Pegloticase is a parenteral, pegylated, recombinant mammalian urate oxidase enzyme. Although the enzyme is present in most mammals, it is not found naturally in humans. The novel mechanism of action of the drug lowers uric acid concentrations by converting uric acid into allantoin, which is a benign metabolite that is easily excreted in the urine. The commercial product is produced by a genetically modified strain of E. coli and then covalently conjugated to monomethoxypoly(ethylene glycol) [mPEG]. In the pre-marketing clinical study of treatment-failure gout, 87.5% of patients treated with pegloticase 8 mg IV infusion every 2 weeks maintained a plasma uric acid concentration of 6 mg/dL or less for the 14-week study duration. For chronic gout management, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) guidelines recommend ULT to achieve a target serum uric acid (sUA) level of less than 6 mg/dL to prevent the formation of crystals and to eliminate crystal deposition, thereby dissolving tophi. A lower target (less than 5 mg/dL) is recommended for patients with severe disease. Allopurinol is usually the first-line treatment agent due to effectiveness and cost considerations unless contraindications exist. Allopurinol and febuxostat appear relatively similar as monotherapy in lowering serum urate concentrations and reducing gout flares with long-term (more than 1 year) of use. Treatment guidelines recommend combination therapy with a uricosuric (e.g., lesinurad) plus a xanthine oxidase inhibitor (XOI) when treatment goals are not met with an XOI alone. The use of pegloticase is usually reserved for severe, refractory chronic gout. In patients with crystal-proven, severe debilitating chronic tophaceous gout and poor quality of life, in whom the serum urate target cannot be reached with any other available drug at the maximal dosage (including combinations), pegloticase is indicated. Once tophi disappear, then oral agents may again be considered. A boxed warning in the pegloticase label warns of the risk for infusion-related and hypersensitivity reactions. Patients must be premedicated with antihistamines and corticosteroids before each dose and monitored for an appropriate time (1 hour) after each infusion. The high cost of the drug relative to oral therapies, the need for intravenous parenteral administration and associated monitoring, and the incidence of anti-pegloticase antibody development (associated with therapy failure and increased hypersensitivity- and infusion-reactions) limit pegloticase use to refractory patients.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Administer via intravenous infusion over at least 120 minutes only; do NOT give by IV push or bolus.
-Administer in a healthcare setting by healthcare providers prepared to manage anaphylaxis and infusion reactions.
Preparation of the IV infusion:
-Use appropriate aseptic technique.
-Withdraw 1 mL (8 mg) of pegloticase from the vial and add it to 250 mL of 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection; do NOT mix or dilute with other solutions or drugs. Discard any remaining drug in the vial.
-Do NOT shake pegloticase solution, instead mix the solution by inverting the bag several times.
-Storage of diluted pegloticase: Store under refrigeration at 2 to 8 degrees C (36 to 46 degrees F) or room temperature at 20 to 25 degrees C (68 to 77 degrees F) for up to 4 hours; refrigeration is preferred. Protect from light. Do NOT freeze. It is recommended that the solution be used within 4 hours of dilution.
IV infusion Administration:
-If refrigerated, allow the solution to come to room temperature before administration; do not artificially warm via microwave or hot water bath.
-Before the infusion, monitor the patient's plasma uric acid concentration; a uric acid concentration of more than 6 mg/dL, particularly if this concentration is more than 6 mg/dL in two consecutive measurements, may indicate therapy failure. Such patients are at increased risk of anaphylaxis and infusion reactions.
-Premedicate all patients with antihistamines and corticosteroids, and at prescriber's discretion, acetaminophen, to minimize the risk of anaphylaxis and infusion reactions.
-Administer by intravenous infusion over no less than 120 minutes via gravity feed, syringe-type pump, or infusion pump.
-Monitor patients appropriately for anaphylactic and infusion reactions during- and for approximately 1 hour post-infusion. If a reaction occurs during infusion, the administration rate may be slowed, or treatment may be stopped and restarted at a slower rate at prescriber's discretion.
Despite pretreatment with oral antihistamines, corticosteroids, and acetaminophen, serious hypersensitivity reactions or anaphylaxis, and infusion-related reactions, including urticaria (10.6%), dyspnea (7.1%), chest discomfort (9.5%), erythema (9.5%), and pruritus (9.5%), were reported in 26% and 41% of patients receiving pegloticase 8 mg every 2 or 4 weeks, respectively, as compared to 5% of placebo-treated patients during placebo-controlled, randomized trials. Chest pain (unspecified) was reported in 9.5% of patients, with chest pain occurring in 6% of patients randomized to pegloticase 8 mg every 2 weeks. In a published, randomized, phase II clinical trial of pegloticase, 18 of 41 study patients experienced an adverse reaction that started within 1 day of dose administration; chest pain or tightness, difficulty breathing or dyspnea, and hypersensitivity reactions were reported infusion-day adverse events. Dyspnea occurred in 10% of patients. Overall, hypersensitivity reactions, including pruritus and rash (unspecified) were reported in 7% of patients, and were classified by investigators as possibly or probably related to pegloticase. Urticaria was observed, and erythema was also noted in 7% of patients. Slowing the infusion rate or stopping the infusion and restarting it at a slower rate reduced some of these infusion reactions. Anaphylaxis was reported in 6.5% of patients treated with pegloticase every 2 weeks and in 4.8% of those receiving the drug every 4 weeks vs. 0% of those receiving placebo. Investigators deemed a reaction as anaphylaxis if skin or mucosal tissue were effected, and, either airway compromise and/or reduced blood pressure (hypotension) with or without associated symptoms occurred with a temporal relationship to the infusion. Anaphylaxis generally occurred within 2 hours of treatment. The incidence of infusion-related and anaphylaxis reactions may have been underestimated due to premedication. Patients at the greatest risk of such reaction appear to be those with high titers of drug antibodies and those treated at a longer treatment interval of every 4 weeks. Pretreat all patients with antihistamines and corticosteroids. Monitor patients during and for an appropriate time after each infusion; further, advise patients of the symptoms of anaphylaxis and infusion-related reactions, and of the importance of seeking medical attention should such symptoms occur.
Similar to other agents used to treat hyperuricemia, gout flare is common is during the months after pegloticase initiation and is expected to decrease with increasing therapy duration; prophylactic therapy with an NSAID and/or colchicine starting 7 days prior to therapy initiation and lasting for at least 6 months, unless not tolerated or otherwise contraindicated, is recommended. Continue pegloticase therapy during gout flares. In pre-marketing clinical trials, study patients experienced an average of 10 episodes of gout flare in the 18 months prior to study enrollment. After trial initiation, and despite prophylaxis with an NSAID and/or colchicine, 77% of patients who received pegloticase 8 mg every 2 weeks experienced flares. In the first 3 months gout flare was reported by 74% of patients receiving pegloticase 8 mg every 2 weeks, 81% of patients receiving pegloticase 8 mg every 4 weeks, and 51% of those receiving placebo; whereas, in months 3 through 6 of study, gout flare was reported by 41% of those on pegloticase every 2 weeks, 57% on pegloticase every 4 weeks, and 67% on placebo. During a phase II randomized trial, 1 or more gout flares were reported in 88% of patients (n = 41). In most cases, gout flares were considered mild to moderate; however, 3 cases of gout-related serious adverse events, 2 of gout flare and 1 of infected tophus, were reported. The temporary increase in gout flare incidence may be the result of the mobilization of uric acid crystals from existing tophi.
Antibody formation to pegloticase occurred in 92% of patients administered pegloticase every 2 weeks and in 28% of those administered placebo; treatment failure and increased incidence of infusion-related reactions are associated with high anti-pegloticase antibody titers. In pre-marketing clinical trials, 53% of patients with high immunogenicity to pegloticase experienced an infusion reaction as compared to 6% of patients who had undetectable or low drug antibody titers. Antibody formation to the PEG-conjugated component was detected in 42% of patients; however, the clinical significance of this finding is unknown. During a phase II randomized trial, 31 patients (76%) had a least 1 positive serum sample of anti-pegloticase antibodies. Seroconversion was associated with a shortened half-life in patients given pegloticase 8 mg, perhaps as a result of increased clearance. In some patients, seroconversion was associated with a reduction in treatment response rate.
Although a drug-effect relationship has not been established, excerebration of congestive heart failure (CHF) has been reported at a higher incidence among patients receiving pegloticase as compared to study patients receiving placebo in pre-marketing clinical trials. CHF excerebrations were reported in 2 of 85 patients (2.4%) administered pegloticase 8 mg every 2 weeks in studies of 6 month duration and in 4 of an unstated number of patients administered the same dose in the open-label trial extension of 2 year duration.
In one pre-marketing trial of pegloticase (n = 85 vs. placebo n = 43), the following gastrointestinal adverse events were reported: nausea (12% pegloticase vs 2% placebo), vomiting (5% vs 2%), and constipation (6% vs 5%). Diarrhea was also reported by 7% of patients receiving pegloticase in one phase II randomized study. Nausea occurred in 10% of patients; nausea and vomiting occurred on the day of infusion. Hypoglycemia was a reported serious adverse event, however causal relationship was not determined.
In a published phase II clinical trial of pegloticase including 41 study patients, arthralgia was frequently reported (12%). Muscle spasms and back pain occurred in 10% and 7% of patients, respectively. Low back pain, muscle spasms, and other musculoskeletal pain including neck pain or stiffness occurred on the day of infusion. During the postmarketing use of pegloticase, asthenia and malaise have been reported.
Although a causal relationship has not been established, patients in phase II study reported contusion or ecchymosis, most not related to the IV infusion (11% pegloticase vs 5% placebo). In this same study, naso-pharyngitis was reported by 7% of patients who received pegloticase compared to 2% of those who received placebo. In addition, the following adverse events were reported in a non-placebo-controlled published phase II study in the treatment of gout: fever (10%), fatigue (7%), cellulitis, and upper respiratory infection (7%).
Adverse CNS effects reported during a phase II study that evaluated the efficacy and safety of pegloticase in lowering plasma urate concentrations included headache and dizziness. Headache was observed in 10% of patients, and dizziness occurred on the day of infusion. Lacunar infarct or stroke was observed in 1 patient; however, a causal relationship was not established.
During a phase II randomized trial, anemia occurred in 4 of 41 pegloticase recipients (10%). One case of anemia was classified as a serious adverse effect due to the need for blood transfusion. The patient continued to receive pegloticase throughout the study without further complications. Hemolytic anemia was not observed.
Nephrolithiasis was reported in 15% of pegloticase-treated patients during a randomized, phase II clinical trial. Reductions in urinary urate concentrations may produce some dissolution of renal stones allowing for movement. Renal colic and renal insufficiency have also been reported.
Life threatening hemolysis and methemoglobinemia have been reported with the use of pegloticase in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Screen patients at risk for G6PD deficiency (e.g., those of African, Mediterranean, and South Asian ancestry) prior to initiation of pegloticase therapy.
Peripheral edema has been reported with the postmarketing use of pegloticase.
Similar to other anti-gout therapies, gout flare was reported after pegloticase initiation, particularly in the first 3 months of therapy; study patients in pre-marketing clinical trials received gout flare prophylaxis of an NSAID and/or colchicine starting 7 days prior to therapy initiation and lasting for at least 6 months unless otherwise contraindicated or not tolerated. Pegloticase does not need to be discontinued during a gout flare.
Pegloticase use is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) or favism. Life threatening hemolysis reactions and methemoglobinemia have been reported with the use of pegloticase in patients with G6PD deficiency. G6PD screening is recommended for patients at higher risk of this condition, including those of African (e.g., some Black patients), Mediterranean (including Southern European and Middle Eastern), and certain Asian patients of South Asian ancestry.
As use of pegloticase is associated with serious hypersensitivity reactions or anaphylaxis and infusion-related reactions in a significant number of recipients, administration precautions are necessary. A boxed warning required within the labeling of this medication advises the following to minimize adverse sequela: (1) administration of this medication requires a specialized care setting and requires an experienced clinician who is prepared to manage anaphylaxis and infusion reactions; (2) monitoring of serum uric acid concentration is needed prior to each infusion with consideration given to discontinuing pegloticase treatment if this concentration increases to above 6 mg/dL (hyperuricemia), particularly if 2 consecutive levels more than 6 mg/dL occur as patients who have lost therapeutic response to pegloticase are at an increased risk of developing anaphylaxis or infusion reactions; (3) premedication of all patients with antihistamines and corticosteroids prior to administration; and (4) monitoring of patients closely during and for an appropriate time after medication infusion. 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 and patients should be advised to seek medical attention if symptoms of such arise. Infusion reactions also may occur at any time during the course of treatment, though the majority occur during the time of infusion. Patients with anti-pegloticase antibodies are at an increased risk of developing infusion reactions; 53% (16 of 30) of patients with anti-pegloticase antibody titers experienced an infusion reaction as compared to 6% of patients who had undetectable or low antibody titers. It is unknown if pegloticase-induced anti-PEG antibody development will affect patients' response to other pegylated products. Patients who discontinue and restart pegloticase therapy may also be at an increased risk of anaphylaxis or infusion reactions; additional caution is recommended in patients who have stopped therapy for 4 or more weeks. Oral urate-lowering therapy may blunt increases in serum uric acid levels. To ensure accurate uric acid concentration monitoring, it is recommended that patients discontinue oral urate-lowering medications prior to treatment and not institute therapy with oral urate-lowering medications while taking pegloticase.
Use pegloticase with caution in patients with pre-existing congestive heart failure (CHF) as exacerbations of such were reported among patients receiving pegloticase in clinical trials; a drug-effect relationship has not been established and formal clinical study has not been undertaken in CHF patients.
The safety and efficacy of pegloticase have not been established in neonates, infants, children, or adolescents.
No adequate studies have been conducted in pregnant women; use pegloticase during pregnancy only when clearly needed, considering the benefit to the mother and potential fetal risk. Data from animal reproductive studies indicate that no structural abnormalities were observed with pegloticase was administered to pregnant rats and rabbits during organogenesis at doses up to 50 and 75 times, respectively, the maximum recommended human dose (MRHD). However, decreases in mean fetal and pup body weights were observed at approximately 50 and 75 times the MRHD, respectively.
It is unknown if pegloticase is excreted in human milk. Pegloticase should not be used during breast-feeding unless the benefit to the mother is greater than the unknown risk to the breast-fed infant.
For the treatment of hyperuricemia due to chronic gout / gouty arthritis in patients refractory to conventional therapy (treatment-failure gout):
Adults: 8 mg IV infusion given over 2 hours and administered every 2 weeks; the optimal treatment duration has not been established. Premedicate with an antihistamine and corticosteroid, plus/minus acetaminophen, before each dose. During pivotal clinical trials, studied patients met the following conditions: (1) baseline serum uric acid (SUA) of at least 8 mg/dL; (2) symptomatic gout with at least 3 gout flares in the previous 18 months or at least 1 gout tophus or gouty arthritis; and (3) medical contraindication to allopurinol or medical history of failure to normalize uric acid (to less than 6 mg/dL) with at least 3 months of xanthine oxidase inhibitor (XOI) treatment at the maximum medically appropriate dose. Patients in trials received prophylaxis for gout flares with an NSAID and/or colchicine starting 1 week prior to initiating therapy unless not tolerated or otherwise contraindicated. LIMITS OF USE: Not for asymptomatic hyperuricemia.
Maximum Dosage Limits:
8 mg IV infusion every 2 weeks.
8 mg IV infusion every 2 weeks.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Allopurinol: (Major) Allopurinol may potentially blunt the rise of serum uric acid levels in patients taking pegloticase. Since patients who have lost therapeutic response to pegloticase are at higher risk of developing anaphylaxis and infusion reactions, oral urate-lowering therapy should be discontinued prior to pegloticase initiation and withheld during the course of treatment.
Colchicine; Probenecid: (Major) Oral urate-lowering medications, including allopurinol, febuxostat, probenecid, and sulfinpyrazone may potentially blunt the rise of serum uric acid levels in patients taking pegloticase. Since patients who have lost therapeutic response to pegloticase are at higher risk of developing anaphylaxis and infusion reactions, oral urate-lowering therapy should be discontinued prior to pegloticase initiation and withheld during the course of treatment.
Febuxostat: (Major) Oral urate-lowering medications, including allopurinol, febuxostat, probenecid, and sulfinpyrazone may potentially blunt the rise of serum uric acid levels in patients taking pegloticase. Since patients who have lost therapeutic response to pegloticase are at higher risk of developing anaphylaxis and infusion reactions, oral urate-lowering therapy should be discontinued prior to pegloticase initiation and withheld during the course of treatment.
Lesinurad; Allopurinol: (Major) Allopurinol may potentially blunt the rise of serum uric acid levels in patients taking pegloticase. Since patients who have lost therapeutic response to pegloticase are at higher risk of developing anaphylaxis and infusion reactions, oral urate-lowering therapy should be discontinued prior to pegloticase initiation and withheld during the course of treatment.
Probenecid: (Major) Oral urate-lowering medications, including allopurinol, febuxostat, probenecid, and sulfinpyrazone may potentially blunt the rise of serum uric acid levels in patients taking pegloticase. Since patients who have lost therapeutic response to pegloticase are at higher risk of developing anaphylaxis and infusion reactions, oral urate-lowering therapy should be discontinued prior to pegloticase initiation and withheld during the course of treatment.
Sulfinpyrazone: (Major) Oral urate-lowering medications, including allopurinol, febuxostat, probenecid, and sulfinpyrazone may potentially blunt the rise of serum uric acid levels in patients taking pegloticase. Since patients who have lost therapeutic response to pegloticase are at higher risk of developing anaphylaxis and infusion reactions, oral urate-lowering therapy should be discontinued prior to pegloticase initiation and withheld during the course of treatment.
Pegloticase is a pegylated recombinant form of a mammalian enzyme known as uricase or urate oxidase; it lowers plasma uric acid concentrations by catalyzing the conversion of uric acid to allantoin. Allantoin is an inert, water-soluble purine metabolite that is readily excreted, primarily by the kidneys. Although most mammals naturally posses uricase, the enzyme is not present in humans and some other higher primates. The inert polymer monomethoxypoly(ethylene glycol) [m-PEG] is covalently conjugated to the uricase enzyme in an attempt to prolong the half-life of the enzyme and reduce the significant immunogenicity associated with other uricase preparations. However, immunogenicity in the form of infusion-related and hypersensitivity reactions is a risk of pegloticase use.
Plasma uric acid concentrations more than 6 to 7 mg/dL lead to the formulation of monosodium urate crystals, which in turn are deposited in joints and tissues. Traditionally, gout therapies have included xanthine oxidase inhibitors (e.g., allopurinol, febuxostat), medications that block the formation of uric acid from its precursor xanthine, and uricosuric agents (e.g., probenecid) that promote the renal excretion of uric acid. By enzymatic conversion of uric acid to allantoin, the use of pegloticase significantly reduces serum uric acid concentrations. In addition to halting further urate deposition and gout progression, such significantly lower uric acid concentrations may allow urate crystals mobilization from tophi and joint stores. Reductions in tophi size have been reported in clinical trials of pegloticase ranging in duration from 12 weeks to 6 months.
Pegloticase is administered by intravenous infusion. The pharmacokinetics of pegloticase seem to best fit a one-compartment model with linear elimination. Based on the results of pharmacokinetic analyses, it appears that the drug remains primarily in the intravascular space after administration , with a mean central volume of distribution of 0.0449 L/kg (range, 0.0278-0.0639 L/kg).The mean elimination half-life of pegloticase in serum was reported to be 12.5 +/- 0.9 days in a single-dose study (n = 24) and approximately 2 weeks (range, 7 to 44 days) in a 12-week study of repeated doses every 2 or 4 weeks (n = 40).
Though not directly proportional, the minimum measured plasma uric acid concentration is inversely related to the dose of pegloticase given within the range of 0.5 mg and 12 mg. Further, one pharmacokinetic trial showed that the AUC of plasma uric acid through Day 21 post-infusion is inversely proportional to the dose of pegloticase administered within the range of 0.5 mg and 8 mg; however, doses of 10 mg and 12 mg resulted in higher serum uric acid AUC as compared to a dose of 8 mg. The pharmacokinetic and pharmacodynamic analysis in a phase II trial (n = 40) demonstrated that most patients experienced a maximal drop in serum uric acid concentration of approximately 83% in response to pegloticase; the dosing regimens studied were 4 mg IV every 2 weeks, 8 mg IV every 2 weeks, 8 mg IV every 4 weeks, and 12 mg IV every 4 weeks.
In a pharmacokinetic study of patients with symptomatic gout, pegloticase serum levels were determined based on uricase enzyme activity. Prior to pegloticase administration, the plasma uricase activity was zero. This activity rose sharply during IV administration and increased with increasing doses of pegloticase within a dosing range of 0.5 mg to 12 mg. After a pegloticase infusion, the onset of action was rapid with mean serum uric acid concentrations falling below 2 mg/dl within 24 hours, and mean nadir uric acid concentrations achieved within 24 to 72 hours.
Although pegloticase is recommended for intravenous administration only, administration via the subcutaneous route has also been studied. Subcutaneous administration of pegloticase (PEG-uricase) to symptomatic gout patients with hyperuricemia in a phase I trial (n = 13) resulted in the following pharmacokinetic measures: maximum uricase activity increased with increasing doses of 4 mg, 8 mg, 12 mg, and 24 mg; a mean time to maximum uricase activity of 7 days (range, 2 to 10 days); and a mean time to plasma uric acid concentration nadir of 7 days. PEG-specific IgG antibodies to pegloticase were detected via ELISA testing in 5 of the 13 study patients at approximately 7 days after administration. The development of antibodies resulted in a faster elimination of pegloticase and a more rapid return of increased plasma uric acid concentrations compared to patients without antibodies. In patients with antibodies, the plasma activity of uricase was not detectable after Day 10 post-administration; however, those without antibodies had a pegloticase elimination half-life ranging from 10.5 to 19.9 days. Further, plasma uric acid concentrations rebounded to 7 mg/dl by Day 14 post-administration and to pretreatment levels by Day 21 in the antibody-positive study patients, while uric acid concentrations remained below 6 mg/dl for the 21-day monitoring period in those who did not develop antibodies. Subcutaneous use of pegloticase is not recommended.
The pharmacokinetics of pegloticase have not been formally studied in patients with hepatic impairment.
The pharmacokinetics of pegloticase have not been formally studied in patients with renal impairment; however, in phase III clinical trials, patients with chronic kidney disease compromised 28% (24 of 85) of the study population, and 32% (27 of 85) had a creatinine clearance <= 62.5 ml/min. There was no noted difference in efficacy based on renal function.
The pharmacokinetics of pegloticase have not been studied in children and adolescents.
According to the manufacturer, the population pharmacokinetic analysis showed that age of adult study patients did not influence the pharmacokinetics of pegloticase.
According to the manufacturer, population pharmacokinetic analysis showed that gender did not influence the pharmacokinetics of pegloticase.
According to the manufacturer, population pharmacokinetic analysis showed that weight did not influence the pharmacokinetics of pegloticase; however, body surface area did affect drug clearance and volume of distribution. Obese patients were included in pre-marketing trials; the mean body mass index (BMI) of phase III study patients was 33 kg/m2. There are no dose adjustments suggested based on patient weight.