Xcopri Titration Pack (Page 5 of 9)

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.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

XCOPRI contains cenobamate and is listed as a Schedule V controlled substance.

9.2 Abuse

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. In a human abuse potential study conducted in recreational sedative abusers (n=39), single doses of XCOPRI (200 mg and 400 mg) were compared to placebo. XCOPRI at single doses of 400 mg produced responses on positive subjective measures such as “Drug Liking,” “Overall Drug Liking,” “Take Drug Again,” and “Good Drug Effects” that were statistically greater than the responses produced on these measures by placebo. In this study, euphoric mood occurred at greater extent with XCOPRI (400 mg) (8%) than with placebo (0%). Phase 1 multiple ascending dose studies in healthy subjects showed rates of euphoria and feeling drunk of about 3% and disturbance in attention of about 5% in subjects who received supratherapeutic doses of cenobamate, but these adverse events were absent in the placebo group. In Phase 2 and 3 studies in subjects with epilepsy, euphoric mood, confusional state, and sedation occurred at low rates in subjects who received XCOPRI (0.5-2.5%).

9.3 Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Clinical studies in healthy subjects indicate that XCOPRI may cause physical dependence and lead to a withdrawal syndrome characterized by insomnia, decreased appetite, depressed mood, tremor, and amnesia. XCOPRI should be withdrawn gradually [see Warnings and Precautions (5.5)].

10 OVERDOSAGE

There is limited clinical experience with XCOPRI overdose in humans.

There is no specific antidote for overdose with XCOPRI. 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 rate and rhythm and vital signs is recommended. A certified poison control center should be contacted for updated information on the management of overdose with XCOPRI. There are no data on the removal of XCOPRI using dialysis.

11 DESCRIPTION

The chemical name of XCOPRI (cenobamate) is [(1R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl) ethyl] carbamate. Its molecular formula is C₁₀ H₁₀ ClN₅ O₂ and its molecular weight is 267.67 g/mol. The chemical structure is:

XCOPRI is a white to off-white crystalline powder. It is very soluble in aqueous solutions (water 1.7 mg/mL) and has higher solubility in organic solvents like ethanol (209.4 mg/mL).

XCOPRI tablets are for oral administration and contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate and film coating agents specified below:

12.5 mg tablets: Not applicable, since 12.5 mg tablets are uncoated.

25 mg and 100 mg tablets: FD&C Blue# 2/indigo carmine aluminum lake, iron oxide red, iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.

50 mg tablets: iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.

150 mg and 200 mg tablets: iron oxide red, iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism by which cenobamate exerts its therapeutic effects in patients with partial-onset seizures is unknown. Cenobamate has been demonstrated to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of the γ-aminobutyric acid (GABA_A ) ion channel.

12.2 Pharmacodynamics

Interactions with Alcohol

No clinically significant differences on objective attention, psychomotor performance, and memory tests, in addition to other subjective CNS tests, were observed following concomitant use of XCOPRI and ethanol (preparation of 40% ethanol in orange juice dosed at 0.7 g/kg for males and 0.57 g/kg for females) in healthy subjects.

Cardiac Electrophysiology

In a placebo-controlled QT study in healthy volunteers, dose-dependent shortening of the QTcF interval has been observed with XCOPRI [see Warnings and Precautions (5.2)]. The mean ΔΔQTc is -11 [-13, -8] 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.