Cenobamate is an oral antiepileptic drug indicated for partial-onset seizures in adults. In placebo-controlled clinical trials, cenobamate significantly decreased seizure frequency in patients with partial-onset seizures with or without secondary generalization who were not adequately controlled with 1 to 3 concomitant antiepileptic drugs. The median reduction in seizure frequency per 28 days was 36.3% in patients treated with cenobamate 100 mg/day (n = 108), 55.2% to 55.6% in patients treated with cenobamate 200 mg/day (n = 222), and 55.3% in patients treated with cenobamate 400 mg/day (n = 111) compared to 21.5% to 24.3% in patients given placebo (n = 214) in 2 clinical trials with 6-week titration phases and 6- to 12-week maintenance phases. A higher percentage of subjects who took cenobamate during placebo-controlled clinical trials had a QT interval shortening of more than 20 milliseconds compared to placebo. Reductions in the QT interval below 300 milliseconds were not observed. Cenobamate is also associated with dose-related dizziness, drowsiness, fatigue, and gait disturbance or coordination-related adverse reactions.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer with or without food.
Oral Solid Formulations
-Tablets may be swallowed whole or crushed and mixed with water for administration as an oral suspension or by nasogastric tube.
Crushed tablets for administration as an oral suspension
-Crush the appropriate number of tablet(s) for the prescribed dose.
-Combine the crushed tablet(s) with 25 mL of water in a cup.
-Swirl to suspend the crushed tablet(s) and administer immediately.
-Rinse the container with 25 mL of water and administer to ensure no tablet residue is left in the container.
-If particles remain in the container, repeat the rinse step.
-Storage: Do not store the tablet-water mixture for later use.
Crushed tablets for nasogastric tube administration
-Crush the appropriate number of tablet(s) for the prescribed dose.
-Combine the crushed tablet(s) with 25 mL of water in an appropriate container.
-Swirl to suspend the crushed tablet(s).
-Instill the suspension with a syringe into the nasogastric tube ensuring no particles are left in the container. Refill the catheter tip syringe again with 10 mL of water, swirl gently, and administer.
-If particles remain in the syringe, repeat the rinse step.
Neurological adverse reactions reported in patients treated with cenobamate include dizziness (18%, 100 mg; 22%, 200 mg; 33%, 400 mg vs. 15%, placebo); drowsiness (19%, 100 mg; 22%, 200 mg; 37%, 400 mg; 11%, placebo); fatigue (12%, 100 mg; 14%, 200 mg; 24%, 400 mg vs. 7%, placebo); sedation (1%, 100 mg; 1%, 200 mg; 2%, 400 mg vs. 0%, placebo); balance disorder (3%, 100 mg; 5%, 200 mg; 9%, 400 mg vs. 1%, placebo); gait disturbance (1%, 100 mg; 3%, 200 mg; 8%, 400 mg vs. 1%, placebo); headache (10%, 100 mg; 12%, 200 mg; 10%, 400 mg vs. 9%, placebo); migraine (0%, 100 mg; 0%, 200 mg; 2%, 400 mg vs. 0%, placebo); dysarthria (2%, 100 mg; 1%, 200 mg; 7%, 400 mg vs. 0%, placebo); nystagmus (3%, 100 mg; 7%, 200 mg; 6%, 400 mg vs. 0%, placebo); ataxia (2%, 100 mg; 3%, 200 mg; 6%, 400 mg vs. 2%, placebo); aphasia (2%, 100 mg; 1%, 200 mg; 4%, 400 mg vs. 0%, placebo); asthenia (0%, 100 mg; 1%, 200 mg; 3%, 400 mg vs. 1%, placebo); dysgeusia (2%, 100 mg; 0%, 200 mg; 2%, 400 mg vs. 0%, placebo); memory impairment (2%, 100 mg; 1%, 200 mg; 2%, 400 mg vs. 0%, placebo); confusion (2%, 100 mg; 2%, 200 mg; 3%, 400 mg vs. 0%, placebo); tremor (0%, 100 mg; 3%, 200 mg; 1%, 400 mg vs. 1%, placebo); vertigo (1%, 100 mg; 1%, 200 mg; 6%, 400 mg vs. 1%, placebo); and head injury (1%, 100 mg; 0%, 200 mg; 2%, 400 mg vs. 0%, placebo). Drowsiness and fatigue-related adverse reactions (i.e., drowsiness, fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy) are dose-related as are dizziness and gait disturbance or coordination-related adverse reactions (i.e., dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, and abnormal coordination). In clinical trials, 31% of patients treated with cenobamate 100 mg/day, 36% of patients treated with cenobamate 200 mg/day, and 57% of patients treated with cenobamate 400 mg/day reported at least 1 somnolence or fatigue-related adverse reaction compared to 19% of patients given placebo. Somnolence and fatigue-related adverse reactions were serious in 0.4% of cenobamate-treated patients compared to no patients given placebo and led to discontinuation in 2% of cenobamate-treated patients compared to 1% of patients given placebo. Similarly, 21% of patients treated with cenobamate 100 mg/day, 31% of patients treated with cenobamate 200 mg/day, and 52% of patients treated with cenobamate 400 mg/day reported at least 1 dizziness or gait disturbance or coordination-related adverse reaction compared to 18% of patients given placebo. Dizziness and gait disturbance or coordination-related adverse reactions were serious in 2% of cenobamate-treated patients compared to no patients given placebo and led to discontinuation in 5% of cenobamate-treated patients compared to 1% of patients given placebo. Further, 6% of patients treated with cenobamate 100 mg/day, 6% of patients treated with cenobamate 200 mg/day, and 9% of patients treated with cenobamate 400 mg/day reported at least 1 cognitive dysfunction related-event (i.e., memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, and psychomotor impairment) compared to 2% of patients given placebo. No cognitive dysfunction-related events were serious in cenobamate-treated patients or in patients given placebo. Cognitive dysfunction-related adverse reactions led to discontinuation in 0.4% of cenobamate-treated patients compared to no patients given placebo.
Euphoria, irritability, and suicidal ideation were reported in 0% to 2% of patients treated with cenobamate and no patients given placebo. Antiepileptic drugs (AEDs) such as cenobamate increase the risk of suicidal ideation and behavior. Monitor all patients taking cenobamate closely for emerging or worsening depression or suicidal ideation. Inform patients and caregivers of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the underlying illness. A pooled analysis of 199 placebo-controlled trials including 11 different AEDs showed that patients (5 years of age and older) receiving AEDs had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), with an adjusted relative risk of 1.8 (95% CI 1.2 to 2.7). Four completed suicides occurred in patients treated with AEDs compared to none among controls. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor and risk was generally consistent among all AEDs examined. Suicidal ideation or behavior have occurred as early as 1 week after AED initiation and may occur at any time during treatment.
Palpitations were reported in 0% to 2% of patients treated with cenobamate compared to no patients given placebo. In a placebo-controlled study of the QT interval in healthy volunteers, a shortened QT interval of more than 20 milliseconds occurred in 31% of patients treated with cenobamate 200 mg, 66% of patients treated with cenobamate 500 mg, and 6% to 17% of patients given placebo. The mean changes in QTc were -11 milliseconds for cenobamate 200 mg once daily and -18 milliseconds for 500 mg once daily (1.25 times the maximum recommended dosage). Reductions in the QT interval below 300 milliseconds were not observed. Use caution when administering cenobamate with 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.
Blurred vision occurred in 2% to 4% of patients treated with cenobamate compared to no patients given placebo. Diplopia occurred in 6% to 15% of patients treated with cenobamate compared to 2% of patients given placebo. No visual change-related events were serious in cenobamate-treated patients or in patients who received placebo. Visual change led to discontinuation in 0.5% of cenobamate-treated patients compared to no patients given placebo.
Nausea was reported in 6% to 9% of patients treated with cenobamate compared to 3% of patients given placebo. Vomiting was reported in 2% to 5% of patients treated with cenobamate; diarrhea and constipation were reported in 1% to 5% and 2% to 8%, respectively, of patients treated with cenobamate. Xerostomia was reported in 1% to 3% of patients treated with cenobamate. Abdominal pain and dyspepsia were reported in 1% to 2% and 0% to 2%, respectively, of patients treated with cenobamate. No patients given placebo experienced vomiting, diarrhea, constipation, xerostomia, abdominal pain, or dyspepsia. In the overall clinical trial safety population, there were 2.9 cases of appendicitis/1,000 patient-years of exposure, which is higher than the expected background rate in the general population.
Nasopharyngitis was reported in 2% to 5% of patients treated with cenobamate compared to 3% of patients given placebo. Pharyngitis was reported in 0% to 2% of patients treated with cenobamate compared to no patients given placebo. Cystitis was reported in 0% to 5% of patients treated with cenobamate compared to 2% of patients given placebo.
Weight loss was reported in 0% to 2% of patients treated with cenobamate compared to no patients given placebo. Anorexia occurred in 1% to 5% of patients treated with cenobamate compared to 1% of patients given placebo.
Back pain was reported in 2% to 5% of patients treated with cenobamate compared to 3% of patients given placebo. Chest musculoskeletal pain was reported in 0% to 2% of patients treated with cenobamate compared to no patients given placebo.
Dysmenorrhea was reported in 1% to 2% of patients treated with cenobamate compared to no patients given placebo. Pollakiuria was reported in 0% to 1% of patients treated with cenobamate compared to no patients given placebo.
Hiccups were reported in 0% to 1% of patients treated with cenobamate compared to no patients given placebo. Dyspnea was reported in 0% to 3% of patients treated with cenobamate compared to no patients given placebo.
Pruritus and maculopapular rash were reported in 0% to 2% of patients treated with cenobamate compared to no patients given placebo.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with cenobamate. DRESS has occurred, including 1 fatality, when cenobamate was titrated rapidly (weekly or faster). No cases of DRESS were reported in an open-label safety study of 1,339 partial-onset seizure patients when cenobamate was initiated at 12.5 mg once daily and titrated every 2 weeks. Although this finding does not establish that the risk of DRESS is prevented by a slower titration, follow recommendations for initial dosing and titration schedule. 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, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. The disorder is variable in its expression, and other organ systems may also be involved. Of note, early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, evaluate patients immediately. Discontinue cenobamate immediately and do not restart if an alternative etiology for the signs or symptoms cannot be identified.
Elevated hepatic enzymes, specifically increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were reported in 1% to 4% and 1% to 3%, respectively, of patients treated with cenobamate compared to no patients given placebo. There was a post-baseline elevation of ALT to more than 3 times the upper limit of normal (ULN) in 1 (0.9%) patient treated with cenobamate 100 mg, 2 (1.8%) patients treated with 200 mg, and 3 (2.7%) patients treated with 400 mg compared to no patients given placebo. The maximum ALT elevation was 7.6 times ULN in patients treated with cenobamate 400 mg. Hepatic failure has been reported during postmarketing experience with cenobamate. There was a post-baseline elevation of potassium values to more than 5 mEq/L (hyperkalemia) in 17 (17%) patients treated with cenobamate 200 mg compared to 8 (7%) patients given placebo. A dose-related distribution where at least 1 post-baseline potassium value was more than 5 mEq/L, occurring in 8.3%, 9.1%, and 10.8% of patients treated with cenobamate 100 mg, 200 mg, and 400 mg, respectively, compared to 5.6% of patients given placebo, was observed in another study. A maximum potassium value of 5.9 mEq/L was noted in 2 patients.
Psychiatric effects, such as hostility, aggression, and psychosis (hallucinations, delusions, or paranoia) have been reported during the postmarketing use of cenobamate. As these are reported voluntarily, the exact incidence of these reactions is unknown.
Cenobamate is contraindicated in patients with hypersensitivity to cenobamate or any of the inactive ingredients in the formulation.
Cenobamate is contraindicated for use in patients with familial short QT syndrome. A higher percentage of subjects who took cenobamate during placebo-controlled clinical trials had a QT interval shortening of more than 20 milliseconds compared to placebo. Reductions in the QT interval below 300 milliseconds were not observed. Familial short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation, which are believed to occur primarily when the corrected QT interval falls below 300 milliseconds. Nonclinical data also indicate that QT shortening is associated with ventricular fibrillation. Use caution when administering cenobamate with other drugs that cause a shortened QT interval as there may be a synergistic effect on the QT interval that would increase the QT shortening risk.
Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving cenobamate closely for emerging or worsening depression or suicidal ideation. Advise patients and caregivers of the increased risk of suicidal thoughts and behaviors and to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the illness being treated. There is an increased risk of suicidal ideation and behavior in patients receiving AEDs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks.
Advise patients to avoid driving or operating machinery until they have gained sufficient experience with cenobamate to gauge whether it adversely affects their ability to drive or operate machinery and that other CNS depressants or alcohol may have additive effects. Cenobamate causes drowsiness, dizziness, fatigue, and gait disturbances.
When discontinuing cenobamate, gradually reduce the dose over at least 2 weeks due to the risk of increased seizure frequency or status epilepticus. If withdrawal is needed because of a serious adverse event, abrupt discontinuation may be considered.
Use cenobamate with caution in persons with mild to moderate hepatic disease (Child-Pugh Class A or B). For persons with mild to moderate hepatic impairment, the maximum recommended dose of cenobamate is 200 mg/day and additional dosage reduction may be considered. Cenobamate is not recommended for use in persons with severe hepatic impairment (Child-Pugh Class C).
Use cenobamate with caution in patients with mild to moderate (CrCl 30 to 89 mL/minute) and severe (CrCl less than 30 mL/minute) renal impairment and consider a dosage reduction. Cenobamate is not recommended for use in patients with end-stage renal disease or renal failure undergoing dialysis.
Use caution in selecting the dose for a geriatric adult, 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. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric adults with a history of falls or fractures. Avoid in at-risk patients, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If cenobamate must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.
There are no adequate data on the developmental risk associated with cenobamate use during human pregnancy. Oral administration of cenobamate (0, 10, 30, or 60 mg/kg/day) to pregnant rats during organogenesis resulted in increased embryofetal mortality, reduced fetal body weights, and incomplete fetal skeletal ossification at the highest dose tested. A small increase in visceral malformations also occurred. 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. Increased embryofetal mortality was also noted in pregnant rabbits given cenobamate at a dose of 36 mg/kg/day during organogenesis. Oral administration of cenobamate (0, 11, 22, or 44 mg/kg/day) to female rats throughout pregnancy and lactation resulted in neurobehavioral impairment (learning and memory deficit and increased auditory startle response) at all doses. Decreased preweaning body weight gain and adverse effects on reproductive function (decreased numbers of corpora lutea, implantations, and live fetuses) were observed at the highest dose. Maternal plasma exposure (AUC) 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. To monitor human fetal outcomes, pregnant women taking cenobamate are encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Patients must enroll themselves by calling the registry at 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org.
There are no data on the presence of cenobamate in human milk, the effects on the breast-fed infant, or the effects on milk production. In animal studies, cenobamate was present in rat milk at concentrations similar to those in maternal plasma. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for cenobamate and any potential adverse effects on the breastfed infant from cenobamate or the underlying maternal condition.
For the treatment of partial seizures:
Oral dosage:
Adults: 12.5 mg PO once daily for weeks 1 and 2, then 25 mg PO once daily for weeks 3 and 4, then 50 mg PO once daily for weeks 5 and 6, then 100 mg PO once daily for weeks 7 and 8, then 150 mg PO once daily for weeks 9 and 10, then 200 mg PO once daily. If necessary based on clinical response and tolerability, may further increase dose by 50 mg PO once daily every 2 weeks up to a maximum of 400 mg PO once daily. To discontinue, gradually reduce the dose over at least 2 weeks due to the risk of increased seizure frequency or status epilepticus. If withdrawal is needed because of a serious adverse event, abrupt discontinuation may be considered.
Maximum Dosage Limits:
-Adults
400 mg/day PO.
-Geriatric
400 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
For persons with mild to moderate hepatic impairment (Child-Pugh Class A or B), the maximum recommended dose of cenobamate is 200 mg PO once daily and additional dosage reduction may be considered. Cenobamate is not recommended for use in persons with severe hepatic impairment (Child-Pugh Class C).
Patients with Renal Impairment Dosing
Use cenobamate with caution in persons with mild to moderate (CrCl 30 to 89 mL/minute) and severe (CrCl less than 30 mL/minute) renal impairment and consider a dosage reduction.
Intermittent hemodialysis
Cenobamate is not recommended for use in persons with end-stage renal disease undergoing dialysis.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Abemaciclib: (Major) Avoid coadministration of cenobamate with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 29% to 53%.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with cenobamate may cause excessive sedation and somnolence. Limit the use of dihydrocodeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing dihydrocodeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of dihydrocodeine as needed. If cenobamate is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Cenobamate is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with cenobamate can decrease dihydrocodeine concentrations, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acetaminophen; Chlorpheniramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acetaminophen; Diphenhydramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cenobamate may cause excessive sedation and somnolence. Limit the use of hydrocodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing hydrocodone cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of hydrocodone as needed. If cenobamate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone concentrations.
Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with cenobamate may cause excessive sedation and somnolence. Limit the use of oxycodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of oxycodone as needed. If cenobamate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Acrivastine; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Alfentanil: (Moderate) Concomitant use of alfentanil with cenobamate may cause excessive sedation and somnolence. Limit the use of alfentanil with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with cenobamate is necessary. If cenobamate is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like cenobamate with alfentanil, a CYP3A4 substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Alprazolam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Amitriptyline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Atorvastatin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Benazepril: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Celecoxib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amobarbital: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and amobarbital. Concurrent use may result in additive CNS depression.
Amoxapine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and amoxapine. Concurrent use may result in additive CNS depression.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Consider alternatives to clarithromycin if treatment with cenobamate is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Apomorphine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and apomorphine. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as apomorphine, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Aripiprazole: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and aripiprazole. Concurrent use may result in additive CNS depression.
Asenapine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and asenapine. Concurrent use may result in additive CNS depression.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and butalbital. Concurrent use may result in additive CNS depression.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and orphenadrine. Concurrent use may result in additive CNS depression.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with cenobamate is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate. Cenobamate is a moderate CYP2C19 inducer. Coadministration could decrease exposure to carisoprodol and increase exposure to meprobamate. The full pharmacological impact of these potential alterations of exposure in terms of either efficacy or safety of carisoprodol is unknown. Additionally, monitor for excessive sedation and somnolence during coadministration of cenobamate and carisoprodol. Concurrent use may result in additive CNS depression.
Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with cenobamate may cause excessive sedation and somnolence. Limit the use of oxycodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of oxycodone as needed. If cenobamate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atazanavir; Cobicistat: (Moderate) Coadministration of cobicistat with cenobamate may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Atogepant: (Major) Avoid use of atogepant and cenobamate when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with cenobamate. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Atropine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and atropine. Concurrent use may result in additive CNS depression.
Atropine; Difenoxin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and atropine. Concurrent use may result in additive CNS depression.
Avacopan: (Major) Avoid concomitant use of avacopan and cenobamate due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Avanafil: (Major) Coadministration of avanafil with cenobamate is not recommended due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Avapritinib: (Major) Avoid coadministration of avapritinib with cenobamate due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Axitinib: (Major) Avoid coadministration of axitinib with cenobamate if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and cenobamate is a moderate CYP3A4 inducer.
Azelastine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and azelastine. Concurrent use may result in additive CNS depression.
Azelastine; Fluticasone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and azelastine. Concurrent use may result in additive CNS depression.
Baclofen: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and baclofen. Concurrent use may result in additive CNS depression.
Bedaquiline: (Major) Avoid coadministration of cenobamate with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased bedaquiline exposure by approximately 20%. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
Belladonna; Opium: (Moderate) Concomitant use of opium with cenobamate may cause excessive sedation and somnolence. Limit the use of opium with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of cenobamate with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and cenobamate is a CYP2C19 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of benzhydrocodone with cenobamate may cause excessive sedation and somnolence. Limit the use of benzhydrocodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of benzhydrocodone as needed. If cenobamate is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Benzodiazepines: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Brexpiprazole: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and brexpiprazole. Concurrent use may result in additive CNS depression.
Brigatinib: (Major) Avoid coadministration of brigatinib with cenobamate due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with cenobamate, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of cenobamate, resume the brigatinib dose that was tolerated prior to initiation of cenobamate. Brigatinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and cenobamate are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; cenobamate is a moderate inducer of CYP3A4.
Brompheniramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Brompheniramine; Phenylephrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Brompheniramine; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Buprenorphine: (Moderate) Concomitant use of buprenorphine with cenobamate may cause excessive sedation and somnolence. Limit the use of buprenorphine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of buprenorphine and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of buprenorphine as needed. If cenobamate is discontinued, consider a dose reduction of buprenorphine and frequently monitor for signs of respiratory depression and sedation. Buprenorphine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease buprenorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine with cenobamate may cause excessive sedation and somnolence. Limit the use of buprenorphine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of buprenorphine and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of buprenorphine as needed. If cenobamate is discontinued, consider a dose reduction of buprenorphine and frequently monitor for signs of respiratory depression and sedation. Buprenorphine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease buprenorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Bupropion: (Major) Increase the dosage of bupropion as needed when coadministered with cenobamate due to the potential for reduced efficacy of bupropion. Multiple doses of cenobamate decreased bupropion exposure by 39%. Bupropion is a sensitive substrate of CYP2B6; cenobamate is a weak CYP2B6 inducer.
Bupropion; Naltrexone: (Major) Increase the dosage of bupropion as needed when coadministered with cenobamate due to the potential for reduced efficacy of bupropion. Multiple doses of cenobamate decreased bupropion exposure by 39%. Bupropion is a sensitive substrate of CYP2B6; cenobamate is a weak CYP2B6 inducer.
Buspirone: (Moderate) If cenobamate is added to a patient receiving a stable buspirone dose, a dose increase of buspirone may be needed to maintain anxiolytic activity. Buspirone is a sensitive CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. CYP3A4 inducers may increase the rate of buspirone metabolism.
Butalbital; Acetaminophen: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and butalbital. Concurrent use may result in additive CNS depression.
Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and butalbital. Concurrent use may result in additive CNS depression.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and butalbital. Concurrent use may result in additive CNS depression.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and butalbital. Concurrent use may result in additive CNS depression.
Butorphanol: (Moderate) Concomitant use of butorphanol with cenobamate may cause excessive sedation and somnolence. Limit the use of butorphanol with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering cenobamate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Cenobamate is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sodium oxybate. Concurrent use may result in additive CNS depression.
Capivasertib: (Major) Avoid coadministration of capivasertib with cenobamate due to decreased capivasertib exposure and risk of decreased efficacy. Capivasertib is a CYP3A substrate; cenobamate is a moderate CYP3A inducer. Coadministration of another moderate CYP3A inducer is predicted to decrease the capivasertib overall exposure by 60%.
Capmatinib: (Major) Avoid coadministration of capmatinib and cenobamate due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
Capsaicin; Metaxalone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and metaxalone. Concurrent use may result in additive CNS depression.
Carbamazepine: (Major) Increase the dosage of carbamazepine as needed when coadministered with cenobamate due to the potential for reduced efficacy of carbamazepine. Multiple doses of cenobamate decreased carbamazepine exposure by 23%.
Carbidopa; Levodopa: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and levodopa. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Carbidopa; Levodopa; Entacapone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and entacapone. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and levodopa. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Carbinoxamine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Cariprazine: (Major) Coadministration of cariprazine with cenobamate is not recommended as the net effect of CYP3A4 induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration of cariprazine with CYP3A4 inducers has not been evaluated. Additionally, concurrent use may result in additive CNS depression.
Carisoprodol: (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with cenobamate is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate. Cenobamate is a moderate CYP2C19 inducer. Coadministration could decrease exposure to carisoprodol and increase exposure to meprobamate. The full pharmacological impact of these potential alterations of exposure in terms of either efficacy or safety of carisoprodol is unknown. Additionally, monitor for excessive sedation and somnolence during coadministration of cenobamate and carisoprodol. Concurrent use may result in additive CNS depression.
Celecoxib; Tramadol: (Moderate) Concomitant use of tramadol with cenobamate may cause excessive sedation and somnolence. Limit the use of tramadol with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of tramadol as needed. If cenobamate is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Cetirizine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and cetirizine. Concurrent use may result in additive CNS depression.
Cetirizine; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and cetirizine. Concurrent use may result in additive CNS depression.
Chlophedianol; Dexbrompheniramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorcyclizine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlordiazepoxide: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Chlordiazepoxide; Clidinium: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Chlorpheniramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cenobamate may cause excessive sedation and somnolence. Limit the use of hydrocodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing hydrocodone cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of hydrocodone as needed. If cenobamate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone concentrations. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorpheniramine; Phenylephrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorpheniramine; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Chlorpromazine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Chlorzoxazone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and chlorzoxazone. Concurrent use may result in additive CNS depression.
Cilostazol: (Major) Reduce cilostazol dose to 50 mg twice daily when coadministered with cenobamate. Coadministration increases systemic exposure of cilostazol active metabolites. Cilostazol is a CYP2C19 substrate; cenobamate is a moderate CYP2C19 inhibitor. Coadministration of another CYP2C19 inhibitor did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%.
Citalopram: (Moderate) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with cenobamate, a moderate CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg/day in patients receiving CYP2C19 inhibitors.
Clarithromycin: (Major) Consider alternatives to clarithromycin if treatment with cenobamate is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Clemastine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Clobazam: (Moderate) Consider a dose reduction of clobazam when coadministered with cenobamate due to the potential for increased clobazam exposure and adverse effects. Also, concomitant use of cenobamate with clobazam may increase the risk of neurological adverse reactions, including sedation and somnolence. Clobazam is a CYP2C19 substrate; cenobamate is a moderate CYP2C19 inhibitor. Moderate inhibitors of CYP2C19 may cause up to a 5-fold increase in exposure to N-desmethylclobazam, the active metabolite of clobazam.
Clomipramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Clonazepam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Clonidine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and clonidine. Concurrent use may result in additive CNS depression.
Clorazepate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Clozapine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and clozapine. Concurrent use may result in additive CNS depression. Additionally, monitor for loss of clozapine effectiveness if coadministered with cenobamate. Consideration should be given to increasing the clozapine dose if necessary. When cenobamate is discontinued, reduce the clozapine dose based on clinical response. Cenobamate is a moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Cobicistat: (Moderate) Coadministration of cobicistat with cenobamate may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with cenobamate due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A4 substrate, and cenobamate is a moderate inducer of CYP3A4. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A4 inducer.
Codeine: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with cenobamate may cause excessive sedation and somnolence. Limit the use of codeine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing codeine cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of codeine as needed. If cenobamate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cenobamate is a moderate CYP3A4 inducer. Concomitant use with cenobamate can increase norcodeine concentrations via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Conjugated Estrogens: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Bazedoxifene: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Medroxyprogesterone: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Cyclobenzaprine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and cyclobenzaprine. Concurrent use may result in additive CNS depression.
Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with cenobamate is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; cenobamate is a moderate CYP3A4 inducer.
Cyproheptadine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Daclatasvir: (Major) Increase the dose of daclatasvir to 90 mg PO once daily if coadministered with cenobamate due to decreased daclatasvir exposure resulting in potential loss of virologic control. Daclatasvir is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer reduced the daclatasvir AUC by 63%.
Dantrolene: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and dantrolene. Concurrent use may result in additive CNS depression.
Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with cenobamate is necessary. Dapsone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis).
Daridorexant: (Major) Avoid concomitant use of daridorexant and cenobamate. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Darunavir: (Moderate) Coadministration of darunavir with cenobamate may result in significant decreases in the plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Darunavir; Cobicistat: (Moderate) Coadministration of cobicistat with cenobamate may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. (Moderate) Coadministration of darunavir with cenobamate may result in significant decreases in the plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of cobicistat with cenobamate may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. (Moderate) Coadministration of darunavir with cenobamate may result in significant decreases in the plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Deflazacort: (Major) Avoid concomitant use of deflazacort and cenobamate. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; cenobamate is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of a strong CYP3A4 inducer resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
Delavirdine: (Moderate) Coadministration of delavirdine with cenobamate may result in decreases in the plasma concentrations of delavirdine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Delavirdine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased delavirdine exposure by 82%.
Desipramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Desogestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Deutetrabenazine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and deutetrabenazine. Concurrent use may result in additive CNS depression.
Dexbrompheniramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Dexchlorpheniramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Dexmedetomidine: (Moderate) Although CNS depression is a desired effect of dexmedetomidine, monitor patients also receiving cenobamate closely for additive CNS depression that may prolong recovery after administration of dexmedetomidine.
Dextromethorphan; Bupropion: (Major) Increase the dosage of bupropion as needed when coadministered with cenobamate due to the potential for reduced efficacy of bupropion. Multiple doses of cenobamate decreased bupropion exposure by 39%. Bupropion is a sensitive substrate of CYP2B6; cenobamate is a weak CYP2B6 inducer.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Diazepam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Dienogest; Estradiol valerate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diltiazem: (Moderate) Avoid coadministration of diltiazem and cenobamate if possible due to decreased plasma concentrations of diltiazem; if unavoidable, monitor blood pressure and heart rate and adjust the diltiazem dose based on clinical response. Diltiazem is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased diltiazem exposure by 69% and decreased exposure to desacetyldiltiazem by 75%.
Dimenhydrinate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Diphenhydramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Diphenhydramine; Ibuprofen: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Diphenhydramine; Naproxen: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Diphenhydramine; Phenylephrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Diphenoxylate; Atropine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and atropine. Concurrent use may result in additive CNS depression.
Dolutegravir: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Dolutegravir; Lamivudine: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering cenobamate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Cenobamate is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Doravirine: (Moderate) Concurrent administration of doravirine and cenobamate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and cenobamate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer.
Doxepin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with cenobamate due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
Doxorubicin: (Major) Avoid coadministration of doxorubicin with cenobamate due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
Doxylamine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Doxylamine; Pyridoxine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Dronabinol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and dronabinol. Concurrent use may result in additive CNS depression. Additionally, monitor for decreased efficacy of dronabinol if coadministration with cenobamate is necessary. Dronabinol is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Formal drug interaction studies have not been conducted; however, inducers of CYP3A4 may decrease dronabinol exposure.
Droperidol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and droperidol. Concurrent use may result in additive CNS depression.
Drospirenone: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Drospirenone; Estetrol: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Drospirenone; Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Drospirenone; Ethinyl Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Duvelisib: (Major) Avoid concomitant use of duvelisib with cenobamate. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily. When cenobamate has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with cenobamate. Duvelisib is a CYP3A substrate; cenobamate is a moderate CYP3A inducer. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%.
Elacestrant: (Major) Avoid concurrent use of elacestrant and cenobamate due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced elacestrant overall exposure by 55% to 73%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Elbasvir; Grazoprevir: (Major) Coadministration of elbasvir with cenobamate is not recommended due to decreased exposure of elbasvir, resulting in decreased virologic response. Elbasvir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. (Major) Coadministration of grazoprevir with cenobamate is not recommended due to decreased exposure of grazoprevir, resulting in decreased virologic response. Grazoprevir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of cobicistat with cenobamate may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. (Moderate) Coadministration of elvitegravir with cenobamate may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of cobicistat with cenobamate may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. (Moderate) Coadministration of elvitegravir with cenobamate may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering cenobamate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Cenobamate is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering cenobamate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Cenobamate is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Entacapone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and entacapone. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Entrectinib: (Major) Avoid coadministration of entrectinib with cenobamate due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Erdafitinib: (Major) If coadministration of erdafitinib and cenobamate is necessary at the initiation of erdafitinib therapy, increase the dose of erdafitinib to 9 mg once daily. Erdafitinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced erdafitinib overall exposure by 45%.
Erlotinib: (Major) Avoid coadministration of erlotinib with cenobamate if possible, due to the risk of decreased erlotinib exposure. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and cenobamate is a moderate CYP3A4 inducer.
Estazolam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Esterified Estrogens: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Esterified Estrogens; Methyltestosterone: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Levonorgestrel: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Estradiol; Norethindrone: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Estradiol; Norgestimate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Estradiol; Progesterone: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estropipate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Eszopiclone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and eszopiclone. Concurrent use increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethinyl Estradiol; Norelgestromin: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Ethinyl Estradiol; Norgestrel: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Etomidate: (Moderate) Although CNS depression is a desired effect of general anesthetics, monitor patients also receiving cenobamate closely for additive CNS depression that may prolong recovery after administration of a general anesthetic.
Etonogestrel: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Etonogestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with cenobamate is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
Fedratinib: (Major) Avoid coadministration of fedratinib with cenobamate as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and cenobamate. Concurrent use may result in additive CNS depression.
Fentanyl: (Moderate) Concomitant use of fentanyl with cenobamate may cause excessive sedation and somnolence. Limit the use of fentanyl with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with cenobamate is necessary. If cenobamate is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like cenobamate with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Finerenone: (Major) Avoid concurrent use of finerenone and cenobamate due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased overall exposure to finerenone by 80%.
Flibanserin: (Major) Coadministration of flibanserin with cenobamate is not recommended due to decreased plasma concentrations of flibanserin. Flibanserin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased flibanserin exposure by approximately 21%. Additionally, additive CNS depression may occur.
Fluphenazine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Flurazepam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Fosamprenavir: (Moderate) Monitor for decreased fosamprenavir efficacy if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of fosamprenavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Fosamprenavir is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Fosphenytoin: (Major) Decrease fosphenytoin dosage by up to 50% as cenobamate is being titrated due to the potential for increased phenytoin exposure. Multiple doses of cenobamate increased phenytoin exposure by 84%.
Fruquintinib: (Major) Avoid coadministration of fruquintinib with cenobamate if possible due to decreased fruquintinib exposure and risk of decreased efficacy. If concomitant use of fruquintinib and cenobamate is necessary, monitor for decreased efficacy. Fruquintinib is a CYP3A substrate; cenobamate is a strong CYP3A inducer. Coadministration of a moderate CYP3A inducer is predicted to decrease fruquintinib exposure by 32%.
Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and gabapentin. Concurrent use may result in additive CNS depression.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and cenobamate due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
General anesthetics: (Moderate) Although CNS depression is a desired effect of general anesthetics, monitor patients also receiving cenobamate closely for additive CNS depression that may prolong recovery after administration of a general anesthetic.
Glasdegib: (Major) Avoid coadministration of glasdegib and cenobamate due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after cenobamate has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with cenobamate is not recommended due to the potential loss of efficacy of glecaprevir. Glecaprevir is a substrate of CYP3A4; cenobamate is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of glecaprevir.
Guanfacine: (Major) Monitor for excessive sedation and somnolence during coadministration of cenobamate and guanfacine. Concurrent use may result in additive CNS depression. Additionally, a dose increase of extended-release (ER) guanfacine should be considered if coadministration with cenobamate is necessary. Consider doubling the recommended dose of guanfacine if therapy is added to a patient already taking cenobamate; increase the dose of guanfacine over 1 to 2 weeks if cenobamate therapy is added to a patient already taking guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Haloperidol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and haloperidol. Concurrent use may result in additive CNS depression.
Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cenobamate may cause excessive sedation and somnolence. Limit the use of hydrocodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing hydrocodone cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of hydrocodone as needed. If cenobamate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone concentrations.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with cenobamate may cause excessive sedation and somnolence. Limit the use of hydrocodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing hydrocodone cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of hydrocodone as needed. If cenobamate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone concentrations.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with cenobamate may cause excessive sedation and somnolence. Limit the use of hydrocodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing hydrocodone cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of hydrocodone as needed. If cenobamate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone concentrations.
Hydromorphone: (Moderate) Concomitant use of hydromorphone with cenobamate may cause excessive sedation and somnolence. Limit the use of hydromorphone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Hydroxyzine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with cenobamate. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with cenobamate may cause excessive sedation and somnolence. Limit the use of oxycodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of oxycodone as needed. If cenobamate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with cenobamate is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; cenobamate is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
Iloperidone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and iloperidone. Concurrent use may result in additive CNS depression.
Imipramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Indinavir: (Moderate) Coadministration of indinavir with cenobamate may result in decreased plasma concentrations of indinavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Although specific recommendations are unavailable for use with cenobamate, an increased indinavir dose is recommended (i.e., 1,000 mg PO every 8 hours) when coadministered with other moderate CYP3A4 inducers. Indinavir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased indinavir exposure by up to 46%.
Infigratinib: (Major) Avoid concurrent use of infigratinib and cenobamate. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Isavuconazonium: (Moderate) Use caution when administering cenobamate and isavuconazonium due to the potential for a synergistic effect on the QT interval that would increase the QT shortening risk. Both cenobamate and isavuconazonium are associated with QT shortening. Nonclinical data indicate that QT shortening is associated with ventricular fibrillation.
Isocarboxazid: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and isocarboxazid. Concurrent use may result in additive CNS depression.
Isoflurane: (Moderate) Although CNS depression is a desired effect of general anesthetics, monitor patients also receiving cenobamate closely for additive CNS depression that may prolong recovery after administration of a general anesthetic.
Isradipine: (Moderate) Monitor for decreased efficacy of isradipine if coadministration with cenobamate is necessary. Isradipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration may decrease isradipine plasma concentrations.
Ketamine: (Moderate) Although CNS depression is a desired effect of general anesthetics, monitor patients also receiving cenobamate closely for additive CNS depression that may prolong recovery after administration of a general anesthetic.
Lamotrigine: (Major) Increase the dosage of lamotrigine as needed when coadministered with cenobamate due to the potential for reduced efficacy of lamotrigine. Coadministration of cenobamate and lamotrigine is expected to decrease lamotrigine concentrations by 21% to 52%.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Consider alternatives to clarithromycin if treatment with cenobamate is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Larotrectinib: (Major) Avoid concurrent use of larotrectinib and cenobamate due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If cenobamate is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cenobamate. Larotrectinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and lasmiditan. Concurrent use may result in additive CNS depression.
Lefamulin: (Major) Avoid coadministration of lefamulin with cenobamate unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer.
Lemborexant: (Major) Avoid coadministration of lemborexant and cenobamate as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Additive CNS effects, such as sedation and psychomotor impairment, are also possible.
Lenacapavir: (Major) Avoid concurrent use of lenacapavir and cenobamate due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Lenacapavir is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced lenacapavir overall exposure by 56%.
Leniolisib: (Major) Avoid concomitant use of leniolisib and cenobamate. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced leniolisib overall exposure by 58%.
Leuprolide; Norethindrone: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Levamlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Levocetirizine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and cetirizine. Concurrent use may result in additive CNS depression.
Levodopa: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and levodopa. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Levonorgestrel: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Levonorgestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Levorphanol: (Moderate) Concomitant use of levorphanol with cenobamate may cause excessive sedation and somnolence. Limit the use of levorphanol with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Lofexidine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and lofexidine. Concurrent use may result in additive CNS depression.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and cenobamate is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Lopinavir; Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Lorazepam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Lorlatinib: (Major) Avoid concomitant use of lorlatinib and cenobamate due to decreased plasma concentrations of lorlatinib, which may reduce its efficacy. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Lorlatinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%.
Loxapine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and loxapine. Concurrent use may result in additive CNS depression.
Lumateperone: (Major) Avoid coadministration of lumateperone and cenobamate as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer.
Lurasidone: (Moderate) If lurasidone is used with cenobamate, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more) with cenobamate. Concurrent use may lead to a decrease in efficacy of lurasidone. Cenobamate is a moderate CYP3A4 inducer; lurasidone is a CYP3A4 substrate. Additionally, monitor for excessive sedation and somnolence during coadministration of cenobamate and lurasidone. Concurrent use may result in additive CNS depression.
Maprotiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and maprotiline. Concurrent use may result in additive CNS depression.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with cenobamate due to risk of heart failure due to systolic dysfunction and risk for reduced mavacamten efficacy. Concomitant use may increase or decrease mavacamten exposure. Mavacamten is a CYP2C19 and CYP3A substrate and cenobamate is a moderate CYP2C19 inhibitor and moderate CYP3A inducer.
Meclizine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Medroxyprogesterone: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with cenobamate is necessary as concurrent use may decrease mefloquine exposure and efficacy. Mefloquine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Melatonin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and melatonin. Concurrent use may result in additive CNS depression.
Meperidine: (Moderate) Concomitant use of meperidine with cenobamate may cause excessive sedation and somnolence. Limit the use of meperidine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Meprobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and meprobamate. Concurrent use may result in additive CNS depression.
Metaxalone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and metaxalone. Concurrent use may result in additive CNS depression.
Metformin; Repaglinide: (Moderate) An increased dose of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with cenobamate is necessary. Repaglinide is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Methadone: (Moderate) Concomitant use of methadone with cenobamate may cause excessive sedation and somnolence. Limit the use of methadone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with cenobamate is necessary; these effects may be more pronounced with cenobamate as it can induce multiple CYP enzymes. Consider increasing the dose of methadone as needed. If cenobamate is discontinued, consider a dose reduction of methadone and frequently monitor for signs or respiratory depression and sedation. Methadone is a substrate of CYP3A4 and CYP2B6; cenobamate is a moderate CYP3A4 inducer and weak CYP2B6 inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Methocarbamol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and methocarbamol. Concurrent use may result in additive CNS depression.
Methohexital: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and methohexital. Concurrent use may result in additive CNS depression.
Methyldopa: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and methyldopa. Concurrent use may result in additive CNS depression.
Metoclopramide: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and metoclopramide. Concurrent use may result in additive CNS depression.
Midazolam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Mirtazapine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and mirtazapine. Concurrent use may result in additive CNS depression.
Mitapivat: (Major) Avoid coadministration of mitapivat with cenobamate, if possible, due to decreased mitapivat efficacy. Coadministration decreases mitapivat concentrations. If concomitant use is necessary, up-titration of mitapivat may be required. Monitor hemoglobin and titrate the mitapivat dose based on response; do not exceed 100 mg PO twice daily. Mitapivat is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased mitapivat overall exposure by 55% to 60%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and cenobamate. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Use of a moderate CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 58%.
Molindone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and molindone. Concurrent use may result in additive CNS depression.
Morphine: (Moderate) Concomitant use of morphine with cenobamate may cause excessive sedation and somnolence. Limit the use of morphine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Morphine; Naltrexone: (Moderate) Concomitant use of morphine with cenobamate may cause excessive sedation and somnolence. Limit the use of morphine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Nabilone: (Moderate) Concomitant use of cenobamate with other CNS depressants may increase the risk of neurological reactions, including sedation and somnolence.
Nalbuphine: (Moderate) Concomitant use of nalbuphine with cenobamate may cause excessive sedation and somnolence. Limit the use of nalbuphine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with cenobamate is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with cenobamate. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Nefazodone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and nefazodone. Concurrent use may result in additive CNS depression.
Neratinib: (Major) Avoid concomitant use of cenobamate with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
Nimodipine: (Moderate) Monitor for decreased efficacy of nimodipine if coadministration with cenobamate is necessary as concomitant use may decrease plasma concentrations of nimodipine. Nimodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of cenobamate is necessary. Concomitant use of nirmatrelvir and cenobamate may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and cenobamate. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with cenobamate as concurrent use may decrease nisoldipine exposure and efficacy. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Norethindrone: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Norethindrone; Ethinyl Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Norgestimate; Ethinyl Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Norgestrel: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Nortriptyline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Olanzapine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and olanzapine. Concurrent use may result in additive CNS depression.
Olanzapine; Fluoxetine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and olanzapine. Concurrent use may result in additive CNS depression.
Olanzapine; Samidorphan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and olanzapine. Concurrent use may result in additive CNS depression.
Olaparib: (Major) Avoid coadministration of olaparib with cenobamate due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and cenobamate is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with a moderate CYP3A inducer is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
Oliceridine: (Moderate) Concomitant use of oliceridine with cenobamate may cause excessive sedation and somnolence. Limit the use of oliceridine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Olutasidenib: (Major) Avoid concurrent use of olutasidenib and cenobamate due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Omaveloxolone: (Major) Avoid concurrent use of omaveloxolone and cenobamate. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxolone is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Opicapone: (Moderate) Opicapone should be given cautiously with other agents that cause CNS depression, including cenobamate, due to the possibility of additive sedation. COMT inhibitors, such as opicapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Orphenadrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and orphenadrine. Concurrent use may result in additive CNS depression.
Oxazepam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Oxycodone: (Moderate) Concomitant use of oxycodone with cenobamate may cause excessive sedation and somnolence. Limit the use of oxycodone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of oxycodone as needed. If cenobamate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Oxymorphone: (Moderate) Concomitant use of oxymorphone with cenobamate may cause excessive sedation and somnolence. Limit the use of oxymorphone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with cenobamate is necessary due to the risk of decreased paclitaxel concentrations of paclitaxel. Paclitaxel is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Pacritinib: (Major) Avoid concurrent use of pacritinib with cenobamate due to the risk of decreased pacritinib exposure which may impair efficacy. Pacritinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Paliperidone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and paliperidone. Concurrent use may result in additive CNS depression.
Palovarotene: (Major) Avoid concomitant use of palovarotene and cenobamate. Concurrent use may decrease palovarotene exposure which may reduce its efficacy. Palovarotene is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and cenobamate due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with cenobamate may cause excessive sedation and somnolence. Limit the use of pentazocine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Pentobarbital: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and pentobarbital. Concurrent use may result in additive CNS depression.
Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to cenobamate therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If cenobamate is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration may decrease perampanel plasma concentrations. Additionally, monitor for excessive sedation and somnolence during coadministration of cenobamate and perampanel. Concurrent use may result in additive CNS depression.
Perindopril; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Perphenazine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Perphenazine; Amitriptyline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Phenelzine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and phenelzine. Concurrent use may result in additive CNS depression.
Phenobarbital: (Major) Consider a dose reduction of phenobarbital when coadministered with cenobamate due to the potential for increased phenobarbital exposure and adverse effects. Multiple doses of cenobamate increased phenobarbital exposure by 37%. Also, concomitant use of cenobamate with phenobarbital may increase the risk of neurological adverse reactions, including sedation and somnolence.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Consider a dose reduction of phenobarbital when coadministered with cenobamate due to the potential for increased phenobarbital exposure and adverse effects. Multiple doses of cenobamate increased phenobarbital exposure by 37%. Also, concomitant use of cenobamate with phenobarbital may increase the risk of neurological adverse reactions, including sedation and somnolence. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and atropine. Concurrent use may result in additive CNS depression. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and scopolamine. Concurrent use may result in additive CNS depression.
Phenothiazines: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Phenytoin: (Major) Decrease phenytoin dosage by up to 50% as cenobamate is being titrated due to the potential for increased phenytoin exposure. Multiple doses of cenobamate increased phenytoin exposure by 84%.
Pimavanserin: (Major) Avoid coadministration of pimavanserin with cenobamate as concurrent use may decrease pimavanserin exposure which may lead to decreased efficacy. Pimavanserin is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Additionally, monitor for excessive sedation and somnolence during coadministration of cenobamate and pimavanserin. Concurrent use may result in additive CNS depression.
Pimozide: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and pimozide. Concurrent use may result in additive CNS depression.
Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and cenobamate due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. If concomitant use is necessary, an empiric pirtobrutinib dosage increase is required. If the current dosage is 200 mg once daily, increase the dose to 300 mg; if the current dosage is 50 mg or 100 mg once daily, increase the dose by 50 mg. Pirtobrutinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Pralsetinib: (Major) Avoid concurrent use of cenobamate and pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is necessary, increase the current dose of pralsetinib (400 mg to 600 mg; 300 mg to 500 mg; 200 mg to 300 mg) starting on day 7 of coadministration. Pralsetinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased the pralsetinib overall exposure by 45%.
Pramipexole: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and pramipexole. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as pramipexole, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Praziquantel: (Major) Avoid concomitant use of praziquantel and cenobamate. Concurrent use may decrease praziquantel exposure which may reduce its efficacy. If concomitant use is necessary, monitor for reduced response to praziquantel. Praziquantel is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. When praziquantel was administered after 13 days of treatment with a moderate CYP3A inducer, the mean praziquantel AUC was 77% lower than when praziquantel was given alone.
Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and pregabalin. Concurrent use may result in additive CNS depression.
Pretomanid: (Major) Avoid coadministration of pretomanid with cenobamate as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy. Pretomanid is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased pretomanid exposure by 35%.
Primidone: (Major) Consider a dose reduction of primidone when coadministered with cenobamate due to the potential for increased phenobarbital exposure and adverse effects. Multiple doses of cenobamate increased phenobarbital (active metabolite of primidone) exposure by 37%. Also, concomitant use of cenobamate with primidone may increase the risk of neurological adverse reactions, including sedation and somnolence.
Prochlorperazine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Progesterone: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Progestins: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Promethazine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Promethazine; Dextromethorphan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Promethazine; Phenylephrine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Propofol: (Moderate) Although CNS depression is a desired effect of general anesthetics, monitor patients also receiving cenobamate closely for additive CNS depression that may prolong recovery after administration of a general anesthetic.
Propranolol: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of cenobamate as concurrent use may increase propranolol exposure. Propranolol is a CYP2C19 substrate and cenobamate is a moderate CYP2C19 inhibitor.
Protriptyline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Pseudoephedrine; Triprolidine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Quazepam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Quetiapine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and quetiapine. Concurrent use may result in additive CNS depression.
Quizartinib: (Major) Avoid concomitant use of cenobamate with quizartinib due to the risk of decreased quizartinib exposure which may reduce its efficacy. Quizartinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased the quizartinib overall exposure by 90%.
Ramelteon: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and ramelteon. Concurrent use may result in additive CNS depression.
Ranolazine: (Contraindicated) Coadministration of ranolazine with cenobamate is contraindicated due to decreased ranolazine exposure and efficacy. Ranolazine is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%.
Rasagiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and rasagiline. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as rasagiline, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Relugolix; Estradiol; Norethindrone acetate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Remifentanil: (Moderate) Concomitant use of remifentanil with cenobamate may cause excessive sedation and somnolence. Limit the use of remifentanil with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Remimazolam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Repaglinide: (Moderate) An increased dose of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with cenobamate is necessary. Repaglinide is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with cenobamate due to decreased repotrectinib exposure and risk of decreased efficacy. Repotrectinib is a CYP3A substrate; cenobamate is a moderate CYP3A inducer.
Rilpivirine: (Moderate) Close clinical monitoring is advised when administering cenobamate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Cenobamate is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Rimegepant: (Major) Avoid coadministration of rimegepant with cenobamate; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Ripretinib: (Major) Avoid coadministration of ripretinib with cenobamate. If concomitant use is unavoidable, increase the frequency of ripretinib dosing from 150 mg once daily to 150 mg twice daily; monitor for clinical response and tolerability. Resume once daily dosing of ripretinib 14 days after discontinuation of cenobamate. Coadministration is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and cenobamate is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Risperidone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and risperidone. Concurrent use may result in additive CNS depression.
Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Ropinirole: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and ropinirole. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as ropinirole, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Rosiglitazone: (Moderate) Monitor for a decrease in rosiglitazone efficacy during concomitant use with cenobamate; adjust the dose of rosiglitazone based on clinical response. Coadministration may decrease the exposure of rosiglitazone. Rosiglitazone is a CYP2C8 substrate and cenobamate is a CYP2C8 inducer.
Rotigotine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and rotigotine. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as rotigotine, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Rufinamide: (Moderate) Use caution when administering cenobamate and rufinamide due to the potential for a synergistic effect on the QT interval that would increase the QT shortening risk. Both cenobamate and rufinamide are associated with QT shortening. Nonclinical data indicate that QT shortening is associated with ventricular fibrillation.
Safinamide: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and safinamide. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as safinamide, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Scopolamine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and scopolamine. Concurrent use may result in additive CNS depression.
Secobarbital: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and secobarbital. Concurrent use may result in additive CNS depression.
Sedating H1-blockers: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Segesterone Acetate; Ethinyl Estradiol: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
Selegiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and selegiline. Concurrent use may result in additive CNS depression.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and cenobamate due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with other moderate CYP3A4 inducers is predicted to decrease selpercatinib exposure by 40% to 70%.
Selumetinib: (Major) Avoid coadministration of selumetinib and cenobamate due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Sevoflurane: (Moderate) Although CNS depression is a desired effect of general anesthetics, monitor patients also receiving cenobamate closely for additive CNS depression that may prolong recovery after administration of a general anesthetic.
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with cenobamate is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A4 inducers.
Siponimod: (Moderate) Concomitant use of siponimod and cenobamate is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of cenobamate. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Sodium Oxybate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sodium oxybate. Concurrent use may result in additive CNS depression.
Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with cenobamate due to the potential for loss of antiviral efficacy. Concurrent use may significantly decrease velpatasvir plasma concentrations. Velpatasvir is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with cenobamate due to the potential for loss of antiviral efficacy. Concurrent use may significantly decrease velpatasvir plasma concentrations. Velpatasvir is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. (Major) Coadministration of voxilaprevir with cenobamate is not recommended due to decreased plasma concentrations of voxilaprevir, potentially resulting in loss of antiviral efficacy. Voxilaprevir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Solifenacin: (Moderate) Monitor for decreased efficacy of solifenacin if coadministration with cenobamate is necessary. Solifenacin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Studies have not been conducted to evaluate the effect of CYP3A4 inducers on solifenacin, but inducers of CYP3A4 may decrease solifenacin plasma concentrations.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and cenobamate; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer for 14 days decreased the geometric mean AUC of sonidegib by 56%; coadministration with a moderate CYP3A4 inducer for 4 months decreased the sonidegib AUC by 69%.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and stiripentol. Concurrent use may result in additive CNS depression.
Sufentanil: (Moderate) Concomitant use of sufentanil with cenobamate may cause excessive sedation and somnolence. Limit the use of sufentanil with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, concurrent use of sufentanil with cenobamate may decrease sufentanil plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of cenobamate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Cenobamate induces CYP3A4; sufentanil is a CYP3A4 substrate.
Suvorexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and suvorexant. Concurrent use may result in additive CNS depression.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with cenobamate is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cenobamate is a moderate CYP3A4 inducer.
Tapentadol: (Moderate) Concomitant use of tapentadol with cenobamate may cause excessive sedation and somnolence. Limit the use of tapentadol with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Tasimelteon: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tasimelteon. Concurrent use may result in additive CNS depression.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with cenobamate as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Telmisartan; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Temazepam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Tetrabenazine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tetrabenazine. Concurrent use may result in additive CNS depression.
Thalidomide: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and thalidomide. Concurrent use may result in additive CNS depression.
Thioridazine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Thiothixene: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and thiothixene. Concurrent use may result in additive CNS depression.
Tizanidine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tizanidine. Concurrent use may result in additive CNS depression.
Tolcapone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tolcapone. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as tolcapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Tramadol: (Moderate) Concomitant use of tramadol with cenobamate may cause excessive sedation and somnolence. Limit the use of tramadol with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of tramadol as needed. If cenobamate is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tramadol; Acetaminophen: (Moderate) Concomitant use of tramadol with cenobamate may cause excessive sedation and somnolence. Limit the use of tramadol with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of tramadol as needed. If cenobamate is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tranylcypromine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tranylcypromine. Concurrent use may result in additive CNS depression.
Trazodone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and trazodone. Concurrent use may result in additive CNS depression.
Triazolam: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Tricyclic antidepressants: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Trifluoperazine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and a phenothiazine. Concurrent use may result in additive CNS depression.
Trimipramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Triprolidine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with cenobamate as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer.
Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and cenobamate is a moderate CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
Valerian, Valeriana officinalis: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and valerian. Concurrent use may result in additive CNS depression.
Valproic Acid, Divalproex Sodium: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and valproic acid. Concurrent use may result in additive CNS depression.
Venetoclax: (Major) Avoid coadministration of venetoclax with cenobamate as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased venetoclax exposure by 71%.
Voclosporin: (Major) Avoid coadministration of voclosporin with cenobamate. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease voclosporin exposure by 70%.
Vonoprazan: (Major) Avoid concomitant use of vonoprazan and cenobamate due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and cenobamate due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan and cenobamate due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) Consider alternatives to clarithromycin if treatment with cenobamate is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Voriconazole: (Moderate) Monitor for reduced efficacy of voriconazole if coadministered with cenobamate as concurrent use may decrease voriconazole exposure. Although specific recommendations are unavailable for use with cenobamate, a dose adjustment may be necessary as a voriconazole dose increase to 400 mg PO twice daily is recommended when administered with another moderate CYP3A4 inducer. Voriconazole is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased voriconazole exposure by 77%.
Voxelotor: (Major) Avoid coadministration of voxelotor and cenobamate as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,000 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A; cenobamate is a moderate CYP3A inducer. Coadministration of voxelotor with a moderate CYP3A inducer is predicted to decrease voxelotor exposure by up to 24%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with cenobamate is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Cenobamate is a moderate CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zaleplon: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and zaleplon. Concurrent use increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Patients should be instructed to contact their provider immediately if these symptoms or behaviors occur.
Zanubrutinib: (Major) Avoid concurrent use of zanubrutinib and cenobamate due to the risk of decreased zanubrutinib exposure which may reduce its efficacy. If concomitant use is necessary, increase the zanubrutinib dose to 320 mg twice daily and monitor response. Resume the previous dose of zanubrutinib if cenobamate is discontinued. Zanubrutinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer decreased zanubrutinib exposure by 44%.
Ziprasidone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and ziprasidone. Concurrent use may result in additive CNS depression.
Zolpidem: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and zolpidem. Concurrent use increases the risk for CNS depression and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Patients should be instructed to contact their provider immediately if these symptoms or behaviors occur. Additionally, monitor for reduced therapeutic response to zolpidem as zolpidem exposure may be decreased. Zolpidem is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer.
Zuranolone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
The exact mechanism by which cenobamate exerts its therapeutic effect for the treatment of partial-onset seizures is not known. Cenobamate reduces repetitive neuronal firing by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of the gamma-aminobutyric acid (GABAA) ion channel.
Cenobamate is administered orally. The apparent volume of distribution of cenobamate is approximately 40 to 50 L. Plasma protein binding of cenobamate is 60% and independent of concentration in vitro. Cenobamate primarily binds to albumin. The primary metabolic pathways of cenobamate are glucuronidation by UGT2B7 and to a lesser extent by UGT2B4, and oxidation by CYP2A6, CYP2B6, CYP2E1 and to a lesser extent by CYP2C19, CYP3A4/5. After administration of radiolabeled cenobamate, unchanged cenobamate accounted for more than 98% of the total AUC of radioactivity in plasma. Unchanged cenobamate accounted for 6.8% of the dose which was mainly excreted in urine (6.4%). A mean of 93% 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. The apparent oral clearance of cenobamate is approximately 0.45 to 0.63 L/hour, and the apparent terminal half-life is 50 to 60 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2A6, CYP2B6, CYP2C19, CYP2E1, CYP3A4/5, UGT2B7, UGT2B4
Cenobamate is a substrate of CYP2A6, CYP2B6, CYP2C19, CYP2E1, CYP3A4/5, UGT2B7, and UGT2B4. Cenobamate inhibits CYP2B6, CYP2C19, and CYP3A. Cenobamate induces CYP2B6, CYP2C8, and CYP3A4.
-Route-Specific Pharmacokinetics
Oral Route
At least 88% of cenobamate is absorbed after oral administration, with median Tmax ranging from 1 to 4 hours. No clinically significant differences in cenobamate pharmacokinetics were observed after administration of a high-fat meal (800 to 1,000 calories with 50% fat). Cenobamate AUC increases in a greater than dose-proportional manner after single oral doses from 5 to 750 mg. Cenobamate Cmax increases in a dose-proportional manner. Steady-state plasma concentrations are reached after approximately 2 weeks. The pharmacokinetics of cenobamate are similar when used as monotherapy or as adjunctive therapy for partial seizures. Plasma Cmax and AUC for cenobamate crushed tablets mixed in water, administered either orally or through a nasogastric tube, were similar to whole tablets. The median Tmax for crushed tablets is 0.5 hours.
-Special Populations
Hepatic Impairment
Cenobamate AUC was 1.9- and 2.3-fold higher in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, respectively, compared to healthy subjects after a single oral 200 mg dose. Cenobamate AUC was 4.2-fold higher in subjects with severe hepatic impairment (Child-Pugh Class C) compared to healthy subjects after a single oral 100 mg dose.
Renal Impairment
Cenobamate AUC was 1.4- and 1.5-fold higher in subjects with mild (CrCl 60 to 89 mL/minute) and moderate (CrCl 30 to 59 mL/minute) renal impairment, respectively, compared to healthy subjects after a single 200 mg dose compared to healthy subjects. Cenobamate AUC did not significantly change in subjects with severe (CrCl less than 30 mL/minute) renal impairment compared to healthy controls after a single oral 100 mg dose. The effect of hemodialysis on cenobamate pharmacokinetics has not been studied.
Geriatric
No clinically significant differences in cenobamate pharmacokinetics were observed based on age (18 to 77 years).
Gender Differences
No clinically significant differences in cenobamate pharmacokinetics were observed based on gender.
Ethnic Differences
No clinically significant differences in cenobamate pharmacokinetics were observed based on race/ethnicity.