deposits, thus preventing long-term joint, bone, cartilage, and tissue destruction.7 8 18

Advice to Patients

  • Pegloticase medication guide must be provided to the patient each time the drug is administered (see REMS Program under Dosage and Administration);5 importance of patient reading the medication guide before initiating therapy and before each subsequent infusion.1 2

  • Importance of informing patients that anaphylaxis and infusion reactions can occur with any infusion.1 Importance of informing patients of the signs and symptoms of anaphylaxis (e.g., wheezing, swelling of the throat or tongue, throat tightness, hoarseness, difficulty swallowing, dizziness, fainting, fast or weak heartbeat, feelings of nervousness, rash, itching, urticaria)1 2 and infusion reactions (e.g., urticaria, erythema, difficulty breathing, flushing, chest discomfort or pain, rash).1

  • Advise patients to seek medical care immediately if they experience any symptoms of an allergic reaction during or at any time after an infusion of pegloticase.1 Counsel patients on the importance of adhering to therapy prescribed to prevent or lessen the severity of these reactions.1

  • Importance of informing patients not to take pegloticase if they have G-6-PD deficiency.1 Counsel patients that they may be tested to determine if they have G-6-PD deficiency.1

  • Importance of informing patients that gout flares may initially increase when starting treatment with pegloticase and that medications to help reduce flares may be taken regularly for the first few months after initiation.1 Advise patients that they should not discontinue pegloticase if flares occur.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal or dietary supplements, as well as any concomitant conditions (e.g., heart failure, G-6-PD deficiency).1 2

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pegloticase

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, concentrate, for IV infusion

8 mg/mL (of uricase protein)

Krystexxa

Savient

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Savient Pharmaceuticals, Inc. Krystexxa (pegloticase) injection prescribing information. East Brunswick, NJ; 2010 Sep.

2. Savient Pharmaceuticals, Inc. Krystexxa (pegloticase) injection patient information. East Brunswick, NJ; 2010 Sep.

3. Sundy JS, Baraf HS, Becker MA, et al. Efficacy and safety of intravenous (IV) pegloticase (PGL) in subjects with treatment failure gout (TFG): phase 3 results from GOUT1 and GOUT2 [abstract]. Arthritis Rheum. 2008; 58:S635.

4. Sundy JS, Baraf HS, Gutierrez-Urena SR, et al.. Chronic use of pegloticase: safety and efficacy update [abstract]. Arthritis Rheum. 2009; 60:S417.

5. Krystexxa (pegloticase) risk evaluation and mitigation strategy (REMS). From FDA website. Accessed 2011 Jan 19.

6. Sundy JS, Ganson NJ, Kelly SJ et al. Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum. 2007; 56:1021-8. [PubMed 17328081]

7. Baraf HS, Matsumoto AK, Maroli AN et al. Resolution of gouty tophi after twelve weeks of pegloticase treatment. Arthritis Rheum. 2008; 58:3632-4. [PubMed 18975338]

8. Anderson A, Singh JA. Pegloticase for chronic gout. Cochrane Database Syst Rev. 2010; :CD008335.

9. Mandel DR, Baraf H, Rehrig C, et al. Use of pegloticase in chronic gout refractory to conventional therapy is associated with significant clinical benefit: tender joint and swollen joint counts and patient global assessment (health assessment questionnaire)[abstract]. Arthritis Rheum. 2010; 62:S166.

10. Wright D, Sundy JS, Rosario-Jansen T. Routine serum uric acid (SUA) monitoring predicts antibody-mediated loss of response in infusion reaction risk during pegloticase therapy [abstract]. Arthritis Rheum. 2009; 60:S1104.

11. Sundy JS, Becker MA, Baraf HS et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum. 2008; 58:2882-91. [PubMed 18759308]

12. Edwards NL. Treatment-failure gout: a moving target. Arthritis Rheum. 2008; 58:2587-90. [PubMed 18759307]

13. Burns CM, Wortmann RL. Gout therapeutics: new drugs for an old disease. Lancet. 2011; 377:165-77. [PubMed 20719377]

14. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website. Accessed 2011 Mar 15.

15. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 125293: Summary review for pegloticase. From FDA website. Accessed 2011 Mar 15.

16. . Pegloticase (Krystexxa) for treatment of refractory gout. Med Lett Drugs Ther. 2011; 53:9-10.

17. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 125293: Immunogenicity review(s) for pegloticase. From FDA website. Accessed 2011 Mar 22.

18. Zhang W, Doherty M, Bardin T et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006; 65:1312-24. [PubMed 16707532]

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