Pegloticase

Risk Summary

There are no adequate and well-controlled studies of pegloticase in pregnant women.

Based on animal reproduction studies, no structural abnormalities were observed when pegloticase was administered by subcutaneous injection to pregnant rats and rabbits during the period of organogenesis at doses up to 50 and 75 times, respectively, the maximum recommended human dose (MRHD). Decreases in mean fetal and pup body weights were observed at approximately 50 and 75 times the MRHD, respectively [see Data].

All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinical recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In 2 separate embryo-fetal developmental studies, pregnant rats and rabbits received pegloticase during the period of organogenesis at doses up to approximately 50 and 75 times the maximum recommended human dose (MRHD), respectively (on a mg/m² basis at maternal doses up to 40 and 30 mg/kg twice weekly, in rats and rabbits, respectively). No evidence of structural abnormalities was observed in rats or rabbits. However, decreases in mean fetal and pup body weights were observed at approximately 50 and 75 times the MRHD in rats and rabbits, respectively (on a mg/m² basis at maternal doses up to 40 and 30 mg/kg every other day, in rats and rabbits, respectively). No effects on mean fetal body weights were observed at approximately 10 and 25 times the MRHD in rats and rabbits, respectively (on a mg/m² basis at maternal doses up to 10 mg/kg twice weekly in both species).

Risk Summary

It is not known whether this drug is excreted in human milk. Therefore, pegloticase should not be used when breastfeeding unless the clear benefit to the mother can overcome the unknown risk to the newborn/infant.

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

The genotoxic potential of pegloticase has not been evaluated.

There was no evidence of impairment on fertility at pegloticase doses up to 40 mg/kg (approximately 50 times the MRHD on mg/m² basis) every other day in rats.

• Anaphylaxis
• Infusion Reactions
• G6PD Deficiency Associated Hemolysis and Methemoglobinemia
• Gout Flares
• Congestive Heart Failure

Clinical Trials Experience

The data described below reflect exposure to pegloticase in patients with chronic gout refractory to conventional therapy in two replicate randomized, placebo-controlled, double-blind 6-month clinical trials: 85 patients were treated with pegloticase 8 mg every 2 weeks; 84 patients were treated with pegloticase 8 mg every 4 weeks; and 43 patients were treated with placebo. These patients were between the ages of 23 and 89 years (average 55 years); 173 patients were male and 39 were female; and 143 patients were White/Caucasian, 27 were Black/African American, 24 were Hispanic/Latino and 18 were all other ethnicities. Common co-morbid conditions among the enrolled patients included hypertension (72%), dyslipidemia (49%), chronic kidney disease (28%), diabetes (24%), coronary artery disease (18%), arrhythmia (16%), and cardiac failure/left ventricular dysfunction (12%).

Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.

The most commonly reported adverse reactions that occurred in greater than or equal to 5% of patients treated with pegloticase 8 mg every 2 weeks are provided in the following table.

Adverse Reactions Occurring in 5% or More of Patients Treated with Pegloticase Compared to Placebo:

* If the same subject in a given group had more than one occurrence in the same preferred term event category, the subject was counted only once.
^† Most did not occur on the day of infusion and could be related to other factors (e.g., concomitant medications relevant to contusion or ecchymosis, insulin dependent diabetes mellitus).

Immunogenicity

Anti-pegloticase antibodies developed in 92% of patients treated with pegloticase every 2 weeks, and 28% for placebo. Anti-PEG antibodies were also detected in 42% of patients treated with pegloticase. High anti-pegloticase antibody titer was associated with a failure to maintain pegloticase-induced normalization of uric acid. The impact of anti-PEG antibodies on patients' responses to other PEG-containing therapeutics is unknown.

There was a higher incidence of infusion reactions in patients with high anti-pegloticase antibody titer: 53% (16 of 30) in the pegloticase every 2 weeks group compared to 6% in patients who had undetectable or low antibody titers.

As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity and assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the comparison of the incidence of antibodies to pegloticase with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of pegloticase. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship.

General disorders and administration site conditions: asthenia, malaise, peripheral swelling