Interactions between antiepileptic drugs
Review
Clinically important drug interactions in
epilepsy: general features and interactions
between antiepileptic drugs
Philip N Patsalos and Emilio Perucca
There are two types of interactions between drugs,
pharmacokinetic and pharmacodynamic. For antiepileptic
drugs (AEDs), pharmacokinetic interactions are the most
notable type, but pharmacodynamic interactions involving
reciprocal potentiation of pharmacological effects at the
site of action are also important. By far the most
important pharmacokinetic interactions are those involving
cytochrome P450 isoenzymes in hepatic metabolism.
Among old generation AEDs, carbamazepine, phenytoin,
phenobarbital, and primidone induce the activity of several
enzymes involved in drug metabolism, leading to decreased
plasma concentration and reduced pharmacological effect
of drugs, which are substrates of the same enzymes
(eg, tiagabine, valproic acid, lamotrigine, and topiramate).
In contrast, the new AEDs gabapentin, lamotrigine,
levetiracetam, tiagabine, topiramate, vigabatrin, and
zonisamide do not induce the metabolism of other AEDs.
Interactions involving enzyme inhibition include the increase
in plasma concentrations of lamotrigine and phenobarbital
caused by valproic acid. Among AEDs, the least potential
interaction is associated with gabapentin and levetiracetam.
Lancet Neurology 2003; 2: 34756
Up to 70% of patients diagnosed with epilepsy can be made
seizure-free by currently available antiepileptic drugs
(AEDs) given as monotherapy. In patients who are
unresponsive to monotherapy, however, a combination of
two or more AEDs may be needed to optimise seizure
control. However, combination therapy may have adverse
effects.1 When two or more AEDs are used, the potential for
drug interactions is substantial, and such interactions may
have a profound effect on patients wellbeing.2,3
In this review we summarise the main mechanisms of
drug interactions, highlight the most important interactions
between AEDs, and provide guidelines on how to anticipate,
prevent, and detect adverse interactions between AEDs.
Interactions between AEDs and drugs prescribed for the
management of other disorders will be discussed in part two
of this article, which will appear in a future issue of The
Lancet Neurology.
Mechanisms of drug interaction
There are two basic types of drug interactions,
pharmacokinetic and pharmacodynamic.2,4 Pharmacokinetic
interactions involve a change in the absorption, distribution,
or elimination of the affected drug and account for most of
the interactions reported to date because they are easily
identifiable by a change in drug concentrations in the
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plasma. Pharmacodynamic interactions, although also
important, are less well recognised and are commonly
inferred to explain apparently drug-induced changes in
clinical status that cannot be attributed to a
pharmacokinetic mechanism.5
Pharmacokinetic interactions
Effects on drug absorption
Although, AED interactions affecting gastrointestinal
absorption are rare, such interactions can be important in
some cases; one example is impaired phenytoin absorption,
which is seen when the drug is given together with certain
nasogastric feeds.38 Phenytoin is thought to bind to
constituents of the feeding formulas to form insoluble
complexes that cannot be absorbed.
Transporters, particularly P-glycoprotein, may play an
important part in the gastrointestinal absorption of many
drugs,9 including digoxin,10 ciclosporin,11,12 paclitaxel,13 and
docetaxel.14 There is evidence that P-glycoprotein is involved
in mediating the efflux of some AEDs, including
carbamazepine,15,16 phenytoin,16,17 phenobarbital,18 lamo-
trigine,18 and felbamate18 across the bloodbrain barrier.
Overexpression of P-glycoprotein in brain tissue may limit
the penetration of AEDs to their sites of action and is being
investigated as a potential mechanism of pharmaco-
resistance in epilepsy.19 Whether P-glycoprotein also plays
an important part in the gastrointestinal absorption of AEDs
is, however, unknown. The distribution of P-glycoprotein
varies substantially across the gastrointestinal tract, and its
role and contribution to drug absorption may differ among
drugs.20 Moreover, the expression of P-glycoprotein in the
gut, and in other tissues, can be induced and inhibited by
other drugs, many of which are also inducers and inhibitors
of the cytochrome P450 (CYP) isoenzyme CYP3A4.2124 On
the basis of these observations, some AED interactions that
are currently ascribed to other mechanisms could be
mediated by modulation of P-glycoprotein function at the
level of drug absorption or distribution, although this
possibility has not been investigated.
PNP is at the Department of Clinical and Experimental Epilepsy,
Institute of Neurology, University College London, London, UK, and
EP is at the Clinical Pharmacology Unit, Department of Internal
Medicine and Therapeutics, University of Pavia, Pavia, Italy.
Correspondence: Dr Philip N Patsalos, Pharmacology and
Therapeutics Unit, Department of Clinical and Experimental
Epilepsy, Institute of Neurology, Queen Square, London, WC1N
3BG, United Kingdom. Tel +44 (0)20 7837 3611 ext 3830;
fax +44 (0)20 7278 5616; email p.patsalos@ion.ucl.ac.uk
347
 Review
Displacement from plasma proteins
Interactions affecting drug distribution may involve
competition between two drugs for binding sites on plasma
proteins. In quantitative terms, these interactions can be
important only for drugs that are over 90% bound to plasma
proteins and, among AEDs, only phenytoin, valproic acid,
diazepam, and tiagabine belong to this category.25 Although
diazepam and tiagabine can be displaced from plasma
proteins by concurrently given highly protein-bound
drugs, they are present in the circulation at nanomolar
concentrations and they would not be expected to
displaceto a substantial extentcompounds with
therapeutic concentrations in the micromolar range.26
The implications of plasma-protein displacement
interactions are frequently misunderstood. Only the
unbound (free) fraction is in equilibrium with the receptor
sites, and only this fraction has pharmacological effects. The
amount of drug that is displaced from plasma proteins is
generally a tiny fraction of the total amount of drug
present in the body and is therefore insufficient to produce a
change in clinical response.27,28 As a rule, displacement
from plasma proteins results in a fall in total drug
concentration (as the displaced drug redistributes rapidly
into tissues and undergoes compensatory elimination), but
the concentration of free drug and magnitude of the
pharmacological effect are practically unchanged. Plasma-
protein binding interactions are clinically relevant for only a
few drugs with exceptional pharmacokinetic characteristics
and none of the available AEDs.29 Nevertheless, awareness of
these interactions is important for interpretation of plasma
drug concentration measurements in clinical practice. In
fact, in the presence of a plasma-protein binding interaction,
therapeutic and toxic effects will occur at low total drug
concentrations; patient management may benefit from the
monitoring of free (unbound) drug concentrations.30,31
The most commonly occurring plasma-protein
displacement interaction involving AEDs is the displacement
of phenytoin by valproic acid:32,33 typically, this interaction
results in a fall in total phenytoin concentration although
the concentration of freepharmacologically active
phenytoin does not change.34 In some patients, a small rise in
the concentration of free phenytoin may be seen owing
to inhibition of phenytoin metabolism by valproic acid,35
or a transient displacement of phenytoin from tissue
binding sites.36 This rise may be associated with signs of
phenytoin toxicity. The most important implication of this
interaction, however, is that in the presence of valproic
acid the therapeutic range of total plasma phenytoin
concentrations is shifted towards lower values. The clinical
significance of a recently reported in vitro concentration-
dependent displacement of tiagabine by valproic acid is
unknown.37
Metabolic drug interactions
By far the most important pharmacokinetic interactions
with AEDs are those related to induction or inhibition of
drug metabolism.38,39
Enzyme induction, which is caused mainly by
carbamazepine, phenytoin, and barbiturates (ie, pheno-
348 THE LANCET Neurology Vol 2 June 2003
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Interactions between antiepileptic drugs
barbital and primidone), is increased synthesis of drug-
metabolising isoenzymes in the liver40 and in other tissues.41
The increase in enzyme activity results in an increase in the
rate of metabolism of drugs that are substrates of those
enzymes, and thus, the plasma concentration of those drugs
is decreased. If the affected drug has an active metabolite,
induction can result in increased metabolite concentration
and possibly an increase in drug toxicity. As enzyme
induction requires synthesis of new enzymes, the time
course of induction (and its reversal upon removal of the
inducer) is dependent on the rate of enzyme synthesis
and degradation and the time to reach steady-state
concentrations of the inducing drug. Thus, the time course
of induction is generally gradual and dose-dependent.40,42,43
Enzyme inhibition is the phenomenon by which a drug
or its metabolite blocks the activity of one or more drug-
metabolising enzymes, which results in a decrease in the rate
of metabolism of the affected drug. This, in turn, will lead to
high plasma concentrations of the drug and, possibly,
clinical toxicity. Inhibition is normally competitive and
dose-dependent, and begins as soon as sufficient
concentrations of the inhibitor are achieved. Substantial
inhibition is seen within 24 h of the inhibitor being given in
many cases.38,39
In recent years, characterisation of the isoenzymes
involved in the metabolism of individual drugs has greatly
improved the prediction of metabolic interactions.26,38,39 At
the level of CYP, four isoenzymes (CYP3A4, CYP2D6,
CYP2C9, and CYP1A2) are known to have a role in the
metabolism of 95% of all drugs, and 5070% of all drugs
might be substrates of CYP3A4.44 Three isoenzymes
(CYP2C9, CYP2C19, and CYP3A4) are of particular
importance in relation to AED interactions. Databases of
substrates, inhibitors, and inducers of different CYP
isoenzymes provide an invaluable resource in helping to
anticipate potential interactions (table 1). For example,
knowledge that carbamazepine is an inducer of CYP3A4
suggests that it will reduce the plasma concentration
of CYP3A4 substrates such as ethosuximide, tiagabine,
steroid oral contraceptives, and dihydropyridine calcium
antagonists.2 Likewise, the ability of erythromycin to inhibit
CYP3A4 explains the clinically important rise in plasma
carbamazepine concentration.2
Uridine glucuronyl transferases (UGTs) catalyse
glucuronidation; there are two distinct families, UGT1 and
UGT2, with eight isoenzymes identified in each. The
UGT1A4 isoenzyme plays an important part in the
glucuronidation of lamotrigine,45 whereas the isoenzyme
isoforms that catalyse the glucuronide conjugation of
valproic acid have not yet been identified. Like CYP-
mediated reactions, glucuronidation is susceptible to
inhibition and induction.
Effects on renal excretion
Drugs that undergo extensive renal elimination in
unchanged form may be susceptible to interactions affecting
the excretion process, particularly when it involves active
transport mechanisms or when the ionised state of the drug
is highly sensitive to changes in urine pH.46 Agents that cause
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 Interactions between antiepileptic drugs
Review

alkalinisation of urine increase the elimination of
phenobarbital by reducing the reabsorption of this acidic
drug from the renal tubuli,47 an effect that can be exploited
therapeutically in severe cases of barbiturate intoxication.
There are no other examples of major AED interactions
involving changes in renal excretion.
Pharmacodynamic interactions
Pharmacodynamic interactions take place directly at the site
of action and result in a modification of pharmacological
effect without any change in drug concentrations in the
plasma. The effects of the interacting drugs can be additive
(when they equal the sum of the effects of the individual
drugs), synergistic (when the combined effects are greater
than expected from the sum of individual effects), or
antagonistic (when the combined effects are less than
additive).48 Pharmacodynamic interactions can be adverse
(when the increase in toxicity is greater than any gain in
anticonvulsant activity) or beneficial (when therapeutic
effects are additive or synergistic, and toxic effects are less
than additive). To some extent, these interactions can be
explained through knowledge of the mechanisms of action

Table 1. Substrates, inhibitors, and inducers of the major (CYP) isoenzymes involved in drug metabolism*
Isoenzymes Substrates Inhibitors Inducers
CYP1A2 Psychotropic drugs: amitriptyline, clozapine, clomipramine, Ciprofloxacin Carbamazepine
fluvoxamine, haloperidol, imipramine, mirtazapine, olanzapine Clarithromycin Phenobarbital
Miscellaneous: caffeine, theophylline, Fluvoxamine Phenytoin
paracetamol, tacrine, tamoxifen, R-warfarin Furafylline Primidone
Cigarette smoke
Charcoal-grilled meat
Rifampicin
CYP2C9 AEDs: phenobarbital, phenytoin, valproic acid Valproic acid Carbamazepine
Non-steroidal anti-inflammatory drugs: celecoxib, diclofenac, Amiodarone Phenobarbital
ibuprofen, naproxen, piroxicam Chloramphenicol Phenytoin
Miscellaneous: fluvastatin, losartan, tolbutamide, torasemide, Fluconazole Primidone
S-warfarin, zidovudine Fluoxetine Rifampicin
Fluvoxamine
Miconazole
Sulfaphenazole
CYP2C19 AEDs: diazepam, S-mephenytoin, methylphenobarbital, phenytoin Felbamate Carbamazepine
Psychotropic drugs: amitriptyline, clomipramine, imipramine, Oxcarbazepine (weak) Phenobarbital
citalopram, moclobemide Topiramate (weak) Phenytoin
Miscellaneous: omeprazole, propranolol, proguanil, R-warfarin Cimetidine Primidone
Fluvoxamine Rifampicin
Omeprazole
Ticlopidine
CYP2D6 Psychotropic drugs: amitriptyline, citalopram, chlorpromazine, Cimetidine No inducer known
clomipramine, clozapine, imipramine, desipramine, fluoxetine, Fluoxetine
fluphenazine, fluvoxamine, haloperidol, mianserine, mirtazapine, Haloperidol
nortriptyline, olanzapine, paroxetine, perphenazine, risperidone, Paroxetine
thioridazine, venlafaxine, zuclopenthixol Perphenazine
Cardiovascular drugs: alprenolol, bufuralol, encainide, flecainide, Propafenone
metoprolol, propafenone, propranolol, timolol, pindolol Quinidine
Miscellaneous: codeine, debrisoquine, dextromethorphan, Thioridazine
phenformin, tramadol
CYP2E1 AEDs: felbamate, phenobarbital Disulfiram Alcohol
Miscellaneous: dapsone, ethanol, halothane, isoniazid, chlorzoxazone Isoniazid
CYP3A4 AEDs: carbamazepine, ethosuximide, tiagabine, zonisamide, Cimetidine Carbamazepine
some benzodiazepines (eg, alprazolam, midazolam, triazolam) Ciclosporin A Phenobarbital
Psychotropic drugs: amitriptyline, clomipramine, clozapine, haloperidol, Diltiazem Phenytoin
imipramine, sertraline, nefazodone, mirtazapine, risperidone, Erythromycin Primidone
ziprasidone, olanzapine Fluconazole Oxcarbazepine
Cardiovascular drugs: amiodarone, atorvastatin, diltiazem, felodipine, Fluvoxamine Topiramate
lovastatin, nimodipine, nifedipine, quinidine, simvastatin, verapamil Grapefruit juice Felbamate
Miscellaneous: alfentanil, astemizole, cisapride, clarithromycin, Indinavir Glucocorticoids
ciclosporin A, cyclophosphamide, erythromycin, fentanyl, Itraconazole St Johns Wort
glucocorticoids, itraconazole, ketoconazole, indinavir, Ketoconazole Rifabutin
oral contraceptive steroids, sildenafil, tacrolimus, tamoxifen, terfenadine Nefazodone Rifampicin
Dextropropoxyphene
Ritonavir
Troleandomycin
Verapamil

*The list is intended for guidance only and should not be regarded as exhaustive. Prediction of drug interactions based on this table should be with caution, because enzyme
induction and inhibition may coexist and because many other factors (Panel) are involved in determining whether a clinically significant drug interaction will or will not occur.
These inducers are weaker or may induce CYP3A4 isoenzymes only in certain tissues.

THE LANCET Neurology Vol 2 June 2003 http://neurology.thelancet.com 349

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 Review
Factors important to the clinical implications of a
potential metabolic interaction
The nature of the interaction at the enzyme site
Is it a substrate, an inhibitor or an inducer?
The spectrum of isoenzymes that are induced or inhibited by the
interacting agent
The potency of the inhibition/induction
A potent effect will result in a more ubiquitous interaction affecting
many/most patients.
The concentration of the inhibitor/inducer at the isoenzyme site
Drugs that achieve low concentrations in blood may never reach the
concentration threshold necessary to elicit an interaction.
The extent of metabolism of the substrate through the particular
isoenzyme
If the affected enzyme causes only a small proportion of the drugs
clearance, inhibition will not result in a substantial interaction.
However, a very large increase in the activity of the affected enzyme
could substantially affect the total clearance of the drug.
The saturability of the isoenzyme
Isoenzymes that are saturable at drug concentrations encountered
clinically are more susceptible to significant inhibitory interactions.
The route of administration
For drugs showing extensive first-pass metabolism, any change in the
plasma concentration of the drug caused by enzyme induction or inhibition
will be much greater after oral than after parenteral administration.
The presence of pharmacologically active metabolites
Such metabolites complicate the outcome of a potential interaction as
they may be enzyme inducers or inhibitors.
The therapeutic window of the substrate
Interactions affecting drugs with a narrow therapeutic window are more
likely to be of clinical significance.
The concentration of the affected drug at baseline
Any change in plasma drug concentration will have important effects if
the baseline concentration is near the threshold of toxicity or near the
threshold required to produce a desirable therapeutic effect.
The genetic predisposition of the individual patient
Patients with deficiency of a genetically polymorphic isoenzyme
(eg, CYP2D6 or CYP2C19) will not have interactions mediated by
induction or inhibition of that isoenzyme.
The susceptibility and the sensitivity of the individual in relation to
adverse effects
Elderly patients are more susceptible to interactions because they are
more likely to receive multiple medications and are more sensitive to the
adverse effects of drugs.
The probability of the potential interacting drugs being prescribed
together
Combinations that are unlikely to be prescribed are of little clinical
relevance.
of individual drugs. For example, the similarity in
mechanisms of action between carbamazepine and
oxcarbazepine may explain why neurotoxic effects are more
common when oxcarbazepine is used with carbamazepine
than when used with other AEDs.49
Susceptibility to drug interactions
The probability of a drug interaction occurring and the
associated clinical consequences are dependent on several
factors (panel). Apart from the characteristics of the drugs,
patient-related factors have an important role. For example,
350
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Interactions between antiepileptic drugs
the effect of a metabolic interaction on a specific CYP
isoenzyme can vary among patients in relation to genetic and
environmental factors that determine the contribution of that
isoenzyme to overall drug elimination. Age is another
important source of variability. Most AED interactions
described in this article have been reported in adults, but they
are expected to happen in children as well. The magnitude
and clinical significance of such interactions, however, may
differ between children and adults owing to age-related
pharmacokinetic and pharmacodynamic variations. In
particular, the contribution of different CYP and UGT
isoenzymes to drug metabolism (and the consequent
implications of inducing or inhibiting these isoenzymes)
undergoes important changes during development.50 CYP-
dependent metabolism is low at birth (about 5070% of adult
levels), but by 23 years of age activity exceeds adult levels.51,52
Although glucuronidation is deficient at birth, owing to low
concentrations of UGTs, adult levels of activity are reached by
34 years.53 Furthermore, children may exhibit higher levels of
induction than adults.54,55 Changes in metabolic profile are
also seen in elderly people. For example, the decline in
metabolic capacity commonly observed in old age is greater
for pathways catalysed by CYP enzymes than for reactions
involving glucuronide conjugation.56,57 Elderly people have
been reported to show a reduced responsiveness to enzyme
induction.58,59 However, a recent study showed no evidence of
this reduction in elderly patients treated with carbamazepine
or phenobarbital.60 Finally, elderly people tend to be more
sensitive to the adverse effects of centrally active drugs, and a
given change in plasma concentrations of AEDs caused by a
drug interaction may have a greater clinical effect in them
than in young people.61
Interactions between AEDs
Interactions mediated by enzyme induction
Carbamazepine, phenytoin, phenobarbital, and primidone
are potent inducers of various CYP isoenzymes (table 1) and
they also induce UGT and epoxide hydrolases.2,25,38,62,63 As
a result, these compounds stimulate the metabolism of
other AEDs, most notably valproic acid,64,65 tiagabine,66
ethosuximide,67 lamotrigine,6870 topiramate,71 zonisamide,72
oxcarbazepine and its active monohydroxy-metabolite,73
felbamate,74 and many benzodiazepine drugs.75,76 (table 2).
The metabolism of carbamazepine can be stimulated by
phenytoin or barbiturates.60,7779
The feature common to all these interactions is a
pronounced decrease in the steady-state plasma
concentration of the affected drug. For example, the plasma
concentration of valproic acid can be reduced on average
by 76%, 49%, and 66% in patients who are also treated
with phenobarbital, phenytoin, and carbamazepine,
respectively.63 In some cases, these interactions have small
clinical consequences because the loss of efficacy caused by
the decreased concentration of the affected drug is
compensated for by the independent anticonvulsant effect of
the enzyme-inducing agent. In other cases, however, the
decrease in plasma concentration of the affected drug has
adverse effects on seizure control (figure 1), and an increase
in dose is then indicated (figure 2). The plasma
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 Interactions between antiepileptic drugs
Review

Table 2. Expected changes in plasma concentrations when an AED is added to a pre-existing regimen
Pre-existing AED
AED added PB PHT PRM ETS CBZ VPA OXC LTG GBP TPM TGB LEV ZNS VGB FBM
PB PHT NCCP ETS CBZ VPA H-OXC LTG TPM TGB ZNS FBM
PHT PB PRM ETS CBZ VPA H-OXC LTG TPM TGB ZNS FBM
PB
PRM NCCP PHT ETS CBZ VPA ? LTG TPM TGB ZNS FBM
ETS NE VPA NE NE NE NE NE NE NE NE NE
CBZ PHT PRM ETS VPA H-OXC LTG TPM TGB ZNS NE FBM
PB
VPA PB PHT* PB ETS CBZ-E LTG TPM NE
OXC PB PHT ? ? CBZ LTG NE ? ? NE ? NE ?
LTG NE NE NE NE NE NE NE NE
GBP NE NE NE NE NE NE NE NE NE
TPM PHT NE VPA ? ? NE ? NE ? NE ?
TGB NE NE NE NE NE NE NE NE NE
LEV NE NE NE NE NE NE NE
ZNS NE NE CBZ ? NE NE NE NE NE ?
VGB PB PHT PRM NE CBZ NE NE NE NE NE NE NE NE
PB
FBM PB PHT ? ? CBZ VPA NE ? ? NE ?
CBZ-E

PB=phenobarbital; PHT=phenytoin; PRM=primidone; ETS=ethosuximide; CBZ=carbamazepine; VPA=valproic acid; OXC=oxcarbazepine; LTG=lamotrigine; GBP=gabapentin;
TPM=topiramate; TGB=tiagabine; LEV=levetiracetum; ZNS=zonisamide; VGB=vigabatrin; FBM=felbamate; H-OXC=10-hydroxy-oxcarbazepine (active metabolite of OXC); CBZ-
E=carbamazepine-10,11-epoxide. NE=none expected; *free (pharmacologically active) concentration may increase; NCCP=not commonly coprescribed; =No change; =a
minor (or inconsistent) decrease in plasma concentration; =a clinically significant decrease in plasma concentration; =a minor (or inconsistent) increase in plasma concentration;
=a clinically significant increase in plasma concentration

concentration of carbamazepine, valproic acid, tiagabine,
and lamotrigine are most significantly affected by enzyme
induction, and doses of these drugs may need to be
increased.62 Clinically important stimulation of lamotrigine
metabolism has also been described in patients also treated
with methsuximide.80,81
When enzyme induction leads to formation of active
metabolites, the consequence of the interaction may be,
paradoxically, a potentiation of the affected drug. One
possible example of this effect is the stimulation of
primidone metabolism in patients also treated with
phenytoin, phenobarbital, or carbamazepine.82 Because
primidone is converted partly to phenobarbital, this
interaction may result in enhanced production of the latter
metabolite and increased pharmacological effects. Although
stimulation of valproic-acid metabolism by enzyme
inducing AEDs typically results in decreased plasma
concentrations and effectiveness of valproic acid, this
interaction may also lead to increased formation of
hepatotoxic metabolites, which may explain why patients
taking phenytoin, phenobarbital, and carbamazepine are
more susceptible to valproate-induced liver toxicity.83
Because enzyme induction is reversible, effects can
appear when the inducing agent is discontinued or
substituted with another AED. Under these circumstances,
the rate of metabolism of the affected agent will gradually
decrease, and its plasma concentration may become toxic.
After regimen change, careful monitoring of drug
concentrations in the plasma and of clinical response is
recommended to determine any need for dose adjustments
as early as possible.30,31,84,85
Among second generation AEDs, gabapentin,86
vigabatrin,87,88 levetiracetam,89 lamotrigine,90 topiramate,91
tiagabine,92,93 and zonisamide 94 have no enzyme inducing
effects on the metabolism of other AEDs. In one study,
topiramate reduced plasma lamotrigine concentrations by
4050% in four of seven patients.95 However, a larger
study did not replicate this finding.96 Oxcarbazepine
stimulates the metabolism of lamotrigine (although less
than carbamazepine),80 felbamate decreases plasma
carbamazepine concentration (while increasing the
concentration of the active metabolite carbamazepine-
10,11-epoxide),97 whereas vigabatrin may decrease the
plasma concentration of phenytoin through an unidentified
mechanism.98100 These interactions are probably of limited
clinical significance, although an increase in lamotrigine
dose requirements may occur in patients who are also being
given oxcarbazepine.80
Interactions mediated by enzyme inhibition
Valproic acid as an enzyme inhibitor
Among commonly used AEDs, valproic acid is the most
notable inhibitor of drug metabolism; its most common
effect is to increase the plasma concentrations of both
phenobarbital101 and lamotrigine.102,103 On average, the
increase in plasma phenobarbital concentration after dosing
with valproic acid is 3050%, but interindividual variability
is large and a reduction in phenobarbital (or primidone)
dose by up to 80% may be required to avoid side-effects
particularly sedation and cognitive impairment.101 Although
the increase in plasma phenobarbital concentrations is
mainly related to inhibition of CYP isoenzymes (probably
CYP2C9 or CYP2C19), the effect of valproic acid on
lamotrigine metabolism involves inhibition of the UGT1A4
enzyme, which glucuronates lamotrigine.39 The inhibition
of lamotrigine metabolism is already maximum at
valproic-acid doses within the typical target range
(500 mg/day in an adult)104 and involves a substantial

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 Review Interactions between antiepileptic drugs

AED monotherapy

Unsatisfactory control in about 30% of patients

Addition of second AED

Improved seizure control Adverse effects Seizure worsening No change in seizure control

Concentrations have Measure plasma concentrations of drug* Concentrations

increased or decreased as expected

Possible pharmacokinetic drug interaction Possible pharmacodynamic drug interaction

Inhibition of the drug metabolising enzymes can cause

high concentrations of either the added or the baseline Synergistic effects can improve seizure
drug and result in either improved seizure control or control or increase adverse effects
increased adverse effects
Or Or

Induction of the drug metabolising enzymes can cause

low concentrations of either the baseline drug to cause Antagonistic effects can result in seizure
worsening of seizure control or of the added drug to worsening or no change in seizure control
cause no change in seizure control

If appropriate, adjust the dose on the basis If appropriate, adjust doses on the basis
of plasma concentrations of drug of clinical response

Figure 1. Effect of AED interactions on therapeutic outcome. *Plasma concentrations of drugs should be measured at the time of the clinical event (eg,
patient complaining of side-effects) and drug dose adjusted accordingly. If the clinical status of the patient is unaffected, plasma drug concentrations
should be measured under steady-state conditions, ideally just before ingestion of the next dose (trough). Reprinted with permission from Epilepsia,
International League Against Epilepsy.2

lengthening of lamotrigine half-life, from 30 h to about
60 h.103 As a result of this, lamotrigine dose requirements are
notably reduced in patients given valproic acid.62 The use of
lamotrigine in a patient already being given valproic acid
should be done with caution: the dose should be started
low (25 mg on alternate days, in adults) and increased
slowly to avoid problems related with a fast increment in
plasma lamotrigine concentration, particularly skin rashes.
However, there is no risk of rash if valproic acid is
introduced in a patient already stabilised on lamotrigine,
although in such a patient a reduction in the dose
of lamotrigine (as a rule of thumb, by about 50%) is
advisable as soon as the dose of valproate reaches about
250500 mg/day in adults. As discussed previously,
lamotrigine metabolism is increased by enzyme-inducing
AEDs, and when a patient receives such an AED together
with valproic acid, enzyme induction and enzyme
inhibition tend to cancel each other out, and the rate of
lamotrigine metabolism will approach that seen in patients
on lamotrigine monotherapy.25
Valproic acid can inhibit the metabolism of other
AEDs. In some patients, valproic acid inhibits phenytoin
metabolism35 and causes an increase in the plasma
concentration of free phenytoin.32 Owing to concurrent
displacement of phenytoin from plasma protein binding
sites, this interaction may not be apparent when monitoring
is based solely on total phenytoin concentrations.36 Valproic
acid can also inhibit the metabolism and increase the
plasma concentration of free diazepam105 and lorazepam.106
Given the high therapeutic index of benzodiazepine drugs,
the latter interactions are probably of limited clinical
significance.
In patients taking carbamazepine, valproic acid can
increase the concentration of the active metabolite
carbamazepine-10,11-epoxide through inhibition of epoxide
hydrolase, without any substantial changes in the
concentration of the parent drug.107109 Valpromide, an amide
derivative of valproic acid that is thought to be
a valproic-acid prodrug, also inhibits epoxide hydrolase
but the effect is much greater than that seen with valproic
acid. Thus, addition of valpromide to the therapeutic
regimen of a patient stabilised on carbamazepine results
in increases of up to eight times in carbamazepine-10,11-
epoxide concentrations and signs of toxicity in many cases.110
For patients treated with carbamazepine, valpromide and
valproic acid should not be used interchangeably.

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 Interactions between antiepileptic drugs
Review

AED monotherapy

Seizure control Unsatisfactory seizure control

Consider introduction of second AED

Second AED associated with Second AED not associated

pharmacokinetic interactions with pharmacokinetic
interactions

Second AED Second AED Metabolism of Metabolism of Introduce second AED

is an enzyme is an enzyme second AED second AED
inducer inhibitor induced by inhibited by
first AED first AED AED dosage need not take into
consideration complications
resulting from pharmacokinetic
Dose adjustments will depend on the type of interaction interactions. Monitor patient
carefully because
pharmacodynamic interactions
Dose of first AED Dose of first AED A higher dose A lower dose of are still possible
may need to be may need to be of the second the second AED
increased to decreased to AED may be may be necessary
optimise seizure avoid adverse necessary to for seizure control
control effects achieve seizure and to avoid
control adverse effects

Figure 2. Drug interaction considerations in AED polytherapy. Reprinted with permission from Epilepsia, International League Against Epilepsy.2

Enzyme inhibition caused by other AEDs
Inhibitory drug interactions caused by AEDs other than
valproic acid are less common. Because phenobarbital and
phenytoin are metabolised by the same enzyme system, they
may each inhibit metabolism of the other but the interaction
is complicated by the fact that both compounds may also act
as enzyme inducers. In general, phenytoin tends to cause a
small increase in plasma phenobarbital concentration,111,112
though this has not been observed in all studies.113 The
reverse interaction is more complex and unpredictable.114,115
Decreases, increases, or no change in plasma concentration
of phenytoin have been described in patients given
adjunctive phenobarbital therapy.115
Oxcarbazepine is a weak inhibitor of the CYP2C19
isoenzyme, which is involved in phenytoin metabolism.
As a result, oxcarbazepineparticularly when used at
high doses (>1800 mg/day)may increase plasma
phenytoin concentrations by up to 40%.49,116 Carbamazepine
can also cause a modest increase in plasma phenytoin
concentration,116 but this interaction is inconsistent.
Topiramate is also a weak inhibitor of CYP2C19, which
might explain its ability to increase plasma concentrations of
phenytoin in a few patients.117 Most of these interactions are
of small clinical significance.
Of all the AEDs, felbamate is by far the most potent and
broad ranging inhibitor of drug metabolism and may
increase plasma concentration of phenytoin,118 valproic
acid,119 phenobarbital,120 carbamazepine-10,11-epoxide,97 and
N-desmethyl-clobazam.121 These interactions are clinically
important, but they will not be discussed in detail because
felbamate, owing to its serious liver and bone marrow
toxicity, is only rarely used in the treatment of epilepsy.
Sultiame, another potent inhibitor of the metabolism of
phenytoin122 and phenobarbital,114 is also rarely used.
Pharmacodynamic interactions
Potentially beneficial interactions
Although the suggestion has been made that the
combination of AEDs with different mechanisms of action
should be pharmacodynamically more advantageous than
combinations of drugs with the same mechanism, our
understanding of the modes of action of individual drugs is
insufficient to allow a fully mechanistic approach to AED
therapy.42,123 Nevertheless, clinical evidence does indicate that
some combinations are more beneficial than others. One
example is the pharmacodynamic interaction between
valproic acid and ethosuximide, which may lead to control
of absence seizures in patients refractory to either drug given
alone.124 Although the combined use of lamotrigine and
valproic acid is complicated by the inhibition of lamotrigine
metabolism, several studies have provided evidence that the
remarkable effectiveness of this combination against
refractory complex partial seizures,125 absence seizures,126
and other seizure types127,128 can only be explained by
a pharmacodynamic interaction. Patients receiving this
combination, however, may also experience pronounced
toxicity, particularly hand tremor, and the dose of
both drugs should be adjusted in such cases.125,129 Other AED
combinations for which favourable pharmacodynamic
interactions have been claimed include carbamazepine

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For personal use. Only reproduce with permission from The Lancet Publishing Group.
 Review Interactions between antiepileptic drugs

with valproic acid,130133 valproic acid with clonazepam,134
carbamazepine with vigabatrin,133 lamotrigine with
vigabatrin,135 lamotrigine with topiramate,136 lamotrigine
with gabapentin,137 and vigabatrin with tiagabine.138 With the
exception of valproic acid with ethosuximide or lamotrigine,
clinical evidence for these positive pharmacodynamic
interactions is mostly anecdotal.
Potentially adverse interactions
Adverse pharmacodynamic AED interactions are equally
common.139 When excessive polytherapy is used, neurotoxic
effects of AEDs may add up without appreciable gain in
seizure control, and in this situation the advantage of
reducing drug load has been clearly documented.140,141 In
some patients, pharmacodynamic interactions related to
excessive drug load may lead to worsening of seizures,142 and
seizure control on reduction of complex combination
therapies is not uncommon. There is also evidence that
specific combinations are less well tolerated than others. In
particular, pharmacodynamic interactions leading to
neurotoxicity have been reported in some patients taking
combinations of carbamazepine with oxcarbazepine49 or
with lamotrigine,127,143 possibly related to additive blockade
of voltage-gated sodium channels. A pharmacodynamic
mechanism may also explain the rare occurrence of an
encephalopathy characterised by stupor or even coma in
some patients given valproate in combination with other
AEDs, particularly phenobarbital.144
Prevention and management of adverse AED
interactions
AED interactions can have substantial effects on clinical
outcome (figure 1), and a therapeutic algorithm for
management options in response to such interactions has
been proposed (figure 2). A few simple rules can help to
limit adverse consequences of AED interactions.2,139 Multiple
drug therapy should be used only when it is clearly
indicated. Most patients with epilepsy can be best managed
with an individualised dose of a single AED. Most
interactions are metabolically based and can be predicted
from knowledge of the isoenzymes involved in the
metabolism of the most commonly used drugs and the
effects of these drugs on the same isoenzymes. Physicians
should be aware of the most important interactions,
underlying mechanisms, and any corrective action required
Search strategy and selection criteria
Data for this review were identified by searches of Medline
and PubMed with the terms antiepileptic drug interactions
combined with individual drug names and drug groups;
references from relevant articles; and searches of the authors
files. Searches were undertaken between the period Sept 2,
2002 and Feb 11, 2003. Abstracts were included only when a
complete published article was not available. Only papers
published in English were reviewed. The purpose of the article
was not to provide an exhaustive review of all interactions,
but to highlight those which, based on the authors judgment,
have the greatest importance in terms of clinical
consequences and probability of concurrent use.
(eg, changes to dose). Combination of AEDs with similar
adverse effect profiles (eg, benzodiazepines and barbiturates)
should be avoided and combinations for which there is
clinical evidence of favourable interactions should be
preferentially selected. The clinical response to new drugs
introduced or discontinued from the patients regimen
should be carefully monitored. Unexpected responses to a
change in the regimen could result from interaction between
AEDs and the dose should be adjusted when appropriate.
If a pharmacokinetic interaction is anticipated, the
plasma concentration of the affected drug should be
monitored. Physicians should be aware that under certain
circumstances (eg, in the presence of drug displacement
from plasma proteins), routine total drug concentration
measurements can be misleading and patient management
may benefit from monitoring of free drug concentrations. In
some cases, dose adjustments may have to be implemented
at the time the interacting drug is added or removed.
Acknowledgments
The work of PNP is supported by the UK National Society for Epilepsy,
University College Hospitals NHS Trust and the Institute of Neurology,
University College London. The work of EP is supported by a
University of Pavia Research Grant (FAR 1999-2002).
Authors contribution
Both authors contributed equally to this work.
Conflict of interest
The authors have no conflicts of interest.
Role of the funding source
Funders of the work of PNP and EP had no role in the writing of this
review or the decision to submit the review for publication.

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