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    Uricosuric Recombinant Enzyme

    BOXED WARNING

    Hyperuricemia, infusion-related reactions, requires a specialized care setting, requires an experienced clinician, serious hypersensitivity reactions or anaphylaxis

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant urate oxidase enzyme; pegylated product; converts uric acid to allantoin, a benign metabolite
    Used in chronic gout refractory to conventional oral therapy; given as IV infusion only; high cost
    Boxed warning for risk of infusion-related and hypersensitivity reactions; premedicate patients with antihistamines and corticosteroids and monitor for 1 hour after each dose

    COMMON BRAND NAMES

    Krystexxa

    HOW SUPPLIED

    Krystexxa Intravenous Inj Sol: 1mL, 8mg

    DOSAGE & INDICATIONS

    For the treatment of hyperuricemia due to chronic gout / gouty arthritis in patients refractory to conventional therapy (treatment-failure gout).
    Intravenous dosage
    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

    Adults

    8 mg IV infusion every 2 weeks.

    Geriatric

    8 mg IV infusion every 2 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    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.

    Intravenous Administration

    Preparation of the IV infusion:[41753]
    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:[41753]
    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.

    STORAGE

    Krystexxa:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Store in original carton in refrigerator (35 to 46 degrees F) until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Asian patients, Black patients, G6PD deficiency, hemolysis, methemoglobinemia

    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.

    Hyperuricemia, infusion-related reactions, requires a specialized care setting, requires an experienced clinician, serious hypersensitivity reactions or anaphylaxis

    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.

    Heart failure

    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.

    Children, infants, neonates

    The safety and efficacy of pegloticase have not been established in neonates, infants, children, or adolescents.

    Pregnancy

    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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    serious hypersensitivity reactions or anaphylaxis / Rapid / 4.8-6.5
    heart failure / Delayed / 2.4-2.4
    stroke / Early / Incidence not known
    methemoglobinemia / Early / Incidence not known

    Moderate

    antibody formation / Delayed / 76.0-92.0
    gout / Delayed / 77.0-88.0
    infusion-related reactions / Rapid / 26.0-26.0
    nephrolithiasis / Delayed / 15.0-15.0
    dyspnea / Early / 7.1-10.0
    anemia / Delayed / 10.0-10.0
    erythema / Early / 7.0-9.5
    chest pain (unspecified) / Early / 9.5-9.5
    constipation / Delayed / 6.0-6.0
    hypotension / Rapid / Incidence not known
    hypoglycemia / Early / Incidence not known
    hemolysis / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    nausea / Early / 10.0-12.0
    arthralgia / Delayed / 12.0-12.0
    ecchymosis / Delayed / 11.0-11.0
    urticaria / Rapid / 10.6-10.6
    fever / Early / 10.0-10.0
    headache / Early / 10.0-10.0
    pruritus / Rapid / 7.0-9.5
    rash / Early / 7.0-7.0
    back pain / Delayed / 7.0-7.0
    infection / Delayed / 7.0-7.0
    fatigue / Early / 7.0-7.0
    pharyngitis / Delayed / 7.0-7.0
    vomiting / Early / 5.0-5.0
    diarrhea / Early / 7.0
    asthenia / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    malaise / Early / Incidence not known
    dizziness / Early / Incidence not known

    DRUG INTERACTIONS

    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.[41753] Although most mammals naturally posses uricase, the enzyme is not present in humans and some other higher primates.[41818] 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.[41818] However, immunogenicity in the form of infusion-related and hypersensitivity reactions is a risk of pegloticase use.[41753]
     
    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.[41753] [41871] [41923]

    PHARMACOKINETICS

    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.

    Intravenous Route

    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.

    Subcutaneous Route

    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.