Included as part of the "PRECAUTIONS" Section
Drug Reaction With Eosinophilia And Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking 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]. 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].
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]. 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]. 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.
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
||Placebo Patients with Events Per 1000 Patients
||Drug Patients with Events Per 1000 Patients
Incidence of Events in Drug Patients/Incidence in Placebo Patients
Additional Drug Patients with Events Per 1000 Patients
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.
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]. 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]. 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.
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]. 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.
XCOPRI causes adverse reactions related to visual changes including diplopia, blurred vision, and impaired vision [see ADVERSE REACTIONS]. 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.
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.
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 and Clinical Studies]. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Instruct patients and caregivers that a fever or rash associated with signs of other organ system involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately. XCOPRI should be discontinued immediately if a serious hypersensitivity reaction is suspected [see WARNINGS AND PRECAUTIONS].
Instruct patients to inform their healthcare provider of all of the medications, over-the-counter medications, and herbal supplements that they are taking. Instruct patients to notify their healthcare provider if they have any symptoms of shortening of the QT interval, including prolonged heart palpitations or a loss of consciousness [see WARNINGS AND PRECAUTIONS].
Suicidal Behavior And Ideation
Counsel patients, their caregivers, and/or families 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].
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].
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].
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].
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].
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].
Abuse And Dependence
There is a pending DEA decision for control of XCOPRI (cenobamate) under the Controlled
Substances Act. A statement about abuse and dependence risks cannot be completed at this time.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Oral administration of cenobamate (0, 5, 15, or 35 mg/kg/day) to Tg.rasH2 mice for up to 26 weeks did not result in an increase in tumors. Oral administration of cenobamate (0, 4, 8, or 20 mg/kg/day) to male and female rats for up to 87 or 90 weeks, respectively, did not result in an increase in tumors. Plasma exposure at the highest dose tested in rats was less than that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.
Cenobamate was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays.
Impairment Of Fertility
Oral administration of cenobamate (0, 11, 22, or 44 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females to Gestation Day 6 did not produce adverse effects on fertility, general reproductive performance, or early embryonic development. Plasma exposure (AUC) at the highest dose tested in rats was less than that in humans at the MRHD.
Use In Specific Populations
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/.
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.
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.
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.
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.
Females And Males Of Reproductive Potential
Women of reproductive potential concomitantly using oral contraceptives should use additional or alternative non-hormonal birth control [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
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.
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].
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].
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 and CLINICAL PHARMACOLOGY]. Use of XCOPRI in patients with severe hepatic impairment is not recommended.