Pegloticase

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

KRYSTEXXA is a clear and colorless solution, containing 8 mg of pegloticase expressed as concentrations of uricase protein available as: Injection: Ready-to-Use 8 mg/50 mL (0.16 mg/mL) in a single-dose vial (with hanger label) [see Dosage and Administration (2.3) ] . Injection: To-be-Diluted 8 mg/mL in a single-dose vial [see Dosage and Administration (2.3) ] . Injection: Ready-to-Use 8 mg/50 mL (0.16 mg/mL) in a single-dose vial ( 3 ) Injection: To-be-Diluted 8 mg/mL in a single-dose vial ( 3 )

KRYSTEXXA is contraindicated in: Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency [see Warnings and Precautions (5.3) ]. Patients with history of serious hypersensitivity reactions, including anaphylaxis, to KRYSTEXXA or any of its components. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. ( 4 ) Patients with history of serious hypersensitivity reactions, including anaphylaxis, to KRYSTEXXA or any of its components. ( 4 )

Anaphylaxis : Anaphylaxis may occur with any KRYSTEXXA infusion. Pre-medicate and monitor patients. ( 5.1 ) Infusion Reactions : Infusion reactions occurred in patients treated with KRYSTEXXA. Pre-medicate and monitor patients. ( 5.2 ) G6PD Deficiency Associated Hemolysis and Methemoglobinemia : Screen patients at risk for G6PD deficiency. Do not administer KRYSTEXXA to patients with G6PD deficiency. ( 5.3 ) Gout Flares : Gout flare prophylaxis is recommended for at least the first 6 months of KRYSTEXXA therapy. ( 5.4 ) Congestive Heart Failure : Congestive heart failure exacerbation may occur. Monitor patients closely following infusion. ( 5.5 )

5.1 Anaphylaxis In a 52-week controlled trial, which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone, subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of anaphylaxis. One subject randomized to the group treated with KRYSTEXXA co-administered with methotrexate (1%) experienced anaphylaxis during the first infusion and no subjects experienced anaphylaxis in the group treated with KRYSTEXXA alone [see Adverse Reactions (6.1) , Clinical Studies (14) ] . During pre-marketing clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Anaphylaxis was reported with a frequency of 6.5% (8/123) of subjects treated with KRYSTEXXA every 2 weeks and 4.8% (6/126) for the every 4-week dosing regimen. There were no cases of anaphylaxis in subjects receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment. 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. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria, nausea or vomiting. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate. KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids. 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. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting. The risk of anaphylaxis 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 discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

5.2 Infusion Reactions In a 52-week, controlled trial which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone [see Adverse Reactions (6.1) , Clinical Studies (14) ] , subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of infusion reactions . Infusion reactions were reported in 4% of subjects in the KRYSTEXXA co-administered with methotrexate group compared to 31% of subjects treated with KRYSTEXXA alone experienced infusion reactions [see Adverse Reactions (6.1) , Clinical Studies (14) ] . In both treatment groups, the majority of infusion reactions occurred at the first or second KRYSTEXXA infusion and during the time of infusion. Manifestations of these infusion reactions were similar to that observed in the pre-marketing trials. During pre-marketing 24-week controlled clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Infusion reactions were reported in 26% of subjects treated with KRYSTEXXA 8 mg every 2 weeks, and 41% of subjects treated with KRYSTEXXA 8 mg every 4 weeks, compared to 5% of subjects treated with placebo. These infusion reactions occurred in subjects being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate. 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. KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate. 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 discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA. 5.3 G6PD Deficiency Associated Hemolysis and Methemoglobinemia Life threatening hemolytic reactions and methemoglobinemia have been reported with KRYSTEXXA in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Because of the risk of hemolysis and methemoglobinemia, do not administer KRYSTEXXA to patients with G6PD deficiency [see Contraindications (4) ] . Screen patients at risk for G6PD deficiency prior to starting KRYSTEXXA. For example, patients of African, Mediterranean (including Southern European and Middle Eastern), and Southern Asian ancestry are at increased risk for G6PD deficiency. […]

The following serious adverse reactions are discussed in greater detail in other sections of the label: Anaphylaxis [see Warnings and Precautions (5.1) ] Infusion Reactions [see Warnings and Precautions (5.2) ] G6PD Deficiency Associated Hemolysis and Methemoglobinemia [see Warnings and Precautions (5.3) ] Gout Flares [see Warnings and Precautions (5.4) ] Congestive Heart Failure [see Warnings and Precautions (5.5) ] Co-administration with methotrexate: The most common adverse reactions (≥ 5% of patients) are gout flares, arthralgia, COVID-19, nausea and fatigue. ( 6.1 ) KRYSTEXXA alone: The most common adverse reactions (≥ 5% of 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 Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience 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. Co-administration with Methotrexate A 52-week, randomized, double-blind trial was conducted in adult subjects with chronic gout refractory to conventional therapy to evaluate administration of KRYSTEXXA 8 mg every 2 weeks co-administered with weekly administration of oral methotrexate 15 mg, compared to KRYSTEXXA alone. In this trial, subjects who were able to tolerate two weeks on methotrexate 15 mg were then randomized to receive four additional weeks on either methotrexate 15 mg or matching placebo prior to initiating KRYSTEXXA therapy. A total of 152 subjects were randomized, and of these, 145 subjects completed the 4-week methotrexate run-in period and received KRYSTEXXA (96 subjects received KRYSTEXXA co-administered with methotrexate and 49 received KRYSTEXXA plus placebo) during the treatment period. All subjects received pre-treatment with an oral antihistamine, intravenous corticosteroid and acetaminophen. These subjects were between the ages of 24 and 83 years (average 55 years); 135 subjects were male and 17 and were female; 105 subjects were White/Caucasian, 22 were Black/African American, 14 were Asian, 5 were Native Hawaiian/Other Pacific Islander and 5 identified as Other; 28 were Hispanic or Latino. Common co-morbid conditions among the enrolled subjects included hypertension (63%), osteoarthritis (25%), hyperlipidemia (24%), gastroesophageal reflux disease (22%), obesity (20%), type 2 diabetes (18%) and depression (16%). Subjects with an eGFR < 40 mL/min/1.73 m 2 were excluded from this trial. The most commonly reported adverse reaction during the methotrexate pre-treatment periods was gout flare. The most commonly reported adverse reactions that occurred in ≥ 5% in either treatment group during the KRYSTEXXA co-administered with methotrexate or KRYSTEXXA alone period are provided in Table 1. Table 1. Adverse Reactions Occurring in 5% or More of Subjects in Either the KRYSTEXXA Co-administered with Methotrexate or KRYSTEXXA Alone Treatment Period Adverse Reaction KRYSTEXXA with Methotrexate (N = 96) n (%) KRYSTEXXA Alone (N = 49) n (%) Gout flare 64 (67%) 35 (71%) Arthralgia 13 (14%) 5 (10%) COVID-19 9 (9%) 3 (6%) Nausea 5 (5%) 6 (12%) Fatigue 5 (5%) 2 (4%) Infusion reaction 4 (4%) Included one case of anaphylaxis. 15 (31%) Pain in extremity 1 (1%) 3 (6%) Hypertension 1 (1%) 3 (6%) Vomiting 0 4 (8%) KRYSTEXXA ALONE The data described below reflect exposure to KRYSTEXXA in subjects with chronic gout refractory to conventional therapy in two replicate randomized, placebo-controlled, double-blind 24-week clinical trials: 85 subjects were treated with KRYSTEXXA 8 mg every 2 weeks; 84 subjects were treated with KRYSTEXXA 8 mg every 4 weeks; and 43 subjects were treated with placebo. These subjects were between the ages of 23 and 89 years (average 55 years); 173 subjects 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 subjects included hypertension (72%), dyslipidemia (49%), chronic kidney disease (28%), diabetes (24%), coronary artery disease (18%), arrhythmia (16%), and cardiac failure/left ventricular dysfunction (12%). During the pre-marketing placebo-controlled clinical trials, the most commonly reported adverse reactions that occurred in greater than or equal to 5% of subjects treated with KRYSTEXXA 8 mg every 2 weeks are provided in Table 2. Table 2. Adverse Reactions Occurring in 5% or More of Subjects Treated with KRYSTEXXA Compared to Placebo Adverse Reaction KRYSTEXXA 8 mg every 2 weeks (N = 85) n 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. (%) Placebo (N = 43) n (%) Gout flare 65 (77%) 35 (81%) Infusion reaction 22 (26%) 2 (5%) Nausea 10 (12%) 1 (2%) Contusion 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). or Ecchymosis 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%)

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of KRYSTEXXA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship. General disorders and administration site conditions : asthenia, malaise, peripheral swelling

7.1 Methotrexate KRYSTEXXA 8 mg every 2 weeks has been studied in patients with chronic gout refractory to conventional therapy taking concomitant oral methotrexate 15 mg weekly [see Clinical Studies (14) ] . Co-administration of methotrexate with KRYSTEXXA may increase pegloticase concentration compared to KRYSTEXXA alone [see Clinical Pharmacology (12.3) ] . 7.2 PEGylated products 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.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of KRYSTEXXA in pregnant women. Based on animal reproduction studies, no structural abnormalities were observed when pegloticase was administered by subcutaneous injection to pregnant rats and rabbits during the period of organogenesis at doses up to 50 and 75 times, respectively, the maximum recommended human dose (MRHD). Decreases in mean fetal and pup body weights were observed at approximately 50 and 75 times the MRHD, respectively [see Data ]. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinical recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In 2 separate embryo-fetal developmental studies, pregnant rats and rabbits received pegloticase during the period of organogenesis at doses up to approximately 50 and 75 times the MRHD, respectively (on a mg/m 2 basis at maternal doses up to 40 and 30 mg/kg twice weekly, in rats and rabbits, respectively). No evidence of structural abnormalities was observed in rats or rabbits. However, decreases in mean fetal and pup body weights were observed at approximately 50 and 75 times the MRHD in rats and rabbits, respectively (on a mg/m 2 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/m 2 basis at maternal doses up to 10 mg/kg twice weekly in both species).

8.2 Lactation Risk Summary 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. In a 52-week, randomized, double-blind trial which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone, 85% of patients had chronic kidney disease based on estimated glomerular filtration rate (eGFR) of ≥ 40 to < 90 mL/min/1.73m 2 at baseline. In the pre-marketing 24-week controlled clinical trials with KRYSTEXXA alone, a total of 32% (27 of 85) of subjects treated with KRYSTEXXA 8 mg every 2 weeks had a creatinine clearance of ≤ 62.5 mL/min. No overall differences in efficacy were observed.

KRYSTEXXA is a uric acid specific enzyme which is a recombinant uricase and achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Allantoin is an inert and water-soluble purine metabolite; it is readily eliminated, primarily by renal excretion.