Data from FDA - Curated by EPG Health - Last updated 04 April 2017

Indication(s)

1 INDICATIONS AND USAGE KRYSTEXXA® (pegloticase) is a PEGylated uric acid specific enzyme indicated for the treatment of chronic gout in adult patients refractory to 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. Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia. KRYSTEXXA® (pegloticase) is a PEGylated uric acid specific enzyme indicated for the treatment of chronic gout in adult patients refractory to conventional therapy. (1) Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Glucose-6-phosphate dehydrogenase ( G6PD ) deficiency [See Warnings and Precautions ( 5.3 )] Glucose-6-phosphate dehydrogenase ( G6PD ) Deficiency (4)
Adverse reactions
6 ADVERSE REACTIONS The most commonly reported serious adverse reactions from pre-marketing controlled clinical trials were anaphylaxis, which occurred at a frequency of 6.5% in patients treated with KRYSTEXXA 8 mg every 2 weeks, compared to none with placebo; infusion reactions, which occurred at a frequency of 26% in patients treated with KRYSTEXXA 8 mg every 2 weeks, compared to 5% treated with placebo; and gout flares, which were more common during the first 3 months of treatment with KRYSTEXXA compared with placebo. All patients in pre-marketing controlled clinical trials were pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen to prevent anaphylaxis and infusion reaction. Patients also received non-steroidal anti-inflammatory drugs or colchicine, or both, for at least 7 days as gout flare prophylaxis before beginning KRYSTEXXA treatment. [see Boxed Warning , Warnings and Precautions (5.1, 5.2, 5.4)] The most common adverse reactions (occurring in at least 5% of KRYSTEXXA-treated patients) are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Horizon Pharma Rheumatology LLC at 1-866-479-6742 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The data described below reflect exposure to KRYSTEXXA in patients with chronic gout refractory to conventional therapy in two replicate randomized, placebo-controlled, double-blind 6-month clinical trials: 85 patients were treated with KRYSTEXXA 8 mg every 2 weeks; 84 patients were treated with KRYSTEXXA 8 mg every 4 weeks; and 43 patients were treated with placebo. These patients were between the ages of 23 and 89 years (average 55 years); 173 patients were male and 39 were female; and 143 patients were White/Caucasian, 27 were Black/African American, 24 were Hispanic/Latino and 18 were all other ethnicities. Common co-morbid conditions among the enrolled patients included hypertension (72%), dyslipidemia (49%), chronic kidney disease (28%), diabetes (24%), coronary artery disease (18%), arrhythmia (16%), and cardiac failure/left ventricular dysfunction (12%). Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice. Anaphylaxis: Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA or placebo injection with no other identifiable cause. Using these clinical criteria, anaphylaxis was identified in 14 (5.1%) of 273 total patients studied in the clinical program of IV KRYSTEXXA. The frequency was 6.5% for the every 2-week dosing regimen (8 of 123 patients), and 4.8% for the 4-week dosing frequency (6 of 126) of KRYSTEXXA. There were no cases of anaphylaxis in patients receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment. This occurred with patients being pre-treated with an oral antihistamine, intravenous corticosteroid, and acetaminophen. [see Boxed Warning , Warnings and Precautions (5.1, 5.2)] Infusion Reactions: Infusion reactions occurred in 26% of patients in the 2 week dosing regimen group and 41% of patients in the 4 week dosing regimen group, compared to 5% of placebo-treated patients. Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion, and approximately 91% occurred during the time of infusion. Some infusion reaction manifestations were reduced with slowing the rate of infusion, or stopping the infusion and restarting the infusion at a slower rate. These infusion reactions occurred with all patients being pre-treated with an oral antihistamine, intravenous corticosteroid and acetaminophen. [see Boxed Warning , Warnings and Precautions (5.1, 5.2)] Gout Flares: Gout flares were common in the study patients before randomization to treatment, with patients experiencing an average of 10 flares in the preceding 18 months prior to study entry. During the controlled treatment period with KRYSTEXXA or placebo, the frequencies of gout flares were high in all treatment groups, but more so with KRYSTEXXA treatment during the first 3 months of treatment, which seemed to decrease in the subsequent 3 months of treatment. The percentages of patients with any flare for the first 3 months were 74%, 81%, and 51%, for KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. The percentages of patients with any flare for the subsequent 3 months were 41%, 57%, and 67%, for KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. Patients received gout flare prophylaxis with colchicine and/or nonsteroidal anti-inflammatory drugs (NSAIDs) starting at least one week before receiving KRYSTEXXA. [see Warnings and Precautions (5.4)] Congestive Heart Failure: Two cases of congestive heart failure exacerbation occurred during the trials in patients receiving treatment with KRYSTEXXA 8 mg every 2 weeks. No cases were reported in placebo-treated patients. Four subjects had exacerbations of pre-existing congestive heart failure while receiving KRYSTEXXA 8 mg every 2 weeks during the open-label extension study. [see Warnings and Precautions (5.5)]. Other Adverse Reactions : The most commonly reported adverse reactions that occurred in greater than or equal to 5% of patients treated with KRYSTEXXA 8mg every 2 weeks are provided in Table 1. Table 1. Adverse Reactions Occurring in 5% or More of Patients Treated with KRYSTEXXA Compared to Placebo Adverse Reaction (Preferred Term) KRYSTEXXA 8 mg e very 2 weeks (N=85) N a (%) Placebo (N=43) N (%) Gout flare 65 (77%) 35 (81%) Infusion reaction 22 (26%) 2 (5%) Nausea 10 (12%) 1 (2%) Contusionb or Ecchymosisb 9 (11%) 2 (5%) Nasopharyngitis 6 (7%) 1 (2%) Constipation 5 (6%) 2 (5%) Chest Pain 5 (6%) 1 (2%) Anaphylaxis 4 (5%) 0 (0%) Vomiting 4 (5%) 1 (2%) a If the same subject in a given group had more than one occurrence in the same preferred term event category, the subject was counted only once. b Most did not occur on the day of infusion and could be related to other factors (e.g. concomitant medications relevant to contusion or ecchymosis, insulin dependent diabetes mellitus). 6.2 Immunogenicity Anti-pegloticase antibodies developed in 92% of patients treated with KRYSTEXXA every 2 weeks, and 28% for placebo. Anti-PEG antibodies were also detected in 42% of patients treated with KRYSTEXXA. High anti-pegloticase antibody titer was associated with a failure to maintain pegloticase-induced normalization of uric acid. The impact of anti-PEG antibodies on patients’ responses to other PEG-containing therapeutics is unknown. There was a higher incidence of infusion reactions in patients with high anti-pegloticase antibody titer: 53% (16 of 30) in the KRYSTEXXA every 2 weeks group compared to 6% in patients who had undetectable or low antibody titers. As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity and assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the comparison of the incidence of antibodies to pegloticase with the incidence of antibodies to other products may be misleading.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION For adult patients 8 mg given as an intravenous infusion every two weeks. (2.1) Do not administer as an intravenous push or bolus. (2.3) Discontinue oral urate-lowering agents before starting KRYSTEXXA (2.3) Monitor serum uric acid levels before each infusion. (2.3) Patients should be pre-medicated with antihistamines and corticosteroids. (2.3, 5.1, 5.2) The KRYSTEXXA admixture should only be administered by intravenous infusion over no less than 120 minutes via gravity feed, syringe-type pump, or infusion pump. (2.3) 2.1 Dosage The recommended dose and regimen of KRYSTEXXA for adult patients is 8 mg (uricase protein) given as an intravenous infusion every two weeks. The optimal treatment duration with KRYSTEXXA has not been established. 2. 2 Preparation Visually inspect KRYSTEXXA for particulate matter and discoloration before administration, whenever solution and container permit. Do not use vials if either is present. [see Dosage Forms and Strengths (3)] Use appropriate aseptic technique. Withdraw 1 mL of KRYSTEXXA from the vial into a sterile syringe. Discard any unused portion of product remaining in the 2 mL vial. Inject into a single 250 mL bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP for intravenous infusion. Do not mix or dilute with other drugs. Invert the infusion bag containing the dilute KRYSTEXXA solution a number of times to ensure thorough mixing. Do not shake. KRYSTEXXA diluted in infusion bags is stable for 4 hours at 2º to 8ºC (36º to 46ºF) and at room temperature (20º to 25ºC, 68º to 77ºF). However it is recommended that diluted solutions be stored under refrigeration, not frozen, protected from light, and used within 4 hours of dilution. [see How Supplied/Storage and Handling (16)] Before administration, allow the diluted solution of KRYSTEXXA to reach room temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid should never be subjected to artificial heating (e.g., hot water, microwave). 2. 3 Administration D o not administer as an intravenous push or bolus. It is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while patients are on KRYSTEXXA therapy. Monitoring Therapy: The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response. 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. [see Warnings and Precautions (5.1, 5.2)] The KRYSTEXXA 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 receive pre-infusion medications (e.g. antihistamines, corticosteroids), to minimize the risk of anaphylaxis and infusion reactions. Administer KRYSTEXXA in a healthcare setting and by healthcare providers prepared to manage anaphylaxis and infusion reactions, and observe patients for an appropriate period of time after administration. [see Warnings and Precautions (5.1, 5.2)] If an infusion reaction occurs during the administration of KRYSTEXXA, the infusion may be slowed, or stopped and restarted at a slower rate, at the discretion of the physician. Since infusion reactions can occur after completion of infusion, observation of patients for approximately an hour post-infusion should be considered. [see Warnings and Precautions (5.2), Adverse Reactions (6.1)]
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of KRYSTEXXA in pregnant women. KRYSTEXXA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pegloticase was not teratogenic in rats and rabbits at approximately 50 and 75 times the maximum recommended human dose (MRHD), respectively (on a mg/m2 basis at maternal doses up to 40 and 30 mg/kg twice weekly, in rats and rabbits, respectively). Statistically significant decreases in mean fetal and pup body weights were observed at approximately 50 and 75 times the MRHD respectively (on a mg/m2 basis at maternal doses up to 40 and 30 mg/kg every other day, in rats and rabbits, respectively). No effects on mean fetal body weights were observed at approximately 10 and 25 times the MRHD in rats and rabbits, respectively (on a mg/m2 basis at maternal doses up to 10 mg/kg twice weekly in both species). 8. 3 Nursing Mothers It is not known whether this drug is excreted in human milk. Therefore KRYSTEXXA should not be used when breastfeeding unless the clear benefit to the mother can overcome the unknown risk to the newborn/infant. 8. 4 Pediatric Use The safety and effectiveness of KRYSTEXXA in pediatric patients less than 18 years of age have not been established. 8. 5 Geriatric Use Of the total number of patients treated with KRYSTEXXA 8 mg every 2 weeks in the controlled studies, 34% (29 of 85) were 65 years of age and older and 12% (10 of 85) were 75 years of age and older. 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. 8. 6 Renal Impairment No dose adjustment is required for patients with renal impairment. A total of 32% (27 of 85) of patients treated with KRYSTEXXA 8 mg every 2 weeks had a creatinine clearance of ≤62.5 mL/min. No overall differences in efficacy were observed.
Pregnancy and lactation
8. 3 Nursing Mothers It is not known whether this drug is excreted in human milk. Therefore KRYSTEXXA should not be used when breastfeeding unless the clear benefit to the mother can overcome the unknown risk to the newborn/infant.

Interactions

7 DRUG INTERACTIONS No studies of interactions of KRYSTEXXA with other drugs have been conducted. Because anti-pegloticase antibodies appear to bind to the PEG portion of the drug, there may be potential for binding with other PEGylated products. The impact of anti-PEG antibodies on patients’ responses to other PEG-containing therapeutics is unknown.

More information

Category Value
Authorisation number BLA125293
Agency product number R581OT55EA
Orphan designation No
Product NDC 75987-080
Date Last Revised 30-09-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 1011653
Marketing authorisation holder Horizon Pharma Inc.
Warnings WARNING: ANAPHYLAXIS AND INFUSION REACTIONS ; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA Anaphylaxis and infusion reactions ha ve been reported to occur during and afte r administration of KRYSTEXXA. [see Warnings and Precautions ( 5.1 , 5.2 )] Anaphylaxis may occur with any infusion, including a first infusion, and generally manifest s within 2 hours of the infusion. However, delayed-type hypersensitivity reac tions 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 antihistamine s and corticosteroid s . Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Monitor serum uric acid level s prior to infusions and consider discontinuing treatment if level s increase to above 6 mg/dL, particularly when 2 consecutive level s above 6 mg/dL are observed. Screen patients at risk 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 patients with G6PD deficiency ( 4 , 5.3 ) WARNING: ANAPHYLAXIS A ND INFUSION REACTIONS ; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA See full prescribing information for complete boxed warning. Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA ( 5.1 , 5.2 ). Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reac tions 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. Screen patients at risk 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 patients with G6PD deficiency ( 4 , 5.3 ).