Knowledge of Antiepileptic Drug Formulations Key to Accurate Prescribing

VBCN - July 2014 Volume 1, No 2

Philadelphia, PA—Multiple formulations and generic equivalents of anti­epileptic drugs are prevalent, and choosing between them can help optimize seizure control and minimize adverse effects, said Carl W. Bazil, MD, PhD, Director, Comprehensive Epilepsy Center, Columbia University Medical Center, New York, at the 2014 American Academy of Neurology (AAN) meeting.

The availability of extended-release (ER/XR) formulations, intravenous (IV) agents, and generic equivalents can complicate the choice for the individual patient.

Extended-Release Formulations
ER formulations are often chosen to minimize fluctuations in antiepileptic drug levels and to increase compliance, because they require fewer daily doses. Carbamazepine (Tegretol, Carbatrol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), phenytoin, topiramate (Topamax), and valproate (Depakote) are all available in ER formulations.

The time to peak concentration is typically much later with ER versus immediate-release formulations. Delivery systems are usually considered proprietary, with the exception of the osmotic system used in Tegretol XR, which differs from the Carbatrol capsule, containing beads with different dissolution times.

Because of the difference in delivery, the bioavailability of ER formulations is usually decreased compared with immediate-release formulations, “requiring a dose increase to maintain similar mean levels compared with immediate release,” said Dr Bazil. The exception is gabapentin, he said, because the delayed-release formulations result in increased bioavailability compared with immediate-release formulations because of saturable absorption.

Note that delivery systems are not equivalent, and “there may be differences between delayed release when more than 1 formulation is available,” Dr Bazil said.

Because peak and trough levels may not be reduced in amplitude with ER formulations, the best way to reduce fluctuation may be to use an ER form twice daily, advised Dr Bazil.

IV Formulations
Antiepileptic drugs that are available in IV formulations include phenobarbital, phenytoin/fosphenytoin, valproate, levetiracetam, and lacosa­mide (Vimpat).

IV antiepileptic drugs have a rapid onset, proving critical in patients who need immediate administration, as in acute repetitive seizures and status epilepticus. A large 1998 trial in status epilepticus showed that IV lorazepam was more effective than phenytoin, with no difference between phenobarbital and diazepam followed by phenytoin.

Generic Equivalents
Although generic substitution may be requested by a patient or an insurer for cost reasons, a switch to the generic version of a drug may have clinical implications. The US Food and Drug Administration (FDA) mandates that peak levels (Cmax) and area under the curve (AUC) for generic preparations must fall between 80% and 125% (on single-dose studies in normal volunteers) compared with the brand drug. Because antiepileptic drugs have narrow therapeutic ranges, it has been argued that this confidence interval may be insufficient for patients with epilepsy. Furthermore, “the variability allowed by the FDA may be amplified when a number of generic preparations are available, as each is compared to the branded drug but not to each other,” Dr Bazil said.

A bioequivalence study of generic antiepileptic drugs that modeled potential changes between multiple generic drugs showed that the AUC varied by >15% only 1% of the time, but that Cmax variations of 15% to 25% occurred in 11% of studies (Krauss GL, et al. Ann Neurol. 2011;70:221-228). These results suggest that trough levels may vary with consequent risk of seizures, Dr Bazil said.

An earlier study by Zachry and colleagues showed that patients with epilepsy with serious events had 81% greater odds of a change between antiepileptic drug formulations within the previous 2 months compared with matched controls without events.

The AAN recommends monitoring drug levels to ensure equivalent absorption when changing to generic formulations.

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