FDA Uses Extrapolation to Expand APTIOM (Eslicarbazepine Acetate) Indication for Partial-Onset Seizures in Adults to Pediatric Patients 4 Years and Older for Adjunctive and Monotherapy Use
On September 13, 2017, the U.S. Food and Drug Administration (FDA) approved APTIOM (eslicarbazepine acetate) for the treatment of partial-onset seizures in patients 4 years of age and older based on extrapolation of adult data. This pathway to support a pediatric indication is based on extrapolating adult efficacy for treatment of partial onset-seizures to pediatric patients age 4 years and older in an adjunctive treatment scenario. This approach allowed determination of a dosing regimen that would provide similar exposures (at levels demonstrated to be effective in adults) in pediatric subjects age 4 years of age and older to eslicarbazepine exposure in adult subjects with partial-onset seizures.
In addition to extrapolating adult efficacy to pediatric patients in an adjunctive treatment scenario, efficacy for partial onset-seizures in a monotherapy treatment scenario was determined based on extrapolation of efficacy in an adjunctive treatment scenario. This pathway to support a monotherapy indication for partial-onset seizures is based on extrapolation of pharmacokinetic information deemed adequate to demonstrate that the proposed dosages of a drug, when used as monotherapy, can be expected to result in exposures that are similar to those demonstrated to be safe and effective when the drug is used as adjunctive therapy for the treatment of partial-onset seizures. This approach requires assessment of possible drug-drug interactions (inhibition or induction) that may alter the metabolism of the drug.
The extrapolation of adult adjunctive efficacy to pediatric adjunctive efficacy as well as adjunctive efficacy to monotherapy efficacy relied on population pharmacokinetic analyses of data from adult patients as well as pediatric patients with partial-onset seizures from Phase 2a and Phase 3 studies.
The approved recommended dosage regimen for APTIOM depends on age, weight, and renal function.
- Adult patients (≥ 18 years of age): The approved recommended initial dosage is 400 mg orally once daily. For some patients, treatment may be initiated at 800 mg orally once daily if the need for seizure reduction outweighs an increased risk of adverse reactions. Increase the dose in weekly increments of 400 mg to 600 mg once daily, 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 (4-17 years of age): The approved recommended initial, maximum titration increment, and maintenance dosages are based on body weight. Increase dosage no more frequently than once per week, based on clinical response and tolerability, to the recommended maintenance dosage.
- 11 to 21 kg: The recommended initial dosage is 200 mg once daily. Increase dosage by no more than 200 mg increments once daily to the recommended maintenance dosage of 400 to 600 mg once daily.
- 22 to 31 kg: The recommended initial dosage is 300 mg once daily. Increase dosage by no more than 300 mg once daily to the recommended maintenance dosage of 500 to 800 mg once daily.
- 32 to 38 kg: The recommended initial dosage is 300 mg once daily. Increase dosage by no more than 300 mg once daily to the recommended maintenance dosage of 600 to 900 mg once daily.
- > 38 kg: The recommended initial dosage is 400 mg once daily. Increase dosage by no more than 400 mg once daily to the recommended maintenance dosage of 800 to 1200 mg once daily.
- Reduce dosage by 50% in patients with moderate or severe renal impairment.
Serious adverse reactions associated with use of APTIOM are suicidal behavior and ideation, serious dermatologic reactions, drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity, anaphylactic reactions and angioedema, hyponatremia, drug induced liver injury, neurologic and hematologic adverse reactions. Adverse reactions in pediatric patients are similar to those seen in adult patients, and most commonly include dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
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