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ESLICARBAZEPINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Eslicarbazepine is an anticonvulsant believed to inhibit voltage-gated sodium channels, and is used as either monotherapy or as adjunctive therapy for the treatment of partial-onset seizures in adults.

Specific Substances

    1) Eslicarbazepine acetate
    2) CAS 104746-04-5 (eslicarbazepine)
    3) CAS 236395-14-5 (eslicarbazepine acetate)
    1.2.1) MOLECULAR FORMULA
    1) C17H16N2O3 (Prod Info APTIOM(R) oral tablets, 2015)

Available Forms Sources

    A) FORMS
    1) Eslicarbazepine is available as 200 mg, 400 mg, 600 mg, and 800 mg tablets (Prod Info APTIOM(R) oral tablets, 2015).
    B) USES
    1) Eslicarbazepine is used as either monotherapy or as adjunctive therapy for the treatment of partial-onset seizures in adults (Prod Info APTIOM(R) oral tablets, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Eslicarbazepine is used as either monotherapy or as adjunctive therapy for the treatment of partial-onset seizures in adults.
    B) PHARMACOLOGY: Although the exact mechanism of action is unknown, it is thought that eslicarbazepine's anticonvulsant activity may be due to inhibition of voltage-gated sodium channels.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects with eslicarbazepine therapy, at an incidence rate of at least 4% and at least 2% greater than placebo, are dizziness, somnolence, nausea, vomiting, headache, diplopia, fatigue, vertigo, ataxia, tremor, and blurred vision.
    2) INFREQUENT: Adverse effects that have occurred less frequently include hypertension, diarrhea, constipation, abdominal pain, gastritis, asthenia, fatigue, peripheral edema, gait disturbance, urinary tract infections, hyponatremia, dysarthria, memory impairment, balance disorder, nystagmus, depression, insomnia, cough, and rash.
    3) RARE: Anaphylaxis, angioedema, Stevens-Johnson syndrome, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been rarely reported
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. During an open-label study, the maximum dose administered as monotherapy was 2400 mg orally once daily. In general, overdose effects are anticipated to be an extension of adverse effects at therapeutic doses, including hyponatremia that may be severe, dizziness, nausea, vomiting, somnolence, euphoria, oral paresthesia, ataxia, walking difficulties, and diplopia.
    0.2.20) REPRODUCTIVE
    A) Eslicarbazepine is classified as FDA pregnancy category C. Although adequate and well-controlled studies have not been conducted in pregnant women, teratogenicity, embryolethality, and fetal growth retardation have been reported during animal studies.

Laboratory Monitoring

    A) Monitor serum electrolytes, particularly sodium, following overdose. Hyponatremia has been reported with eslicarbazepine therapy and may be severe.
    B) Monitor liver enzymes and thyroid function tests in symptomatic patients.
    C) Plasma eslicarbazepine concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat mild hyponatremia with water restriction and/or 0.9% sodium chloride.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Manage severe hyponatremia with 0.9% sodium chloride; 3% sodium chloride may be considered with severe symptomatic hyponatremia.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) HYPONATREMIA
    1) Evaluate for hyponatremia and associated symptoms. Patients with mild symptoms can be managed with water restriction. Patients with moderate to severe symptoms should receive 0.9% sodium chloride (rarely 3% NaCl in patients with very severe symptoms). The goal is slow correction; the serum sodium should not increase more than 2 mEq/L/hour in any 4-hour period or more than 15 mEq/L per day. Rapid correction may cause central pontine myelinolysis. Monitor serum electrolytes, fluid intake and output, and urine volume and electrolytes.
    G) ACUTE ALLERGIC REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    H) ENHANCED ELIMINATION PROCEDURE
    1) Given eslicarbazepine's protein binding (less than 40%), hemodialysis may be useful following overdose.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess serum electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected eslicarbazepine overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    K) PHARMACOKINETICS
    1) Eslicarbazepine is highly bioavailable. Protein binding is less than 40%. Volume of distribution was 60 L for a 70 kg patient based on population pharmacokinetic analysis. Eslicarbazepine acetate is rapidly and extensively metabolized by hydrolytic first-pass metabolism to eslicarbazepine. Eslicarbazepine corresponds to 91% of systemic exposure. More than 90% of the dose of eslicarbazepine acetate is recovered in the urine as eslicarbazepine and glucuronide metabolites, approximately 2/3 as unchanged and 1/3 as glucuronide conjugate. The half-life of eslicarbazepine is 13 to 20 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hyponatremia. Other antiepileptic agents (ie, phenytoin or valproic acid) can lead to CNS depression and nystagmus.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. During an open-label study, the maximum dose administered as monotherapy was 2400 mg orally once daily.
    B) THERAPEUTIC DOSE: ADULTS: The recommended starting dose is 400 mg orally once daily and can be increased to a recommended maintenance dose of 800 to 1600 mg once daily. The maximum daily dose is 1600 mg. CHILDREN: Safety and efficacy in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Eslicarbazepine is used as either monotherapy or as adjunctive therapy for the treatment of partial-onset seizures in adults.
    B) PHARMACOLOGY: Although the exact mechanism of action is unknown, it is thought that eslicarbazepine's anticonvulsant activity may be due to inhibition of voltage-gated sodium channels.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects with eslicarbazepine therapy, at an incidence rate of at least 4% and at least 2% greater than placebo, are dizziness, somnolence, nausea, vomiting, headache, diplopia, fatigue, vertigo, ataxia, tremor, and blurred vision.
    2) INFREQUENT: Adverse effects that have occurred less frequently include hypertension, diarrhea, constipation, abdominal pain, gastritis, asthenia, fatigue, peripheral edema, gait disturbance, urinary tract infections, hyponatremia, dysarthria, memory impairment, balance disorder, nystagmus, depression, insomnia, cough, and rash.
    3) RARE: Anaphylaxis, angioedema, Stevens-Johnson syndrome, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been rarely reported
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. During an open-label study, the maximum dose administered as monotherapy was 2400 mg orally once daily. In general, overdose effects are anticipated to be an extension of adverse effects at therapeutic doses, including hyponatremia that may be severe, dizziness, nausea, vomiting, somnolence, euphoria, oral paresthesia, ataxia, walking difficulties, and diplopia.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) DIPLOPIA: During pooled placebo-controlled clinical trials, diplopia was reported in 9% and 11% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410) respectively, as adjunctive therapy for partial-onset seizures compared with 2% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015)
    2) BLURRED VISION: During pooled placebo-controlled clinical trials, blurred vision was reported in 6% and 5% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410) respectively, as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    3) VISUAL IMPAIRMENT: During pooled placebo-controlled clinical trials, visual impairment was reported in 2% and 1% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410) respectively, as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    4) NYSTAGMUS: During pooled placebo-controlled clinical trials, nystagmus was reported in 1% and 2% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with less than 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, hypertension was reported in 1% and 2% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    B) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, peripheral edema was reported in 2% and 1% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, cough was reported in 2% and 1% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, dizziness was reported in 20% and 28% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 9% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, somnolence was reported in 11% and 18% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 8% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, headaches were reported in 13% and 15% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 9% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    D) ATAXIA
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, ataxia was reported in 4% and 6% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 2% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    E) TREMOR
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, tremor was reported in 2% and 4% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    F) MEMORY IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, memory impairment was reported in 1% and 2% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with less than 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    G) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, asthenia was reported in 2% and 3% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 2% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    H) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, insomnia was reported in 2% of adults receiving either eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410) as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    I) VERTIGO
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, vertigo was reported in 2% and 6% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with less than 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    J) IMPAIRMENT OF BALANCE
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, balance disorder was reported in 3% of adults receiving either eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410) as adjunctive therapy for partial-onset seizures compared with less than 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    K) DYSARTHRIA
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, dysarthria was reported in 1% and 2% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 0% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, nausea and vomiting were reported in 10% and 6% of adults, respectively, receiving eslicarbazepine acetate 800 mg/day (n=415), and 16% and 10% of adults, respectively, receiving eslicarbazepine acetate 1200 mg/day (n=410), as adjunctive therapy for partial-onset seizures compared with 5% and 3% of placebo-treated patients (n=426), respectively (Prod Info APTIOM(R) oral tablets, 2015).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, diarrhea was reported in 4% and 2% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 3% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, abdominal pain was reported in 2% of adults receiving either eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410) as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, constipation was reported in 2% of adults receiving either eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410) as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    E) GASTRITIS
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, gastritis was reported in 2% and less than 1% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410) respectively, as adjunctive therapy for partial-onset seizures compared with less than 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Mild to moderate transaminase elevations more than 3 times the upper limit of normal (ULN), sometimes accompanied by bilirubin elevations of more than 2 times the ULN, have been reported with eslicarbazepine acetate therapy (Prod Info APTIOM(R) oral tablets, 2015).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, urinary tract infections were reported in 2% of adults receiving either eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410) as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) During pooled placebo-controlled clinical trials, rash was reported in 1% and 3% of adults receiving eslicarbazepine acetate 800 mg/day (n=415) or 1200 mg/day (n=410), respectively, as adjunctive therapy for partial-onset seizures compared with 1% of placebo-treated patients (n=426) (Prod Info APTIOM(R) oral tablets, 2015).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome has been reported with eslicarbazepine acetate therapy (Prod Info APTIOM(R) oral tablets, 2015).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) THYROID FUNCTION TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Dose-dependent decreases of both free and total levels of serum triiodothyronine (T3) and thyroxine (T4) have been reported with eslicarbazepine acetate therapy. Other tests associated with hypothyroidism were not abnormal (Prod Info APTIOM(R) oral tablets, 2015).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DRUG HYPERSENSITIVITY SYNDROME
    1) WITH THERAPEUTIC USE
    a) Drug-Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported with eslicarbazepine acetate therapy. This reaction typically presents with fever, rash, or lymphadenopathy associated with other organ systemic involvement (eg, hepatitis, nephritis, myocarditis, hematological abnormalities, myositis, myocarditis) and may mimic an acute viral infection. Eosinophilia may also occur (Prod Info APTIOM(R) oral tablets, 2015).
    B) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis and angioedema have been rarely reported with eslicarbazepine acetate therapy (Prod Info APTIOM(R) oral tablets, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Eslicarbazepine is classified as FDA pregnancy category C. Although adequate and well-controlled studies have not been conducted in pregnant women, teratogenicity, embryolethality, and fetal growth retardation have been reported during animal studies.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Increased incidences of fetal malformations were observed in animal studies with oral administration of doses that were less than the exposure of that at the maximum recommended human dose (MRHD) of 1600 mg/day throughout organogenesis (Prod Info APTIOM(R) oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Eslicarbazepine is classified as FDA pregnancy category C (Prod Info APTIOM(R) oral tablets, 2015).
    B) PREGNANCY REGISTRY
    1) A North American Antiepileptic Drug (NAAED) Pregnancy Registry has been established to monitor the effects of in utero exposure to eslicarbazepine, and patients are encouraged to enroll themselves by calling 1-888-233-2334. Patients may also obtain information on the NAAED on the website: www.aedpregnancyresgistry.org/ (Prod Info APTIOM(R) oral tablets, 2015).
    C) ANIMAL STUDIES
    1) During animal studies, embryolethality occurred at doses less than the MRHD on a mg/m(2) basis throughout organogenesis. Fetal growth retardation and reduction in offspring body weight with delayed physical development and sexual maturation were reported at doses up to 650 mg/kg/day administered during pregnancy and lactation. Decreased motor coordination was observed at an oral dose of 250 mg/kg/day (Prod Info APTIOM(R) oral tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Eslicarbazepine is excreted into human milk; however, the effects on the nursing infant from exposure to the drug in milk have not been determined (Prod Info APTIOM(R) oral tablets, 2015).
    B) BREAST MILK
    1) Because of the potential for serious toxicity in a nursing infant, it is recommended to either discontinue nursing or eslicarbazepine, considering the importance of the drug to the mother (Prod Info APTIOM(R) oral tablets, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Lengthening of the estrus cycle was reported following doses of 250 mg/kg/day administered to male and female rats prior to and throughout the mating period and continuing in females to implantation (Prod Info APTIOM(R) oral tablets, 2015).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) During a 2-year carcinogenicity study in mice, hepatocellular adenomas and carcinomas were reported at oral doses up to 600 mg/kg/day in males and females (Prod Info APTIOM(R) oral tablets, 2015).

Genotoxicity

    A) Eslicarbazepine was not mutagenic in the in vitro Ames assay, and was not clastogenic in the in vivo mouse micronucleus assay nor in the human peripheral blood lymphocytes. However, it was clastogenic in the Chinese hamster ovary cells, with and without metabolic activation, and was positive in the in vitro mouse lymphoma tk assay in the absence of metabolic activation (Prod Info APTIOM(R) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, particularly sodium, following overdose. Hyponatremia has been reported with eslicarbazepine therapy and may be severe.
    B) Monitor liver enzymes and thyroid function tests in symptomatic patients.
    C) Plasma eslicarbazepine concentrations are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) Monitor serum electrolytes, particularly sodium, following overdose. Hyponatremia has been reported with eslicarbazepine therapy and may be severe (Prod Info APTIOM(R) oral tablets, 2015).
    B) Monitor liver enzymes and thyroid function tests in symptomatic patients.
    C) Plasma eslicarbazepine concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess serum electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor serum electrolytes, particularly sodium, following overdose. Hyponatremia has been reported with eslicarbazepine therapy and may be severe.
    B) Monitor liver enzymes and thyroid function tests in symptomatic patients.
    C) Plasma eslicarbazepine concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Treat mild hyponatremia with water restriction and/or 0.9% sodium chloride.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Manage severe hyponatremia with 0.9% sodium chloride; 3% sodium chloride may be considered with severe symptomatic hyponatremia.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes, particularly sodium, following overdose. Hyponatremia has been reported with eslicarbazepine therapy and may be severe (Prod Info APTIOM(R) oral tablets, 2015).
    2) Monitor liver enzymes and thyroid function tests in symptomatic patients.
    3) Plasma eslicarbazepine concentrations are not readily available or clinically useful in the management of overdose.
    C) HYPONATREMIA
    1) Evaluate for hyponatremia and associated symptoms. Patients with mild symptoms can be managed with water restriction. Patients with moderate to severe symptoms should receive 0.9% sodium chloride (rarely 3% NaCl in patients with very severe symptoms). The goal is slow correction; the serum sodium should not increase more than 2 mEq/L/hour in any 4-hour period or more than 15 mEq/L per day. Rapid correction may cause central pontine myelinolysis. Monitor serum electrolytes, fluid intake and output, and urine volume and electrolytes.
    D) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Given eslicarbazepine's protein binding (less than 40%) (Prod Info APTIOM(R) oral tablets, 2015), hemodialysis may be useful following overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. During an open-label study, the maximum dose administered as monotherapy was 2400 mg orally once daily.
    B) THERAPEUTIC DOSE: ADULTS: The recommended starting dose is 400 mg orally once daily and can be increased to a recommended maintenance dose of 800 to 1600 mg once daily. The maximum daily dose is 1600 mg. CHILDREN: Safety and efficacy in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended starting dose is 400 mg orally once daily and can be increased by 400 mg to 600 mg weekly increments to a recommended maintenance dose of 800 to 1600 mg once daily. The maximum daily dose is 1600 mg (Prod Info APTIOM(R) oral tablets, 2015).
    1) In some patients, the starting dose may be 800 mg orally once daily, if the need for seizure reduction outweighs the increased risk of adverse reactions (Prod Info APTIOM(R) oral tablets, 2015).
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established in pediatric patients (Prod Info APTIOM(R) oral tablets, 2015).

Maximum Tolerated Exposure

    A) During an open-label study, the maximum dose administered as monotherapy was 2400 mg orally once daily (Prod Info APTIOM(R) oral tablets, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Although the exact mechanism of action is unknown, it is thought that eslicarbazepine's anticonvulsant activity may be due to inhibition of voltage-gated sodium channels (Prod Info APTIOM(R) oral tablets, 2015).

Physicochemical

Physical Characteristics

    A) Eslicarbazepine acetate is an odorless crystalline solid that is white to off-white. It is very slightly soluble in aqueous solvents (Prod Info APTIOM(R) oral tablets, 2015).

Molecular Weight

    A) 296.32 (Prod Info APTIOM(R) oral tablets, 2015)

References

General Bibliography

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    3) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    4) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    5) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    6) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    7) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    8) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    9) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    10) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    11) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    12) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    13) Product Information: APTIOM(R) oral tablets, eslicarbazepine acetate oral tablets. Sunovion Pharmaceuticals Inc. (per FDA), Marlborough, MA, 2015.
    14) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    15) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    16) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.