----------------------------------CONTRAINDICATIONS-----------------------
`None (4)
`-----------------------WARNINGS AND PRECAUTIONS---------------------
`
` Suicidal Behavior and Ideation: Monitor for suicidal thoughts or
`
`
`behavior (5.2)
`
`
` Neurologic Effects: Monitor for dizziness, gait disturbance, somnolence,
`
`
`and fatigue (5.3)
`
`
`Patients should use caution when driving or operating machinery (5.3)
`
` Falls: Monitor for falls and injuries (5.4)
`
`
` Withdrawal of Antiepileptic Drugs: In patients with epilepsy, there may
`
`be an increase in seizure frequency (5.5)
`-----------------------------ADVERSE REACTIONS-----------------------------
`
`Most common adverse reactions (≥4% and ≥1% higher than placebo)
`include dizziness, somnolence, fatigue, irritability, falls, nausea, weight
`
`gain, vertigo, ataxia, gait disturbance, and balance disorder. (6.1)
`
`------------------------------DRUG INTERACTONS-----------------------------
`
` Contraceptives: 12 mg once daily dose may decrease the effectiveness
`
`
`of hormonal contraceptives containing levonorgestrel (7.1)
`
`Inducers: Carbamazepine, oxcarbazepine and
` Cytochrome P450
`phenytoin increase clearance of perampanel and decrease perampanel
`
`plasma concentrations and decrease FYCOMPA’s effectiveness. There
`is insufficient information to describe dose adjustments that can fully
`correct for this. Phenobarbital and primidone may also decrease
`
`perampanel concentrations. When these enzyme-inducing AEDs are
`introduced or withdrawn, patients should be closely monitored. Dose
`
`
`adjustment of FYCOMPA may be necessary (7.2)
`
`
` Strong CYP3A Inducers Other than AEDs: (e.g., rifampin, St. John’s
`
`
`wort) should be avoided (7.2)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eisai at 1-
`
`or
`contact
`888-274-2378
`or
`FDA
`at
`1-800-FDA-1088
`www.fda.gov/medwatch.
`----------------------USE IN SPECIFIC POPULATIONS----------------------
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`Medication Guide.
`
`
`
`
` Revised: October 2012
`
`
`
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Patients with Hepatic Impairment
`8.7 Patients with Renal Impairment
`
`
`9. DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`
`10. OVERDOSAGE
`
`
`10.1 Signs, Symptoms, and Laboratory Findings of Acute Overdose in
`
`
`
`Humans
`
`10.2 Treatment or 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
`16.1 How Supplied
`16.2 Storage
`17. PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 1
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`FYCOMPA™ safely and effectively. See full prescribing information for
`
`FYCOMPA.
`FYCOMPA (perampanel) tablets, for oral use
`Initial U.S. Approval: 2012
`
`
`WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS
`
`See full prescribing information for complete boxed warning.
`
`
`
` Serious or life-threatening psychiatric and behavioral adverse reactions
`
`including aggression, hostility, irritability, anger, and homicidal ideation
`and threats have been reported in patients taking FYCOMPA (5.1)
`
`
` Monitor patients for these reactions as well as for changes in mood,
`
`behavior, or personality that are not typical for the patient, particularly
`during the titration period and at higher doses (5.1)
`
`
`
` FYCOMPA should be reduced if these symptoms occur and should be
`
`discontinued immediately if symptoms are severe or are worsening (5.1)
`
`
`------------------------------INDICATIONS AND USAGE--------------------------------
`FYCOMPA, a non-competitive AMPA glutamate receptor antagonist, is indicated as
`
`
`adjunctive therapy for the treatment of partial-onset seizures with or without
`
`secondarily generalized seizures in patients with epilepsy aged 12 years and older (1)
`--------------------------DOSAGE AND ADMINISTRATION---------------------------
`
`
` Starting dose is 2 mg once daily at bedtime in patients not on enzyme-inducing
`
`anti-epileptic drugs and 4 mg in patients on enzyme-inducing AEDs (2.1)
`
`
`
`
` May increase based on clinical response and tolerability by a maximum of 2 mg
`once daily at bedtime in weekly increments to a dose of 4 mg to 12 mg once
`
`
`
`daily at bedtime. Dose increases should occur no more frequently than at weekly
`intervals (2.1)
`
` Maximum recommended daily dose is 12 mg once daily at bedtime (2.1)
`
`
` Elderly patients: Maximum frequency for dosage increases is every two weeks.
`
`
` Patients with Mild and Moderate Hepatic Impairment: Maximum recommended
`
`daily dose is 6 mg and 4 mg once daily at bedtime for patients with mild and
`
`
`
`
`moderate hepatic impairment, respectively. Maximum frequency for dosage
`increases is every two weeks (2.2)
`
` Patients with Severe Hepatic Impairment: Not recommended (2.2)
`
`
`
`
` Patients with Severe Renal Impairment or on hemodialysis: Not recommended
`
`(2.3)
`-----------------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`
`Tablets: 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg (3)
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL
`
`REACTIONS
`1.
`INDICATIONS AND USAGE
`
`2. DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`2.2 Dosage Adjustments in Patients with Hepatic Impairment
`2.3 Patients with Renal Impairment
`3. DOSAGE FORMS AND STRENGTHS
`4. CONTRAINDICATIONS
`5. WARNINGS AND PRECAUTIONS
`5.1 Psychiatric and Behavioral Reactions
`5.2 Suicidal Behavior and Ideation
`5.3 Neurologic Effects
`5.4 Falls
`
`5.5 Withdrawal of Antiepileptic Drugs
`
`6. ADVERSE REACTIONS
`
`6.1 Clinical Trial Experience
`
`7. DRUG INTERACTIONS
`7.1 Contraceptives
`
`7.2 Cytochrome P450(CYP) Inducers
`
`7.3 Alcohol and Other CNS Depressants
`
`8. USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3206660
`
`ARGENTUM Exhibit 1212
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, inc.
`IPR2016-00204
`
`Page 00001
`
`

`
`17.8 Missed Doses
`17.9 Pregnancy Registry
`
`* Sections or subsections omitted from the Full Prescribing Information are
`
`not listed.
`
`
`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 2
`
`
`17.1 Serious Psychiatric and Behavioral Reactions
`17.2 Suicidal Thinking and Behavior
`
`17.3 Neurologic Effects: Dizziness, Gait Disturbance, Somnolence, and
`
`Fatigue
`17.4 Falls
`17.5 Withdrawal of Antiepileptic Drugs
`17.6 Contraceptives
`17.7 Alcohol and Other CNS Depressants
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS
`
`
`
` Serious or life-threatening psychiatric and behavioral adverse reactions including aggression,
`hostility, irritability, anger, and homicidal ideation and threats have been reported in patients
`taking FYCOMPA (5.1)
` These reactions occurred in patients with and without prior psychiatric history, prior aggressive
`behavior, or concomitant use of medications associated with hostility and aggression (5.1)
` Advise patients and caregivers to contact a healthcare provider immediately if any of these
`reactions or changes in mood, behavior, or personality that are not typical for the patient are
`observed while taking FYCOMPA or after discontinuing FYCOMPA (5.1)
` Closely monitor patients particularly during the titration period and at higher doses (5.1)
` FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately
`if symptoms are severe or are worsening (5.1)
`
`
`1 INDICATIONS AND USAGE
`FYCOMPA (perampanel) is indicated as adjunctive therapy for the treatment of partial-onset seizures
`with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Information
`
`In the Absence of Enzyme-Inducing AEDs
`The recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase
`
`dosage by 2 mg per day increments no more frequently than every week to a dose of 4 mg to 8 mg once
`
`
`daily taken at bedtime. In elderly patients, dosage increases during titration are recommended no more
`frequently than every two weeks.
`
`The recommended dose range is 8 mg to 12 mg once daily. A dose of 12 mg once daily resulted in
`
`somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial
`increase in adverse reactions. Individual dosing should be adjusted based on clinical response and
`
`tolerability [see Clinical Studies (14)].
`
`
`
`In the Presence of Enzyme-Inducing AEDs
`
`The recommended starting dosage of FYCOMPA in the presence of enzyme-inducing AEDs, including
`
`phenytoin, carbamazepine, and oxcarbazepine, is 4 mg and patients should be monitored closely for
`
`response. Clinical trials revealed a substantially reduced effect on seizure rates in these patients. The
`reduction in seizure frequency was somewhat greater at 12 mg than at 8 mg [see Clinical Studies (14)].
`
`
`
`When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen,
`
`
`patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA
`
`may be necessary.
`
`
`2.2 Dosage Adjustments in Patients with Hepatic Impairment
`
`Reference ID: 3206660
`
`Page 00002
`
`

`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 3
`
`Based on higher exposure and the longer half-life of perampanel in patients with mild and moderate
`hepatic impairment, dosage adjustment is recommended. Starting dose should be 2 mg per day with
`weekly increments of 2 mg per day every two weeks until target dose is achieved. The maximum
`recommended daily dose is 6 mg for patients with mild hepatic impairment and 4 mg for patients with
`moderate hepatic impairment. Dose increases in patients with mild and moderate hepatic impairment, as
`with all patients, should be based on clinical response and tolerability. Use in patients with severe hepatic
`impairment is not recommended [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`
`
`2.3 Patients with Renal Impairment
`FYCOMPA can be used in patients with moderate renal impairment with close monitoring. A slower
`titration may be considered based on clinical response and tolerability. Use in patients with severe renal
`
`impairment or patients undergoing hemodialysis is not recommended [see Use in Specific Populations
`(8.7), Clinical Pharmacology (12.3)].
`
`
`3 DOSAGE FORMS AND STRENGTHS
` 2 mg Tablets: orange, round, debossed with “2” on one side and “Є 275” on the other
` 4 mg Tablets: red, round, debossed with “4” on one side and “Є 277” on the other.
` 6 mg Tablets: pink, round, debossed with “6” on one side and “Є 294” on the other.
` 8 mg Tablets: purple, round, debossed with “8” on one side and “Є 295” on the other.
` 10 mg Tablets: green, round, debossed with “10” on one side and “Є 296” on the other.
` 12 mg Tablets: blue, round, debossed with “12” on one side and “Є 297” on the other.
`
`
`
`
`
`4 CONTRAINDICATIONS
`None.
`
`
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Serious Psychiatric and Behavioral Reactions
`In the controlled Phase 3 epilepsy clinical trials, hostility- and aggression- related adverse reactions
`
`occurred in 12% and 20% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day,
`
`respectively, compared to 6% of patients in the placebo group. These effects were dose-related and
`
`generally appeared within the first 6 weeks of treatment, although new events continued to be observed
`through more than 37 weeks. FYCOMPA-treated patients experienced more hostility- and aggression-
`related adverse reactions that were serious, severe, and led to dose reduction, interruption, and
`discontinuation more frequently than placebo-treated patients.
`
`In general, in placebo-controlled Phase 3 epilepsy trials, neuropsychiatric events were reported more
`frequently in patients being treated with FYCOMPA than in patients taking placebo. These events
`
`included irritability, aggression, anger, and anxiety which occurred in 2% or greater of perampanel treated
`
`patients and twice as frequently as in placebo-treated patients. Other symptoms that were observed with
`perampanel treatment and more commonly than with placebo, included belligerence, affect lability,
`
`agitation, and physical assault. Some of these events were reported as serious and life-threatening. Three
`
`patients out of 4,368 perampanel-treated patients exhibited homicidal ideation or threat in controlled and
`open-label studies, including non-epilepsy studies.
`
`In the Phase 3 epilepsy trials these events occurred in patients with and without prior psychiatric history,
`
`prior aggressive behavior, or concomitant use of medications associated with hostility and aggression.
`Some patients experienced worsening of their pre-existing psychiatric conditions. Patients with active
`
`psychotic disorders and unstable recurrent affective disorders were excluded from the clinical trials. The
`combination of alcohol and perampanel significantly worsened mood and increased anger [see Drug
`Interactions (7.3)]. Patients taking FYCOMPA should avoid the use of alcohol.
`
`
`
`
`
`
`
`
`Reference ID: 3206660
`
`Page 00003
`
`

`
`
`
`
`
`
`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 4
`
`
`
`
`In healthy volunteers taking FYCOMPA, observed psychiatric events included paranoia, euphoric mood,
`
`agitation, anger, mental status changes, and disorientation/confusional state.
`
`
`In the non-epilepsy trials, psychiatric events that occurred in perampanel-treated subjects more often than
`
`placebo-treated subjects included disorientation, delusion, and paranoia.
`
`
`Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of
`psychiatric events. Patients should be monitored during treatment and for at least one month after the last
`dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug
`therapy (titration period) or at other times of dose increases. Dose of FYCOMPA should be reduced if
`
`these symptoms occur. Permanently discontinue FYCOMPA for persistent severe or worsening
`psychiatric symptoms or behaviors and refer for psychiatric evaluation.
`
`
`5.2 Suicidal Behavior and Ideation
`Antiepileptic drugs (AEDs), including FYCOMPA, 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% 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 one case of suicidal thinking
`or behavior for every 530 patients treated. There were four 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 one week after
`starting drug 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 mechanisms 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 (5-100 years) in the clinical trials analyzed.
`
`
`
`
`
`Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
`
`Reference ID: 3206660
`
`Page 00004
`
`

`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 5
`
`
`
`The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical
`trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and
`psychiatric indications.
`
`Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts
`or behavior 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.
`
`5.3 Neurologic Effects
`Dizziness and Gait Disturbance
`FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or
`coordination [see Adverse Reactions (6.1)]. In the controlled Phase 3 epilepsy clinical trials, dizziness
`
`and vertigo were reported in 35% and 47% of patients randomized to receive FYCOMPA at doses of 8
`
`mg and 12 mg/day, respectively, compared to 10% of placebo-treated patients. The gait disturbance
`related events (including ataxia, gait disturbance, balance disorder, and coordination abnormal) were
`reported in 12% and 16% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day,
`respectively, compared to 2% of placebo-treated patients.
`
`
`
`These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3% of
`
`perampanel-treated subjects compared to 1% of placebo-treated patients. Elderly patients had an
`increased risk of these adverse reactions compared to younger adults and adolescents.
`
`Somnolence and Fatigue
`FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events (including fatigue,
`
`asthenia, and lethargy).
`
`In the controlled Phase 3 epilepsy clinical trials, 16% and 18% of patients randomized to receive
`FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported somnolence compared to 7% of
`
`
`
`
`
`Reference ID: 3206660
`
`Table 1. Risk by indication for antiepileptic drugs in the pooled analysis
`Indication
`Placebo Patients
`Drug Patients
`Relative Risk:
`Risk Difference:
`
`Additional Drug
`with Events per
`Incidence of
`with Events per
`1000 patients
`Events in drug
`Patients with
`1000 Patients
`Patients/
`Events per 1000
`Incidence in
`Patients
`Placebo Patients
`3.5
`1.5
`1.9
`1.8
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`2.4
`2.9
`0.9
`1.9
`
`Page 00005
`
`

`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 6
`
` placebo patients. In the controlled Phase 3 epilepsy clinical trials, 12% and 15% of patients randomized
`
`
`to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported fatigue-related events
`
` compared to 5% of placebo patients. Somnolence or fatigue-related events led to discontinuation in 2%
`of perampanel-treated patients and 0.5% of placebo-treated patients. Elderly patients had an increased risk
`of these adverse reactions compared to younger adults and adolescents.
`
`Risk Amelioration
`
`Prescribers should advise patients against engaging in hazardous activities requiring mental alertness,
`such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known.
`
`
`
`In the controlled Phase 3 epilepsy clinical trials these adverse reactions occurred mostly during the
`titration phase.
`
`5.4 Falls
`An increased risk of falls, in some cases leading to serious injuries including head injuries and bone
`fracture, occurred in patients being treated with FYCOMPA (with and without concurrent seizures). In
`the controlled Phase 3 epilepsy clinical trials, falls were reported in 5% and 10% of patients randomized
`
`to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 3% of placebo-treated
`patients. Falls were reported as serious and led to discontinuation more frequently in FYCOMPA-treated
`
`
`patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger
`adults and adolescents.
`
`5.5 Withdrawal of Antiepileptic Drugs
`There is the potential of increased seizure frequency in patients with seizure disorders when anti-epileptic
`drugs are withdrawn abruptly. FYCOMPA has a half-life of approximately 105 hours so that even after
`abrupt cessation, blood levels fall gradually. In anti-epileptic clinical trials FYCOMPA was withdrawn
`without down-titration. Although a small number of patients exhibited seizures following discontinuation,
`
`the data were not sufficient to allow any recommendations regarding appropriate withdrawal regimens. A
`gradual withdrawal is generally recommended with anti-epileptic drugs, but if withdrawal is a response to
`adverse events, prompt withdrawal can be considered.
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed in more detail in other sections of the prescribing
`information:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Serious Psychiatric and Behavioral Reactions[see Warnings and Precautions (5.1)]
`
` Suicidal Behavior and Ideation [see Warnings and Precautions (5.2)]
`
`
` Dizziness and Gait Disturbance [see Warnings and Precautions (5.3)]
`
`
` Somnolence and Fatigue [see Warnings and Precautions (5.3)]
`
`
` Falls [see Warnings and Precautions (5.4)]
`
`
`
`6.1 Clinical Trial 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 to rates in the clinical trials of another drug and
`
`may not reflect the rates observed in clinical practice.
`
`
`A total of 1,038 patients on perampanel (2, 4, 8, or 12 mg once daily) constituted the safety population in
`the pooled analysis of Phase 3 placebo controlled studies (Studies 1, 2, and 3) in patients with partial
`
`onset seizures. Approximately 51% of patients were female and the mean age was 35 years.
`
`
`
`
`Reference ID: 3206660
`
`Page 00006
`
`

`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 7
`
` Adverse Reactions Leading to Discontinuation
`
`In controlled Phase 3 clinical trials (Studies 1, 2, and 3), the rate of discontinuation as a result of an
`adverse reaction was 3%, 8% and 19% in patients randomized to receive FYCOMPA at the recommended
`doses of 4 mg, 8 mg and 12 mg/day, respectively, and 5% in patients randomized to receive placebo [see
`Clinical Studies (14)]. The adverse events most commonly leading to discontinuation (≥1% in the 8 mg or
`
`12 mg FYCOMPA group and greater than placebo) were dizziness, somnolence, vertigo, aggression,
`anger, ataxia, blurred vision, irritability, and dysarthria [see Warnings and Precautions (5.1 and 5.3)].
`
`
`
`
`Most Common Adverse Reactions
`
`Table 2 gives the incidence in the Phase 3 controlled trials (Studies 1, 2, and 3) of the adverse reactions
`that occurred in ≥2% of patients with partial-onset seizures in any FYCOMPA dose group. Overall, the
`most frequently reported dose-related adverse reactions in patients receiving FYCOMPA at doses of 8 mg
`or 12 mg (≥4% and occurring at least 1% higher than the placebo group) included dizziness (36%),
`somnolence (16%), fatigue (10%), irritability (9%), falls (7%), nausea (7%), ataxia (5%), balance disorder
`
`(4%), gait disturbance (4%), vertigo (4%), and weight gain (4%). For almost every adverse reaction, rates
`
`were higher on 12 mg and more often led to dose reduction or discontinuation.
`
`Table 2 Adverse Reactions in Pooled Double-blind Trials in Patients with Partial-Onset Seizures
`(Reactions ≥ 2% of Patients in Highest FYCOMPA Dose (12 mg) Group and More Frequent than
`
`Placebo)
`
`
`Placebo
`n=442
`
`%
`
`
`1
`
`1
`1
`
`2
`5
`3
`
`3
`
`
`1
`3
`1
`<1
`1
`
`1
`
`<1
`
`1
`2
`1
`
`4 mg
`n=172
`
`%
`
`4
`
`1
`1
`
`2
`3
`2
`
`3
`
`
`0
`2
`1
`1
`0
`
`4
`
`0
`
`0
`2
`1
`
`
`Ear and Labyrinth Disorders
`
`Vertigo
`
`Eye Disorders
`
`
`Diplopia
`
` Blurred vision
`Gastrointestinal Disorders
`
` Constipation
`
`Nausea
`
`Vomiting
`
`Infections and Infestations
`
`Upper respiratory tract infection
`Injury, Poisoning and Procedural
`
`Complications
` Contusion
`
` Falls
` Head injury
` Limb injury
` Skin laceration
`
`Investigations
`
` Weight gain
`
`Metabolism & Nutrition disorders
` Hyponatremia
`
`Musculoskeletal and Connective Tissue
`disorders
` Arthralgia
` Back pain
`
` Musculoskeletal pain
`
`
`
`
`
`Reference ID: 3206660
`
`
`
`
`
`FYCOMPA
`8 mg
`
`n=431
`
`%
`
`3
`
`1
`3
`
`2
`6
`3
`
`3
`
`
`2
`5
`1
`1
`2
`
`4
`
`0
`
`3
`2
`1
`
`12 mg
`
`n=255
`
`%
`
`5
`
`3
`4
`
`3
`8
`4
`
`4
`
`
`2
`10
`3
`2
`2
`
`4
`
`2
`
`
`2
`5
`2
`
`Page 00007
`
`

`
`2
`
`1
`1
`
`1
`0
`1
`0
`9
`0
`5
`1
`11
`0
`1
`1
`1
`7
`
`1
`<1
`1
`<1
`0
`
`3
`<1
`
`3
`1
`
`1
`
`0
`1
`
`1
`1
`0
`1
`16
`1
`8
`1
`11
`1
`0
`0
`0
`9
`
`1
`0
`2
`1
`0
`
`4
`1
`
`1
`2
`
`3
`
`3
`2
`
`2
`8
`3
`2
`43
`4
`12
`4
`13
`3
`3
`2
`2
`18
`
`3
`3
`4
`2
`2
`12
`2
`
`4
`2
`
`
`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 8
`
` Myalgia
` Pain in extremity
` Peripheral edema
`Nervous system disorders
`
` Asthenia
`
` Ataxia
` Balance disorder
`
` Coordination abnormal
` Dizziness
`
` Dysarthria
` Fatigue
`
` Gait disturbance
` Headache
` Hypersomnia
`
` Hypoaesthesia
`
` Memory impairment
`
` Paraesthesia
` Somnolence
`Psychiatric disorders
`
` Aggression
` Anger
`
` Anxiety
` Confusional state
` Euphoric mood
` Irritability
`
` Mood altered
`Respiratory, Thoracic and Mediastinal
`Disorders
` Cough
`
` Oropharyngeal pain
`
` Weight Gain
`
`Weight gain has been observed with FYCOMPA use in adults.
`
`In the controlled Phase 3 epilepsy clinical trials, FYCOMPA-treated adults gained an average of 1.1 kg
`
`(2.5 lbs) compared to an average of 0.3 kg (0.7 lbs) in placebo-treated adults with a median exposure of
`19 weeks. The percentages of adults who gained at least 7% and 15% of their baseline body weight in
`FYCOMPA-treated patients were 9.1% and 0.9%, respectively, as compared to 4.5% and 0.2% of
`placebo-treated patients, respectively.
`
`
`1
`
`2
`1
`
`2
`3
`5
`<1
`32
`3
`8
`4
`11
`2
`0
`1
`1
`16
`
`2
`1
`3
`1
`<1
`
`7
`<1
`
`1
`2
`
`
`
`Clinical monitoring of weight is recommended.
`
`Comparison of Sex and Race
`
`No significant sex differences were noted in the incidence of adverse reactions.
`
`
`
`Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions
`compared to Caucasian patients were observed.
`
`7 DRUG INTERACTIONS
`7.1 Contraceptives
`With concomitant use, FYCOMPA at a dose of 12 mg/day reduced levonorgestrel exposure by
`
`approximately 40% [see Clinical Pharmacology (12.3)]. Use of FYCOMPA with oral or implant
`
`
`Reference ID: 3206660
`
`Page 00008
`
`

`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 9
`
`contraceptives containing levonorgestrel may render them less effective. Additional non-hormonal forms
`of contraception are recommended.
`
`
`
`7.2 Cytochrome P450 (CYP) Inducers
`The concomitant use of known CYP enzyme inducers including carbamazepine, phenytoin, or
`
`
`oxcarbazepine with FYCOMPA decreased the plasma levels of perampanel by approximately 50~67%
`[see Clinical Pharmacology (12.3)]. The starting doses for FYCOMPA should be increased in the
`presence of enzyme-inducing AEDs [see Dosage and Administration (2.1)].
`
`
`
`When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen,
`
`patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA
`
`
`may be necessary. As noted, however, the decrease in the therapeutic effect seen in patients on
`concomitant treatment, was not affected by use of higher doses (8 mg to 12 mg) [see Dosage and
`Administration (2.1)].
`
`
`Concomitant use of FYCOMPA with other strong CYP3A inducers (e.g., rifampin, St. John’s wort)
`
`should be avoided.
`
`
`
`7.3 Alcohol and Other CNS Depressants
`The concomitant use of FYCOMPA and CNS depressants including alcohol may increase CNS
`
`depression. A pharmacodynamic interaction study in healthy subjects found that the effects of
`
`
`
`FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment
`effects of alcohol [see Clinical Pharmacology (12.3)]. Multiple dosing of FYCOMPA 12 mg/day also
`
`
`enhanced the effects of alcohol to interfere with vigilance and alertness, and increased levels of anger,
`confusion, and depression. These effects may also be seen when FYCOMPA is used in combination with
`
`other CNS depressants. Care should be taken when administering FYCOMPA with these agents. Patients
`should limit activity until they have experience with concomitant use of CNS depressants (e.g.
`benzodiazepines, narcotics, barbiturates, sedating antihistamines). Advise patients not to drive or operate
`machinery until they have gained sufficient experience on FYCOMPA to gauge whether it adversely
`affects these activities.
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C
`There are no adequate and well-controlled studies in pregnant women. In animal studies, perampanel
`induced developmental toxicity in pregnant rat and rabbit at clinically relevant doses. FYCOMPA should
`
`be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rats throughout organogenesis
`resulted in an increase in visceral abnormalities (diverticulum of the intestine) at all doses tested. In a
`dose-ranging study at higher oral doses (10, 30, or 60 mg/kg/day), embryo lethality and reduced fetal
`body weight were observed at the mid and high doses tested. The lowest dose tested (1 mg/kg/day) is
`similar to a human dose of 8 mg/day based on body surface area (mg/m2).
`
`Upon oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rabbits throughout
`organogenesis, embryo lethality was observed at the mid and high doses tested; the no effect dose for
`embryo-fetal developmental toxicity in rabbit (1 mg/kg/day) is approximately 2 times a human dose of 8
`mg/day based on body surface area (mg/m2).
`
`
`
`
`
`
`Reference ID: 3206660
`
`Page 00009
`
`

`
`NDA 202834
`FDA Approved Labeling Text dated 10/22/2012
`
`Page 10
`
` Oral administration of perampanel (1, 3, or 10 mg/kg/day) to rats throughout gestation and lactation
`
`resulted in fetal and pup deaths at the mid and high doses and delayed sexual maturation in males and
`females at the highest dose tested. No effects were observed on measures of neurobehavioral or
`reproductive function in the offspring. The no-effect dose for pre- and postnatal developmental toxicity
`
`in rat (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m2).
`
`Pregnancy Registry
`To provide information regarding the effects of in utero exposure to FYCOMPA, physicians are advised
`
`to recommend that pregnant patients taking FYCOMPA enroll in the North American Antiepileptic Drug
`(NAAED) Pregnancy Registry. This ca