symptoms, and hallucinations. (5.2)
`
`
`• Dizziness and somnolence: Monitor for dizziness and somnolence.(5.3)
`
`• QT prolongation: QT interval should be monitored in patients taking
`concomitant medications known to increase the QT interval or with
`certain heart conditions. (5.4)
`• Suicidal behavior and ideation: Monitor for suicidal thoughts or
`
`behaviors. (5.5)
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------
`
`The most common adverse reactions (incidence ≥4% and approximately twice
`placebo) are 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)
`
`
`• N-acetyl metabolite of ezogabine may inhibit renal clearance of digoxin, a
`
`P-glycoprotein substrate. Monitor digoxin levels. (7.2)
`
`
`
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------
`
`• Pregnancy: Based on animal data, may cause fetal harm. Pregnancy
`
`registry available. (8.1)
`
`• Pediatric use: 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: 06/2011
`
`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
`
`
`Initial U.S. Approval: 2011
`----------------------------INDICATIONS AND USAGE---------------------
`POTIGA is a potassium channel opener indicated as adjunctive treatment of
`
`partial-onset seizures in patients aged 18 years and older. (1)
`
`
`----------------------- DOSAGE AND ADMINISTRATION ----------------
`
`
`• Administer in 3 divided doses daily, with or without food. (2)
`
`
`• The initial dosage should be 100 mg 3 times daily (300 mg per day) for 1
`
`
`week. (2)
`
`• Titrate to maintenance dosage by increasing the dosage at weekly
`
`intervals by no more than 150 mg per day. (2)
`
`
`• Optimize effective dosage between 200 mg 3 times daily (600 mg per
`
`day) to 400 mg 3 times daily (1,200 mg per day). (2)
`
`In controlled clinical trials, 400 mg 3 times daily (1,200 mg per day)
`
`
`showed limited improvement compared to 300 mg 3 times daily (900 mg
`
`
`per day) with an increase in adverse reactions and discontinuations. (2)
`
`• When discontinuing POTIGA, reduce the dosage gradually over a period
`of at least 3 weeks. (2, 5.6)
`• Dosing adjustments are required for geriatric patients and patients with
`moderate to severe renal or hepatic impairment (2)
`
`
`
`•
`
`
`
`
`--------------------- 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. (5.1)
`
`
`• Neuropsychiatric symptoms: Monitor for confusional state, psychotic
`
`
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
` 
` 
`1
`INDICATIONS AND USAGE
` 
` 
`2 DOSAGE AND ADMINISTRATION
`
` 
` 
`3 DOSAGE FORMS AND STRENGTHS
` 
` 
`4 CONTRAINDICATIONS
` 
` 
`5 WARNINGS AND PRECAUTIONS
` 
` 
`5.1 Urinary Retention
` 
` 
`5.2 Neuro-Psychiatric Symptoms
` 
` 
`5.3 Dizziness and Somnolence
` 
` 
`5.4 QT Interval Effect
` 
` 
`5.5 Suicidal Behavior and Ideation
` 
` 
`5.6 Withdrawal Seizures
` 
` 
`6 ADVERSE REACTIONS
` 
` 
`6.1 Clinical Trials Experience
` 
` 
`7 DRUG INTERACTIONS
`7.1 Antiepileptic Drugs
` 
` 
`7.2 Digoxin
` 
` 
`7.3 Alcohol
` 
` 
`7.4 Laboratory Tests
` 
` 
`8 USE IN SPECIFIC POPULATIONS
` 
` 
`8.1 Pregnancy
` 
` 
`8.2 Labor and Delivery
` 
` 
`8.3 Nursing Mothers
` 
` 
`8.4 Pediatric Use
` 
` 
`8.5 Geriatric Use
`
` 
` 
`8.6 Patients With Renal Impairment
` 
` 
`8.7 Patients With Hepatic Impairment
` 
` 
`9 DRUG ABUSE AND DEPENDENCE
` 
` 
`9.2 Abuse
` 
` 
`9.3 Dependence
` 
` 
`10 OVERDOSAGE
` 
` 
`10.1 Signs, Symptoms, and Laboratory Findings
` 
` 
`
`10.2 Management of Overdose
` 
` 
`11 DESCRIPTION
` 
` 
`12 CLINICAL PHARMACOLOGY
` 
` 
`12.1 Mechanism of Action
` 
` 
`12.2 Pharmacodynamics
` 
` 
`12.3 Pharmacokinetics
` 
` 
`13 NONCLINICAL TOXICOLOGY
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of
` 
`Fertility
` 
` 
`14 CLINICAL STUDIES
` 
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
` 
`
`17 PATIENT COUNSELING INFORMATION
` 
` 
`17.1 Urinary Retention
` 
` 
`17.2 Psychiatric Symptoms
` 
` 
`17.3 Central Nervous System Effects
` 
` 
`17.4 Suicidal Thinking and Behavior
` 
` 
`17.5 Pregnancy
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`Reference ID: 2959210
`
`1
`
`
`ARGENTUM Exhibit 1211
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, inc.
`IPR2016-00204
`
`Page 00001
`
`
`

`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`POTIGA™ is indicated as adjunctive treatment of partial-onset seizures in patients aged
`
`18 years and older.
`
`DOSAGE AND ADMINISTRATION
`2
`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 to 400 mg 3
`times daily (600 to 1,200 mg per day), based on individual patient response and tolerability. This
`information is summarized in Table 1 under General Dosing. 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 to the 300 mg 3 times daily
`dosage. The safety and efficacy of doses greater than 400 mg 3 times daily (1,200 mg per day)
`have not been examined in controlled trials.
`No adjustment in dosage is required for patients with mild renal or hepatic impairment
`
`(see General Dosing, Table 1). Dosage adjustment is required in patients with moderate and
`greater renal or hepatic impairment (see Dosing in Specific Populations, Table 1).
`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.
`
`
`
`Maximum Dose
`
`Table 1: Dosing Recommendations
`
`Titration
`Specific Population
`Initial Dose
`General Dosing
`100 mg 3 times
`Increase by no more 400 mg 3 times daily
`daily
`than 50 mg 3 times
`(1,200 mg per day)
`(300 mg per day)
`daily, at weekly
`intervals
`Dosing in Specific Populations
`50 mg 3 times daily
`Increase by no more 250 mg 3 times daily
`(150 mg per day)
`than 50 mg 3 times
`(750 mg per day)
`daily, at weekly
`50 mg 3 times daily
`200 mg 3 times daily
`intervals
`(150 mg per day)
`(600 mg per day)
`
`General population
`(including patients with
`mild renal or hepatic
`impairment)
`
` Geriatrics
`
`(patients >65 years)
`
` Renal impairment
`(patients with CrCL
`<50 mL per min or end-
`stage renal disease on
`
`
`
`Reference ID: 2959210
`
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`
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`
`

`
`dialysis)
` Hepatic impairment
`
`(patients with Child­
`Pugh >7-9)
`Hepatic impairment
`
`(patients with Child­
`Pugh >9)
`
`
`50 mg 3 times daily
`(150 mg per day)
`
`50 mg 3 times daily
`(150 mg per day)
`
`250 mg 3 times daily
`(750 mg per day)
`
`200 mg 3 times daily
`(600 mg per day)
`
`DOSAGE FORMS AND STRENGTHS
`3
`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 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, 4 (14%) required catheterization, with post-voiding residuals of up to
`1,500 mL. Following discontinuation of POTIGA, all 4 patients who required catheterization for
`urinary retention were able to void spontaneously; however, 1 of the 4 patients also required
`continued intermittent self-catheterization following discontinuation of POTIGA.
`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.
`
`
`
`Reference ID: 2959210
`
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`
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`
`

`
`5.2 Neuro-Psychiatric 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 Neuro-Psychiatric Symptoms in Placebo-Controlled Epilepsy Trials
`
` Number (%) With Adverse Reaction
`Number (%) Discontinuing
`POTIGA
`Placebo
`POTIGA
`Placebo
`Adverse Reaction
`(n = 813)
`(n = 427)
`(n = 813)
`(n = 427)
`75 (9%)
`11 (3%)
`32 (4%)
`4 (<1%)
`Confusional state
`9 (1%)
`0
`6 (<1%)
`0
`Psychosis
`14 (2%)
`2 (<1%)
`6 (<1%)
`0
` Hallucinationsa
`
`a Hallucinations includes visual, auditory, and mixed hallucinations.
`
`5.3 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.
`5.4 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)].
`5.5 Suicidal Behavior and Ideation
`
`
`
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`
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`
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`
`

`
`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 to 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 to 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
`
`Placebo Patients
`With Events per
`1,000 Patients
`1.0
`5.7
`1.0
`2.4
`
`Drug Patients
`With Events per
`1,000 Patients
`3.4
`8.5
`1.8
`4.3
`
`Indication
`Epilepsy
`Psychiatric
`Other
`Total
`
`Relative Risk:
`Incidence of Events in
`Drug Patients/
`Incidence in Placebo
`Patients
`3.5
`1.5
`1.9
`1.8
`
`Risk Difference:
`Additional Drug
`Patients With
`Events per 1,000
`Patients
`2.4
`2.9
`0.9
`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.
`
`
`
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`
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`

`
`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.
`5.6 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)]. The dosage of POTIGA should be reduced over a period of at least 3 weeks,
`unless safety concerns require abrupt withdrawal.
`
` ADVERSE REACTIONS
`
`6
`The following adverse reactions are described in more detail in the Warnings and
`
`Precautions section of the label:
`
`
`• Urinary retention [see Warnings and Precautions (5.1)]
`
`• Neuro-psychiatric symptoms [see Warnings and Precautions (5.2)]
`
`
`
`
`• Dizziness and somnolence [see Warnings and Precautions (5.3)]
`
`
`• QT interval effect [see Warnings and Precautions (5.4)]
`
`• Suicidal behavior and ideation [see Warnings and Precautions (5.5)]
`
`
`
`• Withdrawal seizures [see Warnings and Precautions (5.6)]
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions and for varying
`durations, adverse reaction frequencies observed in the clinical trials of a drug cannot be directly
`compared with frequencies in the clinical trials of another drug and may not reflect the
`frequencies 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
`
`
`
`Reference ID: 2959210
`
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`
`
`Page 00006
`
`

`
`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%). In most cases the
`reactions were of mild or moderate intensity.
`
`Table 4. Adverse Reaction 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
`
`Eye
`Diplopia
` Blurred vision
`Gastrointestinal
`Nausea
`Constipation
`Dyspepsia
`General
`Fatigue
`Asthenia
`Infections and infestations
`Influenza
`Investigations
` Weight increased
`
`Nervous system
` Dizziness
` Somnolence
` Memory impairment
` Tremor
`Vertigo
` Abnormal coordination
` Disturbance in attention
`
`Placebo
`(N = 427)
`%
`
`2
`2
`
`5
`1
`2
`
`6
`2
`
`2
`
`1
`
`9
`12
`3
`3
`2
`3
`<1
`
`POTIGA
`600 mg/day 900 mg/day 1,200 mg/day
`(N = 281)
`(N = 273)
`(N = 259)
`%
`%
`%
`
`
`
`8
`6
`7
`2
`4
`10
`
`
`
`6
`6
`9
`1
`4
`5
`3
`2
`3
`
`
`
`16
`15
`13
`4
`6
`4
`
`
`
`4
`1
`5
`
`
`
`2
`3
`3
`
`
`
`15
`23
`32
`15
`25
`27
`3
`6
`9
`3
`10
`12
`8
`8
`9
`5
`5
`12
`6
`6
`7
`
`All
`(N = 813)
`%
`
`7
`5
`
`7
`3
`2
`
`15
`5
`
`3
`
`3
`
`23
`22
`6
`8
`8
`7
`6
`
`
`
`Reference ID: 2959210
`
`6
`
`Page 00007
`
`

`
` Gait disturbance
`Aphasia
`Dysarthria
` Balance disorder
`Paresthesia
` Amnesia
`Dysphasia
`Psychiatric
` Confusional state
`Anxiety
`Disorientation
`Psychotic disorder
`
`Renal and urinary
`Dysuria
` Urinary hesitation
` Hematuria
` Chromaturia
`
`1
`<1
`<1
`<1
`2
`<1
`<1
`
`3
`2
`<1
`0
`
`<1
`<1
`<1
`<1
`
`2
`1
`4
`3
`3
`<1
`1
`
`4
`3
`<1
`0
`
`1
`2
`2
`<1
`
`5
`3
`2
`3
`2
`3
`1
`
`8
`2
`<1
`<1
`
`2
`1
`1
`2
`
`6
`7
`8
`5
`5
`3
`3
`
`16
`5
`5
`2
`
`4
`4
`2
`3
`
`4
`4
`4
`4
`3
`2
`2
`
`9
`3
`2
`<1
`
`2
`2
`2
`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, 1.2, 1.6, and 2.7 kg in the placebo, 600-mg/day, 900-mg/day, and 1,200-mg/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 older than 65 years.
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`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
`Dose of
`Dose of
`Influence of
`Influence of
`POTIGA on
`AED
`POTIGA
`AED on
`
`(mg/day)
`(mg/day)
`AED
`POTIGA
`600­
`300-1,200
`None
`31% decrease
`2,400
`in AUC,
`23% decrease
`in Cmax
`
`
`AED
`Carbamazepinea,b
`
`Dosage Adjustment
`consider an increase
`in dosage of
`POTIGA when
`adding
`carbamazepinec
`
` consider an increase
`in dosage of
`
`POTIGA when
`adding phenytoinc
`
`
`Phenytoina,b
`
`120-600
`
`300-1,200
`
`None
`
`34% decrease
`in AUC,
`18% decrease
`in Cmax
`
`
`
`
`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 Digoxin
`Data from an in vitro study showed that the N-acetyl metabolite of ezogabine (NAMR)
`
`inhibited P-glycoprotein–mediated transport of digoxin in a concentration-dependent manner,
`indicating that NAMR may inhibit renal clearance of digoxin. Administration of POTIGA at
`therapeutic doses may increase digoxin serum concentrations. Serum levels of digoxin should be
`monitored [see Clinical Pharmacology (12.3)].
`
`7.3 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)].
`
`7.4
`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.
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
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`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, NAMR, similar to or below those expected in humans at the
`maximum recommended human dose (MRHD) of 1,200 mg/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.
`
`Labor and Delivery
`8.2
`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 to adults. In studies in which rats were dosed
`starting on postnatal day 7, ezogabine-related mortality, clinical signs of neurotoxicity, and renal
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`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/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)].
`
`
`
`DRUG ABUSE AND DEPENDENCE
`9
`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 [n = 33], 600 [n = 34], 900 mg [n =6]), the
`sedative-hypnotic alprazolam (1.5 and 3.0 mg), and placebo were administered. Euphoria-type
`
`subjective responses to the 300- 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, 600, 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 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 to 1,200 mg) reported euphoric
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`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.
`
`OVERDOSAGE
`10
`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 POTIGA overdose 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.
`
`DESCRIPTION
`11
`
`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, represe