Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
CRITICAL REVIEW AND INVITED COMMENTARY
Enzyme induction with antiepileptic drugs: Cause for concern?
*Martin J. Brodie, yScott Mintzer, zAlison M. Pack, xBarry E. Gidal,
{Charles J. Vecht, and #Dieter Schmidt
*Epilepsy Unit, Western Infirmary, Glasgow, United Kingdom; yDepartment of Neurology, Thomas Jefferson University, Philadelphia,
Pennsylvania, U.S.A.; zDepartment of Neurology, Columbia University, New York, New York, U.S.A.; xSchool of Pharmacy and
Department of Neurology, University of Wisconsin, Madison, Wisconsin, U.S.A.; {Stichting Epilepsie Instellingen Nederland (SEIN)
Epilepsy Foundation, Heemstede, The Netherlands; and #Epilepsy Research Group, Berlin, Germany
SUMMARY
Several commonly prescribed antiepileptic drugs
(AEDs)including phenobarbital, phenytoin, and carba-
mazepinestimulate the synthesis of a broad range of
monooxygenase and conjugating enzymes. These agents
are well known to reduce the duration and action of many
lipid- and nonlipid-soluble drugs, including anticoagu-
lants, cytotoxics, analgesics, antiretrovirals, glucocortic-
oids, statins, antihypertensives, oral contraceptives,
psychoactive drugs, immunosuppressants, and of course,
other AEDs. This process, therefore, may be associated
with a number of clinical problems including higher can-
cer mortality, progressive AIDS, transplant rejection, and
unwanted pregnancy. Withdrawal of enzyme-inducing
AEDs will increase the concentration of induced drugs,
bringing with it substantial risk of toxicity if doses are not
concomitantly reduced. Yet the potential widespread
The modern treatment of epilepsy began with the discus-
sion of the value of potassium bromide in young women
with catamenial epilepsy by Sir Charles Locock in the pages
of The Lancet in 1857. The next century saw the introduc-
tion of phenobarbital, phenytoin, primidone, and ethosuxi-
mide. In the 1960s and 1970s, carbamazepine and valproic
acid together with the benzodiazepines became available.
The last 20 years can be regarded as the modern era of
antiepileptic drug (AED) development: 15 new agents navi-
gated the regulatory hurdles to reach the market. Many of
these have been integrated into everyday clinical practice,
thereby providing a greater range of options for physicians
and patients (Brodie, 2010).
Enzyme induction was first recognized as a pharmaco-
logic complication of epilepsy treatment >30 years ago
(Perucca, 1978), but awareness of its influence on the
Accepted July 30, 2012; Early View publication September 27, 2012.
Address correspondence to Martin J. Brodie, Epilepsy Unit, Western
Infirmary, Glasgow G11 6NT, U.K. E-mail: mjb2k@clinmed.gla.ac.uk
Wiley Periodicals, Inc.
2012 International League Against Epilepsy
11
adverse health consequences of these interactions, both
with AED initiation and withdrawal, remain largely under-
appreciated. Furthermore, induction also affects enzymes
involved in endogenous metabolic pathways, and can alter
bone biochemistry, gonadal steroids, and lipid markers.
Therefore, enzyme-inducing AEDs may contribute to the
development of a number of comorbidities, including
osteoporosis, sexual dysfunction, and vascular disease.
This process continues as long as the patient takes the
inducer. Modern AEDs that do not possess this property
have similar efficacy for the common epilepsies. Accord-
ingly, perhaps consideration should be given to starting
treatment with, or even switching patients to, non
enzyme-inducing AEDs.
KEY WORDS: Enzyme-inducing antiepileptic drug, Drug
metabolism, Pharmacokinetic interactions, Osteoporo-
sis, Sexual dysfunction, Vascular disease.
metabolism of a range of endogenous substrates is a much
more recent development (Nebert & Russell, 2002). There-
fore, lifelong use of enzyme-inducing AEDs, particularly
phenobarbital, phenytoin, and carbamazepine, has much
broader implications for the patients general health than
just the production of pharmacokinetic interactions (Gidal
et al., 2009). Accordingly, it has been suggested that, given
the range of effective and well-tolerated AEDs now avail-
able, enzyme inducers perhaps should not be regarded as
drugs of first choice in newly diagnosed epilepsy (Mintzer
& Mattson, 2009). This article provides an evidence-based
overview of this potentially important and possibly conten-
tious pharmacotherapeutic issue.
Human Drug Metabolism
Biotransformation of a drug, both in intestinal and hepatic
tissues, is one of the most important determinants of its
pharmacokinetic profile. Drug metabolism can be broadly
segregated into two categories: phase I (oxidation, reduc-
tion, and hydrolysis) and phase II (conjugation). Oxidative
biotransformation processes are mediated primarily by the
12
M. J. Brodie et al.

cytochrome P450 (CYP) family of enzymes (Nelson et al.,
1996), whereas conjugation reactions are conducted largely
by the enzyme uridine 5-diphospho-glucuronyltransferase
(UGT) (Kiang et al., 2005). The activity of CYP and UGT
isozymes can be influenced by genetic, environmental
(exogenous), and endogenous factors resulting in significant
variation among individuals in drug metabolism.
Fifteen CYP isozymes, subdivided into three families, are
known to be involved in human drug metabolism (Nelson
et al., 1996). These enzymes are located on endoplasmic
reticulum and mitochondrial membranes inside cells.
Although most commonly associated with drug metabolism
in the liver, CYP isozymes are found in a variety of tissues
including the intestine, kidney, lung, skin, and brain
(Pelkonen et al., 2008; Ghosh et al., 2010). In the human
liver, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are respon-
sible for the oxidative metabolism of about 80% of drugs
(Table 1). Among these isozymes, CYP3A4 has the greatest
abundance in the liver and intestine, and is responsible for
the metabolism of the largest number of clinically used
drugs, as well as a range of endogenous substrates such as
prostaglandins, steroid hormones, and fatty acids. CYP2D6
does not appear to be inducible.
In humans, UGTs are expressed as two families in the
liver and intestine: UGT1 and UGT2. This group of
enzymes is also involved in the metabolism of endogenous
substrates, such as estrogens, progesterone, testosterone,
eicosanoids, bilirubin, thyroxine, bile acids, and arachidonic
acid (Bock, 2010).
Mechanisms of Enzyme Induction
Enzyme induction is mediated through the binding of one
or more chemical activators to CYP isozyme intracellular
receptors, ultimately producing increased transcription of
CYP genes. This ligand-activated transcription results in
translation of messenger RNA (mRNA) leading to increased
synthesis of the CYP protein. Not all CYP isozymes respond

Table 1. Key cytochrome (CYP) isozymes involved in the metabolism of commonly used drugs
CYP
1A2 2B6 2C8 2C9 2C19 2D6 3A4
Amitriptyline Bupropion Paclitaxel Ibuprofen Lansoprazole Tamoxifen Clarithromycin
Caffeine Cyclophosphamide Repaglinide S-Naproxen Omeprazole Carvedilol Zolpidem
Clomipramine Efavirenz Piroxicam Pantoprazole S-Metoprolol Alprazolam
Clozapine Iphosphamide Glipizide Rabeprazole Timolol Diazepam
Cyclobenzaprine Methadone Losartan Diazepam Amitriptyline Midazolam
Estradiol Irbesartan Phenytoin Clomipramine Triazolam
Fluvoxamine Glyburide Phenobarbitone Desipramine Cyclosporine
Haloperidol Glibenclamide Amitriptyline Fluoxetine Tacrolimus
Imipramine N-DeMe Glipizide Carisoprodol Imipramine Indinavir
Theophylline Amitriptyline Citalopram Paroxetine Ritonavir
Tizanidine Fluoxetine Clomipramine Haloperidol Saquinavir
Verapamil Fluvastatin Clopidogrel Perphenazine Astemizole
R-warfarin Rosiglitazone Cyclophosphamide Risperidone Ziprasidone
Zileuton Tamoxifen Imipramine Thioridazine Amlodipine
Zolmitriptan S-warfarin Nelfinavir Aripiprazole Diltiazem
Progesterone Atomoxetine Felodipine
Propranolol Chlorpheniramine Nifedipine
Teniposide Chlorpromazine Verapamil
R-Warfarin Clonidine Atorvastatin
Codeine Lovastatin
Donepezil Simvastatin
Duloxetine Estradiol
Fluvoxamine Docetaxel
Metoclopramide Progesterone
Nortriptyline Testosterone
Oxycodone Risperidone
Propranolol Aripiprazole
Tramadol Dapsone
Venlafaxine Dexamethasone
Docetaxel
Fentanyl
Haloperidol
Irinotecan
Methadone
Sildenafil

Epilepsia, 54(1):1127, 2013

doi: 10.1111/j.1528-1167.2012.03671.x
 13
Enzyme Induction with AEDs

equally to a particular inducer (Table 2). Exposure to a
chemical activator may result in a greater degree of induc-
tion in one or more CYP isozymes relative to others (Zhu,
2010).
Although variations in the extent of induction may differ
between CYPs, there do appear to be common cellular sig-
naling mechanisms. In general, enzyme induction involves
activation of receptor transcription factors such as pregnane
X receptor (PXR), constitutive androstane receptor (CAR),
and aryl hydrocarbon receptor (AhR) (Tompkins & Wal-
lace, 2007; di Masi et al., 2009). Other nuclear receptors
such as glucocorticoid and estrogen receptors may also par-
ticipate in the induction of certain drugs; however, the tran-
scription factors PXR, CAR, and AhR appear to be broadly
implicated in enzyme induction (Pascussi et al., 2008).
PXR is not widely distributed, being found primarily in
the liver and small intestine. This receptor contains DNA-
binding and ligand-binding domains. Upon activation, PXR
binds to DNA as a heterodimer with retinoid X receptor
(RXR) and is translocated to the cell nucleus to regulate
gene transcription (Fig. 1). PXR response elements have
been found in human CYP3A4/5, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, and CYP1A2 genes and CYP24, a
major enzyme involved in the metabolism of 1,25 (OH)
vitamin D3 (Zhou et al., 2006; Tompkins & Wallace, 2007;
Pelkonen et al., 2008). Induction of CYP3A4 by agents such
as rifampicin, ritonavir, St Johns Wort, topiramate, ox-
carbazepine, phenytoin, and carbamazepine is likely to be
mediated (at least in part) by PXR binding.
Activation of the transcription factor, CAR, may occur
without direct binding to a ligand (Xu et al., 2004), and it is
found primarily in liver and kidney tissue. Similar to PXR,
CAR binds to DNA as a heterodimer with RXR (Fig. 2)
(Tompkins & Wallace, 2007). CAR appears to have a smal-
ler ligand binding domain than PXR, although CAR and
PXR do share some DNA-binding elements, and there is
some overlap in activating compounds. Experimental
evidence suggests that CAR activation by phenobarbital,
phenytoin, and carbamazepine is involved in induction of
CYP1A2, CYP2B6, CYP2C9, and CYP3A4.

Table 2. Enzyme-inducing drugs and their cytochrome (CYP) targets

CYP
1A2 2B6 2C9 2C19 3A4/5
Carbamazepine Carbamazepine Carbamazepine Carbamazepine Carbamazepine
Phenytoin Phenytoin Phenytoin Prednisone Phenytoin
Phenobarbital Phenobarbital Phenobarbital Norethindrone Phenobarbital
Ritonavir Ritonavir Rifampicin Rifampicin Topiramate
Rifampicin Rifampicin St Johns Wort St Johns Wort Oxcarbazepine
Omeprazole Artemisinin Dexamethasone
Polycyclic aromatic hydrocarbons St Johns Wort

Figure 1.
Schematic illustration of PXR
activation by a xenobiotic leading to
CYP3A4 induction. PXR, pregnane
X receptor; PXR-RE, PXR
responsive element; RXR, retinoid
X receptor. Reproduced with
permission from Tompkins and
Wallace (2007).
Epilepsia ILAE

Epilepsia, 54(1):1127, 2013

doi: 10.1111/j.1528-1167.2012.03671.x
14
M. J. Brodie et al.
PXR and CAR have not only been shown to increase de
novo synthesis of CYP protein, but also appear to be impor-
tant in the regulation of genes involved in the expression of
drug transport proteins such as P-glycoprotein (PGP) and
multidrug resistance glycoprotein (MRP). These proteins
are constitutively expressed in a variety of organs including
the small intestine, liver, kidney, placenta, and brain. They
function as efflux pumps, not only influencing the absorp-
tion and ultimate bioavailability of certain drugs, but in their
eventual tissue distribution. Several drugs, including pheno-
barbital, carbamazepine, and phenytoin may upregulate
PGP expression and activity, thereby reducing the intracell-
ular concentrations of substrate drugs (Kim, 2002).
Although it is tempting to speculate that induction of drug
transporters in the brain may provide an explanation for
pharmacoresistance in patients with epilepsy, the data
remain conflicting (Ambroziak et al., 2010).
Time Course of Induction and
Deinduction
Unlike enzyme competitive inhibition, enzyme induction
is a gradual process. The time required to maximally induce
an enzyme is governed by the need to either upregulate or
synthesize new enzyme, assuming that the elimination half-
life of the inducing drug is less than the enzyme turnover or
degradation half-life. For example, time to maximal
induction will be quicker with a short half-life drug such as
rifampicin versus a longer half-life medication such as
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
Figure 2.
Schematic illustration of CAR
activation by PB or a CAR agonist
(TCPOBOP). CAR, constitutive
androstane receptor; Hsp90, heat
shock protein 90; CCRP, CAR
cytoplasmic retention protein; PB,
phenobarbital; PP2A, protein
phosphatase 2A; RE, responsive
element; RXR, retinoid X receptor;
TCPOBOP, CAR agonist. Adapted
from di Masi et al., 2009, Copyright
(2009), with permission from
Elsevier.
Epilepsia ILAE
phenobarbital. Therefore, pharmacokinetics of the inducing
drug cannot be ignored. In most cases, however, enzyme
turnover will be the rate-limiting step in this process. Evi-
dence suggests that CYP3A4 has an enzyme turnover half-
life of about 3 days and CYP1A2 about 4 days (Magnusson
et al., 2008). This would imply that maximal induction of
these important CYPs is likely to take several weeks (Zhu
et al., 2009), although the onset of induction may be evident
much sooner (Fleishaker et al., 1995).
In addition to time of exposure, both in vitro and clinical
studies have demonstrated that the magnitude of induction
of various CYP isozymes appears to be at least partially
dependent upon the dose of the inducing drug (Tomson
et al., 1989; Kanebratt & Andersson, 2008). This dose
dependence is seen not only with the older, traditional AEDs
such as phenobarbital and carbamazepine, but also with
newer agents such as topiramate. Topiramate is frequently
cited as a noninducing medication when, in fact, clinical
studies have shown dose-dependent increases in the clear-
ance of ethinylestradiol in female patients, which are clini-
cally relevant at daily doses of 200 mg and above
(Rosenfeld et al., 1997). In vitro experiments have demon-
strated concentration-dependent increases in CYP3A4 pro-
tein and mRNA with exposure to topiramate (Nallani et al.,
2003).
What happens when an enzyme-inducing drug is discon-
tinued? Deinduction will be related not only to the half-life
of the inducer, but also to enzyme degradation rates. At any
given time, the amount of drug-metabolizing enzyme is

regulated by a zero order rate of enzyme production and a
first-order rate of enzyme degradation. As discussed previ-
ously, during the process of enzyme induction, enzyme
amounts are increased either by increasing the rate of
enzyme production or by stabilization (i.e., decreasing the
rate of degradation). During the process of deinduction,
enzyme amount is decreased (to baseline preinduction lev-
els) by either decreasing production or increasing enzyme
degradation rate. The turnover half-lives of the particular
enzymes involved, therefore, are the primary parameters
governing the rate at which one can expect resolution of an
induction type interaction following discontinuation of an
inducing medication. This implies therefore that the time
course for enzymes to return to baseline or preinduced activ-
ity levels will be gradual. Studies exploring the dissipation
of increased CYP3A activity following discontinuation of
inducers have suggested that this may occur over several
weeks for compounds such as St Johns Wort and rifampicin
(Imai et al., 2008; Reitman et al., 2011). Pharmacokinetic
modeling following discontinuation of carbamazepine sug-
gests a deinduction half-life of approximately 4 days
(Schaffler et al., 1994). Using an enzyme-turnover model in
patients with epilepsy, Punyawudho et al. (2009) estimated
that enzyme induction should be reduced by about half at
3 days and by 75% at 7 days, and enzyme deinduction
would be essentially complete within 2 weeks following
complete discontinuation of carbamazepine.
Deinduction interactions can be particularly insidious.
Although a number of pharmacy computer systems and elec-
tronic databases can alert the clinician to potential interac-
tions following the introduction of a potential inducer, there
are no reliable electronic systems to indicate when an offend-
ing drug is removed. Clinicians should be mindful that dis-
continuation of a drug is not always within their control, for
instance withdrawal by another doctor or nonadherence to
medication. Only a few days abstinence from carbamazepine
is likely to produce substantial reduction of enzyme induc-
tion resulting in a commensurate decrease in the metabolism
of CYP cometabolized medications with an increase in the
concentration of the induced drug and thereby potential toxicity
(Strack et al., 2009). These observations would suggest that
enzyme induction is not merely a yes-no phenomenon,
and that the magnitude of an inducing effect may vary even
within the same patient depending upon their current dosing
regimen and medication-taking behavior. While it is tempt-
ing to predict de-induction or interaction offset times on
the basis of drug half-lives, this will likely underestimate the
time required for complete dissipation of the interaction.
Antidepressant and
Antipsychotic Drugs
Psychiatric comorbidities are commonly found in
patients with epilepsy (Hoppe & Elger, 2011; Kerr et al.,
2011). Recent studies suggest that use of antidepressant and
15
Enzyme Induction with AEDs
antipsychotic drugs is common in patients receiving
enzyme-inducing AEDs, and that this tendency increases
with advancing age (Gidal et al., 2009). As most commonly
used antidepressant and antipsychotic medications are
metabolized by the CYP system, concomitant treatment
with an inducing AED could lower serum concentrations of,
for example, tricyclic antidepressants, serotonin-specific
reuptake inhibitors, and serotonin and norepinephrine reup-
take inhibitors by as much 2550% (Spina & Perucca, 2002;
Mula, 2008). Enzyme-inducing AEDs have also been
reported to lower markedly the serum concentration of a
number of both typical and atypical antipsychotic medica-
tions (Spina & Perucca, 2002; Besag & Berry, 2006; Botts
et al., 2008). The magnitude of this interaction may be quite
pronounced. For example, haloperidol serum concentrations
may be reduced by 5060% when taken with carbamaze-
pine. Carbamazepine has also been shown to increase sig-
nificantly the clearance of olanzapine, an antipsychotic drug
metabolized primarily via CYP1A2 (Lucas et al., 1998). It
is unclear how often these interactions are clinically rele-
vant. Nonetheless, it would seem reasonable to speculate
that individual patients may require increased doses of psy-
chotropic medication to achieve an optimal therapeutic
response. Conversely, patients taking a combination of car-
bamazepine and an antipsychotic drug are at risk of devel-
oping well-recognized side effects, such as akathisia, when
the former drug is withdrawn, unless the dose of the antipsy-
chotic is simultaneously lowered (Strack et al., 2009).
Chemotherapeutic Agents
and Cancer
Numerous studies indicate that concomitant administra-
tion of enzyme-inducing AEDs accelerates the metabolism
of many classes of chemotherapeutic agents (Table 3)
resulting in substantially reduced exposure (Vecht et al.,
2003). Approximately one third of patients with cancer,
particularly those with brain tumors, are at risk of clinically
relevant drugdrug interactions (Riechelmann et al., 2007,
2008) that may compromise their survival.
A number of studies have reported poorer outcomes in
cancer patients receiving enzyme-inducing AEDs. Children
with acute lymphoblastic leukemia had a relapse rate almost
three times higher and worse survival associated with faster
clearance of teniposide and methotrexate, if they were also
receiving enzyme-inducing AEDs (Relling et al., 2000). In
patients with glioblastoma multiforme treated with adjuvant
chemotherapy (mainly lomustine), survival was 3 months
shorter for those on concurrent enzyme-inducing compared
with nonenzyme-inducing AEDs (Oberndorfer et al.,
2005). Use of tipifarnib only led to longer progression-free
survival in recurrent malignant glioma among patients who
were not receiving an enzyme-inducing AED (Cloughesy
et al., 2006). Combined administration of erlotinib and
sirolimus in recurrent glioblastoma resulted in a longer
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
16
M. J. Brodie et al.

Table 3. Effect of enzyme-inducing antiepileptic drugs on the pharmacokinetics of chemotherapeutic,

antiretroviral, and immunosuppressive drugs
Number of subjects
Effect of EIAED on
Concomitant drug EIAED(s) concomitant drug Total EIAED No EIAEDa,b,c References
Chemotherapeutic drugs
Busulphan PHT AUC n = 17 n = 9 n = 8a Hassan et al. (1993)
Methotrexate/teniposide CBZ, PHT, PB Clearance n = 182d n = 12 n = 170b Relling et al. (2000)
Paclitaxel EIAEDs MTD n = 24d n = 18 n = 6a Fetell et al. (1997)
Paclitaxel EIAEDs MTD n = 34d n = 27 n = 7b Chang et al. (1998)
Irinotecan CBZ AUC n = 64d n = 52 n = 12b Santisteban et al. (2009)
PHT AUC
Etoposide PHT, PB Clearance n = 29d n = 7 n = 22b Rodman et al. (1994)
Vincristine CBZ, PHT AUC n = 15 n = 9 n = 6a,b,e Villikka et al. (1999)
Tipifarnib EIAEDs AUC n = 47d n = 23 n = 24c Cloughesy et al. (2005)
Erlotinib PB MTD n = 83d n = 53 n = 30c Prados et al. (2006)
AUC
Erlotinib EIAED Clearance n = 32d n = 32 Raizer et al. (2010)
AUC
Gefitinib/sirolimus EIAEDs AUC n = 34d n = 19 n = 15c Reardon et al. (2006)
MTD
Imatinib EIAEDs MTL n = 224d n = 85 n = 28a Pursche et al. (2008)
n = 111b
Temsirolimus PHT AUC n = 36 n = 17 n = 19a Kuhn et al. (2007)
Antiretroviral drugs
Lopinavir/ritonavir PHT AUC n = 24f n = 24 Lim et al. (2004)
Nevirapine EIAEDs t n = 36f n = 32 n = 4a Lhomme et al. (2006)
Efavirenz CBZ t n = 16f Zhu et al. (2009)
Immunosuppressive drugs
Cyclosporin CBZ Steady-state n=6 n=3 n = 3c Cooney et al. (1995)
concentration
Cyclosporin PHT Clearance Animals DSouza et al. (1988)
AUC, area under the plasma concentration-time curve; CBZ, carbamazepine; EIAED, enzyme-inducing antiepileptic drug; MTD, maximum tolerated dose;
MTL, mean through level; PB, phenobarbital; PHT, phenytoin; SN-38, 7-ethyl-10-hydroxy-camptothecin; t, elimination half-life.
= increased; = decreased.
a
Non-EIAED.
b
No anticonvulsants.
c
Not specified.
d
Prospective series.
e
Includes oxcarbazepine.
f
Healthy volunteers.

progression-free survival for patients taking nonenzyme-
inducing AEDs, even if dosing of targeted therapy was cor-
rected for enzyme induction (Reardon et al., 2010). Concurrent
therapy with enzyme-inducing AEDs can also contribute to
treatment resistance, as chemotherapeutic agents may not
reach sufficiently high concentrations within the target area
because of overexpression of multiple drug-resistance pro-
teins (Marini et al., 2007; Lombardo et al., 2008).
Studies have also reported higher maximum tolerated
doses of chemotherapeutic drugs in patients taking enzyme-
inducing AEDs (Table 3). This may explain, at least in part,
why enzyme-inducing AEDs may lead to a longer survival
in patients with glioblastoma multiforme in some studies
(Jaeckle et al., 2009). These data conflict with those from
another retrospective report that patients with glioblastoma
taking an enzyme-inducing AED had a shorter survival than
those taking an enzyme inhibitor (Oberndorfer et al., 2005).
There is agreement that maximum tolerated doses of new
anticancer agents for brain tumors should be determined
separately in subgroups of patients who are receiving
enzyme-inducing and nonenzyme-inducing AEDs (Gross-
man et al., 1998; Cloughesy et al., 2006; Reardon et al.,
2006; Vredenburgh et al., 2007; Puduvalli et al., 2008).
Accordingly, the substantial effect that enzyme-inducing
AEDs can have on the treatment of brain tumors is reflected
by large differences in the dose regimens of chemotherapeu-
tic agents, depending on whether or not patients receive an
enzyme-inducing AED.
Data from prospective phase I/II trials of chemotherapeu-
tic drugs stratified according to concomitant use of AEDs
have clearly demonstrated the powerful enzyme-inducing
properties of phenobarbital, phenytoin, and carbamazepine
in this setting (Table 3). In principle, anticipated interac-
tions can potentially be avoided by adjusting the dose of the
chemotherapeutic agent. This course of action requires
therapeutic drug monitoring of the chemotherapy together
with dose adjustment at each change of the AED regimen.
Harmful drugdrug interactions may be more common than

Epilepsia, 54(1):1127, 2013

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previously thought, since physicians are often unaware of
the potential for drugs to interact. Because metastatic cancer
is often associated with a poor prognosis, an inadequate
response may be attributed to ineffective therapy rather than
to enzyme induction.
Immunosuppressive and
Antiretroviral Therapy
The use of glucocorticosteroids is widespread in medicine,
including many conditions that require immunosuppressive
therapy or as part of treatment for cancer, in particular pri-
mary brain tumors and brain metastases. Administration of
steroids can easily lead to drugdrug interactions via the
CYP3A4 isoenzyme (Li et al., 1995). In this way, enzyme-
inducing drugs can enhance the clearance of steroids; such
effects have been shown on coadministration of phenytoin
with dexamethasone (Brophy et al., 1983; Chalk et al., 1984)
and prednisolone (Frey & Frey, 1984), phenytoin and pheno-
barbital with methylprednisolone (Stjernholm & Katz, 1975),
or carbamazepine with dexamethasone and other glucocorti-
costeroids (Spina et al., 1996). Conversely, and, although
beyond the scope of this article, dexamethasone may induce
the metabolism of phenytoin with a risk of higher seizure fre-
quency. When dexamethasone is discontinued, phenytoin
concentrations can easily rise to toxic levels (Lackner, 1991).
In addition, dexamethasone may lead to unpredictable inter-
actions, including both enzyme-inducing and enzyme-inhib-
iting effects, thus emphasizing the importance of therapeutic
drug monitoring. The immunosuppressive agents cyclosporin
and tacrolimus are also susceptible to enzyme induction
(Table 3). With concurrent phenytoin, a two to threefold
higher dose of tacrolimus is needed to maintain desired blood
levels (Joerger et al., 2004; Wada et al., 2007).
The efficacy of antiretroviral drugs such as lopinavir, ri-
tonavir, nevirapine, and efavirenz may be compromised by
enzyme-inducing AEDs, as shown by pharmacokinetic
studies in healthy volunteers (Table 3). Monitoring the effi-
cacy of antiretroviral therapy together with disease activity
is essential when enzyme-inducing AEDs are being con-
comitantly prescribed. Evidence-based guidelines have
recently been produced on AED selection for people with
HIV and AIDS (Birbeck et al., 2012). These recommend
that enzyme-inducing AEDs are best avoided in people on
regimens that include protease inhibitors or nonnucleoside
reverse transcriptase inhibitors, as pharmacokinetic interac-
tions can result in virologic failure.
Reproductive Hormones,
Sexual Function, and Oral
Contraceptives in Women
Among women with epilepsy, enzyme-inducing AEDs
have been associated with abnormalities in sex hormone
17
Enzyme Induction with AEDs
profiles (increased sex hormonebinding globulin [SHBG],
low estradiol, low testosterone, low dehydroepiandroster-
one sulfate [DHEAS]), the potential for sexual dysfunction,
as well as increased risk of hormonal contraception failure
(Dana-Haeri et al., 1984; Isojarvi, 1990; Murialdo et al.,
1998; Morrell et al., 2001; Galimberti et al., 2005, 2009).
Reduced sex hormone levels may occur secondary to both
enzyme-induced accelerated metabolism and higher SHBG
levels, which reduce the bioavailable free concentrations of
reproductive hormones, including estradiol and testosterone
(Galimberti et al., 2009). Reported changes in sex hormones
secondary to enzyme-inducing AED exposure are supported
by data from a small prospective study, in which male and
female patients were tapered off enzyme-inducing AEDs
and after 4 months demonstrated significant increases in
total testosterone and free androgen index testosterone (Los-
sius et al., 2007).
The clinical relevance of enzyme-inducing AED effects
on reproductive hormones is demonstrated by reports of sig-
nificant sexual dysfunction in women treated with enzyme-
inducing AEDs. For example, in a study of 57 reproductive-
aged women with epilepsy and 17 controls, women receiv-
ing carbamazepine (n = 12) had lower sexual satisfaction
when compared to women treated with lamotrigine (n = 10)
and gabapentin (n = 5) (Morrell et al., 2005). Moreover,
among women with epilepsy treated with enzyme-inducing
AEDs, there were associations between low estrogen and
increased sexual anxiety, and low DHEAS and arousal
insufficiency.
Induced metabolism of sex steroid hormones by AEDs
(Crawford, 2002) potentially increases the risk of contracep-
tive failure and breakthrough pregnancy (Kenyon, 1972;
Back et al., 1980; Crawford et al., 1990). This important
interaction was well demonstrated by findings from a dou-
ble-blind, randomized, placebo-controlled, crossover study
of healthy reproductive-aged women (n = 10) treated with
carbamazepine in combination with a commonly used low-
dose (20 lg ethinyl estradiol and 100 lg levonorgestrel)
oral contraceptive (Davis et al., 2011). Mean area under the
curve measurements were lower during carbamazepine
cycles compared with placebo for estradiol (p < 0.001) and
levonorgestrel (p = 0.04). Among these women, ovulation
occurred in 5 of 10 carbamazepine cycles compared with 1
of 10 placebo cycles (p = 0.06) and breakthrough bleeding
occurred in 8 of 10 carbamazepine cycles compared with 2
of 10 placebo cycles (p = 0.07). Although not consistently
significant (likely secondary to small sample sizes), these
findings suggest that women treated with carbamazepine
using low-dose oral contraceptive hormones are at increased
risk for decreased levels of contraceptive steroids, increased
breakthrough bleeding, and ovulation. If the enrolled
subjects had been treated with a higher dose hormonal
contraceptive pill, the findings likely would have been
different. It has been recommended repeatedly that women
using enzyme-inducing AEDs who rely on hormonal
Epilepsia, 54(1):1127, 2013
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18
M. J. Brodie et al.
contraceptives use a higher dose oral contraceptive agent, spe-
cifically 50 lg of ethinyl estradiol. In the United States, this
formulation is available only as emergency contraception.
The impact of enzyme-inducing AEDs on other hormonal
forms of contraception including the vaginal ring, contracep-
tive patches, and intrauterine devices needs to be clarified.
Sexual Function and
Fertility in Men
Reproductive disorders are more common among men
with epilepsy than in the general population. Enzyme-
inducing AED exposure can contribute to these disorders.
Enzyme-inducing AEDs increase SHBG, thereby decreas-
ing free androgens (Isojarvi et al., 1991, 1995; Duncan
et al., 1999; Verrotti et al., 2011) and DHEAS (Duncan
et al., 1999). Decreased androgens may result in sexual dys-
function in some men treated with enzyme-inducing AEDs.
For example, Herzog et al. (2005, 2006) studied 85 men
with epilepsy treated with carbamazepine (n = 25), pheny-
toin (n = 25), lamotrigine (n = 25), or no AEDs (n = 10)
and 25 controls. Sexual dysfunction as demonstrated by
lower scores on a standardized sexual function question-
naire was greater in the men treated with carbamazepine
and phenytoin compared with controls as well as men trea-
ted with lamotrigine. Among men treated with carbamaze-
pine, 32% had scores below the control group and 24% of
men treated with phenytoin had scores below the control
group. In contrast, among men using lamotrigine, 4% had
scores below the control group. SHBG was significantly
higher in the carbamazepine and phenytoin groups than in
all other groups. Bioactive testosterone levels, bioactive tes-
tosterone/bioactive estradiol, and bioactive testosterone/
luteinizing hormone were significantly lower in the carba-
mazepine and phenytoin groups compared with both the
control and lamotrigine-treated groups (p < 0.05). Simi-
larly, DHEAS was significantly lower in men treated with
carbamazepine and phenytoin compared with controls and
the lamotrigine group (p < 0.05). This finding supports the
potential risk of sexual dysfunction in men with epilepsy
treated with enzyme-inducing AEDs, as DHEAS triggers
the production of endothelial nitric oxide (Liu & Dillon,
2002), a signaling molecule that has a role in mediating
erectile function. Fertility may also be affected by potential
adverse effects of phenytoin and carbamazepine on sperm
(Roste et al., 2003; Isojarvi et al., 2004). Isojarvi et al.
investigated sperm quality in men with epilepsy treated with
carbamazepine (n = 15) and oxcarbazepine (n = 18) com-
pared with controls (n = 41). The frequency of morphologi-
cally normal sperm was lower among men treated with both
carbamazepine (8%; p < 0.01) and oxcarbazepine (9%;
p < 0.05) than among controls (14%). Carbamazepine treat-
ment was also associated with poor motility of sperm
(p < 0.05) and low sperm concentrations (p < 0.001) when
compared with controls.
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
Most studies evaluating sex steroid hormone profiles in
men and women treated with enzyme-inducing AEDs were
cross-sectional with limited control groups. Although some
reported abnormalities in sex steroid hormones, with the
exception of SHBG the findings were not consistent. In
addition, there is a paucity of information on the effect of
newer generation nonenzyme-inducing AEDs on sex ste-
roid hormones. Well-designed prospective studies, includ-
ing reproductive hormone profiles and clinical outcomes
such as sexual dysfunction, are urgently required.
Bone Health
People with epilepsy have an approximately two- to six-
times greater risk of fracture than the general population
(Pack, 2008). This increased risk is secondary to epilepsy,
AED use and, in particular, enzyme-inducing AED expo-
sure. A population-based study using the General Practice
Research Database (GPRD) of >40,000 patients with epi-
lepsy in the United Kingdom found that, after controlling
for age and gender, the risk of fracture was about double that
in a control group of >80,000 (Souverein et al., 2005). The
impact of AED use on increased fracture risk was demon-
strated by findings from a casecontrol study using data
from a Danish hip register (Tsiropoulos et al., 2008), the
Womens Health Initiative (WHI) study (Carbone et al.,
2010), and a nested casecontrol study using the GPRD
(Souverein et al., 2006). Enzyme-inducing AED use inde-
pendently increased the risk of fracture in the WHI study as
well as in a Danish-population-based casecontrol study
(Vestergaard et al., 2004).
Bone mineral density (BMD) is the most significant pre-
dictor of fracture, and dual-energy X-ray absorptiometry
(DXA) is the most studied and understood technique avail-
able for its assessment. Using DXA, BMD measurements
reveal osteopenia or osteoporosis in 3860% of people with
epilepsy treated with AEDs in specialist epilepsy clinics
(Andress et al., 2002; Farhat et al., 2002). Longer AED use
was associated with decreased BMD (Sheth et al., 1995;
Andress et al., 2002; Farhat et al., 2002). Enzyme-inducing
AEDs independently reduced BMD. Their administration
was associated with reduced BMD in ambulatory subjects
(El-Hajj et al., 2008). Twins and siblings (<3 years age dif-
ference) treated with enzyme-inducing AEDs had lower
BMD compared with untreated twins and siblings (Petty
et al., 2005). Further support for this observation came from
findings in a study of previously drug-naive Koreans in
whom carbamazepine, but not noninducing AEDs, pro-
duced a significant decrease in BMD (Kim et al., 2007).
The abnormalities commonly seen in association with
enzyme-inducing AEDs (increased fracture, decreased
BMD, alterations in bone metabolism) may be directly
related to their hepatic enzyme inducing properties. CYP
enzyme induction can lead to accelerated metabolism of
vitamin D to polar inactive metabolites. Animal and human

studies reported that chronic phenobarbital use was associ-
ated with decreased plasma 3H-labeled vitamin D3 half-
life and increased biliary excretion of polar metabolites
(Hahn et al., 1972; Silver et al., 1974). Liver microsomes
isolated from phenobarbital-treated animals rapidly con-
vert 3H-labeled vitamin D3, 25-hydroxycholecalciferol
and 1,25-dihydroxycholecalciferol into inactive polar
metabolites (Hahn et al., 1972). Reduced active vitamin
D leads to decreased intestinal calcium absorption,
decreased serum calcium concentration, and compensa-
tory hyperparathyroidism (Pack et al., 2008). Persistent
hyperparathyroidism results in increased bone turnover
and reduced BMD. Serologic studies revealing low
calcium, low active vitamin D metabolites, high bone
turnover markers, and high parathyroid hormone underpin
this mechanism (Pack et al., 2008). These findings are
further supported by studies evaluating the effect of
enzyme-inducing AEDs on the expression of specific
CYP isozymes involved in vitamin D metabolism (Pas-
cussi et al., 2005; Zhou et al., 2006).
There are, however, some data contradicting this hypoth-
esis. For example, serum 25-hydroxyvitamin D levels, when
compared among groups of subjects treated with either
enzyme-inducing AEDs or nonenzyme-inducing AEDs,
did not differ in some studies (Stephen et al., 1999; Verrotti
et al., 2000a, 2002; Pack et al., 2005). Others also reported
evidence of significant osteopenia and increased bone
turnover, even though active vitamin D metabolites and
parathyroid hormone levels were normal. Moreover, carba-
mazepine may not be consistently associated with decreased
BMD (Sheth et al., 1995). Further studies are needed to
clarify the mechanisms of enzyme-inducing AED effects on
bone and whether new-generation noninducing AEDs also
impact bone metabolism.
Serologic Markers
of Vascular Risk
Enzyme-inducing AEDs increase a number of serologic
markers of vascular risk, particularly cholesterol. Several
cross-sectional and repeated-measures studies have demon-
strated elevated levels of total cholesterol, low-density lipo-
protein cholesterol and triglycerides among patients treated
with phenobarbital, phenytoin, and carbamazepine relative
to healthy controls (Isojarvi et al., 1993; Verrotti et al.,
1998; Eiris et al., 2000; Bramswig et al., 2003; Nikolaos
et al., 2004; Sonmez et al., 2006; Tomoum et al., 2008;
Chuang et al., 2012). Some of these studies also showed
increases in high-density lipoprotein cholesterol with carba-
mazepine, although the effect size was somewhat smaller.
Furthermore, when patients were crossed over from
enzyme-inducing AEDs (phenytoin or carbamazepine) to
nonenzyme-inducing AEDs (lamotrigine or levetirace-
tam), there was a decrease in total cholesterol averaging
25 mg/dl, including a decline in most lipid fractions
19
Enzyme Induction with AEDs
(Mintzer et al., 2009). Similar results were obtained when
patients were switched from enzyme-inducing AEDs to
low-dose topiramate (Mintzer et al., 2012) or from carba-
mazepine to oxcarbazepine (Isojarvi et al., 1994). These
data suggest a lipid-elevating effect that is specific to the
use of enzyme-inducing AEDs.
Other non-traditional serologic measures appear also
to be affected by enzyme induction. Lipoprotein(a), an
independent risk factor for cardiovascular disease (CVD),
is elevated by carbamazepine (Bramswig et al., 2003),
with levels declining by a comparable amount upon
switching to a nonenzyme-inducing AED (Mintzer et al.,
2009). The inflammatory marker C-reactive protein is ele-
vated in the epilepsy population (Tan et al., 2009). Patients
crossing over from carbamazepine or phenytoin to non
enzyme-inducing AEDs experienced declines in C-reactive
protein of >30% (Mintzer et al., 2009, 2012), indicating
that a substantial portion of the increase can be attributed
to CYP induction. The prothrombotic amino acid homocy-
steine has been implicated as a risk factor for CVD, stroke,
and dementia (McIlroy et al., 2002; Casas et al., 2005;
Ravaglia et al., 2005). Elevations of homocysteine have
been found among carbamazepine-treated patients in a
number of cross-sectional and repeated-measures studies
(Apeland et al., 2000; Verrotti et al., 2000b; Attilakos
et al., 2006; Belcastro et al., 2010; Linnebank et al.,
2011). One recent investigation found no direct effect of
carbamazepine, but demonstrated that switching from phe-
nytoin to a nonenzyme-inducing AED significantly
reduced homocysteine levels (Mintzer et al., 2009). There-
fore, phenytoin and carbamazepine may have different
effects on some serologic markers (Lopinto-Khoury &
Mintzer, 2010). These findings could be explained by dif-
ferences in induction profiles between the drugs, but it is
also possible that some of these effects may be due to
properties other than CYP induction.
Cholesterol synthesis, like most biochemical pathways, is
subject to feedback inhibition at the rate limiting step, which
is the action of hydroxymethylglutaryl-coenzyme A (HMG-
CoA) reductase. However, this inhibition is not provided by
the end product, cholesterol, but by a group of oxysterol
intermediates that are substrates for lanosterol alpha-
desmethylase, an enzyme also known as CYP51A1 (Fig. 3).
When rats are given ketoconazole, a potent inhibitor of CYP
enzymes, the levels of these oxysterol intermediates rise,
HMG-CoA reductase activity drops, and production of cho-
lesterol is reduced (Gibbons, 2002). By analogy, then, one
would predict that CYP induction should drive the meta-
bolic pathway forward, reduce the levels of oxysterol inter-
mediates, reduce feedback inhibition of HMG-CoA
reductase, and increase cholesterol production. This hypoth-
esis fits with the aforementioned clinical data, suggesting
that patients taking enzyme-inducing AEDs (phenytoin or
carbamazepine) show disturbances of cholesterol (Lopinto-
Khoury & Mintzer, 2010).
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
20
M. J. Brodie et al.

Figure 3.
Key steps in the cholesterol
synthesis pathway, highlighting the
role of CYP51A1. HMG-CoA,
hydroxymethylglutaryl-coenzyme A.
Epilepsia ILAE

Vascular Mortality and
Morbidity
The potential importance of these serologic derange-
ments can be seen in epidemiologic studies demonstrating
that patients with epilepsy have significantly elevated rates
of CVD and cerebrovascular disease. Investigations from
around the world have shown standardized mortality ratios
for CVD (Table 4), which are 1.52.5 times higher in peo-
ple with epilepsy than in the general population (Annegers
et al., 1984; Nilsson et al., 1997; Ding et al., 2006; Zhu,
2010; Mu et al., 2011; Neligan et al., 2011; Olesen et al.,
2011). Furthermore, two of these studies examined subsets
of the epilepsy population, which excluded patients with
prior stroke; each found that the incidence of CVD remained
elevated (Annegers et al., 1984; Olesen et al., 2011). There-
fore, increased CVD is not restricted to patients with stroke-
related seizures.
CVD may be caused by a number of different pathophysi-
ologic mechanisms. Carotid intima-media thickness is a
measure of atherosclerotic diathesis that has been shown to
correlate strongly with the risk of both stroke and myocar-
dial infarction in all age groups (OLeary et al., 1999). Four
studies of carotid arteries in patients with epilepsy have
demonstrated significantly increased intima-media thick-
ness relative to normal controls (Schwaninger et al., 2000;
Hamed et al., 2007; Tan et al., 2009; Chuang et al., 2012).
The most recent of these confirmed that carotid thickness

Table 4. Vascular mortality and morbidity in patients with epilepsy

Study Study size Standardized ratio 95% CI
Neligan et al. (2011) 19,114 person-years IHD mortality: 1.5* 1.12.0
CBVD mortality: 2.9* 2.13.9
Olesen et al. (2011) 213,000 person-yearsa (epilepsy patients CVD mortality: 1.6* 1.61.7
without prior history of stroke) MI morbidity: 1.1* 1.01.2
Stroke morbidity: 2.2* 2.12.4
Mu et al. (2011) 7,000 person-yearsa Cardiac disease mortality: 1.6 0.55.2
CBVD mortality: 1.1 0.43.6
Ding et al. (2006) 5,000 person-yearsa MI mortality: 10.7* 5.695.3
Gaitatzis et al. (2004) 23,000 person-yearsa IHD morbidity: 1.3* 1.21.5
IHD morbidity, age 1664: 1.6* 1.32.0
CVA morbidity: 7.0* 6.47.6
CVA morbidity, age 1664: 14.2* 12.016.7
Nilsson et al. (1997) 53,250 person-years IHD mortality: 2.5* 2.32.7
CBVD mortality: 5.3* 4.95.8
Annegers et al. (1984) Approached 10,000 person-years IHD mortality: 1.2 0.91.5
IHD mortality, age 2544: 5.7* 1.813.3
IHD mortality, age 4564: 2.5* 1.44.1
IHD morbidity: 1.6* 1.22.2
IHD morbidity, idiopathic epilepsy only: 1.5* 1.02.2
CI, confidence interval; IHD, ischemic heart disease; CBVD, cerebrovascular disease; CVD, cardiovascular disease; MI, myocardial infarction; CVA, cerebrovas-
cular accident.
Data marked with an asterisk* are statistically significant (i.e., the lower limit of the 95% CI is 1).
a
Person-years calculated by author of this section of the review (SM), not directly given in study.

Epilepsia, 54(1):1127, 2013

doi: 10.1111/j.1528-1167.2012.03671.x

increased with enzyme-inducing AEDs but not with the
noninducer lamotrigine, and that duration of treatment was
significantly correlated with arterial wall thickness (Chuang
et al., 2012). These results corroborate the increased CVD
rates described previously and provide confirmatory evi-
dence to suggest that CVD in this population is atheroscle-
rotic in etiology.
There have been few direct studies of the effects of individ-
ual AEDs on the development of CVD. A recent study from
Denmark found that patients treated with carbamazepine had
significantly elevated rates of myocardial infarction and
stroke relative to those treated with valproate, and signifi-
cantly higher mortality from CVD than those treated with
lamotrigine (Olesen et al., 2011). However, the study also
suggested that death from CVD was even more common
among patients taking oxcarbazepine or phenobarbital rela-
tive to those taking carbamazepine, which would not be
expected if excess CVD were solely linked to CYP induction.
Prior to these observations, the only study of CVD and AEDs
used a casecontrol design and arrived at the opposite conclu-
sion: that enzyme-inducing AEDs were associated with lower
cardiovascular mortality (Muuronen et al., 1985). This study
was performed in Finland, which is noteworthy because a ser-
ies of investigations in that population appeared to demon-
strate that CYP induction was associated with reductions in
serum lipids (Luoma et al., 1983, 1985). Clearly, more work
is needed to clarify these conflicting data.
Cardiovascular Drugs
Most statins are extensively metabolized by the CYP sys-
tem and would be expected to have reduced serum levels in
the presence of an enzyme inducer. This interaction has
been directly demonstrated between simvastatin and carba-
mazepine (Ucar et al., 2004), and between atorvastatin and
phenytoin (Bullman et al., 2011). In addition, there is phar-
macoepidemiologic evidence that patients prescribed
enzyme-inducing AEDs required higher doses of statins and
were more likely to be inadequately treated, indicating that
this interaction is clinically relevant (Candrilli et al., 2010).
Verapamil and many dihydropyridine calcium-channel
blockers are extensively metabolized by CYP3A4 and
CYP3A5 and may be subject to enzyme induction (Spina
et al., 1996). There is also extensive interaction between
enzyme-inducing AEDs and warfarin, and in the case of
phenytoin this can be complex, unpredictable, and hazard-
ous (Panegyres & Rischbieth, 1991).
Clinical Utility of
NonEnzyme-Inducing
Antiepileptic Drugs
Given the range of concerns relating to enzyme induction,
it may be worthwhile exploring the riskbenefit balance of
21
Enzyme Induction with AEDs
using only nonenzyme-inducing AEDs, a number of which
are now available for the treatment of newly diagnosed epi-
lepsy (Glauser et al., 2006). Lamotrigine (Marson et al.,
2007) and levetiracetam (Brodie et al., 2007) have efficacy
and tolerability similar to carbamazepine, and both of these
AEDs are recommended in guidelines as first-line treatment
options for newly diagnosed focal epilepsy (Perucca &
Tomson, 2011). In addition, gabapentin, another non
enzyme-inducing agent, has been included in the American
Academy of Neurology guidelines for treatment of newly
diagnosed focal epilepsy (French et al., 2004), although it
may be less efficacious than carbamazepine for this indica-
tion (Marson et al., 2007). For patients with idiopathic gen-
eralized epilepsy, nonenzyme-inducing AED options
include sodium valproate, lamotrigine, and levetiracetam
(Perucca & Tomson, 2011). In summary, several non
enzyme-inducing AEDs are valid treatment options for
newly diagnosed epilepsy. Generic preparations of non
enzyme-inducing AEDs have made these treatments less
costly.
Modern nonenzyme-inducing AEDs may, therefore, be
preferable alternatives to enzyme-inducing AEDs for
adjunctive treatment of refractory epilepsy provided they
have similar efficacy (Mintzer & Mattson, 2009). Although
there are major differences in the pharmacodynamics of
enzyme-inducing and nonenzyme-inducing AEDs, and
outcome of trials are influenced by study population, design,
and choice of dosages, a meta-analysis has recently shown a
similar responder rate for adjunctive treatment with modern
nonenzyme-inducing and enzyme-inducing AEDs (Beyenburg
et al., 2012). The risk ratio of responder rates was close to 1,
and there was no significant difference in outcome between
enzyme-inducing and nonenzyme-inducing AEDs (0.97;
95% confidence interval 0.731.29; p = 0.825) (Beyenburg
et al., 2012).
Although a change in medical regimen is standard epi-
lepsy care for patients with uncontrolled seizures or side
effects, there is a lack of class I evidence on the riskbenefit
balance of switching from enzyme-inducing to non
enzyme-inducing AEDs. One small randomized study in
patients with uncontrolled seizures or side effects on mono-
therapy has suggested that switching to lamotrigine was as
effective as and better tolerated than carbamazepine or
valproate monotherapy (Fakhoury et al., 2004). In a non-
randomized study, patients with uncontrolled seizures had a
slightly, non-significantly higher odds of remission if they
remained on the same drug compared to switching to lamo-
trigine, levetiracetam or topiramate monotherapy (1.66;
95% CI 0.368.42; p = 0.532) (Wang et al., 2012). Lim
et al. (2009) have suggested in a pilot study that it is safe to
switch patients with occasional seizures or no seizures from
phenytoin to levetiracetam monotherapy following craniot-
omy for supratentorial glioma. However, there is currently
no robust evidence to support the contention that switching
to nonenzyme-inducing AEDs in patients with previously
Epilepsia, 54(1):1127, 2013
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22
M. J. Brodie et al.
uncontrolled seizures or side effects is possible without risk-
ing loss of efficacy or worsening tolerability. Definitive
assessment in double-blind, randomized, controlled trials is
needed (Lim et al., 2009). In addition, well-designed trials
are also required to establish whether the newer non
enzyme-inducing AEDs have detrimental effects on the out-
comes of comorbid conditions.
Switching to another AED (including a nonenzyme-
inducing AED) in seizure-free patients seems to carry a sub-
stantial risk of relapse. In one small non-randomized study
in seizure-free patients who were switched from enzyme-
inducing (carbamazepine, phenytoin) to nonenzyme-indu-
cing AEDs (lamotrigine, levetiracetam and topiramate),
seizure recurrence was reported in 5 (21.7%) of 23 patients
(Wang et al., 2012). Among 46 matched controls, 2 (4.3%)
of 46 had seizure recurrence despite an unchanged regimen
(odds of seizure recurrence 6.53, 95% CI 1.0261.19,
p = 0.06). Therefore, the risk of seizure recurrence attribu-
table to AED change was approximately 18% (Wang et al.,
2012). However, other studies have convincingly demon-
strated that continued AED treatment does not guarantee
seizure freedom either. Recurrences have been reported in
as many as 15% of seizure-free patients, despite continued
AED treatment (Medical Research Council Antiepileptic
Drug Withdrawal Study Group, 1991; Sillanpaa & Schmidt,
2006; Brodie et al., 2012). In seizure-free patients with epi-
lepsy, any decision to switch from an enzyme-inducing
AED to a nonenzyme-inducing agent for reasons of poten-
tial comorbidity is difficult to justify based on the available
evidence. We need properly designed trials of seizure out-
come following switching to nonenzyme-inducing AEDs.
Conclusions
In this article we summarized the available evidence
regarding the potential deleterious effects of long-term
enzyme induction with AEDs. Furthermore, we have tried
to highlight areas of uncertainty. Clinical problems can
occur due to pharmacokinetic interactions with other medi-
cations either on introduction of the inducer or due to its
withdrawal. There is also increasing awareness of endoge-
nous, mostly steroid, pathways, relevant in particular to
vitamin D and cholesterol metabolism, which are targets for
this process. Enzyme induction will continue for as long as
the patient takes the inducer and no-one can predict the
health problems that may arise throughout lifes journey.
These observations have implications for the general health
of people with epilepsy.
Whether or not enzyme-inducing AEDs should still be
used as first-line treatment for newly diagnosed epilepsy,
when many other noninducing, equally effective, alterna-
tives are available, remains a point for discussion. A particu-
lar concern is the possibility that enzyme induction could
contribute to the pandemic of vascular disease (Beaglehole
et al., 2011). There are a number of recognized clinical
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
scenarios requiring a switch to a nonenzyme-inducing
AED, particularly in patients requiring pharmacotherapy for
cancer. At the very least, people with epilepsy who are
established on enzyme-inducing AEDs should be screened
regularly for associated long-term problems, such as osteo-
porosis, hyperlipidemia and sexual dysfunction. There
should be communication with the patients other care pro-
viders regarding the potential for harmful pharmacokinetic
interactions. Consideration may be given to switching
patients to nonenzyme-inducing drugs to avoid these com-
plications, particularly if the epilepsy is not fully controlled.
For seizure-free patients, careful weighing of the risks and
benefits of switching is warranted given the paucity of data
regarding its safety. In all such situations, the benefits and
risks of both courses of action should be discussed with the
patient and his or her family. Nevertheless, the policy of
using noninducing AEDs is likely to be cost-effective, since
it avoids the need for higher doses of a wide range of con-
comitant lipid- and nonlipid-soluble drugs.
Search Strategy and
Selection Criteria
References for this review were identified by a series of searches
of Medline from 1948 to July 2011, Derwent Drug File from 1964 to
June 2011, and Embase from 1980 to June 2011. Search terms used
included: enzyme-inducing; antiepileptic drug; anticonvulsant;
UDP-glucuronosyltransferase; glucuronidation induction; aryl
hydrocarbon receptor; pregnane X receptor; drug interaction; immu-
nosuppressant; chemotherapy; cancer; antiretroviral therapy; bone;
reproductive hormones; hormones; endocrine; lipids; cholesterol;
C-reactive protein; lipoprotein(a); homocysteine; atherosclerosis;
myocardial infarction; coronary artery disease; stroke; peripheral
vascular disease; side-effects; pharmacoeconomics; well-being;
mortality; suicidality. Only articles published in English were
reviewed. The final reference list was selected on the basis of
relevance to the broad scope of this review.
Acknowledgments
UCB Pharma supported the development of this project by bringing the
authors together to discuss the format and content of the review. They also
helped to coordinate the initial literature search. A medical writer, Jennifer
Stewart (QXV Communications Ltd, Macclesfield, United Kingdom)
funded by UCB Pharma, was involved in helping with the creation of the
manuscript. Her role included coordinating the author review process, pro-
duction of original figures, formatting of tables and/or figures, verifying the
accuracy of references, editing and formatting the text, obtaining permis-
sion statements for copyright-protected material, collecting author contri-
bution and conflict of interest statements, and assisting with the on-line
submission process by uploading files. All authors prepared, reviewed, and
approved the review for submission. The corresponding author had final
responsibility for the decision to submit for publication. UCB Pharma was
not involved in the production or content of the manuscript.
Disclosure
Martin J Brodie serves on scientific advisory boards for Pfizer Inc, UCB
Pharma, Eisai, GlaxoSmithKline, Novartis, Valeant Pharmaceuticals,

Sanofi Aventis, Lundbeck Inc, Neuronex, and Medtronic; has received
funding for travel from UCB Pharma; serves as a consultant for Eisai;
serves on speakers bureaus for UCB Pharma, GlaxoSmithKline, Pfizer and
Eisai; and has received research support from UCB, Eisai, and Glaxo-
SmithKline. Scott Mintzer has served as a consultant or advisory board
member for Eisai, Sunovion, SK Life Sciences, Supernus Pharmaceuticals,
Upsher-Smith, and Pfizer; has received payment for lectures from UCB
Pharma and GlaxoSmithKline; and receives research support from the
National Institutes of Health. Alison M Pack is a member of a Safety and
Data Monitoring Board for Pfizer, has received research grants from the
National Institutes of Health, and has received royalties from UpToDate
Inc. Barry E Gidal has received payment for lectures from GlaxoSmith-
Kline and UCB Pharma; and serves as a consultant for Upsher-Smith and
Sunovion. Charles J Vecht has received consultancy fees from UCB
Pharma; research grants from UCB Pharma, Eisai, and GlaxoSmithKline;
and funding for travel from UCB Pharma. Dieter Schmidt serves on scien-
tific advisory boards for ViroPharma Inc.; has received funding for travel
from ViroPharma Inc., Sun Pharma, and Novartis; and serves as a consul-
tant for ViroPharma Inc., Sun Pharma, and Novartis. We confirm that we
have read the Journals position on issues involved in ethical publication
and affirm that this report is consistent with those guidelines.
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