ANTIEPILEPTICOS

16/8/2018 Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects - UpToDate
Author: Steven C Schachter, MD

Section Editor: Paul Garcia, MD
Deputy Editor: John F Dashe, MD, PhD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2018. | This topic last updated: Aug 02, 2018.
INTRODUCTION — While sharing a common property of suppressing seizures, antiseizure drugs 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.
Over the past several decades, the number of available antiseizure drugs has more than doubled. Unlike
some of the earliest antiseizure drugs such as phenobarbital, phenytoin, and carbamazepine (CBZ), many
of the currently available antiseizure drugs have simple pharmacokinetics and more limited effects on liver
metabolism. This translates into a generally lower rate of side effects, reduced need for serum monitoring,
once- or twice-daily dosing for some, and fewer drug-drug interactions. Despite these advantages, however,
there are few data to suggest significant differences in effectiveness among available antiseizure drugs.
Antiseizure drugs 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 drugs are linked with the types of seizures against which they are most
effective. An improved understanding of the molecular effects of existing antiseizure drugs as well as
development of new antiseizure drugs that act against novel targets may allow for more rational polytherapy
in the future.
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 Lexicomp
drug interactions tool. Complete information on US Food and Drug Administration (FDA) labeling for each
drug can be accessed using the FDA searchable database.
The pharmacology of antiseizure drugs is reviewed here. The use of antiseizure drugs in a treatment plan
for patients with seizures is discussed separately. Risks of antiseizure drugs 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 and pregnancy", section on 'Effect of antiseizure
drugs on the fetus'.)
DRUGS THAT AFFECT VOLTAGE-DEPENDENT SODIUM CHANNELS — Alteration of sodium currents is

the most common mechanism of action of existing antiseizure drugs.
Carbamazepine — Carbamazepine (CBZ) has broad use as an antiseizure drug 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.
CBZ 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.
CBZ is approximately 70 percent protein bound. It is metabolized in the liver by cytochrome P450 (CYP)
3A4 and is a potent and broad-spectrum inducer of the CYP system (table 2). The main metabolite, CBZ
10,11-epoxide, has anticonvulsant activity and can be measured in the serum.
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Screening for the HLA-B*1502 allele is recommended prior to starting CBZ in patients with Asian ancestry
due to the risk of Stevens-Johnson syndrome (SJS). (See 'Role of HLA testing' below.)
The usual initial starting dose is 2 to 3 mg/kg per day orally given two, three, or four times daily; the dose is
increased every five days to 10 mg/kg daily. 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. An intravenous (IV) preparation was approved by the US Food and Drug Administration (FDA)
in October 2016 [1]. It is intended for use as short-term replacement therapy in patients on stable oral doses
of CBZ. The recommended IV conversion dose is 70 percent of the total daily oral dose, divided into four
equal doses and given every six hours [2,3].
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 CBZ found a trend
toward improved tolerability for controlled-release CBZ but mixed results on seizure control, with most trials
showing no significant difference between the two formulations [4].
Serum CBZ 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 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 CBZ
doses or concomitant antiseizure drug doses are changed.
A number of drugs can influence the serum concentration of CBZ (table 3A). CBZ may reduce the
effectiveness of most forms of hormonal contraception (table 4). (See "Overview of the management of
epilepsy in adults", section on 'Contraception'.)
Common systemic side effects of CBZ include nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, and
fluid retention (table 5A-B). Patients who develop a rash with CBZ are more likely to develop one with
oxcarbazepine, lamotrigine (LTG), phenytoin, or phenobarbital, and vice versa [5]. Men taking CBZ have
higher rates of sexual dysfunction and low testosterone levels, which may be reversible if CBZ is withdrawn
[6,7]. Decreased thyroid hormone levels of uncertain clinical significance have been reported in patients
taking CBZ [8,9].
Neurotoxic side effects include drowsiness, dizziness, blurred or double vision, lethargy, and headache.
Hyponatremia related to CBZ and oxcarbazepine is discussed separately. (See 'Hyponatremia' below.)
Other potentially life-threatening adverse events related to CBZ include SJS and toxic epidermal necrolysis
(TEN) (see 'Role of HLA testing' below) and bone marrow suppression.
Leukopenia occurs in approximately 12 percent of children and 7 percent of adults with CBZ treatment [10].
It may be transient or persistent and does not usually require immediate discontinuation of CBZ 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 CBZ treatment may be at higher risk for developing CBZ-
induced leukopenia or neutropenia.
Aplastic anemia (pancytopenia) is a rare, idiosyncratic, nondose-related side effect that is most likely to
occur within the first three or four months after initiating CBZ therapy. Daily laboratory checks would be
necessary to monitor for aplastic anemia, agranulocytosis, and thrombocytopenia because of their rapid
onset [10], and such frequent monitoring is neither practical nor necessary for most patients taking CBZ. A
more suitable approach is to monitor for aplastic anemia by informing patients and clinicians to carefully
watch for signs and symptoms [10]. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and
diagnosis".)
Some experts recommend monitoring WBC counts of high-risk patients during the first three months of CBZ
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 CBZ dose with
frequent WBC monitoring, or CBZ discontinuation [10].
Role of HLA testing — CBZ has been associated with SJS/TEN. Most cases occur during the first eight
weeks of therapy [11,12].
● HLA-B*1502 – Severe hypersensitivity reactions due to CBZ are significantly more common (estimated
incidence of 5 percent) in patients with the HLA-B*1502 allele, which occurs almost exclusively in
patients of Asian ancestry [13-15], including South Asian Indians [16]. Screening for this allele in
patients with Asian ancestry is recommended prior to starting CBZ. If genetic testing results are positive
for the presence of at least one copy of the HLA-B*1502 allele, CBZ should be avoided [17].
In one high-risk population in Taiwan, a program of screening individuals for the HLA-B*1502 allele
prior to initiating CBZ successfully eliminated cases of SJS/TEN in the study population (n = 4877);
approximately 10 cases would have been expected according to historical incidence estimates [18].
Other studies have found low adherence with screening in clinical practice, possibly due to factors such
as cost and test turnaround time, as well as a shift in prescriptions away from CBZ to alternative
antiseizure drugs, independent of HLA testing or results [19,20].
● HLA-A*3101 – A similar association has been identified for the HLA-A*3101 allele, which is prevalent in
a broader range of ethnic groups, although data are more limited. In a cohort of Northern European
patients, the presence of this allele increased the risk of CBZ-induced SJS/TEN from 5 to 26 percent
[21]. This association was replicated in Japanese patients [22] and in a case control study of Canadian
children with CBZ-induced hypersensitivity syndrome (HSS), in which the HLA-A*3101 allele increased
the risk of CBZ HSS by more than 25-fold [23].
The HLA-A*3101 allele is prevalent in 2 to 5 percent of Northern Europeans and in higher proportions
in certain ethnic groups, including Japanese (10 percent) and those of Aboriginal American and Latin
American descent (up to 50 percent in certain subpopulations). The number of patients needed to
screen to prevent one adverse reaction based upon one study was estimated to be 83 [21], a number
similar to that for screening at-risk populations for the HLA-B*1502 allele. At least one consensus panel
has recommended screening all CBZ-naïve patients for the HLA-A*3101 allele prior to starting
treatment, regardless of race or ethnicity, since the allele is prevalent in most ethnic groups [24]. (See
"Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and
diagnosis" and "An approach to the patient with drug allergy", section on 'HLA type'.)
● HLA-A*2402 – A third allele, HLA-A*2402, has also been identified as an independent risk factor for
SJS/TEN due to CBZ and other aromatic antiseizure drugs (eg, phenytoin, LTG) in a southern Chinese
Han population [25]. In this case control study, the presence of either HLA-A*2402 or HLA-B*1502
conferred a three- to fivefold increase in the odds of SJS/TEN, whereas the presence of both alleles
conferred a 25-fold increase in odds compared with the absence of both alleles. More limited data
suggest that the HLA-A*2402 allele confers risk in other populations as well, although further studies
are needed.
Eslicarbazepine — Eslicarbazepine is structurally similar to CBZ 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 [26].
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 five randomized controlled trials,
patients treated with eslicarbazepine once daily were significantly more likely to achieve a greater than 50
percent reduction in seizure frequency compared with those receiving placebo (risk ratio [RR] 1.71, 95% CI
1.42-2.05) [27]. In the largest individual randomized trial (n = 640), a greater than 50 percent reduction in
seizures (responder rate) was observed in significantly more patients treated with eslicarbazepine 1200 mg
per day than placebo (43 versus 23 percent) [28]. 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.
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.
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 [29].
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 2). Eslicarbazepine undergoes extensive metabolism via
glucuronidation, and coadministration with UGT inducers such as CBZ 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 3B).
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 [30]. Women of child-bearing potential should use additional or
alternative nonhormonal contraception [30,31]. Eslicarbazepine may alter warfarin concentrations [32].
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.
The most common side effects 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 [28]. Eslicarbazepine has been
associated with an increase in the PR interval, abnormal liver function tests (LFTs), and hyponatremia.
Concomitant treatment with CBZ increases the incidence of diplopia, abnormal coordination, and dizziness
(table 3A). 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 [30]. Eslicarbazepine should not be used in patients with a history of
hypersensitivity due to oxcarbazepine or CBZ, 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 CBZ. (See 'Role of HLA testing' above.)
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
[33,34]. Lacosamide also binds to the collapsin response mediator protein 2 (CRMP2), which may be
involved in epileptogenesis.
Oral lacosamide is FDA approved for use as monotherapy or adjunctive therapy for focal-onset seizures in
patients aged four years and older. 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 [33,35-38]. 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 [36]. 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 [39]. Other reports document similar efficacy for focal-onset seizures in
younger patients, ages 1 to 21 years [40-43], and after conversion to monotherapy in adults [44].
Lacosamide is available as an oral tablet or solution (10 mg/mL) and as an IV injection (approved in adults
17 years and older). It is completely absorbed after oral administration with 100 percent bioavailability and is
eliminated by renal excretion and biotransformation. Dose adjustment should be made in patients with
hepatic or renal impairment and should be supplemented after hemodialysis. 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 2).
Lacosamide should be initiated at a dose of 50 mg twice per day as adjunctive therapy in adults; the
recommended starting dose as monotherapy is 100 mg twice per day. The dose may be increased at
weekly intervals by 100 mg per day to a maintenance dose of 200 to 400 mg per day. Children should be
dosed according to body weight.
Lacosamide tends to be well tolerated. Dizziness, nausea, vertigo, abnormal coordination, and ataxia are
the most frequently reported side effects [33,37,39,45]. One case series described an increase in these
symptoms when lacosamide was coprescribed with other antiseizure drugs that block voltage-dependent
sodium channels [46]. Another case series describes exacerbation of seizures with lacosamide in three
patients with Lennox-Gastaut syndrome (LGS) [47].
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, sick
sinus syndrome 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 drug regimen that included CBZ, which is also associated with prolongation of the PR interval
[48]. One case report describes atrial flutter/fibrillation in a patient on high-dose lacosamide, which resolved
with drug discontinuation [49]. 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 [50].
Lamotrigine — The cellular mechanism of action of LTG is not completely understood, and it may have
multiple effects. In rodent brain preparations, LTG blocks the repetitive firing of neurons by inactivating
voltage-dependent sodium channels. However, there is some evidence that LTG, unlike CBZ and phenytoin,
may selectively influence neurons that synthesize glutamate and aspartate, since it diminishes the release
of these excitatory neurotransmitters [51]. These findings suggest that the anticonvulsant effect of LTG may
relate to actions on synaptic as well as membrane functions.
LTG is approved by the FDA for the adjunctive treatment of focal seizures in adults and children as young
as two years old, as well as for adjunctive therapy for primary generalized tonic-clonic seizures and LGS
[52-56]. Guidelines published by the American Academy of Neurology (AAN) support use of LTG as initial
therapy in patients with newly diagnosed focal epilepsy and idiopathic generalized epilepsy, as well as
mixed seizure disorders [52]. LTG may also be used for the treatment of newly diagnosed absence seizures
in children [52]. 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 [57,58].
An extended-release formulation of LTG, 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 [59]. Substitution of
extended-release LTG in the same total daily dose as immediate-release LTG results in maintenance of
trough concentrations [60].
LTG 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 LTG to inactive glucuronide conjugates excreted in the urine (table 2).
Drug levels are markedly increased by an interaction with VPA, which inhibits glucuronidation, the main
metabolic pathway of LTG (table 3A-C). Levels are decreased in the presence of enzyme-inducing drugs
that induce LTG glucuronidation (including phenytoin, CBZ, phenobarbital, primidone, estrogen-containing
oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir) [61].
Detailed information on additional drugs that can affect serum LTG levels can be obtained by using the Lexi-
Interact tool, which can be accessed from the UpToDate online search page or through the individual drug
information topics in the section on Drug interactions.
These interactions lead to three different dosing schemes:
● For patients not taking drugs that induce glucuronidation (eg, CBZ, phenytoin, rifampin) or VPA, the
initial 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 patients taking an antiseizure drug or other drug that induces LTG glucuronidation (eg, CBZ,
phenytoin, rifampin), the initial 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 patients taking VPA, the initial dose is 12.5 to 25 mg every other day, with increases of 25 to 50 mg
per day every two weeks as needed to a usual maintenance dose of 100 to 200 mg per day with VPA
alone and 100 to 400 mg per day with VPA and other drugs that induce glucuronidation (eg, rifampin,
certain protease inhibitors).
Therapeutic serum levels of LTG have not been definitively established. However, data from 811 patients
who took LTG as monotherapy or adjunctive therapy revealed a significant correlation between LTG serum
concentrations and clinical toxicity [62]. Toxicity was defined as any side effect that required a dose
decrease or discontinuation of LTG. The following observations were made:
● Toxicity increased with increasing serum LTG 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 LTG level encountered in any of the major LTG clinical trials was 8.8
mcg/mL, and most patients in those trials had LTG levels in the low single digits (1.53 to 3.60 mcg/mL) [62].
Thus, the authors of this study suggest an initial target range of 1.5 to 10 mcg/mL for LTG therapy, while
noting that efficacy may increase at higher levels for patients with refractory seizures.
Hormone replacement therapy and hormonal contraceptives increase LTG clearance and are associated
with decreased LTG blood levels [63-69]. 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 LTG levels [68,69]. Conversely, LTG may reduce the effectiveness of combined
estrogen-progestin contraceptives (table 4) [70]. (See "Overview of the management of epilepsy in adults",
section on 'Contraception'.)
LTG clearance also increases by approximately 65 percent in pregnancy and may lead to an increase in
seizures [71,72]. Comedication with VPA appears to attenuate the increased clearance of LTG that is
associated with pregnancy and oral contraceptive use [73]. Frequent monitoring of LTG 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 LTG levels. (See "Management of
epilepsy and pregnancy", section on 'Drug levels and dose adjustment'.)
LTG is excreted in breast milk and may lead to significant serum levels in breastfed infants, although the
clinical significance of these findings is uncertain [74]. (See "Management of epilepsy and pregnancy",
section on 'Breast feeding'.)
In older adults, LTG clearance is reduced by approximately 20 percent compared with younger adults,
leading to a concomitant increase in adverse effects in this population [75].
Systemic side effects of LTG 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 drug are more likely to experience
rash with LTG [5,12,76]. 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. LTG is also rarely associated with acute
multiorgan failure, hypersensitivity reactions, and disseminated intravascular coagulation.
Neurotoxic side effects are predominantly dizziness and somnolence. In rare cases, LTG has exacerbated
or initiated myoclonus and even myoclonic status in juvenile myoclonic and other idiopathic generalized
epilepsies and also in Unverricht-Lundborg disease [77,78]. This disappears with withdrawal of the
medication and sometimes with lowering the dose. The risk of this side effect is low, and LTG is still
considered a treatment option in these patients. LTG intoxication after deliberate overdose has been
associated with status epilepticus in one patient with localization-related epilepsy [79].
Aseptic meningitis was reported in the FDA Adverse Event Reporting System in 40 patients taking LTG,
according to a 2012 report [80]. 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".)
Oxcarbazepine — Oxcarbazepine is a compound with a similar chemical structure to CBZ and likely a
similar mechanism of action. The efficacy of oxcarbazepine is comparable to CBZ and other first-line
therapies for focal and secondarily generalized tonic-clonic seizures [52,53,81,82].
Oxcarbazepine is almost completely absorbed regardless of food intake. Serum concentrations of its active
metabolite, 10-monohydroxy 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 and pregnancy", section on 'Drug levels and dose adjustment'.)
Metabolism of oxcarbazepine occurs in the liver, but only minimally affects the CYP system (table 2). This
represents a major advantage over CBZ, 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 4). (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.)
Monotherapy in adults begins with 300 to 600 mg/day, increasing to a dose of 900 to 3000 mg/day in two or
three divided doses. An extended-release formulation is also available. When more rapid seizure control is
desired, oral loading with oxcarbazepine in a dose of 30 mg/kg appears to be safe and generally well
tolerated [83]. 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 [84].
The most common side effects of oxcarbazepine are sedation, headache, dizziness, rash, vertigo, ataxia,
nausea, hyponatremia, and diplopia (table 5A-B). With the exception of hyponatremia, these side effects
appear to occur in a frequency similar to patients taking CBZ [81,85]. 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 [86,87]. (See "Drug interactions with thyroid hormones",
section on 'Drugs that affect thyroid hormone metabolism'.)
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 [12]. As with CBZ, the HLA-B*1502 allele has been associated with increased risk of SJS/TEN in
patients with Asian ancestry treated with oxcarbazepine (see 'Role of HLA testing' above) [88-90]. However,
the incidence and severity of SJS/TEN related to oxcarbazepine appear to be lower compared with CBZ,
and the positive predictive value of HLA-B*1502 for SJS/TEN was less than 1 percent in one study [90].
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 [91]. Oxcarbazepine, CBZ, and
phenytoin should be avoided in patients carrying the HLA-B*1502 allele unless the estimated benefits
clearly outweigh the risks.
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 [92].
Hyponatremia — Hyponatremia is a well-described adverse effect of both oxcarbazepine and CBZ, 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'.)
The reported prevalence of oxcarbazepine- and CBZ-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 CBZ [93-99]. 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 CBZ were 48 and 26 percent, respectively
[98]. Rates of severe hyponatremia (sodium ≤128 mEq/L) were 22 and 7 percent.
Risk factors for hyponatremia appear to be similar for oxcarbazepine and CBZ and include:
● Older age
● Concomitant use of other antiseizure drugs
● Concomitant antihypertensive medications, especially diuretics
● History of hyponatremia with prior exposure to either drug
A clear dose response relationship between oxcarbazepine and hyponatremia has not been established,
and data are conflicting.
Hyponatremia may develop gradually over the first few months of therapy, and many patients are
asymptomatic [100]. 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 CBZ.
Measurement of serum sodium concentration is recommended prior to initiation of oxcarbazepine or CBZ

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 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 drug. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone
secretion (SIADH) and reset osmostat".)
Phenytoin — 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). Similar to CBZ, it blocks voltage-dependent neuronal sodium
channels [101]. 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. 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 2). Phenytoin may reduce the effectiveness of most forms of hormonal contraception
(table 4). (See "Overview of the management of epilepsy in adults", section on 'Contraception'.)
Phenytoin can be administered orally or IV; 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 or two divided doses. Fosphenytoin is administered in phenytoin
equivalents (PE). 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 VPA), 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.
Like all antiseizure drugs, 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).
A number of drugs, including many antiseizure drugs, can influence the serum concentration of phenytoin
(table 3B). 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, but CYP2C9 genotyping is not yet widely performed or
mandated. 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 [102]. These dosing recommendations are considered preliminary, however, and have not been
validated by prospective studies. (See "Overview of pharmacogenomics".)
Commercially available brand and generic phenytoin products may differ in phenytoin content and other
formulation characteristics that can affect bioavailability [103]. These differences may occasionally result in
an increase [104] or decrease [105] 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.
The major systemic side effects of phenytoin are gingival hypertrophy, body hair increase, rash, folic acid
depletion, and decreased bone density (table 5A-B).
● Patients who develop a rash with phenytoin are more likely to develop one with CBZ and vice versa [5].
Phenytoin has been associated with SJS and TEN, particularly during the first eight weeks of therapy
[11,12]. As with CBZ, this reaction appears to be more common in patients with the HLA-B*1502 allele,
which occurs almost exclusively in patients of Asian ancestry, including South Asian Indians [106,107].
However, the magnitude of the risk of phenytoin in these patients is less clear than with CBZ. The FDA
recommends avoiding substituting phenytoin for CBZ in patients who are known to be positive for HLA-
B*1502 unless the estimated benefits clearly outweigh the risks. (See 'Role of HLA testing' above.)
● Folic acid supplementation 0.5 mg/day was associated with a reduced incidence of gingival hyperplasia
(21 versus 88 percent) after six months in a randomized trial of children (ages 6 to 15 years) who were
recently started on phenytoin [108].
● 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 "Antiepileptic drugs 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 [6].
Neurotoxic side effects include confusion, slurred speech, double vision, ataxia, and neuropathy (with long-
term use).
Rufinamide — Rufinamide is structurally unrelated to other marketed antiseizure drugs. Rufinamide

modulates the activity of sodium channels, prolonging the inactive state. This action is particularly effective
in depolarized neurons.
Rufinamide is approved by the FDA as an adjunctive treatment for seizures associated with 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
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placebo [109]. Observational studies suggest that rufinamide may be effective as adjunctive therapy in
children with other refractory epilepsy syndromes as well [110-112].
Rufinamide may have efficacy in focal epilepsy as well [113,114]. 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 [115]. Another randomized study in 357 patients with refractory focal epilepsy found that
rufinamide was effective as adjunctive therapy [116].
Pharmacokinetic studies show slow absorption (four to six hours to peak concentration) after oral ingestion.
Coingestion with food increases the extent of absorption. Rufinamide is not metabolized by CYP
mechanisms and has little effect on the pharmacokinetics of other antiseizure drugs [117]. However, potent
CYP inducers (CBZ, phenytoin, primidone, phenobarbital) may increase the clearance of rufinamide. VPA is
associated with reduced clearance of rufinamide. Rufinamide may reduce the effectiveness of oral hormonal
contraceptives. Elimination of rufinamide occurs primarily through renal excretion.
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.
Rufinamide is well tolerated [118]. 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 HSS described with other antiseizure drugs has been reported
in patients taking rufinamide; all cases have occurred within four weeks of start of treatment.
Zonisamide — Zonisamide is a sulfonamide derivative that is chemically and structurally unrelated to other
anticonvulsants. Its primary mechanism of action appears to be to blocking both voltage-dependent sodium
and T-type calcium channels.
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 [119,120]. Zonisamide also
has activity in myoclonic epilepsy. Observational studies and one randomized noninferiority trial with a
comparison with CBZ suggest that it is effective in monotherapy as well [121-124].
Zonisamide is metabolized primarily in the liver by CYP and non-CYP transformations but is not a CYP
inducer (table 2). Dose adjustments are needed for mild renal or hepatic insufficiency, and the drug is not
recommended in patients with moderate or severe renal insufficiency.
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.
Drug interactions are limited; however, clearance may be increased when used with CBZ, phenytoin, or
phenobarbital [125]. Adjustments of zonisamide dose may be required when these drugs are added or
removed.
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 [126]. 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 [127]. 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 [128]. (See "Nephrolithiasis in renal tubular
acidosis", section on 'Carbonic anhydrase inhibitors'.)
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) [129].
Ethosuximide — Ethosuximide diminishes T-type calcium currents in thalamic neurons, which are further
reduced as membrane potentials become more hyperpolarized [130]. The metabolite of trimethadione,
another antiseizure drug for absence seizures, acts similarly.
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 (VPA), and
lamotrigine (LTG) in 453 children with childhood absence epilepsy [131]. Ethosuximide and valproic acid
were found to be more effective than LTG in eliminating seizures; ethosuximide had a more favorable
adverse-event profile compared with valproic acid. (See "Childhood absence epilepsy".)
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). There are no significant reactions reported with other drugs. The
major side effects include nausea, vomiting, sleep disturbance, drowsiness, and hyperactivity (table 5A-B).
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 drugs 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 drugs have been designed to imitate the action of GABA,
while still others improve endogenous GABA-mediated inhibition.
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.
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.
Clobazam — Clobazam was approved by the US Food and Drug Administration (FDA) in 2011 for use
as an adjunctive therapy in patients >2 years of age with Lennox-Gastaut syndrome (LGS) and has been
available outside the United States for many years (see "Epilepsy syndromes in children", section on
'Lennox-Gastaut syndrome'). Clobazam is widely used in other countries for the treatment of focal seizures.
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
2).
Adverse effects include somnolence and sedation, dysarthria, drooling, aggression or other behavioral
changes, infections, and constipation; of these, tiredness and behavioral changes are most common [132].
In clinical trials, the incidence of adverse effects was not significantly different in low-dose, high-dose, or
placebo-treated patients [133,134].
Rare cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have also been
reported; such reactions can occur at any time, but the likelihood is greater during the first eight weeks of
treatment or when the drug is stopped and restarted [92].
In patients greater than two years of age, clobazam may be started at 5 mg per day in one dose, typically
given at bedtime. The dose may be increased in intervals no shorter than every seven days to a maximum
of 40 mg per day in a divided schedule (maximum 20 mg per day for weight ≤30 kg).
Others — Clonazepam 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.
The starting dose of clonazepam in adults is 0.5 to 1 mg/day with weekly increments of 0.5 to 1 mg/day as
needed. Lorazepam and diazepam (especially rectal diazepam) are usually 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:
Treatment and prognosis".)
Phenobarbital — Phenobarbital is among the oldest antiseizure drugs still in use. It is effective for the
treatment of generalized and focal seizures. However, its clinical utility is limited by its sedating effects (table
5A-B).
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 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 2).
The oral dose of phenobarbital is 1 to 5 mg/kg per day; it may also be administered intravenously (IV).
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 3A-C). Phenobarbital may reduce the effectiveness of most forms of
hormonal contraception (table 4). (See "Overview of the management of epilepsy in adults", section on
'Contraception'.)
Tiagabine — Tiagabine (TGB) is a second-generation antiseizure drug that is used as adjunctive treatment
for focal seizures [52,53,135]. It is a potent enhancer of GABA action via specific inhibition of GABA
reuptake into presynaptic neurons and glia in vitro [136]. Thus, it decreases the elimination of GABA from
the synaptic space, making endogenously produced GABA more available for postsynaptic inhibitory
effects.
TGB is metabolized in the liver by CYP and non-CYP transformations but is not a CYP inducer (table 2).
The initial dose of TGB 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. TGB has no significant drug interactions. Major side effects include dizziness, lack of energy,
somnolence, nausea, nervousness, tremor, difficulty concentrating, and abdominal pain (table 5A-B) [137].
In one study, however, cognitive function after one year of TGB monotherapy was similar to that in untreated
controls and those on carbamazepine (CBZ) monotherapy [138].
There is concern that TGB has a potential proconvulsive effect. As of February 2005, the FDA had reviewed
more than 30 reports of seizures, including seven cases of status epilepticus, that were associated with off-
label use of TGB for patients without epilepsy [92,139]. This issue is not resolved.
The apparent discrepancy between this risk in seizure and nonseizure patients may be explainable [140]:
● TGB was developed and is approved for use as an adjunctive treatment for epilepsy. Virtually all
patients treated with TGB in clinical trials were taking at least one hepatic-enzyme-inducing antiseizure
drug, which decreased the concentration of TGB; it is likely that patients without epilepsy have
increased concentrations of TGB.
● Another potential contributor is the fact that patients taking TGB for off-label indications (psychiatric
disease and pain) may also be on other medications that potentially lower seizure threshold.
TGB 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 [141]. In a retrospective review of patients with localization-related epilepsy, 7.8 percent
of 90 TGB-treated patients developed nonconvulsive status epilepticus compared with 2.7 percent of the
1165 patients not receiving TGB [142]. The frequency of generalized convulsive status epilepticus was not
increased. (See "Localization-related (focal) epilepsy: Causes and clinical features".)
Vigabatrin — Vigabatrin (VGB) is an irreversible inhibitor of GABA-T that raises the concentration of GABA
in the central nervous system. It is effective as an add-on agent in patients with refractory focal seizures
[143]. It is also useful as monotherapy [144], although probably less effective than CBZ for this purpose
[145,146]. Clinical observations also suggest that it may be particularly effective for infantile spasms in
children with tuberous sclerosis. (See "Management and prognosis of infantile spasms", 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.
Because of the FDA boxed warning in the United States, prescribers, patients, and pharmacies must
participate in the Risk Evaluation and Mitigation Strategies (REMS) program.
In adults, VGB is started at 500 mg twice daily and increased weekly in 500 mg increments to a total
recommended dose of 3 g per day [147]. VGB is excreted renally, and dose adjustments are required in
patients with renal insufficiency. It does not undergo hepatic metabolism but is an inducer of CYP2C9 (table
2).
A boxed warning for VGB alerts clinicians to safety concerns regarding permanent vision loss with this
medication [92]. 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 [148-153]. A similar risk
has been estimated in children, although studies are more limited [154,155]. Most studies have found that
higher cumulative dose and male gender increase the risk of vision loss [150,153,154,156,157]. 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 [158]. VGB treatment in laboratory rats is associated with irreversible injury of cone
photoreceptors [159].
These findings indicate that VGB should be reserved for patients with epilepsy that is refractory to other
drugs. Visual field testing should be performed before starting therapy and repeated every six months
[158,160]. Optical coherence tomography may be useful to monitor vision in patients who are unable to
perform visual field perimetry [161]. 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 [162].
VGB has also been reported to produce magnetic resonance imaging (MRI) abnormalities, specifically
hyperintense lesions on T2-weighted images with restricted diffusion on diffusion-weighted imaging in the
basal ganglia, thalamus, brainstem, and dentate nucleus of the cerebellum [163-165]. These abnormalities
appear to occur primarily in infants and only in those who are treated for infantile spasms. The incidence
overall is 32 percent and appears to be a dose-related phenomenon. These abnormalities are not clearly
associated with new neurologic deficits and normalize when VGB is discontinued. In a few cases, they have
been observed to resolve even while VGB was continued.
Other frequent adverse events with VGB include drowsiness, fatigue, headache, and dizziness [145].
Depression and weight gain can occur. Severe hypersensitivity reactions and angioedema have also been
reported [92].
DRUGS THAT AFFECT GLUTAMATE RECEPTORS — 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 [166]. There is currently one AMPA antagonist approved for treatment of seizures, and
two other antiseizure drugs (felbamate and topiramate [TPM]) that are thought to act in part through NMDA
antagonism.
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 [167].
It is approved by the US Food and Drug Administration (FDA) for use in patients aged 12 years and older
for treatment of focal-onset seizures and as adjunctive treatment of primary generalized tonic-clonic
seizures [30]. 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 [168-171]. Improved efficacy
has been observed with higher doses [172]. Perampanel also decreased the frequency of primary
generalized seizures compared with placebo in a trial of 162 patients with drug-resistant idiopathic
generalized epilepsy [173].
Perampanel is extensively metabolized by the liver, primarily via cytochrome P450 (CYP) 3A4, CYP3A5,
glucuronidation, and potentially other pathways. It has a prolonged and variable half-life (mean 105 hours),
which may complicate dose titration and safety wash-out. 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 drugs such as phenytoin and carbamazepine (CBZ) (table 3A and table 3B)
[172,174]. Strong inhibitors of CYP34A may modestly increase perampanel exposure (table 2). When dosed
at 12 mg daily, perampanel can decrease the efficacy of levonorgestrel-containing hormonal contraception.
The recommended starting dose 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 drugs, the recommended starting dose is 4 mg.
The most common side effects observed in randomized trials include dizziness, somnolence, headache,
fatigue, irritability, gait disturbance, falls, nausea, and weight gain (table 5A) [168,169,175,176]. Labeling
information includes a boxed warning of serious neuropsychiatric effects including alteration of mood and
aggression [30]. 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) [177]. 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 [178], 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) [179]. 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 [180].
DRUGS WITH MULTIPLE MECHANISMS OF ACTION — A number of antiseizure drugs have multiple
potential mechanisms by which they prevent seizures.
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 [181].
Felbamate can be used to treat focal seizures and can also be used to treat the Lennox-Gastaut syndrome
(LGS), a mixed seizure disorder of childhood onset associated with multiple seizure types, slow spike-wave
electroencephalograms (EEGs), mental retardation, and resistance to standard antiseizure drugs [182-184].
However, felbamate has been associated with fatal aplastic anemia and hepatic failure (table 5A-B).
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".)
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.
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 2). Felbamate can increase toxicity
of valproate (VPA), phenytoin, and the active epoxide metabolite of carbamazepine (CBZ) [185-187].
Felbamate is not recommended for first-line therapy of seizures because of the potential for serious adverse
reactions; use of this drug is mostly confined to cases of LGS [188]. The manufacturer recommends that
written consent be obtained prior to beginning therapy.
Topiramate — Topiramate (TPM) 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 NMDA-glutamate receptor. It also weakly inhibits carbonic anhydrase in the central nervous
system.
TPM is effective as adjunctive therapy for the treatment of adults and children over two years in age with
focal seizures, and may have efficacy for other seizure types [52,53,189]. One randomized trial in 151
children (ages 6 to 15 years) reported efficacy for TPM as monotherapy for newly diagnosed epilepsy;
seizures were focal onset or generalized onset tonic-clonic [190]. A randomized study in infants aged 1 to
24 months found that adjunctive TPM (5, 15, or 25 mg/kg per day) was not effective in reducing refractory
focal-onset seizures [191].
American Academy of Neurology (AAN) guidelines state that TPM may be used as initial therapy for newly
diagnosed focal and mixed seizure disorders [53]; the guidelines also state that TPM may be used as
monotherapy for refractory generalized tonic-clonic convulsions and focal seizures in adults and children
[192]. TPM is not approved by the US Food and Drug Administration (FDA) for use in children younger than
two years of age [30].
The starting dose of TPM is 50 mg/day for one week, titrated at weekly increments of 50 mg to an effective
dose. One study suggests that the dose can be started at 100 mg/day without significant adverse effects
[193]. 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. TPM's
clearance is increased twofold by enzyme-inducing agents (eg, phenytoin, CBZ), requiring twofold-
increased doses in this setting (table 2).
TPM may increase phenytoin concentration, but there do not appear to be any clinically significant
interactions with VPA (table 3A-C). Serum levels of TPM may decline by approximately 30 percent during
pregnancy. Conversely, TPM may reduce the effectiveness of most forms of hormonal contraception (table
4). (See "Management of epilepsy and pregnancy", section on 'Drug levels and dose adjustment' and
"Overview of the management of epilepsy in adults", section on 'Contraception'.)
Weight loss is a common dose-related side effect [194,195]. In a double-blind placebo-controlled trial of
TPM added to existing antiseizure drugs in 264 patients, TPM was associated with a 2.0 kg mean decrease
in weight at three months [195]. 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 [196]. 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 [197].
Impaired cognition and expressive language is a reported side effect in a minority of patients taking TPM,
but it is a common reason for discontinuing therapy [195,198]. 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 [199-204]. Impaired cognitive measures with TPM 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 (LTG) and CBZ [199-201,205,206]. Cognitive and behavioral worsening has
also been observed in children with mental retardation [207]. Adults treated for epilepsy and children treated
for obesity have similar cognitive side effects from TPM [202,203]. The observed cognitive deficits are broad
in spectrum but appear to be reversible when the drug is discontinued and attenuated with dose reductions
[200,203,208].
Other side effects of TPM include paresthesias, headache, fatigue, dizziness, depression, and mood
problems (table 5A-B) [209]. The incidence of most side effects decreases with continued dosing; weight
loss and paresthesia are the exceptions [195]. Slower titration of the dose following initiation of therapy may
also improve tolerance [210]. Despite reports of a high frequency of somnolence when TPM was used as
add-on therapy in patients with epilepsy [211], monotherapy with TPM 200 mg/day does not appear to
impair daytime vigilance in adult patients [212].
TPM 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 [213,214].
Acute myopia and secondary angle glaucoma, characterized by the acute onset of decreased visual acuity
and/or ocular pain, also have been reported with TPM therapy (23 cases out of approximately 825,000
users), typically within one month of initiating treatment [215,216]. Chronic users of TPM do not appear to
be at increased risk of glaucoma. A few case reports have linked TPM with an apparently irreversible
maculopathy [217]. Visual field defects independent of elevated intraocular pressure have also been
reported in association with TPM [30].
Metabolic acidosis may result from renal bicarbonate loss due to the inhibitory effect of TPM on carbonic
anhydrase, which can cause both proximal and distal acidification defects. The following observations have
been made [218-220]:
● Metabolic acidosis is common, occurring in 32 to 44 percent of adults and 67 percent of children.
● It is dose related and usually mild, with an average decrease in serum bicarbonate of 4 mEq/L (4
mmol/L) at daily doses of TPM 400 mg in adults and 6 mg/kg per day in children. However, reductions
in serum bicarbonate of as much as 10 mEq/L (10 mmol/L) have been described.
● Reductions in serum bicarbonate are most likely to begin early in treatment and persist in patients on
chronic therapy.
The main clinical manifestation of metabolic acidosis is tachypnea, although calcium phosphate
nephrolithiasis can occur [221], presumably via a mechanism similar to that seen with other carbonic
anhydrase inhibitors such as acetazolamide [222,223] and perhaps zonisamide [128]. It is not known if the
risk of nephrolithiasis is increased when two carbonic anhydrase inhibitors are used concurrently, although
the low incidence observed in patients receiving both TPM and zonisamide suggests that any additive effect
must be modest [224]. In one series of children on TPM for one year or longer, an ultrasound revealed
asymptomatic kidney stones in 5 percent [225]. If this finding is confirmed, this frequency may warrant use
of baseline and follow-up ultrasound in children on chronic TPM therapy. (See "Nephrolithiasis in renal
tubular acidosis", section on 'Carbonic anhydrase inhibitors'.)
Measuring serum bicarbonate at baseline and periodically (for example, every two to four months) is
recommended. Gradual dose reduction or cessation of TPM (after tapering) is advised if significant
metabolic acidosis develops. Alkali treatment may be helpful if TPM is continued in patients with symptoms
or more marked acidosis [218]. (See "Treatment of distal (type 1) and proximal (type 2) renal tubular
acidosis".)
TPM exposure in utero has been associated with an increased risk of oral clefts and low birth weight. (See
"Risks associated with epilepsy and pregnancy", section on 'Topiramate'.)
Valproate — Valproate (valproic acid, VPA) is a broad-spectrum antiseizure drug that is used alone and in
combination for the treatment of generalized and focal seizures.
It has multiple cellular mechanisms of action consistent with its broad clinical effectiveness [226-229]. VPA
seems to suppress high-frequency, repetitive neuronal firing by blocking voltage-dependent sodium
channels, but at sites different than CBZ and phenytoin. VPA increases brain GABA concentrations at
clinically relevant doses, although the basis of this effect is debated. VPA does not seem to have any direct
effects on the GABA(A) receptor, but GABA release may be enhanced by a presynaptic effect of VPA on
GABA(B) receptors. Inhibition of nerve terminal GABA transaminase (GABA-T) probably also increases
presynaptic GABA levels. Furthermore, VPA may increase GABA synthesis by activating glutamic acid
decarboxylase (GAD). Finally, VPA acts against T-type calcium currents, although this action is weaker than
that observed with ethosuximide.
VPA 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 2). In the presence of hypoalbuminemia, unbound
VPA concentrations can be elevated despite normal or low total VPA concentrations and may correlate
better with toxicity [230]. VPA is contraindicated in patients with known urea cycle disorders due to an
increased risk of severe hyperammonemia [231]. (See "Urea cycle disorders: Management".)
The initial dose of VPA is 15 mg/kg per day in three divided doses; it may be increased by 5 to 10 mg/kg per
day every week as needed. A serum level should be checked one to two weeks after the initial dose;
therapeutic concentrations are usually in the 50 to 125 mcg/mL (346 to 875 micromol/L) range. 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.
A number of drugs affect the serum level of VPA (table 3C). Oral contraceptive agents may increase VPA
clearance and their use is associated with decreased VPA blood levels (median decline 23 percent) during
active treatment and higher concentrations during the "placebo" week that is used with many oral hormonal
contraceptives [68].
VPA can be delivered intravenously (IV). Current prescribing information recommends slow administration
of IV VPA 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 [232]. In emergency situations such as status epilepticus,
accumulating evidence suggests that a loading dose of VPA 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 [233-238]. Rapid IV loading
may be desirable as a way to achieve serum concentrations >100 mcg/mL (>693 micromol/L) quickly.
Side effects of VPA include nausea, vomiting, hair loss, easy bruising, and tremor (table 5A-B). VPA is
associated with weight gain, obesity, insulin resistance, and the metabolic syndrome [239-242]. VPA can
also cause thrombocytopenia and other coagulation disturbances [243,244] and has also been associated
with subclinical hypothyroidism with mild to moderate elevations in thyrotropin (TSH) levels [8,86,245,246].
VPA has also been linked to the polycystic ovarian syndrome [247,248]. A number of case reports have
linked VPA to Fanconi syndrome in children with severe disabilities [249]. (See "Drug interactions with
thyroid hormones", section on 'Drugs that affect thyroid hormone metabolism' and "Epidemiology and
genetics of the polycystic ovary syndrome in adults".)
VPA exposure in utero is associated with major malformations and other adverse effects, including
neurodevelopmental abnormalities. VPA should be avoided in pregnancy when possible. (See "Risks
associated with epilepsy and pregnancy", section on 'Valproate' and "Risks associated with epilepsy and
pregnancy", section on 'Long-term effects'.)
Approximately 5 to 10 percent of patients develop alanine aminotransferase (ALT) elevations during long-
term VPA therapy; most of the time these abnormalities are asymptomatic and can even resolve with
continuation of the drug. In addition, there are more serious forms of hepatotoxicity that can occur with VPA:
● VPA-related hyperammonemic encephalopathy (VHE) causes lethargy, increased seizures, and rarely
coma and death. VHE can occur without abnormalities of liver function tests (LFTs) or elevated serum
VPA levels [250]. The syndrome resolves within a few days of stopping VPA 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 VPA dose and plasma concentrations and concomitant use of enzyme-inducing antiseizure
drugs, carbonic anhydrase inhibitors, and antipsychotic drugs [251,252]. (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 VPA. In
some cases this is associated with fulminant liver failure and death. Risk factors include age under two,
polytherapy, and coexistent congenital metabolic disorders [253,254]. 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.
VPA can rarely cause acute pancreatitis [255,256]. 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 'Drugs'.)
A number of case reports and case series have described a syndrome of reversible parkinsonism and
cognitive decline associated with VPA use [257-261]. The reported frequency of this adverse effect ranges
from 1.4 to 5 percent among patients with epilepsy who are treated with VPA. 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 VPA is discontinued.
VPA has been associated with increased sleep duration in children over six years of age [262]. This is
significant only in a minority of patients and appears to resolve off treatment.
DRUGS WITH OTHER MECHANISMS OF ACTION
Brivaracetam — Like levetiracetam (LEV), brivaracetam binds to the synaptic vesicle protein SV2A, which
has been linked in animal models to epilepsy [263,264]. Brivaracetam is approved as monotherapy or
adjunctive therapy for focal-onset seizures in patients 16 years 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 [265-268]. 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 [265]. More limited data
suggest that brivaracetam has activity in adults with generalized epilepsy [269] but not in children with
progressive myoclonic epilepsy [270]. It does not appear to add benefit in combination with LEV.
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
2). Nonetheless, clinicians should be aware of several potential interactions with concomitant antiseizure
drugs. Brivaracetam may increase the plasma concentrations of phenytoin and the active (10,11-epoxide)
metabolite of carbamazepine (CBZ) via inhibition of epoxide hydroxylase. Of note, routine CBZ serum
measurements do not assess for accumulation of active CBZ-epoxide metabolite, but this metabolite can be
measured as a separate test (see 'Carbamazepine' above). The concurrent use of phenytoin, CBZ,
phenobarbital, and other CYP2C19 inducers is associated with decreased plasma concentrations of
brivaracetam (table 3A).
The manufacturer's recommended starting dose is 50 mg twice daily [271,272]. The dose can be increased
to 100 mg twice daily if needed based on response. Lower doses are recommended for patients with
hepatic impairment. The drug is available in both oral and intravenous (IV) formulations [273]. The dose and
frequency for the IV preparation are the same as for the oral tablets and oral solution.
The most common side effects 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) [271]. In the largest individual trial, the most common
psychiatric side effects 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) [265]. Severe hypersensitivity reactions have
been reported, including bronchospasm and angioedema (table 5B).
The comparative tolerability between brivaracetam and LEV is not yet known. One retrospective
postmarketing study included 35 patients with behavioral adverse effects on LEV who were switched to
brivaracetam; among these, 57 percent reported improved behavioral symptoms after the transition [274]. In
the overall cohort, patients with a history of behavioral adverse effects on LEV were at increased risk for
behavioral adverse effects from brivaracetam (odds ratio 3.5).
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 [275].
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 [276,277].
Gabapentin is used as add-on therapy for refractory focal seizures [53,278]. The American Academy of
Neurology (AAN) guidelines state that gabapentin may also be used as initial monotherapy in newly
diagnosed focal epilepsy [52], although it is not approved by the US Food and Drug Administration (FDA)
for this indication.
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 [279]. 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 2). Gabapentin should be taken at least two hours after the use of antacids since
concurrent administration decreases its bioavailability.
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 [278,280].
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 [281].
The major side effect 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
[282,283].
Gabapentin may be transported across the placenta and accumulate in breast milk, but the clinical
significance of these findings is not clear. (See "Management of epilepsy and pregnancy", section on 'Breast
feeding'.)
Levetiracetam — The mechanism of action of LEV is unknown. However, LEV binds to the synaptic vesicle
protein SV2A, which has been linked in animal models to epilepsy [284,285]. Binding at this site may
modulate synaptic transmission through alteration of vesicle fusion [286]. There is also evidence that LEV
indirectly modulates gamma-aminobutyric acid (GABA) [287,288].
LEV is a broad-spectrum antiseizure drug and is approved as adjunctive therapy to treat focal-onset
seizures in children and adults 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 [289-292].
A randomized, placebo-controlled trial [293] and open-label studies [294-297] have found that LEV is also
effective as adjunctive therapy in very young children (neonates to age four years). Uncontrolled studies
suggest that LEV may also be effective as monotherapy in patients with focal seizures [298-300].
The ease-of-use features of LEV include [301]:
● Metabolism is independent of the CYP system, limiting the potential for pharmacokinetic interaction
with other antiseizure drugs. Some studies have found that coadministration of enzyme-inducing
antiseizure drugs is associated with an approximate 25 percent increase in LEV clearance; however,
this is felt to have limited clinical significance [302].
● LEV does not act as an inducer of the CYP system; thus, there is little potential for pharmacokinetic
interactions with other drugs, such as hormonal contraception or immunosuppressant drugs commonly
used in organ transplantation [303,304].
● LEV does not require a titration period, and it 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 LEV 500 mg twice-daily treatment compared with placebo [305].
● The drug is relatively well tolerated. The most common adverse events include fatigue, somnolence,
dizziness, and infection (upper respiratory) [291]. Most adverse events associated with LEV 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.
● An IV formulation of LEV has been approved for use in clinical situations when patients are temporarily
unable to take oral medication [295,306,307]. IV infusion of LEV is bioequivalent to oral tablets.
● An extended-release formulation of LEV is available; studies suggest that it is comparably effective and
well tolerated as a once-daily medication [308-310].
In a postmarketing surveillance study of 373 patients at a single epilepsy center, both the efficacy of LEV
and the cumulative probability of remaining on LEV at 12 months (74 percent) compared favorably with
published data for vigabatrin (VGB), lamotrigine (LTG), and topiramate (TPM) [311]. This was corroborated
in a larger, multicenter study in which a 58 percent three-year retention rate was estimated [312]. Sedation
was the most common side effect of LEV, occurring in 38 patients (10.7 percent), but mood disturbance was
not rare (17 patients or 4.8 percent), and was more likely to lead to discontinuation [311]. Psychiatric
adverse effects led to discontinuation in an additional nine patients (2.5 percent), including behavioral
disturbance in eight and psychosis in one. In children, behavioral problems and somnolence are the most
commonly reported side effects (11 and 8 percent, respectively) [313].
Other anecdotal reports and observational studies describe increased agitation and aggression with LEV
that may be problematic in some patients, particularly those who are intellectually disabled and have
baseline behavioral problems [314-316]. This patient population may also be at increased risk of a
paradoxic worsening of seizures in the first few weeks of starting LEV, particularly when high doses are
used [317]. Some have reported that problematic weight loss occurs in a small proportion of patients taking
LEV [318-320]. A reversible thrombocytopenia has been linked to LEV in a small number of patients [321-
323].
Treatment with LEV is initiated at 500 mg twice daily. It is 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 [324]. Doses up to 4000
mg daily have been found to be beneficial in observational studies [291], 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 [325,326]. 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 [327]. 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 [328].
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 [329,330]. Pregabalin also modulates the release of several neurotransmitters
including glutamate, noradrenaline, and substance P. The net result of pregabalin's action appears to be
inhibition of neuronal excitability [331].
Pregabalin has efficacy as an adjunctive therapy for focal seizures and for the treatment of neuropathic pain
associated with diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia.
Pregabalin is renally excreted virtually unchanged, and it is not hepatically metabolized. Pregabalin does
not induce or inhibit the CYP system (table 2). In addition, it does not bind to plasma proteins. Thus,
pregabalin does not have significant interactions with other antiseizure drugs and is not expected to have
pharmacokinetic interactions with other drugs [332-334].
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 [335]. Experimental data
suggest that the pharmacodynamic half-life (ie, anticonvulsant effect) of pregabalin is longer than the six-
hour pharmacokinetic half-life [336]. The Tmax may be delayed to approximately three hours if the drug is
taken with food, but total absorption is not affected by food [333]. Steady state is achieved within 24 to 48
hours.
Pregabalin is effective for the adjunctive treatment of focal seizures as demonstrated in randomized
controlled trials [337-341]. 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 [342]. In the only randomized trial testing pregabalin as monotherapy for
newly diagnosed focal seizures, pregabalin was less effective than LTG but similarly tolerated [343].
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 [340,344]. 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.
The most common side effects with pregabalin in randomized trials were dizziness, somnolence, and ataxia
(table 5A-B) [337-339,345,346]. Other side effects include weight gain, peripheral edema, blurred or double
vision, asthenia, tremor, and abnormal thinking (most often impaired concentration). 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 [347].
SUMMARY
● While sharing a common property of suppressing epileptic seizures, antiseizure drugs 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. For drug-specific summaries
refer to 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 2)
• Common and rare side effects (table 5A and table 5B)
• Some important drug interactions (table 3A and table 3B and table 3C and table 4)
● Another important feature of these drugs is their different rates of efficacy for some specific epilepsy
syndromes or seizure types. With the exception of ethosuximide, which has a narrow spectrum of
activity limited to absence seizures, nearly all of the available antiseizure drugs have potential efficacy
against focal-onset seizures as well as generalized seizures. However, some drugs have the potential
to worsen certain generalized seizure types (eg, absence seizures, myoclonic seizures) (table 6 and
table 7).
● A discussion of antiseizure drug selection in specific patient situations is presented separately. (See
"Initial treatment of epilepsy in adults", section on 'Selection of an antiseizure drug'.)
● 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
Lexicomp drug interactions tool.
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 2221 Version 73.0

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16/8/2018 Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects - UpToDate

Author: Steven C Schachter, MD

DRUGS THAT AFFECT VOLTAGE-DEPENDENT SODIUM CHANNELS — Alteration of sodium currents is

It is a weak inducer of CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and a

According to manufacturer pharmacokinetic data, eslicarbazepine can, in a dose-related manner, decrease

Lacosamide — Lacosamide selectively enhances slow inactivation of voltage-dependent sodium channels;

Dose-dependent PR interval prolongations on electrocardiogram (ECG) in some studied patients suggest

These interactions lead to three different dosing schemes:

● Concomitant use of other antiseizure drugs

● Concomitant antihypertensive medications, especially diuretics

● History of hyponatremia with prior exposure to either drug

Measurement of serum sodium concentration is recommended prior to initiation of oxcarbazepine or CBZ

Cessation of oxcarbazepine therapy because of hyponatremia is uncommon, being required in only 1

Rufinamide — Rufinamide is structurally unrelated to other marketed antiseizure drugs. Rufinamide

Perampanel — Perampanel is an orally active, noncompetitive AMPA-type glutamate receptor antagonist. It

● Metabolic acidosis is common, occurring in 32 to 44 percent of adults and 67 percent of children.

DRUGS WITH OTHER MECHANISMS OF ACTION

Brivaracetam is metabolized primarily (approximately 60 percent) by cytochrome P450 (CYP)-independent

Gabapentin — Gabapentin binds to the auxiliary alpha-2-delta subunit of a voltage-dependent calcium

The ease-of-use features of LEV include [301]:

• Known or suspected mechanism of action (table 1)

• Important pharmacologic properties (table 2)

• Common and rare side effects (table 5A and table 5B)

Use of UpToDate is subject to the Subscription and License Agreement.

1. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206030s000lbl.pdf (Accessed on Novemb

270. Kälviäinen R, Genton P, Andermann E, et al. Brivaracetam in Unverricht-Lundborg disease (EPM1):

Epilepsia 2012; 53:111.

Topic 2221 Version 73.0

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