Interactions between antiepileptic

Interactions between antiepileptic drugs


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: 347–56

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

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.3–8 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 blood–brain 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 CYP3A4.21–24 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.

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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


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Interactions between antiepileptic drugs

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 displace—to a substantial extent—compounds 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 free—pharmacologically 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-


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 50–70% 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


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


Ciprofloxacin Clarithromycin Fluvoxamine Furafylline

Valproic acid Amiodarone Chloramphenicol Fluconazole Fluoxetine Fluvoxamine Miconazole Sulfaphenazole

Felbamate Oxcarbazepine (weak) Topiramate (weak) Cimetidine Fluvoxamine Omeprazole Ticlopidine

Cimetidine Fluoxetine Haloperidol Paroxetine Perphenazine Propafenone Quinidine Thioridazine


Cimetidine Ciclosporin A Diltiazem Erythromycin Fluconazole Fluvoxamine Grapefruit juice Indinavir

Itraconazole Ketoconazole Nefazodone Dextropropoxyphene Ritonavir Troleandomycin Verapamil


Carbamazepine Phenobarbital Phenytoin


Cigarette smoke Charcoal-grilled meat Rifampicin

Carbamazepine Phenobarbital Phenytoin Primidone Rifampicin

Carbamazepine Phenobarbital Phenytoin Primidone Rifampicin

No inducer known

Alcohol Isoniazid

Carbamazepine Phenobarbital Phenytoin Primidone Oxcarbazepine† Topiramate† Felbamate† Glucocorticoids† St John’s Wort Rifabutin Rifampicin






Psychotropic drugs: amitriptyline, clozapine, clomipramine, fluvoxamine, haloperidol, imipramine, mirtazapine, olanzapine Miscellaneous: caffeine, theophylline,

paracetamol, tacrine, tamoxifen, R-warfarin

AEDs: phenobarbital, phenytoin, valproic acid

Non-steroidal anti-inflammatory drugs: celecoxib, diclofenac, ibuprofen, naproxen, piroxicam

Miscellaneous: fluvastatin, losartan, tolbutamide, torasemide, S-warfarin, zidovudine

AEDs: diazepam, S-mephenytoin, methylphenobarbital, phenytoin Psychotropic drugs: amitriptyline, clomipramine, imipramine, citalopram, moclobemide

Miscellaneous: omeprazole, propranolol, proguanil, R-warfarin

Psychotropic drugs: amitriptyline, citalopram, chlorpromazine, clomipramine, clozapine, imipramine, desipramine, fluoxetine, fluphenazine, fluvoxamine, haloperidol, mianserine, mirtazapine, nortriptyline, olanzapine, paroxetine, perphenazine, risperidone, thioridazine, venlafaxine, zuclopenthixol

Cardiovascular drugs: alprenolol, bufuralol, encainide, flecainide, metoprolol, propafenone, propranolol, timolol, pindolol Miscellaneous: codeine, debrisoquine, dextromethorphan, phenformin, tramadol

AEDs: felbamate, phenobarbital

Miscellaneous: dapsone, ethanol, halothane, isoniazid, chlorzoxazone

AEDs: carbamazepine, ethosuximide, tiagabine, zonisamide,

some benzodiazepines (eg, alprazolam, midazolam, triazolam) Psychotropic drugs: amitriptyline, clomipramine, clozapine, haloperidol, imipramine, sertraline, nefazodone, mirtazapine, risperidone, ziprasidone, olanzapine

Cardiovascular drugs: amiodarone, atorvastatin, diltiazem, felodipine, lovastatin, nimodipine, nifedipine, quinidine, simvastatin, verapamil Miscellaneous: alfentanil, astemizole, cisapride, clarithromycin, ciclosporin A, cyclophosphamide, erythromycin, fentanyl, glucocorticoids, itraconazole, ketoconazole, indinavir,

oral contraceptive steroids, sildenafil, tacrolimus, tamoxifen, terfenadine

*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.

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Interactions between antiepileptic drugs

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 drug’s 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,


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 50–70% of adult levels), but by 2–3 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 3–4 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,68–70 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.60,77–79

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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Table 2. Expected changes in plasma concentrations when an AED is added to a pre-existing regimen

AED added



·· PHT↑↓ NCCP PB↑ ·· PRM↓



ETS⇓ CBZ⇓ VPA⇓ ·· ↔ VPA↓ ETS⇓ ·· VPA⇓

ETS↑↓ CBZ-E↑ ··

? CBZ↓ ↔ NE ↔↔ NE ↔↔ NE ↔ VPA↓ NE ↔↔ NE ↔↔ NE CBZ↑↓ ↔ NE CBZ↑ ↔










↔ NE ↔ ? NE ? ↔ NE NE NE NE NE ? NE ? NE NE NE NE NE NE ·· NE ? NE ·· NE

? ↔ ··







PHT↑ ?

↔ NE

↔ NE PHT↑ ↔ ↔↔ ↔↔ ↔NE PHT↓ PRM↓

↔ LTG⇑ ↔ TPM↓ ↔ ·· LTG↓ NE ? ? NE ·· NE NE NE NE NE ·· NE NE ? ? NE ·· ? NE NE NE NE ·· NE ↔ ↔ NE NE ? ↔ NE NE NE NE NE NE NE NE

↔ ↔ NE ??


↔ ↔ NE NE ·· NE NE





Pre-existing AED

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 40–50% 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.98–100 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 30–50%, 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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Interactions between antiepileptic drugs

AED monotherapy

Addition of second AED

Improved seizure control

Adverse effects

Seizure worsening

No change in seizure control

Synergistic effects can improve seizure control or increase adverse effects

Antagonistic effects can result in seizure worsening or no change in seizure control

If appropriate, adjust doses on the basis of clinical response

Concentrations have increased or decreased

Possible pharmacokinetic drug interaction


Unsatisfactory control in about 30% of patients

Measure plasma concentrations of drug* Concentrations as expected

Possible pharmacodynamic drug interaction


Inhibition of the drug metabolising enzymes can cause high concentrations of either the added or the baseline drug and result in either improved seizure control or increased adverse effects

Induction of the drug metabolising enzymes can cause low concentrations of either the baseline drug to cause worsening of seizure control or of the added drug to cause no change in seizure control

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

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 250–500 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.107–109 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


Consider introduction of second AED

Introduce second AED

AED monotherapy

Seizure control

Unsatisfactory seizure control

Second AED associated with pharmacokinetic interactions

Second AED not associated with pharmacokinetic interactions

Second AED is an enzyme inducer

Second AED is an enzyme inhibitor

Metabolism of second AED induced by first AED

Metabolism of second AED inhibited by first AED

Dose adjustments will depend on the type of interaction

Dose of first AED may need to be decreased to avoid adverse effects

A higher dose of the second AED may be necessary to achieve seizure control

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, oxcarbazepine—particularly 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

For personal use. Only reproduce with permission from The Lancet Publishing Group.

A lower dose of the second AED may be necessary for seizure control and to avoid adverse effects

AED dosage need not take into consideration complications resulting from pharmacokinetic interactions. Monitor patient carefully because pharmacodynamic interactions are still possible

Dose of first AED may need to be increased to optimise seizure control


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Interactions between antiepileptic drugs

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.

with valproic acid,130–133 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

(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 patient’s 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.


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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with permission from The Lancet Publishing Group.

THE LANCET Neurology Vol 2 June 2003

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