APTIOM® (eslicarbazepine acetate) tablets

APTIOM® (eslicarbazepine acetate) tablets

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APTIOM® (eslicarbazepine acetate) tablets

The chemical name of APTIOM (eslicarbazepine acetate) is (S)-10-Acetoxy-10,11-dihydro-5Hdibenz[b,f]azepine-5-carboxamide. APTIOM is a dibenz[b,f]azepine-5-carboxamide derivative. Its molecular formula is C17H16N2O3 and its molecular weight is 296.32.

APTIOM is a white to off-white, odorless crystalline solid. It is insoluble in hexane, very slightly soluble in aqueous solvents and soluble in organic solvents such as acetone, acetonitrile, and methanol.

Each APTIOM tablet contains 200 mg, 400 mg, 600 mg or 800 mg of eslicarbazepine acetate and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and povidone.

Indications and usage

APTIOM is indicated for the treatment of partial-onset seizures in patients 4 years of age and older.

Mechanism of Action

APTIOM is extensively converted to eslicarbazepine, which is considered to be responsible for therapeutic effects in humans. The precise mechanism(s) by which eslicarbazepine exerts anticonvulsant activity is unknown but is thought to involve inhibition of voltage-gated sodium channels.

Dosage and administration

Instruct patients to administer APTIOM either as whole or as crushed tablets. Instruct patients to take APTIOM either with or without food. The APTIOM dosing regimen depends on age, weight, and renal function.

Adult Patients: The recommended initial dosage of APTIOM is 400 mg administered orally once daily. For some patients, treatment may be initiated at 800 mg once daily if the need for seizure reduction outweighs an increased risk of adverse reactions during initiation

  • Dosage should be increased in weekly increments of 400 mg to 600 mg, based on clinical response and tolerability, to a recommended maintenance dosage of 800 mg to 1600 mg once daily.
  • For patients on APTIOM monotherapy, the 800 mg once daily maintenance dose should generally be considered in patients who are unable to tolerate a 1200 mg daily dose.
  • For patients on APTIOM adjunctive therapy, the 1600 mg daily dose should generally be considered in patients who did not achieve a satisfactory response with a 1200 mg daily dose

Pediatric Patients (4 to 17 Years of Age): In pediatric patients 4 to 17 years of age, the recommended dosing regimen is dependent upon body weight and is administered orally once daily

Body Weight RangeInitial and Maximum Titration Increment Dosage (mg/day)Maintenance Dosage (mg/day)
11 to 21 kg200400 to 600
22 to 31 kg300500 to 800
32 to 38 kg300600 to 900
more than 38 kg400800 to 1200

Dosage Modifications in Patients with Renal Impairment: In patients with moderate and severe renal impairment (i.e., creatinine clearance < 50 mL/min), the initial, titration, and maintenance dosages should generally be reduced by 50%. Titration and maintenance dosages may be adjusted according to clinical response.

Patients with Hepatic Impairment: Dose adjustments are not required in patients with mild to moderate hepatic impairment. Use of APTIOM in patients with severe hepatic impairment has not been studied, and use in these patients is not recommended

Discontinuation of APTIOM: When discontinuing APTIOM, reduce the dosage gradually and avoid abrupt discontinuation in order to minimize the risk of increased seizure frequency and status epilepticus.

Contraindications

APTIOM is contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine.

Warnings and precautions

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including APTIOM, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Serious Dermatologic Reactions: Serious dermatologic reactions including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with APTIOM use. Serious and sometimes fatal dermatologic reactions, including TEN and SJS, have also been reported in patients using oxcarbazepine or carbamazepine which are chemically related to APTIOM.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking APTIOM. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present.

Anaphylactic Reactions and Angioedema: Rare cases of anaphylaxis and angioedema have been reported in patients taking APTIOM. Anaphylaxis and angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with APTIOM, the drug should be discontinued.

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Hyponatremia: Clinically significant hyponatremia (sodium <125 mEq/L) can develop in patients taking APTIOM. Measurement of serum sodium and chloride levels should be considered during maintenance treatment with APTIOM, particularly if the patient is receiving other medications known to decrease serum sodium levels, and should be performed if symptoms of hyponatremia develop (e.g., nausea/vomiting, malaise, headache, lethargy, confusion, irritability, muscle weakness/spasms, obtundation, or increase in seizure frequency or severity). Cases of symptomatic hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during postmarketing use

Neurological Adverse Reactions:

  • Dizziness and Disturbance in Gait and Coordination
  • Somnolence and Fatigue
  • Cognitive Dysfunction
  • Visual Changes

Withdrawal of AEDs: As with all antiepileptic drugs, APTIOM should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus, but if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

Drug Induced Liver Injury: Hepatic effects, ranging from mild to moderate elevations in transaminases (>3 times the upper limit of normal) to rare cases with concomitant elevations of total bilirubin (>2 times the upper limit of normal) have been reported with APTIOM use.

Adverse reactions

  • Most common adverse reactions in adult patients receiving APTIOM (≥4% and ≥2% greater than placebo): dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor.
  • Adverse reactions in pediatric patients are similar to those seen in adult adverse reactions.

Drug interactions

Other Antiepileptic Drugs: Several AEDs (e.g., carbamazepine, phenobarbital, phenytoin, and primidone) can induce enzymes that metabolize APTIOM and can cause decreased plasma concentrations of eslicarbazepine. Higher doses of Aptiom may be needed.

CYP2C19 Substrates: APTIOM can inhibit CYP2C19, which can cause increased plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., phenytoin, clobazam, and omeprazole). Dose adjustment may be needed.

CYP3A4 Substrates: In vivo studies suggest that APTIOM can induce CYP3A4, decreasing plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., simvastatin, lovastatin). Dose adjustment of simvastatin and lovastatin may be needed if a clinically significant change in lipids is noted.

Oral Contraceptives: Because concomitant use of APTIOM and ethinylestradiol and levonorgestrel is associated with lower plasma levels of these hormones, females of reproductive potential should use additional or alternative non-hormonal birth control.

Use in specific populations

Pregnancy: Limited available data with APTIOM use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.

Lactation: Eslicarbazepine is present in human milk. The effects of APTIOM on the breastfed infant or on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for APTIOM and any potential adverse effects on the breastfed infant from APTIOM or from the underlying maternal condition.

Contraception: Use of APTIOM with hormonal contraceptives containing ethinylestradiol or levonorgestrel is associated with lower plasma levels of these hormones. Advise women of reproductive potential taking APTIOM who are using a contraceptive containing ethinylestradiol or levonorgestrel to use additional or alternative non-hormonal birth control.

Pediatric Use: Safety and effectiveness of APTIOM have been established in the age groups 4 to 17 years

Overdosage

Symptoms of overdose are consistent with the known adverse reactions of APTIOM and include hyponatremia (sometimes severe), dizziness, nausea, vomiting, somnolence, euphoria, oral paraesthesia, ataxia, walking difficulties, and diplopia. The maximum dosage studied in open-label adult monotherapy treatment following withdrawal of concomitant AEDs was 2400 mg once daily.

Treatment or Management of Overdose

There is no specific antidote for overdose with APTIOM. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.

Standard hemodialysis procedures result in partial clearance of APTIOM. Hemodialysis may be considered based on the patient’s clinical state or in patients with significant renal impairment.

Storage and Handling

Store APTIOM tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)

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