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POTIGA(EZOGABINE)TABLET ORAL

2013-03-21 05:45:49  作者:新特药房  来源:互联网  浏览次数:262  文字大小:【】【】【
简介: 瑞替加滨(RTG)又称依佐加滨(Ezogabine),是由万安特公司和葛兰素史克公司联合开发的一种用于治疗癫痫的药物,商品名为Potiga/Trobalt。FDA药物评价和研究中心神经学产品部主任Russell Katz, M.D说:“约 ...

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。
Potig获准用于局部癫痫发作,这是一种最常见类型癫痫。癫痫属于脑部疾病,癫痫患者大脑中的神经细胞出现异常或活动过度。部分性发作癫痫仅影响大脑有限或局部区域,但会扩散到大脑的其它部分。癫痫发作可引起广泛症状,包括重复的肢体运动(痉挛)、行为异常、意识丧失和抽搐。
使用现有的治疗手段约有三分之一癫痫患者病情无法获得满意控制,因此能为患者提供多种治疗选择就显得十分重要。也就是说本品对癫痫症状未能获得控制的患者带来了希望。
Potiga是首个神经元钾通道开放制剂。美国食品和药品监督管理局批准抗惊厥药Potiga(ezogabine)作为癫痫患者局部癫痫的辅助用药,其活性成分于今年3月份获得欧洲药品管理局的批准,将于年底进入美国市场。癫痫患者有复发癫痫倾向,由突发脑电活动诱发,导致大脑超负荷。脑细胞间的信息传播系统出现短暂紊乱。局部癫痫仅影响大脑部分区域,但可传导至大脑其他部位。


HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use POTIGA safely and effectively. See full prescribing information for POTIGA.
POTIGA (ezogabine) tablets, for oral use, CV
Initial U.S. Approval: 2011
WARNING: RETINAL ABNORMALITIES AND POTENTIAL VISION LOSSSee full prescribing information for complete boxed warning.
• POTIGA can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, which are known to result in damage to the photoreceptors and vision loss. (5.1)
• Some patients with retinal abnormalities have been found to have abnormal visual acuity. It is not possible to determine whether POTIGA caused this decreased visual acuity. (5.1)
• The rate of progression of retinal abnormalities and their reversibility are unknown. (5.1)
• Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from POTIGA. (5.1)
• All patients taking POTIGA should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional. Testing should include visual acuity and dilated fundus photography. (5.1)
• 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. (5.1)
INDICATIONS AND USAGE
POTIGA is a potassium channel opener indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity. (1)
DOSAGE AND ADMINISTRATION
• Administer in 3 divided doses daily, with or without food. (2.1)
• Initial dosage: 100 mg 3 times daily (300 mg per day) for 1 week. ( 2.1)
• Titrate to maintenance dosage by increasing the dosage at weekly intervals by no more than 150 mg per day. ( 2.1)
• Maintenance dosage: 200 mg 3 times daily (600 mg per day) to 400 mg 3 times daily (1,200 mg per day). ( 2.1)
• In controlled clinical trials, 400 mg 3 times daily (1,200 mg per day) showed limited improvement compared with 300 mg 3 times daily (900 mg per day) with an increase in adverse reactions and discontinuations. ( 2.1)
• When discontinuing POTIGA, reduce the dosage gradually over a period of at least 3 weeks. ( 2.1, 5.8)
• POTIGA may cause retinal abnormalities with long-term use; therefore, treatment should be discontinued if patients fail to show substantial clinical benefit after adequate titration. ( 2.2)
• Testing of visual function should be done at baseline and every 6 months during therapy with POTIGA. ( 2.2)
• 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. ( 2.2)
• Dosing adjustments are recommended in geriatric patients and in patients with moderate or severe renal or hepatic impairment. ( 2.3)
DOSAGE FORMS AND STRENGTHS
Tablets: 50 mg, 200 mg, 300 mg, and 400 mg. (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
• Urinary retention: Patients should be carefully monitored for urologic symptoms. ( 5.2)
• POTIGA can cause skin discoloration. If a patient develops skin discoloration, serious consideration should be given to an alternative treatment. ( 5.3)
• Neuropsychiatric symptoms: Monitor for confusional state, psychotic symptoms, and hallucinations. ( 5.4)
• Monitor for dizziness and somnolence. ( 5.5)
• QT prolongation: QT interval should be monitored in patients taking concomitant medications known to increase the QT interval or with certain heart conditions. ( 5.6)
• Monitor for suicidal thoughts or behaviors. ( 5.7)
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥4% and twice placebo) were dizziness, somnolence, fatigue, confusional state, vertigo, tremor, abnormal coordination, diplopia, disturbance in attention, memory impairment, asthenia, blurred vision, gait disturbance, aphasia, dysarthria, and balance disorder. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Ezogabine plasma levels may be reduced by concomitant administration of phenytoin or carbamazepine. An increase in dosage of POTIGA should be considered when adding phenytoin or carbamazepine. (7.1)
USE IN SPECIFIC POPULATIONS
• Pregnancy: Based on animal data, may cause fetal harm. ( 8.1)
• Safety and effectiveness in patients under 18 years of age have not been established. ( 8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 5/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE

POTIGA® is indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity [see Warnings and Precautions (5.1)].
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
The initial dosage should be 100 mg 3 times daily (300 mg per day). The dosage should be increased gradually at weekly intervals by no more than 50 mg 3 times daily (increase in the daily dose of no more than 150 mg per day) up to a maintenance dosage of 200 mg to 400 mg 3 times daily (600 mg to 1,200 mg per day), based on individual patient response and tolerability. This information is summarized in Table 1 under Dosing in Specific Populations. In the controlled clinical trials, 400 mg 3 times daily showed limited evidence of additional improvement in seizure reduction, but an increase in adverse events and discontinuations, compared with the 300 mg 3 times daily dosage. The safety and efficacy of dosages greater than 400 mg 3 times daily (1,200 mg per day) have not been examined in controlled trials.
POTIGA should be given orally in 3 equally divided doses daily, with or without food.
POTIGA tablets should be swallowed whole.
If POTIGA is discontinued, the dosage should be gradually reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal.
2.2. Dosing Considerations to Mitigate the Risk of Visual Adverse Reactions
Because POTIGA may cause retinal abnormalities with long-term use, patients who fail to show substantial clinical benefit after adequate titration should be discontinued from POTIGA. Testing of visual function should be done at baseline and every 6 months during therapy with POTIGA. Patients who cannot be monitored should usually not be treated with POTIGA. 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 [see Warnings and Precautions (5.1)].
2.3 Dosing in Specific Populations
No adjustment in dosage is recommended in patients with mild renal or hepatic impairment (see Table 1). Dosage adjustment is recommended in geriatric and patients with moderate or severe renal or hepatic impairment (see Table 1).
Table 1. Dosing in Specific Populations

Specific Population

Initial Dose

Titration

Maximum Dosage

General Dosing

General population (including patients with mild renal or hepatic impairment)

100 mg 3 times daily

(300 mg per day)

Increase by no more than 50 mg 3 times daily, at weekly intervals

400 mg 3 times daily

(1,200 mg per day)

Dosing in Specific Populations

Geriatrics

(patients ≥65 years)

50 mg 3 times daily

(150 mg per day)

Increase by no more than 50 mg 3 times daily, at weekly intervals

250 mg 3 times daily

(750 mg per day)

Hepatic impairment

(patients with Child-Pugh 7-9)

250 mg 3 times daily

(750 mg per day)

Hepatic impairment

(patients with Child-Pugh >9)

200 mg 3 times daily

(600 mg per day)

Renal impairment

(patients with CrCL <50 mL per min or end-stage renal disease on dialysis)

200 mg 3 times daily

(600 mg per day)

3 DOSAGE FORMS AND STRENGTHS
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

Adverse Reaction

Number (%) with Adverse Reaction

Number (%) Discontinuing

POTIGA

(n = 813)

Placebo

(n = 427)

POTIGA

(n = 813)

Placebo

(n = 427)

Confusional state

75 (9%)

11 (3%)

32 (4%)

4 (<1%)

Psychosis

9 (1%)

0

6 (<1%)

0

Hallucinationsa

14 (2%)

2 (<1%)

6 (<1%)

0

aHallucinations includes visual, auditory, and mixed hallucinations.
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

Indication

Placebo Patients with Events per 1,000 Patients

Drug Patients with Events per 1,000 Patients

Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients

Risk Difference: Additional Drug Patients with Events per 1,000 Patients

Epilepsy

1.0

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1.0

1.8

1.9

0.9

Total

2.4

4.3

1.8

1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications.
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.)

Body System/
Adverse Reaction

Placebo

POTIGA

600 mg/day

900 mg/day

1,200 mg/day

All

(N = 427)

%

(n = 281)

%

(n = 273)

%

(n = 259)

%

(N = 813)

%

Eye
Diplopia

2

8

6

7

7

Blurred vision

2

2

4

10

5

Gastrointestinal
Nausea

5

6

6

9

7

Constipation

1

1

4

5

3

Dyspepsia

2

3

2

3

2

General
Fatigue

6

16

15

13

15

Asthenia

2

4

6

4

5

Infections and infestations
Influenza

2

4

1

5

3

Investigations
Weight increased

1

2

3

3

3

Nervous system
Dizziness

9

15

23

32

23

Somnolence

12

15

25

27

22

Memory impairment

3

3

6

9

6

Tremor

3

3

10

12

8

Vertigo

2

8

8

9

8

Abnormal coordination

3

5

5

12

7

Disturbance in attention

<1

6

6

7

6

Gait disturbance

1

2

5

6

4

Aphasia

<1

1

3

7

4

Dysarthria

<1

4

2

8

4

Balance disorder

<1

3

3

5

4

Paresthesia

2

3

2

5

3

Amnesia

<1

<1

3

3

2

Dysphasia

<1

1

1

3

2

Psychiatric
Confusional state

3

4

8

16

9

Anxiety

2

3

2

5

3

Disorientation

<1

<1

<1

5

2

Psychotic disorder

0

0

<1

2

<1

Renal and urinary
Dysuria

<1

1

2

4

2

Urinary hesitation

<1

2

1

4

2

Hematuria

<1

2

1

2

2

Chromaturia

<1

<1

2

3

2

Other adverse reactions reported in these 3 studies in <2% of patients treated with POTIGA and numerically greater than placebo were increased appetite, hallucinations, myoclonus, peripheral edema, hypokinesia, dry mouth, dysphagia, hyperhydrosis, urinary retention, malaise, and increased liver enzymes.
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)

AED

Dosage of AED

(mg/day)

Dosage of POTIGA

(mg/day)

Influence of POTIGA on AED

Influence of AED on POTIGA

Dosage Adjustment

Carbamazepinea,b

600-2,400

300-1,200

None

31% decrease in AUC,

23% decrease in Cmax

consider an increase in dosage of POTIGA when adding carbamazepinec

Phenytoina,b

120-600

300-1,200

None

34% decrease in AUC,

18% decrease in Cmax

consider an increase in dosage of POTIGA when adding phenytoinc

a Based on results of a Phase 2 study.
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:


The empirical formula is C16H18FN3O2, representing a molecular weight of 303.3. Ezogabine is a white to slightly colored, odorless, tasteless, crystalline powder. At room temperature, ezogabine is practically insoluble in aqueous media at pH values above 4, while the solubility is higher in polar organic solvents. At gastric pH, ezogabine is sparingly soluble in water (about 16 g/L). The pKa is approximately 3.7 (basic).
POTIGA is supplied for oral administration as 50-mg, 200-mg, 300-mg, and 400-mg film-coated immediate-release tablets. Each tablet contains the labeled amount of ezogabine and the following inactive ingredients: carmine (50-mg and 400-mg tablets), croscarmellose sodium, FD&C Blue No. 2 (50-mg, 300-mg, and 400-mg tablets), hypromellose, iron oxide yellow (200‑mg and 300-mg tablets), lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism by which ezogabine exerts its therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability. In vitro studies suggest that ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents.
12.2 Pharmacodynamics
The QTc prolongation risk of POTIGA was evaluated in healthy subjects. In a randomized, double-blind, active- and placebo-controlled parallel-group study, 120 healthy subjects (40 in each group) were administered POTIGA titrated up to the final dose of 400 mg 3 times daily, placebo, and placebo and moxifloxacin (on day 22). After 22 days of dosing, the maximum mean (upper 1-sided, 95% CI) increase of baseline- and placebo-adjusted QTc interval based on Fridericia correction method (QTcF) was 7.7 msec (11.9 msec) and was observed at 3 hours after dosing in subjects who achieved 1,200 mg per day. No effects on heart rate, PR, or QRS intervals were noted.
Patients who are prescribed POTIGA with medicines known to increase QT interval or who have known prolonged QT interval, congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia should be observed closely [see Warnings and Precautions (5.6)].
12.3 Pharmacokinetics
The pharmacokinetic profile is approximately linear in daily doses between 600 mg and 1,200 mg in patients with epilepsy, with no unexpected accumulation following repeated administration. The pharmacokinetics of ezogabine are similar in healthy volunteers and patients with epilepsy.
Absorption
After both single and multiple oral doses, ezogabine is rapidly absorbed with median time to maximum plasma concentration (Tmax) values generally between 0.5 and 2 hours. Absolute oral bioavailability of ezogabine relative to an intravenous dose of ezogabine is approximately 60%. High-fat food does not affect the extent to which ezogabine is absorbed based on plasma AUC values, but it increases peak concentration (Cmax) by approximately 38% and delays Tmax by 0.75 hour.
POTIGA can be taken with or without food.
Distribution
Data from in vitro studies indicate that ezogabine and NAMR are approximately 80% and 45% bound to plasma protein, respectively. Clinically significant interactions with other drugs through displacement from proteins are not anticipated. The steady-state volume of distribution of ezogabine is 2 to 3 L/kg following intravenous dosing, suggesting that ezogabine is well distributed in the body.
Metabolism
Ezogabine is extensively metabolized primarily via glucuronidation and acetylation in humans. A substantial fraction of the ezogabine dose is converted to inactive N-glucuronides, the predominant circulating metabolites in humans. Ezogabine is also metabolized to NAMR that is also subsequently glucuronidated. NAMR has antiepileptic activity, but it is less potent than ezogabine in animal seizure models. Additional minor metabolites of ezogabine are an N-glucoside of ezogabine and a cyclized metabolite believed to be formed from NAMR. In vitro studies using human biomaterials showed that the N-acetylation of ezogabine was primarily carried out by NAT2, while glucuronidation was primarily carried out by UGT1A4, with contributions by UGT1A1, UGT1A3, and UGT1A9.
In vitro studies showed no evidence of oxidative metabolism of ezogabine or NAMR by cytochrome P450 enzymes. Coadministration of ezogabine with medications that are inhibitors or inducers of cytochrome P450 enzymes is therefore unlikely to affect the pharmacokinetics of ezogabine or NAMR.
Elimination
Results of a mass balance study suggest that renal excretion is the major route of elimination for ezogabine and NAMR. About 85% of the dose was recovered in the urine, with the unchanged parent drug and NAMR accounting for 36% and 18% of the administered dose, respectively, and the total N-glucuronides of ezogabine and NAMR accounting for 24% of the administered dose. Approximately 14% of the radioactivity was recovered in the feces, with unchanged ezogabine accounting for 3% of the total dose. Average total recovery in both urine and feces within 240 hours after dosing is approximately 98%.
Ezogabine and its N-acetyl metabolite have similar elimination half-lives (t½) of 7 to 11 hours. The clearance of ezogabine following intravenous dosing was approximately 0.4 to 0.6 L/h/kg. Ezogabine is actively secreted into the urine.
Specific Populations
Race: No study has been conducted to investigate the impact of race on pharmacokinetics of ezogabine. A population pharmacokinetic analysis comparing Caucasians and non-Caucasians (predominately African American and Hispanic patients) showed no significant pharmacokinetic difference. No adjustment of the ezogabine dose for race is recommended.
Gender: The impact of gender on the pharmacokinetics of ezogabine was examined following a single dose of POTIGA to healthy young (aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. The AUC values were approximately 20% higher in young females compared with young males and approximately 30% higher in elderly females compared with elderly males. The Cmax values were approximately 50% higher in young females compared with young males and approximately 100% higher in elderly females compared with elderly males. There was no gender difference in weight-normalized clearance. Overall, no adjustment of the dosage of POTIGA is recommended based on gender.
Pediatric Patients: The pharmacokinetics of ezogabine in pediatric patients have not been investigated.
Geriatric: The impact of age on the pharmacokinetics of ezogabine was examined following a single dose of ezogabine to healthy young (aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. Systemic exposure (AUC) of ezogabine was approximately 40% to 50% higher and terminal half-life was prolonged by approximately 30% in the elderly compared with the younger subjects. The peak concentration (Cmax) was similar to that observed in younger subjects. A dosage reduction in the elderly is recommended [see Dosage and Administration (2.3), Use in Specific Populations (8.5)].
Renal Impairment: The pharmacokinetics of ezogabine were studied following a single 100-mg dose of POTIGA in subjects with normal (CrCL >80 mL/min), mild (CrCL ≥50 to ≤80 mL/min), moderate (CrCL ≥30 to <50 mL/min), or severe renal impairment (CrCL <30 mL/min) (n = 6 in each cohort) and in subjects with ESRD requiring hemodialysis (n = 6). The ezogabine AUC was increased by approximately 30% in patients with mild renal impairment and doubled in patients with moderate impairment to ESRD (CrCL <50 mL/min) relative to healthy subjects. Similar increases in NAMR exposure were observed in the various degrees of renal impairment. The effect of hemodialysis on ezogabine clearance has not been established. Dosage reduction is recommended for patients with creatinine clearance <50 mL/min and for patients with ESRD receiving dialysis [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].
Hepatic Impairment: The pharmacokinetics of ezogabine were studied following a single 100-mg dose of POTIGA in subjects with normal, mild (Child-Pugh score 5 to 6), moderate (Child-Pugh score 7 to 9), or severe hepatic (Child-Pugh score >9) impairment (n = 6 in each cohort). Relative to healthy subjects, ezogabine AUC was not affected by mild hepatic impairment, but was increased by approximately 50% in subjects with moderate hepatic impairment and doubled in subjects with severe hepatic impairment. There was an increase of approximately 30% in exposure to NAMR in patients with moderate to severe impairment. Dosage reduction is recommended in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.7)].
Drug Interactions
In vitro studies using human liver microsomes indicated that ezogabine does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5. In addition, in vitro studies in human primary hepatocytes showed that ezogabine and NAMR did not induce CYP1A2 or CYP3A4/5 activity. Therefore, ezogabine is unlikely to affect the pharmacokinetics of substrates of the major cytochrome P450 isoenzymes through inhibition or induction mechanisms.
Ezogabine is not an inhibitor of the transporters P-glycoprotein (P-gp), organic anion transporter 1 (OAT1), or organic cation transporter 2 (OCT2) or a substrate for P-gp efflux. Ezogabine is a weak inhibitor of the transporter OAT3. Ezogabine’s metabolite, NAMR, is also a weak inhibitor of P-gp efflux.
Interactions with Antiepileptic Drugs: The interactions between POTIGA and concomitant AEDs are summarized in Table 6.
Table 6. Interactions between POTIGA and Concomitant Antiepileptic Drugs (AEDs)

AED

Dose of AED

(mg/day)

Dose of POTIGA

(mg/day)

Influence of POTIGA on AED

Influence of AED on POTIGA

Dosage Adjustment

Carbamazepinea,b

600-2,400

300-1,200

None

31% decrease in AUC,

23% decrease in Cmax,

28% increase in clearance

consider an increase in dosage of POTIGA when adding carbamazepinec

Phenytoina,b

120-600

300-1,200

None

34% decrease in AUC,

18% decrease in Cmax,

33% increase in clearance

consider an increase in dosage of POTIGA when adding phenytoinc

Topiramatea

250-1,200

300-1,200

None

None

None

Valproatea

750-2,250

300-1,200

None

None

None

Phenobarbital

90

600

None

None

None

Lamotrigine

200

600

18% decrease in AUC,

22% increase in clearance

None

None

Othersd

None

None

None

aBased on results of a Phase 2 study.
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


Figure 2 shows changes from baseline in the 28-day total partial seizure frequency by category for patients treated with POTIGA and placebo in an integrated analysis across the 3 clinical trials. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in five categories.
Figure 2. Proportion of Patients by Category of Seizure Response for POTIGA and Placebo across All Three Double-blind Trials


16 HOW SUPPLIED/STORAGE AND HANDLING
POTIGA is supplied as film-coated immediate-release tablets for oral administration containing 50 mg, 200 mg, 300 mg, or 400 mg of ezogabine in the following packs:
• 50-mg Tablets: purple, round, film-coated tablets debossed with “RTG 50” on one side in bottles of 90 tablets with desiccant (NDC 0173-0810-59).
• 200-mg Tablets: yellow, oblong, film-coated tablets debossed with “RTG-200” on one side in bottles of 90 tablets with desiccant (NDC 0173-0812-59).
• 300-mg Tablets: green, oblong, film-coated tablets debossed with “RTG-300” on one side in bottles of 90 tablets with desiccant (NDC 0173-0813-59).
• 400-mg Tablets: purple, oblong, film-coated tablets debossed with “RTG-400” on one side in bottles of 90 tablets with desiccant (NDC 0173-0814-59).
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature.]
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Retinal Abnormalities and Potential Vision Loss
Inform patients of the risk of retinal abnormalities and possible risk of vision loss, which may be permanent [see Warnings and Precautions 5.1]. All patients taking POTIGA should participate in baseline and periodic ophthalmologic monitoring of vision by an ophthalmic professional. Inform patients that if they suspect any vision changes, they should notify their physician immediately.
Urinary Retention
Inform patients that POTIGA can cause urinary retention (including urinary hesitation and dysuria). Instruct patients to seek immediate medical assistance if they experience any symptoms of urinary retention, inability to urinate, and/or pain with urination [see Warnings and Precautions (5.2)]. Urologic consultation may be helpful for patients who cannot reliably report symptoms of urinary retention (for example, patients with cognitive impairment).
Skin Discoloration
Inform patients that POTIGA can cause discoloration of nails, lips, skin, palate, and parts of the eye and that it is not known if the discoloration is reversible upon drug discontinuation [see Warnings and Precautions 5.3]. Most skin discoloration has been reported after at least 2 years of treatment with POTIGA, but may happen earlier. Inform patients that the possibility of more extensive systemic involvement has not been excluded. Instruct patients to notify their physician if they develop skin discoloration.
Psychiatric Symptoms
Inform patients that POTIGA can cause psychiatric symptoms such as confusional state, disorientation, hallucinations, and other symptoms of psychosis. Instruct patients and their caregivers to notify their physicians if they experience psychotic symptoms [see Warnings and Precautions (5.4)].
Central Nervous System Effects
Inform patients that POTIGA may cause dizziness, somnolence, memory impairment, abnormal coordination/balance, disturbance in attention, and ophthalmological effects such as diplopia or blurred vision. Advise patients taking POTIGA not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with POTIGA [see Warnings and Precautions (5.5)].
Suicidal Thinking and Behavior
Inform patients, their caregivers, and families that AEDs, including POTIGA, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct them to immediately report behaviors of concern to healthcare providers [see Warnings and Precautions (5.7)].
Pregnancy
Advise patients to notify their physicians if they become pregnant or intend to become pregnant during therapy. Advise patients to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry collects information about the safety of AEDs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations (8.1)].
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c60979b-489d-4e7b-8893-468ae00c44bb

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