New generation AEDs Flashcards
New generation AEDs
The new-generation antiepileptic drugs (AEDs) became available in the USA after 1993, following a 15-year hiatus during which no new drugs were introduced for the treatment of epilepsy. In general, the newer AEDs have not improved on the efficacy of carbamazepine, the AED to which they have been most often com- pared. However, many of the newer antiepileptic drugs have advantages in terms of pharmacoki-netics (Table 17.1), interactions, and tolerability [1, 2].
Felbamate
Felbamate was first approved in the USA in 1993. Felbamate has several mechanisms of action, including NMDA antagonism, enhancing GABA, blocking sodium channels, and blocking high-voltage activated calcium channels.
It has excellent oral bioavailability, greater than 90%. It is only 25% protein-bound, which is not clinically significant. It is metabolized via CYP3A4. Between 40 and 50% of the absorbed dose appears unchanged in the urine and the rest as inactive metabolites and conjugates. Its half-life in monotherapy is 20–23 h. The half-life is shorter in children and also shorter in the presence of enzyme inducers.
Felbamate has many interactions. It is an inhibitor of CYP 2C19, CYP 1A2, and beta-oxidation. As a result, it inhibits the metabolism and increases the serum concentration of phenobarbital, phenytoin, valproate, carbamazepine epoxide, and warfarin. On the other hand, felbamate induces CYP 3A4 and thus decreases carbamazepine level and also reduces oral contraceptive efficacy.
Felbamate is affected by enzyme-inducing antiepileptic drugs which accelerate felbamate clearance and reduce its serum concentration.
Common adverse effects of felbamate are anorexia, nausea, vomiting, and weight loss. Stomach irritation can be improved by adminis- tration with food and by the use of H2 blockers or proton pump inhibitors. Felbamate may also cause insomnia, irritability, and headache.
Felbamate was discovered to have serious idiosyncratic potential adverse effects. It may cause aplastic anemia with an estimated risk of 1 in 5000–8000 patients. Aplastic anemia has not been reported below age 13. The onset of aplastic anemia is after 2.5–6 months of treatment. It is highly unlikely to occur after one year of treat- ment. It has risk factors including prior cytope- nia, allergy to or significant toxicity with other antiepileptic drugs, and underlying autoimmune disease [3]. Another serious idiosyncratic potential adverse effect is hepatic failure, with an estimated risk of 1 26,000-1 and 54,000. The onset of this toxicity has been after 25–959 days of treatment, with a mean of 217 days. Neither aplastic anemia nor liver failure can be prevented by monitoring of CBC and liver enzymes. Nev- ertheless, it is recommended to check CBC and liver function tests prior to starting felbamate, then every 2 weeks for 6 months, then every 2– 3 months after 6 months, and then every 6 months after the first year.
Felbamate is a wide-spectrum antiepileptic drug, although its efficacy in generalized seizure types of idiopathic generalized epilepsy has not been evaluated in class I studies. The official FDA indications are: “Either monotherapy or adjunctive therapy in the treatment of partial sei- zures, with or without generalization, in adults with epilepsy and adjunctive therapy in the treat- ment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children.” The FDA indication specifies that “felbamate is not indicated as a first-line treatment; it is rec- ommended only in those who respond inade- quately to alternative treatments and whose epilepsy is so severe that the risk of aplastic ane- mia and/or liver failure is deemed acceptable.” A written informed consent is needed.
The suggested felbamate therapeutic range is 40–100 mg/L.
Gabapentin
Gabapentin was first approved in the USA in 1994. The mechanism of action is binding to the alpha-2 delta subunit of voltage-gated calcium channels. This binding reduces the influx of calcium and reduces neurotransmitter release under hyperex- citable conditions. Despite its name, gabapentin does not interact with GABA receptors.
Gabapentin bioavailability is low, with considerable inter-subjective variability. In addition, oral bioavailability decreases with increasing gabapentin dose. For example, bioavailability is 60% after a single 300 mg dose, but only 29% for 1600 mg t.i.d. and 36% for 1200 mg p.o. q.i. d. (bioavailability improves with dividing the dose) [4]. The reason for the above is that gabapentin is transported from the gut into the bloodstream by the L-amino acid transport system, which is saturable. Gabapentin protein binding is minimal at less than 50%. Gabapentin is not metabolized in humans. It is eliminated unchanged in the urine as a result requires dose reduction with renal impairment. Its half-life is 5–7 h.
Gabapentin has no known interactions, which is predicted by the absence of metabolism, the absence of enzyme induction or inhibition, and the absence of protein binding. However, antacids including aluminum hydroxide or magnesium hydroxide may reduce gabapentin bioavailability if taken within 2 h from gabapentin intake.
Gabapentin adverse effects include sedation, dizziness, ataxia, asthenia, and weight gain. It may cause myoclonus. It may be associated with cognitive slowing in the elderly, and emotional lability or hostility in children. It has been assigned pregnancy category C.
Gabapentin is a narrow-spectrum agent against focal seizures. It failed clinical trials against absence and primary generalized tonic– clonic seizures [5, 6]. It may cause exacerbation of myoclonus [7]. The official FDA indication is for adjunctive therapy for partial seizures. It is also approved for the treatment of postherpetic neuralgia. An extended-release preparation (gabapentin enacarbil) has been approved for the treatment of restless leg syndrome.
Lamotrigine
Lamotrigine was first approved in the USA in 1995, but was licensed in Europe in 1991. Its mechanism of action is blocking sodium channels. This secondarily results in blocking the release of glutamate. Lamotrigine also inhibits high-voltage activated calcium channels.
Lamotrigine has an excellent oral bioavailability of about 98%. The time to maximum concentration is 1–1.5 h with the immediate release preparation and 4–11 h with the extended-release preparation. Its protein binding is only 55%. Lamotrigine is extensively metabolized in the liver, predominantly by glucuronidation (to lamotrigine 2–N-glucuronide), then excreted by the kidney. About 94% is eliminated in the urine, about 10% as unchanged drug, and 90% as glucuronide conjugates. The half-life is about 24 h in monotherapy, 48–60 h when used with valproate, and 12 h when used with an enzyme inducer.
Lamotrigine is associated with a mild autoinduction. It is a weak inhibitor of dihydrofolate reductase (not clinically relevant). Lamotrigine slightly increases topiramate level and slightly decreases valproate level. However, it is mark- edly affected by some other drugs. Its clearance is increased in the presence of enzyme-inducing drugs, estrogen containing oral contraceptives, and pregnancy. On the other hand, lamotrigine clearance is markedly decreased by valproate.
Dose-related adverse effects include dizziness, ataxia, blurred vision, diplopia, nausea, and vomiting. Headache and tremor may also occur. Rash is seen in about 3%, but the risk is higher in children, with coadministration of valproate, with faster titration, and with higher doses. As a result of increased risk of rash with faster titration, lamotrigine has to be titrated very slowly. The rate of titration is slower in the presence of valproate.
Rare serious idiosyncratic adverse effects include Stevens–Johnson syndrome, toxic epi- dermal necrolysis, or hypersensitivity syndrome (1 in 4000). It is assigned pregnancy category C.
Lamotrigine is a wide-spectrum antiepileptic drug effective against partial–onset as well as generalized tonic–clonic seizures. It is FDA indicated as adjunctive therapy or for conversion to monotherapy for partial seizures, adjunctive therapy for generalized tonic–clonic seizures, and adjunctive therapy for Lennox–Gastaut syndrome. Efficacy against generalized absence seizures is less than valproate and ethosuximide. Its efficacy against myoclonic seizures is variable, and lamotrigine may exacerbate myoclonic seizures in some individuals. The recommended therapeutic range for lamotrigine is 2–20 mg/L [8].
Lamotrigine is also FDA indicated for maintenance treatment of bipolar I disorder to delay a mood episode.
Topirimate
Topiramate is a sulfamate-substituted monosaccharide. It was approved in the USA in 1996.
It has multiple mechanisms of action including blocking of voltage-gated sodium channels, augmentation of GABA activity, antagonism of AMPA/kainate receptors, inhibition of high-voltage activated calcium channels, and weak inhibition of carbonic anhydrase activity.
Topiramate has a good oral bioavailability of 80–95%. Its protein binding is only 15–40%. Topiramate is not extensively metabolized. About 70% is eliminated unchanged in the urine. Its hepatic metabolism by the p450 enzyme system is via hydroxylation, hydrolysis, and glucuronidation, to form inactive metabolites. There is evidence of renal tubular reabsorption. The half-life is about 21 h.
Drug interactions are minimal. Topiramate is a mild inhibitor of CYP 2C19, so that it may increase phenytoin levels when used at a higher dose. It is also a mild inducer of CYP 3A4, so that it may reduce the efficacy of the oral con- traceptive when used at a dose of 200 mg per day or more. Hyperammonemia may occur when topiramate is used in conjunction with valproate. Enzyme-inducing antiepileptic drugs may reduce topiramate levels by up to 50%.
Topiramate adverse effects include sedation, fatigue, dizziness, and ataxia, which are helped by slower titration. Topiramate may cause cognitive difficulties including memory disturbance, word-finding difficulty, and cognitive slowing. There may be depression. Kidney stones occur in about 1.5% of individuals. Acute myopia and secondary angle-closure glaucoma are reported rarely. Paresthesias in the hands and feet may occur as a result of the carbonic anhydrase activity. Oligohydrolysis, hyperthermia, and metabolic acidosis are more common in children. Weight loss may occur.
Topiramate is assigned pregnancy category D due to increased risk of oral clefts in exposed infants [9].
Topiramate is a wide-spectrum antiepileptic drug. However, it is not effective against general- ized absence seizures as demonstrated in a ran- domized controlled clinical trial [10]. The FDA indications are for initial monotherapy or adjunc- tive therapy for partial–onset or primary general- ized tonic–clonic seizures in adults and children 2 years or older, and as adjunctive therapy for adult and pediatric patients with seizures associated with Lennox–Gastaut syndrome. Topiramate is also indicated for prophylaxis of migraine. Topiramate requires a slow titration to improve tolerability.
Tiagabine
Tiagabine was first approved in the USA in 1997. It is a designer drug, the mechanism of which is inhibition of GABA reuptake at the synapse.
Tiagabine has an excellent oral bioavailabil- ity. It is highly protein-bound (96%). It is extensively metabolized in the liver mainly by CYP 3A4. Only 2% is excreted unchanged; 63% is excreted in the feces and 25% in the urine. The half-life is 7–9 h in monotherapy and 2–5 h in the presence of enzyme inducers. As a result of the short half-life, it requires t.i.d. dosing.
Tiagabine does not affect other medications. Even though it is highly protein-bound, its serum concentration is low and it is unlikely to compete for protein binding; in addition, tiagabine dosing decisions are not usually based on serum con- centration. Tiagabine metabolism, however, is accelerated by enzyme-inducing drugs.
The most commonly reported tiagabine adverse effects were dizziness, asthenia, nervousness, tremor, depression, and emotional lability. Adverse effects are more common dur- ing titration, and slow titration is thus required. Tiagabine may be associated with dose-related episodes of nonconvulsive status epilepticus or encephalopathy, which may occur even in the absence of epilepsy [11, 12]. It has been assigned pregnancy category C.
Tiagabine is a narrow-spectrum agent effective against focal seizures only. It is not effective against and may exacerbate generalized absence or myoclonic seizures. Its FDA indication is for adjunctive therapy only. It is used off label in the treatment of addiction, to increase proportion of deep sleep, and in the management of spasticity in multiple sclerosis.
Levetiracetam
Levetiracetam was first approved in USA in 1999. Its mechanism of action is binding to the synaptic vesicle protein SV2A. This seems to result in nonspecific decrease in neurotransmitter release. There is a functional correlation between SV2A binding affinity and anticonvulsant potency of levetiracetam analogues.
Levetiracetam is available in oral and IV formulations. It has an excellent oral bioavail- ability of about 100%. Time to maximum con- centration is about 1 h (1.5 h with food). Its protein binding is less than 10%. Levetiracetam has no hepatic metabolism. It is partly hydrolyzed to inactive compounds; 66% is excreted unchanged in the urine. The half-life is 6–8 h, but shorter in children and longer in the elderly.
There are no known significant pharmacoki- netic interactions. However, some studies have suggested lower levetiracetam levels in the presence of enzyme inducers.
Levetiracetam adverse effects include som- nolence, dizziness, and asthenia. Irritability and hostility may occur, more commonly in children. Risk factors for these behavioral adverse effects include symptomatic generalized epilepsy, his- tory of psychiatric diagnosis, and fastelevetiracetam titration [13]. There have been rare reports of psychosis [14].
Levetiracetam is a wide-spectrum drug. The official FDA indications are adjunctive therapy for partial–onset seizures in adults and children 4 years or older; adjunctive therapy for myo- clonic seizures in adults and adolescents 12 years or older with juvenile myoclonic epilepsy; and adjunctive therapy for primary generalized tonic– clonic seizures in adults and children 6 years or older with idiopathic generalized epilepsy. L
evetiracetam is not FDA approved for monotherapy in the USA, but it is approved for initial monotherapy in Europe. The optimal therapeutic level is unknown. One study sug- gested that 11 mg/L may be a threshold con- centration for therapeutic response [15]. The upper limit of the therapeutic range is unknown.
Zonisamide
Zonisamide is structurally related to sulfonamides. It was approved in Japan in 1989. However, it was first approved in the USA in 2000.
The mechanism of action is blocking sodium channels, reducing T-type calcium currents, and weak inhibition of carbonic anhydrase activity (it is 100–200 times less potent than acetazolamide).
Oral bioavailability is about 100%. Protein binding is only 40–50%. It is metabolized in the liver by acetylation and reduction, mediated by CYP 3A4, then glucuronidation. Its metabolites are inactive and cleared by renal excretion. It has a long half-life of about 60 h.
Zonisamide is not a hepatic enzyme inducer or inhibitor and has no effect on the pharma- cokinetics of other commonly used antiepileptic drugs. However, it is affected by CYP 3A4 inducers or inhibitors. The addition of enzyme- inducing antiepileptic drugs decreases zon- isamide half-life and plasma level. On the other hand, zonisamide concentration is increased by CYP 3A4 inhibitors such as ketoconazole or cyclosporine.
Zonisamide adverse effects include sedation, ataxia, dizziness, nausea, fatigue, agitation/irritability, and anorexia. Weight loss may occur. Cognitive slowing and difficulty with concen- tration may be seen, particularly at higher doses. Kidney stones occur as frequently as 4%. Rarely, depression and psychosis may occur. Serious rash such as Stevens–Johnson syndrome and toxic epidermal necrolysis occur rarely. Oligo- hydrolysis, hyperthermia, and metabolic acidosis may occur, more often in children. Zonisamide was assigned pregnancy category C.
Zonisamide is a wide-spectrum antiepileptic drug but has undergone class I trials only for partial–onset seizures. The official FDA indica- tion is for adjunctive therapy in the treatment of partial seizures in adults with epilepsy. In Eur- ope, it is indicated as initial monotherapy for partial seizures. In Japan, it is also indicated as monotherapy for generalized seizures. The sug- gested therapeutic range is 10–14 mg/L.
Pregabalin
Pregabalin was first approved in USA in 2005. Its mechanism of action is similar to gabapentin. It binds to the alpha-2 delta subunit of voltage- gated calcium channels, reducing the influx of calcium and reducing neurotransmitter release under hyperexcitable conditions.
Unlike gabapentin, pregabalin has very good oral bioavailability, greater than 90%. The bioavailability is also independent of dose. The time to maximum concentration is 1 h, but is delayed up to 3 h when ingested with food. It has no protein binding.
Pregabalin is not metabolized in humans. It is excreted unchanged in the urine, thus requiring dose reduction in patients with renal impairment. Pregabalin half-life is about 6 h.
Pregabalin has no known pharmacokinetic interactions, which is predicted by the absence of metabolism, the absence of enzyme induction or inhibition, and the absence of protein binding.
Pregabalin can cause increased appetite and weight gain. There may be peripheral edema. Myoclonus may occur in some individuals, particularly with higher doses. Pregabalin is classified with pregnancy category C.
Pregabalin is a narrow-spectrum drug against partial–onset seizures. The official FDA epilepsy indication is an adjunctive therapy for adult patients with partial–onset seizures. Pregabalin is also indicated for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia.
Lacosamide
Lacosamide was first approved in the USA in 2008. Its mechanism of action is enhancing slow inactivation of sodium channels. This is to be distinguished from other antiepileptic drugs that interact with the sodium channel, all of which enhance fast inactivation of sodium channels.
Lacosamide is available in oral and intra- venous formulations. The oral bioavailability is about 100%. Protein binding is less than 15%.
Lacosamide is metabolized by demethylation in the liver to inactive O-desmethyl metabolite via CYP 2C19. Approximately 95% is excreted in the urine, 40% as unchanged drug, and 30% as O-desmethyl metabolite. The half-life is approximately 13 h.
Lacosamide has no known pharmacokinetic interactions despite the CYP 2C19 metabolism. However, it does have pharmacodynamic interactions with other antiepileptic drugs that act on the sodium channel.
The dose-related adverse effects include dizziness, headache, nausea, diplopia, and seda- tion. All these are more likely when lacosamide is used in conjunction with other sodium channel blockers. It may also cause a small asymptomatic increase in the PR interval.
Lacosamide is a narrow-spectrum antiepilep- tic drug against partial–onset seizures. The offi- cial FDA indication is for adjunctive therapy of partial–onset seizures in patients 17 years or older. The parenteral formulation is indicated as short-term replacement when oral administration is not feasible in patients taking oral lacosamide.
Vigabatrin
Vigabatrin was initially licensed in Europe in 1989, but was first approved in the USA in 2009. Its mechanism of action is irreversible inhibition of GABA transaminase, resulting in the accu- mulation of GABA.
Vigabatrin has excellent oral bioavailability, which is nearly complete. It has no protein binding. It is not significantly metabolized and is eliminated unchanged in the urine. The half-life is 10.5 h in young adults and 5–6 h in infants.
Vigabatrin is a weak inducer of CYP 2C9. This results in slight reduction of phenytoin levels with the addition of vigabatrin.
Vigabatrin adverse effects include sedation, fatigue, dizziness, and ataxia. There may be irritability, behavioral changes, psychosis, and depression. Weight gain may occur. The most concerning adverse effect is bilateral concentric visual field constriction, which is progressive and permanent. This occurs in up to 30–40% of individuals [16]. The risk increases with increased daily dose and increased duration of therapy [17]. As a result of the retinal visual toxicity, periodic visual assessment is required at baseline and every 3 months. In cooperative adult and pediatric patients, the monitoring can be accomplished with perimetry. Optional testing includes electroretinography and retinal imaging with optical coherence tomography. MRI chan- ges may occur in treated infants, consisting of increased T2 and restricted diffusion in deep white matter, basal ganglia, thalamus, and corpus callosum. These MRI changes are asymptomatic and reversible. Vigabatrin was assigned preg- nancy category C.
Vigabatrin is a narrow-spectrum drug effec- tive against focal seizures. It may worsen absence and myoclonic seizures in idiopathic generalized epilepsy [7]. The official FDA indi- cations are “adjunctive therapy for adults and pediatric patients 10 years of age or older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss” and “monotherapy for pediatric patients with infantile spasms one month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss.” Because of the visual toxicity, treatment with vigabatrin should be continued only if there is considerable benefit observed in the first 3 months of treatment.
Rufinamide
Rufinamide was first approved in USA in 2008. Its mechanism of action is binding to the sodium channels, prolonging the inactive state of sodium channels.
Oral bioavailability is about 85% with food, but less without food. Food increases the absorption by more than 30%. Protein binding is about 55%. Rufinamide is metabolized by enzymatic hydrolysis to an inactive metabolite. This is not dependent on the P450 enzyme system. The inactive metabolites are eliminated by excretion in the urine. The half-life is approximately 6–10 h.
Rufinamide is a weak inhibitor of CYP 2E1 (it increases olanzapine level) and a weak inducer of CYP 3A4 (it decreases oral contra- ceptive efficacy). Rufinamide is a weak inducer of UDP–GT (it increases the clearance of lamotrigine). The addition of enzyme-inducing antiepileptic drugs increases rufinamide clearance and decreases rufinamide level. On the other hand, the addition of valproate decreases rufinamide clearance and increases rufinamide levels by up to 70%.
Rufinamide adverse effects include dizziness, fatigue, somnolence, and headache. Vomiting may occur in children. Rufinamide may cause a shortening of the QT interval. It was assigned pregnancy category C.
Rufinamide is FDA indicated as adjunctive treatment of seizures associated with Lennox– Gastaut syndrome in children 4 years and older and adults. Although rufinamide was found to be effective for partial seizures, it has not been FDA approved for this indication.
Ezogabine
Ezogabine was first approved in the USA in 2011. It has a normal mechanism of action as a potassium channel opener. It enhances the activity and prolongs the opening of neuron specific KCNQ2/3 (Kv7.2/7.3) voltage-gated potassium channels, thereby activating the M current. Ezogabine also potentiates GABA- evoked currents in cortical neurons at much higher concentration than that needed to activate potassium currents.
Ezogabine oral bioavailability is about 60%. It is about 80% protein-bound. Ezogabine is extensively metabolized, pri- marily via glucuronidation and acetylation. It is metabolized to the active N-acetyl metabolite (NAMR), which is also subsequently glu- curonidated. About 85% of the absorbed dose is recovered in the urine, 36% as unchanged ezo- gabine, and 18% as NAMR. The half-life is 7–11 h for both ezogabine and NAMR.
Ezogabine does not significantly affect other antiepileptic drugs except for a 22% increase in lamotrigine clearance. NAMR may inhibit renal clearance of digoxin. Enzyme-inducing antiepileptic drugs reduce ezogabine levels.
The most common ezogabine adverse effects are dizziness, somnolence, fatigue, confusion, blurred vision, tremor, and nausea, most often during titration. Urinary retention may occur. There may be QT prolongation. Long-term use has been associated with skin, nail, and retinal pigmentation. Weight gain may occur. Ezo- gabine was assigned pregnancy category C.
Ezogabine is FDA indicated for adjunctive treatment of partial–onset seizures in patients aged 18 years and older. It is not known whether ezogabine is effective against other seizure types.
Perampanel
Perampanel was approved in the USA in 2012. Its mechanism of action is noncompetitive antagonism of AMPA glutamate receptors.
Perampanel has excellent oral bioavailability of about 100%. It is 95% protein-bound. Perampanel is extensively metabolized by primary oxidation mediated by CYP 3A4, fol- lowed by glucuronidation. It is excreted as inac- tive metabolites, 30% in the urine and 70% in the feces. It has a long half-life of 105 h on average.
Perampanel does not affect other antiepileptic drugs. However, perampanel at a dose of 12 mg per day reduces levonorgestrel by about 40%. This effect is not seen at the dose of 8 mg per day. Enzyme inducers will decrease perampanel levels.
Perampanel adverse effects include dizziness, somnolence, headache, fatigue, ataxia, and blur- red vision. Aggression and hostility may occur— at a dose of 12 mg per day, its incidence is estimated at 20%. Perampanel is assigned preg- nancy category C.
Perampanel is FDA indicated for the treat- ment of partial–onset seizures with or without secondary generalization in patients with epi- lepsy aged 12 years or older. It is not yet known whether perampanel is effective against general- ized onset seizures.
Eslicarbazepine
Eslicarbazepine acetate was approved for mar- keting in the USA in 2014. It is rapidly converted to the active metabolite (S)-licarbazepine by hydrolytic first-pass metabolism. (S)-licarbaze- pine is the active enantiomer of the monohy- droxy derivative, which is the active metabolite for oxcarbazepine. The monohydroxy derivative from oxcarbazepine is a racemic mixture of the active (S)-licarbazepine and the inactive (R)- licarbazepine.
Eslicarbazepine acts by blocking sodium channels and stabilizing the inactive state of the voltage-gated sodium channel.
Eslicarbazepine has excellent bioavailability, greater than 90%. Its protein binding is less than 40%. Eslicarbazepine is metabolized to inactive compounds. About 60% of the absorbed dose is excreted in the urine as unchanged eslicarbazepine, 0% as the glucuronide conjugates, and 10% as other metabolites. The half-life of eslicarbazepine is 13–20 h in plasma and 20–24 h in CSF, justi- fying once daily dosing used in clinical trials. Eslicarbazepine is not subject to autoinduc- tion. However, it can induce CYP 3A4, thus decreasing plasma concentrations of estrogen and drugs metabolized by this enzyme. It also has a moderate inhibitory effect on CYP 2C19, potentially increasing plasma concentration of phenytoin and other drugs metabolized by this enzyme. Enzyme inducers may reduce her esli- carbazepine serum concentration.
The most common eslicarbazepine adverse effects are dizziness, headache, diplopia, som- nolence, vertigo, nausea, vomiting, fatigue, and ataxia. Hyponatremia (defined as less than 125 mEq per liter) is reported in up to 1.5% of individuals taking 1200 mg per day. Rash occurs in up to 3% of individuals at 1200 mg per day.
Eslicarbazepine is effective against partial– onset (focal) seizures. It is currently FDA indi- cated as adjunctive treatment for partial–onset seizures. Monotherapy trials have been com- pleted but have not yet been considered to change the FDA indication.
Pharmokinetics of new generation AEDs
