nal and urinary tract toxicities were observed at doses ≥2 mg/kg/day. The no-effect level was associated with plasma ezogabine exposures (AUC) less than those expected in human adults at the MRHD of 1,200 mg per day. In studies in which dosing began on postnatal day 28, acute central nervous system effects, but no apparent renal or urinary tract effects, were observed at doses of up to 30 mg/kg/day. These doses were associated with plasma ezogabine exposures less than those achieved clinically at the MRHD.
8.5 Geriatric Use
There were insufficient numbers of elderly patients enrolled in partial-onset seizure controlled trials (n = 8 patients on ezogabine) to determine the safety and efficacy of POTIGA in this population. Dosage adjustment is recommended in patients aged 65 years and older [see Dosage and Administration (2), Clinical Pharmacology (12.3)].
POTIGA may cause urinary retention. Elderly men with symptomatic BPH may be at increased risk for urinary retention.
8.6 Patients With Renal Impairment
Dosage adjustment is recommended for patients with creatinine clearance <50 mL/min or patients with end-stage renal disease (ESRD) receiving dialysis treatments [see Dosage and Administration (2), Clinical Pharmacology (12.3)].
8.7 Patients With Hepatic Impairment
No dosage adjustment is required for patients with mild hepatic impairment.
In patients with moderate or severe hepatic impairment, the initial and maintenance dosage of POTIGA should be reduced [see Dosage and Administration (2), Clinical Pharmacology (12.3)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
POTIGA is a Schedule V controlled substance.
9.2 Abuse
A human abuse potential study was conducted in recreational sedative-hypnotic abusers (n = 36) in which single oral doses of ezogabine (300 mg [n = 33], 600 mg [n = 34], 900 mg [n =6]), the sedative-hypnotic alprazolam (1.5 mg and 3.0 mg), and placebo were administered. Euphoria-type subjective responses to the 300-mg and 600-mg doses of ezogabine were statistically different from placebo but statistically indistinguishable from those produced by either dose of alprazolam. Adverse events reported following administration of single oral doses of 300 mg, 600 mg, and 900 mg ezogabine given without titration included euphoric mood (18%, 21%, and 33%, respectively; 8% from placebo), hallucination (0%, 0%, and 17%, respectively; 0% from placebo) and somnolence (18%, 15%, and 67%, respectively; 15% from placebo).
In Phase 1 clinical studies, healthy individuals who received oral ezogabine (200 mg to 1,650 mg) reported euphoria (8.5%), feeling drunk (5.5%), hallucination (5.1%), disorientation (1.7%), and feeling abnormal (1.5%).
In the 3 randomized, double-blind, placebo-controlled Phase 2 and 3 clinical studies, patients with partial seizures who received oral ezogabine (300 mg to 1,200 mg) reported euphoric mood (0.5%) and feeling drunk (0.9%), while those who received placebo did not report either adverse event (0%).
9.3 Dependence
There are no adequate data to assess the ability of ezogabine to induce symptoms of withdrawal indicative of physical dependence. However, the ability of ezogabine to produce psychological dependence is suggested by adverse event reports of euphoric mood (18% [6 of 33 subjects] to 33% [2 of 6 subjects]) in sedative-hypnotic abusers in the human abuse potential study and adverse event reports of euphoria (8.5%) in healthy individuals who participated in Phase 1 studies.
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