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
" THESE REACTIONS OCCURRED IN PATIENTS WITH AND WITHOUT PRIOR PSYCHIATRIC HISTORY, PRIOR AGGRESSIVE BEHAVIOR, OR CONCOMITANT USE OF MEDICATIONS ASSOCIATED WITH HOSTILITY AND AGGRESSION
" 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
" CLOSELY MONITOR PATIENTS PARTICULARLY DURING THE TITRATION PERIOD AND AT HIGHER DOSES
" FYCOMPA SHOULD BE REDUCED IF THESE SYMPTOMS OCCUR AND SHOULD BE DISCONTINUED IMMEDIATELY IF SYMPTOMS ARE SEVERE OR ARE WORSENING
INDICATIONS
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.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
" 2 MG TABLETS: ORANGE, ROUND, DEBOSSED WITH "2" ON ONE SIDE AND "? 275" ON THE OTHER
" 4 MG TABLETS: RED, ROUND, DEBOSSED WITH "4" ON ONE SIDE AND "? 277" ON THE OTHER.
" 6 MG TABLETS: PINK, ROUND, DEBOSSED WITH "6" ON ONE SIDE AND "? 294" ON THE OTHER.
" 8 MG TABLETS: PURPLE, ROUND, DEBOSSED WITH "8" ON ONE SIDE AND "? 295" ON THE OTHER.
" 10 MG TABLETS: GREEN, ROUND, DEBOSSED WITH "10" ON ONE SIDE AND "? 296" ON THE OTHER.
" 12 MG TABLETS: BLUE, ROUND, DEBOSSED WITH "12" ON ONE SIDE AND "? 297" ON THE OTHER.
STORAGE AND HANDLING
FYCOMPA (PERAMPANEL) TABLETS 2 MG ARE ORANGE, ROUND, BICONVEX, FILM-COATED TABLETS DEBOSSED WITH "2" ON ONE SIDE AND "? 275" ON THE OTHER. THEY ARE SUPPLIED AS FOLLOWS:
BOTTLES OF 30 NDC 62856-272-30
BOTTLES OF 90 NDC 62856-272-90
FYCOMPA (PERAMPANEL) TABLETS 4 MG ARE RED, ROUND, BICONVEX, FILM-COATED TABLETS DEBOSSED WITH "4" ON ONE SIDE AND "? 277" ON THE OTHER. THEY ARE SUPPLIED AS FOLLOWS:
BOTTLES OF 30 NDC 62856-274-30
BOTTLES OF 90 NDC 62856-274-90
FYCOMPA (PERAMPANEL) TABLETS 6 MG ARE PINK, ROUND, BICONVEX, FILM-COATED TABLETS DEBOSSED WITH "6" ON ONE SIDE AND "? 294" ON THE OTHER. THEY ARE SUPPLIED AS FOLLOWS:
BOTTLES OF 30 NDC 62856-276-30
BOTTLES OF 90 NDC 62856-276-90
FYCOMPA (PERAMPANEL) TABLETS 8 MG ARE PURPLE, ROUND, BICONVEX, FILM-COATED TABLETS DEBOSSED WITH "8" ON ONE SIDE AND "? 295" ON THE OTHER. THEY ARE SUPPLIED AS FOLLOWS:
BOTTLES OF 30 NDC 62856-278-30
BOTTLES OF 90 NDC 62856-278-90
FYCOMPA (PERAMPANEL) TABLETS 10 MG ARE GREEN, ROUND, BICONVEX, FILM-COATED TABLETS DEBOSSED WITH "10" ON ONE SIDE AND "? 296" ON THE OTHER. THEY ARE SUPPLIED AS FOLLOWS:
BOTTLES OF 30 NDC 62856-280-30
BOTTLES OF 90 NDC 62856-280-90
FYCOMPA (PERAMPANEL) TABLETS 12 MG ARE BLUE, ROUND, BICONVEX, FILM-COATED TABLETS DEBOSSED WITH "12" ON ONE SIDE AND "? 297" ON THE OTHER. THEY ARE SUPPLIED AS FOLLOWS:
BOTTLES OF 30 NDC 62856-282-30
BOTTLES OF 90 NDC 62856-282-90
STORAGE
STORE AT 25°C (77°F); EXCURSIONS PERMITTED TO 15-30°C (59-86°F). [SEE USP CONTROLLED ROOM TEMPERATURE]
MANUFACTURED AND MARKETED BY EISAI INC., WOODCLIFF LAKE, NJ 07677. REVISED: FEBRUARY 2014
DOSAGE AND ADMINISTRATION
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].
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].
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.
DOSAGE ADJUSTMENTS IN PATIENTS WITH HEPATIC IMPAIRMENT
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, CLINICAL PHARMACOLOGY].
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, CLINICAL PHARMACOLOGY].
SIDE EFFECTS
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]
" SUICIDAL BEHAVIOR AND IDEATION [SEE WARNINGS AND PRECAUTIONS]
" DIZZINESS AND GAIT DISTURBANCE [SEE WARNINGS AND PRECAUTIONS]
" SOMNOLENCE AND FATIGUE [SEE WARNINGS AND PRECAUTIONS]
" FALLS [SEE WARNINGS AND PRECAUTIONS]
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.
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]. 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].
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 % FYCOMPA
4 MG
N=172 % 8 MG
N=431 % 12 MG
N=255 %
EAR AND LABYRINTH DISORDERS
VERTIGO 1 4 3 5
EYE DISORDERS
DIPLOPIA 1 1 1 3
BLURRED VISION 1 1 3 4
GASTROINTESTINAL DISORDERS
CONSTIPATION 2 2 2 3
NAUSEA 5 3 6 8
VOMITING 3 2 3 4
INFECTIONS AND INFESTATIONS
UPPER RESPIRATORY TRACT INFECTION 3 3 3 4
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
CONTUSION 1 0 2 2
FALLS 3 2 5 10
HEAD INJURY 1 1 1 3
LIMB INJURY < 1 1 1 2
SKIN LACERATION 1 0 2 2
INVESTIGATIONS
WEIGHT GAIN 1 4 4 4
METABOLISM & NUTRITION DISORDERS
HYPONATREMIA < 1 0 0 2
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
ARTHRALGIA 1 0 3 2
BACK PAIN 2 2 2 5
MUSCULOSKELETAL PAIN 1 1 1 2
MYALGIA 2 1 1 3
PAIN IN EXTREMITY 1 0 2 3
PERIPHERAL EDEMA 1 1 1 2
NERVOUS SYSTEM DISORDERS
ASTHENIA 1 1 2 2
ATAXIA 0 1 3 8
BALANCE DISORDER 1 0 5 3
COORDINATION ABNORMAL 0 1 < 1 2
DIZZINESS 9 16 32 43
DYSARTHRIA 0 1 3 4
FATIGUE 5 8 8 12
GAIT DISTURBANCE 1 1 4 4
HEADACHE 11 11 11 13
HYPERSOMNIA 0 1 2 3
HYPOAESTHESIA 1 0 0 3
MEMORY IMPAIRMENT 1 0 1 2
PARAESTHESIA 1 0 1 2
SOMNOLENCE 7 9 16 18
PSYCHIATRIC DISORDERS
AGGRESSION 1 1 2 3
ANGER < 1 0 1 3
ANXIETY 1 2 3 4
CONFUSIONAL STATE < 1 1 1 2
EUPHORIC MOOD 0 0 < 1 2
IRRITABILITY 3 4 7 12
MOOD ALTERED < 1 1 < 1 2
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
COUGH 3 1 1 4
OROPHARYNGEAL PAIN 1 2 2 2
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.
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.
READ THE FYCOMPA (PERAMPANEL TABLETS, FOR ORAL USE) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
SIGNS, SYMPTOMS, AND LABORATORY FINDINGS OF ACUTE OVERDOSE IN HUMANS
THERE IS LIMITED CLINICAL EXPERIENCE WITH FYCOMPA OVERDOSE. THE HIGHEST REPORTED OVERDOSE (APPROXIMATELY 264 MG) WAS INTENTIONAL. THIS PATIENT EXPERIENCED SERIOUS ADVERSE REACTIONS OF ALTERED MENTAL STATUS, AGITATION, AND AGGRESSIVE BEHAVIOR AND RECOVERED WITHOUT SEQUELAE. IN GENERAL, THE ADVERSE REACTIONS ASSOCIATED WITH OVERDOSES WERE SIMILAR TO THE REACTIONS AT THERAPEUTIC DOSES WITH DIZZINESS REPORTED MOST FREQUENTLY. THERE WERE NO REPORTED SEQUELAE.
TREATMENT OR MANAGEMENT OF OVERDOSE
THERE IS NO AVAILABLE SPECIFIC ANTIDOTE TO THE OVERDOSE REACTIONS OF FYCOMPA. 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 FYCOMPA. DUE TO ITS LONG HALF-LIFE, THE REACTIONS CAUSED BY FYCOMPA COULD BE PROLONGED.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
PERAMPANEL IS A NON-COMPETITIVE ANTAGONIST OF THE IONOTROPIC ?-AMINO-3-HYDROXY-5-METHYL-4ISOXAZOLEPROPIONIC ACID (AMPA) GLUTAMATE RECEPTOR ON POSTSYNAPTIC NEURONS. GLUTAMATE IS THE PRIMARY EXCITATORY NEUROTRANSMITTER IN THE CENTRAL NERVOUS SYSTEM AND IS IMPLICATED IN A NUMBER OF NEUROLOGICAL DISORDERS CAUSED BY NEURONAL OVER EXCITATION.
THE PRECISE MECHANISM BY WHICH FYCOMPA EXERTS ITS ANTIEPILEPTIC EFFECTS IN HUMANS HAS NOT BEEN FULLY ELUCIDATED.
PHARMACODYNAMICS
PSYCHOMOTOR PERFORMANCE
IN A HEALTHY VOLUNTEER STUDY TO ASSESS THE EFFECTS OF FYCOMPA ON PSYCHOMOTOR PERFORMANCE USING A STANDARD BATTERY OF ASSESSMENTS INCLUDING SIMULATED DRIVING, SINGLE AND MULTIPLE DAILY DOSES OF FYCOMPA 4 MG DID NOT IMPAIR SIMPLE PSYCHOMOTOR TASKS, DRIVING PERFORMANCE OR SENSORI-MOTOR COORDINATION. SINGLE AND MULTIPLE DOSES OF 8 MG AND 12 MG IMPAIRED PSYCHOMOTOR PERFORMANCE IN A DOSE-RELATED MANNER. CAR HANDLING ABILITY WAS IMPAIRED AFTER DOSING OF FYCOMPA 12 MG, BUT POSTURAL STABILITY WAS NOT SIGNIFICANTLY IMPAIRED. PERFORMANCE TESTING RETURNED TO BASELINE WITHIN 2 WEEKS OF CESSATION OF FYCOMPA DOSING.
INTERACTIONS WITH ALCOHOL
IN THE ABOVE STUDY (SEE PSYCHOMOTOR PERFORMANCE), WHEN ADMINISTERED TO HEALTHY SUBJECTS RECEIVING ALCOHOL TO ACHIEVE A BLOOD CONCENTRATION OF 80-100MG/100ML, FYCOMPA CONSISTENTLY IMPAIRED SIMPLE PSYCHOMOTOR PERFORMANCE AFTER SINGLE DOSES OF 4 TO 12 MG, AND AFTER 21 DAYS OF MULTIPLE 12 MG/DAY DOSES. THE EFFECTS OF FYCOMPA ON COMPLEX TASKS SUCH AS DRIVING ABILITY WERE ADDITIVE OR SUPRA-ADDITIVE TO THE IMPAIRMENT EFFECTS OF ALCOHOL. FYCOMPA ENHANCED THE EFFECTS OF ALCOHOL ON VIGILANCE AND ALERTNESS, AND INCREASED LEVELS OF ANGER, CONFUSION, AND DEPRESSION.
POTENTIAL TO PROLONG QT INTERVAL
IN A PLACEBO-CONTROLLED THOROUGH QT STUDY OF PERAMPANEL IN HEALTHY SUBJECTS, THERE WAS NO EVIDENCE THAT PERAMPANEL CAUSED QT INTERVAL PROLONGATION OF CLINICAL SIGNIFICANCE AT DOSES OF 6 OR 12 MG (I.E., THE UPPER BOUND OF THE 95% CONFIDENCE INTERVAL FOR THE LARGEST PLACEBO-ADJUSTED BASELINE-CORRECTED QTC WAS BELOW 10 MSEC). THE EXPOSURES OBSERVED WITH THE 12 MG DOSE IN THIS STUDY WILL NOT COVER THE EXPOSURES EXPECTED IN PATIENTS WITH HEPATIC IMPAIRMENT TAKING DOSES OVER 6 MG/DAY. AT THE MAXIMUM RECOMMENDED DOSE (12 MG), PERAMPANEL DID NOT PROLONG THE QTC INTERVAL TO ANY CLINICALLY RELEVANT EXTENT.
PHARMACOKINETICS
PHARMACOKINETICS OF PERAMPANEL ARE SIMILAR IN HEALTHY SUBJECTS AND PATIENTS WITH PARTIAL-ONSET SEIZURES. THE HALF-LIFE OF PERAMPANEL IS ABOUT 105 HOURS, SO THAT STEADY STATE IS REACHED IN ABOUT 2-3 WEEKS. AUC OF PERAMPANEL INCREASED IN A DOSE-PROPORTIONAL MANNER AFTER SINGLE-DOSE ADMINISTRATION OF 0.2-12 MG AND AFTER MULTIPLE-DOSE ADMINISTRATION OF 1-12 MG ONCE DAILY.
ABSORPTION
PERAMPANEL IS RAPIDLY AND COMPLETELY ABSORBED AFTER ORAL ADMINISTRATION WITH NEGLIGIBLE FIRST-PASS METABOLISM. MEDIAN TMAX RANGED FROM 0.5 TO 2.5 HOURS UNDER FASTED CONDITION. FOOD DOES NOT AFFECT THE EXTENT OF ABSORPTION (AUC), BUT SLOWS THE RATE OF ABSORPTION. UNDER FED CONDITIONS, CMAX OF PERAMPANEL WAS DECREASED BY 28-40% AND TMAX WAS DELAYED BY 2-3 HOURS COMPARED TO THAT UNDER FASTED CONDITIONS.
DISTRIBUTION
DATA FROM IN VITRO STUDIES INDICATE THAT, IN THE CONCENTRATION RANGE OF 20 TO 2000 NG/ML, PERAMPANEL IS APPROXIMATELY 95-96% BOUND TO PLASMA PROTEINS, MAINLY BOUND TO ALBUMIN AND ?1-ACID GLYCOPROTEIN. BLOOD TO PLASMA RATIO OF PERAMPANEL IS 0.55-0.59.
METABOLISM
PERAMPANEL IS EXTENSIVELY METABOLIZED VIA PRIMARY OXIDATION AND SEQUENTIAL GLUCURONIDATION. OXIDATIVE METABOLISM IS MEDIATED BY CYP3A4 AND/OR CYP3A5 BASED ON RESULTS OF IN VITRO STUDIES USING RECOMBINANT HUMAN CYPS AND HUMAN LIVER MICROSOMES. OTHER CYP ENZYMES MAY ALSO BE INVOLVED.
FOLLOWING ADMINISTRATION OF RADIOLABELED PERAMPANEL, UNCHANGED PERAMPANEL ACCOUNTED FOR 74-80% OF TOTAL RADIOACTIVITY IN SYSTEMIC CIRCULATION, WHEREAS ONLY TRACE AMOUNTS OF INDIVIDUAL PERAMPANEL METABOLITES WERE DETECTED IN PLASMA.
ELIMINATION
FOLLOWING ADMINISTRATION OF A RADIOLABELED PERAMPANEL DOSE TO 8 HEALTHY ELDERLY SUBJECTS, 22% OF ADMINISTERED RADIOACTIVITY WAS RECOVERED IN THE URINE AND 48% IN THE FECES. IN URINE AND FECES, RECOVERED RADIOACTIVITY WAS PRIMARILY COMPOSED OF A MIXTURE OF OXIDATIVE AND CONJUGATED METABOLITES. POPULATION PHARMACOKINETIC ANALYSIS OF POOLED DATA FROM 19 PHASE 1 STUDIES REPORTED THAT T½ OF PERAMPANEL WAS 105 HOURS ON AVERAGE. APPARENT CLEARANCE OF PERAMPANEL IN HEALTHY SUBJECTS AND PATIENTS WAS APPROXIMATELY 12 ML/MIN.
SPECIFIC POPULATIONS
HEPATIC IMPAIRMENT
THE PHARMACOKINETICS OF PERAMPANEL FOLLOWING A SINGLE 1 MG DOSE WERE EVALUATED IN 12 SUBJECTS WITH MILD AND MODERATE HEPATIC IMPAIRMENT (CHILD-PUGH A AND B, RESPECTIVELY) COMPARED WITH 12 DEMOGRAPHICALLY MATCHED HEALTHY SUBJECTS. THE TOTAL (FREE AND PROTEIN BOUND) EXPOSURE (AUC0-INF) OF PERAMPANEL WAS 50% GREATER IN SUBJECTS WITH MILD HEPATIC IMPAIRMENT AND MORE THAN DOUBLED (2.55-FOLD) IN SUBJECTS WITH MODERATE HEPATIC IMPAIRMENT COMPARED TO THEIR HEALTHY CONTROLS. THE AUC0-INF OF FREE PERAMPANEL IN SUBJECTS WITH MILD AND MODERATE HEPATIC IMPAIRMENT WAS 1.8-FOLD AND 3.3-FOLD, RESPECTIVELY, OF THOSE IN MATCHED HEALTHY CONTROLS. THE T½ WAS PROLONGED IN SUBJECTS WITH MILD IMPAIRMENT (306 VS. 125 HOURS) AND MODERATE IMPAIRMENT (295 VS. 139 HOURS). PERAMPANEL HAS NOT BEEN STUDIED IN SUBJECTS WITH SEVERE HEPATIC IMPAIRMENT [SEE DOSAGE AND ADMINISTRATION, USE IN SPECIFIC POPULATIONS].
RENAL IMPAIRMENT
A DEDICATED STUDY HAS NOT BEEN CONDUCTED TO EVALUATE THE PHARMACOKINETICS OF PERAMPANEL IN PATIENTS WITH RENAL IMPAIRMENT. POPULATION PHARMACOKINETIC ANALYSIS WAS PERFORMED ON POOLED DATA FROM PATIENTS WITH PARTIAL-ONSET SEIZURES AND RECEIVING FYCOMPA UP TO 12 MG/DAY IN PLACEBO-CONTROLLED CLINICAL TRIALS. RESULTS SHOWED THAT PERAMPANEL APPARENT CLEARANCE WAS DECREASED BY 27% IN PATIENTS WITH MILD RENAL IMPAIRMENT (CREATININE CLEARANCE 50-80 ML/MIN) COMPARED TO PATIENTS WITH NORMAL RENAL FUNCTION (CREATININE CLEARANCE > 80 ML/MIN), WITH A CORRESPONDING 37% INCREASE IN AUC. CONSIDERING THE SUBSTANTIAL OVERLAP IN THE EXPOSURE BETWEEN NORMAL AND MILDLY IMPAIRED PATIENTS, NO DOSAGE ADJUSTMENT IS NECESSARY FOR PATIENTS WITH MILD RENAL IMPAIRMENT. PERAMPANEL HAS NOT BEEN STUDIED IN PATIENTS WITH SEVERE RENAL IMPAIRMENT AND PATIENTS UNDERGOING HEMODIALYSIS [SEE DOSAGE AND ADMINISTRATION, USE IN SPECIFIC POPULATIONS].
SEX
IN A POPULATION PHARMACOKINETIC ANALYSIS OF PATIENTS WITH PARTIAL-ONSET SEIZURES RECEIVING FYCOMPA IN PLACEBO-CONTROLLED CLINICAL TRIALS, PERAMPANEL APPARENT CLEARANCE IN FEMALES (0.605 L/HR) WAS 17% LOWER THAN IN MALES (0.730 L/HR). NO DOSAGE ADJUSTMENT IS NECESSARY BASED ON SEX.
PEDIATRIC PATIENTS
FYCOMPA HAS NOT BEEN STUDIED IN PATIENTS < 12 YEARS OLD. IN A POPULATION PHARMACOKINETIC ANALYSIS OF PATIENTS WITH PARTIAL-ONSET SEIZURES RANGING IN AGE FROM 12 TO 74 YEARS RECEIVING FYCOMPA IN PLACEBO-CONTROLLED TRIALS, APPARENT CLEARANCE OF PERAMPANEL IN ADOLESCENTS (0.787 L/HR) WAS SLIGHTLY, BUT NOT SIGNIFICANTLY, HIGHER THAN THAT IN ADULTS. PEDIATRIC PATIENTS ABOVE 12 YEARS OLD CAN BE DOSED SIMILARLY TO ADULTS.
GERIATRICS
IN A POPULATION PHARMACOKINETIC ANALYSIS OF PATIENTS WITH PARTIAL-ONSET SEIZURES RANGING IN AGE FROM 12 TO 74 YEARS RECEIVING FYCOMPA IN PLACEBO-CONTROLLED TRIALS, NO SIGNIFICANT EFFECT OF AGE ON PERAMPANEL APPARENT CLEARANCE WAS FOUND [SEE DOSAGE AND ADMINISTRATION, USE IN SPECIFIC POPULATIONS].
RACE
IN A POPULATION PHARMACOKINETIC ANALYSIS OF PATIENTS WITH PARTIAL-ONSET SEIZURES WHICH INCLUDED 576 CAUCASIANS, 14 BLACKS, 97 NON-CHINESE ASIANS, AND 62 CHINESE RECEIVING FYCOMPA IN PLACEBO-CONTROLLED TRIALS, NO SIGNIFICANT EFFECT OF RACE ON PERAMPANEL APPARENT CLEARANCE WAS FOUND. NO DOSAGE ADJUSTMENT IS NECESSARY.
DRUG INTERACTION STUDIES
IN VITRO ASSESSMENT OF DRUG INTERACTIONS
DRUG METABOLIZING ENZYMES
IN HUMAN LIVER MICROSOMES, PERAMPANEL AT A CONCENTRATION OF 30 ?MOL/L, ABOUT 10 FOLD THE STEADY STATE CMAX AT A 12 MG DOSE, HAD A WEAK INHIBITORY EFFECT ON CYP2C8, CYP3A4, UGT1A9 AND UGT2B7. PERAMPANEL DID NOT INHIBIT CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A1, UGT1A4 AND UGT1A6 AT A CONCENTRATION OF 30 ?MOL/L.
COMPARED WITH POSITIVE CONTROLS (INCLUDING PHENOBARBITAL AND RIFAMPIN), PERAMPANEL WAS FOUND TO WEAKLY INDUCE CYP2B6 (30?MOL/L) AND CYP3A4/5 ( ? 3?MOL/L) IN CULTURED HUMAN HEPATOCYTES. PERAMPANEL ALSO INDUCED UGT1A1 ( ? 3?MOL/L) AND UGT1A4 (30?MOL/L). PERAMPANEL DID NOT INDUCE CYP1A2 AT CONCENTRATIONS UP TO 30 ?MOL/L.
TRANSPORTERS
IN VITRO STUDIES SHOWED THAT PERAMPANEL IS NOT A SUBSTRATE OR SIGNIFICANT INHIBITOR OF THE FOLLOWING: ORGANIC ANION TRANSPORTING POLYPEPTIDES 1B1 AND 1B3; ORGANIC ANION TRANSPORTERS 1, 2, 3, AND 4; ORGANIC CATION TRANSPORTERS 1, 2, AND 3; EFFLUX TRANSPORTERS P-GLYCOPROTEIN AND BREAST CANCER RESISTANCE PROTEIN.
IN VIVO ASSESSMENT OF DRUG INTERACTIONS
DRUG INTERACTIONS WITH AEDS
EFFECT OF CONCOMITANT AEDS ON FYCOMPA:
CARBAMAZEPINE. AS AN INDUCER OF CYP ENZYMES, CARBAMAZEPINE INCREASES PERAMPANEL CLEARANCE. STEADY STATE ADMINISTRATION OF CARBAMAZEPINE AT 300 MG BID IN HEALTHY SUBJECTS REDUCED THE CMAX AND AUC0-INF OF A SINGLE 2 MG DOSE OF PERAMPANEL BY 26% AND 67% RESPECTIVELY. THE T½ OF PERAMPANEL WAS SHORTENED FROM 56.8 HOURS TO 25 HOURS. IN CLINICAL STUDIES EXAMINING PARTIAL-ONSET SEIZURES, A POPULATION PHARMACOKINETIC ANALYSIS SHOWED THAT PERAMPANEL AUC WAS REDUCED BY 67% IN PATIENTS ON CARBAMAZEPINE COMPARED TO THE AUC IN PATIENTS NOT ON ENZYME-INDUCING AEDS [SEE DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
OXCARBAZEPINE. IN CLINICAL STUDIES EXAMINING PARTIAL-ONSET SEIZURES, A POPULATION PHARMACOKINETIC ANALYSIS SHOWED THAT PERAMPANEL AUC WAS REDUCED BY HALF IN PATIENTS ON OXCARBAZEPINE COMPARED TO PATIENTS NOT ON ENZYME-INDUCING AEDS [SEE DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
PHENYTOIN. IN CLINICAL STUDIES EXAMINING PARTIAL-ONSET SEIZURES, A POPULATION PHARMACOKINETIC ANALYSIS SHOWED THAT PERAMPANEL AUC WAS REDUCED BY HALF IN PATIENTS ON PHENYTOIN COMPARED TO PATIENTS NOT ON ENZYME-INDUCING AEDS [SEE DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
PHENOBARBITAL AND PRIMIDONE: IN A POPULATION PHARMACOKINETIC ANALYSIS OF PATIENTS WITH PARTIAL-ONSET SEIZURES IN CLINICAL TRIALS (37 PATIENTS COADMINISTERED PHENOBARBITAL AND 9 PATIENTS COADMINISTERED PRIMIDONE) NO SIGNIFICANT EFFECT ON PERAMPANEL AUC WAS FOUND. A MODEST EFFECT OF PHENOBARBITAL AND PRIMIDONE ON PERAMPANEL CONCENTRATIONS CANNOT BE EXCLUDED.
TOPIRAMATE: POPULATION PHARMACOKINETIC ANALYSIS OF PATIENTS WITH PARTIAL-ONSET SEIZURES IN CLINICAL TRIALS SHOWED THAT PERAMPANEL AUC WAS REDUCED BY APPROXIMATELY 20% IN PATIENTS ON TOPIRAMATE COMPARED TO PATIENTS NOT ON ENZYME-INDUCING AEDS.
OTHER AEDS: POPULATION PHARMACOKINETIC ANALYSIS OF PATIENTS WITH PARTIAL-ONSET SEIZURES IN CLINICAL TRIALS SHOWED THAT CLOBAZAM, CLONAZEPAM, LAMOTRIGINE, LEVETIRACETAM, VALPROATE, AND ZONISAMIDE DID NOT HAVE AN EFFECT ON PERAMPANEL CLEARANCE.
OTHER STRONG CYP3A INDUCERS (E.G., RIFAMPIN, ST. JOHN'S WORT) MAY ALSO GREATLY INCREASE CLEARANCE OF PERAMPANEL AND REDUCE PERAMPANEL PLASMA CONCENTRATIONS [SEE DRUG INTERACTIONS].
EFFECT OF FYCOMPA ON CONCOMITANT AEDS:
FYCOMPA UP TO 12 MG/DAY DID NOT SIGNIFICANTLY AFFECT THE CLEARANCE OF CLONAZEPAM, LEVETIRACETAM, PHENOBARBITAL, PHENYTOIN, TOPIRAMATE, OR ZONISAMIDE BASED ON A POPULATION PHARMACOKINETIC ANALYSIS OF PATIENTS WITH PARTIAL-ONSET SEIZURES IN CLINICAL TRIALS. FYCOMPA HAD A STATISTICALLY SIGNIFICANT EFFECT ON THE CLEARANCE OF CARBAMAZEPINE, CLOBAZAM, LAMOTRIGINE, AND VALPROIC ACID, BUT THE INCREASES IN CLEARANCE OF THESE DRUGS WERE EACH LESS THAN 10% AT THE HIGHEST PERAMPANEL DOSE EVALUATED (12 MG/DAY). FYCOMPA COADMINISTRATION RESULTED IN A 26% DECREASE IN OXCARBAZEPINE CLEARANCE AND INCREASED ITS CONCENTRATIONS. THE CONCENTRATIONS OF 10-MONOHYDROXY METABOLITE (MHD), THE ACTIVE METABOLITE OF OXCARBAZEPINE, WERE NOT MEASURED.
DRUG-DRUG INTERACTION STUDIES WITH OTHER DRUGS
EFFECT OF OTHER DRUGS ON FYCOMPA
KETOCONAZOLE. COADMINISTRATION OF SINGLE 1-MG DOSE OF PERAMPANEL WITH 400 MG ONCE DAILY DOSES OF KETOCONAZOLE, A STRONG CYP3A4 INHIBITOR, FOR 8 DAYS IN HEALTHY SUBJECTS PROLONGED PERAMPANEL T½ BY 15% (67.8 VS. 58.4 HOURS) AND INCREASED AUC0-INF BY 20%.
ORAL CONTRACEPTIVES. PERAMPANEL CMAX AND AUC0-72H WERE NOT ALTERED WHEN A SINGLE 6-MG DOSE OF PERAMPANEL WAS ADMINISTERED TO HEALTHY FEMALE SUBJECTS FOLLOWING A 21-DAY COURSE OF ORAL CONTRACEPTIVES CONTAINING ETHINYLESTRADIOL 30 ?G AND LEVONORGESTREL 150 ?G.
EFFECT OF FYCOMPA ON OTHER DRUGS
MIDAZOLAM. PERAMPANEL ADMINISTERED AS 6 MG ONCE DAILY DOSES FOR 20 DAYS DECREASED AUC0-INF AND CMAX OF MIDAZOLAM (A CYP3A4 SUBSTRATE) BY 13% AND 15%, RESPECTIVELY, IN HEALTHY SUBJECTS.
ORAL CONTRACEPTIVES. COADMINISTRATION OF PERAMPANEL 4 MG ONCE DAILY WITH AN ORAL CONTRACEPTIVE CONTAINING ETHINYLESTRADIOL 30 ?G AND LEVONORGESTREL 150 ?G FOR 21 DAYS DID NOT ALTER CMAX OR AUC0-24H OF EITHER ETHINYLESTRADIOL OR LEVONORGESTREL IN HEALTHY FEMALE SUBJECTS. IN ANOTHER STUDY, A SINGLE DOSE OF THE ORAL CONTRACEPTIVE WAS ADMINISTERED FOLLOWING 21-DAY ONCE DAILY DOSING OF FYCOMPA 12 MG OR 8 MG IN HEALTHY FEMALES. FYCOMPA AT 12 MG DID NOT ALTER AUC0-24H OF ETHINYLESTRADIOL BUT DECREASED ITS CMAX BY 18%, AND ALSO DECREASED CMAX AND AUC0-24H OF LEVONORGESTREL BY 42% AND 40%, RESPECTIVELY. FYCOMPA AT 8 MG DID NOT HAVE SIGNIFICANT EFFECT ON CMAX OR AUC0-24H OF EITHER ETHINYLESTRADIOL OR LEVONORGESTREL, WITH A SMALL DECREASE IN AUC0-24H OF LEVONORGESTREL (9%) [SEE DRUG INTERACTIONS].
LEVODOPA. PERAMPANEL ADMINISTERED AS 4 MG ONCE DAILY DOSES FOR 19 DAYS HAD NO EFFECT ON CMAX AND AUC0-INF OF LEVODOPA IN HEALTHY SUBJECTS.
CLINICAL STUDIES
THE EFFICACY OF FYCOMPA IN PARTIAL-ONSET SEIZURES, WITH OR WITHOUT SECONDARY GENERALIZATION, WAS STUDIED IN PATIENTS WHO WERE NOT ADEQUATELY CONTROLLED WITH 1 TO 3 CONCOMITANT AEDS IN 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER TRIALS (STUDIES 1, 2, AND 3) IN ADULT AND ADOLESCENT PATIENTS (AGED 12 YEARS AND OLDER). ALL TRIALS HAD AN INITIAL 6 WEEK BASELINE PERIOD, DURING WHICH PATIENTS WERE REQUIRED TO HAVE MORE THAN FIVE SEIZURES IN ORDER TO BE RANDOMIZED. THE BASELINE PERIOD WAS FOLLOWED BY A 19 WEEK TREATMENT PERIOD CONSISTING OF A 6 WEEK TITRATION PHASE AND A 13 WEEK MAINTENANCE PHASE. PATIENTS IN THESE 3 TRIALS HAD A MEAN DURATION OF EPILEPSY OF APPROXIMATELY 21 YEARS AND A MEDIAN BASELINE SEIZURE FREQUENCY RANGING FROM 9.3 TO 14.3 SEIZURES PER 28 DAYS. DURING THE TRIALS, MORE THAN 85% OF PATIENTS WERE TAKING 2 TO 3 CONCOMITANT AEDS WITH OR WITHOUT CONCURRENT VAGAL NERVE STIMULATION, AND APPROXIMATELY 50% WERE ON AT LEAST ONE AED KNOWN TO INDUCE CYP3A4, AN ENZYME CRITICAL TO THE METABOLISM OF FYCOMPA (I.E., CARBAMAZEPINE, OXCARBAZEPINE, OR PHENYTOIN), RESULTING IN A SIGNIFICANT REDUCTION IN FYCOMPA'S SERUM CONCENTRATION [SEE DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
EACH STUDY EVALUATED PLACEBO AND MULTIPLE FYCOMPA DOSAGES (SEE FIGURE 1). DURING THE TITRATION PERIOD IN ALL 3 TRIALS, PATIENTS ON FYCOMPA RECEIVED AN INITIAL 2 MG ONCE DAILY DOSE, WHICH WAS SUBSEQUENTLY INCREASED IN WEEKLY INCREMENTS OF 2 MG PER DAY TO THE FINAL TARGET DOSE. PATIENTS EXPERIENCING INTOLERABLE ADVERSE REACTIONS WERE PERMITTED TO HAVE THEIR DOSE REDUCED TO THE PREVIOUSLY TOLERATED DOSE.
THE PRIMARY ENDPOINT IN STUDIES 1, 2, AND 3 WAS THE PERCENT CHANGE IN SEIZURE FREQUENCY PER 28 DAYS DURING THE TREATMENT PERIOD AS COMPARED TO THE BASELINE PERIOD. THE CRITERION FOR STATISTICAL SIGNIFICANCE WAS P < 0.05. TABLE 3 SHOWS THE RESULTS OF THESE STUDIES. A STATISTICALLY SIGNIFICANT DECREASE IN SEIZURE RATE WAS OBSERVED AT DOSES OF 4 TO 12 MG PER DAY. DOSE RESPONSE WAS APPARENT AT 4 TO 8 MG WITH LITTLE ADDITIONAL REDUCTION IN FREQUENCY AT 12 MG PER DAY.
TABLE 3: MEDIAN TREATMENT DIFFERENCE (DRUG - PLACEBO) OF THE PERCENT REDUCTION FROM BASELINE DURING THE 19 WEEK TREATMENT PERIOD.
DOSAGE GROUP N MEDIAN BASELINE FREQUENCY (PER 28 DAYS) MEDIAN TREATMENT EFFECT (DRUG-PLACEBO) P VALUE
STUDY 1
8 MG/DAY 133 14.3 -13.50% 0.0261
12 MG/DAY 133 12 -14.20% 0.0158
STUDY 2
8 MG/DAY 129 13 -19.10% 0.0008
12 MG/DAY 121 13.7 -13.70% 0.0105
STUDY 3
2 MG/DAY 180 10.1 -4.40% 0.4197
4 MG/DAY 172 10 -13.70% 0.0026
8 MG/DAY 169 10.9 -20.10% < 0.0001
TABLE 4 PRESENTS AN ANALYSIS COMBINING DATA FROM ALL 3 STUDIES, GROUPING PATIENTS BASED UPON WHETHER OR NOT CONCOMITANT AED INDUCERS (CARBAMAZEPINE, OXCARBAZEPINE, OR PHENYTOIN) WERE USED. THE ANALYSIS REVEALED A SUBSTANTIALLY REDUCED EFFECT IN THE PRESENCE OF INDUCERS.
TABLE 4: MEDIAN TREATMENT EFFECT (DRUG - PLACEBO) FOR COMBINED STUDIES (STUDY 1, 2 AND 3) BASED ON THE PRESENCE OR ABSENCE OF CONCOMITANT FYCOMPA INDUCING AEDS (CARBAMAZEPINE, OXCARBAZEPINE, PHENYTOIN)A
MEDIAN PERCENT REDUCTION FROM PLACEBO RESPONDER RATEB (DRUG - PLACEBO)
WITHOUT INDUCERS WITH INDUCERS WITHOUT INDUCERS WITH INDUCERS
2 MG/DAY 8.20% 0.50% 6.30% 1.90%
4 MG/DAY 15.30% 11.90% 15.40% 8.10%
8 MG/DAY 25.70% 14.40% 28.20% 13.00%
12 MG/DAY 33.20% 19.20% 39.30% 12.30%
A PATIENTS FROM LATIN AMERICAN REGION ARE EXCLUDED BECAUSE OF A SIGNIFICANT TREATMENT-BY-REGION INTERACTION DUE TO HIGH PLACEBO RESPONSE.
B THE PROPORTION OF PATIENTS WITH AT LEAST A 50% DECREASE IN SEIZURE FREQUENCY
FIGURE 1 SHOWS THE PROPORTION OF PATIENTS WITH DIFFERENT PERCENT REDUCTIONS DURING THE MAINTENANCE PHASE OVER BASELINE ACROSS ALL THREE TRIALS. PATIENTS IN WHOM THE SEIZURE FREQUENCY INCREASED ARE SHOWN AT LEFT AS "WORSE." PATIENTS IN WHOM THE SEIZURE FREQUENCY DECREASED ARE SHOWN IN THE REMAINING FIVE CATEGORIES. THUS, THE PERCENTAGES OF PATIENTS WITH A 40 TO < 60% REDUCTION IN SEIZURE FREQUENCY WERE 13.2%, 17.4%, 19.0%, AND 15.8% FOR PLACEBO, 4, 8, AND 12 MG, RESPECTIVELY.
FIGURE 1: PROPORTION OF PATIENTS EXHIBITING DIFFERENT PERCENT REDUCTIONS DURING THE MAINTENANCE PHASE OVER BASELINE ACROSS ALL THREE TRIALS.
THE PERCENTAGES OF PATIENTS WITH A 50% OR GREATER REDUCTION IN SEIZURE FREQUENCY WERE 19.3%, 28.5%, 35.3%, 35.0% FOR PLACEBO, 4, 8, AND 12 MG, RESPECTIVELY.