Xcopri Drug Information

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

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

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, is included in Table 1. Table 1: Recommended Dosage for Partial-Onset Seizures in Adults

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

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. 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.

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.

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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions and for varying durations, 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. 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. 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 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. 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.

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.

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.

Hepatobiliary Disorders: Hepatic failure

Effect of XCOPRI on Other Drugs Table 5 summarizes the effect of XCOPRI on other drugs. Table 5: Pharmacokinetic Drug Interactions

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.

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.

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. 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 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.

When cenobamate 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.

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.

XCOPRI is contraindicated in patients with: Hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI Familial Short QT syndrome Hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI. Familial Short QT syndrome.

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.