Center for Continuing Education
About The Cleveland Clinic Center for Continuing Education | Call or Email Us | About The Cleveland Clinic
Live Cleveland Clinic CME Courses |  Regularly Scheduled Series (RSS) Registration | Regulary Scheduled Series (RSS) Schedule (pdf)
Disease Management Project Clinical Decisions Cases |  Hepatitis C Management |  Managing Problem Patients with Anti-TNF Inhibitors |  More
Medicine Today Series |  B Cell Series |  Emerging Therapies in Heart Disease Webcast Series |  More
Disease Management Project |  CCJM 1-Minute Consult |  Pharmacotherapy Update Newsletter |  Algorithms for the MICU |  More
Cleveland Clinic Foundation CME Home Contact Us Live CME Courses Online CME Topics Webcasts Online Medical Publications my CME Search Sitemap e-mail Newsletter

  VolVol. IV, No. VI
  November/December 2001

  Rhonda Rhea, Pharm.D.

 Return to
 Update Index


New Oral Antiepileptic Agents

Introduction: Over the past eight years, several new oral antiepileptic drugs (AEDs) have been approved by the U.S. Food and Drug Administration for use in patients with epilepsy. Among these new AEDs, only one has undergone comparative studies (oxcarbazepine), however, this was conducted with old AEDs. Currently, there have been no head-to-head trials of new AEDs. Most of the comparative data are derived from meta-analyses from which no superior efficacy was established. Dose-related adverse effects occur at the start of treatment and improve or resolve over time without a change of dose. Idiosyncratic reactions, such as hypersensitivity reactions and hepatic adverse effects are most likely to occur within 2 to 8 weeks of treatment. Combination AED therapy increases the risk for an adverse event. The mechanism of action of all AEDs occurs by one or more of the following: modulation of voltage-dependent ion channels involved in propagating the action potential, enhancement of inhibitory activity (GABA), and/or inhibition of excitatory activity (glutamate or aspartate). Traditionally, AEDs are initiated slowly with gradual titration in order to minimize potential CNS-related adverse effects. The doses of oral antiepileptic agents are increased until a patient becomes seizure-free or experiences intolerable side effects. If a patient does not respond to an AED, a new AED is added and titrated to a target dose while the previous AED is slowly removed. This practice minimizes the risk of rebound seizures. Routine therapeutic drug monitoring, as seen with the traditional antiepileptic agents (See Table 2), cannot be recommended for the newer agents due to lack of data for target concentration ranges. It should be remembered that these medications help to prevent recurrent seizures but are not a cure for epilepsy.

Table 1. Classification of Seizure Disorders

Type Description

Bilaterally symmetrical
(both hemispheres of brain involved at onset)

  • Absence=Interruption of activities, blank stare, brief upward rotation of eyes
  • Tonic-clonic=Sudden sharp contraction of muscles followed by rigidity
  • Atonic=Sudden loss of muscle tone
  • Myotonic=Brief shock-like muscular contractions of the face, trunk, and extremities

Seizures begin locally
(only one hemisphere of brain involved at onset)

  • Simple=Without impairment of consciousness
  • Complex=With impairment of consciousness; associated with aura
  • Secondarily generalized=Partial onset evolving to generalized tonic-clonic seizures


Inadequate/incomplete data or cannot be classified into above-mentioned categories

Felbamate (Felbatol®): Felbamate is classified as a dicarbamate. It is believed to be an antagonist of the glycine receptor site on the N-methyl-D-aspartate (NMDA) receptor, thereby increasing seizure threshold and reducing the occurrence of seizures. In vitro studies indicate that felbamate also has weak GABA receptor binding effects. Please see Table 3 for FDA-approved indications and Table 4 for dosing information.

Oral bioavailability is greater than 90% and absorption is not affected by food. About 50 to 60% of the dose is metabolized in the liver by hydroxylation and conjugation, and the rest is excreted unchanged in the urine. Protein binding is minimal (25%). Felbamate is a hepatic enzyme inducer and inhibitor, resulting in numerous drug interactions. Felbamate inhibits the clearance of phenytoin (PHT) and valproate (VPA), therefore the doses of these drugs need to be decreased by 30%. If felbamate is added to carbamazepine (CBZ), the CBZ concentrations decrease by 30%; however, the 10,11-epoxide (CBZ's active metabolite) concentrations increase by 55%. The addition of PHT or CBZ to a regimen containing felbamate necessitates a 40% dose increase in felbamate.

Felbamate carries a black box warning due to marked increases in aplastic anemia and hepatic failure. It should only be initiated or continued in patients who have severe seizures that are refractory to alternative therapies and where the benefit of the drug outweighs the risk. Aplastic anemia, which may occur after 5 to 30 weeks of therapy, and acute hepatic failure, which may occur after 30 weeks of therapy, have been reported in 21 and 10 cases, respectively. Aplastic anemia may not manifest itself for months and patients may remain at risk for an undetermined amount of time after treatment is stopped. A baseline CBC with differentials and liver function tests should be obtained before initiating therapy with this agent. These tests should be repeated bi-weekly until a stable dose is achieved, and then every 3 months. This medication is typically not used with any underlying hepatic or hematological disorders. If any hepatic abnormality is detected, felbamate should be discontinued immediately. Common adverse effects include gastrointestinal (GI) disturbances (e.g., anorexia, weight loss, nausea, vomiting, constipation, and dyspepsia) and nervous system effects (e.g., headache, somnolence, insomnia, fatigue, dizziness). Felbamate is rated as a pregnancy-risk category C.

Gabapentin (Neurontin®): Gabapentin was designed to structurally and pharmacologically mimic the inhibitory neurotransmitter, GABA, and cross the blood-brain barrier (unlike GABA). Mechanistically, it does not behave like GABA. It has been shown that human brain GABA levels are elevated after gabapentin binds to an amino acid carrier protein. Please see Table 3 for FDA-approved indications and Table 4 for dosing information.

Gabapentin has a half-life of 5 to 7 hours and is eliminated exclusively by the kidneys; therefore, the dose needs to be adjusted in renal dysfunction. It does not induce or inhibit hepatic enzymes. Human plasma protein binding is also minimal. Addition of gabapentin to an existing AED regimen does not significantly alter steady-state plasma concentrations. Further monitoring and dosage adjustments are not necessary. The only known contraindication to gabapentin is hypersensitivity to the drug. In patients who are taking gabapentin with antacids, 2 hours should elapse before and after administration, since the bioavailability of gabapentin is reduced by 20%.

Common adverse effects include nervous system effects (e.g., somnolence, dizziness, or ataxia), GI effects (e.g., dyspepsia, dry mouth, or constipation), and muscle jerks. Weight gain is also a potential dose-related adverse effect. Additionally, children may rarely display aggression or worsening of behavior while on gabapentin therapy. It is rated as a pregnancy-risk category C.

Lamotrigine (Lamictal®): Lamotrigine is a phenyltriazine that stabilizes neuronal membranes by blocking voltage-sensitive sodium channels, which inhibit glutamate and aspartate (excitatory amino acid neurotransmitter) release. This drug is specifically indicated in patients converting from monotherapy with a hepatic enzyme-inducing AED (e.g., PHT, CBZ, phenobarbital, and primidone). The manufacturer states that the use of lamotrigine in the following situations has not been established: initial monotherapy, conversion from monotherapy with AEDs that do not induce hepatic enzymes, or simultaneous conversion to monotherapy from > 2 AEDs. The dosage regimen for lamotrigine depends on whether it is being used in combination with hepatic enzyme-inducing AEDs or VPA (hepatic enzyme inhibitor) or a combination of both. Please see Table 3 for FDA-approved indications and Table 4 for dosing information.

Lamotrigine is 98% bioavailable and absorption is not affected by food. Protein binding is not clinically relevant (55%). Lamotrigine undergoes extensive glucuronide metabolism in the liver and the remaining 10% is excreted unchanged in the urine. Patients with moderate (Child-Pugh class B) to severe (Child-Pugh class C) hepatic insufficiency should have their dose empirically decreased by 50% and 75%, respectively. Dose reduction is also mandated with significant renal impairment. The half-life of lamotrigine is decreased up to 50% by AEDs that induce hepatic metabolism (e.g., CBZ, PHT, phenobarbital, and primidone). Conversely, when combined with VPA, the half life of lamotrigine may be more than doubled.

The most common adverse effects are diplopia, drowsiness, ataxia, and headache. The adverse effect most frequently associated with discontinuance of the drug was rash which occurred in 10% of adult patients in controlled clinical trials and caused 3.4% to stop therapy. When VPA and lamotrigine are used concurrently, the incidence of potentially life-threatening rashes, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema with fever, facial swelling and lymphadenopathy increase. Because it is not possible to tell whether a rash is benign or may become severe, systemic, and life-threatening, a black box warning (added in 1997) states that lamotrigine should be discontinued at the first sign of drug-related rash. This incidence of rash, however, is declining due to the lower starting doses and slower dosing titrations. Lamotrigine is rated as a pregnancy-risk category C.

Tiagabine (Gabitril®): Tiagabine is a nipecotic acid derivative. Its mechanism of action is primarily GABA-mediated. Specifically it inhibits pre-synaptic reuptake of GABA into glial and other neuronal elements, increasing the amount of GABA available for postsynaptic receptor binding. Please see Table 3 for FDA-approved indications and Table 4 for dosing information.

It should be noted that all clinical trials dosed tiagabine in combination with a hepatic microsomal enzyme inducing AED. Accordingly, doses need to be reduced in patients taking a non-hepatic enzyme inducing AED (e.g., gabapentin, levetiracetam, lamotrigine, and VPA). Tiagabine itself does not appear to induce or inhibit hepatic enzymes, although its primary route of metabolism is via the liver by CYP3A4 enzymes. Tiagabine has a short half-life in both healthy volunteers and in those on hepatic enzyme inducers, 6 to 9 hours and 4 to 8 hours, respectively. A dosage reduction should occur with hepatic impairment, although no specific guidelines are available. No dosage reduction is necessary in patients with renal impairment. The drug should be taken with food to slow absorption and reduce side effects.

The most frequently reported adverse effect was transient dizziness. Other less common events (which were mild to moderate in severity) associated with dose titration were: asthenia, nervousness, tremor, diarrhea, and mild bouts of depression. There have also been reports of psychosis and nonconvulsive status. Tiagabine is rated as a pregnancy-risk category C.

Topiramate (Topamax®): Topiramate is a sulfamate-substituted derivative of the monosaccharide D-fructose. It exerts an anticonvulsant effect by blocking sodium channels and enhancing GABA activity. The scope of activity is similar to PHT and CBZ. It is also a weak carbonic anhydrase inhibitor; however, this does not contribute to its anticonvulsant activity. Please see Table 3 for FDA-approved indications and Table 4 for dosing information.

Topiramate is 80% bioavailable and protein binding is minimal (20%). The half-life is 20 to 30 hours. Excretion is primarily renal, with 50 to 80% of each dose excreted unchanged. Doses of topiramate should be decreased by 50% in those with a CrCl < 70 mL/min. In patients undergoing hemodialysis, a supplemental dose of the drug individualized to the patient may be required because the clearance of topiramate is 4 to 6 times more rapid than in healthy individuals. No modification of dose is necessary in geriatric patients with normal renal function. CBZ, PHT, and other inducers may significantly increase topiramate's metabolism and subsequent elimination. When PHT is added to topiramate therapy, levels increase by 25%, whereas VPA levels decrease by 11%. This is due to topiramate's ability to inhibit CYP2C19.

Rapid titration (over 3 to 6 weeks) and excessive doses have been associated with an increase in adverse effects. The main adverse effects of topiramate are ataxia, impaired concentration, confusion, dizziness, fatigue, paresthesia, and abnormal thinking. Additionally, it has been documented that topiramate can cause secondary glaucoma. Nephrolithiasis also occurs at a rate of 1.5% with long-term use and may be due to carbonic anhydrase inhibition. Concomitant use of carbonic anhydrase inhibitors (e.g., acetazolamide) should be avoided. Topiramate is rated as a pregnancy-risk category C.

Oxcarbazepine (Trileptal®): Oxcarbazepine has been available in 50 countries since 1990 and is indicated for initiation of monotherapy. It is structurally related to carbamazepine and is considered a prodrug. Oxcarbazepine s metabolite, 10-monohydroxy (MHD), exerts its pharmacological action by blocking voltage-sensitive sodium channels. Please see Table 3 for FDA-approved indications and Table 4 for dosing information.

The half-life of the parent compound and MHD is 2 hours and 9 hours, respectively. Plasma protein binding is not significant (40%). Metabolism from oxcarbazepine to MHD occurs rapidly by cytosolic enzymes in the liver, and approximately 80% of MHD and its metabolites are excreted in the urine. Oxcarbazepine is not an "auto-inducer" like carbamazepine.

When converting from carbamazepine to oxcarbazepine, 1.5 times the total daily dose of the latter is required. This is due to the deinduction of hepatic metabolism which may result in adverse effects due to the rising concentration of medications that are extensively metabolized (e.g., warfarin, lamotrigine, topiramate, VPA). It is interesting to note that metabolism via CYP2C19 is inhibited and CYP3A4 is induced. A dosage reduction in concomitant AEDs that use the above-mentioned CYP450 pathways (e.g., phenytoin, phenobarbital) may also be necessary. Plasma levels of MHD have been shown to decrease by 29 to 40% when given in conjunction with enzyme-inducing AEDs. Dosing adjustments are only required with severe hepatic failure. In patients with impaired renal function (CrCl <30 mL/min), therapy should be initiated at one-half the usual starting dose (150 mg BID). Efficacy of oral contraceptives and calcium channel blockers are decreased when administered concomitantly with oxcarbazepine.

Common adverse effects are central nervous system (CNS) related. The most significant are cognitive symptoms (e.g., psychomotor slowing, difficulty with concentration, and speech or language problems), somnolence or fatigue, and coordination abnormalities (e.g., ataxia and gait disturbances). Hyponatremia (sodium < 125 mmol/L) occurred in 2.5% of patients in premarketing clinical trials; however, this generally occurred in patients receiving sodium-depleting diuretics. In patients who have had allergic reactions to carbamazepine, there is a 25 to 30% cross reactivity with oxcarbazepine. However, severe allergic skin reactions (e.g., epidermal necrolysis and Stevens-Johnson syndrome) and hematologic toxicity (e.g., leukopenia and thrombocytopenia) are less common with oxcarbazepine overall. This observation is reinforced by the lack of a boxed warning in the product labeling (as is found in that of carbamazepine). Oxcarbazepine is rated as a pregnancy-risk category C.

Levetiracetam (Keppra®): Levetiracetam is a derivative of piracetam (a drug that improves cognition). This drug inhibits seizure activity via an unknown mechanism that does not involve excitatory or inhibitory neuronal pathways. Please seeTable 3 for FDA-approved indications and Table 4 for dosing information.

Oral bioavailability of levetiracetam is about 100%. Peak time to absorption after oral administration is one hour, and steady state is achieved in two days with twice-daily administration. Protein binding is minimal (10%). Its volume of distribution is similar to intra- and extra-cellular water. Renal excretion of unchanged drug in the urine accounts for 66% of the dose. Levetiracetam is increased in the elderly and those with renal impairment. No dosage adjustments are required for hepatic dysfunction. Both pharmacokinetic and protein-binding interactions are unlikely, because levetiracetam is not a substrate or inhibitor of the CYP450, epoxide hydrolase, or UPD-glucuronidation enzymes. No interactions between levetiracetam and warfarin, digoxin, or oral contraceptives exist.

Commonly reported adverse effects in clinical trials include the following: somnolence, fatigue, coordination difficulties, and behavioral abnormalities. RBC and WBC counts, hemoglobin, and hematocrit may all be decreased by levetiracetam. Levetiracetam is classified as a pregnancy-risk category C.

Zonisamide (Zonegran™): Zonisamide is a sulfonamide antiepileptic drug that has been available in Japan for more than 10 years. While the mechanism of action is unclear, blocking sodium and calcium channels while increasing dopamine and serotonin neurotransmission are two components. It is also a weak carbonic anhydrase inhibitor, although this does not contribute to its antiepileptic activity. Please see Table 3 for FDA-approved indications and Table 4 for dosing information.

The half-life in plasma is around 63 hours; therefore, up to two weeks may be required to achieve steady state levels upon dosage adjustment. Zonisamide extensively binds to red blood cells, resulting in an eight-fold higher concentration versus plasma and the half-life increases to 105 hours. Protein binding of zonisamide is minimal (40%). Metabolism occurs in the liver via the CYP3A4 enzyme system. Zonisamide is not an auto-inducer. When PHT, CBZ, or phenobarbital are used concomitantly, the dose of zonisamide needs to be increased. Seven deaths from severe rash (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in Japan. If a patient develops a rash while taking zonisamide, the drug should either be discontinued or the patient should be monitored closely while continuing therapy. Frequent adverse effects include: dizziness, ataxia, somnolence, nausea, anorexia, abdominal pain, agitation, insomnia, and cognitive problems (e.g., confusion, difficulty in concentration, and speech abnormalities). Oligohydrosis and hyperthermia were reported in 13 pediatric patients in Japan. Zonisamide is not FDA-approved for pediatrics in the United States. This medication has also been reported to induce reversible psychosis (an idiosyncratic reaction). Combination use with topiramate could increase risk of renal stone formation. Patients should be counseled to drink 6 to 8 glasses of water per day to minimize kidney stone formation. Zonisamide is contraindicated in patients with a sulfa allergy. This agent is classified as a pregnancy-risk category C.

Conclusion: Prior to 1993, there were only six drugs available for the treatment of epilepsy. Despite these six agents, it is estimated that 25 to 40% of patients with epilepsy continued to have seizures despite optimal treatment with traditional antiepileptic drugs. With the advent of the newer oral antiepileptic agents, refractory epilepsy patients now have new options for treatment.

Table 5 shows the average wholesale price for select oral antiepileptic agents.

References Available Upon Request