cause of a potential for reduced efficacy of these drugs, increase the dosage of lamotrigine or carbamazepine, as needed, when used concomitantly with xcopri. carbamazepine ↓ plasma concentrations phenytoin ↑ plasma concentrations because of a potential 2-fold increase in phenytoin levels, gradually decrease phenytoin dosage by up to 50% as xcopri is being titrated. phenobarbital ↑ plasma concentrations because of a potential for an increase in the risk of adverse reactions from these drugs, consider a reduction in dosage of phenobarbital or clobazam, as clinically appropriate, when used concomitantly with xcopri. desmethylclobazam, the active metabolite of clobazam ↑ plasma concentrations cyp2b6 substrates ↓ plasma concentrations because of a potential for reduced efficacy of these drugs, increase the dosage of cyp2b6 or cyp3a4 substrates, as needed, when used concomitantly with xcopri. cyp3a substrates ↓ plasma concentrations oral contraceptives ↓ plasma concentrations because of the potential for reduced efficacy of oral contraceptives, women should use additional or alternative non-hormonal birth control while taking xcopri. cyp2c19 substrates ↑ plasma concentrations because of a potential for an increase in the risk of adverse reactions from these drugs, consider a reduction in dosage of cyp2c19 substrates, as clinically appropriate, when used concomitantly with xcopri. 7.2 drug that shorten the qt interval xcopri can shorten the qt interval; therefore, caution should be used when administering xcopri and other drugs that shorten the qt interval [see warnings and precautions ( 5.2 ) and clinical pharmacology ( 12.2 )]. 7.3 cns depressants and alcohol concomitant use of xcopri with other cns depressants, including alcohol, may increase the risk of neurological adverse reactions, including sedation and somnolence [see warnings and precautions ( 5.4 )] .

aking xcopri. dress has occurred, including one fatality, when xcopri was titrated rapidly (weekly or faster titration). no cases of dress were reported in an open-label safety study of 1339 partial-onset seizure patients when xcopri was initiated at 12.5 mg once daily and titrated every two weeks. this finding does not establish that the risk of dress is prevented by a slower titration; however, xcopri should be initiated at 12.5 mg once daily and titrated every two weeks [see dosage and administration ( 2.2 )] . dress typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. eosinophilia is often present. this disorder is variable in its expression, and other organ systems not noted here may be involved. it is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. if such signs or symptoms are present, the patient should be evaluated immediately. xcopri should be discontinued immediately and not restarted if an alternative etiology for the signs or symptoms cannot be established [see contraindications ( 4 )] . 5.2 qt shortening in a placebo-controlled study of the qt interval, a higher percentage of subjects who took xcopri (31% at 200 mg and 66% at 500 mg) had a qt shortening of greater than 20 msec compared to placebo (6-17%). reductions of the qtc interval below 300 msec were not observed [see clinical pharmacology ( 12.2 )] . familial short qt syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. such events in this syndrome are believed to occur primarily when the corrected qt interval falls below 300 msec. nonclinical data also indicate that qt shortening is associated with ventricular fibrillation. patients with familial short qt syndrome should not be treated with xcopri [see contraindications ( 4 )] . caution should be used when administering xcopri and other drugs that shorten the qt interval as there may be a synergistic effect on the qt interval that would increase the qt shortening risk. 5.3 suicidal behavior and ideation antiepileptic drugs (aeds), including xcopri, 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 rate 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 3 shows absolute and relative risk by indication for all evaluated aeds. table 3: risk of suicidal thoughts or behaviors by indication for antiepileptic drugs in the pooled analysis indication placebo patients with events per 1000 patients drug patients with events per 1000 patients relative risk: incidence of events in drug patients/incidence in placebo patients risk differences: additional drug patients with events per 1000 patients epilepsy 1.0 3.4 3.5 2.4 psychiatric 5.7 8.5 1.5 2.9 other 1.0 1.8 1.9 0.9 total 2.4 4.3 1.8 1.9 the relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications. anyone considering prescribing xcopri 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. 5.4 neurological adverse reactions somnolence and fatigue xcopri causes dose-dependent increases in somnolence and fatigue-related adverse reactions (somnolence, fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy) [see adverse reactions ( 6.1 )] . in study 1 and study 2, 31% of patients randomized to receive xcopri at 100 mg/day, 36% of patients randomized to receive xcopri at 200 mg/day, and 57% of patients randomized to receive xcopri at 400 mg/day reported at least one of these adverse reactions, compared to 19% of patients who received placebo. somnolence and fatigue-related adverse reactions were serious in 0.4% of xcopri-treated patients compared to no patients who received placebo and led to discontinuation in 2% of xcopri-treated patients compared to 1% of patients who received placebo. dizziness and disturbance in gait and coordination xcopri causes dose-dependent adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, and abnormal coordination) [see adverse reactions ( 6.1 )] . in study 1 and study 2, 21% of patients randomized to receive xcopri at 100 mg/day, 31% of patients randomized to receive xcopri at 200 mg/day, and 52% of patients randomized to receive xcopri at 400 mg/day reported at least one of these adverse reactions, compared to 18% of patients who received placebo. dizziness and disturbance in gait and coordination adverse reactions were serious in 2% of xcopri-treated patients compared to no patients who received placebo and led to discontinuation in 5% of xcopri-treated patients compared to 1% of patients who received placebo. cognitive dysfunction xcopri causes adverse reactions related to cognitive dysfunction related-events (i.e., memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, and psychomotor retardation) [see adverse reactions ( 6.1 )] . in study 1 and study 2, 6% of patients randomized to receive xcopri at 100 mg/day, 6% of patients randomized to receive xcopri at 200 mg/day, and 9% of patients randomized to receive xcopri at 400 mg/day reported at least one of these adverse reactions, compared to 2% of patients who received placebo. no cognitive dysfunction-related events were serious in xcopri-treated patients or in patients who received placebo. cognitive dysfunction related adverse reactions led to discontinuation in 0.4% of xcopri-treated patients compared to no patients who received placebo. visual changes xcopri causes adverse reactions related to visual changes including diplopia, blurred vision, and impaired vision [see adverse reactions ( 6.1 )] . in study 1 and study 2, 9% of patients randomized to receive xcopri at 100 mg/day, 9% of patients randomized to receive xcopri at 200 mg/day, and 18% of patients randomized to receive xcopri at 400 mg/day reported at least one of these adverse reactions, compared to 2% of patients who received placebo. no visual change-related events were serious in xcopri-treated patients or in patients who received placebo. visual change led to discontinuation in 0.5% of xcopri-treated patients compared to no patients who received placebo. 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 xcopri is known. patients should be carefully observed for signs of central nervous system (cns) depression, such as somnolence and sedation, when xcopri is used with other drugs with sedative properties because of potential additive effects. 5.5 withdrawal of antiepileptic drugs as with most antiepileptic drugs, xcopri should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see dosage and administration ( 2.4 ) and clinical studies ( 14 )] . but if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

week 1 and 2 12.5 mg once daily titration regimen week 3 and 4 25 mg once daily week 5 and 6 50 mg once daily week 7 and 8 100 mg once daily week 9 and 10 150 mg once daily maintenance dosage week 11 and thereafter 200 mg once daily maximum dosage if needed based on clinical response and tolerability, dose may be increased above 200 mg by increments of 50 mg once daily every two weeks to 400 mg. 400 mg once daily 2.3 dosage modifications in patients with hepatic impairment for patients with mild to moderate (5-9 points on child-pugh assessment) hepatic impairment, the maximum recommended dosage is 200 mg once daily [see use in specific populations ( 8.7 )] . xcopri is not recommended for use in patients with severe hepatic impairment [see clinical pharmacology ( 12.3 )] . 2.4 discontinuation of xcopri if xcopri is discontinued, the dosage should be gradually reduced over a period of at least 2 weeks, unless safety concerns require abrupt withdrawal [see warnings and precautions ( 5.1 , 5.5 )] .

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. in all controlled and uncontrolled trials performed in adult partial-onset seizure patients, xcopri was administered as adjunctive therapy to 1944 patients. of these patients, 1575 were treated for at least 6 months, 710 for at least 12 months, 349 for at least 24 months, and 320 for at least 36 months. a total of 658 patients (442 patients treated with xcopri and 216 patients treated with placebo) constituted the safety population in the pooled analysis of placebo-controlled studies in patients with partial-onset seizures (studies 1 and 2) [see clinical studies ( 14 )] . the adverse reactions presented in table 4 are based on this safety population; the median length of treatment in these studies was 18 weeks. of the patients in those studies, approximately 49% were male, 76% were caucasian, and the mean age was 39 years. in study 1 and study 2, adverse events occurred in 77% of patients treated with xcopri and 68% treated with placebo. table 4 gives the incidence of adverse reactions that occurred in subjects with partial-onset seizures in any xcopri treatment group and for which the incidence was greater than placebo during the controlled clinical trials. the most common adverse reactions that occurred in xcopri-treated patients (incidence at least 10% and greater than placebo) were somnolence, dizziness, fatigue, diplopia, and headache. the discontinuation rates because of adverse events were 11%, 9%, and 21% for patients randomized to receive xcopri at doses of 100 mg/day, 200 mg/day, and 400 mg/day, respectively, compared to 4% in patients randomized to receive placebo. the adverse reactions most commonly (1% or greater in any xcopri treatment group, and greater than placebo) leading to discontinuation, in descending order of frequency, were ataxia, dizziness, somnolence, diplopia, nystagmus, and vertigo. table 4: adverse reactions in pooled placebo-controlled adjunctive therapy studies in patients with partial-onset seizures with xcopri frequency in any treatment arm greater than 1% over placebo * reported as an adverse reaction; see laboratory abnormalities for alt changes from collected laboratory values adverse reaction xcopri placebo 100mg 200mg 400mg n = 108 % n= 223 % n=111 % n=216 % cardiac disorders palpitations 0 0 2 0 ear and labyrinth disorders vertigo 1 1 6 1 eye disorders diplopia 6 7 15 2 vision blurred 2 2 4 0 gastrointestinal disorders nausea 6 6 9 3 constipation 2 4 8 0 diarrhea 1 3 5 0 vomiting 2 4 5 0 dry mouth 1 1 3 0 abdominal pain 2 2 1 0 dyspepsia 2 2 0 0 infections and infestations nasopharyngitis 2 4 5 3 pharyngitis 1 2 0 0 urinary tract infection 2 5 0 2 injury, poisoning and procedural complications head injury 1 0 2 0 investigations alanine aminotransferase increased* 1 1 4 0 aspartate aminotransferase increased 1 1 3 0 weight decreased 2 0 1 0 metabolism and nutrition disorders decreased appetite 3 1 5 1 musculoskeletal and connective tissue disorders back pain 4 2 5 3 musculoskeletal chest pain 2 1 0 0 nervous system disorders somnolence 19 22 37 11 dizziness 18 22 33 15 fatigue 12 14 24 7 headache 10 12 10 9 balance disorder 3 5 9 1 gait disturbance 1 3 8 1 dysarthria 2 1 7 0 nystagmus 3 7 6 0 ataxia 2 3 6 2 aphasia 2 1 4 0 asthenia 0 1 3 1 dysgeusia 2 0 2 0 memory impairment 2 1 2 0 migraine 0 0 2 0 sedation 1 1 2 0 tremor 0 3 1 1 psychiatric disorders confusional state 2 2 3 0 euphoric mood 0 0 2 0 irritability 1 0 2 0 suicidal ideation 2 1 0 0 renal and urinary disorders pollakiuria 0 1 0 0 reproductive system and breast disorders dysmenorrhea 1 2 1 0 respiratory, thoracic and mediastinal disorders hiccups 0 1 1 0 dyspnea 0 3 0 0 skin and subcutaneous tissue disorders pruritus 2 1 0 0 rash papular 2 0 0 0 laboratory abnormalities hepatic transaminases in study 2, there was a post-baseline elevation of alanine aminotransferase (alt) to greater than 3 times the upper limit of normal (uln) in 1 (0.9%) patient treated with 100 mg xcopri, 2 (1.8%) patients treated with 200 mg, and 3 (2.7%) patients treated with 400 mg, compared to no patients who took placebo. the maximum alt elevation was 7.6 times uln in patients treated with 400 mg xcopri. potassium in clinical studies, there was a post-baseline elevation of potassium values greater than 5 meq/l (upper reference range) in patients treated with xcopri. in study 1, there were 17 (17%) patients treated with xcopri 200 mg compared to 8 (7%) patients who took placebo with normal baseline potassium values who had at least one post-baseline maximum value greater than 5 meq/l. in study 2, there was a dose-related distribution where at least one post-baseline potassium value was greater than 5 meq/l, occurring in 8.3%, 9.1%, and 10.8% of the patients treated with xcopri 100 mg, 200 mg, and 400 mg, respectively, compared to 5.6% of patients who took placebo. two patients had a maximum potassium value of 5.9 meq/l. other adverse reactions gastrointestinal disorders: there was an incidence of appendicitis in the overall clinical trial safety population of 2.9 cases of appendicitis/1000 patient-years of exposure that is in excess of the expected background rate in the general population. adverse reactions based on gender no significant gender differences were noted in the incidence of adverse reactions. 6.2 postmarketing experience the following adverse reactions have been identified during post approval use of xcopri. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. psychiatric disorders: psychosis (hallucinations, delusions/paranoia), hostility, aggression.

cause of a potential for reduced efficacy of these drugs, increase the dosage of lamotrigine or carbamazepine, as needed, when used concomitantly with xcopri. carbamazepine ↓ plasma concentrations phenytoin ↑ plasma concentrations because of a potential 2-fold increase in phenytoin levels, gradually decrease phenytoin dosage by up to 50% as xcopri is being titrated. phenobarbital ↑ plasma concentrations because of a potential for an increase in the risk of adverse reactions from these drugs, consider a reduction in dosage of phenobarbital or clobazam, as clinically appropriate, when used concomitantly with xcopri. desmethylclobazam, the active metabolite of clobazam ↑ plasma concentrations cyp2b6 substrates ↓ plasma concentrations because of a potential for reduced efficacy of these drugs, increase the dosage of cyp2b6 or cyp3a4 substrates, as needed, when used concomitantly with xcopri. cyp3a substrates ↓ plasma concentrations oral contraceptives ↓ plasma concentrations because of the potential for reduced efficacy of oral contraceptives, women should use additional or alternative non-hormonal birth control while taking xcopri. cyp2c19 substrates ↑ plasma concentrations because of a potential for an increase in the risk of adverse reactions from these drugs, consider a reduction in dosage of cyp2c19 substrates, as clinically appropriate, when used concomitantly with xcopri. 7.2 drug that shorten the qt interval xcopri can shorten the qt interval; therefore, caution should be used when administering xcopri and other drugs that shorten the qt interval [see warnings and precautions ( 5.2 ) and clinical pharmacology ( 12.2 )]. 7.3 cns depressants and alcohol concomitant use of xcopri with other cns depressants, including alcohol, may increase the risk of neurological adverse reactions, including sedation and somnolence [see warnings and precautions ( 5.4 )] .

r visiting http://www.aedpregnancyregistry.org/. risk summary there are no adequate data on the developmental risk associated with the use of xcopri in pregnant women. in animal studies, administration of cenobamate during pregnancy or throughout pregnancy and lactation resulted in adverse effects on development (increased embryofetal mortality, decreased fetal and offspring body weights, neurobehavioral and reproductive impairment in offspring) at clinically relevant drug exposures [see data ] . in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. data animal data oral administration of cenobamate (0, 10, 30, or 60 mg/kg/day) to pregnant rats during the period of organogenesis resulted in increased embryofetal mortality, reduced fetal body weights, and incomplete fetal skeletal ossification at the highest dose tested, which was associated with maternal toxicity. there was a small increase in visceral malformations at the high dose; however, teratogenic potential could not be fully evaluated because of the high rate of embryofetal deaths, which resulted in an inadequate number of fetuses examined. maternal plasma exposure (auc) at the no-effect dose for adverse effects on embryofetal development (30 mg/kg/day) was less than that in humans at the maximum recommended human dose (mrhd) of 400 mg. oral administration of cenobamate (0, 4, 12, or 36 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality at the highest dose tested, which was associated with maternal toxicity. maternal plasma exposure at the no-effect dose (12 mg/kg/day) for adverse effects on embryofetal development was less than that in humans at the mrhd. when cenobamate (0, 11, 22, or 44 mg/kg/day) was orally administered to female rats throughout pregnancy and lactation, neurobehavioral impairment (learning and memory deficit and increased auditory startle response) was observed in the offspring at all doses and decreased preweaning body weight gain and adverse effects on reproductive function (decreased numbers of corpora lutea, implantations, and live fetuses) were seen in the offspring at the high dose. maternal plasma exposure at the lowest effect dose (11 mg/kg/day) for adverse effects on pre- and postnatal development was less than that in humans at the mrhd. 8.2 lactation risk summary there are no data available on the presence of cenobamate in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. cenobamate was present in rat milk at concentrations similar to those in maternal plasma. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for xcopri and any potential adverse effects on the breastfed infant from xcopri or from the underlying maternal condition. 8.3 females and males of reproductive potential contraception women of reproductive potential concomitantly using oral contraceptives should use additional or alternative non-hormonal birth control [see drug interactions ( 7.1 ) and clinical pharmacology ( 12.3 )] . 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. juvenile animal toxicity data cenobamate was administered orally to juvenile rats from postnatal day (pnd) 7 to 70. to maintain consistent plasma drug exposures, doses were increased during the dosing period, up to 120 and 80 mg/kg/day in males and females, respectively. adverse effects included mortality, delayed sexual maturation, neurological (decreased grip strength) and neurobehavioral (learning and memory deficits) impairment, decreased sperm count, decreased brain weight, and ocular histopathology. recovery from these effects was observed following discontinuation of dosing. overall, a no-effect dose for adverse effects on postnatal development was not identified. at the lowest doses tested, plasma cenobamate exposures (auc) were less than that in humans at the maximum recommended human dose (mrhd) of 400 mg. 8.5 geriatric use clinical studies of xcopri did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of xcopri in the elderly population. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see clinical pharmacology ( 12.3 )] . 8.6 renal impairment xcopri should be used with caution and dosage reduction may be considered in patients with mild to moderate (clcr 30 to less than 90 ml/min) and severe (clcr less than 30 ml/min) renal impairment. use in patients with end-stage renal disease undergoing dialysis is not recommended [see clinical pharmacology ( 12.3 )] . 8.7 hepatic impairment xcopri should be used with caution and in patients with mild to moderate (5-9 points on child-pugh assessment; class a or b) hepatic impairment. in these patients, the maximum recommended dosage is 200 mg once daily and additional dosage reduction may be considered [see dosage and administration ( 2.3 ) and clinical pharmacology ( 12.3 )] . use of xcopri in patients with severe hepatic impairment is not recommended.

ized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. data animal data oral administration of cenobamate (0, 10, 30, or 60 mg/kg/day) to pregnant rats during the period of organogenesis resulted in increased embryofetal mortality, reduced fetal body weights, and incomplete fetal skeletal ossification at the highest dose tested, which was associated with maternal toxicity. there was a small increase in visceral malformations at the high dose; however, teratogenic potential could not be fully evaluated because of the high rate of embryofetal deaths, which resulted in an inadequate number of fetuses examined. maternal plasma exposure (auc) at the no-effect dose for adverse effects on embryofetal development (30 mg/kg/day) was less than that in humans at the maximum recommended human dose (mrhd) of 400 mg. oral administration of cenobamate (0, 4, 12, or 36 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality at the highest dose tested, which was associated with maternal toxicity. maternal plasma exposure at the no-effect dose (12 mg/kg/day) for adverse effects on embryofetal development was less than that in humans at the mrhd. when cenobamate (0, 11, 22, or 44 mg/kg/day) was orally administered to female rats throughout pregnancy and lactation, neurobehavioral impairment (learning and memory deficit and increased auditory startle response) was observed in the offspring at all doses and decreased preweaning body weight gain and adverse effects on reproductive function (decreased numbers of corpora lutea, implantations, and live fetuses) were seen in the offspring at the high dose. maternal plasma exposure at the lowest effect dose (11 mg/kg/day) for adverse effects on pre- and postnatal development was less than that in humans at the mrhd.

] msec for 200 mg once daily and -18 [-22, -15] msec for 500 mg once daily (1.25 times the maximum recommended dosage). a higher percentage of xcopri-treated subjects (31% at 200 mg and 66% at 500 mg) had a qt shortening of greater than 20 msec compared to placebo (6-17%). reductions of the qtc interval below 300 msec were not observed. 12.3 pharmacokinetics cenobamate auc increases in a greater than dose-proportional manner following single oral doses from 5 to 750 mg (0.0125 to 1.88 times the maximum recommended dosage). cenobamate c max increases in a dose proportional manner. steady-state plasma concentrations are attained after approximately two weeks of once daily dosing. the pharmacokinetics of cenobamate are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures, except plasma cenobamate multiple-dose exposure (c max , auc) decreased with co-administration of phenytoin by 27-28%. absorption at least 88% of xcopri is absorbed following oral administration, with median t max ranging from 1 to 4 hours. effect of food no clinically significant differences in cenobamate pharmacokinetics were observed following administration of a high-fat meal (800-1000 calories with 50% fat). distribution the apparent volume of distribution (vd/f) of cenobamate after oral administration of xcopri is approximately 40-50 l. plasma protein binding of cenobamate is 60% and independent of concentration in vitro . cenobamate primarily binds with human albumin protein. elimination the apparent terminal half-life of cenobamate is 50-60 hours and apparent oral clearance is approximately 0.45-0.63 l/hour over a dose range from 100 mg/day to 400 mg/day. metabolism cenobamate is extensively metabolized. the primary metabolic pathways are by glucuronidation via ugt2b7 and to a lesser extent by ugt2b4, and by oxidation via cyp2e1, cyp2a6, cyp2b6, and to a lesser extent by cyp2c19 and cyp3a4/5. following administration of radiolabeled cenobamate, unchanged cenobamate accounted for greater than 98% of the total auc of radioactivity in plasma. unchanged cenobamate accounted for 6.8% of the dose which was mainly excreted in the urine (6.4%). excretion following administration of radiolabeled cenobamate, a mean of 93.0% of the total radioactive dose was recovered in urine (87.8%) and feces (5.2%). more than 50% of the radioactivity was excreted within 72 hours of dosing. specific populations no clinically significant differences in the pharmacokinetics of cenobamate were observed based on age based on data from subjects age 18 years to 77 years, sex, or race/ethnicity based on data from subjects categorized as asian, black, caucasian, hispanic, or other. patients with renal impairment cenobamate plasma auc was 1.4 fold to 1.5 fold higher in subjects with mild (clcr 60 to less than 90 ml/min) and moderate (clcr 30 to less than 60 ml/min) following a single oral 200 mg dose of xcopri compared to healthy controls. in subjects with severe (clcr less than 30 ml/min) renal impairment, cenobamate plasma auc did not change significantly compared to healthy controls following single oral 100 mg dose of xcopri [see use in specific populations ( 8.6 )] . the effect of hemodialysis on cenobamate pharmacokinetics has not been studied. patients with hepatic impairment cenobamate plasma auc was 2.1-fold and 2.3-fold higher in subjects with mild (5-6 points on child-pugh assessment) and moderate (7-9 points on child-pugh assessment) hepatic impairment, respectively, following a single oral 200 mg dose of xcopri compared to matched healthy controls [see dosage and administration ( 2.3 ) and use in specific populations ( 8.7 )] .the effect of severe hepatic impairment on cenobamate pharmacokinetics has not been studied. drug interaction studies clinical studies alcohol no clinically significant pharmacokinetic differences were observed for either cenobamate or alcohol when administered concomitantly. aeds multiple doses of concomitant xcopri 200 mg once daily increased phenytoin mean c max and auc by 70% and 84%, respectively, and phenobarbital mean c max and auc by 34% and 37%, respectively [see drug interactions ( 7.1 )] . multiple doses of concomitant xcopri 200 mg once daily decreased carbamazepine mean c max and auc each by 23% [see drug interactions ( 7.1 ] . no clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with cenobamate: valproic acid, levetiracetam or lacosamide. based on population pk analyses, during treatment within the 100-400 mg/day xcopri dose range, lamotrigine concentrations are expected to decrease by 21-52% [see drug interactions ( 7.1 )] ; and levetiracetam concentrations are expected to decrease by 4-13%, which is not expected to be clinically significant. in subjects treated with xcopri in study 1 and study 2, there was no clear relationship between efficacy and concomitant oxcarbazepine use. as such, the efficacy data from study 1 and study 2 do not support the existence of a clinically relevant interaction perpetrated by xcopri against oxcarbazepine. cyp substrates multiple doses of concomitant xcopri 200 mg once daily decreased total bupropion (cyp2b6 substrate) mean c max and auc by 23% and 39%, respectively, and decreased midazolam (cyp3a substrate) mean c max and auc by 61% and 72%, respectively [see drug interactions ( 7.1 )] . multiple doses of concomitant xcopri 200 mg once daily increased the omeprazole (cyp2c19 substrate) mean c max and auc by 83% and 107%, respectively [see drug interactions ( 7.1 )] . no clinically significant differences in the pharmacokinetics of warfarin (cyp2c9 substrate) were observed when used concomitantly with cenobamate. the effects of concomitant aeds on cenobamate pk plasma cenobamate multiple-dose exposure (c max , auc) decreased with co-administration of phenytoin by 27-28%. however, repeated dosing of valproate, phenobarbital, and carbamazepine did not have any significant impact on plasma cenobamate multiple-dose exposure. in vitro studies cyp enzymes cenobamate inhibits cyp2b6, cyp2c19, and cyp3a, but cenobamate does not inhibit cyp1a2, cyp2c8, cyp2c9, or cyp2d6. cenobamate induces cyp2b6, cyp2c8, and cyp3a4, but cenobamate does not induce cyp1a2, cyp2c9, or cyp2c19. transporters systems cenobamate was not a substrate of p-gp, bcrp, oat1, oat3, oct2, mate1, or mate2-k, and cenobamate did not inhibit p-gp, oat1, oct1, oct2, oatp1b3, bsep, oat3, or oatp1b1.

on of xcopri is approximately 40-50 l. plasma protein binding of cenobamate is 60% and independent of concentration in vitro . cenobamate primarily binds with human albumin protein. elimination the apparent terminal half-life of cenobamate is 50-60 hours and apparent oral clearance is approximately 0.45-0.63 l/hour over a dose range from 100 mg/day to 400 mg/day. metabolism cenobamate is extensively metabolized. the primary metabolic pathways are by glucuronidation via ugt2b7 and to a lesser extent by ugt2b4, and by oxidation via cyp2e1, cyp2a6, cyp2b6, and to a lesser extent by cyp2c19 and cyp3a4/5. following administration of radiolabeled cenobamate, unchanged cenobamate accounted for greater than 98% of the total auc of radioactivity in plasma. unchanged cenobamate accounted for 6.8% of the dose which was mainly excreted in the urine (6.4%). excretion following administration of radiolabeled cenobamate, a mean of 93.0% of the total radioactive dose was recovered in urine (87.8%) and feces (5.2%). more than 50% of the radioactivity was excreted within 72 hours of dosing. specific populations no clinically significant differences in the pharmacokinetics of cenobamate were observed based on age based on data from subjects age 18 years to 77 years, sex, or race/ethnicity based on data from subjects categorized as asian, black, caucasian, hispanic, or other. patients with renal impairment cenobamate plasma auc was 1.4 fold to 1.5 fold higher in subjects with mild (clcr 60 to less than 90 ml/min) and moderate (clcr 30 to less than 60 ml/min) following a single oral 200 mg dose of xcopri compared to healthy controls. in subjects with severe (clcr less than 30 ml/min) renal impairment, cenobamate plasma auc did not change significantly compared to healthy controls following single oral 100 mg dose of xcopri [see use in specific populations ( 8.6 )] . the effect of hemodialysis on cenobamate pharmacokinetics has not been studied. patients with hepatic impairment cenobamate plasma auc was 2.1-fold and 2.3-fold higher in subjects with mild (5-6 points on child-pugh assessment) and moderate (7-9 points on child-pugh assessment) hepatic impairment, respectively, following a single oral 200 mg dose of xcopri compared to matched healthy controls [see dosage and administration ( 2.3 ) and use in specific populations ( 8.7 )] .the effect of severe hepatic impairment on cenobamate pharmacokinetics has not been studied. drug interaction studies clinical studies alcohol no clinically significant pharmacokinetic differences were observed for either cenobamate or alcohol when administered concomitantly. aeds multiple doses of concomitant xcopri 200 mg once daily increased phenytoin mean c max and auc by 70% and 84%, respectively, and phenobarbital mean c max and auc by 34% and 37%, respectively [see drug interactions ( 7.1 )] . multiple doses of concomitant xcopri 200 mg once daily decreased carbamazepine mean c max and auc each by 23% [see drug interactions ( 7.1 ] . no clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with cenobamate: valproic acid, levetiracetam or lacosamide. based on population pk analyses, during treatment within the 100-400 mg/day xcopri dose range, lamotrigine concentrations are expected to decrease by 21-52% [see drug interactions ( 7.1 )] ; and levetiracetam concentrations are expected to decrease by 4-13%, which is not expected to be clinically significant. in subjects treated with xcopri in study 1 and study 2, there was no clear relationship between efficacy and concomitant oxcarbazepine use. as such, the efficacy data from study 1 and study 2 do not support the existence of a clinically relevant interaction perpetrated by xcopri against oxcarbazepine. cyp substrates multiple doses of concomitant xcopri 200 mg once daily decreased total bupropion (cyp2b6 substrate) mean c max and auc by 23% and 39%, respectively, and decreased midazolam (cyp3a substrate) mean c max and auc by 61% and 72%, respectively [see drug interactions ( 7.1 )] . multiple doses of concomitant xcopri 200 mg once daily increased the omeprazole (cyp2c19 substrate) mean c max and auc by 83% and 107%, respectively [see drug interactions ( 7.1 )] . no clinically significant differences in the pharmacokinetics of warfarin (cyp2c9 substrate) were observed when used concomitantly with cenobamate. the effects of concomitant aeds on cenobamate pk plasma cenobamate multiple-dose exposure (c max , auc) decreased with co-administration of phenytoin by 27-28%. however, repeated dosing of valproate, phenobarbital, and carbamazepine did not have any significant impact on plasma cenobamate multiple-dose exposure. in vitro studies cyp enzymes cenobamate inhibits cyp2b6, cyp2c19, and cyp3a, but cenobamate does not inhibit cyp1a2, cyp2c8, cyp2c9, or cyp2d6. cenobamate induces cyp2b6, cyp2c8, and cyp3a4, but cenobamate does not induce cyp1a2, cyp2c9, or cyp2c19. transporters systems cenobamate was not a substrate of p-gp, bcrp, oat1, oat3, oct2, mate1, or mate2-k, and cenobamate did not inhibit p-gp, oat1, oct1, oct2, oatp1b3, bsep, oat3, or oatp1b1.

uc) at the highest dose tested in rats was less than that in humans at the mrhd.

sted in rats was less than that in humans at the mrhd.

o establish a baseline seizure frequency, following which patients were randomized to a treatment arm. patients entered a treatment period consisting of an initial titration phase (6 weeks), and a subsequent maintenance phase (6 weeks for study 1 and 12 weeks for study 2). in study 1, patients were started on a daily dose of 50 mg (a higher starting dose than currently recommended) and subsequently increased by 50 mg/day every two weeks, until the final daily target dose of 200 mg/day was achieved. in study 2, patients were started on a daily dose of 50 mg (a higher starting dose than currently recommended) and subsequently increased by 50 mg/day every week (a faster titration than currently recommended) until 100 mg/day or 200 mg/day was reached and then increased by 100 mg/day every week in patients randomized to 400 mg/day [see dosage and administration ( 2.2 ), warnings and precautions ( 5.1 ), and adverse reactions ( 6.1 )] . the primary efficacy outcome in study 1 and study 2 was the percent change from baseline in seizure frequency per 28 days in the treatment period. table 6 summarizes the results of the primary endpoint for xcopri in each study. table 6: percent change from baseline in seizure frequency per 28 days in the treatment period (study 1 and study 2) * a negative percent change from baseline in seizure frequency indicates reduction in seizure frequency from baseline. ** statistically significant compared to placebo n median percent change from baseline in seizure frequency per 28 days (%) * p-value (compared to placebo) study 1 placebo 108 -21.5 -- xcopri 200 mg/day 113 -55.6 <0.0001 ** study 2 placebo 106 -24.3 -- xcopri 100 mg/day 108 -36.3 0.006 ** xcopri 200 mg/day 109 -55.2 <0.001 ** xcopri 400 mg/day 111 -55.3 <0.001 ** figure 1 and figure 2 show the proportion of patients with different percent reductions during the maintenance phase over baseline in study 1 and study 2, respectively. patients in whom the seizure frequency increased are shown in the left-most column as “worse.” patients in whom the seizure frequency decreased are shown in the remaining four categories. figure 1: proportion of patients exhibiting different percent reductions during the maintenance phase over baseline in study 1 figure 2: proportion of patients exhibiting different percent reductions during the maintenance phase over baseline in study 2 in study 2, 4 of 102 (4%) patients in the xcopri 100 mg/day group, 11 of 98 (11%) patients in the xcopri 200 mg/day group, and 20 of 95 (21%) patients in the xcopri 400 mg/day group and 1 of 102 (1%) of patients in the placebo group reported no partial seizures during the maintenance phase. figure 1 figure 2

the other side 50 mg per day for 14 days, then 100 mg per day for 14 days 71699-202-28 50 mg (14-count) film coated round yellow tablets with sk on one side and 50 on the other side 100 mg (14-count) film coated round brown tablets with sk on one side and 100 on the other side 150 mg per day for 14 days, then 200 mg per day for 14 days 71699-203-28 150 mg (14-count) film coated round light orange tablets with sk on one side and 150 on the other side 200 mg (14-count) film coated modified oval light orange tablets with sk on one side and 200 on the other side maintenance blister packs; 28-day daily dose ndc number supplied as [strength(quantity)] tablet description (color, shape, markings) 250 mg per day 71699-104-56 100 mg (28-count) film coated round brown tablets with sk on one side and 100 on the other side 150 mg (28-count) film coated round light orange tablets with sk on one side and 150 on the other side 350 mg per day 71699-103-56 150 mg (28-count) film coated round light orange tablets with sk on one side and 150 on the other side 200 mg (28-count) film coated modified oval light orange tablets with sk on one side and 200 on the other side 16.2 storage and handling store xcopri tablets at 20°c to 25°c (68°f to 77°f) with excursions permitted to 15°c to 30°c (59°f to 86°f) (see usp controlled room temperature) .

that antiepileptic drugs, including xcopri, may increase the risk of suicidal thoughts and behavior, and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm. advise patients, their caregivers, and/or families to report behaviors of concern immediately to a healthcare provider [see warnings and precautions ( 5.3 )] . neurological adverse reactions counsel patients that xcopri causes somnolence, fatigue, dizziness, and gait disturbance. these adverse reactions, if observed, are more likely to occur early in treatment but can occur at any time. advise patients not to drive or operate machinery until they have gained sufficient experience on xcopri to gauge whether it adversely affects their ability to drive or operate machinery and that other cns depressants or alcohol may have additive effects [see warnings and precautions ( 5.4 )] . withdrawal of xcopri advise patients not to discontinue use of xcopri without consulting with their healthcare provider. xcopri should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see warnings and precautions ( 5.5 )] . contraceptives counsel females of reproductive potential that xcopri may decrease the efficacy of oral contraceptives and advise them to use additional or alternative non-hormonal birth control [see drug interactions ( 7.1 )] . pregnancy advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during xcopri therapy. encourage patients to enroll in the north american antiepileptic drug pregnancy registry if they become pregnant. this registry is collecting information about the safety of antiepileptic drugs during pregnancy [see use in specific populations ( 8.1 )] . dosing instructions counsel patients that xcopri may be taken any time with or without food. instruct patients that xcopri tablets should be swallowed whole with liquid and not chewed or crushed [see dosage and administration ( 2.1 )] . abuse and dependence advise patients that xcopri is a federally controlled substance (cv) because it can be abused or lead to dependence [see drug abuse and dependence ( 9 )] . advise patients to keep their medication in a safe place to prevent misuse and abuse. manufactured for: sk life science, inc. paramus, nj 07652 phone: 1-866-657-5574 © 2019 sk life science, inc. xcopri ® is a registered trademark of sk life science, inc. or its affiliates and protected by u.s. patent 7,598,279