Krystexxa

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Anaphylaxis

During pre-marketing controlled clinical trials, anaphylaxis was reported with a frequency of 6.5% of patients treated with KRYSTEXXA (pegloticase injection) every 2 weeks, compared to none with placebo. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria. 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. [See ADVERSE REACTIONS]

KRYSTEXXA (pegloticase injection) 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 (pegloticase injection) . 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 consider discontinuing treatment if levels increase to above 6 mg/dL.

Infusion Reactions

During pre-marketing controlled clinical trials, infusion reactions were reported in 26% of patients treated with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks, and 41% of patients treated with KRYSTEXXA (pegloticase injection) 8 mg every 4 weeks, compared to 5% of patients treated with placebo. These infusion reactions occurred in patients being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate. [See ADVERSE REACTIONS]

KRYSTEXXA (pegloticase injection) should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA (pegloticase injection) should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

The risk of infusion reaction 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 consider discontinuing treatment if levels increase to above 6 mg/dL.

Gout Flares

Gout flares may occur after initiation of KRYSTEXXA. [see ADVERSE REACTIONS] An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA (pegloticase injection) therapy and lasting at least 6 months, unless medically contraindicated or not tolerated. KRYSTEXXA (pegloticase injection) does not need to be discontinued because of a gout flare. The gout flare should be managed concurrently as appropriate for the individual patient, [see DOSAGE AND ADMINISTRATION]

Congestive Heart Failure

KRYSTEXXA (pegloticase injection) has not been formally studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation, [see ADVERSE REACTIONS] Exercise caution when using KRYSTEXXA (pegloticase injection) in patients who have congestive heart failure and monitor patients closely following infusion.

Re-treatment with KRYSTEXXA (pegloticase injection)

No controlled trial data are available on the safety and efficacy of re-treatment with KRYSTEXXA (pegloticase injection) after stopping treatment for longer than 4 weeks. Due to the immunogenicity of KRYSTEXXA (pegloticase injection) , patients receiving re-treatment may be at increased risk of anaphylaxis and infusion reactions. Therefore, patients receiving re-treatment after a drug-free interval should be monitored carefully, [see ADVERSE REACTIONS]

Patient Counseling Information

See Medication Guide

General Information

Provide and instruct patients to read the accompanying Medication Guide before starting treatment and before each subsequent treatment.

Anaphylaxis and Infusion Reactions

  • Anaphylaxis and infusion reactions can occur at any infusion while on therapy. Counsel patients on the importance of adhering to any prescribed medications to help prevent or lessen the severity of these reactions.
  • Educate patients on the signs and symptoms of anaphylaxis, including wheezing, peri-oral or lingual edema, hemodynamic instability, and rash or urticaria.
  • Educate patients on the most common signs and symptoms of an infusion reaction, including urticaria (skin rash), erythema (redness of the skin), dyspnea (difficulty breathing), flushing, chest discomfort, chest pain, and rash.
  • Advise patients to seek medical care immediately if they experience any symptoms of an allergic reaction during or at any time after the infusion of KRYSTEXXA. [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency

Inform patients not to take KRYSTEXXA (pegloticase injection) if they have a condition known as G6PD deficiency. Explain to patients that G6PD deficiency is more frequently found in individuals of African or Mediterranean ancestry land that they may be tested to determine if they have G6PD deficiency, unless already known. [See CONTRAINDICATIONS]

Gout Flares

Explain to patients that gout flares may initially increase when starting treatment with KRYSTEXXA (pegloticase injection) , and that medications to help reduce flares may need to be taken regularly for the first few months after KRYSTEXXA (pegloticase injection) is started, [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS] Advise patients that they should not stop KRYSTEXXA (pegloticase injection) therapy if they have a flare.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of pegloticase.

The genotoxic potential of pegloticase has not been evaluated. Fertility studies in animals have not been performed.

Animal Toxicology and/or Pharmacology

In a 12-week intravenous repeat-dose study in dogs, there was a dose-dependent increase in vacuolated macrophages in the spleen. The presence of vacuolated macrophages likely reflects accumulated removal of injected pegloticase (foreign) material from the circulation. There was no evidence of degeneration, inflammation, or necrosis associated with the vacuoles findings, however there was evidence of decreased functional response to liposaccharides.

In a 39-week, repeat dose dog study, there was a dose dependent increase in vacuolated cells in several organs, including the spleen, adrenal gland , liver, heart, duodenum and jejunum. In the spleen, liver, duodenum and jejunum, these vacuoles were within macrophages and most likely represented phagocytic removal of pegloticase from the circulation. However, the vacuolated cells in the heart and adrenal gland did not stain as macrophages. In the aortic outflow tract of the heart, vacuoles were in the cytoplasm of endothelial cells in the intimal lining of the aorta. In the adrenal gland, vacuoles were located within cortical cells in the zona reticularis and zona fasciculata. The clinical significance of these findings and the functional consequences are unknown.

Use In Specific Populations

Pregnancy

Pregnancy Category C

A complete evaluation of the reproductive and developmental toxicity of pegloticase has not been completed. Adequate animal reproduction studies have not been conducted with KRYSTEXXA (pegloticase injection) . It is not known whether KRYSTEXXA (pegloticase injection) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled studies in pregnant women, KRYSTEXXA (pegloticase injection) should be used during pregnancy only if clearly needed.

Pegloticase was not teratogenic in rats administered 0, 5,10, or 40 mg/kg twice weekly by the intravenous route on gestation days 6 through 16 (the doses are approximately 6-fold to 50-fold higher than the maximum recommended human dose (MRHD) of 8 mg (0.133 mg/kg (based on a 60 kg person) every 2 weeks based on a mg/m2 comparison).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious, adverse reactions in nursing infants, it is not recommended to administer KRYSTEXXA (pegloticase injection) to a nursing mother.

Pediatric Use

The safety and effectiveness of KRYSTEXXA (pegloticase injection) in pediatric patients less than 18 years of age have not been established.

Geriatric Use

Of the total number of patients treated with KRYSTEXXA (pegloticase injection) 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 individual cannot be ruled out. No dose adjustment is needed for patients 65 years of age and older.

Renal Impairment

No dose adjustment is required for patients with renal impairment. A total of 32% (27 of 85) of patients treated with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks had a creatinine clearance of ≤ 62.5 mL/min. No overall differences in efficacy were observed.

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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