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2011年6月13日，美国FDA批准依佐加滨（ezogabine）片剂用于成人部分性癫痫发作的辅助治疗，该药是第一个治疗癫痫的神经元钾通道开放剂。
50 mg, purple, round, film-coated tablets debossed with “RTG 50” on one side. 200 mg, yellow, oblong, film-coated tablets debossed with “RTG-200” on one side. 300 mg, green, oblong, film-coated tablets debossed with “RTG-300” on one side. 400 mg, purple, oblong, film-coated tablets debossed with “RTG-400” on one side. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Retinal Abnormalities and Potential Vision Loss POTIGA can cause abnormalities of the retina. The abnormalities seen in patients treated with POTIGA have funduscopic features similar to those seen in retinal pigment dystrophies that are known to result in damage to photoreceptors and vision loss. The retinal abnormalities observed with POTIGA have been reported in patients who were originally enrolled in clinical trials with POTIGA and who have generally taken the drug for a long period of time in 2 ongoing extension trials. Approximately one third of the patients who had eye examinations performed after approximately 4 years of treatment were found to have retinal pigmentary abnormalities. However, an earlier onset cannot be ruled out, and it is possible that retinal abnormalities were present earlier in the course of exposure to POTIGA. POTIGA causes skin, scleral, nail, and mucous membrane discoloration and it is not clear whether this discoloration is related to retinal abnormalities [see Warnings and Precautions (5.3)]. Approximately 15% of patients with retinal pigmentary abnormalities had no such discoloration. Funduscopic abnormalities have most commonly been described as perivascular pigmentation (bone spicule pattern) in the retinal periphery and/or as areas of focal retinal pigment epithelium clumping. Although some of the patients with retinal abnormalities have been found to have abnormal visual acuity, it is not possible to assess whether POTIGA caused their decreased visual acuity, as baseline assessments are not available for these patients. Two patients with retinal abnormalities have had more extensive diagnostic retinal evaluations. The results of these evaluations were consistent with a retinal dystrophy, including abnormalities in the electroretinogram and electrooculogram of both patients, with abnormal fluorescein angiography and diminished sensitivity on visual field testing in one patient. The rate of progression of retinal abnormalities and the reversibility after drug discontinuation are unknown. Because of the observed ophthalmologic adverse reactions, POTIGA should only be used in patients who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential vision loss. Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from POTIGA. Patients should have baseline ophthalmologic testing by an ophthalmic professional and follow-up testing every 6 months. The best method of detection of these abnormalities and the optimal frequency of periodic ophthalmologic monitoring are unknown. Patients who cannot be monitored should usually not be treated with POTIGA. The ophthalmologic monitoring program should include visual acuity testing and dilated fundus photography. Additional testing may include fluorescein angiograms (FA), optical coherence tomography (OCT), perimetry, and electroretinograms (ERG). If retinal pigmentary abnormalities or vision changes are detected, POTIGA should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss. 5.2 Urinary Retention POTIGA caused urinary retention in clinical trials. Urinary retention was generally reported within the first 6 months of treatment, but was also observed later. Urinary retention was reported as an adverse event in 29 of 1,365 (approximately 2%) patients treated with POTIGA in the open-label and placebo-controlled epilepsy database [see Clinical Studies (14)]. Of these 29 patients, 5 (17%) required catheterization, with post-voiding residuals of up to 1,500 mL. POTIGA was discontinued in 3 of the 5 patients who required catheterization, and all were able to void spontaneously; however, 1 of the 3 patients continued intermittent self-catheterization. Two patients continued treatment with POTIGA and were able to void spontaneously after catheter removal. Hydronephrosis occurred in 2 patients, one of whom had associated renal function impairment that resolved upon discontinuation of POTIGA. Hydronephrosis was not reported in placebo patients. In the placebo-controlled epilepsy trials, “urinary retention,” “urinary hesitation,” and “dysuria” were reported in 0.9%, 2.2%, and 2.3% of patients on POTIGA, respectively, and in 0.5%, 0.9%, and 0.7% of patients on placebo, respectively. Because of the increased risk of urinary retention on POTIGA, urologic symptoms should be carefully monitored. Closer monitoring is recommended for patients who have other risk factors for urinary retention (e.g., benign prostatic hyperplasia [BPH]), patients who are unable to communicate clinical symptoms (e.g., cognitively impaired patients), or patients who use concomitant medications that may affect voiding (e.g., anticholinergics). In these patients, a comprehensive evaluation of urologic symptoms prior to and during treatment with POTIGA may be appropriate. 5.3 Skin Discoloration POTIGA can cause skin discoloration. The skin discoloration is generally described as blue, but has also been described as grey-blue or brown. It is predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement of the face and legs has also been reported. Discoloration of the palate, sclera, and conjunctiva has also been reported. Approximately 10% of patients in long-term clinical trials developed skin discoloration, generally after 2 or more years of treatment and at higher doses (900 mg or greater) of POTIGA. Among patients in whom the status of both skin, nail, lip, or mucous membrane discoloration and retinal pigmentary abnormalities are reported, approximately a quarter of those with skin, nail, lip, or mucous membrane discoloration had concurrent retinal pigmentary abnormalities [see Warnings and Precautions (5.1)]. Information on the consequences, reversibility, time to onset, and pathophysiology of the skin abnormalities remains incomplete. The possibility of more extensive systemic involvement has not been excluded. If a patient develops skin discoloration, serious consideration should be given to changing to an alternate medication. 5.4 Neuropsychiatric Symptoms Confusional state, psychotic symptoms, and hallucinations were reported more frequently as adverse reactions in patients treated with POTIGA than in those treated with placebo in placebo-controlled epilepsy trials (see Table 2). Discontinuations resulting from these reactions were more common in the drug-treated group (see Table 2). These effects were dose-related and generally appeared within the first 8 weeks of treatment. Half of the patients in the controlled trials who discontinued POTIGA due to hallucinations or psychosis required hospitalization. Approximately two-thirds of patients with psychosis in controlled trials had no prior psychiatric history. The psychiatric symptoms in the vast majority of patients in both controlled and open-label trials resolved within 7 days of discontinuation of POTIGA. Rapid titration at greater than the recommended doses appeared to increase the risk of psychosis and hallucinations. Table 2. Major Neuropsychiatric Symptoms in Placebo-Controlled Epilepsy Trials
5.5 Dizziness and Somnolence POTIGA causes dose-related increases in dizziness and somnolence [see Adverse Reactions (6.1)]. In placebo-controlled trials in patients with epilepsy, dizziness was reported in 23% of patients treated with POTIGA and 9% of patients treated with placebo. Somnolence was reported in 22% of patients treated with POTIGA and 12% of patients treated with placebo. In these trials 6% of patients on POTIGA and 1.2% on placebo discontinued treatment because of dizziness; 3% of patients on POTIGA and <1.0% on placebo discontinued because of somnolence. Most of these adverse reactions were mild to moderate in intensity and occurred during the titration phase. For those patients continued on POTIGA, dizziness and somnolence appeared to diminish with continued use. 5.6 QT Interval Effect A study of cardiac conduction showed that POTIGA produced a mean 7.7-msec QT prolongation in healthy volunteers titrated to 400 mg 3 times daily. The QT-prolonging effect occurred within 3 hours. The QT interval should be monitored when POTIGA is prescribed with medicines known to increase QT interval and in patients with known prolonged QT interval, congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia [see Clinical Pharmacology (12.2)]. 5.7 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including POTIGA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive-therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3. Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis
Anyone considering prescribing POTIGA or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 5.8 Withdrawal Seizures As with all AEDs, when POTIGA is discontinued, it should be withdrawn gradually when possible to minimize the potential of increased seizure frequency [see Dosage and Administration (2.1)]. The dosage of POTIGA should be reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal. 6 ADVERSE REACTIONS The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: • Retinal abnormalities and potential vision loss [see Warnings and Precautions (5.1)] • Urinary retention [see Warnings and Precautions (5.2)] • Skin discoloration [see Warnings and Precautions (5.3)] • Neuropsychiatric symptoms [see Warnings and Precautions (5.4)] • Dizziness and somnolence [see Warnings and Precautions (5.5)] • QT interval effect [see Warnings and Precautions (5.6)] • Suicidal behavior and ideation [see Warnings and Precautions (5.7)] • Withdrawal seizures [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. POTIGA was administered as adjunctive therapy to 1,365 patients with epilepsy in all controlled and uncontrolled clinical studies during the premarketing development. A total of 801 patients were treated for at least 6 months, 585 patients were treated for 1 year or longer, and 311 patients were treated for at least 2 years. Adverse Reactions Leading to Discontinuation in All Controlled Clinical Studies In the 3 randomized, double-blind, placebo-controlled studies, 199 of 813 patients (25%) receiving POTIGA and 45 of 427 patients (11%) receiving placebo discontinued treatment because of adverse reactions. The most common adverse reactions leading to withdrawal in patients receiving POTIGA were dizziness (6%), confusional state (4%), fatigue (3%), and somnolence (3%). Common Adverse Reactions in All Controlled Clinical Studies Overall, the most frequently reported adverse reactions in patients receiving POTIGA (≥4% and occurring approximately twice the placebo rate) were dizziness (23%), somnolence (22%), fatigue (15%), confusional state (9%), vertigo (8%), tremor (8%), abnormal coordination (7%), diplopia (7%), disturbance in attention (6%), memory impairment (6%), asthenia (5%), blurred vision (5%), gait disturbance (4%), aphasia (4%), dysarthria (4%), and balance disorder (4%) (see Table 4). In most cases the reactions were of mild or moderate intensity. Table 4. Adverse Reactions Incidence in Placebo-Controlled Adjunctive Trials in Adult Patients with Partial-Onset Seizures (Adverse reactions in at least 2% of patients treated with POTIGA in any treatment group and numerically more frequent than in the placebo group.)
Most of the adverse reactions appear to be dose related (especially those classified as psychiatric and nervous system symptoms), including dizziness, somnolence, confusional state, tremor, abnormal coordination, memory impairment, blurred vision, gait disturbance, aphasia, balance disorder, constipation, dysuria, and chromaturia. POTIGA was associated with dose-related weight gain, with mean weight increasing by 0.2 kg, 1.2 kg, 1.6 kg, and 2.7 kg in the placebo, 600 mg per day, 900 mg per day, and 1,200 mg per day groups, respectively. Additional Adverse Reactions Observed during All Phase 2 and 3 Clinical Trials Following is a list of adverse reactions reported by patients treated with POTIGA during all clinical trials: rash, nystagmus, dyspnea, leukopenia, muscle spasms, alopecia, nephrolithiasis, syncope, neutropenia, thrombocytopenia, euphoric mood, renal colic, coma, encephalopathy. Comparison of Gender, Age, and Race The overall adverse reaction profile of POTIGA was similar for females and males. There are insufficient data to support meaningful analyses of adverse reactions by age or race. Approximately 86% of the population studied was Caucasian, and 0.8% of the population was aged 65 years or older. 7 DRUG INTERACTIONS 7.1 Antiepileptic Drugs The potentially significant interactions between POTIGA and concomitant AEDs are summarized in Table 5. Table 5. Significant Interactions between POTIGA and Concomitant Antiepileptic Drugs (AEDs)
b Inducer for uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs). c A decrease in dosage of POTIGA should be considered when carbamazepine or phenytoin is discontinued. [See Clinical Pharmacology (12.3).] 7.2 Alcohol Alcohol increased systemic exposure to POTIGA. Patients should be advised of possible worsening of ezogabine’s general dose-related adverse reactions if they take POTIGA with alcohol [see Clinical Pharmacology (12.3)]. 7.3 Laboratory Tests Ezogabine has been shown to interfere with clinical laboratory assays of both serum and urine bilirubin, which can result in falsely elevated readings. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. POTIGA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal studies, doses associated with maternal plasma exposures (AUC) to ezogabine and its major circulating metabolite, N-acetyl metabolite of ezogabine (NAMR), similar to or below those expected in humans at the maximum recommended human dose (MRHD) of 1,200 mg per day produced developmental toxicity when administered to pregnant rats and rabbits. The maximum doses evaluated were limited by maternal toxicity (acute neurotoxicity). Treatment of pregnant rats with ezogabine (oral doses of up to 46 mg/kg/day) throughout organogenesis increased the incidences of fetal skeletal variations. The no-effect dose for embryo-fetal toxicity in rats (21 mg/kg/day) was associated with maternal plasma exposures (AUC) to ezogabine and NAMR less than those in humans at the MRHD. Treatment of pregnant rabbits with ezogabine (oral doses of up to 60 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal skeletal variations. The no-effect dose for embryo-fetal toxicity in rabbits (12 mg/kg/day) was associated with maternal plasma exposures to ezogabine and NAMR less than those in humans at the MRHD. Administration of ezogabine (oral doses of up to 61.9 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased pre- and postnatal mortality, decreased body weight gain, and delayed reflex development in the offspring. The no-effect dose for pre- and postnatal developmental effects in rats (17.8 mg/kg/day) was associated with maternal plasma exposures to ezogabine and NAMR less than those in humans at the MRHD. Pregnancy Registry To provide information regarding the effects of in utero exposure to POTIGA, physicians are advised to recommend that pregnant patients taking POTIGA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website www.aedpregnancyregistry.org. 8.2 Labor and Delivery The effects of POTIGA on labor and delivery in humans are unknown. 8.3 Nursing Mothers It is not known whether ezogabine is excreted in human milk. However, ezogabine and/or its metabolites are present in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants from POTIGA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of POTIGA in patients under 18 years of age have not been established. In juvenile animal studies, increased sensitivity to acute neurotoxicity and urinary bladder toxicity was observed in young rats compared with adults. In studies in which rats were dosed starting on postnatal day 7, ezogabine-related mortality, clinical signs of neurotoxicity, and renal 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 (2.3), Clinical Pharmacology (12.3)]. POTIGA may cause urinary retention. Elderly men with symptomatic BPH may be at increased risk for urinary retention. 8.6 Renal Impairment Dosage adjustment is recommended in patients with creatinine clearance <50 mL/min or patients with end-stage renal disease (ESRD) receiving hemodialysis [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment is recommended in patients with mild hepatic impairment. Dosage adjustment is recommended in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), 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 In a 28-day physical dependence study in which rats received daily ezogabine administration, abrupt drug discontinuation produced behavioral changes that included piloerection, increases in high step gait, and tremors, compared with vehicle-treated animals. These data show that ezogabine produces a withdrawal syndrome indicative of physical dependence. 10 OVERDOSAGE 10.1 Signs, Symptoms, and Laboratory Findings There is limited experience of overdose with POTIGA. Total daily doses of POTIGA over 2,500 mg were reported during clinical trials. In addition to adverse reactions seen at therapeutic doses, symptoms reported with overdose of POTIGA included agitation, aggressive behavior, and irritability. There were no reported sequelae. In an abuse potential study, cardiac arrhythmia (asystole or ventricular tachycardia) occurred in 2 volunteers within 3 hours of receiving a single 900-mg dose of POTIGA. The arrhythmias spontaneously resolved and both volunteers recovered without sequelae. 10.2 Management of Overdose There is no specific antidote for overdose with POTIGA. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with POTIGA. 11 DESCRIPTION The chemical name of ezogabine is N-[2-amino-4-(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester, and it has the following structure:
bInducer for uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs). cA decrease in dose of POTIGA should be considered when carbamazepine or phenytoin is discontinued. dZonisamide, valproic acid, clonazepam, gabapentin, levetiracetam, oxcarbazepine, phenobarbital, pregabalin, topiramate, clobazam, and lamotrigine, based on a population pharmacokinetic analysis using pooled data from Phase 3 clinical trials. Digoxin: A repeat-dose trial of ezogabine 600 mg to 1,200 mg administered to healthy subjects (n = 29) resulted in a small increase of the systemic exposure of digoxin (AUC range of 8% to 18%) that did not appear to be dose related. No dose adjustment is necessary for digoxin when coadministered with POTIGA. Oral Contraceptives: In one study examining the potential interaction between ezogabine (150 mg 3 times daily for 3 days) and the combination oral contraceptive norgestrel/ethinyl estradiol (0.3 mg/0.03 mg) tablets in 20 healthy females, no significant alteration in the pharmacokinetics of either drug was observed. In a second study examining the potential interaction of repeated ezogabine dosing (250 mg 3 times daily for 14 days) and the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg) tablets in 25 healthy females, no significant alteration in the pharmacokinetics of either drug was observed. Alcohol: In a healthy volunteer study, the coadministration of ethanol 1g/kg (5 standard alcohol drinks) over 20 minutes and ezogabine (200 mg) resulted in an increase in the ezogabine Cmax and AUC by 23% and 37%, respectively [see Drug Interactions (7.2)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 1-year neonatal mouse study of ezogabine (2 single-dose oral administrations of up to 96 mg/kg on postnatal days 8 and 15), a dose-related increase in the frequency of lung neoplasms (bronchioalveolar carcinoma and/or adenoma) was observed in treated males. No evidence of carcinogenicity was observed in rats following oral administration of ezogabine (oral gavage doses of up to 50 mg/kg/day) for 2 years. Plasma exposure (AUC) to ezogabine at the highest doses tested was less than that in humans at the maximum recommended human dose (MRHD) of 1,200 mg per day. Mutagenesis Highly purified ezogabine was negative in the in vitro Ames assay, the in vitro Chinese hamster ovary (CHO) Hprt gene mutation assay, and the in vivo mouse micronucleus assay. Ezogabine was positive in the in vitro chromosomal aberration assay in human lymphocytes. The major circulating metabolite of ezogabine, NAMR, was negative in the in vitro Ames assay, but positive in the in vitro chromosomal aberration assay in CHO cells. Impairment of Fertility Ezogabine had no effect on fertility, general reproductive performance, or early embryonic development when administered to male and female rats at doses of up to 46.4 mg/kg/day (associated with a plasma ezogabine exposure [AUC] less than that in humans at the MRHD) prior to and during mating, and continuing in females through gestation day 7. 14 CLINICAL STUDIES The efficacy of POTIGA as adjunctive therapy in partial-onset seizures was established in 3 multicenter, randomized, double-blind, placebo-controlled studies in 1,239 adult patients. The primary endpoint consisted of the percent change in seizure frequency from baseline to the double-blind treatment phase (titration through maintenance). Patients enrolled in the studies had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs, with or without concomitant vagus nerve stimulation. More than 75% of patients were taking 2 or more concomitant AEDs. During an 8-week baseline period, patients experienced at least 4 partial-onset seizures per 28 days on average with no seizure-free period exceeding 3 to 4 weeks. Patients had a mean duration of epilepsy of 22 years. Across the 3 studies, the median baseline seizure frequency ranged from 8 to 12 seizures per month. The criteria for statistical significance was P<0.05. Patients were randomized to the total daily maintenance dosages of 600 mg per day, 900 mg per day, or 1,200 mg per day, each administered in 3 equally divided doses. During the titration phase of all 3 studies, treatment was initiated at 300 mg per day (100 mg 3 times per day) and increased in weekly increments of 150 mg per day to the target maintenance dosage. Figure 1 shows the median percent reduction in 28-day seizure frequency (baseline to double-blind phase) as compared with placebo across all 3 studies. A statistically significant effect was observed with POTIGA at doses of 600 mg per day (Study 1), at 900 mg per day (Studies 1 and 3), and at 1,200 mg per day (Studies 2 and 3). Figure 1. Median Percent Reduction from Baseline in Seizure Frequency per 28 Days by Dose
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