Integrating New Antiepileptic Medications into Clinical Practice: Ezogabine and Eslicarbazepine

Several new antiepileptic drugs have recently been approved in the United States. In a symposium at the American Epilepsy Society in Seattle, Washington, Professor Martin J. Brodie, MD, director of the epilepsy unit of the Western Infirmary in Glasgow, Scotland, discussed some considerations with ezogabine and eslicarbazepine.

More than 30 antiepileptic drugs (AEDs) are available in the treatment armamentarium of epilepsy pharmacotherapy. Joining these medications are 8 new medications that are approved, or available for compassionate use, in the United States; these medications are ezogabine, eslicarbazepine, stiripentol, vigabatrin, lacosamide, perampanel, clobazam, and rufinamide. Understanding the appropriate uses of these medications is an important priority for health care professionals caring for patients with epilepsy.

In a presentation by Professor Martin J. Brodie, MD, director of the epilepsy unit of the Western Infirmary in Glasgow, Scotland, at the at the 2014 American Epilepsy Society, Brodie discussed the appropriate use of 2 of these medications: ezogabine and eslicarbazepine.

Ezogabine is licensed for use in the adjunctive treatment of drug-resistant focal seizures with or without secondary generalization in adults, and should be prescribed only when other medication combinations have proved inadequate. This medication enhances the flow of potassium channel M currents through the KCNQ channel, and has proved effective in animal models.¹

With regard to pharmacokinetics and pharmacodynamics, ezogabine is 60% orally bioavailable, with protein binding of approximately 80%, and a short elimination half-life of 6 to 10 hours. Importantly, taking this medication with a high-fat meal delays and decreases the maximum concentration of the medication. Ezogabine must be taken intact and should not be chewed or crushed.¹

In terms of drug interactions, ezogabine does not substantially affect the circulating concentrations of other AEDs, but phenobarbital, phenytoin, and carbamazepine can all reduce exposure to ezogabine by approximately one-third.¹

In clinical trials, patients treated with ezogabine experienced a 39% to 47% reduction in seizure frequency, depending on the dosage. Ezogabine is typically initiated at a total daily dose of 300 mg split into 3 doses of 100 mg. This dose may be increased by up to 150 mg weekly, and most patients do not exceed the maximum daily dose of 1200 mg. Common adverse events include somnolence, confusion, dizziness tremor, vertigo, asthenia, and abnormal thinking. However, ezogabine can also prolong the QT interval and may cause a blue discoloration of the skin, sclera, and mucous membranes with prolonged use. Decreases in visual acuity have also been documented with ezogabine use, possibly related to retinal pigmentation.^2,3

Eslicarbazepine acetate is licensed for adjunctive treatment of adults with focal seizures with or without secondary generalization. Although eslicarbazepine has some structural similarities to carbamazepine and oxcarbazepine, evidence suggests that eslicarbazepine is substantially different from previous medications. For instance, in humans, while oxcarbazepine metabolizes to form R and S forms of licarbazepine in a 1:4 ratio, eslicarbazepine is much more selective for the S metabolite, forming those 2 metabolites in a 1:20 ratio. In addition, eslicarbazepine has enhanced selectivity for specific, rapidly firing neurons that have been implicated in epilepsy pathophysiology, modifies the slow inactivation states of the sodium channel, and inhibits inward currents of calcium into cells. Together, these data suggest a mechanism of eslicarbazepine that is distinct from that of carbamazepine and oxcarbazepine.^4-6

Eslicarbazepine also has high bioavailability that is unaffected by food and has an effective half-life of 20 to 24 hours that enables once-daily dosing. Drug interactions with eslicarbazepine include increased clearance of carbamazepine, lamotrigine, and topiramate by approximately 12% to 16%. In addition, use with carbamazepine may lower the level of eslicarbazepine by approximately 32%. Also important are reductions in the effectiveness of oral contraceptives and increased metabolism of warfarin, simvastatin, and rosuvastatin that may occur in patients using eslicarbazepine.⁶

Dosing must be titrated upward slowly, starting at a daily dose of 400 mg for 1 to 2 weeks, then increasing to 800 mg daily, and further increasing to a maximum dosage of 1200 mg per day, depending on clinical response. In clinical studies, use of eslicarbazepine reduced seizure frequency by approximately 33% to 39%, depending on the dosage used. At the highest dose, eslicarbazepine approximately doubled the percentage of patients experiencing a 50% or greater reduction in seizure frequency (43.5% with eslicarbazepine 1200 mg daily versus 21.5% with placebo; P <.0001).^6,7

The side effects of eslicarbazepine are similar to those of other AEDs and may include dizziness, nausea, somnolence, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremors. In approximately 0.5% to 3.2% of patients, idiosyncratic rash occurred, although more severe rashes and cutaneous drug toxicities were rare. Another important potential side effect is hyponatremia, which occurs in 1% to 2% of patients.6

Regarding these 2 medications, Brodie noted, “They are as different as chalk and cheese.” Brodie explained the origin of this expression: “If you were a cheese maker, and you put a bit of chalk in, and sold the cheese, you would make twice as much money because half of the cheese is chalk.” Although eslicarbazepine has relatively few side effects, the side effects of ezogabine suggest it is, according to Brodie, “arguably a drug of last choice.”

As more and more drugs are approved for the treatment of epilepsy, more modalities are available, which is particularly important for patients who have not responded to previous treatments. Understanding the nuances of dosage titration, drug interactions, and potential side effects with new medications is an important priority for health care professionals, including pharmacists, caring for patients with epilepsy.

References

1. Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents. CNS Drugs. 2011;25(2):89-107.

2. Brodie MJ, Lerche H, Gil-Nagel A, et al. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology. 2010;75(20):1817-1824.

3. French JA, Abou-Khalil BW, Leroy RF, et al. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology. 2011;76(18):1555-1563.

4. Almeida L, Soares-da-Silva P. Eslicarbazepine acetate (BIA 2-093). Neurotherapeutics. 2007;4(1):88-96.

5. Bonifácio MJ, Sheridan RD, Parada A, Cunha RA, Patmore L, Soares-da-Silva P. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia. 2001;42(5):600-608.

6. Keating GM. Eslicarbazepine acetate: a review of its use as adjunctive therapy in refractory partial-onset seizures. CNS Drugs. 2014;28(7):583-600.

7. Gil-Nagel A, Elger C, Ben-Menachem E, et al. Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies. Epilepsia. 2013;54(1):98-107.