Xcopri Titration Pack (Page 4 of 9)

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.

7 DRUG INTERACTIONS

7.1 Effect of XCOPRI on Other Drugs

Table 5 summarizes the effect of XCOPRI on other drugs [see Clinical Pharmacology (12.3)].

Table 5: Pharmacokinetic Drug Interactions

Drug or Substrate Type	Effect of XCOPRI on Drug or Substrate	Clinical Recommendation
Antiepileptic Drugs
lamotrigine	↓ plasma concentrations	Because 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)].

8 USE IN SPECIFIC POPULATIONS

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.

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)].