Xcopri

Dosage and Administration (

Dosage and Administration (

XCOPRI is indicated for the treatment of partial-onset seizures in adult patients.

• Prior to initiating XCOPRI, obtain serum transaminases (ALT and AST)
  and total bilirubin, if not recently available (i.e., within 3 months), to establish baseline liver function. (
  2.1 Assessments Prior to Initiating XCOPRI

  Liver Function Tests

  Prior to initiating XCOPRI, obtain serum transaminases (ALT and AST) and total bilirubin, if not recently available (i.e., within 3 months), to establish baseline liver function

  [see Warnings and Precautions ]

  . For patients with baseline hepatic impairment, dosage modifications are recommended

  [see Dosage and Administration ]

  .
  ,
  5.4 Liver Injury

  Clinically significant liver injury has been reported in patients treated with XCOPRI in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic transaminases with elevated total bilirubin, have been reported after administration. Acute liver failure requiring transplantation has been reported in the postmarketing setting. Elevations of serum hepatic transaminases occurred in patients receiving XCOPRI in clinical trials

  [see Adverse Reactions ]

  .

  Obtain serum transaminases (ALT and AST) and total bilirubin, if not recently available (i.e., within 3 months), before initiation of XCOPRI to establish baseline liver function. Monitor for signs and symptoms of any hepatic injury during treatment

  [see Dosage and Administration ]

  , and obtain serum ALT and AST and total bilirubin promptly in patients who develop clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, jaundice, dark urine). Interrupt or discontinue treatment with XCOPRI in patients who develop liver injury without an alternative etiology.

  Elevation of serum hepatic transaminases greater than three times the reference range with elevated total bilirubin greater than two times the reference range is an important predictor of severe liver injury. Early identification of elevated serum hepatic transaminases and total bilirubin and interruption or discontinuation of XCOPRI may decrease the risk of a serious outcome.
  )
  
• The recommended initial dosage of XCOPRI is 12.5 mg once daily, titrated to the recommended maintenance dosage of 200 mg once daily. The recommended titration schedule should not be exceeded. The maximum dosage is 400 mg once daily. (
  2.2 Recommended Dosage

  Monotherapy and Adjunctive Therapy

  XCOPRI is administered orally once daily with or without food. The recommended dosage and titration, which should not be exceeded because of the potential for serious adverse reactions

  [see Warnings and Precautions ]

  , is included in Table 1.

  Table 1: Recommended Dosage for Partial-Onset Seizures in Adults

  Initial Dosage
  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
  )
• Hepatic impairment: For patients with mild or moderate hepatic impairment, the maximum recommended dosage is 200 mg once daily. (
  2.3 Recommended Dosage in Patients with Hepatic Impairment

  For patients with mild to moderate (Child-Pugh Class A to B) hepatic impairment, the maximum recommended dosage is 200 mg once daily

  [see Use in Specific Populations ]

  . XCOPRI is not recommended for use in patients with severe (Child-Pugh Class C) hepatic impairment

  [see Dosage and Administration

  and

  see Clinical Pharmacology ]

  .
  ,
  8.7 Hepatic Impairment

  XCOPRI should be used with caution 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 and Clinical Pharmacology ]

  . Use of XCOPRI in patients with severe (10-15 points on Child-Pugh assessment; Class C) hepatic impairment is not recommended.
  ,
  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_maxincreases 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_maxranging from 1 to 4 hours.

  Plasma C_maxand AUC for XCOPRI crushed tablets mixed in water, administered either orally or through a nasogastric tube, were similar to whole tablets. The median T_maxfor crushed tablets is 0.5 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 ]

  . The effect of hemodialysis on cenobamate pharmacokinetics has not been studied.

  Patients with Hepatic Impairment

  Cenobamate plasma AUC was 1.9-fold, 2.3-fold, and 4.2-fold higher in subjects with mild (5-6 points, Child-Pugh Class A), moderate (7-9 points, Child-Pugh Class B), and severe (10-15 points, Child-Pugh Class C) hepatic impairment, respectively, following a single oral 200 mg dose of XCOPRI in subjects with mild and moderate hepatic impairment and 100 mg dose of XCOPRI in subjects with severe hepatic impairment compared to matched healthy controls

  [see Dosage and Administration and Use in Specific Populations ]

  .

  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_maxand AUC by 70% and 84%, respectively, and phenobarbital mean C_maxand AUC by 34% and 37%, respectively

  [see Drug Interactions ]

  . Multiple doses of concomitant XCOPRI 200 mg once daily decreased carbamazepine mean C_maxand AUC each by 23%

  [see Drug Interactions ]

  ; 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_maxand AUC by 23% and 39%, respectively, and decreased midazolam (CYP3A substrate) mean C_maxand AUC by 61% and 72%, respectively

  [see Drug Interactions ]

  . Multiple doses of concomitant XCOPRI 200 mg once daily increased the omeprazole (CYP2C19 substrate) mean C_maxand AUC by 83% and 107%, respectively

  [see Drug Interactions ]

  . 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.
  )
• XCOPRI can be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube. (
  2.4 Administration Instructions

  XCOPRI can be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube, as described below

  [see Clinical Pharmacology ].

  Administration of Crushed Tablets by Mouth as Oral Suspension

  • Crush the appropriate number of tablet(s) for the prescribed dose.
  • In a cup, combine the crushed tablet(s) and 25 mL of water.
  • Swirl to suspend the crushed tablet(s).
  • Drink the suspension immediately. Do not store the tablet-water mixture for later use.
  • To ensure no tablet residue is left in the container, rinse the container with 25 mL of water and drink.
  • Visually confirm that no particles are left in the container. If particles remain, repeat step 5.

  Administration of Crushed Tablets via Nasogastric (NG) Tube

  • Crush the appropriate number of tablet(s) for the prescribed dose.
  • In an appropriate container, combine the crushed tablet(s) and 25 mL of water.
  • Swirl to suspend the crushed tablet(s).
  • Ensuring no particles are left in the container, instill the suspension with a syringe into the NG tube.
  • Refill the catheter-tip syringe again with 10 mL of water, swirl gently, and administer.
  • Visually confirm that no particles are left in the syringe. If particles remain, repeat step 5.
  )

XCOPRI tablets are available in the following strengths, shapes, colors, and tablet markings (Table 2).

• Pregnancy: Based on animal data, may cause fetal harm. (
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as XCOPRI, during pregnancy. Encourage women who are taking XCOPRI during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll-free number 1-888-233-2334 or 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.
  )
• Renal Impairment: Use with caution and dosage reduction may be considered in patients with mild to moderate (CLcr 30 to < 90 mL/min) and severe (CLcr < 30 mL/min) renal impairment. Use not recommended in end-stage renal disease (CLcr < 15 mL/min) undergoing dialysis. (
  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 ]

  .
  )
• Hepatic Impairment: Use with caution in patients with mild to moderate hepatic impairment; lower maximum dosage and additional dosage reduction may be considered. Use of XCOPRI in patients with severe hepatic impairment is not recommended. (
  2.2 Recommended Dosage

  Monotherapy and Adjunctive Therapy

  XCOPRI is administered orally once daily with or without food. The recommended dosage and titration, which should not be exceeded because of the potential for serious adverse reactions

  [see Warnings and Precautions ]

  , is included in Table 1.

  Table 1: Recommended Dosage for Partial-Onset Seizures in Adults

  Initial Dosage
  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
  ,
  8.7 Hepatic Impairment

  XCOPRI should be used with caution 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 and Clinical Pharmacology ]

  . Use of XCOPRI in patients with severe (10-15 points on Child-Pugh assessment; Class C) hepatic impairment is not recommended.
  ,
  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_maxincreases 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_maxranging from 1 to 4 hours.

  Plasma C_maxand AUC for XCOPRI crushed tablets mixed in water, administered either orally or through a nasogastric tube, were similar to whole tablets. The median T_maxfor crushed tablets is 0.5 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 ]

  . The effect of hemodialysis on cenobamate pharmacokinetics has not been studied.

  Patients with Hepatic Impairment

  Cenobamate plasma AUC was 1.9-fold, 2.3-fold, and 4.2-fold higher in subjects with mild (5-6 points, Child-Pugh Class A), moderate (7-9 points, Child-Pugh Class B), and severe (10-15 points, Child-Pugh Class C) hepatic impairment, respectively, following a single oral 200 mg dose of XCOPRI in subjects with mild and moderate hepatic impairment and 100 mg dose of XCOPRI in subjects with severe hepatic impairment compared to matched healthy controls

  [see Dosage and Administration and Use in Specific Populations ]

  .

  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_maxand AUC by 70% and 84%, respectively, and phenobarbital mean C_maxand AUC by 34% and 37%, respectively

  [see Drug Interactions ]

  . Multiple doses of concomitant XCOPRI 200 mg once daily decreased carbamazepine mean C_maxand AUC each by 23%

  [see Drug Interactions ]

  ; 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_maxand AUC by 23% and 39%, respectively, and decreased midazolam (CYP3A substrate) mean C_maxand AUC by 61% and 72%, respectively

  [see Drug Interactions ]

  . Multiple doses of concomitant XCOPRI 200 mg once daily increased the omeprazole (CYP2C19 substrate) mean C_maxand AUC by 83% and 107%, respectively

  [see Drug Interactions ]

  . 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.
  )