Anaphylaxis and Infusion Reactions, G6PD Deficiency associated Hemolysis and Methemoglobinemia

Anaphylaxis

In a 52-week controlled trial, which evaluated pegloticase co-administered with methotrexate compared to pegloticase alone, patients were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with pegloticase if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of pegloticase therapy to reduce the risk of anaphylaxis. One patient randomized to the group treated with pegloticase co-administered with methotrexate (1%) experienced anaphylaxis during the first infusion and no patients experienced anaphylaxis in the group treated with pegloticase alone [see Adverse Reactions (6.1), Clinical Studies (14)].

During pre-marketing clinical trials with pegloticase alone, pegloticase 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 patients treated with pegloticase every 2 weeks and 4.8% (6/126) for the every 4-week dosing regimen. There were no cases of anaphylaxis in patients 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 pegloticase 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.

Pegloticase 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 pegloticase . 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 pegloticase may potentially blunt the rise of serum uric acid levels, it is recommended that before starting pegloticase patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking pegloticase.

Infusion Reactions

In a 52-week, controlled trial which evaluated pegloticase co-administered with methotrexate compared to pegloticase alone [see Adverse Reactions (6.1), Clinical Studies (14)], patients were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with pegloticase if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of pegloticase therapy to reduce the risk of infusion reactions. Infusion reactions were reported in 4% of patients in the pegloticase co-administered with methotrexate group compared to 31% of patients treated with pegloticase alone experienced infusion reactions [see Adverse Reactions (6.1), Clinical Studies (14). In both treatment groups, the majority of infusion reactions occurred at the first or second pegloticase infusion and during the time of infusion. Manifestations of these infusion reactions were similar to that observed in the pre-marketing trials.

During pre-marketing 24-week controlled clinical trials with pegloticase alone, pegloticase was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Infusion reactions were reported in 26% of patients treated with pegloticase 8 mg every 2 weeks, and 41% of patients treated with pegloticase 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.

Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion, and approximately 91% occurred during the time of infusion.

Pegloticase should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. pegloticase 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 discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and pegloticase may potentially blunt the rise of serum uric acid levels, it is recommended that before starting pegloticase patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking pegloticase.

G6PD Deficiency Associated Hemolysis and Methemoglobinemia

Life threatening hemolytic reactions and methemoglobinemia have been reported with pegloticase in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Because of the risk of hemolysis and methemoglobinemia, do not administer pegloticase to patients with G6PD deficiency [see Contraindications (4)]. Screen patients at risk for G6PD deficiency prior to starting pegloticase . For example, patients of African, Mediterranean (including Southern European and Middle Eastern), and Southern Asian ancestry are at increased risk for G6PD deficiency.