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Eslicarbazepine

Pronunciation

(es li kar BAZ e peen)

Index Terms

  • Eslicarbazepine Acetate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Aptiom: 200 mg [scored]

Aptiom: 400 mg

Aptiom: 600 mg, 800 mg [scored]

Brand Names: U.S.

  • Aptiom

Pharmacologic Category

  • Anticonvulsant, Miscellaneous

Pharmacology

Eslicarbazepine acetate is extensively converted to eslicarbazepine, which is considered responsible for therapeutic effects. A precise mechanism has not been defined, but is thought to involve inhibition of voltage-gated sodium channels.

Distribution

Vd: 0.87 L/kg

Metabolism

Rapidly and extensively metabolized by hydrolytic first-pass metabolism to the major active metabolite eslicarbazepine and minor active metabolites (R)-licarbazepine and oxcarbazepine; active metabolites are further metabolized to inactive glucuronides.

Excretion

Urine (90%; ~66% eslicarbazepine, ~33% glucuronide conjugate forms, ~10% other minor metabolites)

Time to Peak

Eslicarbazepine: 1-4 hours

Half-Life Elimination

13-20 hours

Protein Binding

<40%

Special Populations: Renal Function Impairment

Following a single 800 mg dose, systemic exposure was increased by 62% with mild renal impairment (CrCl 50-80 mL/minute), 2-fold with moderate renal impairment (CrCl 30-49 mL/minute), and 2.5-fold with severe renal impairment (CrCl <30 mL/minute). Repeated hemodialysis removes metabolites from systemic circulation in patients with end stage renal disease.

Use: Labeled Indications

Partial-onset seizures (epilepsy): Monotherapy or adjunctive therapy in the treatment of partial-onset seizures

Contraindications

Hypersensitivity to eslicarbazepine, oxcarbazepine, or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to carbamazepine; history of, or presence of, second- or third-degree atrioventricular block

Dosing: Adult

Partial-onset seizures (epilepsy):

Monotherapy: Oral: Initial: 400 mg once daily; may initiate treatment at 800 mg once daily if seizure reduction outweighs risk of adverse reactions during initiation. Increase in weekly increments of 400 mg to 600 mg based on clinical response and tolerability. Maintenance: 800 mg to 1,600 mg once daily. Note: Consider 800 mg once daily for maintenance therapy in patients not tolerating 1,200 mg once daily.

Adjunctive therapy: Oral: Initial: 400 mg once daily; may initiate treatment at 800 mg once daily if seizure reduction outweighs risk of adverse reactions during initiation. Increase in weekly increments of 400 mg to 600 mg, based on clinical response and tolerability. Maintenance: 800 mg to 1,600 mg once daily. Note: Consider 1,600 mg once daily for maintenance therapy in patients not achieving response on 1,200 mg daily dosage.

Dosage adjustment with concomitant antiepileptic drugs (AEDs):

Adjunctive therapy:

Carbamazepine: Dose adjustment of eslicarbazepine or carbamazepine may be needed for efficacy or tolerability.

Other enzyme-inducing antiepileptic drugs (eg, phenobarbital, phenytoin, primidone): Dosage of eslicarbazepine may need to be increased.

Oxcarbazepine: Concomitant use is not recommended.

Dosing: Renal Impairment

Mild impairment (CrCl ≥50 to 80 mL/minute): There are no dosage adjustments provided in the manufacturer’s labeling; systemic exposure increased 62% following a single 800 mg dose.

Moderate to severe renal impairment (CrCl <50 mL/minute): Reduce initial, titration, and maintenance dosage by 50%; may base titration and maintenance dosage adjustments on clinical response.

End-stage renal disease (ESRD) undergoing hemodialysis: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Repeated dialysis removes metabolites.

Dosing: Hepatic Impairment

Mild to moderate hepatic impairment: No dosage adjustment necessary.

Severe hepatic impairment: Use is not recommended (has not been studied).

Administration

Administer with or without food; tablets may be swallowed whole or crushed.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Avoid combination

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Avoid combination

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Avoid combination

CarBAMazepine: May enhance the adverse/toxic effect of Eslicarbazepine. CarBAMazepine may decrease the serum concentration of Eslicarbazepine. Monitor therapy

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clarithromycin: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Clarithromycin. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and impair its efficacy. Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CloZAPine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CloZAPine. Monitor therapy

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Avoid combination

Contraceptives (Estrogens): Eslicarbazepine may decrease the serum concentration of Contraceptives (Estrogens). Management: Alternative non-hormonal means of birth control should be considered for women of child-bearing potential. Consider therapy modification

Contraceptives (Progestins): Eslicarbazepine may decrease the serum concentration of Contraceptives (Progestins). Management: Alternative, non-hormonal means of birth control should be considered for women of child-bearing potential. Consider therapy modification

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP3A4 Substrates: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

Dasabuvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dasabuvir. Avoid combination

Elbasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir. Avoid combination

Estriol (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical). Monitor therapy

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Monitor therapy

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Avoid combination

Fosphenytoin: May decrease the serum concentration of Eslicarbazepine. (based on studies with phenytoin) Eslicarbazepine may increase the serum concentration of Fosphenytoin. (based on studies with phenytoin) Monitor therapy

Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with moderate CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if moderate CYP3A4 inducer therapy is just beginning. Consider therapy modification

HYDROcodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Management: Although moderate CYP3A inducers are not specifically contraindicated with ibrutinib, prescribing information indicates that they may decrease AUC up to 3-fold. If possible, alternatives with less CYP3A induction should be considered. Consider therapy modification

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy

Mirodenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenafil. Monitor therapy

NiMODipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine. Monitor therapy

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Avoid combination

Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy

OXcarbazepine: Eslicarbazepine may enhance the adverse/toxic effect of OXcarbazepine. Avoid combination

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers. Consider therapy modification

PHENobarbital: May decrease the serum concentration of Eslicarbazepine. Monitor therapy

Phenytoin: May decrease the serum concentration of Eslicarbazepine. Eslicarbazepine may increase the serum concentration of Phenytoin. Monitor therapy

Primidone: May decrease the serum concentration of Eslicarbazepine. (based on studies with phenobarbital) Monitor therapy

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Avoid combination

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Management: Monitor for reduced rolapitant response. Recommended dexamethasone regimens should be used with rolapitant. Higher dexamethasone doses or more prolonged use may increase the potential for a significant interaction. Monitor therapy

Rosuvastatin: Eslicarbazepine may decrease the serum concentration of Rosuvastatin. Monitor therapy

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Avoid combination

Simvastatin: Eslicarbazepine may decrease the serum concentration of Simvastatin. Monitor therapy

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Avoid combination

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Avoid combination

Warfarin: Eslicarbazepine may decrease the serum concentration of Warfarin. Specifically, S-warfarin serum concentrations may be decreased. Monitor therapy

Zolpidem: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zolpidem. Monitor therapy

Adverse Reactions

Frequency not always defined.

Cardiovascular: Hypertension (2%), peripheral edema (2%)

Central nervous system: Dizziness (20% to 28%), drowsiness (16% to 28%, including fatigue, hypersomnia, sedation, lethargy, and malaise), headache (13% to 15%), fatigue (7%), cognitive dysfunction (4% to 7%, including aphasia, lack of concentration, psychomotor retardation, speech disturbance), ataxia (4% to 6%), vertigo (2% to 6%), depression (3%), equilibrium disturbance (3%), falling (3%), abnormal gait (2%), insomnia (2%), dysarthria (1% to 2%), memory impairment (1% to 2%)

Dermatologic: Skin rash (3%)

Endocrine & metabolic: Decreased serum sodium (>10 mEq/L: 5%), hyponatremia (serum sodium <125 mEq/L: 1% to 2%), hypercholesterolemia, increased LDL cholesterol, increased serum triglycerides

Gastrointestinal: Nausea (10% to 16%), vomiting (6% to 10%), diarrhea (4%), abdominal pain (2%), constipation (2%), gastritis (2%)

Genitourinary: Urinary tract infection (2%)

Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin

Neuromuscular & skeletal: Tremor (2% to 4%), weakness (3%), increased creatine phosphokinase

Ophthalmic: Diplopia (9% to 11%), blurred vision (5% to 6%), decreased visual acuity (2%), nystagmus (1% to 2%)

Frequency not defined, postmarketing, and/or case reports (Limited to important or life-threatening): Amnesia, anaphylaxis, angioedema, bradyphrenia, confusion, decreased T3 level, decreased T4 (free and total), disorientation, DRESS syndrome, hypochloremia (concurrent with hyponatremia), increased serum bilirubin (>2 x ULN), increased serum transaminases (>3 x ULN), prolongation P-R interval on ECG (mild [Vas-da-Silva 2012]), severe dermatological reaction, Stevens-Johnson syndrome

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Use has been associated with dose-dependent CNS-related adverse events, most significant of these were cognitive symptoms (eg, memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, psychomotor retardation), somnolence or fatigue, dizziness and coordination abnormalities (eg, ataxia, vertigo, balance disorder, gait disturbance, nystagmus, abnormal coordination), and visual changes (eg, diplopia, blurred vision, impaired vision). There was an increased risk of visual changes and dizziness and coordination abnormalities during the titration period, in patients >60 years of age, and with concomitant carbamazepine use; consider dosage modifications in patients using eslicarbazepine and carbamazepine concomitantly. Caution patients about performing tasks which require mental alertness (eg, operating machinery or driving).

• Dermatologic reactions: Potentially serious, sometimes fatal, dermatologic reactions including Stevens-Johnson syndrome (SJS) have been reported; monitor for signs and symptoms of skin reactions; discontinuation and conversion to alternate therapy may be required. Avoid use in patients with prior dermatologic reaction with either oxcarbazepine or eslicarbazepine.

• Hepatic effects: Hepatic effects ranging from mild to moderate elevations in transaminases (>3 times the upper limit of normal) to rare cases of concomitant elevations of total bilirubin (>2 times the upper limit of normal) have been reported. Perform baseline liver laboratory tests. Discontinue in patients with jaundice or other evidence of significant liver injury.

• Hypersensitivity reactions: Rare cases of anaphylaxis and angioedema have been reported. Permanently discontinue should symptoms occur. Avoid use in patients with a prior anaphylactic-type reaction with either oxcarbazepine or eslicarbazepine.

• Hyponatremia: Clinically-significant hyponatremia (serum sodium <125 mmol/L) and concurrent hypochloremia may develop during use; in controlled trials effects were dose-related and appeared within the first 8 weeks of treatment (as early as after 3 days). Consider monitoring serum sodium and chloride levels during maintenance treatment, especially in patients at risk for hyponatremia and if symptoms of hyponatremia develop. Depending on the severity of hyponatremia, the dose of eslicarbazepine may need to be reduced or discontinued.

• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, have been reported. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Evaluate immediately if signs or symptoms are present. Discontinuation and conversion to alternate therapy may be required. Avoid use in patients with a prior DRESS reaction with either oxcarbazepine or eslicarbazepine.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; patients should be instructed to notify healthcare provider immediately if symptoms occur.

• Thyroid function: Dose-dependent decreases in serum T3 and T4 (free and total) values have been observed; changes were not associated with other abnormal thyroid function tests suggesting hypothyroidism.

Disease-related concerns:

• Renal impairment: Clearance is decreased in patients with impaired renal function; dosage adjustment is necessary in patients with CrCl <50 mL/minute.

• Hepatic impairment: Avoid use in patients with severe hepatic impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Monitoring Parameters

Seizure frequency; liver enzymes (baseline); serum sodium and chloride as deemed necessary during maintenance treatment, particularly in patients receiving other medications known to decrease sodium levels or if symptoms of hyponatremia develop; symptoms of CNS depression (dizziness, disturbance in gait and coordination, somnolence); visual changes; hypersensitivity reactions. Monitor for suicidality (eg, suicidal thoughts, depression, behavioral changes). For adjunctive therapy, serum levels of concomitant antiepileptic drugs during titration as necessary.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Eslicarbazepine may decrease plasma concentrations of hormonal contraceptives; additional or alternative nonhormonal contraceptives are recommended in women of reproductive potential.

Patients exposed to eslicarbazepine during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, vomiting, fatigue, or tremors. Have patient report immediately to prescriber signs of infection, signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), enlarged lymph nodes, shortness of breath, excessive weight gain, swelling of arms or legs, angina, severe dizziness, passing out, severe muscle pain, severe muscle weakness, severe loss of strength and energy, vision changes, seizures, bruising, bleeding, involuntary eye movements, difficulty walking, agitation, irritability, panic attacks, mood changes, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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