ANTIEPILEPTIC DRUGS: ADVERSE EFFECTS AND DRUG INTERACTIONS

William O. Tatum IV ABSTRACT

The goal of epilepsy treatment is no seizures and no side effects. Antiepileptic drugs (AEDs) are the mainstay of treatment. Chronic use, however, often leads to serial drug changes over time, exposing patients with epilepsy (PWE) to recurrent risks due to adverse effects (AEs) and drug interactions. Both unwanted acute and chronic AEs may occur that are usually dose-related, suggested by AED pharmacology, and addressed with appropriate use of serum drug concentrations. Idiosyncratic AEs can pose significant health issues for PWE and be lifesaving with early identification. AED pharmacokinetics and pharmacodynamic properties serve as the foundation for a number of drug interactions. Hepatic enzyme systems may facilitate AED interaction with other coadministered medication through induction or inhibition of drug metabolism and result in AEs or seizures from drug interactions. A working knowledge of AED pharmacology is an essential component of good clinical practice to help clinicians predict potential AEs and DIs in the treatments of PWE
Continuum Lifelong Learning Neurol 2010;16(3):136158.

Note: Text referenced in the Quintessentials Preferred Responses, which appear later in this issue, is indicated in yellow shading throughout this chapter.

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INTRODUCTION Antiepileptic drug (AED) treatment is the most important means of preventing seizures in the lives of 3 million PWE in the United States.1 The antiepileptic benefits, despite a large number of AEDs (Table 7-1), are tempered by the fact that they do not prevent epileptogenesis or provide a cure in most patients.1 More than 25% of patients discontinue treatment because of adverse effects (side effects) with the initial AED chosen, and up to one-third are refractory despite repeated AEDs, potentially leading to recurrent adverse events (AEs) and drug interactions.2 Safety profiles

and tolerability are among the most important considerations in selecting AEDs in the absence of clear differences in efficacy.3 The clinical profile, including age, sex, comorbidity, cost, and co-medication, helps individualize AED use.3,4 Since 1993, an explosion of new (second)generation AEDs has become available for PWE. These possess favorable pharmacokinetics, including low protein binding, absent hepatic metabolism, and unique mechanisms that minimize AEs and drug interactions with a greater ease of use.1,35 Both AEs and some drug interactions reflect adverse drug reactions (ADRs) of AEDs

Relationship Disclosure: Dr Tatum has received personal compensation for activities with the American Board of Clinical Neurophysiology, Cyberonics, Inc., H. Lunbeck A/S, Pfizer Inc, and UCB. Dr Tatum has received research support from Esai Inc., King Pharmaceuticals, Inc., and UBC. Unlabeled Use of Products/Investigational Use Disclosure: Dr Tatum has nothing to disclose.

Copyright # 2010, American Academy of Neurology. All rights reserved.

TABLE 7-1

Antiepileptic Drugs Available for Clinical Use in the United States

TABLE 7-1

Continued

"

Benzodiazepines Diazepam Clonazepama Lorazepam Clorazepate

"

Hydantoins Phenytoina Ethotoin Mephenytoin

"

-Aminobutyric Acid Analog Gabapentina Pregabalina Vigabatrina

"

Barbiturates Phenobarbitala Primidonea Mephobarbital Methabarbital

"

Structurally Distinct Topiramatea Levetiracetama Rufinamidea Lacosamide

a

"

Carboxamides Carbamazepinea Oxcarbazepinea

"

Succinimides Ethosuximidea Methsuximide Phensuximide

a Antiepileptic drug of major clinical relevance in patients with epilepsy.

Adapted from Tatum WO, Kaplan PW, Jallon P. Epilepsy A to Z. 2nd ed. New York: Demos, 2009:27.

" " "

Carbamates Felbamate Triazine Derivative Lamotriginea Sulfonamide Derivative Zonisamidea

capable of causing major morbidity and mortality. A heightened level of awareness is therefore necessary for good clinical practice. PHARMACOLOGY AEDs are currently grouped according to their principal mode of action, although for many the precise means of their efficacy and toxicity remains incompletely defined, imprecise, or associated with multiple actions.5 AEDs were initially developed based on their ability to prevent seizures in animal models. (Abbreviations for most of the AEDs mentioned in this chapter are shown in Box 7-1.) Some newer AEDs have unique mechanisms (eg, efficacy in retarding kindling in animal models seen with levetiracetam [LEV]) and newer sites of activity (collapsing response mediator protein-2 activity with lacosamide [LCS]); and other AEDs are structurally distinct (eg, rufinamide [RUF]) from
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"

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Oxazolidinediones Paramethadione Trimethadione

" " "

Phenylureas Phenacemide Carboxylic Acids Valproic acida Carbonic Anhydrase Inhibitor Acetazolamide

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Box 7-1
ANTIEPILEPTIC DRUG ABBREVIATIONS
BZ CBZ ETH FBM GBP GVG LCS LEV LTG MHD OXC PB PGB PHT PRM RUF TGB TPM VPA ZNS Benzodiazepine Carbamazepine Ethosuximide Felbamate Gabapentin Vigabatrin Lacosamide Levetiracetam Lamotrigine Monohydroxy derivative Oxcarbazepine Phenobarbital Pregabalin Phenytoin Primidone Rufinamide Tiagabine Topiramate Valproic acid Zonisamide

bidity and even mortality but are also associated with financial costs, which exceeded $175 billion in 2000.8 More than 100,000 hospitalized patients die from ADRs each year with AEDs among the most frequent offending drugs.6 Spontaneous reports of AEs are voluntarily reported postmarketing to MedWatch, the US Food and Drug Administration Safety Information and Adverse Event Reporting Program,9 and have been studied by individual investigators.1 The Physicians Desk Reference stratifies AEs that may be potentially harmful by a black-box warning, warning, or precautions in order of decreasing intensity.9,10 Acute and Chronic Acute AEs often include those affecting the CNS and the gastrointestinal (GI) system.3 Acute AEs include both symptomatic AEs and drug-induced (idiosyncratic) hypersensitivity syndromes. Acute dose-dependent AEs (overdose) may be intentional but are more often iatrogenic, occurring with higher serum levels, although acute AEs may reflect drug sensitivity independent of dose.3,4 Switching AEDs is advisable when acute AEs are encountered with an AED that interferes with ones quality of life.4 If AEs are mild and intermittent, increasing the frequency of dosing may be helpful to maximize tolerability to AEs.4 AEDs with short half-lives (t1/2) may have better tolerability with 3-times-daily versus routine 2-times-daily dosing. The initial choice of the AED should be selected with chronic AEs in mind since many patients continue AEDs for years.4 Chronic AEs are unique to an individuals level of tolerability.7 Chronic AEDs may affect multiple organ systems, causing neuropsychiatric, GI, hematologic, metabolic, endocrine, dermatologic, and systemic consequences (Table 7-3).1,3,4,1016 A differential effect between individual AEDs has been known for more than 20 years with phenobarbital (PB) and primidone

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older aromatic ring configurations.5 The major sites of AED activity target the sodium and calcium (T-, L-, N- subtypes) channels, decrease glutamate-aspartate neurotransmission, and increase aminobutyric acid (GABA) neurotransmission. While many structures and processes, including neurons, ion channels, receptors, and glia, are involved, the overall clinical effect is designed to favor neuronal inhibition over excitation.1,4 ADVERSE EFFECTS More than two million people in the United States each year develop serious AEs from drugs.6 AEs may be acute or chronic, dose dependent or idiosyncratic to reflect clinical toxicity (Table 7-2). One survey of more than 5000 Europeans receiving AEDs found that 88% experienced at least one AE, while a US study of 200 outpatients reported 83% with at least two AEs, although 50% were on polytherapy.7 AEs not only cause morContinuum Lifelong Learning Neurol 2010;16(3)

TABLE 7-2

Antiepileptic Drugs and Their Common Acute, Chronic, and Idiosyncratic Adverse Effects Acute Adverse Effects

Antiepileptic Drug

Chronic Affects
Hyperactive (children), learning, depression Neuropathy, gum hyperplasia, hirsutism, low thyroid, osteoporosis
Behavioral changes, irritability, nervousness, confusion, psychosis

Idiosyncratic Affects
Rash, connective-tissue disorders, hepatoxicity SJS, lupuslike reactions, pseudolymphoma, hepatitis, blood dyscrasias SJS, lupuslike reaction, blood dyscrasias, hepatoxicity, generalized Sz increase SJS, hepatoxicity, aplastic anemia/low white blood cell count Liver/pancreatic failure, low platelets, birth defects SJS, aplastic anemia, hepatic failure

Phenobarbital (PB)/ Sedation, fatigue, ataxia, primidone (PRM) blurry vision Phenytoin (PHT) Somnolence, dizziness, ataxia, blurry vision, N Somnolence, N/V/diarrhea, dizziness, anorexia, abdominal pain Somnolence, fatigue, rash, diplopia, dizziness, ataxia, N/V Abdominal pain, N/V/ diarrhea, hyperammonemia Headache, N/V, rash

Ethosuximide (ETH)

Carbamazepine (CBZ) Valproic acid (VPA) Felbamate (FBM)

Behavioral changes, low sodium, weight gain/edema Tremor, alopecia, amenorrhea, weight gain Anorexia, weight loss, insomnia

Gabapentin (GBP)/ Somnolence, fatigue, ataxia, pregabalin (PGB) dizziness, blurry vision Lamotrigine (LTG) Topiramate (TPM) Dizziness, diplopia, blurry vision, N/V, ataxia Somnolence, dizziness, fatigue, anorexia, N

Weight gain, pedal edema, None established behavior changes (children), creatine phosphokinase Headache, insomnia, incoordination, tic Mental slowing, speech and memory disturbance, paresthesias, weight loss, renal stones Abnormal thinking, tremor, nervousness Hyponatremia (elderly), insomnia, headache Irritability, anger, anxiety, depression Lost appetite, speech, paresthesias, weight loss, renal stones, apathy Incoordination, ataxia, shortened QT interval Headache, tremor, ataxia, incoordination, depression SJS, TEN, DRESS, myoclonic Sz increase Hepatic failure, oligohidrosis, glaucoma

Tiagabine (TGB) Oxcarbazepine (OXC) Levetiracetam (LEV) Zonisamide (ZNS) Rufinamide (RUF) Lacosamide (LCS) Vigabatrin (GVG)

Headache, dizziness, fatigue, N/V, abdominal pain Somnolence, dizziness, fatigue, N/V Somnolence, dizziness, fatigue, N Somnolence, ataxia, N/V, dizziness, fatigue Somnolence, N/V, headache, dizziness, fatigue Somnolence, dizziness, N, fatigue, diplopia

Nonconvulsive spike-wave stupor SJS, TEN None established Rash, hypersensitivity reactions (sulfa) Rash, DRESS None established Permanent visual field loss, psychosis

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Somnolence, dizziness, fatigue Weight gain, edema, blurred vision, arthralgia neuropathy, depression

N = nausea; SJS = Steven-Johnson syndrome; V = vomiting; Sz = seizure; TEN = toxic epidermal necrolysis; DRESS = drug reactions with eosinophilia and systemic symptoms.

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TABLE 7-3

Pharmacology and Pharmacokinetics of the Antiepileptic Drugs Important for Adverse Events and Drug Interactions Protein Binding
50% 90% 75% 40% 90% NS 8098% NS NS NS NS <15% 55% Low <20% NS NS NS

AED
Phenobarbital (PB)/ primidone (PRM) Phenytoin (PHT) Carbamazepine (CBZ) Oxcarbazepine Valproic acid (VPA) Ethosuximide (ETH) Benzodiazepine (BNZO) Gabapentin (GBP) Pregabalin (PGB) Levetiracetam (LEV) Lacosamide (LCS) Lamotrigine (LTG) Topiramate (TPM) Zonisamide (ZNS) Rufinamide (RUF) Vigabatrin (GVG)

Seizure Types
P, G P, G Partial Partial P, G Absence seizures P, G Partial Partial P, G Partial P, G P, G Partial P, G P, G

Chemical Structure
Aromatic; weak acid Aromatic; weak acid Aromatic; tricyclic Aromatic Carboxylic acid Succinimide Benzodiazepine GABA analogue GABA analogue Novel Novel Triazine Sulfamated monosaccharide Sulfonamide Triazole GABA analogue

MOA
Na+ Na+ Na+ Na+ Mixed Ca++ L-type Cl Ca++ L-type Ca++ L-type SV2A Na+ CRP-2 Na+ Mixed Mixed Na+ GABA

AED = antiepileptic drug; MOA = mechanism of action; PK = pharmacokinetics; CYP = cytochrome P450 enzyme; P = partial; G = generalized; Na+ = sodium; A = administered as monotherapy; C = co-administered with enzyme-inducing AEDs; IR = immediate release; MHD = monohydroxy derivative; UDPGT = uridine diphosphate glucuronosyltransferase; NS = not significant; GABA = -aminobutyric acid.
a b

Gabapentin absorption is saturable and dose limiting. Valproic acid unbound fraction is dose-dependent and nonlinear at higher doses.

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Data from French,1 Perucca and Meador,3 French and Pedley,4 Patsalos and colleagues,13 French and colleagues,15 Patsalos and Perruca,24 Levy and colleagues,26 and Thorneycroft and colleagues.38

(PRM) more commonly associated with AEs than carbamazepine (CBZ) and phenytoin (PHT).17 Overall, while the newer AEDs may demonstrate better tolerability, larger clinical trials reveal similar efficacy between first- and secondgeneration AEDs when used in PWE.1,3,18 When potentially long-term consequences for PWE, either direct (eg, weight gain) or indirect (eg, teratogenesis) and an alternative AED exist, a change in drug should be considered and pursued.4
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Dose-Related In most cases AEs are dose-dependent and explained by high or increasing serum concentrations.3,4 Dose-related AEs can adversely affect quality of life but are often reversible with dosage adjustment.3,7 To assist with taxonomy, AEs have been grouped into common classes, based on prior categories from the literature, that affect cognitive/coordination, mood/emotion, sleep, weight/cephalgia, and tegument/mucosa.7 Weight increases

PK
Linear Nonlinear Linear; autoinduce Linear Linear usually Linear Linear Linear; absorbed Linear Linear Linear Linear Linear Linear Linear Linear

Liver Metabolism
Yes Yes Yes; epoxide Yes; MHD Yes Yes Yes No No No; hydrolysis Yes; 2C19 Yes Yes Yes Yes No

CYP
Yes 2C9 (19) Yes 2C9 (19) Yes 3A4 + + Yes 3A4 Yes (varies) No No No No No Yes Yes 3A4 No No

Other Paths
+ + + Yes Yes UDPGT B-oxide No Yes (some) No No No No Yes UDPGT (1A4) No + Acetylation Yes; hydrolysis No

Level (g/L)
1540 100 412 337 50100 4060 Variable 2v10 19 337 ? 418 220 1040 ? ?

Half-Life (Hours)
46136 PRM 312 2224 A 16 C 16 (IR) 1535 816 4060 A 3040 C 2095 57 Renal 6 Renal 68 Renal 13 1260 24 6070 6v10 5v7 Renal

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may occur with valproic acid (VPA), gabapentin (GBP), pregabalin (PGB), and CBZ, while topiramate (TPM) and zonisamide (ZNS) may lead to weight loss. Some AEDs (eg, VPA and TPM) have dose-related beneficial effects on headache.10 Clinical toxicity may occur if too high a total daily dose is used, too large a single dose is used, or a relative decrease in renal clearance occurs. Some patient populations, such as those that are drug na ve, may be more susceptible to AEs simply from a lack of prior exposure; others may demonstrate repeated drug sensitivities.1,3 AEDs with narrow therapeutic windows or toxic metabolites or the use of polypharmacy may predispose to dose-related AEs (Table 7-3).1,3,4,7 This translates to a higher risk of dose-related AEs at peaks and breakthrough seizures during trough levels. Dosing intervals that are too long (eg, daily PB or PHT) can have problems of tolerability when a single bolus is
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given, especially with higher baseline levels.11 Dosing schedules can have a major impact on AED tolerability. Most AEs that affect the CNS are dose related.3 Some AEDs are associated with somnolence, fatigue, cognitive slowing, dizziness, blurry vision, and ataxia. These actions may be related to a predominance of GABA-ergic inhibitory neurotransmission induced by drugs such as barbiturates, benzodiazepines (BZs), VPA, GBP, tiagabine (TGB), and vigabatrin (GVG),19 although in many cases comparative AED trials have demonstrated that the second-generation AEDs may be better tolerated.5 Many important favorable and unfavorable psychiatric effects of the AEDs result from the variety of pharmacologic mechanisms of action.9 Some AEDs have positive psychotropic effects (eg, VPA and lamotrigine [LTG]) with proven benefit in mood disorders.10 Selecting AEDs with sedating qualities may be a better choice for patients with baseline activated profiles (eg, insomnia, agitation, anxiety, racing thoughts, weight loss).19 GABA neurotransmission facilitated by AEDs, such as the barbiturates, benzodiazepines, VPA, GBP (perhaps PGB), and GVG may be considered.19 Patients with baseline sedation or anhedonic profiles (hypersomnia, fatigue, apathy, depression, sluggish cognition, weight gain) may benefit from antiglutamatergic AEDs.19 Serious psychiatric AEs may occur with TPM, LEV, ZNS, LCS, and GVG,10 leading to suicidal ideation, suicidal behavior, and even completed suicide. On December 16, 2008, the US Food and Drug Administration (FDA) released a warning of an increased risk of suicidality from AEDs.9 From 199 placebo-controlled trials, 11 AEDs were evaluated, including CBZ, VPA, felbamate (FBM), GBP, LTG, TPM, TGB, LEV, oxcarbazepine (OXC), ZNS, and PGB, and were found to be associated with twice the risk of suicidal behavior or ideation (0.43%) compared to patients
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receiving placebo (0.22%).9 The risks were observed as early as 1 week through 24 weeks and were greatest in those with a previous suicide attempt. In general, suicide risk is higher in PWE,9,17,19 and all patients should be closely monitored when starting a new AED. Therapeutic Drug Measurement The routine use of therapeutic drug levels has not yet been demonstrated to be associated with a beneficial influence on reduction in AEs or seizure control.11 Interpretation of plasma AED levels is best when individualized and when it conforms to known AED pharmacology.1 The therapeutic range is a guide reflecting a drug level at which a majority of treated patients will become seizure free without AEs. The newer AEDs have a wider therapeutic range, which probably reflects greater individual variability.3,17 Some newer AEDs have very short t1/2 with the efficacy based on a pharmacodynamic effect produced by binding to targeted brain receptors as opposed to the pharmacokinetic effect mediated through obtaining therapeutic serum concentrations.12 Serum levels therefore may neither reflect the true CNS activity nor detect idiosyncratic AEs.20 Infrequent dosing with short t1/2 AEDs may create substantial level fluctuation up to 50% or more.1,11 Comparison of levels at similar times of the day allows for a direct comparison (peak or trough). Extended-release formulations should cause little variation in blood levels so that deviations greater than 20% to 25% suggest noncompliance.11 Measurement of unbound (free) fraction may be helpful in dynamic states of polypharmacy, in the setting of hypoalbuminemia, in elderly patients, or during pregnancy when pharmacokinetics are altered or change over time. The potential discordance between total and free levels for highly protein-bound AEDs may help explain clinical toxicity and normal

levels.11,20 Levels may be misleading in polypharmacy because ranges are based on monotherapy.11 However, therapeutic drug measurement is recommended during pregnancy with CBZ, LTG, and PHT (Level B), as well as LEV and OXC (Level C) given the association with increased AED clearance and the subsequent possibility of breakthrough seizures.21 Idiosyncratic Idiosyncratic AEs are rare events that are not dose related, are host dependent, and are frequently serious, leading to death in less than 0.1% of the general population and in 10% of all ADRs.20 They are unpredictable responses, usually involving immune-mediated responses or toxic effects from drug-drug interactions. Despite brain targets, AEDs may worsen seizures (eg, absence and myoclonic from PHT and CBZ/OXC) or not prevent them (eg, generalized seizures with ethosuximide [ETH]) in some PWE.3 They produce parkinsonism, encephalopathy (even stupor), and reversible pseudoatrophy of the brain (eg, VPA),3,10,20 or create movement disorders such as choreoathetosis (eg, PHT), tic (eg, LTG), and myoclonus (eg, GBP or PGB).20 The common idiosyncratic AEs include skin, GI, and bone marrow involvement.8 Drug-related rashes are the easiest and most frequent idiosyncratic AE to recognize. They may occur in 5% to 15% of people22 and range in severity from mild transitory maculopapular eruptions to potentially life-threatening hypersensitivity syndromes. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, and drug reaction with eosinophilia and systemic symptoms (DRESS) require immediate AED discontinuation to prevent a fatal outcome. Death occurs in up to 40% of symptomatic patients with a diffuse maculopapular erythematous rash in addition to fe-

ver, arthralgias, lymphadenopathy, and multiorgan failure.22 Most serious rashes occur within the first 4 months of treatment, and all the first-generation AEDs, including PB, PRM, PHT (2 to 5 per 10,000), CBZ (1 to 4 per 10,000), ETH, and VPA, have been associated with serious skin reactions prompting hospitalization.20 Newer AEDs, with the exception of LTG, are less likely to produce serious rash.23 A cross-reactivity of 40% to 60% for the occurrence of recurrent rash may be seen when switching aromatic AEDs (eg, PHT to CBZ).23 Genetic markers are increasingly playing a role in predicting patient-specific risks.20,24 Gastrointestinal AEs usually involve the liver, given the high exposure to AED concentrations after absorption. Hepatotoxicity caused by chronic direct hepatocellular damage or as an immunemediated ADR may occur. Fortunately, acute or subacute hepatitis is rare (0.1% or less for VPA, PHT, CBZ, and PB).3 VPA has the best known association with liver toxicity, occurring in 1:37,000 (monotherapy), but 3 times more often with polytherapy. The greatest risk is in children younger than 2 years of age with inborn errors of metabolisms (eg, urea cycle) on polytherapy (risk is 1:500).3,20 Abdominal pain, vomiting, mental status changes, and seizure increase typically occur. FBM is now a third-line AED because it is associated with fatal hepatotoxicity in 1:26,000 to 1:34,000 exposures.20 LTG hepatotoxicity associated with DRESS has shown reversibility.20 Fatal hemorrhagic pancreatitis is another rare serious idiosyncratic AE in 1:40,000 on VPA, and the diagnosis is suggested by abdominal pain, vomiting, diarrhea, and anorexia (amylase may be normal).20 Prognosis is worst with DRESS, and rechallenge is contraindicated.20 In drug-induced blood dyscrasias, reduced survival and apoptosis during hematopoiesis occur in one or more cell lines.25 Leukopenia commonly occurs with CBZ, although it is not linked to
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immunosuppression in most cases. Severe leukopenia with a white blood cell count of less than 2500 cells/L of blood (or absolute neutrophil count less than 1000) will rarely be encountered and necessitate discontinuing therapy.20 FBM has a risk of aplastic anemia caused by reactive metabolites in 1:5000 to 1:10,000.20 Aplastic anemia is the most serious blood dyscrasia and occurs 9 times more commonly in PWE on AEDs (PHT, ETH, CBZ, VPA, FBM) versus controls (9.2% versus 0.8%).25 CBZ has been associated with a risk of aplastic anemia estimated between 1:50,000 and 1:200,000.20 Anemia and macrocytosis are not uncommon in association with folate deficiency with enzyme-inducing antiepileptic drugs (EIAEDs), although pure red cell aplasia may also occur with VPA and LTG.10 Conditions mimicking lymphoma (pseudolymphoma) may occur with EIAEDS (eg, PHT) and lead to mistreatment with chemotherapy.20 Special Populations Age is an important factor in the occurrence of ADRs, although differences in sex and race may be encountered.26 Dermatologic AEs, such as StevensJohnson syndrome due to LTG,23 and systemic ADRs, including fatal hepatotoxicity due to VPA, may be increased in children younger than 2 years of age.20 Faster rates of cytochrome P450 enzyme (CYP)-mediated reactions in infants and children compared with adults may lead to greater production of reactive metabolites, increasing susceptibility in younger age groups.5 Sex may influence susceptibility to AEs. Females may be at higher risk for some drug-induced skin reactions.23 Teratogenicity is unique to females and has demonstrated a differential effect between AEDs. Avoiding VPA (Case 7-1) and AED polytherapy in pregnancy is recommended (Level B).21 Additionally, avoiding PHT and PB should be considered as well because of their association
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with an increased risk of congenital malformations, compromised cognitive outcomes, and potential risks associated with small for gestational age births, and Apgar scores less than 7.21 CBZ and LTG have been associated with cleft palate but appear safer with regard to major congenital malformation and cognitive outcome.21 Patients with cognitive and learning disabilities have demonstrated a lower risk for skin reactions, which is postulated to be due to their greater environmental exposure and subsequent reduction in their threshold for potential allergenic reactions.23 Older individuals with or without cognitive impairments have lower clearance rates of AEDs; AEs may be encountered at routine doses so that lower mean doses are necessary.3 DRUG INTERACTIONS Many drug interactions occur between various AEDs and other drugs. Pharmacokinetic properties differ and mathematically express the time course of a drug in the body during absorption, distribution, metabolism, and excretion. When taken regularly, AEDs are administered based on elimination t1/2. Most AEDs in clinical use have t1/2 of 7 to more than 24 hours, allowing dosing one to three times daily27; however, these parameters are commonly altered during combination drug therapy (polytherapy). PHARMACOKINETICS The duration and intensity of an AED is determined by the rate at which it is metabolized. AEDs are first absorbed by passive diffusion and pass into the enterohepatic circulation. Antacids may limit gut absorption (eg, PHT and GBP). Protein binding is competitive and varies among AEDs. Introduction of an AED that causes displacement from protein-binding sites may result in toxic AEs (Case 7-2). Distribution balances absorption and excretion. AED structure,

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Case 7-1
A 28-year-old female athlete with depression and juvenile myoclonic epilepsy presented for evaluation. She was taking PHT, fluoxetine, and birth control pills after failing treatment with phenobarbital and CBZ. While she was on PHT, daytime fatigue, gingival hyperplasia, and hirsutism were noted, with incomplete control of generalized tonic-clonic seizures (serum level of 18 g/L). Valproic acid was substituted for phenytoin but required relatively high doses for seizure freedom (level = 100 g/L). Initial sleepiness, dizziness, and incoordination resolved after fluoxetine dose reduction. She became pregnant despite known risks of birth defects and delivered a healthy son (later diagnosed with a learning disability). A second pregnancy was complicated with fetal spina bifida and hydrocephalus (Figure 7-1). She opted for termination, her marriage dissolved, and she was temporarily lost to follow-up. About 7 years later she re-presented in a new relationship. Trials of LTG (seizures), LEV (anger), and TPM (excessive weight loss) were unsuccessful. Because she was allergic to sulfa, treatment with zonisamide was not attempted. FIGURE 7-1 Cross-sectional level 2 ultrasonography depicted in the second trimester of an She requested uncomplicated intrauterine pregnancy return to demonstrating fetal hydrocephalus after valproic acid treatment for juvenile myoclonic epilepsy. treatment with VPA. Comment. This case illustrates the importance of AEs in drug-sensitive individuals. Common symptomatic dose-related AEs to PHT and idiosyncratic AEs to VPA resulting in birth defects were encountered. Fluoxetine interactions with PHT and VPA were overcome with dose reduction.

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GI integrity, and alteration in pharmacokinetics may promote AEs. Elimination of a drug from the body begins with metabolism and biotransformation of the AED into water-soluble metabolites prior to excretion. GBP, PGB, LEV, and GVG are predominantly eliminated by renal clearance. Compromised renal function will prolong t1/2, leading to AED toxicity. For most AEDs the rate of clearance is proportional to the serum concentration (first-order kinetics), although rarely other AEDs (eg,

PHT) possess a nonlinear (zero-order kinetics) dose relationship. Hepatic Metabolism: Inducing Antiepileptic Drugs The cytochrome P450 monooxygenase system is the most important hepatic metabolic pathway. Drugs or conditions that stimulate enzyme synthesis (induction) increase the rate of metabolism of another drug and reduce the duration and intensity of the drugs desired effect. PB, PRM, PHT, and CBZ
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Case 7-2
A 36-year-old man with generalized epilepsy with febrile seizures plus was refractory to multiple AEDs and became HIV positive. He was taking VPA and PHT and presented to epilepsy clinic because of sleepiness, daytime fatigue, dizziness, and intermittent blurry vision in the morning. Serum AED concentrations were therapeutic with PHT 15 g/L and VPA 75 g/L. LTG was started and titrated to 50 mg/wk, but then he called after hours reporting a rash. He was seen in clinic the following day. On inspection, he had multifocal papular and pustular lesions primarily on his back (Figure 7-2) but sparing his legs in a distribution uncharacteristic of drug rash. He later described that he had been outside in the yard the day before while wearing only long pants when he had a seizure and fell into an ant mound. LTG was continued with seizure reduction and resolution of PHT toxicity (free levels PHT 3.2 g/L; VPA 12 g/L) FIGURE 7-2 A 36-year-old man with epilepsy developed a rash over his torso after being treated after LTG-PHT with lamotrigine. On closer inspection a substitution. The multifocal papular-pustular lesion typical of insect bites (ants use of a vagus in this case) was evident. nerve stimulator led to further overall improvement. Comment. This case illustrates the importance of identifying (and validating) AEs from drug interactions in PWE. The initial dose-related AEs were caused by the drug interaction between PHT and displacement by VPA resulting from protein binding. Replacing an AED combination with another combination containing favorable pharmacodynamic interactions led to seizure improvement and resolution of AEs in this patient. Examination of a PWE that develops a skin rash is critical to avoid assuming that every cutaneous eruption seen during drug treatment is caused by the AED.

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are potent EIAEDs, while TPM and OXC are weak inducers. Three families (CYP 1-3) with 7 CYP P450 isoenzymes, commonly induced by EIAEDs, include CYP 1A2, CYP 3A4, CYP 2C9, and CYP 2C19 (Table 7-4).27 Infrequently AEDs (eg, CBZ) facilitate their own metabolism (autoContinuum Lifelong Learning Neurol 2010;16(3)

induction) or are associated with active metabolites (eg, 10,11 epoxide of CBZ, 10-monohydroxy derivative of OXC, PB as a metabolite of PRM). EIAEDs often reduce concentrations of the coadministered AED by up to 50%.20 For example, LTG has a t1/2 of 24 hours in

TABLE 7-4

Hepatic Enzyme Effects and Elimination Pathways of Antiepileptic Drugs Overall Renal Antiepileptic Excretion Drug Effect
25% (PB)/ Induction 50% (PRM) <5% <1% 10% <3% 60%70% 25% 20%25% >90% 66% 35% >90% <4% 60%70% None/None None/Decr Induction Induction Induction (weak) Inhibition Inhibition (weak) Induction (weak) Inhibition Induction None None None None None Induction (weak) Inhibition (weak) None None/None

Antiepileptic Drug Activated Pathways

Phenobarbital (PB)/ primidone (PRM) Phenytoin (PHT) Carbamazepine (CBZ) Lamotrigine (LTG) Valproic acid (VPA) Topiramate (TPM) Oxcarbazepine (OXC) Ethosuximide (ETH) Gabapentin (GBP)/ Pregabalin (PGB) Levetiracetam (LEV) Zonisamide (ZNS) Lacosamide (LCS) Rufinamide (RUF) Vigabatrin (GVG) LCS None/Decr GVG None/None CYP: 2C, 1A2, 2B6, 3A4 EH, and UDPGT CYP: 2C, 1A2, 2B6, 3A4 EH, and UDPGT CYP: 3A4, 1A2, 2B6, 2C EH, and UDPGT UDPGT CYP: 2C9, EH, and UDPGT CYP: 2C19 CYP: 3A4 CYP: 2C19 CYP: 3A4 None None None None None CYP: 3A4 CYP: 2E1 None None/Decr

+/ Decr/Decr None/None None/None None/None

CYP = cytochrome P450 enzyme; EH = epoxide hydrolase; UDPGT = uridine diphosphate glucuronosyltransferase.
Adapted from Pollard JR, Delanty N. Antiepileptic drug interactions. Continuum Lifelong Learning Neurol 2007;13(4):91105. Copyright # 2007, American Academy of Neurology. All rights reserved.

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monotherapy; however, in the presence of an EIAED, the t1/2 falls to 12 hours, potentially necessitating a change in dosing from 2 times daily to 3 times daily. AEDs may also compete as a substrate with other medicines. Through CYP-mediated EIAEDs, steroids (hormonal contraceptives), immunosuppressants (cyclosporin), anticoagulants (warfarin), anesthetics (vecuronium), and bronchodilators (theoph-

ylline) may have lowered plasma concentrations that compromise the drugs effect, producing an undesirable outcome (eg, seizures, unwanted pregnancy, transplant rejection, or clotting). Hepatic Metabolism: Inhibition Inhibition of biotransformation through competitive enzyme binding prevents normal metabolism that may lead to a
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precipitous rise in serum concentration of the affected drug.13 In contrast to the weeks that are required for induction, inhibition can have immediate clinical effects leading to AEs from drug interactions within 1 day. For example, when VPA is added to PB, an increase in serum levels of about 30% quickly occurs because of P450 enzyme inhibition, necessitating PB dose reduction. Some AEDs have a mixed effect; for example, OXC raises PHT (inhibition) but lowers CBZ (induction) levels despite similar pharmacology of the two drugs.10,13 When some AEDs (ie, RUF or FBM) are used, variable interactions are expected based on the adjunct drug utilized. For example, RUF may increase the clearance of CBZ and LTG with lower serum concentrations, decrease the clearance of PHT and PB with higher concentrations, and have its own clearance significantly decreased by VPA, which often leads to clinical toxicity. When these complex drug-specific interactions occur, predicting the precise clinical response is more challenging and the need for dosing modification anticipated.27 Therefore, drug interactions may require preventive dosage adjustments. Coadministration of non-neurologic drugs is equally important to consider when combining AEDs that use the same metabolic pathways. For example, some of the macrolide antibiotics, such as erythromycin or clarithromycin, may act to inhibit the CYP system (CYP 3A4 isoenzyme) and thereby result in a dramatic rise in CBZ levels and leading to clinical toxicity.13 Hepatic Metabolism: Other Pathways Other active hepatic metabolic enzyme systems include the uridine diphosphate glucuronosyltransferase (UDPGT) system and are best exemplified by LTG, but others may share this pathway (Table 7-2). When UDPGT-metabolized AEDs are combined with CYP EIAEDs, higher doses become necessary. When
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UDPGT-inhibiting AEDs, such as VPA (as little as 500 mg/d), are combined with LTG, inhibition of LTG metabolism occurs within hours and may lead to clinical toxicity.13 The microsomal enzyme epoxide hydrolase is another important hepatic system. Other metabolic pathways include cytosolic reduction (OXC), extrahepatic hydrolysis (LEV, RUF), and enzymatic catabolism (FBM by esterases and fosphenytoin by phosphatases). Physiologic and pathologic factors can also influence drug metabolism with variations dependent on age, race, sex differences, genetic predisposition, and individual biological variation (eg, GI transit time).13,15,26,27 Naturally occurring foodstuffs may also induce or inhibit CYP activity. Grapefruit may inhibit CYP3A4-mediated metabolism of AEDs (eg, CBZ) leading to clinical toxicity.28 St-Johns-wort may alter AED metabolism (Table 7-5), and genetic testing to detect physiologic variants in the CYP 450 isoenzymes is becoming available.15 Cigarette smoking can induce the CYP 450 system (1A2) and accelerate the metabolism of AEDs by the same isoenzyme.14 Additional pathologic conditions, such as liver and kidney disease, can affect drug metabolism. PHARMACODYNAMIC RESPONSES Pharmacodynamic drug interactions occur when the pharmacologic actions of an AED increase the therapeutic or toxic effects of another drug independent of serum concentration.14 Drug load is higher with polytherapy, and the risk for cumulative AEs is greater when duplicating similar neurotoxic profiles. Synergism in polytherapy has been shown, although the risks of overtreatment are significant.13 AEDs and non-AEDs with sedative/ hypnotic profiles, including barbiturates, BZs, GBP, PGB, and TPM, may produce additive CNS depressant effects. Some pharmacodynamic drug interactions can have mixed risks and benefits. VPA plus

TABLE 7-5

Table Showing Two-Way Interaction Between Antiepileptic Drugsa Phenobarbital/ Primidone Phenytoin
None/none None/decr None/decr None/none None/decr +/ Incr/decr +/ Incr/decr None/none None/decr None/none Incr/decr None/decr

Antiepileptic Drug
Gabapentin (GBP) Lamotrigine (LTG) Topiramate (TPM)

Valproic Ethosuximide Carbamazepine Acid

None/none None/none None/none None/none None/none None/none None/none None/none None/none None/none None/decr None/decr None/incr MHD None/none None/decr None/none Decr/decr None/decr None/none None/none +/ Decr/incr None/decr None/none None/none None/none None/none None/incr None/none None/none

Oxcarbazepine (OXC) Incr/decr Levetiracetam (LEV) Zonisamide (ZNS) Pregabalin (PGB) Rufinamide (RUF) Lacosamide (LCS) Vigabatrin (GVG) None/none None/decr None/none Incr/decr None/decr None/none

+/ Decr/decr None/none

Decr = decrease; Incr = increase; MHD = monohydroxy derivative.

a

The box has the first anticipated effect of a second-generation antiepileptic drug (AED) on a first-generation AED. The second effect is of the firstgeneration AED on the second-generation AED.

LTG, for example, may demonstrate synergy relative to efficacy but increase safety and tolerability concerns.3 Because empiric information is not possible to represent the many AED combinations, a rational approach to drug combinations has been suggested based on AED mechanism of action,29 although the precise knowledge of AED mechanisms and pathophysiology is limiting.30 Isobolographic analyses are graphic constructs that compare the individual dose-response curves of two drugs relative to a median effective dose (ED50) or toxic dose (TD50).31 A line of additivity (isobole) is developed to graphically connect the TD50 (or ED50) for two drugs in anticipation of estimating additive AEs based on preclinical results. Experimental results are plotted in a fixed relationship (eg, 1:1, 1:3, or 3:1 dose ratios), and when AEs are additive, the points of the dose pairs fall on the isobole and therefore have no interaction. When they fall below the line of additivity, the two drugs act with a greater effect (supra-additive) than

either one alone, and AEs would be expected when toxicity is the metric. LTG and OXC demonstrate supra-additivity for neurotoxic effects in combination.31 INDIVIDUAL ANTIEPILEPTIC DRUGS The profile of AEs may not only drive physician-directed drug selection but also influence patient-related compliance with side effects or fears of side effects potentially limiting therapy.30 Many effective AEDs currently in use are subdivided into first-generation AEDs and second-generation AEDs. Selection of the ideal drug for each individual patient should be based on a number of factors including AEs and drug interactions (Table 7-5).2,32 First-Generation Antiepileptic Drugs Enzyme inducing. PHT has one of the most problematic drug interaction profiles because of its high protein binding (greater than 90%) and significant enzyme
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induction of the CYP P450 enzyme system. Major metabolic pathways include CYP 2C9 isoenzyme induction, but whites can have a mutant CYP 2C9*2 and CYP 2C9*3 allele that reduce enzymatic activity, potentially leading to toxicity.26 Polymorphisms in the gene for CYP 2C19 may also be responsible for interindividual variability in expressing AEs resulting from PHT. EIAEDs have variable and unpredictable effects on PHT, either increasing or decreasing PHT because of competition for the same enzyme sites for metabolism. Valproate raises levels of PHT by displacing it from protein-binding sites and inhibiting CYP 2C9 metabolism. GVG and EIAEDs may lower PHT, while OXC and TPM may raise levels. PHT, as an EIAED, decreases levels of many other AEDs and non-AEDs. Interaction with non-AEDs utilizing similar isoenzymes (Table 7-6) would be anticipated. CBZ may cause drug interactions because of induction of the hepatic P450 enzyme system (Table 7-5) and an active metabolite.2 CBZ increases clearance of other AEDs (eg, ETH, LTG, TGB, TPM, ZNS), leading to reduction by 20% to 50%; doubling of the dose of the coadministered drug may be needed. PRM may be reduced with conversion to increased PB levels. FBM decreases CBZ but increases the epoxide intermediate, while CBZ decreases monohydroxy derivative (MHD) when given with OXC. With the addition of VPA, a small decrease in CBZ may occur with an increase in the epoxide concentration through epoxide hydrolase inhibition; some patients note AEs. Propoxyphene, erythromycin, diltiazem, verapamil, and cimetidine interact with CBZ by inhibiting CYP 2C19 and cause a notable increase in CBZ and with clinical AEs. PB remains in widespread use today because of its low cost and long safety history. Primidone is grouped with PB as a barbiturate AED, and the clinical use is similar to PB in epilepsy management.18 PB/PRM added to other EIAEDs
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may produce an increase, decrease, or no change in the blood levels of other AEDs as a result of enzyme induction and inhibition variability that occurs with combination use. In addition, the effect on PB by EIAEDs is variable. With EIAEDs a decrease in PRM may occur with an increase in PB. Increases in PB may occur with the coadministration of VPA through inhibition of glucuronidation and hydroxylation of PB, and, therefore, PB/PRM doses should be reduced by 20% to 30% when VPA is added on to PB. The addition of PB/PRM to other non-AEDs may result in enhancement of the hepatic clearance of the coadministered drugs. Warfarin may require a 25% to 50% increase in dosage with up to 4 weeks to induce or de-induce hepatic enzymes; frequent monitoring of the international normalized ratio may identify important changes. Enzyme Inhibiting Significant displacement of unbound free VPA fractions occurs with hypoalbuminemia or coadministration with aspirin or heparin, which inhibit the  -oxidation pathway. Valproate inhibits CYP 2C9, UDPGT (1A3 and 2B7), and epoxide hydrolase, delaying hydroxylation and clearance of other AEDs, including PB, the 10,11 epoxide intermediary of CBZ, and LTG, resulting in elevated concentrations and the potential for AEs (Case 7-2). Tricyclic antidepressants and some retroviral agents may be increased through VPA-mediated inhibition, although fluoxetine seems to inhibit VPA via glucuronidation to increase VPA levels.10 VPA is affected by EIAEDs with a marked decrease in serum concentrations that may require an increase in dosage. Metabolized; Noninducer, Noninhibitor Drug interactions with ETH have been limited since it is neither an enzymeinducing nor enzyme-inhibiting AED. ETH may reduce VPA, although interactions

TABLE 7-6

Table Showing Antiepileptic Drugs and Nonantiepileptic Drugs That Are Inducers and Inhibitors of the Major Cytochrome P450 Hepatic Isoenzymes Responsible for Antiepileptic Drug Metabolism and Their Substrates Substratesa

CYP 450 Isoenzyme Inducers

2C9

Inhibitors

Phenobarbital (PB)/ Valproic acid (VPA) Antiepileptic drugs primidone (PRM) Phenytoin (PHT) Carbamazepine (CBZ) Rifampin Chloramphenicol Fluconazole Fluoxetine PB, PHT, VPA Nonantiepileptic drugs Celecoxib, ibuprofen, naproxen, piroxicam, diclofenac Fluvastatin, losartan, zidovudine Warfarin, tolbutamide Zidovudine

Fluvoxamine Miconazole Sulfaphenazole 2C19 PB/PRM PHT CBZ Rifampin Cimetidine Felbamate (FBM) Fluvoxamine Omeprazole Oxcarbazepine (OXC) (weak) Topiramate (TPM) (weak) 3A4 PB/PRM PHT Cimetidine Cyclosporin

Antiepileptic drugs Diazepam, PHT, lacosamide Nonantiepileptic drugs Tricyclic antidepressants, citalopram, moclobemide Omeprazole, propranolol Warfarin

151

Antiepileptic drugs CBZ, ethosuximide, felbamate (FBM), tiagabine, zonisamide, rufinamide (RUF) some benzodiazepines Nonantiepileptic drugs Tricyclic antidepressants, clozapine, haloperidol

CBZ FBM (weak)

Diltiazem Erythromycin

continued on next page

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TABLE 7-6

Continued

CYP 450 Isoenzyme Inducers

3A4 Glucocorticoids

Inhibitors

Substratesa

Fluconazole

Selective serotonin reuptake inhibitors, mirtazapine Risperidone, olanzapine Statins, diltiazem, nifedipine Verapamil, quinidine, amiodarone Alfentanil, astemizole, ketoconazole Clarithromycin, erythromycin Cyclosporin, tacrolimus, indinavir Steroids (birth control pills), fentanyl Tamoxifen, cyclophosphamide

OXC (weak) Rifampin RUF St-Johns-wort TPM (weak)

Fluvoxamine Grapefruit juice Indinavir Ketoconazole Nefazodone Propoxyphene Ritonavir Verapamil

CYP = cytochrome P450 enzyme; TCA = tricyclic antidepressants.

a

Bolded items are subcategories of substrates that utilize the corresponding CYP 450 isoenzyme for metabolism.

Adapted with permission from Patsalos PN, Perruca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003;2(6):347356. Copyright # 2003, Elsevier.

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have been variable. ETH is extensively metabolized by the hepatic CYP system (primarily 3A4), and other EIAEDs may reduce ETH by 20% to 50%, necessitating dose increases. Antituberculosis drugs, when coadministered with ETH, may have different effects (Table 7-5). Nearly 24 BZs exist for treatment although, despite similar mechanisms of action, a variety of uses, tolerability, and PK and PD interactions exist. They are not significant enzyme inducers or inhibitors. However, some BZs are metabolized by the CYP 450 hepatic isoenzymes (eg, diazepam: 2C19 and CYP 3A4); others undergo glucuronidation (eg, lorazepam). Drugs that inhibit
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those isoenzymes (eg, TPM, OXC, FBM [2C19]) and cimetidine, ketoconazole, fluoxetine, omeprazole, and verapamil (3A4) may lead to increased sedation. Pharmacodynamic interactions are common, and the pharmacology of drugs with CNS depressant effects (eg, other BZs, PB, PRM, TPM, and GBP/PGB) and sedating non-AED, including alcohol, may augment sedative AEs.10 Second-Generation Antiepileptic Drugs No hepatic metabolism interactions. GBP is an effective adjunctive therapy for partial-onset seizures. PGB is 4 to 6 times more potent than GBP with a

similar mechanism of action. No protein binding and lack of appreciable hepatic metabolism make GBP/PGB favorable selections for patients with multiple drug regimens or compromised hepatic function. Drug interactions are not expected to occur from GBP or PGB. Pharmacodynamic interactions with CNS depressants that promote sedation or dependency (PGB is schedule V) and angiotensin-converting enzyme inhibitors that might lead to angioedema deserve caution. Significant drug interactions with LEV on other drugs, or from other drugs on LEV, are not expected to occur in adults.33 A non-significant effect of EIAEDs (22% increased clearance of LEV) was seen in pediatric patients.10 Metabolized (CYP 450 cyclooxygenase); noninducer, noninhibitor. Drug interactions with ZNS have minimal effects on other drugs metabolized by the CYP P450 system. However, serum concentrations of ZNS are reduced twofold when given with EIAEDs. VPA may prolong the t1/2 of ZNS. ZNS may also be inhibited by coadministering medications that inhibit the CYP 3A4 pathway, leading to prolongation of the serum t1/2 and the potential for AEs. No drug interactions are anticipated with LCS and AEDs or common nonneurologic agents.34 Population pharmacokinetics results showed small reductions (less than 20%) in LCS when coadministered with EIAEDs, although changes in dose are not expected.10 Metabolized (glucuronidation); noninducer, noninhibitor. LTG is altered by EIAEDs such as PHT, CBZ, and PB/PRM with reduction of the t1/2 to 12 to 14 hours and may prompt LTG dose increases or change in dose frequency. Precipitous increases of LTG leading to clinical toxicity may occur when VPA is coadministered with LTG as a result of metabolic inhibition, and t1/2 prolongation (up to 60 hours) may occur. Adding VPA to LTG is more dif-

ficult than reversing drug initiation since simultaneous LTG dose reduction and VPA dose initiation are required. Hormonal contraceptives are also subject to interaction with LTG. Lamotrigine does not significantly affect hormonal contraception despite weak enzyme induction (UDPGT). One-sided interaction by hormonal contraception on LTG reduces the t1/2 to potentially lower levels that could be clinically significant unless doseadjustments are anticipated (Table 7-7).13,21 Metabolized; (weak) inducer and inhibitor. TPM has minimal drug interactions with weak induction and inhibition of CYP metabolism with a differential effect on other drugs. As an inhibitor of CYP 2C19, PHT serum concentrations may increase by 40% and become significant because of PHT zeroorder pharmacokinetics. AEs during TPM
TABLE 7-7 Effect of Antiepileptic Drugs on Hormonal Contraception Interaction
Yes Yes Yes Yes; LTG reduced Yes; at 200 mg/d or more Yes No No No No No No No Noa

Antiepileptic Drug
Phenobarbital (PB)/primidone (PRM) Carbamazepine (CBZ)/ oxcarbazepine (OXC) Phenytoin (PHT) Lamotrigine (LTG) Topiramate (TPM) Rufinamide (RUF) Valproic acid (VPA) Ethosuximide (ETH) Gabapentin (GBP)/pregabalin (PGB) Benzodiazepine (BZO) Levetiracetam (LEV) Zonisamide (ZNS) Lacosamide (LCS) Vigabatrin (GVG)
a

153

Interactions with hormonal contraception are unknown but not anticipated to occur.

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initiation to PHT should prompt PHT therapeutic drug measurement. EIAEDs may reduce levels of TPM by up to 40%,2 necessitating a dosage adjustment. As a weak inducer of CYP 3A4, VPA may decrease TPM by 10% to 15%, but this is unlikely to be clinically significant. However, hormonal contraception containing ethinyl estradiol drops approximately 20% at a TPM dose of 200 mg/d. While no significant changes in norethindrone plasma concentrations have been shown, caution is recommended at doses greater than 200 mg/d, and at least 50 ug of ethinyl estradiol is recommended with monitoring for resolution of breakthrough bleeding.13 OXC has mixed functions with induction and inhibition of the CYP 450 system and unlike CBZ does not undergo autoinduction. Because of inhibiting properties (CYP 2C19) at greater than 1200 mg/d, an elevation of PHT plasma concentrations up to 40% may be observed. Because of its enzyme-inducing effects (CYP 3A4) OXC interacts with hormonal contraception, reducing the circulating estrogen and progesterone components and making unplanned pregnancy possible.1 OXC does not have the same drug interactions as CBZ with VPA, erythromycin, clarithromycin, cimetidine, warfarin, or propoxyphene. Metabolized (extrahepatic); (weak) inducer and inhibitor. RUF may slightly increase the clearance of CBZ and LTG as a weak inducer (CYP 3A4) while slightly decreasing the clearance of PHT and PB as a weak inhibitor (CYP 2E1). The use of VPA may increase RUF concentrations by 70% and be clinically significant.31 EIAEDs will decrease RUF concentrations. Patients should be warned that RUF may reduce the efficacy of hormonal contraception. Less Commonly Used Antiepileptic Drugs FBM is a third-line AED because of safety issues, and regularly obtaining complete
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blood count and liver function tests is recommended if the drug is used. It has a mixed mechanism of action and mixed pharmacokinetics as both an inhibitor (CYP 2C19) and an inducer (3A4) of the CYP 450 enzyme system. As a CYP inhibitor, FBM increases PHT and VPA; as an inducer, it decreases CBZ preferentially, increasing the 10,11 epoxide intermediary. This requires simultaneous dose adjustments of other coadministered AEDs during FBM titration. TGB has received limited use as a narrow-spectrum adjunctive AED for PWE and partial-onset seizures. TGB is metabolized by the CYP 450 (3A4) system and is not an inducer or an inhibitor of the CYP 450 system. Therefore, TGB is not expected to have significant effects on other AEDs or non-AEDs. EIAEDs increase TGB clearance, potentially requiring higher doses when coadministered. GVG is a newly approved AED for infantile spasms (1 month to 2 years) and adults with refractory complex partial seizures. Progressive and permanent bilateral concentric visual field constriction may occur. Periodic testing and withdrawal are recommended in patients who do not show substantial clinical benefit after 1 to 3 months. GVG increases the clearance of CBZ. Lower plasma concentrations are anticipated with both CBZ and PHT. PREVENTION One of the major challenges in AED use is preventing, eliminating, and managing adverse effects.1 Patients may now be identified as at risk even before treatment with the use of pharmacogenetic studies that address the rate of metabolism or risk for certain AEs.26 A reliable biomarker has been found for PWE of Asian ancestry and should be considered (inherited variant of human leukocyte antigen [HLA]-B*1502) before treatment with CBZ or OXC to minimize the potential risk of serious

rash.34 Genetic biomarkers for specific CYP isoenzymes, including 2C9, 2C19, 2D6, and 1A2, may measure levels of activity and differ between populations of individuals.26 Patients with slow, intermediate, and extensive metabolic rates may be identifiable.20 Slow metabolizers require lower than recommended doses, whereas more commonly rapid metabolizers may require doses that are higher than FDA-approved limits. Genetic CYP polymorphisms may account for individual variation seen during drug metabolism with deficiencies occurring in 1% to 30% of people depending on their ethnic backgound26 and allelic variation seen in 59% of patients from drugs that produce ADRs.6 Further differences in AED metabolism include individual variation between slow and fast acetylators with slow acetylators more prone to dose-dependent toxicity. Predicting drug interactions by identifying drugs with additive mechanisms of action is the easiest way to prevent drug interactions and AEs when combining drugs.35 AED interactions may be prevented by a knowledge of pharmacokinetics (Table 7-5). Anticipating non-AED drug interactions (Table 7-6) caused by EIAEDs that may affect antihypertensives (eg, propranolol, verapamil), immune modulation (eg, cyclosporine), corticosteroid use (eg, dexamethasone), chemotherapy (eg, vincristine), and anticoagulation (eg, warfarin) among others is critical to avoid

potentially catastrophic results36 in PWE.13 Understanding drug interactions with hormonal contraception deserves special mention since it potentially involves two people when birth control is compromised (Table 7-7).37 COMMENTS Increasingly greater numbers of effective AEDs exist or are in the process of becoming available in the future. New advances in genomics, pharmacogenetics, molecular biology, and biomarkers will potentially yield more beneficial and cost-effective health care by targeting AED therapy not only for efficacy, but also for safety and tolerability.38 Neuronal mechanisms of AEs and drug interactions could potentially serve as the basis for new compound development in the future with improved patient results.7 To date, the FDA has relied primarily on analysis of case reports from health care professionals or pharmaceutical manufacturers to identify AEs. It is to be hoped that a national sentinel system will have the potential to identify and quantify AEs with unprecedented power and speed in the future.39 The drug interactions capable of producing potentially life-threatening results in patients requiring AEDs should be clinically anticipated, based on the pharmacology of the AEDs used. Minimizing polytherapy and selecting AEDs with favorable pharmacokinetic profiles may help minimize drug interactions and AEs.

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4. French JA, Pedley TA. Initial management of epilepsy. N Engl J Med 2008;359(2): 166176. 5. Loscher W, Schmidt D. New horizons in the development of antiepileptic drugs: innovative strategies. Epilepsy Res 2006;69(3):183272. 6. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):12001205. 7. Perucca P, Carter J, Vahle V, Gilliam FG. Adverse antiepileptic drug effects: toward a clinically and neurobiologically relevant taxonomy. Neurology 2009;72(14): 12231229. 8. Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: updating the cost-of-illness model. J Am Pharm Assoc 2001;41(2):192199. 9. US Food and Drug Administration. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. www.fda.gov/Safety/MedWatch. Updated August 4, 2009. Accessed August 5, 2009. 10. 2009 Physicians Desk Reference. 63rd ed. Montvale, NJ: Thomson PDR, 2009. 11. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313(3):145151. 12. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblended randomized controlled trial. Lancet 2007;369(9566):10001015. 13. Patsalos PN, Berry DJ, Cloyd JC, et al. Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008;47(7):12391276. 14. Ketter TA, Post RM, Theodore WH. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology 1999;53(5 suppl 2):S53S67.

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