Pegloticase

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.

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.

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

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

5 WARNINGS AND PRECAUTIONS 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

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 )

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.