Krystexxa

Dosage and Administration ( 2.1 , 2.3 ) 8/2025

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION Recommended Dosage The recommended dosage is KRYSTEXXA 8 mg every two weeks given as an intravenous infusion, co-administered with weekly methotrexate 15 mg orally. KRYSTEXXA alone may be used in patients for whom methotrexate is contraindicated or not clinically appropriate. ( 2.2 ) Methotrexate with folic acid or folinic acid supplementation should be initiated at least 4 weeks prior to initiating, and throughout treatment with KRYSTEXXA. ( 2.2 ) Discontinue oral urate-lowering agents before starting KRYSTEXXA. ( 2.1 ) Monitor serum uric acid levels before each infusion. ( 2.1 ) Pre-medicate patients with antihistamines and corticosteroids. ( 2.1 , 5.1 , 5.2 ) Preparation and Administration Do not administer as an intravenous push or bolus. ( 2.1 ) KRYSTEXXA injection is supplied as a Ready-to-Use (with hanger label) single-dose vial or a To-be-Diluted single-dose vial. ( 2.3 ) See full prescribing information for information on preparation and administration for each vial presentation. ( 2.1 , 2.2 , 2.3 ) 2.1 Important Administration Instructions Precautions Prior to Treatment 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 infusion reactions, including anaphylaxis, is higher in patients who have lost therapeutic response. Monitor serum uric acid levels prior to each infusion and discontinue 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) ]. Infusion Reaction Precautions KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions, including anaphylaxis. Observe patients for an appropriate period of time after administration [see Warnings and Precautions (5.1 , 5.2) ]. Patients should receive pre-infusion medications (e.g., antihistamines, corticosteroids), to minimize the risk of infusion reactions, including anaphylaxis. 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) ]. Administration Precautions Do not administer KRYSTEXXA as an intravenous push or bolus. KRYSTEXXA should only be administered by intravenous infusion. An infusion pump may be used for the Ready-to-Use vial. Gravity feed, syringe-type pump, or infusion pump may be used for the To-Be-Diluted vial [see Dosage and Administration (2.3) ] . 2.2 Recommended Dosage and Administration The recommended dosage is KRYSTEXXA 8 mg given as an intravenous infusion every two weeks, co-administered with weekly oral methotrexate 15 mg and folic acid or folinic acid supplementation. KRYSTEXXA alone may be used in patients for whom methotrexate is contraindicated or not clinically appropriate. If co-administering with methotrexate, start weekly methotrexate and folic acid or folinic acid supplementation at least 4 weeks prior to initiating, and throughout treatment with KRYSTEXXA [see Clinical Studies (14) ] . Refer to the Full Prescribing Information for methotrexate. The optimal treatment duration with KRYSTEXXA has not been established. 2.3 Preparation and Administration Instructions KRYSTEXXA injection is supplied as either a Ready-to-Use single-dose vial (with hanger label) or a To-be-Diluted single-dose vial. Ready-to-Use KRYSTEXXA 8 mg/50 mL (0.16 mg/mL) single-dose vial (with hanger label) Step 1: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not …

3 DOSAGE FORMS AND STRENGTHS 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 )

4 CONTRAINDICATIONS 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 )

6 ADVERSE REACTIONS 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 eve …

7 DRUG INTERACTIONS 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 USE IN SPECIFIC POPULATIONS 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.

12.1 Mechanism of Action 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.

11 DESCRIPTION Pegloticase is a uric acid specific enzyme which is a PEGylated product that consists of recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of Escherichia coli. Uricase is covalently conjugated to monomethoxypoly (ethylene glycol) [mPEG] (10 kDa molecular weight). The cDNA coding for uricase is based on mammalian sequences. Each uricase subunit has a molecular weight of approximately 34 kDa per subunit. The average molecular weight of pegloticase (tetrameric enzyme conjugated to mPEG) is approximately 540 kDa. Ready-to-Use KRYSTEXXA (pegloticase) injection 8 mg/50 mL (0.16 mg/mL) single-dose vial is supplied as a sterile, preservative-free, clear and colorless solution intended for intravenous infusion and does not require further dilution. Each 8 mg/50 mL (0.16 mg/mL) single-dose vial contains 50 mL of deliverable volume including 8 mg of uricase protein (conjugated to 24 mg of 10 kDa mPEG), Disodium Hydrogen Phosphate (57.5 mg), Sodium Chloride (438.3 mg), Sodium Dihydrogen Phosphate (11.4mg), and Water for Injection to deliver 8 mg of pegloticase (as uricase protein). To-be-Diluted KRYSTEXXA (pegloticase) injection 8 mg/mL single-dose vial is supplied as a sterile, preservative-free, clear and colorless solution intended for intravenous infusion after dilution. KRYSTEXXA (pegloticase) concentrations are expressed as concentrations of uricase protein. Each 8 mg/mL single-dose vial contains 1 mL of deliverable volume including 8 mg of uricase protein (conjugated to 24 mg of 10 kDa mPEG), Disodium Hydrogen Phosphate Dihydrate (2.18 mg), Sodium Chloride (8.77 mg), Sodium Dihydrogen Phosphate Dihydrate (0.43 mg), and Water for Injection to deliver 8 mg of pegloticase (as uricase protein).

10 OVERDOSAGE No reports of overdosage with KRYSTEXXA have been reported. The maximum dose that has been administered as a single intravenous dose is 12 mg as uricase protein. Patients suspected of receiving an overdose should be monitored, and general supportive measures should be initiated as no specific antidote has been identified.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied KRYSTEXXA (pegloticase) injection is supplied as a sterile, clear and colorless solution containing 8 mg of pegloticase as follows for intravenous infusion: One Ready-to-Use 8 mg/50 mL (0.16 mg/mL) single-dose vial (NDC 75987-058-01) One To-be-Diluted 8 mg/mL single-dose vial (NDC 75987-080-10) Storage and Handling Before the preparation for use, KRYSTEXXA must be stored in the carton and maintained at all times under refrigeration between 2°C to 8°C (36°F to 46°F). Protect from light. Do not shake or freeze. Do not use beyond the expiration date stamped.