Antiseizure medications: Mechanism of action, pharmacology, and adverse effects

INTRODUCTION — While sharing a common property of suppressing seizures, antiseizure medications have many different pharmacologic profiles that are relevant when selecting and prescribing these agents in patients with epilepsy and other conditions. This includes pharmacokinetic properties, propensity for drug-drug interactions, and side effect profiles and toxicities.

The pharmacology of antiseizure medications is reviewed here. The use of antiseizure medications in a treatment plan for patients with seizures is discussed separately. Risks of antiseizure medications in pregnancy are also discussed separately. (See "Initial treatment of epilepsy in adults" and "Overview of the management of epilepsy in adults" and "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Effects of ASMs on the fetus and child'.)

PHARMACOLOGIC PROFILES

Mechanisms of action — Antiseizure medications are typically grouped by their principal mode of action, although for many drugs, the precise mechanism of action is not known or multiple actions are suspected (table 1). To some degree, the cellular effects of antiseizure medications are linked with the types of seizures against which they are most effective. An improved understanding of the molecular effects of existing antiseizure medications as well as development of new antiseizure medications that act against novel targets may allow for more rational polytherapy in the future.

●Drugs that affect voltage-dependent sodium channels – Alteration of sodium currents is the most common mechanism of action of available antiseizure medications (table 1).

●Drugs that affect calcium currents – There are three types of calcium channels in neurons, each of which is distinguished by its rate of reactivation and voltage dependency. Low-threshold T-type calcium currents inactivate quickly and have been described in experimental preparations of thalamic relay neurons. These neurons probably are an integral component of the thalamocortical circuits associated with absence seizures, a subtype of generalized seizures associated with brief episodes of staring and a characteristic three-per-second spike and wave pattern on the electroencephalogram (EEG) [1].

Ethosuximide diminishes T-type calcium currents in thalamic neurons, which are further reduced as membrane potentials become more hyperpolarized. (See 'Ethosuximide' below.)

Gabapentin and pregabalin bind to the auxiliary alpha-2-delta subunit of a voltage-dependent calcium channel, which may inhibit inward calcium currents and attenuate neurotransmitter release. (See 'Gabapentin' below and 'Pregabalin' below.)

●Drugs that affect GABA activity – Gamma-aminobutyric acid (GABA) is a neurotransmitter that is widely distributed throughout the central nervous system and exerts postsynaptic inhibition. The GABA(A) receptor complex has binding sites for GABA, benzodiazepines, and phenobarbital. Picrotoxin and other similar proconvulsants bind to the GABA(A) receptor and block chloride channels, thereby preventing postsynaptic inhibition. Thus, reduced GABAergic tone is viewed as proconvulsant, while increasing GABAergic tone generally has an anticonvulsant effect.

Synthesis of GABA is dependent upon the enzyme glutamic acid decarboxylase (GAD), which requires pyridoxine as a coenzyme. Pyridoxine-deficient infants lack the capacity to synthesize GABA normally and are prone to seizures. The metabolism of GABA to succinate occurs in presynaptic neurons and glia by means of the mitochondrial enzyme GABA transaminase (GABA-T).

Over time, several antiseizure medications have been designed to increase the supply of GABA by lowering GABA metabolism by GABA-T, reducing the reuptake of GABA into neurons and glia, or increasing the production of GABA by GAD. Other antiseizure medications have been designed to imitate the action of GABA, while still others improve endogenous GABA-mediated inhibition.

As examples, benzodiazepines bind to the GABA(A) receptor and facilitate the attachment of GABA to its binding site on the receptor. The inhibitory action of endogenous GABA is magnified because benzodiazepines increase the occurrence of chloride channel openings. Phenobarbital also binds to the GABA(A) receptor. Tiagabine is a potent enhancer of GABA action via specific inhibition of GABA reuptake into presynaptic neurons and glia, and vigabatrin is an irreversible inhibitor of GABA-T that raises the concentration of GABA in the central nervous system. (See 'Benzodiazepines' below and 'Phenobarbital' below and 'Tiagabine' below and 'Vigabatrin' below.)

●Drugs that affect the glutamate receptor – Glutamate is the most prevalent excitatory neurotransmitter. There are two types of glutamate receptors: ionotropic, which form ion channels that are activated by glutamate binding, and metabotropic, which indirectly activate ion channels via the G protein signalling cascade. Two ionotropic glutamate receptors, N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), are thought to play a role in the generation and spread of seizures [2]. As examples, perampanel is a noncompetitive AMPA-type glutamate receptor antagonist, and felbamate and topiramate are thought to act in part through NMDA antagonism. (See 'Perampanel' below and 'Felbamate' below and 'Topiramate' below.)

●Drugs with other mechanisms of action – Levetiracetam and brivaracetam bind to the synaptic vesicle protein SV2A; binding at this site may modulate synaptic transmission through alteration of vesicle fusion. (See 'Levetiracetam' below and 'Brivaracetam' below.)

Pregabalin is chemically related to gabapentin and, like gabapentin, it binds to the alpha-2-delta subunit of voltage-gated calcium channels and modulates calcium currents. Pregabalin also modulates the release of several neurotransmitters including glutamate, noradrenaline, and substance P. (See 'Pregabalin' below.)

Therapeutic spectrum — Some antiseizure medications are used primarily to treat a broad range of seizures types (both focal and generalized onset) while others are used primarily for focal seizures. These are summarized in the table (table 2).

For detailed prescribing information, readers should refer to the individual drug information topics within UpToDate. Comprehensive information on drug-drug interactions can be determined using the drug interactions program. Complete information on US Food and Drug Administration (FDA) labeling for each drug can be accessed using the FDA searchable database.

Newer-generation agents — Over the past several decades, the number of available antiseizure medications has more than doubled. Unlike some of the earliest antiseizure medications such as phenobarbital, phenytoin, and carbamazepine, many of the currently available antiseizure medications have simple pharmacokinetics and more limited effects on liver metabolism [3]. This translates into a generally reduced need for serum monitoring, once- or twice-daily dosing for some, fewer drug-drug interactions, and perhaps a lower rate of adverse effects. Despite these advantages, however, there are few data to suggest significant differences in effectiveness among available antiseizure medications.

ANTISEIZURE MEDICATIONS

Benzodiazepines — Benzodiazepines bind to the GABA(A) receptor and facilitate the attachment of GABA to its binding site on the receptor. The inhibitory action of endogenous GABA is magnified because benzodiazepines increase the occurrence of chloride channel openings. Drugs in this class include clobazam, clonazepam, clorazepate, diazepam, and lorazepam.

Clobazam (see 'Clobazam' below) is used as adjunctive therapy for the treatment of drop seizures in patients with Lennox-Gastaut syndrome (LGS) and is used in other countries outside of the United States for the treatment of focal seizures. Clonazepam (see 'Clonazepam' below) is most often used as an adjunctive therapy for myoclonic and atonic seizures. Clorazepate, diazepam, and lorazepam are effective for those seizure types as well as for focal and generalized tonic-clonic seizures.

Lorazepam, diazepam (especially rectal or nasal diazepam), and nasal midazolam are typically used as rescue medications for acute repetitive seizures or status epilepticus. This is discussed in more detail elsewhere. (See "Management of convulsive status epilepticus in children" and "Convulsive status epilepticus in adults: Management".)

As a class, the benzodiazepines may be associated with the development of tolerance, limiting their usefulness in the chronic treatment of epilepsy. Side effects include sedation, irritability, ataxia, and depression. Sudden discontinuation of benzodiazepines may lead to withdrawal seizures.

Brivaracetam — Like levetiracetam, brivaracetam binds to the synaptic vesicle protein synaptic vesicle glycoprotein 2A (SV2A), which has been linked in animal models to epilepsy [4,5].

●Indications and efficacy – Brivaracetam is approved as monotherapy or adjunctive therapy for focal-onset seizures in patients one month of age and older.

Randomized trials in adults with refractory focal epilepsy have explored daily doses of brivaracetam ranging from 20 to 200 mg/day [6-9]. In the largest individual trial (n = 768), the proportion of patients with a ≥50 percent reduction in seizure frequency was 39 percent for patients randomly assigned to brivaracetam 100 mg/day, 38 percent for brivaracetam 200 mg/day, and 22 percent for placebo [6]. More limited data suggest that brivaracetam has activity in adults with generalized epilepsy [10] but not in children with progressive myoclonic epilepsy [11]. It does not appear to add benefit in combination with levetiracetam.

●Metabolism and interactions – Brivaracetam is metabolized primarily (approximately 60 percent) by cytochrome P450 (CYP)-independent hydrolysis and secondarily (approximately 30 percent) via hepatic CYP2C19 to inactive metabolites. The CYP2C19 gene is polymorphic, and polymorphisms associated with reduced CYP2C19 function have the potential to diminish brivaracetam metabolism and thereby increase toxicity. (See "Overview of pharmacogenomics", section on 'CYP isoenzymes and drug metabolism'.)

Brivaracetam does not induce drug-metabolizing enzymes in the liver and weakly inhibits CYP2C19 (table 3). Nonetheless, clinicians should be aware of several potential interactions with concomitant antiseizure medications. Brivaracetam may increase the plasma concentrations of phenytoin and the active (10,11-epoxide) metabolite of carbamazepine via inhibition of epoxide hydroxylase. Of note, routine carbamazepine serum measurements do not assess for accumulation of active carbamazepine-epoxide metabolite, but this metabolite can be measured as a separate test (see 'Carbamazepine' below). The concurrent use of phenytoin, carbamazepine, phenobarbital, and other CYP2C19 inducers is associated with decreased plasma concentrations of brivaracetam (table 4A) [12]. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The manufacturer's recommended starting dose for adults and children 16 years of age and older is 50 mg twice daily [13]. The dose can be adjusted down to 25 mg twice daily or increased to 100 mg twice daily based upon therapeutic response and tolerability. Lower doses are recommended for patients with hepatic impairment. For children one month to less than 16 years of age, the dose is based upon body weight and is administered twice daily. The drug is available in both oral and intravenous (IV) formulations [14]. When oral administration is temporarily not feasible, brivaracetam may be given by IV administration. The dose and frequency for the IV preparation are the same as for the oral tablets and oral solution.

●Adverse effects – The most common side effects of brivaracetam are somnolence, dizziness, fatigue, and nausea (table 5A). Across multiple randomized trials, psychiatric adverse effects occurred more commonly in patients treated with brivaracetam than placebo (13 versus 8 percent) [13]. In a randomized controlled trial of 760 patients, the most common psychiatric side effects of brivaracetam were irritability (3 versus 0.4 percent), anxiety (2.2 versus 1.1 percent), insomnia (2 versus 1.1 percent), and depression (0.8 versus 0.4 percent) [6]. Severe hypersensitivity reactions have been reported, including bronchospasm and angioedema (table 5B).

The comparative tolerability between brivaracetam and levetiracetam is not yet known. A 2021 systematic review identified five studies that included a subset of people with epilepsy who switched from levetiracetam to brivaracetam, which was associated with improvement in behavioral adverse events in 33 to 83 percent of patients [15]. Still, a retrospective postmarketing study included in the systematic review also found that patients with a history of behavioral adverse effects on levetiracetam were at increased risk for behavioral adverse effects from brivaracetam (odds ratio 3.5) [16].

Cannabidiol — The mechanism of action that underlies the antiseizure properties of cannabidiol is not well understood, but it does not appear to involve its effects on cannabinoid receptors.

●Indications and efficacy – Cannabidiol (pharmaceutical) is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients one year of age and older. The efficacy of cannabidiol for treating seizures associated with Lennox-Gastaut syndrome and Dravet syndrome is reviewed separately. (See "Lennox-Gastaut syndrome", section on 'Management' and "Dravet syndrome: Management and prognosis", section on 'Cannabidiol'.)

●Metabolism and interactions – Cannabidiol (pharmaceutical) is metabolized in the liver by CYP3A4 and CYP2C19 [17]. It is also a substrate of UGT1A7, UGT1A9, UGT2B7, and an inhibitor of CYP2C19 and BSEP/ABCB11, with the potential for multiple drug interactions. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – Cannabidiol (pharmaceutical) is an oral solution (100 mg/mL) [18]. The initial dose is 2.5 mg/kg twice daily by mouth. For seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, the dose can be increased after one week to the suggested maintenance dose of 5 mg/kg twice daily, and may be increased, if needed for further seizure control, up to a maximum of 10 mg/kg twice daily (total 20 mg/kg per day). For seizures associated with tuberous sclerosis complex, the dose may be increased each week by 2.5 mg/kg twice daily, as tolerated, to a recommended maintenance dose of 12.5 mg/kg twice daily (total 25 mg/kg per day).

●Adverse effects – The most common adverse reactions with cannabidiol are diarrhea, somnolence, decreased appetite, transaminase elevations, fatigue, malaise, insomnia and other sleep problems, and infections [18].

Serum transaminase (alanine transaminase [ALT] and aspartate transaminase [AST]) and total bilirubin levels should be obtained at baseline and then at one, three, and six months after starting treatment, and periodically thereafter as clinically indicated, or within one month of change in cannabidiol dosing or with changes in other medications that affect liver function [18]. Cannabidiol should be discontinued or interrupted if symptoms or signs of liver dysfunction develop.

Carbamazepine — Carbamazepine binds to voltage-dependent sodium channels, probably after they change from the activated to the inactivated state. This binding extends the inactivated phase and inhibits the generation of rapid action potentials when the cell is experiencing incoming depolarizing trains. This effect increases with the rate of neuronal firing.

●Indications and efficacy – Carbamazepine has broad use as an antiseizure medication for the treatment of focal and generalized seizures. It is also effective for the treatment of affective illnesses such as bipolar disorder and chronic pain syndromes such as trigeminal neuralgia. In a 2013 systematic review, the International League Against Epilepsy (ILAE) concluded that carbamazepine is established as effective as initial monotherapy for adults with focal seizures, and is possibly effective for children with focal seizures [19]. It is potentially effective as initial monotherapy for adults and children with generalized-onset tonic clonic seizures.

●Metabolism and interactions – Carbamazepine is approximately 70 percent protein bound. It is metabolized in the liver by CYP3A4 and is a potent and broad-spectrum inducer of the CYP system (table 3). The main metabolite, carbamazepine 10,11-epoxide, has anticonvulsant activity and can be measured in the serum.

A number of drugs can influence the serum concentration of carbamazepine (table 4A). Comprehensive information on drug-drug interactions can be determined using the drug interactions program. Carbamazepine may reduce the effectiveness of most forms of hormonal contraception (table 6). (See "Overview of the management of epilepsy in adults", section on 'Contraception'.)

●Dosing – The usual initial starting dose of carbamazepine is 2 to 3 mg/kg per day orally (eg, 100 to 200 mg daily for most patients) given two, three, or four times daily; the dose is increased every five days to 10 mg/kg daily (eg, 800 to 1200 mg/day). Generally, three-times-daily dosing of the immediate-release formulation is recommended. However, if patients experience side effects two to four hours after a dose, then the total daily dose could be redistributed over four doses or a switch made to an extended-release formulation. Measurement of serum sodium concentration is suggested prior to initiation of therapy and again once the patient reaches a therapeutic dose. (See 'Hyponatremia' below.)

Extended-release oral formulations allow for twice-daily dosing with more stable blood levels. A systematic review of 10 randomized trials comparing immediate-release with controlled-release carbamazepine found a trend toward improved tolerability for controlled-release carbamazepine but mixed results on seizure control, with most trials showing no significant difference between the two formulations [20].

Serum carbamazepine levels should be measured initially at three, six, and nine weeks, with a goal level of 4 to 12 mcg/mL (17 to 51 micromol/L). Frequent levels are needed early in therapy due to autoinduction, which results in decreased serum concentrations. Further increases up to 15 to 20 mg/kg per day (up to 2 grams per day or higher in selected patients) may be necessary after two to three months because of CYP autoinduction. Serum levels subsequently should be checked at least every two months until successive determinations are constant, more frequently if carbamazepine doses or concomitant antiseizure medication doses are changed.

●Adverse effects – Common systemic side effects of carbamazepine include nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, and fluid retention (table 5A-B). Patients who develop a rash with carbamazepine are more likely to develop one with oxcarbazepine, lamotrigine, phenytoin, or phenobarbital, and vice versa [21]. Men taking carbamazepine have higher rates of sexual dysfunction and low testosterone levels, which may be reversible if carbamazepine is withdrawn [22,23]. Decreased thyroid hormone levels of uncertain clinical significance have been reported in patients taking carbamazepine [24,25].

Neurotoxic side effects include drowsiness, dizziness, blurred or double vision, lethargy, and headache. Hyponatremia related to carbamazepine is discussed separately. (See 'Hyponatremia' below.)

Potentially life-threatening adverse events related to carbamazepine include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and bone marrow suppression:

•SJS/TEN – Most cases of SJS/TEN occur during the first eight weeks of therapy [26,27]. Screening for the HLA-B*1502 allele is recommended prior to starting carbamazepine in patients with Asian ancestry due to the risk of SJS and TEN. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

•Bone marrow suppression – Leukopenia occurs in approximately 12 percent of children and 7 percent of adults with carbamazepine treatment [28]. It may be transient or persistent and does not usually require immediate discontinuation of carbamazepine therapy. The onset is typically within the first three months of treatment. Patients who have a low or low-normal white blood cell (WBC) or neutrophil count before carbamazepine treatment may be at higher risk for developing carbamazepine-induced leukopenia or neutropenia.

Aplastic anemia (pancytopenia) is a rare, idiosyncratic, non-dose-related side effect that is most likely to occur within the first three or four months after initiating carbamazepine therapy. Daily laboratory checks would be necessary to monitor for aplastic anemia, agranulocytosis, and thrombocytopenia because of their rapid onset [28], and such frequent monitoring is neither practical nor necessary for most patients taking carbamazepine. A more suitable approach is to monitor for aplastic anemia by informing patients and clinicians to carefully watch for signs and symptoms [28]. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Some experts recommend monitoring WBC counts of high-risk patients during the first three months of carbamazepine treatment, with the monitoring frequency determined by results of each laboratory value. WBC counts less than 3000/microL or neutrophil counts below 1000/microL warrant either a decrease in carbamazepine dose with frequent WBC monitoring or carbamazepine discontinuation [28].

Cenobamate — Cenobamate, a tetrazole alkyl carbamate derivative, is an inhibitor of voltage-dependent sodium channels and may enhance gamma-aminobutyric acid (GABA) inhibition through modulation of the GABA(A) receptor.

●Indications and efficacy – Cenobamate was approved in late 2019 by the US Food and Drug Administration (FDA) for the treatment of focal (partial-onset) seizures in adults [29]. Cenobamate should be reserved for adults with treatment-resistant focal seizures.

The efficacy of cenobamate was established in two randomized controlled trials that enrolled over 650 adults with focal seizures [29-31]. In one of these trials, 437 adults who were refractory to treatment with at least one antiseizure medication were assigned in a 1:1:1:1 ratio to once daily treatment with either cenobamate 100 mg, 200 mg, 400 mg, or placebo [30]. After a 6-week titration phase and 12-week maintenance phase, the median percentage reductions in seizure frequency for the cenobamate 100 mg/day, 200 mg/day, and 400 mg/day dose groups were 35.5, 55, and 55 percent respectively, compared with 24 percent for the placebo group. Responder rates (ie, the percentage of patients achieving a ≥50 percent reduction in seizures) for the cenobamate 100 mg/day, 200 mg/day, and 400 mg/day dose groups were 40, 56, and 64 percent, respectively, compared with 25 percent for the placebo group.

●Metabolism and interactions – Cenobamate is primarily metabolized by glucuronidation via UGT2B7 and to a lesser extent by UGT2B4, and by oxidation via CYP2E1, CYP2A6, CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5. Cenobamate may increase the serum concentrations of clobazam, phenobarbital, phenytoin, and CYP2C19 substrates, and may decrease the serum concentrations of carbamazepine, lamotrigine, and CYP2B6 and CYP3A substrates. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The recommended initial dose of oral cenobamate is 12.5 mg once daily for the first two weeks, followed by a slow upward titration: 25 mg once daily for weeks 3 and 4, 50 mg once daily for weeks 5 and 6, 100 mg once daily for weeks 7 and 8, 150 mg once daily for weeks 9 and 10, and 200 mg once daily (the recommended maintenance dose) for week 11 and thereafter [32]. The dose may be further increased by 50 mg once daily every two weeks if necessary based upon response and tolerability, to a maximum dose of 400 mg once daily. When cenobamate is discontinued, the dose should be titrated down gradually over at least two weeks.

Cenobamate is not recommended for patients with severe hepatic impairment or end-stage renal disease; the maximum dose should not exceed 200 mg/day for patients with mild to moderate hepatic impairment [32]. Lower doses may be needed for patients with mild to moderate renal disease.

●Adverse effects – The most frequent adverse events in clinical trials of cenobamate were dose-dependent somnolence, dizziness, headache, fatigue, and diplopia [30,32]. Patients should be monitored for drowsiness, fatigue, and suicidal ideation and behavior. The label recommends advising patients not to drive or operate machinery until they have gained sufficient experience with cenobamate [32]. Other potential adverse effects include QT shortening and rare occurrences of drug reaction with eosinophilia and systemic symptoms (DRESS, also known as multi-organ hypersensitivity). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Familial short QT syndrome and hypersensitivity to cenobamate are contraindications to its use.

There are few data regarding the risk of cenobamate use in pregnancy or lactation, but animal data suggests possibility of fetal harm [32].

Clobazam — Clobazam, a benzodiazepine, binds to the GABA(A) receptor and facilitates the inhibitory action of endogenous GABA by increasing neuronal membrane permeability to chloride ions.

●Indications and efficacy – Clobazam is approved by the FDA for use as an adjunctive therapy in patients two years of age and older with Lennox-Gastaut syndrome (LGS) (see "Lennox-Gastaut syndrome"). Clobazam is widely used in other countries outside the United States for the treatment of focal seizures.

In a systematic review, the ILAE concluded that clobazam was potentially effective as initial monotherapy for children with focal seizures [19]. However, data are limited to support its use as monotherapy [33]; clobazam is typically used as adjunctive therapy. The evidence for clobazam in LGS is reviewed separately. (See "Lennox-Gastaut syndrome", section on 'Management'.)

●Metabolism and interactions – Clobazam is metabolized in the liver by cytochrome P450 (CYP) and non-CYP transformations and is a moderate inhibitor of CYP2D6. Dose adjustments are required in patients with hepatic insufficiency (table 3). Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – For patients two years of age or older and ≤30 kg body weight, clobazam may be started at 5 mg per day in one dose, typically given at bedtime [34]. The dose may be increased in intervals no shorter than every seven days to a maximum total dose of 20 mg per day; doses >5 mg should be given in divided doses twice daily. For patients >30 kg body weight, clobazam may be started at 10 mg in two divided doses and increased in intervals no shorter than every seven days to a maximum total dose of 40 mg per day.

●Adverse effects – Adverse effects of clobazam include somnolence and sedation, dysarthria, drooling, aggression or other behavioral changes, infections, and constipation; of these, tiredness and behavioral changes are most common [35]. In clinical trials, the incidence of adverse effects was not significantly different in low-dose, high-dose, or placebo-treated patients [36,37].

Rare cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have also been reported; such reactions can occur at any time, but the likelihood may be greater during the first eight weeks of clobazam treatment or when the drug is stopped and restarted [34,38-40].

Clonazepam — Clonazepam, a benzodiazepine, binds to the GABA(A) receptor and facilitates the inhibitory action of endogenous GABA by increasing neuronal membrane permeability to chloride ions.

●Indications and efficacy – Clonazepam is most often used as an adjunctive therapy for myoclonic and atonic seizures. It is FDA-approved for use in Lennox-Gastaut syndrome (akinetic and myoclonic seizures) and absence seizures unresponsive to succinimides. Clonazepam is seldom used to treat childhood absence epilepsy, but has a role in complex epilepsy syndromes with hard-to-treat absence seizures.

In a systematic review, the ILAE concluded that clonazepam was potentially effective as initial monotherapy for adults and children with focal seizures [19]. However, data are limited to support its use as monotherapy [33,41]; clonazepam is typically used as adjunctive therapy.

●Metabolism and interactions – Clonazepam is metabolized in the liver, mainly by cytochrome P450 isoenzyme 3A4 (CYP3A4), with potential for interactions involving other CYP3A4 substrates. Drug-drug interactions can be searched using the drug interactions program.

●Dosing – The starting dose of clonazepam in adults is 0.5 to 1 mg/day when used as adjunct therapy, or 0.5 to 1.5 mg/day when used as monotherapy, with weekly increments of 0.5 to 1 mg/day as needed and tolerated (maximum 20 mg daily). The usual maintenance dose is 2 to 8 mg daily in one or two divided doses. The dose in infants, children, and adolescents is based upon weight.

●Adverse effects – Adverse effects of clonazepam include mainly drowsiness, ataxia, and behavioral changes [42].

Eslicarbazepine — Eslicarbazepine is structurally similar to carbamazepine and oxcarbazepine, with which it shares some metabolites. It is thought to act through preferential blockade of voltage-gated sodium channels in rapidly firing neurons, although there may be other mechanisms of action [43].

●Indications and efficacy – Eslicarbazepine is approved as monotherapy and for the adjunctive treatment of focal-onset seizures in adults and children as young as four years of age. In a meta-analysis of seven randomized controlled trials, patients treated with eslicarbazepine once daily were more likely to achieve a greater than 50 percent reduction in seizure frequency compared with those receiving placebo (risk ratio [RR] 1.57, 95% CI 1.34-1.83) [44]. In the largest individual randomized trial (n = 640), a greater than 50 percent reduction in seizures (responder rate) was observed in more patients treated with eslicarbazepine 1200 mg per day than placebo (43 versus 23 percent) [45]. The responder rate was also improved in patients treated with eslicarbazepine 800 mg per day versus placebo (31 versus 23 percent), but the result was not statistically significant. Adverse effects led to treatment discontinuation in 26 percent of those treated at 1200 mg per day, 12 percent of those treated at 800 mg per day, and 8 percent of those treated with placebo.

●Metabolism and interactions – Eslicarbazepine is given orally as an acetate prodrug that is converted to its active form in the liver. Eslicarbazepine achieves a maximum concentration in two to three hours after oral ingestion [46]. Concentrations are unaltered by food. The elimination half-life of eslicarbazepine is 13 to 20 hours.

It is a weak inducer of CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and a moderate inhibitor of CYP2C19 (table 3). Eslicarbazepine undergoes extensive metabolism via glucuronidation, and coadministration with UGT inducers such as carbamazepine and phenytoin has been associated with decreased eslicarbazepine drug levels. Conversely, phenytoin levels may increase with coadministration of eslicarbazepine, and adjustment of phenytoin dose may be needed (table 4B). Eslicarbazepine is not subject to autoinduction.

According to manufacturer pharmacokinetic data, eslicarbazepine can, in a dose-related manner, decrease concentrations of coadministered CYP3A4 substrates (eg, simvastatin) and levonorgestrel- and ethinyl estradiol-containing hormonal contraceptives [47]. Women of childbearing potential should use additional or alternative nonhormonal contraception [47,48]. Eslicarbazepine may alter warfarin concentrations [49]. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

Eslicarbazepine and oxcarbazepine share the same main active metabolite (S-licarbazepine or S-10-monohydroxy metabolite [MHD]), and combined use should be avoided due to the increased risk for adverse or toxic effects.

●Dosing – The recommended starting dose in adults is 400 mg once daily, which can be increased after one to two weeks to a recommended maintenance dose of 800 mg daily. Depending upon response, daily dose may be further increased to a maximum of 1200 mg. Dose adjustment is needed for renal impairment. Its use is not recommended in patients with severe liver impairment.

●Adverse effects – The most common side effects of eslicarbazepine are dizziness, drowsiness, nausea, headache, diplopia, fatigue, vertigo, ataxia, blurred vision, and tremor (table 5A). In clinical trials, these side effects occurred more frequently during initial use and when given at the maximum dose of 1200 mg daily [45]. Eslicarbazepine has been associated with an increase in the PR interval, abnormal liver function tests (LFTs), and hyponatremia. Concomitant treatment with carbamazepine increases the incidence of diplopia, abnormal coordination, and dizziness (table 4A). Measurement of serum sodium concentration is suggested prior to initiation of therapy and again once the patient reaches a therapeutic dose. (See 'Hyponatremia' below.)

Rare but serious adverse effects include SJS/TEN. In clinical trials, 1 to 3 percent of patients who received eslicarbazepine developed rash [47]. Eslicarbazepine should not be used in patients with a history of hypersensitivity due to oxcarbazepine or carbamazepine, as these drugs are structurally related. Its use should be discontinued if dermatologic reaction or other signs of hypersensitivity develop. Risk factors for hypersensitivity have not been established, and it is not yet known whether certain HLA alleles increase the risk of serious dermatologic reactions, as is the case with carbamazepine. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'HLA polymorphism and pharmacogenetics'.)

Ethosuximide — Ethosuximide diminishes T-type calcium currents in thalamic neurons, which are further reduced as membrane potentials become more hyperpolarized [50]. The metabolite of trimethadione, another antiseizure medication for absence seizures, acts similarly.

●Indications and efficacy – Ethosuximide is effective for the treatment of absence seizures; it has no activity against generalized tonic-clonic or focal seizures. A randomized clinical trial compared ethosuximide, valproate, and lamotrigine in 453 children with childhood absence epilepsy [51]. Ethosuximide and valproic acid were found to be more effective than lamotrigine in eliminating seizures; ethosuximide had a more favorable adverse-event profile compared with valproic acid. (See "Childhood absence epilepsy".)

●Metabolism and interactions – Ethosuximide is metabolized in the liver via CYP3A. There are no significant reactions reported with other drugs. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The recommended dose of ethosuximide is 20 to 40 mg/kg per day in one to three divided doses. Blood levels should be checked initially after one to three weeks, with a goal therapeutic concentration of 40 to 100 mcg/mL (280 to 700 micromol/L).

●Adverse effects – The major side effects include nausea, vomiting, sleep disturbance, drowsiness, and hyperactivity (table 5A-B).

Felbamate — The mechanism of action of felbamate is not well understood. It blocks the channel at the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor and augments gamma-aminobutyric acid (GABA) function in rat hippocampal neuronal cultures [52].

●Indications and efficacy – Felbamate can be used to treat focal seizures and is mainly used to treat the Lennox-Gastaut syndrome (LGS), a mixed seizure disorder of childhood onset associated with multiple seizure types, slow spike-wave pattern on the interictal electroencephalogram (EEG), intellectual disability, and resistance to standard antiseizure medications. (See "Lennox-Gastaut syndrome".)

However, felbamate is not recommended for first-line therapy of seizures because of the potential for serious adverse reactions [53]. The manufacturer recommends that written consent be obtained prior to beginning therapy.

In a placebo-controlled randomized trial of 73 patients with LGS, adjunctive treatment with felbamate was effective for reducing the frequency of seizures [54], and the improvement was sustained in an open-label follow-up study [55].

●Metabolism and interactions – Felbamate is metabolized in the liver by the cytochrome P450 (CYP) system (primarily CYP3A4) and approximately 50 percent is excreted renally as unchanged drug (table 3). Felbamate can increase toxicity of valproate, phenytoin, and the active epoxide metabolite of carbamazepine [56-58]. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The initial dose of felbamate for adults and adolescents age 14 years or more is 1200 mg/day in three to four divided doses, increasing by 600 mg to 1200 mg per week, based upon response and tolerance, to a maximum total daily dose of 3600 mg [33]. For children ages 2 to 14 years, the initial dose is 15 mg/kg per day given in three to four divided doses, increasing by 15 mg/kg per day at weekly intervals based upon response and tolerance, with a maximum total daily dose of 45 mg/kg per day or 3600 mg per day, whichever is less.

Therapeutic blood levels of felbamate have not been established, but patients should have baseline laboratory testing including a complete blood count and liver enzymes. These tests should continue to be monitored every one to two months, and monitoring of the blood counts should continue following cessation of therapy.

●Adverse effects – The most frequent adverse effects associated with felbamate are anorexia, nausea, and vomiting [33]. Others include insomnia, irritability, headache, and weight loss.

Felbamate has been associated with fatal aplastic anemia and hepatic failure (table 5A-B). These severe toxicities have been reported in a higher proportion of patients treated with felbamate compared with those treated with other antiseizure medications. Aplastic anemia may not occur for several months after the start of therapy, may not be reliably detected by routine testing, and may continue to be a risk for patients even after cessation of the drug. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Gabapentin — Gabapentin binds to the auxiliary alpha-2-delta subunit of a voltage-dependent calcium channel, which may inhibit inward calcium currents and attenuate neurotransmitter release [59]. Structure/activity studies of gabapentin and related compounds show a strong correlation between binding at this receptor and anticonvulsant activity, further supporting that this is the site of action relevant in epilepsy [60,61].

●Indications and efficacy – Gabapentin is used as add-on therapy for refractory focal seizures [62,63]. The American Academy of Neurology (AAN) guidelines state that gabapentin is considered possibly effective for initial monotherapy in patients age 60 years and older with newly diagnosed focal epilepsy [64], although it is not approved by the FDA for this indication [65]. There is moderate-quality evidence that gabapentin is effective as adjunctive treatment for patients with drug-resistant focal epilepsy [63].

●Metabolism and interactions – Gabapentin is absorbed by means of saturable amino acid transport systems in the gut. Though less convenient, more frequent dosing will result in increased bioavailability when daily doses >3600 mg are required [66]. The drug does not bind to plasma protein and is not metabolized; it is excreted entirely in the urine, corresponding with the creatinine clearance; dose adjustments are required in patients with impaired renal function (table 3). Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – Initial dosing suggested by the manufacturer (eg, 300 mg three times daily or 300 mg the first day, 300 mg twice daily the second day, 300 mg three times a day on the third day) may not be well tolerated in some patients, especially older adults, and a lower initial dose and slower titration are often prudent. The dose can be gradually increased as needed to 1800 mg/day in three divided doses. The antiseizure effects of gabapentin are dose related, and the therapeutic effects of doses less than 900 mg/day may be small. Doses of up to 2400 mg/day have been tolerated in long-term studies in patients with epilepsy [63,67].

Gabapentin should be taken at least two hours after the use of antacids since concurrent administration decreases its bioavailability.

There are no established therapeutic serum levels. Toxic side effects are more common in patients with renal insufficiency, especially in older patients and those with comorbidity. One study found that patients with chronic kidney disease commonly receive inappropriately high doses of gabapentin for their kidney function [68].

●Adverse effects – The major adverse effect of gabapentin is sedation (table 5A-B), and it should be used with caution in combination with other medications that cause sedation, including opioids and benzodiazepines. Additional common side effects include dizziness, ataxia, and weight gain. Misuse and diversion of gabapentin are increasingly recognized; risk factors include a history of substance abuse, especially opioids, and psychiatric comorbidities [69,70]. Respiratory depression, potentially fatal, can occur when gabapentinoids are used with other central nervous system (CNS) depressants such as opioids, or when used to treat elderly patients or patients with respiratory risk factors such as chronic obstructive pulmonary disease (COPD) [71-74]. (See "Acute opioid intoxication in adults".)

Gabapentin may be transported across the placenta and accumulate in breast milk, but the clinical significance of this finding is not clear. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Breastfeeding'.)

Lacosamide — Lacosamide selectively enhances slow inactivation of voltage-dependent sodium channels; this results in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing [75,76]. Lacosamide also binds to the collapsin response mediator protein 2 (CRMP2), which may be involved in epileptogenesis.

●Indications and efficacy – Oral lacosamide is FDA-approved for use as monotherapy or adjunctive therapy for focal-onset seizures in patients one month of age and older, and for adjunctive treatment of primary generalized tonic-clonic seizures in patients four years of age and older [77]. In randomized trials, a 50 percent or greater reduction in seizure frequency for placebo, lacosamide 200 mg per day, and lacosamide 400 mg per day occurred in 23, 34, and 40 percent respectively [75,78-81]. The efficacy of lacosamide 600 mg per day was similar to 400 mg per day but was less well tolerated. Secondary efficacy analysis suggested that the 600-mg-per-day dose of lacosamide may provide additional benefits in certain subgroups of patients, specifically those with secondary generalized seizures [79]. An open-label extension of one clinical trial demonstrated that lacosamide was safe and generally well tolerated, with maintenance of efficacy among responders up to five years after treatment initiation [82]. Other reports document similar efficacy for focal-onset seizures in younger patients, ages 1 to 21 years [83-86], and after conversion to monotherapy in adults [87].

●Metabolism and interactions – Lacosamide is completely absorbed after oral administration with 100 percent bioavailability and is eliminated by renal excretion and biotransformation. Lacosamide is not a significant hepatic-enzyme inducer, but strong CYP inhibitors (eg, valproate) may decrease elimination in the presence of hepatic or renal impairment (table 3). Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – Lacosamide is available as an oral tablet, oral solution, and IV injection. It is FDA-approved for the treatment of partial-onset seizures in patients one month of age and older and as adjunctive therapy for primary generalized tonic-clonic seizures in patients four years of age and older [77]. Lacosamide is also available as extended-release capsules, which are FDA-approved for the treatment of partial-onset seizures in adults and children weighing at least 50 kg [88].

Lacosamide (regular release) should be initiated at a dose of 50 mg twice daily (total 100 mg per day) as adjunctive therapy in adults; the recommended starting dose as monotherapy is 100 mg twice per day (total 200 mg per day) [77]. The dose may be increased at weekly intervals by 100 mg per day to a maintenance dose of 200 to 400 mg (total) per day for adjunctive therapy, and 300 to 400 mg (total) per day for monotherapy. Children should be dosed according to body weight.

To achieve maintenance dosage more quickly when clinically indicated, an alternative dosing strategy for adults and children weighing at least 50 kg is to start lacosamide with a 200 mg loading dose, followed 12 hours later by starting 100 mg twice daily (total 200 mg per day). The dose may be increased at weekly intervals by 100 mg per day to a maintenance dose of 200 to 400 mg (total) per day for adjunctive therapy, and 300 to 400 mg (total) per day for monotherapy. Children weighing less than 50 kg are dosed according to body weight.

In adults, extended-release lacosamide for partial-onset seizures is started at 100 mg once daily as adjunctive therapy, and at 200 mg once daily as monotherapy [88]. The maximum recommended dose for both adjunctive therapy and monotherapy is 400 mg once daily. For children weighing at least 50 kg, the initial dose is 100 mg once daily.

Dose adjustment should be made in patients with hepatic or renal impairment and should be supplemented after hemodialysis [77,88].

The clinical utility of lacosamide drug level monitoring has not been established. However, levels could be helpful to guide therapy in children and adolescents [89,90], in patients on concomitant enzyme inducing antiseizure medications [90], and in circumstances for which antiseizure levels are generally useful (eg, if nonadherence is suspected, concurrent medications are changed, or as a baseline when a therapeutic dose is established for an individual patient).

●Adverse effects – Lacosamide tends to be well tolerated. Dizziness, nausea, vertigo, abnormal coordination, and ataxia are the most frequently reported side effects [75,80,82,91]. One case series described an increase in these symptoms when lacosamide was co-prescribed with other antiseizure medications that block voltage-dependent sodium channels [92]. Another case series describes exacerbation of seizures with lacosamide in three patients with Lennox-Gastaut syndrome (LGS) [93].

Dose-dependent PR interval prolongations on electrocardiogram (ECG) in some studied patients suggest caution in prescribing lacosamide to those with known conduction problems (eg, atrioventricular block, sinus node dysfunction without a pacemaker, Brugada syndrome), severe ischemic or structural heart disease, or concomitant use of medications that prolong the PR interval. In such patients, a baseline ECG is recommended prior to starting lacosamide and after the maintenance dose has been achieved. Symptomatic second-degree atrioventricular block occurred in a patient after lacosamide was added to an antiseizure medication regimen that included carbamazepine, which is also associated with prolongation of the PR interval [94]. One case report describes atrial flutter/fibrillation in a patient on high-dose lacosamide, which resolved with drug discontinuation [95]. Another case report describes second-degree AV heart block and cardiac arrest in a neonate after starting lacosamide [96]. Syncope was reported in 1.2 percent of patients with diabetic neuropathy treated with lacosamide, compared with 0 percent of placebo-treated patients, primarily in patients receiving >400 mg/day; other cases of syncope have occurred in association with cardiac risk factors and concomitant use of drugs that slow atrioventricular conduction [77].

Lamotrigine — The cellular mechanism of action of lamotrigine is not completely understood, and it may have multiple effects. In rodent brain preparations, lamotrigine blocks the repetitive firing of neurons by inactivating voltage-dependent sodium channels. However, there is some evidence that lamotrigine, unlike carbamazepine and phenytoin, may selectively influence neurons that synthesize glutamate and aspartate, since it diminishes the release of these excitatory neurotransmitters [97]. These findings suggest that the anticonvulsant effect of lamotrigine may relate to actions on synaptic as well as membrane functions.

●Indications and efficacy – Lamotrigine is approved by the FDA for the adjunctive treatment of focal-onset seizures in adults and children as young as two years of age, as well as for adjunctive therapy for primary generalized tonic-clonic seizures and LGS [98-100]. Guidelines published by the American Academy of Neurology (AAN) support use of lamotrigine as initial therapy in patients with newly diagnosed focal epilepsy and unclassified generalized tonic-clonic seizures [64]. In randomized controlled trials, lamotrigine as add-on therapy was effective for reducing seizure frequency in adults and children with focal seizures [64,100]. One prospective study in more than 200 patients suggested that it is safe and possibly efficacious for focal seizures in infants aged 1 to 24 months [101,102].

●Metabolism and interactions – Lamotrigine is quickly and totally absorbed when given orally, and plasma concentrations have an apparent linear relationship to dose. The drug is approximately 55 percent bound to plasma proteins, and the liver metabolizes lamotrigine to inactive glucuronide conjugates excreted in the urine (table 3). In older adults, lamotrigine clearance is reduced by approximately 20 percent compared with younger adults, leading to a concomitant increase in adverse effects in this population [103].

Hormone replacement therapy and hormonal contraceptives increase lamotrigine clearance and are associated with decreased blood levels [104-110]. This can result in increased concentrations during the "placebo" week used with many oral contraceptives, with decreases when the active drug is resumed. This effect appears to be limited to combined estrogen-progestin contraceptives; progestin-only contraceptives have not been found to alter lamotrigine levels [109,110]. Conversely, lamotrigine may reduce the effectiveness of combined estrogen-progestin contraceptives (table 6) [111]. (See "Overview of the management of epilepsy in adults", section on 'Contraception'.)

Lamotrigine clearance also increases by approximately 65 percent in pregnancy and may lead to an increase in seizures [112,113]. Comedication with valproate appears to attenuate the increased clearance of lamotrigine that is associated with pregnancy and oral contraceptive use [114]. Frequent monitoring of lamotrigine serum levels and appropriate dose adjustments are advised when hormonal contraception is initiated or withdrawn and during pregnancy and after delivery to avoid clinically significant fluctuations in lamotrigine levels. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Antiseizure medication monitoring and dose adjustment'.)

Drug levels are markedly increased by an interaction with valproate, which inhibits glucuronidation, the main metabolic pathway of lamotrigine (table 4A-C). Levels are decreased in the presence of enzyme-inducing drugs that induce lamotrigine glucuronidation (including phenytoin, carbamazepine, phenobarbital, primidone, estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir) [115]. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

Lamotrigine is excreted in breast milk and may lead to significant serum levels in breastfed infants, although the clinical significance of these findings is uncertain [116]. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Breastfeeding'.)

●Dosing – The interactions of lamotrigine with other drugs lead to three different dosing schemes [117]:

•For patients not taking valproate and not taking drugs that induce glucuronidation (eg, carbamazepine, phenytoin, rifampin), the initial lamotrigine dose is 25 mg every day, increasing to 50 mg per day after two weeks and titrating upward by 50 mg per day every one to two weeks as needed to a usual maintenance dose of 225 to 375 mg per day (in two divided doses) for immediate-release lamotrigine or 300 to 400 mg per day for extended-release lamotrigine.

•For patients taking an antiseizure medication or other drug that induces lamotrigine glucuronidation (eg, carbamazepine, phenytoin, rifampin), the initial lamotrigine dose is 25 mg twice daily, increasing to 50 mg twice daily after two weeks and titrating upward by 100-mg-per-day increments every one to two weeks as needed to a usual maintenance dose of 300 to 500 mg per day for immediate-release lamotrigine or 400 to 600 mg per day for extended-release lamotrigine.

•For patients taking valproate, which inhibits lamotrigine glucuronidation, the initial lamotrigine dose is 12.5 to 25 mg every other day, transitioning to daily dosing with the next scheduled dose change, and increasing by 25 to 50 mg per day every two weeks as needed to a usual maintenance dose of 100 to 200 mg per day for immediate-release lamotrigine or 200 to 250 mg per day for extended-release lamotrigine with valproate alone, and 100 to 400 mg per day (immediate- or extended-release lamotrigine) for patients taking valproate along with drugs that induce glucuronidation (eg, rifampin, certain protease inhibitors).

When transitioning from adjunctive lamotrigine therapy to monotherapy, the appropriate lamotrigine dose escalation schedule must be adhered to, if a dose increase of lamotrigine is planned, in order to reduce the risk of serious hypersensitivity (ie, use the escalation schedule that is specific to the presence or absence of a concomitant interacting drug). The maintenance dose of lamotrigine monotherapy is usually 250 to 300 mg/day, although a maintenance dose of up to 400 mg per day (immediate-release) may be warranted in some patients; the concurrent antiseizure medication is gradually withdrawn so as to avoid subtherapeutic serum concentrations, particularly in patients with seizures that are difficult to control.

An extended-release formulation of lamotrigine, which can be given once as opposed to twice daily, provides more stable serum concentrations than the immediate-release formulation, and in one trial was shown to be effective as an adjunctive therapy for focal seizures in individuals greater than 12 years [118]. Substitution of extended-release lamotrigine in the same total daily dose as immediate-release lamotrigine results in maintenance of trough concentrations [119].

Therapeutic serum levels of lamotrigine have not been definitively established. However, data from 811 patients who took lamotrigine as monotherapy or adjunctive therapy revealed a significant correlation between lamotrigine serum concentrations and clinical toxicity [120]. Toxicity was defined as any side effect that required a dose decrease or discontinuation of lamotrigine. Toxicity increased with increasing serum lamotrigine levels; 7 percent of patients developed toxicity at <5 mcg/mL compared with 59 percent at >20 mcg/mL; toxicity was uncommon at the most frequently encountered serum concentrations (<10 mcg/mL). To put this in perspective, the highest lamotrigine level encountered in any of the major clinical trials was 8.8 mcg/mL, and most patients in those trials had lamotrigine levels in the low single digits (1.53 to 3.60 mcg/mL) [120]. Thus, the authors of this study suggest an initial target range of 1.5 to 10 mcg/mL for lamotrigine therapy, while noting that efficacy may increase at higher levels for patients with refractory seizures.

●Adverse effects – Systemic side effects of lamotrigine include rash and nausea (table 5A-B). A benign rash may develop in up to 10 percent of patients during the initial one to two months of therapy and necessitates discontinuation of the drug. Patients who have previously had a rash with another antiseizure medication are more likely to experience rash with lamotrigine [21,27,121]. The risk of developing a life-threatening rash such as SJS, TEN, or angioedema is approximately 1 in 1000 adults; this risk is increased in children. The risk of serious rash may be increased if lamotrigine is started at a dose that exceeds the recommended initial dose, if dose escalation is too rapid, or if lamotrigine is coadministered with valproate.

Lamotrigine is contraindicated in patients with hypersensitivity to the drug [117]. Due to its pro-arrhythmic potential, lamotrigine should be avoided in patients who have cardiac conduction disorders (eg, second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (eg, myocardial ischemia, heart failure, structural heart disease, Brugada syndrome or other sodium channelopathies). The concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.

Lamotrigine is rarely associated with acute multiorgan failure, hypersensitivity reactions including drug reaction with eosinophilia and systemic symptoms (DRESS), hemophagocytic lymphohistiocytosis, and disseminated intravascular coagulation [122-124]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)" and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Neurotoxic side effects are predominantly dizziness and somnolence. In rare cases, lamotrigine has exacerbated or initiated myoclonus and even myoclonic status in juvenile myoclonic and other idiopathic generalized epilepsies and also in Unverricht-Lundborg disease [125,126]. This disappears with withdrawal of the medication and sometimes with lowering the dose. The risk of this side effect is low, and lamotrigine is still considered a treatment option in these patients. Lamotrigine intoxication after deliberate overdose has been associated with status epilepticus in one patient with localization-related epilepsy [127].

Aseptic meningitis was reported in the FDA Adverse Event Reporting System in 40 patients taking lamotrigine, according to a 2012 report [128]. Fifteen cases were associated with a recurrence of symptoms on rechallenge, which suggests that the association is likely causal; however, drug-induced meningitis always requires exclusion of an infectious etiology. (See "Aseptic meningitis in adults".)

Levetiracetam — The mechanism of action of levetiracetam is unknown. However, levetiracetam binds to the synaptic vesicle protein SV2A, which has been linked in animal models to epilepsy [129,130]. Binding at this site may modulate synaptic transmission through alteration of vesicle fusion [131]. There is also evidence that levetiracetam indirectly modulates gamma-aminobutyric acid (GABA) [132,133].

●Indications and efficacy – Levetiracetam is a broad-spectrum antiseizure medication that is widely used as first-line monotherapy for focal and generalized tonic-clonic seizures [134].

Levetiracetam is approved by the FDA as adjunctive therapy to treat focal-onset seizures in patients one month of age and older with epilepsy, as adjunctive therapy in treating myoclonic seizures in patients aged 12 years or older with juvenile myoclonic epilepsy, and as adjunctive therapy for primary generalized tonic-clonic seizures in patients six years of age and older with idiopathic generalized epilepsy [135-141]. It is also approved as initial monotherapy in Europe for patients 16 years of age and older with newly diagnosed epilepsy to treat partial-onset seizures with or without secondary generalization [142].

Evidence from observational studies and randomized trials supports the efficacy of levetiracetam as monotherapy for patients with focal seizures [19,143-146] and suggests that it may be effective as monotherapy for generalized seizures [147-149].

In a postmarketing surveillance study of 373 patients at a single epilepsy center, both the efficacy of levetiracetam and the cumulative probability of remaining on levetiracetam at 12 months (74 percent) compared favorably with published data for vigabatrin, lamotrigine, and topiramate [150]. This was corroborated in a larger, multicenter study in which a 58 percent three-year retention rate was estimated [151].

●Metabolism and interactions – Metabolism of levetiracetam is independent of the CYP system, limiting the potential for pharmacokinetic interaction with other antiseizure medications, hormonal contraception, or immunosuppressant drugs commonly used in organ transplantation [152,153]. Some studies have found that coadministration of enzyme-inducing antiseizure medications is associated with an approximate 25 percent increase in levetiracetam clearance; however, this is felt to have limited clinical significance [154]. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – Treatment with levetiracetam is initiated at 500 mg twice daily. levetiracetam appears to have a very rapid onset of action as demonstrated by a significant increase in the proportion of patients who achieved seizure-free status on the first day of levetiracetam 500 mg twice-daily treatment compared with placebo [155]. Levetiracetam may be titrated by 1000 mg every two weeks as needed for seizure control, to a maximum dose of 4000 mg daily. However, doses higher than 3000 mg daily are not established to have additional benefit and may be more likely to cause somnolence [156]. Doses up to 4000 mg daily have been found to be beneficial in observational studies [139], but there is no evidence from randomized controlled trials that 4000 mg daily is more effective than 3000 mg daily in a population of patients with epilepsy [62,64]. Nonetheless, it is possible that individual patients may have better seizure control at 4000 mg than 3000 mg.

In one report, an oral load of 1500 mg in a single dose was well tolerated and rapidly yielded therapeutic serum concentrations in 37 adult patients with epilepsy [157]. Weight-based dosing is recommended for children under 16 years: 10 mg/kg twice daily producing levels approximating those of the 500 mg twice daily dose in adults, with 20 mg/kg twice daily a usual target dose for therapeutic concentrations [158].

An IV formulation of levetiracetam is approved for use in clinical situations when patients are temporarily unable to take oral medication [159-161]. IV infusion of levetiracetam is bioequivalent to oral tablets.

An extended-release formulation of levetiracetam is available; studies suggest that it is comparably effective and well tolerated as a once-daily medication [162-164].

Routine monitoring of levetiracetam levels is not required. However, serum levels may be useful in certain conditions expected to influence levetiracetam levels, such as pregnancy, renal insufficiency, and concomitant use of enzyme-inducing drugs (eg, carbamazepine). In addition, serum levels can be useful to assess adherence to treatment and to document the level at which seizure control is achieved or the level at which significant adverse events occur.

●Adverse effects – Levetiracetam is relatively well tolerated. The most common adverse events include fatigue, somnolence, dizziness, and infection (upper respiratory) [139]. Most adverse events associated with levetiracetam are mild to moderate in intensity and most often occur during the initial titration phase (table 5A-B).

Neuropsychiatric side effects can emerge beyond the initial titration period and may be the most common reason for drug discontinuation. In a postmarketing survey of 354 patient, sedation was the most common side effect of levetiracetam, occurring in 11 percent, but mood disturbance was not rare (5 percent), and was more likely to lead to discontinuation [150]. Psychiatric adverse effects (behavioral disturbance or psychosis) led to discontinuation in an additional 3 percent. In children, behavioral problems and somnolence are the most commonly reported side effects (11 and 8 percent, respectively) [165]. Some reports suggest that pyridoxine supplementation may reduce the neuropsychiatric adverse effects of levetiracetam, but the studies are mainly retrospective and low quality, failing to control for potential biases [166].

Other anecdotal reports and observational studies describe increased agitation and aggression with levetiracetam that may be problematic in some patients, particularly those who are intellectually disabled and have baseline behavioral problems [167-170]. This patient population may also be at increased risk of a paradoxic worsening of seizures in the first few weeks of starting levetiracetam, particularly when high doses are used [171]. Some have reported that problematic weight loss occurs in a small proportion of patients taking levetiracetam [172-174]. A reversible thrombocytopenia has been linked to levetiracetam in a small number of patients [175-177]. Rare cases of drug reaction with eosinophilia and systemic symptoms (DRESS) related to levetiracetam have also been reported [40].

Oxcarbazepine — Oxcarbazepine is a compound with a similar chemical structure to carbamazepine and likely a similar mechanism of action. Oxcarbazepine and its active metabolite, 10-monohydroxy metabolite (MHD), block voltage-sensitive sodium channels, increase potassium conductance, and modulate the activity of high-voltage activated calcium channels.

●Indications and efficacy – Oxcarbazepine is indicated as monotherapy in the treatment of focal seizures in patients 4 years of age and older, and as adjunctive therapy for focal seizures in patients 2 years of age and older [178]. The efficacy of oxcarbazepine is comparable to carbamazepine and other first-line therapies for focal and secondarily generalized tonic-clonic seizures [179,180].

●Metabolism and interactions – Oxcarbazepine is almost completely absorbed regardless of food intake. Serum concentrations of its active metabolite, MHD, reach a peak in 4 to 6 hours, with a half-life of 8 to 10 hours. The half-life does not change significantly with chronic administration due to a lack of autoinduction. The concentration of this metabolite decreases during pregnancy and increases after delivery, suggesting the need for close clinical monitoring of women taking the drug during pregnancy. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Antiseizure medication monitoring and dose adjustment'.)

Metabolism of oxcarbazepine occurs in the liver, but only minimally affects the CYP system (table 3). This represents a major advantage over carbamazepine, particularly in patients who require polytherapy. Oxcarbazepine does have the potential to reduce the effectiveness of most forms of hormonal contraception, however, and alternative methods of contraception should be reviewed (table 6). (See "Overview of the management of epilepsy in adults", section on 'Contraception'.)

Oxcarbazepine should not be used in combination with eslicarbazepine, which is an active metabolite of oxcarbazepine. (See 'Eslicarbazepine' above.)

Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – Monotherapy in adults begins with 300 to 600 mg/day, increasing to a dose of 900 to 2400 mg/day in two or three divided doses. An extended-release formulation is also available. In infants and young children, one study showed that higher maintenance doses (60 mg/kg per day) were significantly more effective than lower doses (10 mg/kg per day) when used as adjunctive therapy for focal seizures [181].

Measurement of serum sodium concentration is recommended prior to initiation of oxcarbazepine or carbamazepine therapy and again once the patient reaches a therapeutic dose. (See 'Hyponatremia' below.)

●Adverse effects – The most common side effects of oxcarbazepine are sedation, headache, dizziness, rash, vertigo, ataxia, nausea, hyponatremia (see 'Hyponatremia' below), and diplopia (table 5A-B). With the exception of hyponatremia, these side effects appear to occur in a frequency similar to patients taking carbamazepine [179,182]. Studies have also found decreased thyroid hormone levels in patients on both short- and long-term treatment with oxcarbazepine; the clinical significance of these findings is not yet known [183,184]. (See "Drug interactions with thyroid hormones", section on 'Drugs that affect thyroid hormone metabolism or clearance'.)

Rare but serious hypersensitivity reactions, including SJS, TEN, and multiorgan hypersensitivity, have been associated with oxcarbazepine use in both children and adults, usually within the first few weeks of starting the drug [27]. As with carbamazepine, the HLA-B*1502 allele has been associated with increased risk of SJS/TEN in patients with Asian ancestry treated with oxcarbazepine [185-187]. However, the incidence and severity of SJS/TEN related to oxcarbazepine appear to be lower compared with carbamazepine, and the positive predictive value of HLA-B*1502 for SJS/TEN was less than 1 percent in one study [187]. Due to the chemical similarity between the two drugs, available clinical information, and preclinical data showing a direct interaction between oxcarbazepine and HLA-B*1502 protein, the FDA revised the oxcarbazepine label in 2014 to suggest testing for the HLA-B*1502 allele in genetically at-risk populations (ie, those with Asian ancestry) before initiating treatment with oxcarbazepine [178]. Oxcarbazepine, carbamazepine, and phenytoin should be avoided in patients carrying the HLA-B*1502 allele unless the estimated benefits clearly outweigh the risks. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'HLA polymorphism and pharmacogenetics'.)

Rare cases of anaphylaxis and angioedema have also been reported in patients taking a first or subsequent dose of oxcarbazepine. If a patient develops a hypersensitivity reaction, the drug should be discontinued permanently. There have been rare reports of pancytopenia, agranulocytosis, and leukopenia associated with oxcarbazepine [178].

Perampanel — Perampanel is an orally active, noncompetitive AMPA-type glutamate receptor antagonist. It appears to inhibit AMPA-induced increases in intracellular calcium, reducing neuronal excitability [188].

●Indications and efficacy – Perampanel is approved by the FDA for the treatment of focal-onset seizures with or without secondary generalization in patients with epilepsy four years of age and older, and as adjunctive treatment of primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older [189]. Randomized trials have found that adjunctive therapy with once-daily perampanel (4 to 12 mg per day) resulted in a >50 percent reduction in seizure frequency in 29 to 36 percent of patients with refractory focal epilepsy, compared with 14 to 26 percent in placebo patients [190-193]. Improved efficacy has been observed with higher doses [194]. Perampanel also decreased the frequency of primary generalized seizures compared with placebo in a trial of 162 patients with drug-resistant idiopathic generalized epilepsy [195]. A 2022 review identified eight studies, mainly retrospective, evaluating perampanel as monotherapy for treating epilepsy and concluded that perampanel monotherapy was associated with favorable safety and efficacy, in line with evidence from clinical trials testing perampanel as adjunctive therapy [196].

●Metabolism and interactions – Perampanel is extensively metabolized by the liver, primarily via CYP3A4, CYP3A5, glucuronidation, and potentially other pathways. It has a prolonged and variable half-life (mean 105 hours), which may complicate dose titration and safety washout. Dose adjustments are recommended for patients with mild and moderate hepatic impairment, and the drug is not recommended for patients with severe hepatic or renal impairment, including those on hemodialysis.

Clearance of perampanel is increased, and clinical effect decreased, in patients taking concomitant enzyme-inducing antiseizure medications such as phenytoin and carbamazepine (table 4A and table 4B) [194,197]. Strong inhibitors of CYP3A4 may modestly increase perampanel exposure (table 3). When dosed at 12 mg daily, perampanel can decrease the efficacy of levonorgestrel-containing hormonal contraception. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The recommended starting dose of perampanel is 2 mg taken once daily at bedtime, increasing by 2 mg/day no more frequently than once per week, to a maximum dose of 12 mg daily. Given the long half-life of perampanel, it may take up to two weeks to evaluate the full effect (steady state) of a dose adjustment. In patients taking enzyme-inducing antiseizure medications, the recommended starting dose is 4 mg.

●Adverse effects – The most common side effects observed in randomized trials include dizziness, somnolence, headache, fatigue, irritability, gait disturbance, falls, nausea, and weight gain (table 5A) [190,191,198,199]. Labeling information includes a boxed warning of serious neuropsychiatric effects including alteration of mood and aggression [189]. In a pooled analysis of the safety data from three randomized trials, the risk of psychiatric adverse effects was dose dependent and was increased compared with placebo for overall psychiatric symptoms (22, 17, and 12 percent for perampanel 12 mg, 8 mg, and placebo) as well as for more narrowly defined symptoms of hostility/aggression (6, 3, and 0.7 percent, respectively) [200]. A majority of patients with psychiatric adverse effects continued on study, some with dose reductions, and the proportion of patients with a psychiatric adverse effect who discontinued therapy completely was relatively low (14 percent).

A smaller randomized trial in adolescents found similar results [201], whereas a retrospective review of 24 patients aged 12 to 18 years treated with perampanel at a tertiary care center reported a much higher rate of discontinuation (63 percent) [202]. Behavioral side effects were the most common reason for discontinuation and were considered severe in six patients (eg, homicidal ideation, self-harm, physical and verbal aggression). One patient developed oculogyric crisis related to perampanel.

Perampanel is classified as a Schedule III drug by the United States Drug Enforcement Administration (DEA) due to its potential for abuse [203].

Phenobarbital — Phenobarbital binds to the GABA(A) receptor, improving the effect of GABA by extending the duration of GABA-mediated chloride channel openings. This process permits an increasing flow of chloride ions across the membrane, causing neuronal hyperpolarization (eg, membrane inhibition to depolarization).

Phenobarbital is among the oldest antiseizure medications still in use.

●Indications and efficacy – Phenobarbital is effective for the treatment of generalized and focal seizures [33]. However, its clinical utility is limited by its sedating effects (table 5A-B).

●Metabolism and interactions – Phenobarbital is metabolized primarily in the liver by the CYP system and 25 percent is excreted renally as unchanged drug. It is a potent and broad-spectrum inducer of CYP and uridine diphosphate-glucuronosyltransferase (UGT)-glucuronidation (table 3). Phenobarbital may reduce the effectiveness of most forms of hormonal contraception (table 6). (See "Overview of the management of epilepsy in adults", section on 'Contraception'.)

Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The oral dose of phenobarbital is 1 to 5 mg/kg per day; it may also be administered intravenously. Serum phenobarbital concentrations should be checked three to four weeks after the initial dose, with a goal therapeutic level of 10 to 40 mcg/mL (43 to 172 micromol/L). A number of drugs can influence the serum concentration of phenobarbital (table 4A-C).

●Adverse effects – The most frequent adverse effects of phenobarbital are sedation, reduced concentration, and mood changes including depression [33]. Children may exhibit hyperactivity. Chronic use is associate with an increased risk of decreased bone density, Dupuytren contractures, plantar fibromatosis, and frozen shoulder. Teratogenicity with pregnancy is another risk, with a relatively high rate of major malformations in fetuses exposed to phenobarbital. In addition, in-utero exposure is associated with diminished cognitive ability.

Phenytoin and fosphenytoin — Phenytoin blocks voltage-dependent neuronal sodium channels, similar to carbamazepine [204]. Other effects of phenytoin include diminishing synaptic transmission, limiting fluctuation of neuronal ionic gradients via sodium-potassium ATPase, and affecting second messenger systems by inhibiting calcium-calmodulin protein phosphorylation.

Fosphenytoin is the water-soluble prodrug of phenytoin.

●Indications and efficacy – Phenytoin was introduced in the 1930s for use in epilepsy and is still widely prescribed for focal and generalized seizures, for status epilepticus, and as a second-line agent for patients with mixed seizures (myoclonic and tonic-clonic).

●Metabolism and interactions – The first step in the metabolism of phenytoin, which takes place in the liver, involves arene oxidase, which has nonlinear kinetics. Phenytoin is metabolized in the liver and is a potent and broad-spectrum inducer of CYP and UGT-glucuronidation (table 3). Phenytoin may reduce the effectiveness of most forms of hormonal contraception (table 6). (See "Overview of the management of epilepsy in adults", section on 'Contraception'.)

A number of drugs, including many antiseizure medications, can influence the serum concentration of phenytoin (table 4B). Renal failure impairs the protein binding of phenytoin; the pharmacologically active free concentration may increase relative to the total concentration. CYP2C9 pharmacogenetic polymorphisms affect phenytoin metabolism and drug levels, although CYP2C9 genotyping is not yet widely performed or mandated. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – Phenytoin can be administered orally or intravenously; the prodrug fosphenytoin has largely replaced phenytoin for IV use, however. The initial oral dose of phenytoin is 15 mg/kg in three divided doses, followed by a maintenance dose of 5 mg/kg daily in one dose or two divided doses, starting 24 hours after the loading dose. Alternatively, fixed (nonweight) dosing can be used, starting with an initial oral phenytoin dose of 1 gram in three divided doses followed by a maintenance dose of 300 to 400 mg daily in two or three divided doses. For obese patients, the upper limit of the initial loading dose is generally 1 gram.

Fosphenytoin is administered in phenytoin equivalents (PE).

Like all antiseizure medications, phenytoin dosing should be guided primarily by effect (ie, seizure control) and tolerability. Most, but not all, patients who have normal renal function and serum albumin levels can achieve seizure freedom without side effects with a serum phenytoin concentration of 10 to 20 mcg/mL (40 to 79 micromol/L).

Maintenance oral and IV phenytoin doses are roughly equivalent. Initial blood levels should be obtained two to three weeks after the first dose with a goal concentration of 10 to 20 mcg/mL (40 to 79 micromol/L) in patients with normal renal function. In the presence of low serum albumin or other highly protein-bound drugs (such as valproate), free levels should be followed with a goal of 1 to 2 mcg/mL (4 to 8 micromol/L).

After an oral or IV loading dose, the initial phenytoin blood level can be drawn several hours after the conclusion of the loading dose. The results can be used to guide the determination of the maintenance dose or the need for additional loading. Given the long half-life of phenytoin, serum levels should always be checked within five to seven days following any change (increase or decrease) in the daily dose in order to determine the steady-state serum concentration at the new maintenance dose.

In individuals known to be poor or intermediate CYP2C9 metabolizers prior to phenytoin initiation, guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) suggest reducing the starting maintenance dose of phenytoin by 50 percent to help avoid phenytoin-related toxicities [205]. These dosing recommendations are considered preliminary, however, and have not been validated by prospective studies. Furthermore, CYP2C9 genotyping is generally not needed in routine clinical practice, particularly since there are many alternatives to phenytoin for antiseizure medication treatment. (See "Overview of pharmacogenomics".)

Commercially available brand and generic phenytoin products may differ in phenytoin content and other formulation characteristics that can affect bioavailability [206]. These differences may occasionally result in an increase [207] or decrease [208] in serum phenytoin levels, which in turn might adversely affect seizure control or cause toxicity when patients are switched from one preparation to another. Therefore, more frequent serum levels and heightened clinical vigilance may be warranted when substituting phenytoin formulations in patients with difficult-to-control seizures or those prone to side effects, particularly in light of phenytoin's nonlinear kinetics and relatively narrow therapeutic window.

●Adverse effects – The major systemic side effects of phenytoin are gingival hypertrophy, body hair increase, rash, folic acid depletion, and decreased bone density (table 5A-B). Neurotoxic side effects include confusion, slurred speech, double vision, ataxia, and neuropathy (with long-term use).

Patients who develop a rash with phenytoin are more likely to develop one with carbamazepine and vice versa [21]. Phenytoin has been associated with SJS and TEN, particularly during the first eight weeks of therapy [26,27]. As with carbamazepine, this reaction appears to be more common in patients with the HLA-B*1502 allele, which occurs almost exclusively in patients from Asia or with Asian ancestry, including those from South Asia [209,210]. However, the magnitude of the risk of phenytoin in these patients is less clear than with carbamazepine. The FDA recommends avoiding substituting phenytoin for carbamazepine in patients who are known to be positive for HLA-B*1502 unless the estimated benefits clearly outweigh the risks. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'HLA polymorphism and pharmacogenetics'.)

Phenytoin is associated with altered bone and mineral metabolism and decreased bone density, related in part to induction of the CYP enzyme system and increased vitamin D catabolism. Calcium and vitamin D supplementation as well as bone mineral density testing are suggested in patients on chronic therapy. (See "Antiseizure medications and bone disease", section on 'Treatment and prevention'.)

Age-related sexual dysfunction and low testosterone levels are more common in men taking phenytoin than in controls [22].

Pregabalin — Pregabalin is chemically related to gabapentin and, like gabapentin, also has multiple potential mechanisms of action. It binds to the alpha-2-delta subunit of voltage-gated calcium channels and modulates calcium currents [211,212]. Pregabalin also modulates the release of several neurotransmitters including glutamate, noradrenaline, and substance P. The net result is inhibition of neuronal excitability [213].

●Indications and efficacy – Pregabalin is indicated as adjunctive therapy for focal seizures. Pregabalin is effective for the adjunctive treatment of focal seizures as demonstrated in randomized controlled trials [214,215]. An open-label study in 19 children with refractory epilepsy suggested that pregabalin may be effective in this population as well; however, worsening of seizures was noted in two patients with myoclonic epilepsy [216]. In a randomized trial testing pregabalin as monotherapy for newly diagnosed focal seizures, pregabalin was less effective than lamotrigine but similarly tolerated [217].

●Metabolism and interactions – Pregabalin is renally excreted virtually unchanged, and it is not hepatically metabolized. Pregabalin does not induce or inhibit the CYP system (table 3). In addition, it does not bind to plasma proteins. Thus, pregabalin does not have significant interactions with other antiseizure medications and is not expected to have pharmacokinetic interactions with other drugs [218-220]. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

Pregabalin exhibits linear pharmacokinetics, and has a time to maximal plasma drug concentration (Tmax) of approximately one hour and a plasma half-life (T1/2) of approximately six hours [221]. Experimental data suggest that the pharmacodynamic half-life (ie, anticonvulsant effect) of pregabalin is longer than the six-hour pharmacokinetic half-life [222]. The Tmax may be delayed to approximately three hours if the drug is taken with food, but total absorption is not affected by food [219]. Steady state is achieved within 24 to 48 hours.

●Dosing – The starting dose of pregabalin for the treatment of focal seizures is 150 mg daily given with or without food in either two or three divided doses [223,224]. Pregabalin may be increased to a daily dose of 300 mg after one week and to a maximum daily dose of 600 mg after an additional week, based on patient response and tolerability.

●Adverse effects – The most common side effects with pregabalin in randomized trials were dizziness, somnolence, and ataxia (table 5A-B) [215,225-228]. Other side effects include weight gain, peripheral edema, blurred or double vision, asthenia, tremor, and abnormal thinking (most often impaired concentration). Respiratory depression, potentially fatal, can occur when gabapentinoids are used with other central nervous system (CNS) depressants such as opioids, or when used to treat elderly patients or patients with respiratory risk factors such as chronic obstructive pulmonary disease (COPD) [71-74].

Pregabalin may also cause euphoria and is classified as a schedule V controlled substance. New-onset myoclonus has been reported in patients taking pregabalin for epilepsy [229].

Primidone — Primidone is converted into two active metabolites, phenobarbital and phenylethylmalonamide (PEMA). Phenobarbital binds to the GABA(A) receptor, thereby extending the duration of GABA-mediated chloride channel openings. PEMA may enhance the activity of phenobarbital.

●Indications and efficacy – Primidone is indicated for focal seizures and generalized tonic-clonic seizures [33].

●Metabolism and interactions – Primidone is metabolized in the liver and is a potent inducer of CYP 450 enzymes, with multiple drug interactions. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The starting dose of primidone for adults and children age 8 years and older is 100 to 125 mg/day at bedtime for the first three days, increasing to 200 to 250 mg/day in two divided doses for days four to six, 300 to 375 mg/day in three divided for days seven to nine, and 750 mg/day in three divided doses beginning on day 10. The usual maintenance dose is 750 to 1,500 mg/day in three to four divided doses, with a maximum total dose of 2 g/day. For patients already receiving other antiseizure medications, primidone is started at 100 to 125 mg at bedtime, gradually increasing to the maintenance dose as the other antiseizure medication is gradually decreased. When conversion to primidone monotherapy is the goal, the conversion should be completed over at least two weeks or longer.

For children under 8 years of age, the weight-based maintenance range is 10 to 25 mg/kg per day given in two to three divided doses; the initial dose is lower and titrated upward. One fixed-dose regimen begins with 50 mg at bedtime for the first three days, increasing to 100 mg/day in two divided doses for days four to six, 200 mg/day in two divided for days seven to nine, and 375 to 750 mg/day in three divided doses beginning on day 10.

●Adverse effects – Common adverse effects of primidone are similar to phenobarbital and include sedation, impaired concentration, and mood changes. Primidone may cause an acute toxic reaction, thought unrelated to phenobarbital, and characterized by potentially severe sedation, dizziness, ataxia, nausea, and vomiting [33].

Rufinamide — Rufinamide is structurally unrelated to other marketed antiseizure medications. Rufinamide modulates the activity of sodium channels, prolonging the inactive state. This action is particularly effective in depolarized neurons.

●Indications and efficacy – Rufinamide is approved by the FDA as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome (LGS). In a randomized study of 138 patients with LGS, rufinamide was associated with a greater reduction in seizure frequency (33 versus 12 percent), drop attacks (43 versus 1 percent), and seizure severity compared with placebo [230]. Observational studies suggest that rufinamide may be effective as adjunctive therapy in children with other refractory epilepsy syndromes as well [231-233].

Rufinamide may have efficacy in focal epilepsy as well [234,235]. In a randomized trial of 313 adolescents and adults with refractory focal seizures, rufinamide 3200 mg/day was effective as an adjunctive agent, producing a >50 percent seizure reduction in 28 percent of patients, compared with 19 percent of placebo-treated patients [236]. Another randomized study in 357 patients with refractory focal epilepsy found that rufinamide was effective as adjunctive therapy [237].

●Metabolism and interactions – Pharmacokinetic studies show slow absorption (four to six hours to peak concentration) after oral ingestion. Co-ingestion with food increases the extent of absorption. Elimination of rufinamide occurs primarily through renal excretion. Rufinamide is not metabolized by CYP mechanisms and has little effect on the pharmacokinetics of other antiseizure medications [238]. However, potent CYP inducers (eg, carbamazepine, phenytoin, primidone, phenobarbital) may increase the clearance of rufinamide. Valproate is associated with reduced clearance of rufinamide. Rufinamide may reduce the effectiveness of oral hormonal contraceptives. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – In children, treatment with rufinamide is initiated at a daily dose of 10 mg/kg per day in two divided doses, increased by 10 mg/kg increments every other day to a target dose of 45 mg/kg per day or 3200 mg/day. Adults are treated initially at 400 to 800 mg per day in two divided doses, increased by 400 to 800 mg per day every two days until maximum daily dose of 3200 mg is achieved.

●Adverse effects – Rufinamide is well-tolerated [239]. The most common side effects are somnolence and vomiting. Observed shortening of the QT interval on ECG studies of patients taking rufinamide was not associated with clinical events; however, rufinamide should be avoided in patients with short QT syndrome or taking other drugs that shorten the QT interval. The multiorgan hypersensitivity reaction, also known as drug reaction with eosinophilia and systemic symptoms (DRESS) described with other antiseizure medications has been reported in patients taking rufinamide; all cases have occurred within four weeks of start of treatment.

Stiripentol — Stiripentol is an allosteric modulator of the gamma-aminobutyric acid A (GABA-A) receptor with direct activating effects [240]. It also inhibits CYP enzymes, thereby increasing blood levels of some antiseizure medications, especially clobazam [241].

●Indications and efficacy – Stiripentol is approved by the FDA as adjunct therapy for seizures associated with Dravet syndrome in patients six months of age and older and weighing 7 kg or more who are taking clobazam [242]. Small randomized controlled trials demonstrated that stiripentol as add-on therapy improved seizure control in patients with Dravet syndrome [243-245].

●Metabolism and interactions – Metabolism of stiripentol is mainly hepatic. Stiripentol is a minor substrate of CYP1A2 and a major substrate of CYP2C19 and CYP3A4. Stiripentol is a moderate inhibitor of both CYP1A2 and CYP2C19. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The starting dose for stiripentol is listed at 50 mg/kg per day, administered in two or three divided doses [246], but some experts start at 25 mg/kg per day. The dose can be increased in increments of 10 mg/kg per day every one to two weeks to a maximum total daily dose of 3000 mg. The typical tolerated dose in children is 75 mg/kg per day [247], although some children may require up to 100 mg/kg per day.

●Adverse effects – The most common adverse effects of stiripentol are somnolence, decreased appetite, agitation, ataxia, weight loss, hypotonia, nausea, tremor, dysarthria, and insomnia. In a retrospective study of 82 children with DS, stiripentol adverse effects were reported as mild and not requiring treatment discontinuation in the majority [248].

Tiagabine — Tiagabine is a second-generation antiseizure medication It is a potent enhancer of GABA action via specific inhibition of GABA reuptake into presynaptic neurons and glia in vitro [249]. Thus, it decreases the elimination of GABA from the synaptic space, making endogenously produced GABA more available for postsynaptic inhibitory effects.

●Indications – Tiagabine is used as adjunctive treatment for focal seizures for adults and children 12 years of age and older [250,251].

●Metabolism and interactions – Tiagabine is metabolized in the liver by CYP and non-CYP transformations but is not a CYP inducer (table 3). Tiagabine has no significant drug interactions. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The initial dose of tiagabine is 4 to 8 mg/day. It can be titrated in adults at weekly increments of 4 to 8 mg/day until there is a clinical response, or up to 56 mg/day in divided doses. There are no established therapeutic serum levels.

●Adverse effects – Major side effects of tiagabine include dizziness, lack of energy, somnolence, nausea, nervousness, tremor, difficulty concentrating, and abdominal pain (table 5A-B) [250]. In one study, however, cognitive function after one year of tiagabine monotherapy was similar to that in untreated controls and those on carbamazepine monotherapy [252].

There is concern that tiagabine has a proconvulsive effect. In postmarketing reports, new-onset seizures and nonconvulsive status epilepticus have been associated with off-label use of tiagabine for patients without epilepsy [251,253]. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".)

The apparent discrepancy between this risk in seizure and nonseizure patients may be explainable [254]: tiagabine was developed and is approved for use as an adjunctive treatment for epilepsy. Virtually all patients treated with tiagabine in clinical trials were taking at least one hepatic-enzyme-inducing antiseizure medication, which decreased the concentration of tiagabine; it is likely that patients without epilepsy have increased concentrations of tiagabine. Furthermore, patients taking tiagabine for off-label indications (psychiatric disease and pain) may also be on other medications that potentially lower the seizure threshold.

Tiagabine has been associated with nonconvulsive status epilepticus in patients being treated for focal epilepsy in a number of case reports, but this was not observed in randomized, controlled clinical trials or in long-term safety studies [255]. In a retrospective review of patients with localization-related epilepsy, 7.8 percent of 90 tiagabine-treated patients developed nonconvulsive status epilepticus compared with 2.7 percent of the 1165 patients not receiving tiagabine [256]. The frequency of generalized convulsive status epilepticus was not increased. (See "Focal epilepsy: Causes and clinical features".)

Topiramate — Topiramate also has multiple mechanisms of action. It blocks voltage-dependent sodium channels, enhances the activity of GABA at a nonbenzodiazepine site on GABA(A) receptors, and antagonizes an AMPA/kainate-glutamate receptor [257]. It also weakly inhibits carbonic anhydrase in the central nervous system.

●Indications and efficacy – Topiramate is approved as initial monotherapy in patients ≥2 years of age for focal-onset or primary generalized tonic-clonic seizures [257]. Topiramate is also approved as adjunctive therapy for patients ≥2 years of age with focal seizures or seizures associated with the Lennox-Gastaut syndrome [64,257,258]. One randomized trial in 151 children (ages 6 to 15 years) reported efficacy for topiramate as monotherapy for newly diagnosed epilepsy; seizures were focal onset or generalized onset tonic-clonic [259]. A randomized study in infants aged 1 to 24 months found that adjunctive topiramate (5, 15, or 25 mg/kg per day) was not effective in reducing refractory focal-onset seizures [260]. Topiramate is not approved by the FDA for use in children younger than two years of age [257].

●Metabolism and interactions – Topiramate is metabolized to a minor degree in the liver and is mostly eliminated in the urine [33]. Topiramate may increase phenytoin concentration, but there do not appear to be any clinically significant interactions with valproate (table 4A-C). Serum levels of topiramate may decline by approximately 30 percent during pregnancy. Conversely, topiramate may reduce the effectiveness of most forms of hormonal contraception (table 6). (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Antiseizure medication monitoring and dose adjustment' and "Overview of the management of epilepsy in adults", section on 'Contraception'.)

Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The starting dose of topiramate is 50 mg/day for one week, given in two divided doses titrated at weekly increments of 50 mg to an effective dose. Gradual titration is necessary because of cognitive adverse effects [33]. The recommended total daily dose for adjunctive therapy is 200 mg twice daily. A once-daily extended-release formulation is also available. Therapeutic levels have not been established. Topiramate clearance is increased twofold by enzyme-inducing agents (eg, phenytoin, carbamazepine), requiring twofold-increased doses in this setting (table 3).

●Adverse effects – Adverse side effects of topiramate include cognitive impairment, weight loss, sedation, paresthesia, fatigue, dizziness, depression, and mood problems (table 5A-B) [33,257,261]. Metabolic acidosis is common, mainly in children. Kidney stones occur with therapy in <3 percent. Acute myopia and secondary angle-closure glaucoma are rare. The incidence of most side effects decreases with continued dosing; weight loss and paresthesia are the exceptions [262]. Slower titration of the dose following initiation of therapy may improve tolerance [263]. Topiramate has been associated with decreased sweating leading to heat intolerance and hyperthermia, particularly in children; there have also been case reports of decreased sweating in adults [264,265].

Topiramate exposure in utero has been associated with an increased risk of oral clefts and low birth weight. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Topiramate'.)

•Impaired cognition and expressive language is a reported side effect in a minority of patients taking topiramate, but it is a common reason for discontinuing therapy [262,266]. Studies suggest that this may be a more common phenomenon than patient complaints would indicate, and, at least in some studies, appears to be dose related [267-272]. Impaired cognitive measures with topiramate have been recorded in studies of healthy adult volunteers and children compared with their own baseline as well as with nondrug control patients and with patients taking lamotrigine and carbamazepine [267-269,273,274]. Cognitive and behavioral worsening has also been observed in children with intellectual disability [275]. Adults treated for epilepsy and children treated for obesity have similar cognitive side effects from topiramate [270,271]. The observed cognitive deficits are broad in spectrum but appear to be reversible when the drug is discontinued and attenuated with dose reductions [268,271,276].

•Weight loss is a common dose-related side effect [262,277]. In a double-blind placebo-controlled trial of topiramate added to existing antiseizure medications in 264 patients, topiramate was associated with a 2.0 kg mean decrease in weight at three months [262]. A smaller, uncontrolled trial found that at one year, weight loss occurred in 86 percent with a mean cumulative weight loss of 5.9 kg [278]. Weight loss is associated with fat loss and correlates with reduced caloric intake. Follow-up studies suggest that weight loss stabilizes after two to three years of taking the medication [279].

•Metabolic acidosis may result from renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase, which can cause both proximal and distal acidification defects [280-282]. The main clinical manifestation of metabolic acidosis is tachypnea; calcium phosphate nephrolithiasis can also occur [283].

Measuring serum bicarbonate at baseline and periodically (for example, every two to four months) is recommended. Gradual dose reduction or cessation of topiramate (after tapering) is advised if significant metabolic acidosis develops. Alkali treatment may be helpful if topiramate is continued in patients with symptoms or more marked acidosis [280]. (See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis".)

•Decreased bone mineral density may occur as a result of metabolic acidosis, which increases bone resorption [257].

•Acute myopia and secondary angle glaucoma, characterized by the acute onset of decreased visual acuity and/or ocular pain, occurs rarely in children and adults with topiramate therapy (23 cases out of approximately 825,000 users in one postmarketing report [284]), typically within one month of initiating treatment [257,285]. Chronic users of topiramate do not appear to be at increased risk of glaucoma. A few case reports have linked topiramate with an apparently irreversible maculopathy [286]. Visual field defects independent of elevated intraocular pressure have also been reported in association with topiramate [257].

Valproate — Valproate (valproic acid) has multiple cellular mechanisms of action consistent with its broad clinical effectiveness [287-290]. Valproate seems to suppress high frequency, repetitive neuronal firing by blocking voltage-dependent sodium channels, but at sites different than carbamazepine and phenytoin. Valproate increases brain GABA concentrations at clinically relevant doses, although the basis of this effect is debated. Valproate does not seem to have any direct effects on the GABA(A) receptor, but GABA release may be enhanced by a presynaptic effect of valproate on GABA(B) receptors. Inhibition of nerve terminal GABA transaminase (GABA-T) probably also increases presynaptic GABA levels. Furthermore, valproate may increase GABA synthesis by activating glutamic acid decarboxylase (GAD). Finally, valproate acts against T-type calcium currents, although this action is weaker than that observed with ethosuximide.

●Indications and efficacy – Valproate is a broad-spectrum antiseizure medication that is used alone and in combination for the treatment of generalized and focal seizures. Valproate is considered the most effective antiseizure medication for idiopathic generalized epilepsy with generalized tonic-clonic seizures [33,291]. It is also effective for absence epilepsy but less well tolerated compared with ethosuximide. (See "Childhood absence epilepsy", section on 'Treatment'.)

●Metabolism and interactions – Valproate is tightly protein bound. It is metabolized in the liver and is a moderate broad-spectrum inhibitor of the CYP system and uridine diphosphate-glucuronosyltransferase (UGT)-glucuronidation. Dose adjustments are required in patients with hepatic insufficiency (table 3). In the presence of hypoalbuminemia, unbound valproate concentrations can be elevated despite normal or low total valproate concentrations and may correlate better with toxicity [292]. Valproate is contraindicated in patients with known urea cycle disorders due to an increased risk of severe hyperammonemia [293]. (See "Urea cycle disorders: Management".)

A number of drugs affect the serum level of valproate (table 4C). Oral contraceptive agents may increase valproate clearance and their use is associated with decreased valproate blood levels (median decline 23 percent) during active treatment and higher concentrations during the "placebo" week that is used with many oral hormonal contraceptives [109]. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The initial dose of oral valproate is 10 to 15 mg/kg per day for focal-onset seizures with impairment of consciousness or awareness (previously called complex-partial seizures) and 15 mg/kg per day for generalized-onset nonmotor seizures (previously called absence seizures), given in three divided doses. The dose may be increased at one-week intervals by 5 to 10 mg/kg per day as needed. A serum level should be checked one to two weeks after the initial dose, but can be checked three to four days after initiation or dose adjustment; therapeutic concentrations are usually in the 50 to 125 mcg/mL (346 to 875 micromol/L) range.

In general, trough serum levels are used to monitor therapy and should be drawn just prior to the next dose for oral valproate and for 24-hour extended-release preparations when the latter is dosed once daily; the timing of the serum level is less important when 24-hour extended-release preparations are dosed twice daily because such dosing results in serum levels that are relatively stable throughout the day. Trough levels can be difficult to obtain in some patients because of logistical problems in having blood drawn at the suggested times. In addition, the optimal timing of serum blood levels for patients taking delayed-release preparations of valproate is uncertain because of the variability in gastrointestinal absorption. In such situations, it is best to obtain serum levels at a time interval relative to the last dose that is feasible, and to use that time consistently.

If patients consistently experience side effects after a dose and redistributing the total daily intake into more doses is not feasible, then consider switching to an extended-release formulation, which generally allows for less frequent dosing with more stable blood levels.

Valproate can be delivered intravenously. Current prescribing information recommends slow administration of IV valproate over 60 minutes at a rate of ≤20 mg/minute, or more rapid infusion of single doses up to 15 mg/kg over 5 to 10 minutes at 1.5 to 3 mg/kg per minute [294]. In emergency situations such as status epilepticus, accumulating evidence suggests that a loading dose of valproate of up to 30 mg/kg can be infused safely at rate 10 mg/kg per minute without adverse effects on blood pressure or heart rate [295-300]. Rapid IV loading may be desirable as a way to achieve serum concentrations >100 mcg/mL (>693 micromol/L) quickly.

●Adverse effects – Adverse effects of valproate include nausea, vomiting, hair loss, easy bruising, and tremor (table 5A-B). Valproate is also associated with weight gain, obesity, insulin resistance, and the metabolic syndrome [301-304]. Nocturnal enuresis, likely related to impaired sleep efficiency, has been reported in children [305]. Approximately 5 to 10 percent of patients develop alanine aminotransferase (ALT) elevations during long-term valproate therapy; these abnormalities are usually asymptomatic and can even resolve with continuation of the drug. In addition, there are more serious forms of toxicity that can occur with valproate, including hyperammonemic encephalopathy, acute hepatocellular injury, and acute pancreatitis, as discussed below.

Valproate can cause thrombocytopenia and other coagulation disturbances [306-308] and has also been associated with subclinical hypothyroidism with mild to moderate elevations in thyrotropin (TSH) levels [24,183,309,310]. Valproate has also been linked to the polycystic ovarian syndrome [311,312]. A number of case reports have linked valproate to Fanconi syndrome in children with severe disabilities [313]. (See "Drug interactions with thyroid hormones", section on 'Drugs that affect thyroid hormone metabolism or clearance' and "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults".)

Valproate monotherapy is associated with the highest rate of teratogenicity of all marketed antiseizure medications. Valproate exposure in utero is associated with major malformations and other adverse effects, including neurodevelopmental abnormalities. Valproate should be avoided in pregnancy when possible. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Valproate'.)

A number of case reports and case series have described a syndrome of reversible parkinsonism and cognitive decline associated with valproate use [314-318]. The reported frequency of this adverse effect ranges from 1.4 to 5 percent among patients with epilepsy who are treated with valproate. Advanced age and prolonged duration of therapy may be risk factors. The parkinsonism does not respond to levodopa therapy, but usually reverses within a few weeks to months after valproate is discontinued.

•Valproate-related hyperammonemic encephalopathy (VHE) causes acute or subacute encephalopathy, increased seizures, and rarely coma and death [319]. VHE can occur without abnormalities of liver function tests (LFTs) or elevated serum valproate levels. The syndrome resolves within a few days of stopping valproate but may reverse more rapidly with carnitine supplementation or renal hemodialysis. Mild to moderate hyperammonemia, often asymptomatic, occurs in approximately 25 to 30 percent of patients. Risk factors for hyperammonemia include high valproate dose and plasma concentrations and concomitant use of enzyme-inducing antiseizure medications, carbonic anhydrase inhibitors, and antipsychotic drugs. (See "Valproic acid poisoning", section on 'Valproate-related hyperammonemic encephalopathy'.)

•Acute hepatocellular injury with jaundice can occur, usually within the first six months of starting valproate. In some cases this is associated with fulminant liver failure and death. Risk factors include age under two, polytherapy, and coexistent congenital metabolic disorders [320,321]. A Reye-like syndrome has been described in children who develop fever and lethargy followed by confusion, stupor and coma, raised ammonia levels, and marked ALT elevations. (See "Drugs and the liver: Metabolism and mechanisms of injury", section on 'Epidemiology' and "Acute liver failure in children: Etiology and evaluation".)

Although routine monitoring of hepatic function has not been shown to permit early identification of serious toxicity or improve outcome, many clinicians choose to obtain LFTs once or twice a year in patients who are clinically asymptomatic. The FDA recommends checking LFTs prior to initiating treatment and at frequent intervals thereafter, especially during the first six months.

•Acute pancreatitis is a rare complication of valproate therapy [322,323]. Symptoms (abdominal pain and vomiting) are similar to those from pancreatitis from other causes. Patients typically recover, but deaths have been reported. This adverse effect is idiosyncratic and is not related to dose or duration of therapy; rechallenge frequently results in relapse. (See "Etiology of acute pancreatitis", section on 'Medications'.)

Vigabatrin — Vigabatrin (VGB) is an irreversible inhibitor of GABA-T that raises the concentration of GABA in the central nervous system.

●Indications and efficacy – It is effective as an add-on agent in patients with refractory focal seizures [324]. It is also useful as monotherapy [325], although probably less effective than carbamazepine for this purpose [326,327]. Clinical observations also suggest that it may be particularly effective for infantile spasms in children with tuberous sclerosis. (See "Infantile epileptic spasms syndrome: Management and prognosis", section on 'Vigabatrin'.)

VGB was approved by the FDA in 2009 for the treatment of infantile spasms and for adjunctive treatment of adults with refractory focal seizures. It is licensed in Canada and in many countries of Europe and Asia. Due to the associate risk of visual loss, VGB should be reserved for patients with epilepsy that is refractory to other drugs.

●Metabolism and interactions – Vigabatrin does not undergo hepatic metabolism but is a weak inducer of CYP2C9 (table 3). It is eliminated without change in the urine. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – VGB is started at 500 mg twice daily and increased weekly in 500 mg increments to a total recommended dose of 3000 mg per day for adults age 17 years and older and 2000 mg per day for children age 10 to 16 years [328]. VGB is excreted renally, and dose adjustments are required in patients with renal insufficiency. Dosing for infantile spasms is reviewed separately. (See "Infantile epileptic spasms syndrome: Management and prognosis", section on 'Vigabatrin'.)

Because of the FDA boxed warning in the United States about the risk of permanent vision loss, prescribers, patients, and pharmacies must participate in the Risk Evaluation and Mitigation Strategies (REMS) program. Visual field testing should be performed before starting therapy and repeated every six months [329,330]. Optical coherence tomography may be useful to monitor vision in patients who are unable to perform visual field perimetry [331]. While animal studies suggest the possibility that reduced light exposure and dietary supplementation with taurine may ameliorate this adverse event, this has not been established in humans [332].

●Adverse effects – Frequent adverse events with VGB include drowsiness, fatigue, headache, and dizziness [326]. Depression and weight gain can occur. Severe hypersensitivity reactions and angioedema have also been reported.

A boxed warning for VGB alerts clinicians to safety concerns regarding permanent vision loss with this medication [333]. As many as 30 to 50 percent of adults with long-term exposure to VGB have developed irreversible concentric visual field loss of varying severity that is often asymptomatic [334-339]. A similar risk has been estimated in children, although studies are more limited [340,341]. Most studies have found that higher cumulative dose and male gender increase the risk of vision loss [336,339,340,342,343]. Visual field deficits have been noted as early as nine months after initiation of treatment, with a mean time to onset of approximately five years [329]. VGB treatment in laboratory rats is associated with irreversible injury of cone photoreceptors [344].

VGB has also been reported to produce magnetic resonance imaging (MRI) abnormalities, specifically hyperintense lesions on T2-weighted images and/or restricted diffusion on diffusion-weighted imaging, which involve the basal ganglia, thalamus, brainstem, dentate nucleus of the cerebellum, anterior commissure, and hippocampus [345-349]. These abnormalities are usually bilateral and symmetric. They occur primarily in infants and only in those who are treated for infantile spasms and seem to be a dose-related phenomenon. The prevalence is 22 to 47 percent [345,346,348,350]. These abnormalities are not clearly associated with new neurologic deficits and normalize when VGB is discontinued [345,346,349]. In a few cases, they have been observed to resolve even while VGB was continued.

Zonisamide — Zonisamide is a sulfonamide derivative that is chemically and structurally unrelated to other antiseizure medications. Its primary mechanism of action appears to be to blocking both voltage-dependent sodium and T-type calcium channels.

●Indications and efficacy – Zonisamide is a broad-spectrum agent that has been proven effective in randomized, controlled trials as add-on therapy for both focal and generalized seizures in adults and children [351,352]. Zonisamide also has activity in myoclonic epilepsy. Observational studies and one randomized noninferiority trial with a comparison with carbamazepine suggest that it is effective in monotherapy as well [353-356].

●Metabolism and interactions – Zonisamide is metabolized primarily in the liver by CYP and non-CYP transformations but is not a CYP inducer (table 3). Dose adjustments are needed for mild renal or hepatic insufficiency, and the drug is not recommended in patients with moderate or severe renal insufficiency.

Drug interactions are limited; however, clearance may be increased when used with carbamazepine, phenytoin, or phenobarbital [357]. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.

●Dosing – The recommended initial daily dose is 100 to 200 mg per day in two divided doses. Because of its long half-life, once-a-day dosing is often effective. The dose is increased at two-week intervals to a target maintenance dose of 400 to 600 mg per day, although higher doses may be necessary in some patients. Adjustments of zonisamide dose may be required when carbamazepine, phenytoin, or phenobarbital are added or removed.

●Adverse effects – The most commonly reported side effects of zonisamide are somnolence, ataxia, anorexia, confusion, abnormal thinking, nervousness, fatigue, and dizziness; in children, decreased sweating and fever have been reported (table 5A-B). Most of these are self-limited, and the likelihood of adverse effects can be reduced by gradually titrating the dose over four to eight weeks. However, in one study, cognitive deficits associated with initiation of zonisamide treatment were dose related and persisted one year after treatment was started [358]. In another study, cognitive and psychiatric side effects (including depression, psychosis, and aggression) led to discontinuation of zonisamide in 5.8 and 6.9 percent of patients, respectively [359]. A past history of psychiatric symptoms and symptomatic generalized epilepsy were risk factors for psychiatric side effects.

Zonisamide is a weak carbonic anhydrase inhibitor. Nephrolithiasis was reported in 4 percent of patients in an early clinical trial, but later studies found a much lower risk [360]. (See "Nephrolithiasis in renal tubular acidosis", section on 'Carbonic anhydrase inhibitors'.)

ADVERSE EFFECTS

Common adverse effects — Common adverse effects of antiseizure medications are summarized in the table (table 5A) and reviewed individually for each of the antiseizure medications listed above. (See 'Antiseizure medications' above.)

Hyponatremia — Hyponatremia is a well-described adverse effect of both oxcarbazepine and carbamazepine, due at least in part to increased responsiveness of collecting tubules to antidiuretic hormone. It has also been observed with eslicarbazepine. It is considered to be one of the forms of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Drugs'.)

●Frequency – The reported prevalence of oxcarbazepine- and carbamazepine-induced hyponatremia varies widely, in part due to differences in the threshold used to define hyponatremia and differences in study populations. Estimates range from approximately 25 to 75 percent for oxcarbazepine and from 5 to 40 percent for carbamazepine [361-367]. In one large cohort study of nearly 1500 patients with epilepsy taking either drug, rates of any hyponatremia (sodium ≤134 mEq/L) among those taking oxcarbazepine and carbamazepine were 48 and 26 percent, respectively [366]. Rates of severe hyponatremia (sodium ≤128 mEq/L) were 22 and 7 percent.

●Risk factors – Risk factors for hyponatremia appear to be similar for oxcarbazepine and carbamazepine and include older age, high serum levels of carbamazepine or oxcarbazepine, antiseizure medication polytherapy, concomitant antihypertensive medications, especially diuretics, and a history of hyponatremia with prior exposure to either drug [366,367].

A clear dose response relationship between oxcarbazepine and hyponatremia has not been established, and data are conflicting.

●Manifestations – Hyponatremia may develop gradually over the first few months of therapy, and many patients are asymptomatic [368]. Although symptoms attributable to hyponatremia are to some degree related to the severity of the abnormality, the rate of onset is of primary importance. Acute or severe hyponatremia can cause cerebral edema, which can lead to lethargy, encephalopathy, headaches, and seizures. Because of a cerebral adaptation, the degree of cerebral edema is less with chronic hyponatremia, and most patients seem to be asymptomatic. (See "Manifestations of hyponatremia and hypernatremia in adults".)

Oxcarbazepine-related hyponatremia tends to be mild, asymptomatic, and reversible, and overall tolerability of oxcarbazepine appears to be better than that of carbamazepine-related hyponatremia.

●Management – Measurement of serum sodium concentration is recommended prior to initiation of oxcarbazepine or carbamazepine therapy and again once the patient reaches a therapeutic dose. Serum sodium should be checked in patients on chronic therapy if the patient develops symptoms suggestive of hyponatremia (eg, lethargy, encephalopathy, headaches), especially in the presence of a predisposing factor such as renal failure or a central nervous system lesion that itself can cause SIADH. (See "Causes of hypotonic hyponatremia in adults".)

Cessation of oxcarbazepine therapy because of hyponatremia is uncommon, being required in only 1 percent of patients in a postmarketing study. Mild to moderate asymptomatic hyponatremia can typically be managed with fluid restriction with or without increased salt intake. Patients who cannot comply with fluid restriction and have severe or symptomatic hyponatremia should be transitioned to an alternative antiseizure medication. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

Bone disease — Patients with epilepsy are at higher risk for bone disease because of a higher risk for falls and physical trauma related to seizures themselves, the neurologic disease that underlies the epilepsy (eg, stroke, cerebral palsy), and the effects of certain antiseizure medications that impair gait stability and alter bone and mineral metabolism. These issues are reviewed in detail separately. (See "Antiseizure medications and bone disease".)

Severe adverse reactions — Rare but serious adverse effects of antiseizure medications are summarized in the table (table 5B). Some severe reactions that are common to more than one antiseizure medication include the following:

●Suicidality – As a class, antiseizure medications have been associated with an increased risk of suicidal ideation and suicidal behavior [369].

●SJS, TEN, and DRESS – Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are rare but severe idiosyncratic reactions that have been associated with the use of carbamazepine, oxcarbazepine, lamotrigine, phenytoin, phenobarbital, primidone, zonisamide, and (less commonly) other antiseizure medications. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

SUMMARY

●Pharmacologic profiles of antiseizure medications – While sharing a common property of suppressing epileptic seizures, antiseizure medications have many different pharmacologic profiles that are relevant when selecting and prescribing these agents in patients with epilepsy and other conditions. These include pharmacokinetic properties and propensity for drug-drug interactions, as well as side effect profiles and toxicities. (See 'Pharmacologic profiles' above.)

For drug-specific summaries, refer to the specific drug headings above. Summaries of different properties are also listed in the tables:

•Known or suspected mechanism of action (table 1)

•Important pharmacologic properties (table 3)

•Some important drug interactions (table 4A and table 4B and table 4C and table 6)

●Initial selection of antiseizure medication – A discussion of antiseizure medication selection in specific patient situations is presented separately. (See "Initial treatment of epilepsy in adults", section on 'Selection of an antiseizure medication'.)

●Adverse effects – Common and rare adverse effects of antiseizure medications are listed in the tables (table 5A and table 5B). While most antiseizure medications are potentially effective against focal seizures and generalized convulsive seizures (ethosuximide is a notable exception), some also have the potential to worsen certain generalized seizure types (eg, absence seizures, myoclonic seizures) (table 2 and table 7).

•Oxcarbazepine, carbamazepine, and eslicarbazepine may cause hyponatremia. (See 'Hyponatremia' above.)

•Patients with epilepsy are at higher risk for bone disease, due in part to the effects of certain antiseizure medications that impair gait stability and alter bone and mineral metabolism. These issues are reviewed in detail separately. (See "Antiseizure medications and bone disease".)

•Antiseizure medications as a class have been associated with an increased risk of suicidal ideation and suicidal behavior. Certain antiseizure medications are associated with a risk of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). (See 'Severe adverse reactions' above.)

●Detailed prescribing information – For detailed prescribing information, readers should refer to the individual drug information topics within UpToDate. Comprehensive information on drug-drug interactions can be determined using the drug interactions program.