Oxcarbazepine (Trileptal) approved as monotherapy in children with epilepsy

This is the first such drug approval in 25 years

The U.S. Food and Drug Administration has approved the first antiepileptic drug for monotherapy in children since 1978.

Oxcarbazepine (Trileptal) tablets and oral suspension has been approved as monotherapy in children ages 4 years or older with partial seizures. "This is the first indication in 25 years that highlights to the clinician that we now have a drug that has a rational scientific basis on which to dose it," says Tracy Glauser, MD, associate professor of pediatrics and neurology, director of the Compre-hensive Epilepsy Program at the Cincinnati Children’s Hospital Medical Center.

Oxcarbazepine has been previously approved for adjunctive and monotherapy in adults, and adjunctive therapy for children ages 4-16 with partial epileptic seizures. Glauser was the lead investigator on the pivotal trial for the add-on therapy in children with partial seizures that led to that indication.

The monotherapy indication is based on data from multicenter, randomized, double-blind, controlled trials. The safety profile in children was established from data in more than 1,000 children from 20 studies.

Oxcarbazepine has held up well in four head-to-head trials against other drugs, Glauser says. (None of these trials were directly used to get the monotherapy indication.) Participants were either adults with new-onset partial seizures or children with new-onset partial seizures and generalized tonic-clonic seizures. In two trials — one with adults and one with children — oxcarbazepine was compared to phenytoin. Oxcarbazepine also was compared to carbamazepine in one trial in adults, and compared to valproic acid in adults in the fourth trial.

All these drugs had the same efficacy, Glauser says. The difference was in tolerability, which was a primary outcome variable in these studies. "Oxcarbazepine showed better tolerability in terms of the lower rate of premature discontinuation compared to phenytoin for both children and adults and compared to carbamazepine in adults. It showed similar tolerability to valproic acid."

Adverse events similar with peds and adults

As monotherapy and adjunctive therapy in pediatric patients, adverse events with oxcarbazepine were similar to those found in adults. The most common side effects (occurring in at least 5% of patients treated with oxcarbazepine in clinical studies and substantially more frequently than in placebo patients) were dizziness, sleepiness, double vision, fatigue, nausea, vomiting, incoordination, abnormal vision, abdominal pain, tremor, indigestion, and abnormal gait — these were typically mild-to-moderate in severity. Use of the drug is not associated with cosmetic side effects or weight gain. Hyponatremia also has been observed in some patients treated with oxcarbazepine.

Starting with lower dose

The drug’s package insert recommends that oxcarbazepine be initiated in pediatric patients at a daily dose of 8-10 mg/kg. Glauser, however, usually starts at a lower dose — 4 or 5 mg/kg/day. "From a clinical point of view, starting at a lower dose is reasonable."

He then titrates over a period of about three or four weeks to a target dose of 30 mg/kg/day. "If I continue to see a response and the patient is tolerating it, I will continue to go higher," he says. "The most I ever give is 150 mg bid."

Oxcarbazepine also has twice-a-day dosing, which is important for kids, he says. The problems with three-times-a-day dosing can be underplayed. "Three-times-a-day dosing means the school-age child often needs to get something from school. There is a lot of not only inconvenience, but stigma, too, and a chance for missing a dose that occurs from having to take it midday."

This approval is definitely a step forward in the treatment of childhood epilepsy, Glauser says. "Good tolerability, two-a-day dosing, good formulations that can be used across the whole pediatric spectrum, and a track record of efficacy distinguishes it."