irc; years of age and older and 12% (10 of 85) were 75Â 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 individuals cannot be ruled out. No dose adjustment is needed for patients 65Â years of age and older.
8.6 Renal Impairment
No dose adjustment is required for patients with renal impairment. A total of 32% (27 of 85) of patients treated with KRYSTEXXA 8 mg every 2 weeks had a creatinine clearance of ≤62.5 mL/min. No overall differences in efficacy were observed.
10 OVERDOSAGE
No reports of overdosage with KRYSTEXXA have been reported. The maximum dose that has been administered as a single intravenous dose is 12Â mg as uricase protein.
Patients suspected of receiving an overdose should be monitored, and general supportive measures should be initiated as no specific antidote has been identified.
11 DESCRIPTION
KRYSTEXXA (pegloticase) is a uric acid specific enzyme which is a PEGylated product that consists of recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of Escherichia coli. Uricase is covalently conjugated to monomethoxypoly(ethylene glycol) [mPEG] (10Â kDa molecular weight). The cDNA coding for uricase is based on mammalian sequences. Each uricase subunit has a molecular weight of approximately 34Â kDa per subunit. The average molecular weight of pegloticase (tetrameric enzyme conjugated to mPEG) is approximately 540Â kDa.
KRYSTEXXA is intended for intravenous infusion.
KRYSTEXXA is a sterile, clear, colorless solution containing 8Â mg/mL pegloticase in phosphate-buffered saline.
KRYSTEXXA (pegloticase) concentrations are expressed as concentrations of uricase protein. Each mL of KRYSTEXXA contains 8 mg of uricase protein (conjugated to 24 mg of 10 kDa mPEG), 2.18 mg Disodium Hydrogen Phosphate Dihydrate (NaHPO•2HO), 8.77 mg Sodium Chloride (NaCl), 0.43 mg Sodium Dihydrogen Phosphate Dihydrate (NaHPO•2HO), and Water for Injection to deliver 8 mg of pegloticase (as uricase protein).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
KRYSTEXXA is a uric acid specific enzyme which is a recombinant uricase and achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Allantoin is an inert and water soluble purine metabolite. It is readily eliminated, primarily by renal excretion.
12.2 Pharmacodynamics
Approximately 24Â hours following the first dose of KRYSTEXXA, mean plasma uric acid levels for subjects in the KRYSTEXXA groups were 0.7Â mg/dL for the KRYSTEXXA 8Â mg every 2Â weeks group. In comparison, the mean plasma uric acid level for the placebo group was 8.2Â mg/dL.
In a single-dose, dose-ranging trial, following 1-hour intravenous infusions of 0.5, 1, 2, 4, 8 or 12Â mg of pegloticase in 24Â patients with symptomatic gout (n=4Â subjects/dose group), plasma uric acid decreased with increasing pegloticase dose or concentrations. The duration of suppression of plasma uric acid appeared to be positively associated with pegloticase dose. Sustained decrease in plasma uric acid below the solubility concentration of 6Â mg/dL for more than 3 |
