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  • CLASSES

    Carboxamide Anticonvulsants

    DEA CLASS

    Rx

    DESCRIPTION

    Oral anticonvulsant
    Indicated as monotherapy or adjunctive treatment of partial seizures
    May be better tolerated than oxcarbazepine

    COMMON BRAND NAMES

    Aptiom

    HOW SUPPLIED

    Aptiom Oral Tab: 200mg, 400mg, 600mg, 800mg

    DOSAGE & INDICATIONS

    For monotherapy or adjunctive treatment of partial seizures.
    NOTE: Eslicarbazepine is a prodrug for the active metabolite of oxcarbazepine and should therefore not be used as adjunctive therapy with oxcarbazepine.
    Oral dosage
    Adults

    Initially, 400 mg PO once daily. Treatment may be initiated at 800 mg PO once daily if the need for seizure reduction outweighs an increased risk of adverse reactions during initiation. Increase the dose in weekly increments of 400 to 600 mg based on clinical response and tolerability to the recommended maintenance dosage of 800 to 1,600 mg PO once daily. For monotherapy, consider the 800 mg PO once daily maintenance dose in patients who are unable to tolerate a 1,200 mg PO once daily dose. For adjunctive therapy, consider the 1,600 mg PO once daily maintenance dose in patients who do not achieve a satisfactory response with a 1,200 mg PO once daily dose. When discontinuing therapy, gradually withdraw eslicarbazepine because of the risk of seizures and status epilepticus.

    Children and Adolescents 4 to 17 years weighing more than 38 kg

    Initially, 400 mg PO once daily. Increase the dose in weekly increments of 400 mg based on clinical response and tolerability to the recommended maintenance dosage of 800 to 1,200 mg PO once daily. When discontinuing therapy, gradually withdraw eslicarbazepine because of the risk of seizures and status epilepticus.

    Children and Adolescents 4 to 17 years weighing 32 to 38 kg

    Initially, 300 mg PO once daily. Increase the dose in weekly increments of 300 mg based on clinical response and tolerability to the recommended maintenance dosage of 600 to 900 mg PO once daily. When discontinuing therapy, gradually withdraw eslicarbazepine because of the risk of seizures and status epilepticus.

    Children and Adolescents 4 to 17 years weighing 22 to 31 kg

    Initially, 300 mg PO once daily. Increase the dose in weekly increments of 300 mg based on clinical response and tolerability to the recommended maintenance dosage of 500 to 800 mg PO once daily. When discontinuing therapy, gradually withdraw eslicarbazepine because of the risk of seizures and status epilepticus.

    Children and Adolescents 4 to 17 years weighing 11 to 21 kg

    Initially, 200 mg PO once daily. Increase the dose in weekly increments of 200 mg based on clinical response and tolerability to the recommended maintenance dosage of 400 to 600 mg PO once daily. When discontinuing therapy, gradually withdraw eslicarbazepine because of the risk of seizures and status epilepticus.

    MAXIMUM DOSAGE

    Adults

    1,600 mg/day PO.

    Geriatric

    1,600 mg/day PO.

    Adolescents

    weighing more than 38 kg: 1,200 mg/day PO.
    weighing 32 to 38 kg: 900 mg/day PO.
    weighing 22 to 31 kg: 800 mg/day PO.

    Children

    4 to 12 years weighing more than 38 kg: 1,200 mg/day PO.
    4 to 12 years weighing 32 to 38 kg: 900 mg/day PO.
    4 to 12 years weighing 22 to 31 kg: 800 mg/day PO.
    4 to 12 years weighing 11 to 21 kg: 600 mg/day PO.
    1 to 3 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments recommended for mild to moderate hepatic impairment. The effects of severe hepatic impairment have not been evaluated, therefore use in this population is not recommended.

    Renal Impairment

    CrCl >= 50 mL/min: No dosage adjustment needed.
    CrCl < 50 mL/min: Reduce initial, titration, and maintenance dosages by 50%. May adjust titration and maintenance dosages according to clinical response.

    ADMINISTRATION

    Oral Administration

    May be taken with or without food.
    May be administered as a whole tablet or crushed.

    STORAGE

    Aptiom:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Eslicarbazepine hypersensitivity, oxcarbazepine hypersensitivity

    Eslicarbazepine is contraindicated in patients with a history of eslicarbazepine hypersensitivity or oxcarbazepine hypersensitivity.

    Abrupt discontinuation

    In general, abrupt discontinuation of anticonvulsants may precipitate rebound seizures. Gradually withdraw eslicarbazepine because of the risk of seizures and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.[56436]

    Depression, suicidal ideation

    In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. 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). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants 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—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. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised 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. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Hyponatremia

    Clinically significant hyponatremia (sodium < 125 mmol/L) may develop during treatment with eslicarbazepine. This is typically dose-related and appeared within the first 8 weeks of treatment and as early as after 3 days. Monitoring of sodium levels should be considered if eslicarbazepine is used with other medications known to decrease sodium levels or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity). Dosage adjustment or discontinuation may be needed depending on the severity of hyponatremia.

    Renal impairment

    The clearance of eslicarbazepine is reduced in patients with renal impairment. Dosage adjustments are recommended in patients with moderate to severe renal impairment (i.e., CrCl < 50 mL/min).

    Hepatic disease

    Use caution in patients with hepatic disease. No dosage adjustments are needed in patients with mild to moderate hepatic impairment; however, eslicarbazepine has not been studied in patients with severe hepatic impairment and is therefore not recommended in this population. Baseline evaluations of liver laboratory tests are recommended.

    Driving or operating machinery, ethanol intoxication

    Central nervous system effects, including somnolence and dizziness, are among the most frequently reported adverse effects of eslicarbazepine. Patients should be cautioned about engaging in tasks requiring mental alertness such as driving or operating machinery until they know how the drug will affect their cognition. Patients should also be informed about the additive central nervous system depressant effects of alcohol when used with anticonvulsants, acute ethanol intoxication should generally be avoided.

    Pregnancy

    No adequate and well controlled studies have been conducted with eslicarbazepine in pregnant women. Although there are no clinical trials documenting its effect in pregnant women, results of some animal studies indicate that eslicarbazepine may be teratogenic in humans. The documented cases of human teratogenicity of a related compound, carbamazepine, support this theory. Therefore, eslicarbazepine should only be used during pregnancy if the benefits of treatment clearly outweigh the risks to the fetus. Physicians are advised to recommend that pregnant patients receiving eslicarbazepine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry. Information on the registry can also be found at http://www.aedpregnancyregistry.org.

    Breast-feeding

    Eslicarbazepine is present in breast milk. The effects of eslicarbazepine are unknown. Consider the developmental and health benefits of breast-feeding along with the mothers clinical need for eslicarbazepine and any potential adverse effects on the breastfed infant. Previous American Academy of Pediatrics (AAP) recommendations consider the related drug, carbamazepine, to be usually compatible with breast-feeding; however, the AAP has not evaluated eslicarbazepine. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Use eslicarbazepine with caution in the geriatric adult due to the insufficient numbers of the elderly in epilepsy trials. Dose adjustment is necessary if creatinine clearance (CrCl) is less than 50 mL/minute in any patient.[56436] According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients 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 eslicarbazepine must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, some anticonvulsants may be used to treat disorders other than seizures (e.g., bipolar disorder, schizoaffective disorder, chronic neuropathic pain, migraine prevention). Determine effectiveness and tolerability to adjust doses. Therapeutic drug monitoring is not required or available for most anticonvulsants. Significant signs and symptoms of toxicity can occur at normal or low serum concentrations, and symptom control for seizures or behavior can occur at subtherapeutic serum concentrations. Obtaining serum medication concentrations may assist in identifying toxicity. Consider dose adjustments if high or toxic serum concentrations occur. Anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Anticonvulsants may also cause nausea/vomiting, dizziness, ataxia, somnolence/lethargy, incoordination, blurred or double vision, restlessness, toxic encephalopathy, anorexia, and headaches; these effects can increase the risk for falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity per the OBRA guidelines.[60742]

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 1.0-2.0
    angioedema / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    suicidal ideation / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    megaloblastic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known

    Moderate

    impaired cognition / Early / 4.0-7.0
    ataxia / Delayed / 4.0-6.0
    blurred vision / Early / 5.0-6.0
    depression / Delayed / 1.0-3.0
    constipation / Delayed / 2.0-2.0
    gastritis / Delayed / 0-2.0
    hyponatremia / Delayed / 2.0-2.0
    nystagmus / Delayed / 1.0-2.0
    memory impairment / Delayed / 1.0-2.0
    dysarthria / Delayed / 1.0-2.0
    peripheral edema / Delayed / 1.0-2.0
    hypertension / Early / 1.0-2.0
    cystitis / Delayed / 2.0-2.0
    hyperbilirubinemia / Delayed / 0-1.0
    hypochloremia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    aphasia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    physiological dependence / Delayed / Incidence not known

    Mild

    dizziness / Early / 20.0-28.0
    drowsiness / Early / 11.0-18.0
    nausea / Early / 10.0-16.0
    headache / Early / 13.0-15.0
    diplopia / Early / 9.0-11.0
    vomiting / Early / 6.0-10.0
    fatigue / Early / 4.0-7.0
    vertigo / Early / 2.0-6.0
    diarrhea / Early / 2.0-4.0
    tremor / Early / 2.0-4.0
    rash / Early / 1.0-3.0
    asthenia / Delayed / 2.0-3.0
    insomnia / Early / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    cough / Delayed / 1.0-2.0
    malaise / Early / Incidence not known
    lethargy / Early / Incidence not known
    psychomotor impairment / Early / Incidence not known

    DRUG INTERACTIONS

    Abemaciclib: (Major) Avoid coadministration of eslicarbazepine 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 eslicarbazepine 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 53%, 41%, and 29% respectively.
    Acetaminophen; Butalbital: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Acetaminophen; Butalbital; Caffeine: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered. (Moderate) Concomitant use of codeine with eslicarbazepine can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Eslicarbazepine is a moderate CYP3A4 inducer.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with eslicarbazepine can decrease dihydrocodeine levels, 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. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Eslicarbazepine is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with eslicarbazepine can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Eslicarbazepine is a moderate CYP3A4 inducer.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with eslicarbazepine is necessary; consider increasing the dose of oxycodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and eslicarbazepine 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.
    Aliskiren; Amlodipine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Additionally, eslicarbazepine is an inducer of the hepatic CYP3A4 isoenzyme thereby having the potential to lower the plasma levels of medications metabolized through these pathways. The effectiveness of medications such as alprazolam could theoretically be decreased.
    Amiodarone: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amiodarone, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of amiodarone if coadministered with eslicarbazepine.
    Amlodipine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Amlodipine; Atorvastatin: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary. (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as atorvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of atorvastatin if coadministered with eslicarbazepine. Adjust the dose of atorvastatin if clinically significant alterations in serum lipids are noted.
    Amlodipine; Benazepril: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Amlodipine; Olmesartan: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Amlodipine; Telmisartan: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Amlodipine; Valsartan: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Amobarbital: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Coadministration of eslicarbazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of lansoprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of eslicarbazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of omeprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Amphetamines: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Aprepitant, Fosaprepitant: (Major) Use caution if eslicarbazepine and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Eslicarbazepine is a moderate CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
    Aripiprazole: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as aripiprazole, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of aripiprazole if coadministered with eslicarbazepine. Dosage adjustments of aripirazole may be necessary. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.
    Artemether; Lumefantrine: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered. (Moderate) Concomitant use of codeine with eslicarbazepine can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Eslicarbazepine is a moderate CYP3A4 inducer.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with eslicarbazepine can decrease dihydrocodeine levels, 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. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Eslicarbazepine is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol: (Minor) Eslicarbazepine may inhibit the CYP2C19-mediated metabolism of carisoprodol resulting in increased concentrations of carisoprodol. Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. The formation of meprobamate (active metabolite of carisoprodol) is catalyzed by CYP2C19. CYP2C19 inhibitors such as eslicarbazepine could increase carisoprodol plasma concentrations and decrease meprobamate concentrations, with potential for enhanced CNS depressant effects. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with eslicarbazepine can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Eslicarbazepine is a moderate CYP3A4 inducer. (Minor) Eslicarbazepine may inhibit the CYP2C19-mediated metabolism of carisoprodol resulting in increased concentrations of carisoprodol. Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. The formation of meprobamate (active metabolite of carisoprodol) is catalyzed by CYP2C19. CYP2C19 inhibitors such as eslicarbazepine could increase carisoprodol plasma concentrations and decrease meprobamate concentrations, with potential for enhanced CNS depressant effects. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Aspirin, ASA; Omeprazole: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of omeprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with eslicarbazepine is necessary; consider increasing the dose of oxycodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and eslicarbazepine 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: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as atazanavir, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of atazanavir if coadministered with eslicarbazepine.
    Atazanavir; Cobicistat: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration may result in significant decreases in the plasma concentrations of the CYP3A4 substrates, cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as atazanavir, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of atazanavir if coadministered with eslicarbazepine.
    Atorvastatin: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as atorvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of atorvastatin if coadministered with eslicarbazepine. Adjust the dose of atorvastatin if clinically significant alterations in serum lipids are noted.
    Atorvastatin; Ezetimibe: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as atorvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of atorvastatin if coadministered with eslicarbazepine. Adjust the dose of atorvastatin if clinically significant alterations in serum lipids are noted.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Axitinib: (Major) Avoid coadministration of axitinib with eslicarbazepine 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 primarily metabolized by CYP3A4. Eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Barbiturates: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Bedaquiline: (Major) Avoid concurrent use of eslicarbazepine with bedaquiline. Eslicarbazepine is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with eslicarbazepine may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of eslicarbazepine may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If eslicarbazepine is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Eslicarbazepine is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Boceprevir: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; boceprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of boceprevir may decrease, resulting in decreased boceprevir efficacy. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of eslicarbazepine and boceprevir. Close clinical monitoring is advised when administering eslicarbazepine with boceprevir due to the potential for boceprevir treatment failure. If eslicarbazepine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment.
    Brigatinib: (Major) Avoid coadministration of brigatinib with eslicarbazepine 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 eslicarbazepine, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of eslicarbazepine, resume the brigatinib dose that was tolerated prior to initiation of eslicarbazepine. Brigatinib is a CYP3A4 substrate and eslicarbazepine 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 eslicarbazepine 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; eslicarbazepine is a moderate inducer of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and eslicarbazepine may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; eslicarbazepine induces CYP3A4.
    Buprenorphine: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer, such as eslicarbazepine, is used with a CYP3A4 substrate, such as buprenorphine. Moderate to strong CYP3A4 inducers may increase the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if a CYP3A4 inducer is added. Conversely, buprenorphine doses may need to be decreased if the CYP3A4 inducer discontinued. The effect of CYP3A4 inducers on buprenorphine implants has not been studied.
    Buprenorphine; Naloxone: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer, such as eslicarbazepine, is used with a CYP3A4 substrate, such as buprenorphine. Moderate to strong CYP3A4 inducers may increase the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if a CYP3A4 inducer is added. Conversely, buprenorphine doses may need to be decreased if the CYP3A4 inducer discontinued. The effect of CYP3A4 inducers on buprenorphine implants has not been studied.
    Butabarbital: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Carbamazepine: (Major) Because carbamazepine and eslicarbazepine are chemically related, coadministration may result in an increased incidence of adverse reactions. In addition, carbamazepine reduces the plasma concentration of eslicarbazepine. Dosage adjustment of eslicarbazepine and carbamazepine may be necessary based on efficacy and tolerability.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as eslicarbazepine, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
    Carisoprodol: (Minor) Eslicarbazepine may inhibit the CYP2C19-mediated metabolism of carisoprodol resulting in increased concentrations of carisoprodol. Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. The formation of meprobamate (active metabolite of carisoprodol) is catalyzed by CYP2C19. CYP2C19 inhibitors such as eslicarbazepine could increase carisoprodol plasma concentrations and decrease meprobamate concentrations, with potential for enhanced CNS depressant effects. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with eslicarbazepine can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Eslicarbazepine is a moderate CYP3A4 inducer.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with eslicarbazepine can decrease dihydrocodeine levels, 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. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Eslicarbazepine is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with eslicarbazepine can decrease dihydrocodeine levels, 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. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Eslicarbazepine is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Citalopram: (Moderate) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with eslicarbazepine, a CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors.
    Clarithromycin: (Major) Coadministration of eslicarbazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
    Clindamycin: (Moderate) Concomitant use of clindamycin and eslicarbazepine may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; eslicarbazepine is a moderate inducer of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clobazam: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated metabolism of clobazam resulting in increased concentrations of clobazam. Metabolism of the active metabolite of clobazam occurs primarily through CYP2C19. Extrapolation of pharmacogenomic data indicates that concurrent administration of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. A dosage reduction of clobazam may be necessary during co-administration of eslicarbazepine.
    Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of eslicarbazepine. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; eslicarbazepine is a CYP2C19 inhibitor.
    Clozapine: (Moderate) Eslicarbazepine is an inducer of CYP3A4, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary. In addition, clozapine can lower the seizure threshold, potentially reducing the effectiveness of eslicarbazepine in treating seizures. Monitor for increased seizure activity during concurrent use.
    Cobicistat: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration may result in significant decreases in the plasma concentrations of the CYP3A4 substrates, cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with eslicarbazepine due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and eslicarbazepine is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
    Codeine: (Moderate) Concomitant use of codeine with eslicarbazepine can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Eslicarbazepine is a moderate CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with eslicarbazepine can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Eslicarbazepine is a moderate CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with eslicarbazepine can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Eslicarbazepine is a moderate CYP3A4 inducer.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with eslicarbazepine can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Eslicarbazepine is a moderate CYP3A4 inducer.
    Cyclosporine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as cyclosporine, may result in decreased serum concentrations of the substrate. Cyclosporine concentrations should be monitored closely to avoid loss of clinical efficacy until a new steady-state cyclosporine concentration is achieved when eslicarbazepine is added to an existing cyclosporine regimen; conversely, if eslicarbazepine is discontinued, cyclosporine concentrations could increase.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as eslicarbazepine. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with eslicarbazepine is necessary. Dapsone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis).
    Darunavir: (Severe) Plasma concentrations of darunavir may be reduced if administered concurrently with eslicarbazepine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Darunavir is a substrates of CYP3A4.
    Darunavir; Cobicistat: (Severe) Plasma concentrations of darunavir may be reduced if administered concurrently with eslicarbazepine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Darunavir is a substrates of CYP3A4. (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration may result in significant decreases in the plasma concentrations of the CYP3A4 substrates, cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Severe) Plasma concentrations of darunavir may be reduced if administered concurrently with eslicarbazepine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Darunavir is a substrates of CYP3A4. (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration may result in significant decreases in the plasma concentrations of the CYP3A4 substrates, cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concurrent administration of eslicarbazepine with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir, which may result in decreased antiviral activity. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are metabolized by this enzyme. (Severe) Concurrent administration of eslicarbazepine with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir, which may result in decreased antiviral activity. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are metabolized by this enzyme. (Major) Concurrent administration of eslicarbazepine with ritonavir may result in decreased plasma concentrations of ritonavir. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Caution and close monitoring for decreased antiviral efficacy are advised if these drugs are administered together.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and eslicarbazepine. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; eslicarbazepine is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
    Dexlansoprazole: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of dexlansoprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Dienogest; Estradiol valerate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with eslicarbazepine can decrease dihydrocodeine levels, 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. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If eslicarbazepine is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Eslicarbazepine is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Dolutegravir; Rilpivirine: (Severe) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. CYP3A4 is primarily responsible for the metabolism of rilpivirine. The related anticonvulsants, carbamazepine and oxcarbazepine are contraindicated in combination with rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. Although not specifically mentioned by the manufacturer of rilpivirine, it may be prudent to avoid coadministration of eslicarbazepine and rilpivirine given the potential for an interaction based on the pharmacokinetic parameters of the drugs.
    Donepezil: (Moderate) The elimination of donepezil may be increased by concurrent administration of moderate to strong inducers of CYP3A4, such as carbamazepine, eslicarbazepine, or oxcarbazepine. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
    Donepezil; Memantine: (Moderate) The elimination of donepezil may be increased by concurrent administration of moderate to strong inducers of CYP3A4, such as carbamazepine, eslicarbazepine, or oxcarbazepine. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
    Doravirine: (Moderate) Concurrent administration of doravirine and eslicarbazepine may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and eslicarbazepine may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer.
    Doxorubicin: (Major) Eslicarbazepine is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of eslicarbazepine and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with eslicarbazepine is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; eslicarbazepine is a moderate inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as dronedarone, may result in decreased serum concentrations of the substrate. The concomitant use of dronedarone and CYP3A4 inducers should be avoided.
    Drospirenone: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Drospirenone; Estradiol: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Drospirenone; Ethinyl Estradiol: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Elbasvir; Grazoprevir: (Major) If possible, avoid concurrent administration of elbasvir with eslicarbazepine. Eslicarbazepine is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with eslicarbazepine. Eslicarbazepine is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response.
    Elvitegravir: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of elvitegravir, may result in significant decreases in the plasma concentrations of the CYP3A4 substrate, elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration may result in significant decreases in the plasma concentrations of the CYP3A4 substrates, cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of elvitegravir, may result in significant decreases in the plasma concentrations of the CYP3A4 substrate, elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration may result in significant decreases in the plasma concentrations of the CYP3A4 substrates, cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of elvitegravir, may result in significant decreases in the plasma concentrations of the CYP3A4 substrate, elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Severe) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. CYP3A4 is primarily responsible for the metabolism of rilpivirine. The related anticonvulsants, carbamazepine and oxcarbazepine are contraindicated in combination with rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. Although not specifically mentioned by the manufacturer of rilpivirine, it may be prudent to avoid coadministration of eslicarbazepine and rilpivirine given the potential for an interaction based on the pharmacokinetic parameters of the drugs.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Severe) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. CYP3A4 is primarily responsible for the metabolism of rilpivirine. The related anticonvulsants, carbamazepine and oxcarbazepine are contraindicated in combination with rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. Although not specifically mentioned by the manufacturer of rilpivirine, it may be prudent to avoid coadministration of eslicarbazepine and rilpivirine given the potential for an interaction based on the pharmacokinetic parameters of the drugs.
    Encorafenib: (Major) Avoid coadministration of encorafenib and eslicarbazepine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Entrectinib: (Major) Avoid coadministration of entrectinib with eslicarbazepine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; eslicarbazepine 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 eslicarbazepine is necessary at the initiation of erdafitinib therapy, administer the dose of erdafitinib as recommended (8 mg once daily with potential to increase the dose to 9 mg on days 14 to 21 based on phosphate levels and tolerability). If eslicarbazepine must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21), increase the dose of erdafitinib up to 9 mg. If eslicarbazepine is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Erlotinib: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with eslicarbazepine; however, the risk has not been clearly defined. 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 eslicarbazepine is a moderate CYP3A4 inducer.
    Escitalopram: (Moderate) The plasma concentration of escitalopram, a CYP2C19 and CYP3A4 substrate, may be altered when administered concurrently with eslicarbazepine, a CYP2C19 inhibitor and CYP3A4 inducer. Because escitalopram is extensively metabolized by both CYP2C19 and CYP3A4, the outcome of the interaction is unpredictable. If these drugs are used together, monitor for reduced efficacy of escitalopram as well as escitalopram-associated adverse reactions.
    Esomeprazole: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of esomeprazole; both enzymes are involved in the metabolism of esomeprazole. It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Esomeprazole; Naproxen: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of esomeprazole; both enzymes are involved in the metabolism of esomeprazole. It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Estradiol; Levonorgestrel: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Estradiol; Norethindrone: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Estradiol; Norgestimate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Desogestrel: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Etonogestrel: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Levonorgestrel: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Norelgestromin: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Norethindrone: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Norgestimate: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethinyl Estradiol; Norgestrel: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide if used concomitantly with eslicarbazepine. Eslicarbazepine is an inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer (phenytoin) resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp) (valproic acid).
    Exemestane: (Moderate) Use caution if coadministration of exemestane with eslicarbazepine is necessary, and monitor for a possible decrease in the efficacy of exemestane. Exemestane is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. In a pharmacokinetic interaction study (n = 10) with a strong CYP3A4 inducer, rifampicin (600 mg daily for 14 days), the mean Cmax and AUC of exemestane (single dose) decreased by 41% and 54%, respectively. The manufacturer of exemestane recommends a dose increase when concomitant use with a strong CYP3A4 inducer is necessary; recommendations are not available for moderate CYP3A4 inducers.
    Ezetimibe; Simvastatin: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as simvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of simvastatin if coadministered with eslicarbazepine. Adjust the dose of simvastatin if clinically significant alterations in serum lipds are noted.
    Fedratinib: (Major) Avoid coadministration of fedratinib with eslicarbazepine as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as eslicarbazepine, is not recommended.
    Fosamprenavir: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of the CYP3A4 substrate, fosamprenavir, may result in decreased serum concentrations of fosamprenavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral and anticonvulsant drugs are unknown. If fosamprenavir is added to anticonvulsant therapy, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen.
    Fosphenytoin: (Major) Phenytoin (and fosphenytoin) may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered. In addition, eslicarbazepine may inhibit the CYP2C19-mediated metabolism of phenytoin resulting in increased concentrations of phenytoin. Monitor phenytoin plasma concentrations if coadministered with eslicarbazepine and adjust the dose of phenytoin or fosphenytoin based on clinical response and serum concentration.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Guanfacine: (Major) Eslicarbazepine may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if eslicarbazepine is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If eslicarbazepine is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and eslicarbazepine is a moderate CYP3A4 inducer.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Hydrocortisone: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Hydrocodone is metabolized by CYP3A4. Coadministration may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with eslicarbazepine.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as eslicarbazepine. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Ibrutinib: (Moderate) Use ibrutinib and eslicarbazepine together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with eslicarbazepine is necessary; consider increasing the dose of oxycodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and eslicarbazepine 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 eslicarbazepine is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; eslicarbazepine is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Isavuconazonium: (Major) Concomitant use of isavuconazonium with eslicarbazepine may result in decreased serum concentrations of isavuconazonium and the potential for treatment failure. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; eslicarbazepine is an inducer of this enzyme. Caution and close monitoring for decreased antifungal efficacy are advised if these drugs are used together.
    Isocarboxazid: (Severe) MAOIs should not be coadministered at the same time with eslicarbazepine, a dibenzazepine-related drug. Hypertensive crises, seizures, coma, or circulatory collapse may occur in patients receiving this combination. At least 7 days should elapse between discontinuation of eslicarbazepine and initiation of an MAOI. MAOIs should be discontinued for a minimum of 14 days or longer if the clinical situation permits, before administering eslicarbazepine. When starting MAOI therapy after discontinuing eslicarbazepine, it is advised to begin the MAOI at one-half the normal starting dosage for at least the first week of therapy. Carefully monitor the patient. Watch carefully for other effects besides effects on blood pressure, such as sedation, confusion, and increased CNS depression. If eslicarbazepine is used for the treatment of epilepsy, be aware that MAOI effects can include lowering of seizure threshold in some patients.
    Ivabradine: (Major) Avoid coadministration of ivabradine and eslicarbazepine. Ivabradine is primarily metabolized by CYP3A4; eslicarbazepine is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g., eslicarbazepine), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lansoprazole: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of lansoprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Lansoprazole; Naproxen: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of lansoprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Lefamulin: (Major) Avoid coadministration of lefamulin with eslicarbazepine unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer.
    Leuprolide; Norethindrone: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Levonorgestrel: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and eslicarbazepine may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; eslicarbazepine induces CYP3A4.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with eslicarbazepine. Loperamide is metabolized by the hepatic enzyme CYP3A4; eslicarbazepine is an inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with eslicarbazepine. Loperamide is metabolized by the hepatic enzyme CYP3A4; eslicarbazepine is an inducer of this enzyme.
    Lopinavir; Ritonavir: (Major) Concurrent administration of eslicarbazepine with ritonavir may result in decreased plasma concentrations of ritonavir. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Caution and close monitoring for decreased antiviral efficacy are advised if these drugs are administered together.
    Lorlatinib: (Major) Avoid coadministration of lorlatinib with eslicarbazepine due to the potential for serious hepatotoxicity; the efficacy of lorlatinib may also be decreased. If concomitant use is unavoidable, monitor AST, ALT, and bilirubin 48 hours after initiating lorlatinib and at least 3 times during the first week after initiating lorlatinib. Monitor for changes in clinical response to lorlatinib. Depending upon the relative importance of each drug, discontinue lorlatinib or eslicarbazepine for persistent Grade 2 or higher hepatotoxicity. Lorlatinib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Severe hepatotoxicity occurred in healthy subjects receiving a single 100-mg dose of lorlatinib with multiple daily doses of a strong CYP3A4 inducer (n = 12); both drugs were also pregnane X receptor agonists (PXR). The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity with the concomitant use of moderate CYP3A inducers is unknown.
    Lovastatin: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as lovastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of lovastatin if coadministered with eslicarbazepine. Adjust the dose of lovastatin if clinically significant alterations in serum lipds are noted.
    Lovastatin; Niacin: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as lovastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of lovastatin if coadministered with eslicarbazepine. Adjust the dose of lovastatin if clinically significant alterations in serum lipds are noted.
    Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may occur when the drug is co-administered with inducers of CYP3A4 such as eslicarbazepine. Concurrent use of lurasidone and eslicarbazepine may lead to a decrease in efficacy of lurasidone. If lurasidone is used with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more).
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with eslicarbazepine is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and eslicarbazepine is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
    Mephobarbital: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Mestranol; Norethindrone: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Methohexital: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Monoamine oxidase inhibitors: (Severe) MAOIs should not be coadministered at the same time with eslicarbazepine, a dibenzazepine-related drug. Hypertensive crises, seizures, coma, or circulatory collapse may occur in patients receiving this combination. At least 7 days should elapse between discontinuation of eslicarbazepine and initiation of an MAOI. MAOIs should be discontinued for a minimum of 14 days or longer if the clinical situation permits, before administering eslicarbazepine. When starting MAOI therapy after discontinuing eslicarbazepine, it is advised to begin the MAOI at one-half the normal starting dosage for at least the first week of therapy. Carefully monitor the patient. Watch carefully for other effects besides effects on blood pressure, such as sedation, confusion, and increased CNS depression. If eslicarbazepine is used for the treatment of epilepsy, be aware that MAOI effects can include lowering of seizure threshold in some patients.
    Neratinib: (Major) Avoid concomitant use of eslicarbazepine with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. The effect of moderate CYP3A4 induction on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inducer decreased neratinib exposure by 87% and decreased exposure to active metabolites M6 and M7 by 37% to 49%. Because of the significant impact on neratinib exposure from strong CYP3A4 induction, the potential impact on neratinib efficacy from concomitant use with moderate CYP3A4 inducers should be considered as they may also significantly decrease neratinib exposure.
    Niacin; Simvastatin: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as simvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of simvastatin if coadministered with eslicarbazepine. Adjust the dose of simvastatin if clinically significant alterations in serum lipds are noted.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with eslicarbazepine due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and eslicarbazepine is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Norethindrone: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Norgestrel: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Olaparib: (Major) Avoid the coadministration of olaparib with eslicarbazepine due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concurrent administration of eslicarbazepine with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir, which may result in decreased antiviral activity. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are metabolized by this enzyme. (Major) Concurrent administration of eslicarbazepine with ritonavir may result in decreased plasma concentrations of ritonavir. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Caution and close monitoring for decreased antiviral efficacy are advised if these drugs are administered together.
    Omeprazole: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of omeprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Omeprazole; Sodium Bicarbonate: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of omeprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Oral Contraceptives: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Oxcarbazepine: (Severe) Eslicarbazepine is a prodrug for the active metabolite of oxcarbazepine and should therefore not be used as adjunctive therapy with oxcarbazepine.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with eslicarbazepine is necessary; consider increasing the dose of oxycodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and eslicarbazepine 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.
    Pentobarbital: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with eslicarbazepine due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of eslicarbazepine occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Eslicarbazepine is a CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Perindopril; Amlodipine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Phenelzine: (Severe) MAOIs should not be coadministered at the same time with eslicarbazepine, a dibenzazepine-related drug. Hypertensive crises, seizures, coma, or circulatory collapse may occur in patients receiving this combination. At least 7 days should elapse between discontinuation of eslicarbazepine and initiation of an MAOI. MAOIs should be discontinued for a minimum of 14 days or longer if the clinical situation permits, before administering eslicarbazepine. When starting MAOI therapy after discontinuing eslicarbazepine, it is advised to begin the MAOI at one-half the normal starting dosage for at least the first week of therapy. Carefully monitor the patient. Watch carefully for other effects besides effects on blood pressure, such as sedation, confusion, and increased CNS depression. If eslicarbazepine is used for the treatment of epilepsy, be aware that MAOI effects can include lowering of seizure threshold in some patients.
    Phenobarbital: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Phenytoin: (Moderate) An increased dose of eslicarbazepine may be necessary if these drugs are coadministered. Phenytoin may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. In addition, eslicarbazepine may inhibit the CYP2C19-mediated metabolism of phenytoin resulting in increased concentrations of phenytoin. Monitor phenytoin plasma concentrations if coadministered with eslicarbazepine and adjust the dose of phenytoin based on clinical response and serum concentration.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as eslicarbazepine. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Praziquantel: (Moderate) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with eslicarbazepine, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Primidone: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Quetiapine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4 thereby having the potential to lower the plasma levels of medications metabolized through these pathways. The effectiveness of CNS medications such as quetiapine could theoretically be decreased.
    Rabeprazole: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of rabeprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Ranolazine: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers. In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with eslicarbazepine may result in decreased ranolazine plasma concentrations and decreased efficacy.
    Rilpivirine: (Severe) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. CYP3A4 is primarily responsible for the metabolism of rilpivirine. The related anticonvulsants, carbamazepine and oxcarbazepine are contraindicated in combination with rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. Although not specifically mentioned by the manufacturer of rilpivirine, it may be prudent to avoid coadministration of eslicarbazepine and rilpivirine given the potential for an interaction based on the pharmacokinetic parameters of the drugs.
    Ritonavir: (Major) Concurrent administration of eslicarbazepine with ritonavir may result in decreased plasma concentrations of ritonavir. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Caution and close monitoring for decreased antiviral efficacy are advised if these drugs are administered together.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and eslicarbazepine may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Eslicarbazepine is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
    Secobarbital: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Selegiline: (Severe) MAOIs should not be coadministered at the same time with eslicarbazepine, a dibenzazepine-related drug. Hypertensive crises, seizures, coma, or circulatory collapse may occur in patients receiving this combination. At least 7 days should elapse between discontinuation of eslicarbazepine and initiation of an MAOI. MAOIs should be discontinued for a minimum of 14 days or longer if the clinical situation permits, before administering eslicarbazepine. When starting MAOI therapy after discontinuing eslicarbazepine, it is advised to begin the MAOI at one-half the normal starting dosage for at least the first week of therapy. Carefully monitor the patient. Watch carefully for other effects besides effects on blood pressure, such as sedation, confusion, and increased CNS depression. If eslicarbazepine is used for the treatment of epilepsy, be aware that MAOI effects can include lowering of seizure threshold in some patients.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and eslicarbazepine. Induction of CYP3A4 by eslicarbazepine may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Simvastatin: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as simvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of simvastatin if coadministered with eslicarbazepine. Adjust the dose of simvastatin if clinically significant alterations in serum lipds are noted.
    Simvastatin; Sitagliptin: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as simvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of simvastatin if coadministered with eslicarbazepine. Adjust the dose of simvastatin if clinically significant alterations in serum lipds are noted.
    Siponimod: (Moderate) Concomitant use of siponimod and eslicarbazepine 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; eslicarbazepine 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) Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Agents that induce CYP3A4, such as eslicarbazepine, may affect absorption and elimination of sirolimus leading to decreased blood concentrations. Monitor sirolimus serum concentrations carefully if an inducer of CYP3A4 needs to be used concomitantly.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with eslicarbazepine. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; eslicarbazepine is an inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with eslicarbazepine. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; eslicarbazepine is an inducer of CYP3A4. (Major) Avoid coadministration of voxilaprevir (a CYP3A4 substrate) with moderate to strong inducers of CYP3A4, such as eslicarbazepine. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and eslicarbazepine; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and eslicarbazepine is a CYP3A4 inducer in vitro. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if eslicarbazepine must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with eslicarbazepine is necessary; consider increasing the dose of sufentanil injection as needed. If eslicarbazepine is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Sunitinib: (Major) Avoid coadministration of eslicarbazepine with sunitinib if possible due to decreased exposure to sunitinib which could decrease efficacy. If concomitant use is unavoidable, consider increasing the dose of sunitinib in 12.5 mg increments based on individual safety and tolerability to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily; monitor carefully for toxicity. The maximum daily dose administered in the pNET study was 50 mg. Sunitinib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Tacrolimus: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Tacrolimus is a CYP3A4 substrate. Eslicarbazepine may potentially accelerate the hepatic metabolism of tacrolimus. Clinicians should be alert to decreased effectiveness of tacrolimus; dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and eslicarbazepine. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as eslicarbazepine, may reduce the efficacy of tasimelteon.
    Telaprevir: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Telaprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of telaprevir may decrease, resulting in decreased telaprevir efficacy. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of eslicarbazpine and telaprevir. Close clinical monitoring is advised when administering eslicarbazpine with telaprevir due to the potential for telaprevir treatment failure.
    Terbinafine: (Moderate) Caution is advised when administering terbinafine with eslicarbazepine. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C19 and CYP3A4; eslicarbazepine is an inducer of CYP3A4 and an inhibitor of CYP2C19. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
    Thiopental: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
    Tolvaptan: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Tolvaptan is metabolized by CYP3A4. Coadministration of eslicarbazepine with tolvaptan may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy. The concomitant use of tolvaptan and CYP3A4 inducers should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and eslicarbazepine is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducer.
    Tranylcypromine: (Severe) MAOIs should not be coadministered at the same time with eslicarbazepine, a dibenzazepine-related drug. Hypertensive crises, seizures, coma, or circulatory collapse may occur in patients receiving this combination. At least 7 days should elapse between discontinuation of eslicarbazepine and initiation of an MAOI. MAOIs should be discontinued for a minimum of 14 days or longer if the clinical situation permits, before administering eslicarbazepine. When starting MAOI therapy after discontinuing eslicarbazepine, it is advised to begin the MAOI at one-half the normal starting dosage for at least the first week of therapy. Carefully monitor the patient. Watch carefully for other effects besides effects on blood pressure, such as sedation, confusion, and increased CNS depression. If eslicarbazepine is used for the treatment of epilepsy, be aware that MAOI effects can include lowering of seizure threshold in some patients.
    Triazolam: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4 thereby having the potential to lower the plasma levels of medications metabolized through these pathways. The effectiveness of medications such as triazolam could theoretically be decreased.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and eslicarbazepine is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and eslicarbazepine; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Vinblastine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Use caution when administering vinblastine concurrently with a CYP3A4 inducer. Vinblastine is metabolized by CYP3A4 and eslicarbazepine may decrease vinblastine plasma concentrations.
    Vincristine Liposomal: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including eslicarbazepines. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vincristine: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including eslicarbazepines. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and eslicarbazepine. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with eslicarbazepine, a CYP3A inducer.
    Voxelotor: (Major) Avoid coadministration of voxelotor and eslicarbazepine as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,500 mg PO once daily. Voxelotor is a substrate of CYP3A4; eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease voxelotor exposure by up to 60%.
    Warfarin: (Moderate) Coadministration of eslicarbazepine and warfarin may result in decreased efficacy of warfarin. Monitoring of INR during coadministration, particularly during eslicarbazepine titration and upon discontinuation of concomitant therapy, is recommened. Adjust the warfarin dose accordingly.
    Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and eslicarbazepine. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. The AUC of zanubrutinib is predicted to decrease by 60% when coadministered with another moderate CYP3A4 inducer.
    Ziprasidone: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with eslicarbazepine.
    Zolpidem: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as eslicarbazepine. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamics effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate and well controlled studies have been conducted with eslicarbazepine in pregnant women. Although there are no clinical trials documenting its effect in pregnant women, results of some animal studies indicate that eslicarbazepine may be teratogenic in humans. The documented cases of human teratogenicity of a related compound, carbamazepine, support this theory. Therefore, eslicarbazepine should only be used during pregnancy if the benefits of treatment clearly outweigh the risks to the fetus. Physicians are advised to recommend that pregnant patients receiving eslicarbazepine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry. Information on the registry can also be found at http://www.aedpregnancyregistry.org.

    Eslicarbazepine is present in breast milk. The effects of eslicarbazepine are unknown. Consider the developmental and health benefits of breast-feeding along with the mothers clinical need for eslicarbazepine and any potential adverse effects on the breastfed infant. Previous American Academy of Pediatrics (AAP) recommendations consider the related drug, carbamazepine, to be usually compatible with breast-feeding; however, the AAP has not evaluated eslicarbazepine. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Eslicarbazepine acetate is a voltage-gated sodium channel (VGSC) blocker. Like most anticonvulsants, the exact mechanism of action of eslicarbazepine acetate as an antiepileptic drug is unknown. In vitro studies indicate that eslicarbazepine and its metabolites competitively interact with site 2 of the inactivated state of VGSC, inhibiting sustained repetitive neuronal firing. Eslicarbazepine has a much higher affinity for the inactivated state of VGSC than the resting state, suggesting an enhanced inhibitory selectivity for rapidly firing neurons over those displaying normal activity. Eslicarbazepine does not appear to interact with benzodiazepine, GABA, and glutamate receptors.

    PHARMACOKINETICS

    Eslicarbazepine acetate is administered orally. Plasma protein binding is relatively low (less than 40%) and independent of concentration. Eslicarbazepine acetate is rapidly metabolized to the primary active metabolite eslicarbazepine via hydrolytic first-pass metabolism. The metabolites are primarily renally excreted unchanged and as glucuronide conjugates. In healthy subjects with normal renal function, the renal clearance of eslicarbazepine is substantially lower than glomerular filtration rate (approximately 20 mL/minute vs. 80 to 120 mL/minute, respectively), suggesting that renal tubular reabsorption occurs. The apparent plasma half-life in epileptic patients was 13 to 20 hours.
     
    Affected cytochrome P450 isoenzymes: CYP2C19, CYP3A4
    In in vitro studies, eslicarbazepine acetate was found to be a moderate inhibitor of CYP2C19 and an inducer of CYP3A4. No clinically relevant inhibitory effects were noted on CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, and CYP3A4. In studies with eslicarbazepine in fresh human hepatocytes, there was no induction of enzymes involved in glucuronidation and sulfation of 7-hydroxy-coumarin. A mild activation of UGT1A1-mediated glucuronidation was observed in human hepatic microsomes. Eslicarbazepine does not appear to undergo autoinduction.

    Oral Route

    After oral administration, peak plasma concentrations are reached within 1 to 4 hours while steady state levels are attained within 4 to 5 days of once daily dosing. Food has no effect on the pharmacokinetics of eslicarbazepine.