Pegloticase

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Krystexxa: 8 mg/mL (1 mL)

Pharmacology

Mechanism of Action

Pegloticase is a pegylated recombinant form of urate-oxidase enzyme, also known as uricase (an enzyme normally absent in humans and high primates), which converts uric acid to allantoin (an inactive and water soluble metabolite of uric acid); it does not inhibit the formation of uric acid.

Pharmacokinetics/Pharmacodynamics

Excretion

Urine (as allantoin)

Onset of Action

~24 hours following the first dose, serum uric acid concentrations decreased

Duration of Action

>300 hours (12.5 days)

Half-Life Elimination

Median: ~14 days

Use: Labeled Indications

Gout: Treatment of chronic gout in adults refractory to conventional therapy

Limitations of use: Not for the treatment of asymptomatic hyperuricemia

Contraindications

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Dosage and Administration

Dosing: Adult

Note: Discontinue use of oral antihyperuricemic agents prior to initiating pegloticase and do not initiate during the course of therapy. Premedicate with antihistamines and corticosteroids. Gout flare prophylaxis with either NSAIDs or colchicine is also recommended, beginning at least 1 week prior to initiation and continuing for at least 6 months.

Gout: IV: 8 mg every 2 weeks

Dosing: Geriatric

Refer to adult dosing.

Reconstitution

To prepare solution for administration, withdraw 1 mL (8 mg) and add to a 250 mL bag of NS or ¹/₂NS; invert bag several times to mix thoroughly (do not shake). Do not use vial if particulate matter is present or if solution is discolored (solution should be a clear and colorless). After withdrawal, discard any unused portion of the product remaining in the vial.

Administration

IV: Administer diluted solution by IV infusion over ≥120 minutes via gravity feed or an infusion pump or syringe-type pump. Do not administer by IV push or bolus. Administer in a healthcare setting by healthcare providers prepared to manage potential anaphylaxis. Monitor closely for infusion reactions during infusion and for an appropriate period of time after the infusion (anaphylaxis has been reported within 2 hours of the infusion). In the event of a less severe infusion reaction, infusion may be slowed, or stopped and restarted at a slower rate, based on the discretion of the physician.

Storage

Prior to use, vials must be stored in the carton to protect from light and kept under refrigeration between 2°C to 8°C (36°F to 46°F) at all times. Do not shake or freeze.

Diluted solution may be stored up to 4 hours at 2°C to 8°C (36°F to 46°F). Diluted solution is also stable for 4 hours at room temperature of 20°C to 25°C (68°F to 77°F); however, refrigeration is preferred. The diluted solution should be protected from light, not frozen, and used within 4 hours of dilution. Prior to administration, allow the diluted solution to reach room temperature; do not warm to room temperature using any form of artificial heating such as a microwave or warm water bath.

Drug Interactions

Allopurinol: May enhance the adverse/toxic effect of Pegloticase. Specifically, Allopurinol may blunt increases in serum urate that would signal an increased risk of anaphylaxis and infusion reactions. Avoid combination

Febuxostat: May enhance the adverse/toxic effect of Pegloticase. Specifically, Febuxostat may blunt increases in serum urate that would signal an elevated risk of anaphylaxis and infusion reactions. Avoid combination

Pegvaliase: PEGylated Drug Products may enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Monitor therapy

PEGylated Drug Products: Pegloticase may diminish the therapeutic effect of PEGylated Drug Products. Monitor therapy

Probenecid: May enhance the adverse/toxic effect of Pegloticase. Specifically, Probenecid may blunt increases in serum urate that would signal an elevated risk of anaphylaxis and infusion reactions. Avoid combination

Adverse Reactions

>10%:

Dermatologic: Urticaria (11%)

Endocrine & metabolic: Gout (flare: 74%; within the first 3 months)

Gastrointestinal: Nausea (12%)

Hematologic & oncologic: Bruise (11%)

Immunologic: Antibody development (antipegloticase antibodies: 92%; anti-PEG antibodies: 42%)

Miscellaneous: Infusion-related reaction (26%)

1% to 10%:

Cardiovascular: Chest discomfort (10%), chest pain (6% to 10%), exacerbation of congestive heart failure (2%)

Dermatologic: Erythema (10%), pruritus (10%)

Gastrointestinal: Constipation (6%), vomiting (5%)

Hypersensitivity: Anaphylaxis (5% to 7%)

Respiratory: Dyspnea (7%), nasopharyngitis (7%)

<1%, postmarketing, and/or case reports: Asthenia, malaise, peripheral edema, type IV hypersensitivity reaction

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity/anaphylactoid reactions: [US Boxed Warning]: Anaphylaxis and infusion reactions have been reported during and after administration; patients should be closely monitored during infusion and for an appropriate period of time after the infusion. Therapy should be administered in a health care facility by skilled medical personnel prepared for the immediate treatment of anaphylaxis. All patients should be premedicated with antihistamines and corticosteroids. Anaphylaxis may occur at any time during treatment (including the initial dose). Reactions generally occur within 2 hours of administration; however, delayed hypersensitivity reactions have also been reported. Infusion reactions are varied; symptoms range from chest pain, pruritus/urticaria, erythema, or dyspnea to a clinical presentation of anaphylaxis (eg, hemodynamic instability, perioral or lingual edema). If a less severe (nonanaphylactic) infusion reaction occurs, the infusion may be slowed, or stopped and restarted at a slower rate, at the physician’s discretion. Risk of an infusion reaction is increased in patients whose uric acid is >6 mg/dL; therefore, monitor serum uric acid concentrations prior to infusion and consider discontinuing treatment if concentrations exceed 6 mg/dL, particularly in the event of 2 consecutive concentrations >6 mg/dL. Since oral antihyperuricemic agents may blunt the rise of serum uric acid levels, discontinue use prior to and do not initiate during the course of pegloticase therapy.
• Gout flares: Therapy with antihyperuricemic agents commonly results in gout flare, particularly upon initiation due to rapid lowering of urate concentrations; gout flare-ups during treatment do not warrant discontinuation of therapy. Gout flare prophylaxis is recommended, using nonsteroidal anti-inflammatory agents (NSAID) or colchicine, unless contraindicated, beginning ≥1 week before initiation of pegloticase and continuing for at least 6 months.

Disease-related concerns:

• Heart failure: Exacerbation of heart failure has been observed in clinical trials; use caution in patients with preexisting heart failure.
• G6PD deficiency: [US Boxed Warning]: Life-threatening hemolytic reactions and methemoglobinemia have been reported with pegloticase in patients with G6PD deficiency. Due to the risk for hemolysis and methemoglobinemia, pegloticase is contraindicated in patients with G6PD deficiency. Patients at increased risk for G6PD deficiency (eg, African, Mediterranean [including Southern European and Middle Eastern], and Southern Asian ancestry) should be screened prior to initiation of therapy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Oral antihyperuricemic agents: Use with oral antihyperuricemic agents may delay interpretations of ineffective pegloticase treatment (ie, serum uric acid >6 mg/dL) and ultimately increase risk for anaphylactoid and/or infusion reactions. Discontinue use of oral antihyperuricemic agents prior to and do not initiate during the course of pegloticase therapy.

Other warnings/precautions:

• Immunogenicity: Potential for immunogenicity exists with the use of therapeutic proteins. Antipegloticase antibodies and antiPEG antibodies commonly occurred during clinical trials in pegloticase-treated patients. High antipegloticase antibody titers were associated with failure to maintain uric acid normalization and were also associated with a higher incidence of infusion reactions. Due to potential for immunogenicity, closely monitor patients who reinitiate therapy after discontinuing treatment for >4 weeks; patients may be at increased risk for anaphylaxis and infusion reactions.

Monitoring Parameters

Serum uric acid levels (prior to infusions; consider discontinuation if levels increase to >6 mg/dL, especially if two consecutive levels of >6 mg/dL are observed); infusion reactions and anaphylaxis (during infusion and post-infusion), G6PD deficiency screening (in patients at high risk for deficiency)

Pregnancy

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies.

Patient Education

What is this drug used for?

• It is used to treat gout.

Frequently reported side effects of this drug

• Bruising
• Constipation
• Nausea
• Vomiting
• Sore throat
• Stuffy nose

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infusion reaction
• Chest pain
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.