Epilepsy

&
Behavior
Epilepsy & Behavior 5 (2004) 301–307
www.elsevier.com/locate/yebeh

Review

Extended-release formulations: simplifying strategies in

the management of antiepileptic drug therapyq
John M. Pellock,a,* Michael C. Smith,b James C. Cloyd,c Basim Uthman,d,e
and B.J. Wilderd
a
Division of Child Neurology, Virginia Commonwealth University, Medical College of Virginia, PO Box 980211 VCU-MCV,
Richmond, VA 23298-0211, USA
b
Rush Epilepsy Center, Rush Medical College, Chicago, IL 60612, USA
c
College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
d
College of Medicine, University of Florida, Gainesville, FL 32606, USA
e
Malcom Randell Department of Veterans Affairs Medical Center, Gainesville, FL 32608, USA
Received 12 December 2003; revised 26 January 2004; accepted 27 January 2004
Available online 27 February 2004

Abstract

Advances in our understanding, diagnosis, and treatment of seizure disorders have transformed the management of epilepsy. As the
number of antiepileptic drugs and their formulations increase, so do the expectations of therapy. Once limited to attaining complete
control of seizures, epilepsy management now strives to enable patients to lead lifestyles consistent with their own capabilities.
Extended-release antiepileptic drug formulations can help achieve the primary treatment goals for many patients with epilepsy:
preventing occurrence of seizures and preventing or reducing side effects. The dosing flexibility and consistency of serum levels (without
marked peak-to-trough fluctuations) conferred by extended-release formulations help achieve these goals. These same attributes of
extended-release formulations may also improve compliance, quality of life, and patient satisfaction with treatment.
Ó 2004 Elsevier Inc. All rights reserved.

Keywords: Divalproex; Carbamazepine; Phenytoin; Extended-release; Epilepsy; Compliance; Once-daily dosing

1. Introduction of adequate AED therapy by an epileptologist. They

Epilepsy is one of the more common neurologic dis-
orders, affecting approximately 1% of the US population,
or 2.75 million people [1,2]. Antiepileptic drugs (AEDs)
remain the cornerstone of therapy. The primary treat-
ment goal is to achieve complete control of seizures
without adverse events. For many patients, however,
becoming seizure-free remains a challenge. Drawing on
data from the Veterans Affairs Epilepsy Cooperative
studies, Mattson et al. [3] assessed the likelihood of pa-
tients remaining seizure-free for 12 months after initiation
q
Proceedings from the a closed meeting supported through an
unrestricted educational grant from Abbott Laboratories (Simplified
Strategies in the Management of AED Therapy) and held on January
18, 2003, in Ixtapa, Mexico.
*
Corresponding author. Fax: 1-804-828-6690.
E-mail address: jpellock@hsc.vcu.edu (J.M. Pellock).
found that the percentage of patients expected to remain
seizure-free ranged from 61 to 70% for those with only
generalized tonic–clonic seizures and from 21 to 28% for
those with only complex partial seizures. Since these
studies were completed, 8 new AEDs have been approved
for the treatment of epilepsy. Despite the availability of
new AEDs, the percentage of patients with epilepsy who
are seizure-free remains relatively unchanged [4].
Issues associated with toxicity and poor adherence to
AED therapy are two common reasons why achieving
seizure freedom is problematic [5–8]. To this end, a recent
strategy in epilepsy management is to simplify AED reg-
imens. One approach has been expanding the use of ex-
tended-release AED formulations. The addition of
extended-release formulations represents a desire to
simplify AED treatment using effective drugs with pre-
dictable and manageable side effect profiles. The follow-
ing discussion presents clinical perspectives on how

1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.yebeh.2004.01.009
302 J.M. Pellock et al. / Epilepsy & Behavior 5 (2004) 301–307
extended-release formulations can improve medication
compliance, modify AED pharmacokinetics, and provide
clinicians with greater ability to individualize therapy.
2. Adherence and complexity of AED regimens
The complexity of a medication regimen (i.e., dosing
frequency, number of drugs), as well as its tolerability,
can influence patient adherence to therapy and, ulti-
mately, seizure control. In a national patient survey of
661 patients with epilepsy, the odds of experiencing a
seizure following a missed dose was highest among those
taking AED therapy four times daily and among those
taking a greater number of pills per day [6]. In a separate
study by the same investigators, improved adherence to
AED therapy was associated with regimens with less
frequent daily dosing [5]. Improvement in AED adher-
ence has also been shown to result in reduced rates of
breakthrough or recurrent seizures [5–8]. In addition,
numerous studies have shown that monotherapy is a
preferred and maximally effective approach for most
patients [4,5,9–11]. Taken together, AEDs that can be
used as monotherapy, are taken once or twice daily, and
require fewer pills at each scheduled dose may minimize
drug-related adherence issues for patients with epilepsy.
3. Pharmacokinetic considerations
One step to simplifying AED regimens is by using
agents that may be administered on a once- or twice-
daily basis. Such an approach requires that the regimen
maintain plasma AED concentrations over the dosing
interval needed for seizure control, while avoiding
Fig. 1. Simulated plasma concentration–time curve at steady state of immediate-release and extended-release antiepileptic drug administered once
daily over 2 days. Adapted from Cloyd JC, personal communication.
plasma concentrations associated with side effects. It is
generally recognized that there is an optimal concen-
tration range for most AEDs. In all patients, however,
there comes a point when administering higher doses of
an AED confers no additional seizure control and may
induce adverse events, including seizure exacerbation.
Immediate-release formulations of AEDs with short
half-lives necessitate frequent administration to main-
tain drug concentrations over the dosing interval [12].
Even with relatively frequent dosing, these formulations
produce wide fluctuations in drug concentrations
throughout the day (Fig. 1). In some patients taking
these formulations, optimal seizure control may require
doses that produce peak drug concentrations (shortly
after dosing) above the optimal therapeutic range for
seizure control/drug tolerability, increasing the likeli-
hood of toxicity. Hoppener et al. [13] followed 43 pa-
tients with epilepsy who took an immediate-release
formulation of carbamazepine and complained of in-
termittent side effects. Patients experienced wide fluctu-
ations in mean serum levels of the active drug
throughout the day (Cmin ¼ 5:0; Cmax ¼ 10:0 mg/L),
and complaints of CNS side effects occurred when serum
blood levels of carbamazepine rose above 8 mg/L.
Just prior to the next dose, drug concentration reach
a trough. If the trough concentration falls below the
minimum effective concentration, seizure control may
become compromised, increasing the risk of break-
through seizures. Inconsistent dosing or missed doses
can also lead to breakthrough seizures and perceived
treatment failure, as was reported in a case series by
Rowan et al. [14].
The use of extended-release technology permits once-
or twice-daily dosing, while minimizing fluctuations in
drug levels over the course of the day (Fig. 1). When
 J.M. Pellock et al. / Epilepsy & Behavior 5 (2004) 301–307
extended-release formulations are used appropriately,
drug levels remain within the patientÕs therapeutic zone,
thereby minimizing or eliminating patient exposure to
fluctuating drug levels that may precipitate side effects
or induce breakthrough seizures. Because extended-re-
lease formulations can reduce peak concentrations, it
may also be possible to adjust doses upward when
needed without precipitating side effects associated with
peak concentrations.
4. Extended-release AED formulations
4.1. Divalproex sodium
The extended-release formulation for divalproex so-
dium (Depakote ER, Abbott Laboratories) is a polymer
matrix technology designed for once-daily administra-
tion. Tablet strengths are 250 and 500 mg. After ad-
ministration, the outer layer of the polymer becomes
partially hydrated, forming a gel layer that permits drug
release. Once the outer layer becomes fully hydrated, it
erodes and is released from the tablet. Fluid continues to
penetrate toward the tablet core, resulting in continued
drug release over an extended period.
Bioavailability studies in both healthy volunteers and
patients with epilepsy have shown that the conventional
formulation and extended-release formulation of dival-
proex sodium are bioequivalent when the extended-re-
lease preparation is dosed 8 to 20% higher than the
standard preparation [15,16]. Sommerville et al. [16]
demonstrated the bioequivalence of the extended-release
formulation of divalproex when given in proportionally
adjusted doses in adult patients with epilepsy (Fig. 2).
The doses of divalproex administered were: conven-
tional formulation 875 to 4250 mg divided into three
doses taken at 8-h intervals and extended-release for-
mulation 1000–5000 mg once daily in the morning.
These results were achieved in patients who were
receiving enzyme-inducing AED therapy (i.e., carbam-
azepine, oxcarbazepine, phenobarbital, phenytoin, pri-
midone, or topiramate), which would be expected to
cause greater fluctuations in valproic acid concentra-
tions. The extended-release formulation of divalproex
produced a lower Cmax (P ¼ 0:0001) and less fluctuation
in valproate plasma concentrations (P < 0:001) com-
pared with standard divalproex. Differences in average
Cmin values were similar in the two groups.
The pharmacokinetic profile of the extended-release
formulation of divalproex has also been assessed in
children and adolescents with epilepsy [17]. A total of 14
children (age range: 8–11 years), 12 adolescents (age
range: 12–17 years), and 14 adults (historical controls)
were included in a phase 1 open-label study. Children
and adolescents were receiving the standard formulation
of divalproex prior to the switch to divalproex extended-
303
Fig. 2. Plasma concentration–time curves for divalproex extended-re-
lease (ER) (once-daily administration) and standard divalproex (ad-
ministered three times daily) in patients with epilepsy. Adapted with
permission, from Sommerville et al. [16].
release. Divalproex extended-release was given once
daily on Days 1 through 6 (range: 250–1750 mg); phar-
macokinetic assessment began prior to and after the fi-
nal dose on Day 7. Plasma valproic acid levels were
similar among children, adolescents, and historical adult
controls. Children exhibited higher clearance per body
weight compared with adolescents and adults.
One report of an uncontrolled case series details the
clinical experience of converting to the extended-release
formulation 20 patients with epilepsy who were receiv-
ing standard divalproex [18]. Seizure types included 6
patients with generalized tonic–clonic seizures (1 with
absence, 1 with complex partial seizures), 12 patients
with complex partial seizures (4 with secondary gen-
eralized, 1 with drop attacks, 1 with absence and drop
attacks, 1 with generalized tonic–clonic, 1 with myo-
clonic, absence), 1 patient with primary generalized, and
another patient with secondary generalized partial sei-
zures. Patients received the extended-release formula-
tion, administered twice daily at doses approximately 10
to 20% higher than the previous total daily dose of
standard divalproex. The incidence of tremors decreased
from 75 to 5% (Fig. 3). Following conversion, there were
also no further reports of weight gain. Further benefits
included a reduction in reports of lethargy, ataxia, and
hair loss among those receiving the extended-release
formulation of divalproex. Additional studies are needed
to confirm these encouraging, preliminary findings.
4.2. Carbamazepine
There are two carbamazepine extended-release for-
mulations; both are designed for twice-daily adminis-
tration. However, the two formulations use different
extended-release technologies. One (Carbatrol, Shire
Pharmaceuticals) uses Microtrol (Shire Pharmaceuti-
cals), a multibeadlet technology. Capsule strengths are
100, 200, and 300 mg. Each capsule contains drug-filled
beadlets of three different sizes. Patterns of release of
304 J.M. Pellock et al. / Epilepsy & Behavior 5 (2004) 301–307

symptoms (P < 0:01). In addition, the monthly seizure

frequency decreased slightly from a median of 1.5 to 1.0
with the extended-release formulation (P ¼ 0:2).

4.3. Phenytoin

The extended-release formulation for phenytoin so-

dium (Phenytek, Bertek Pharmaceuticals; Dilantin
Kapseals, Pfizer Inc.) is an erodible matrix delivery sys-
tem that is designed to release medication in stages as the
capsule and its contents become wet. Capsule strengths
are 200 and 300 mg. The 300-mg capsule contains three
100-mg cylindrical erodible tablets, while the 200-mg
capsule contains two 100-mg cylindrical erodible tablets.
After administration, the extended-release phenytoin
sodium capsule dissolves, which exposes the erodible-
Fig. 3. Reduction in tremors following the conversion to divalproex
matrix tablet. A gel layer forms and drug begins to be
extended-release from the standard preparation. Adapted, with per-
mission, from Zielinski and Smith [18]. released. Over time, the gel layer expands and the matrix
begins to erode, releasing more drug. As the matrix
continues to erode, release of soluble and insoluble drug
drug from the beadlets are a function of the beadlet size continues. This process of extended drug release is lost if
(immediate-, extended-, and enteric-release). The three the capsule is chewed, crushed, or broken open. Thus,
bead types are combined in a specific ratio. Carbatrol the capsule needs to be swallowed whole for the ex-
may be administered orally either as an intact capsule or tended-release technology to work properly. Bioavail-
by sprinkling the contents on food or in a liquid. ability studies in healthy volunteers have shown that the
The other carbamazepine extended-release product 300-mg extended-release phenytoin sodium capsule is
(Tegretol XR, Novartis Pharmaceuticals) uses the Oral bioequivalent to three 100-mg capsules of the immediate-
Osmotic Delivery System (OROS, Alza) technology. release formulation of phenytoin [22].
Tablet strengths are 100, 200, and 400 mg. The tablet
comprises an osmotically active component and an
opening in the capsule covering for drug release. After 5. Initiating therapy with extended-release AEDs
the capsule is administered, fluid expands the osmoti-
cally active portion, which in turn pushes drug through 5.1. Diagnostic considerations
the capsule opening at a fixed rate. This technology re-
quires that the capsule covering remains intact and, Because several conditions have symptoms that re-
therefore, it is not absorbable and is excreted in the feces semble seizures, the first step in diagnosing epilepsy is
unchanged. In addition, this formulation of carbamaz-
epine does not allow for the contents of the capsule to be
sprinkled on food or in a liquid. Bioavailability studies
in patients with epilepsy have shown that the carbam-
azepine extended-release formulations are bioequivalent
to the immediate-release formulations [19,20].
Miller et al. [21] have shown that the central nervous
system (CNS) side effects associated with immediate-re-
lease formulation of carbamazepine were reduced when
patients were switched to an extended-release formula-
tion. A total of 63 patients with partial-onset seizures
had received immediate-release carbamazepine (mean
total daily dose: 961 mg) for 1 year before switching to
the extended-release formulation, which was then ad-
ministered twice daily (mean total daily dose: 989 mg),
for 1 year. Thirty-one patients (48%) had CNS toxicity
during treatment with immediate-release carbamazepine
(i.e., sedation, confusion, dizziness, ataxia, or diplopia) Fig. 4. Reduction in CNS toxicity following the conversion to car-
(Fig. 4). After conversion to the extended-release prep- bamazepine extended-release from the immediate-release preparation.
aration, only 16 (25%) patients continued to have these

P < 0:001. Adapted, with permission, from Miller et al. [21].
 J.M. Pellock et al. / Epilepsy & Behavior 5 (2004) 301–307
confirming that the patient has seizures. Careful history-
taking and correct interpretation of clinical data remain
the cornerstone of accurate diagnosis and successful
treatment. Because the majority of patients with new-
onset seizures are initially treated in the emergency room
or primary care setting, treatment is often started with
incomplete diagnostic information. The certainty of di-
agnosis for both the seizure type and epilepsy syndrome
depends on the extent of workup, including the history/
physical examination and electroencephalogram (EEG)
studies, and appropriate neuroimaging used to assess
brain structure. The urgency/severity of the clinical sit-
uation at presentation and whether the patient is at risk
for a second episode in the near future are additional
factors that affect AED selection.
5.2. Rational choice and sequencing of AEDs
AEDs with seizure-specific efficacy (i.e., effective
against a limited number of seizure types) are useful
when there is relative certainty of diagnosis and char-
acterization of the corresponding seizure type(s). How-
ever, initiating such agents prematurely, before an
accurate diagnosis of seizure type is made, may para-
doxically aggravate or worsen specific seizure types in
some epilepsy syndromes (Table 1) [23]. This is partic-
ularly common in some of the generalized epilepsies.
Further, when combination therapy is used, the likeli-
hood of toxicity or seizure exacerbation may be greater.
While seizure-specific treatment approach is theoret-
ically ideal, it is often not practically possible, especially
in the emergency room, primary care, and managed care
settings. Thus, in cases where precise diagnosis of the
seizure type is lacking, initiating a patient on a broad-
spectrum AED may provide the seizure coverage needed
while diagnostic options are investigated. The use of a
broad-spectrum AED provides a foundation from which
more seizure-specific AEDs may later be selected or
added if additional seizure coverage is needed. Some
clinicians favor this approach. The rational choice and
sequencing of AEDs are not based on a single criterion,
but rather consideration of the patientÕs individual cir-
Table 1
Possible aggravation of seizures or epilepsy syndromes
Absence
Myoclonic
Juvenile myoclonic epilepsy
Lennox–Gastaut syndrome
Benign epilepsy of childhood with centrotemporal spikes
Severe myoclonic epilepsy in infancy
Landau–Kleffner syndrome/electrical status epilepticus
during slow sleep
a
CBZ, carbamazepine; PHT, phenytoin; LTG, lamotrigine; GBP, gabapentin; VGB, vigabatrin; TGB, tiagabine; BDZ, benzodiazepine.
Source: Reprinted, with permission, from Bourgeois [23].
305
cumstances. A few general principles apply to sequenc-
ing AEDs, including efficacy appropriate for a broad
spectrum of patients, mechanisms of action, no evidence
of therapeutic tolerance, favorable safety profile, good
tolerability with dose management techniques, and
simplified monotherapy whenever possible.
5.3. Extended-release formulations
Among the AEDs, only divalproex (a broad-spec-
trum agent), carbamazepine (a seizure-specific drug),
and phenytoin (a seizure-specific drug) are available as
extended-release formulations [23,24]. The extended-re-
lease preparations for divalproex, carbamazepine, and
phenytoin are approved for monotherapy and for ad-
junctive therapy, have well-defined therapeutic concen-
tration ranges, have been shown to decrease the
incidence of common adverse events typically associated
with the standard formulations of each drug, and are
relatively inexpensive. However, clinicians should rec-
ognize that there are differences among these extended-
release formulations that should be considered when
selecting an individualized AED regimen (Table 2). In
addition to the difference in their spectrum of activity,
divalproex and phenytoin extended-release formulations
may be quickly titrated to the desired effect. Carbam-
azepine, due to autoinduction, generally require a longer
titration period, often 10 days to 4 weeks, before the
optimal maintenance dose is attained. In addition, car-
bamazepine autoinduction may necessitate future dose
adjustments as part of dose titration [25]. The bio-
availability of divalproex extended-release is reduced
compared with that of conventional divalproex, which
necessitates a dose adjustment when switching patients
from the standard to the extended-release formulation
(see below).
5.4. Dosing
In patients with newly diagnosed epilepsy, the ex-
tended-release formulation of divalproex should be
initiated at 10 to 15 mg/kg/day. As required for all
CBZa PHT LTG GBP VGB TGB BDZ
+ + + + +
+ + + + +
+ + +
+ + + + + +
+ +
+ + +
+ +
306 J.M. Pellock et al. / Epilepsy & Behavior 5 (2004) 301–307
Table 2
Clinical characteristics of extended-release options
Monotherapy
Add-on therapy
Broad-spectrum AED
Time to titrate to effect when initiating therapy
Dosing frequency
Therapeutic range (mg/L)
Autoinduction
Common adverse events decreased with extended-release
Compilation of data from Levy et al. [24].
divalproex preparations, the dosage should be increased
by 5 to 10 mg/kg/week to achieve an optimal clinical
response, with a recommended maximum dose of 60 mg/
kg/day. Higher doses may be required for some indi-
viduals, especially for those taking enzyme-inducing
AEDs or for younger children [26]. When converting
patients from the standard formulation to the extended-
release formulation of divalproex, the dose of the ex-
tended-release formulation may need to be increased by
approximately 8 to 20%. For example, in patients who
are receiving up to 2250 mg per day of the standard
formulation of divalproex, 250 mg should be added to
the extended-release dosage. For patients receiving
2500 mg per day or more of the standard formulation of
divalproex, 500 mg should be added to the extended-
release dosage for that patient.
In most adults, both extended-release formulations of
carbamazepine can be initiated at 200 mg twice daily.
The dosage should be increased up to 200 mg at 1-week
intervals to achieve optimal clinical response. No dose
conversion is needed for the carbamazepine extended-
release preparations, and therefore the extended-release
preparations can be substituted on a milligram-for-mil-
ligram basis from the standard formulations.
According to prescribing information, once-daily
extended-release phenytoin sodium (either Dilantin or
Phenytek) may be considered for adults if seizure
control is first established with divided doses of three
100-mg capsules of the same formulation. The 300- and
100-mg extended-release phenytoin capsules are bio-
equivalent; hence, no dose conversion is needed. The
200-mg extended-release phenytoin capsule may be
useful in simplifying a dosage regimen when a patient is
taking a daily extended-release phenytoin dose of 200 or
400 mg using the 100-mg capsules. Careful monitoring
is recommended when the use of extended phenytoin
results in a change of dosage forms or brand.
6. Conclusions
Successful long-term treatment of patients with epi-
lepsy requires selection of the appropriate AED, deter-
Divalproex Carbamazepine Phenytoin
Yes Yes Yes
Yes Yes Yes
Yes No No
<1 week 3–5 weeks 7–10 days
Once daily Twice daily Once daily
50–100 3–12 10–20
No Yes No
Yes Yes Yes
mination of the optimal dose, patient compliance, and
clinical observation. Selection of an AED for an indi-
vidual patient is based on many factors, including sei-
zure type/epilepsy syndrome, balance between likely
efficacy versus adverse effects and/or impact on comor-
bidities, pharmacokinetic profile, potential for drug in-
teractions, and preference for monotherapy with first
drug. For example, treatment of epilepsy in the elderly
may benefit from starting with low doses and titrating
slowly upward to the desired effect because of decreased
renal or hepatic clearance with age [27,28]. Additionally,
elderly patients may be most sensitive to fluctuations in
AED serum levels, which may lead to disruption of
therapy due to adverse events, drug interactions, or
noncompliance. Another example are women with epi-
lepsy, who present with a number of special concerns
related to use of oral contraceptives (decreased efficacy
in AEDs that induce liver enzymes), pregnancy (poten-
tial teratogenic effects of AEDs), and menopause (fluc-
tuations in seizure patterns) [29–33].
The availability of different AEDs and formulations
allows the physician the opportunity to individualize
therapy. This is particularly true for children with epi-
lepsy. For example, the general principles of AED
treatment in pediatrics include awareness of age-related
differences in the expression of seizure type and epilepsy
syndrome, consideration of the expected severity of
seizure type, avoidance of AEDs that may worsen cur-
rent medical problems, and knowledge of potential drug
interactions. Whenever possible, it is ideal to use AED
therapy in children that does not require dosing during
school hours. Thus, for children with epilepsy, the va-
riety of formulation options for seizure medication al-
lows physicians to individualize and modify AED
therapy throughout childhood [26,34,35].
A recent addition to the AED armamentarium is
extended-release formulations, which enhance the clini-
cianÕs ability to tailor therapy to the individual patient.
Extended-release formulations improve care associated
with many of the issues noted above. Studies indicate
that extended-release AED formulations provide several
potential benefits for patients with epilepsy, including
the convenience of once- or twice-daily dosing, blunting
 J.M. Pellock et al. / Epilepsy & Behavior 5 (2004) 301–307
of peak/tough fluctuations in drug concentrations,
minimization of troublesome side effects, and potential
improvement in compliance and facilitation of treat-
ment synchronization. For these reasons, extended-re-
lease AED formulations should be considered in
patients with epilepsy when the potential benefits of
these formulations would be advantageous.
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