E, Therapeutic Advances in Drug Safety
`
`Review
`
`New generation antiepileptic drugs:
`what do they offer in terms of improved
`tolerability and safety?
`
`Jacqueline A. French and Deana M. Gazzola
`
`Ther Adv Drug Saf
`
`120111 214) 141-158
`
`DOI: 10.1177/
`2042098611411127
`
`© The Author(s), 2011.
`Reprints and permissions:
`http://www.sagepub.co.uk/
`journalsPermissions.nav
`
`Abstract: Over the last two decades a total of 11 antiepileptic drugs (AEDs) have been intro-
`duced to the US market. Randomized, placebo-controlled trials have yielded information about
`each drug's efficacy, tolerability, and safety profile; however, few studies have compared the
`newer generation AEDs directly with the older generation. Comparative studies are not always
`straightforward in their interpretation, as many characteristics of drugs, both favorable and
`unfavorable, may not be highlighted by such studies. In general, findings from the literature
`suggest that the newer generation AEDs (including vigabatrin, felbamate, gabapentin, lamo-
`trigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, zonisamide, pregabalin, rufina-
`mide, and lacosamide) enjoy both improved tolerability and safety compared with older agents
`such as phenobarbital, phenytoin, carbamazepine, and valproate. This is partially supported by
`some of the findings of the QSS and the TTA Committee of the American Academy of Neurology
`(AAN), whose review of four AEDs (gabapentin, lamotrigine, topiramate, and tiagabine) is dis-
`cussed. Briefly, when compared with carbamazepine, lamotrigine was better tolerated; topir-
`amate adverse events (AEs) were fairly comparable to carbamazepine and valproate; and
`tiagabine compared with placebo was associated with a higher discontinuation rate due to AEs.
`The findings of the SANAD trial are also presented; when administered to patients with partial
`epilepsy, carbamazepine was most likely to fail due to AEs, and lamotrigine and gabapentin
`were least likely to fail due to AEs. When administered to patients with idiopathic generalized
`epilepsy, topiramate was most frequently associated with AE-related discontinuation, followed
`by valproate; and while valproate was the most efficacious drug in this arm of the study,
`lamotrigine was more tolerable. What makes the SANAD study valuable and somewhat unique
`is its head-to-head comparison of one drug with another. Such comparative trials are overall
`lacking for new AEDs, although some conclusions can be drawn from the available data. In the
`end, however, AED selection must be based on individual patient and drug characteristics.
`
`Keywords: adverse event, antiepileptic drug, safety, SANAD, tolerability, toxicity
`
`Introduction
`Determining the most appropriate antiepileptic
`drug (AED) for a patient can be a daunting
`task. A physician's selection is often driven by
`three main drug properties: efficacy, tolerability,
`and safety. Although drug efficacy may be one of
`the most important features to consider, a drug's
`tolerability and safety profile can be the main rea-
`sons a patient becomes disenchanted with and
`discontinues a drug. For years when only a lim-
`ited number of AEDs were available, many
`patients were forced to choose between a life of
`seizures or a life of intolerable drug side effects.
`
`With the newer generation of AEDs came the
`hope of not simply superior efficacy, but also
`reduced adverse events (AEs) and improved
`safety.
`
`The perfect drug would be one that is rapidly
`absorbed, reaches a steady state within one or
`two doses, can be dosed once daily, and does
`not interact with or alter the metabolism of
`other medications. Such a drug would act discri-
`minately at a specific neuronal receptor thus
`avoiding unwanted, extraneous actions. The
`drug would have no untoward side effects,
`
`Correspondence to:
`Jacqueline A. French, MD
`New York University
`School of Medicine, NYU
`Comprehensive Epilepsy
`Center, 223 East 34th
`Street, New York, NY
`10016, USA
`jacqueline.frenchla
`nyumc.org
`
`Deana M. Gazzola, MD
`New York University
`School of Medicine, NYU
`Comprehensive Epilepsy
`Center, New York, NY, USA
`
`http://taw.sagepub.com
`
`ARGENTUM Exhibit 1077
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`would be excellently tolerated by patients, and
`would not cause central nervous system (CNS)
`or systemic toxicities. Unfortunately, such a drug
`does not exist in the current antiepileptic arma-
`mentarium, and epileptologists must select
`among existing drugs to find the optimal choice
`for a given patient.
`
`Antiepileptic drugs can be compared in two ways.
`The first is to identify AEs that occurred in ran-
`domized placebo-controlled add-on trials of one
`drug versus another drug. It is not easy to com-
`pare new and old drugs in this fashion, because
`randomized trials were performed with different
`methodology at the time that the older drugs
`underwent clinical trials. Another way is to per-
`form a randomized head-to-head trial directly
`comparing the new drug with an old drug. This
`has been done for a number of the newer drugs,
`including gabapentin, topiramate, levetiracetam,
`lamotrigine, tiagabine, and vigabatrin. Where
`such data are available, they have been included.
`For the drugs that have only surfaced in the last
`several years, such comparative studies are not
`available. In these cases, common AEs seen in
`placebo-controlled add-on trials have been iden-
`tified. However, it is important to keep in mind
`that add-on trials may amplify the occurrence of
`AEs due to pharmacodynamic factors. For many
`of the brand-new drugs, such as rufinamide and
`lacosamide, side-effect profiles are not available
`for use as monotherapy.
`
`It is important to keep in mind that AEs may be
`experienced very differently by individual
`patients. Also, specific patient characteristics,
`such as age, gender, concomitant therapies, and
`concurrent medical and neurologic conditions
`may increase the likelihood that any given patient
`will experience AEs. It is for this reason that AED
`selection must be individualized.
`
`In light of the above, it is not difficult to under-
`stand why randomized controlled comparison
`trials may not be as useful for selection of ideal
`drugs for a given patient. Controlled trials, by
`their nature, provide an assessment of AE fre-
`quency within populations. Populations consist
`of a number of subpopulations that may react dif-
`ferently, thereby limiting the AE data specificity
`when applied to individual patients. However,
`randomized trials do provide information on
`overall incidence of AEs experienced, and this in
`and of itself can be useful.
`
`Another issue in the comparison of two drugs in a
`head-to-head trial is that of dose. In some trials,
`patients are titrated to the effective dose needed
`to control seizures. In other head-to-head trials,
`however, a single dose is selected for all partici-
`pants. In these cases, the likelihood of AEs will be
`very highly associated with the dose that was
`chosen for the trial. If a high dose was selected,
`this may make the treatment appear less well tol-
`erated. For this reason, we have included doses in
`all of our discussions below.
`
`A number of different categories of AEs may
`occur as a result of administration of medication.
`Head-to-head trials are most useful for assessing
`dose-related AEs. These are AEs that occur in
`few patients at lower doses, whereas at higher
`doses the majority of patients may experience
`them. Head-to-head trials are less useful for
`assessing other types of AEs such as idiosyncratic
`AEs. These include serious drug reactions such
`as Stevens Johnson syndrome, hepatic failure,
`pancreatitis, and aplastic anemia. These events
`tend to occur very infrequently, and often not a
`single event will occur among the several hun-
`dred patients enrolled in a typical head-to-head
`comparison trial. Other types of AEs that are
`poorly evaluated in head-to-head trials are those
`that occur only after the patient has been exposed
`to the drug for some period of time. Examples
`would be cerebellar ataxia from phenytoin
`use, and bone density reduction from enzyme-
`inducing AEDs. Most head-to-head trials involve
`monotherapy. Therefore, the pharmacodynamic
`AEs (those caused by combining one drug with
`another) are not addressed. Another category of
`AEs that is not addressed by head-to-head trials
`is that of teratogenicity. For all of these types of
`AEs, other sources of data will be necessary.
`
`Lastly, a drug's mechanism of action (MOA) may
`help to explain why certain AEs are experienced
`by patients. An extensive review of each AED's
`MOA is beyond the scope of this review; how-
`ever, a summary is provided in Table 1 for the
`reader's reference.
`
`Historical perspective
`In 1857, Sir Charles Locock first used potassium
`bromide to treat patients with catamenial epilepsy
`[Krall et al. 1978; Copelman and Andreev, 1962],
`although who should receive the credit for its
`introduction as a true `antiepileptic' agent is
`debatable [Friedlander, 2000]. Although clinical
`controlled trials were nonexistent, bromides were
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`Table 1. Antiepileptic drugs (AEDs): mechanisms of action.
`
`JA French and DM Gazzola
`
`AED name
`
`The older generation
`Bromides
`
`Phenobarbital (PB)
`Primidone (PRM)
`
`Phenytoin (PHT)
`
`Ethosuximide (ESM)
`
`Carbamazepine (CBZ)
`
`Valproate (VPA)
`
`The newer generation
`Vigabatrin (VGB)
`
`Felbamate (FBM)
`
`Gabapentin (GBP) and pregabalin (PGB)
`
`Lamotrigine (LTG)
`
`Tiagabine (TGB)
`
`Topiramate (TPM)
`
`Levetiracetam (LEV)
`
`Oxcarbazepine (OXC)
`
`Zonisamide (ZNS)
`
`Rufinamide (RFN)
`
`Lacosamide (LCM)
`
`Primary mechanism(s) of action
`
`Unknown; potentially stabilize neuronal membranes via hyperpolarization
`[Ryan and Baumann, 1999]
`Enhance y-aminobutyric acid (GABA) inhibition [Bourgeois, 2011]
`May act synergistically with potassium bromide to reduce high-frequency
`repetitive neuronal firing [Bourgeois, 2011]
`Use-dependent inhibition of sodium channels, thus blocking repetitive firing of
`action potentials [Morita and Glauser, 2011]
`Reduction of low-threshold T-type calcium currents in thalamic neurons
`[Kanner et al. 2011]
`Use-dependent inhibition of sodium channels, thus blocking repetitive firing of
`action potentials [Guerreiro, 2011]
`Precise mechanism unknown; multiple GABA-related actions, N-methyl
`D-aspartate (NMDA) receptor antagonist, and histone deacetylase inhibitor
`[Birnbaum et al. 2011]
`
`Specifically and irreversibly inhibits GABA-T; may also stimulate GABA release
`[Thiele, 2011]
`Binds to open channels of the NMDA subtype glutamate receptor (thus,
`blocking sodium and calcium conduction); also possesses other properties,
`such as inhibition of voltage-gated sodium channels [Faught, 2011]
`Precise mechanism unknown; bind to the a28 modulatory subunit of voltage-
`sensitive calcium channels [Mclean and Gidal, 2011]
`Blocks sodium channels; inhibits high-voltage-activated calcium currents
`[Gilliam and Gidal, 2011]
`Enhances GABA-mediated inhibition by blocking GABA reuptake [Ekstein and
`Schachter, 2011]
`Multiple mechanisms: blocks the kainate/a-amino-3-hydroxy-5-methylisoxa-
`zole-4-proprionic acid (AMPA) glutamate receptor subtype; blocks voltage-
`activated sodium channels; enhances GABA-mediated chloride flux at
`GABAA receptors; reduces amplitude of high-voltage-activated calcium
`currents; and activates potassium conduction [Rosenfeld, 2011].
`Precise mechanism unknown; binds SV2A, a presynaptic protein, on synaptic
`vesicles [Sirven and Drazkowski, 2011]
`Blocks voltage-dependent ionic membrane conduction (particularly sodium,
`potassium, and calcium) thereby stabilizing membranes and reducing syn-
`aptic impulse propagation; acts on N-type calcium channels [Guerreiro and
`Guerreiro, 2011]
`Blocks T-type calcium channels, inhibits slow sodium channels, and inhibits
`glutamate release [Welty, 2011]
`Exact mechanism of action unknown; prolongs inactivation of voltage-depen-
`dent sodium channels [Krauss and Darnley, 2011]
`Selectively enhances the slow inactivation of voltage-gated sodium channels;
`inhibits the collapsing response mediator protein 2 (CRMP-2) thereby pos-
`sibly inhibiting neuronal growth that may occur in chronic epilepsy [Sheth
`and Abram, 2011]
`
`found to reduce seizure frequency and became
`more widely used. Physicians who were dubious
`of their antiepileptic potential combined bromides
`with other agents such as borax and belladonna
`to increase efficacy [Shorvon, 2009; Livingston
`and Pearson, 1953]. Patients treated with bro-
`mides often remained on the drug for long periods
`of time, and many developed side effects including
`but not limited to dose-related drowsiness, rest-
`lessness, headache, delirium, acneiform rashes,
`granulomatous skin lesions, loss of appetite,
`
`and psychosis [Ryan and Baumann, 1999;
`Krall et al. 1978; Livingston and Pearson, 1953].
`Many patients suffered through the AEs of
`bromides likely due to a lack of alternative treat-
`ment options. Their present day use is quite
`uncommon.
`
`Phenobarbital became widely used as a seda-
`tive and hypnotic agent in 1912 and was subse-
`quently recommended for epilepsy treatment
`by Hauptmann in 1919 [Shorvon, 2009].
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`Therapeutic Advances in Drug Safety 2 (41
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`It gradually gained in popularity during the 1920s,
`eventually supplanting bromide therapy as the
`mainstay of epilepsy treatment by the 1940s
`[Shorvon, 2009]. Like bromide therapy, the use
`of phenobarbital was not preceded by formal clin-
`ical trials, its use largely determined by clinical
`experience in the community [Krall et al. 1978].
`Although phenobarbital continues to be an effec-
`tive AED and has less toxicity than bromides
`[Krall et al. 1978] it is not without side effects,
`the more common being sedation, depression,
`and paradoxical hyperactivity in children [West-
`ward, 2009]. Neurologic toxicity (such as ataxia,
`nystagmus, dysarthria) can occur with increased
`doses [Bourgeois, 2011]. More extreme respira-
`tory and circulatory collapse can also occur, par-
`ticularly when toxic amounts of the drug have
`been ingested [Wolf and Forsythe, 1978].
`
`It was not until the introduction of Merritt and
`Putnam's electroshock model of epilepsy that a
`platform existed to test compounds preclinically
`for their antiepileptic potential [Putnam and
`Merritt, 1937]. Prior to its introduction to the
`market in 1938, phenytoin underwent preclinical
`testing using the Merritt—Putnam animal (cat)
`electroshock model, demonstrating its efficacy
`in seizure prevention [Putnam and Merritt,
`1937]. This was a pivotal event in the future
`shaping of preclinical drug trials. Soon thereafter
`safety requirements were added via the Federal
`Food, Drug, and Cosmetic Act of 1938 in order
`for a drug to receive approval [Krall et al. 1978].
`The introduction of toxicity testing by Goodman
`followed in 1949 [Krall et al. 1978]. Over the
`ensuing years more regulations and requirements
`were added, increasing the cost of drug develop-
`ment but also leading to improved understanding
`of potential toxicities of agents. It is likely in large
`part due to the latter evolution in drug develop-
`ment that present-day AEDs in general are safer
`and better tolerated by patients. Tolerability and
`safety of the new generation AEDs was addressed
`in 2004 by the Therapeutics and Technology
`Assessment (TTA) Subcommittee and the
`Quality Standards Subcommittee (QSS); com-
`parisons were made between the newer genera-
`tion and older generation of drugs. The findings
`and conclusions are discussed below.
`
`Adverse effects and safety profiles of specific
`AEDs: new versus old
`The tolerability and toxicities of two older gener-
`ation AEDs (bromides and phenobarbital) were
`discussed in the previous section. Phenytoin,
`
`which was introduced in 1938 and later officially
`approved by the US Food and Drug
`Administration (FDA) in 1953, is known for its
`various side effects affecting the CNS and other
`organ systems, including but not limited to nys-
`tagmus, ataxia, diplopia, drowsiness, impaired
`concentration, gingival hyperplasia, hirsutism,
`acne, hepatotoxicity, and idiosyncratic reactions
`including lupus-like reactions and aplastic
`anemia [Morita and Glauser, 2011; Ziegler,
`1978]. Ethosuximide was marketed in 1960,
`and possesses a fairly narrow therapeutic indica-
`tion for absence epilepsy. Its AE profile includes
`but is not limited to nausea, abdominal discom-
`fort, anorexia, drowsiness, dizziness, and numer-
`ous idiosyncratic reactions [Goren and Onat,
`2007]. Carbamazepine was introduced in 1974.
`Common AEs include drowsiness, loss of coordi-
`nation, vertigo, and weight gain [Hogan et al.
`2000; Pellock, 1987]. Rash, hyponatremia, leu-
`copenia, rare cases of hepatotoxicity, and other
`idiosyncratic reactions have also been reported
`[Bjornsson, 2008; Dong et al. 2005; Tohen
`et al. 1995; Mattson et al. 1985]. Valproate
`came to the market in 1978 and has since been asso-
`ciated with various side effects, some of the more
`common and/or formidable being dose-related
`tremor (less with controlled-release formulations),
`hair loss, weight gain, nausea, vomiting, hepatotox-
`icity, acute hemorrhagic pancreatitis, thrombocy-
`topenia, and hyperammonemia; lethargy is also
`reported, but less commonly [Gerstner et al.
`2008; Rinnerthaler et al. 2005; Davis et al. 1994].
`Valproate is also associated with the greatest risk for
`major congenital malformations (MCMs) among
`the existing AEDs [Morrow et aL 2006]. Dates of
`introduction to the US market of both the older
`generation and newer generation AEDs are pro-
`vided in Table 2.
`
`A 10-center Veterans Administration (VA)
`Center study conducted in the 1980s compared
`the efficacy, toxicity, and tolerability of carba-
`mazepine, phenobarbital, phenytoin, and primi-
`done in partial and secondarily generalized
`tonic—clonic seizures [Mattson et al. 1985].
`They found that primidone caused a higher inci-
`dence of intolerable side effects such as nausea,
`vomiting, dizziness, and sedation compared with
`the other agents [Mattson et al. 1985].
`Phenobarbital was associated with the lowest
`incidence of motor disturbance and gastrointes-
`tinal (GI) side effects compared to the other
`AEDs, but with more sedation and hyperactivity,
`while phenytoin caused more dysmorphic side
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`Table 2. Introduction of old and new generation antiepileptic drugs (AEDs).
`Time of approval for use in the United States
`
`AED name
`
`JA French and DM Gazzola
`
`The older generation
`Bromides
`Phenobarbital (PB) and other barbiturates
`Phenytoin (PHT)
`Ethosuximide (ESM1
`Carbamazepine (CBZ)
`Valproate (VPA)
`The newer generation
`Vigabatrin (VGB)
`Felbamate (FBM)
`Gabapentin (GBP)
`Lamotrigine (LTG)
`Tiagabine (TGB)
`Topiramate (1-PM)
`Levetiracetam (LEV)
`Oxcarbazepine (0XC)
`Zonisamide (ZNS)
`Pregabalin (PGB)
`Rufinamide (RFN)
`Lacosamide (LCM)
`
`*Indicates time of development.
`FDA, US Food and Drug Administration.
`
`1857*
`1920s-1940s*
`1938*; approved in 1953 by the FDA
`1960
`1974
`1978
`
`Received initial approval in Europe in 1989, approved for use in the US in 2009
`1993
`1993
`1994
`1997
`1997
`1999
`2000
`2000
`2005
`2008
`2009
`
`effects and rash. Toxicity alone was least likely to
`cause patient dropouts in those patients on car-
`bamazepine therapy, which appeared to be better
`tolerated by patients. Overall, potentially life-
`threatening side effects were rare, with one case
`each of lymphoma and a lupus-like syndrome in
`patients treated with phenytoin, and two cases of
`transient psychosis with primidone [Mattson
`et al. 1985]. Laboratory abnormalities (decreases
`in white blood cell counts and elevations in liver
`enzymes) were documented commonly, but no
`clinically important changes were noted
`[Mattson et al. 1985].
`
`Numerous randomized controlled trials have
`compared the efficacy and tolerability of newer
`generation AEDs to the older drugs [Beghi,
`2004; Perucca, 2002]. In 2004, the QSS and
`the TTA Committee of the American Academy
`of Neurology (AAN) developed a practice param-
`eter which considered the efficacy and tolerability
`of newer generation AEDs, including gabapentin,
`lamotrigine, topiramate, tiagabine, oxcarbaze-
`pine, levetiracetam, and zonisamide [French
`et al. 2004]. An extensive review of the literature
`dating from 1987-2003 was conducted. One
`major question the meta-analysis sought to
`answer was 'How do the efficacy and tolerability
`of the new AEDs compare with those of older
`AEDs in patients with newly diagnosed epilepsy?'
`[French et al. 2004].
`
`Breaking the QSS/TTA study down by drug
`
`Gabapen tin
`One class I study [Chadwick et al. 1998] was
`found comparing three different doses of gaba-
`pentin (300, 900, and 1800 mg/day) with carba-
`mazepine dosed at 600 mg/day; discontinuation
`rate due to AEs was higher in the carbamaze-
`pine-treated patients than among the higher-
`dosed gabapentin-treated patients, with dizziness,
`fatigue, and somnolence more frequent in
`the carbamazepine-treated group. Pooled infor-
`mation from four class I add-on placebo-
`controlled trials [Anhut et al. 1999; The US
`Gabapentin Study Group No. 5, 1993; Sivenius
`et al. 1991; UK Gabapentin Study Group, 1990]
`revealed a discontinuation rate due to AEs of
`3-11.5% in gabapentin-treated patients [French
`et al. 2004]. Again, the most frequent AEs were
`somnolence, dizziness, and fatigue [French et al.
`2004]. Reports of serious idiosyncratic reactions
`to gabapentin have been few. Gabapentin is not
`known to cause blood dyscrasias, hepatic toxicity,
`Stevens Johnson syndrome or serious hypersensi-
`tivity syndromes.
`
`Lamotrigine
`Three studies were analyzed: one comparing the
`efficacy and safety of lamotrigine (titrated to
`150 mg/day) versus immediate-release carbamaze-
`pine (titrated to 600 mg/day) [Brodie et al. 1995];
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`one comparing efficacy and safety of lamotrigine
`(maximum dose of 500 mg/day) in elderly
`patients with immediate-release carbamazepine
`(maximum dose of 2000 mg/day) [Brodie et al.
`1999]; and one comparing lamotrigine (dosed
`between 150-400 mg/day) with phenytoin
`(dosed at 300-600 mg/day) [Steiner et al. 1999].
`The two lamotrigine versus carbamazepine studies
`found that a higher number of patients experi-
`enced side effects resulting in discontinuation
`when taking carbamazepine, and one study
`found a significantly higher rate of rash in the
`carbamazepine-treated group [French et al.
`2004]. Interestingly, the lamotrigine versus phe-
`nytoin study found a fairly similar discontinuation
`rate due to AEs in each treatment group; however,
`a higher incidence of asthenia, somnolence and
`ataxia was noted in the phenytoin-treated group.
`Rash occurred more frequently in the lamotrigine
`group. Lamotrigine is not known to cause hepa-
`totoxicity. However, it is associated with serious
`hypersensitivity reactions that increase in fre-
`quency with rapidity of titration, with decreasing
`age, and with concomitant valproate use. This
`has led to the current recommendation of very
`slow initiation. Nonetheless, Stevens Johnson
`syndrome, toxic epidermal necrolysis and other
`hypersensitivity reactions occur at a frequency
`of between 1 and 10 per 10,000 new users
`[Mockenhaupt et al. 2005]. Other neurologic
`AEs include dizziness, nausea, and headache
`most commonly, particularly when administered
`in combination with valproate [Steiner et al.
`1999].
`
`Topiramate
`One study compared the efficacy and safety of
`different doses of topiramate (100 and 200 mg/
`day) with valproate (1250 mg/day) and carba-
`mazepine (600 mg/day) [Privitera et al. 2003].
`Discontinuation rates due to AEs were fairly
`comparable between the three drugs, ranging
`between 19% and 28% in the topiramate-treated
`patients (varied based on dose used), 23% in the
`valproate-treated patients, and 25% in the carba-
`mazepine-treated patients [Privitera et al. 2003].
`Topiramate is not associated with blood dyscra-
`sias. Rare hepatic failure has been reported, par-
`ticularly with concomitant valproate use [Bumb
`et aL 2003]. The most common idiosyncratic
`adverse event associated with topiramate use is
`renal calculi, which may occur in 1.5% of
`patients with chronic use [Shorvon, 1996].
`Other side effects include paresthesias, hypohy-
`drosis (especially in children), and metabolic
`
`acidosis. Cognitive impairment, including diffi-
`culty with naming and memory can occur in a
`dose-dependent fashion [Loring et al. 2011].
`
`Tiagabine
`Tiagabine has found limited use as an add-on
`agent in partial epilepsy largely due to its rare
`association with nonconvulsive status epilepticus
`[Eckardt and Steinhoff, 1998]. Overall, it is a
`well-tolerated medication, the most common
`AEs being dizziness, asthenia, amnesia, nervous-
`ness, and abdominal pain [Kalviainen et al. 1998;
`Schacter et al. 1998; Sachdeo et al. 1997]. Three
`studies [Uthman et al. 1998; Sachdeo et al. 1997;
`Richens et al. 1993] were included in the QSS
`and TTA meta-analysis; tiagabine doses ranging
`from 15 to 56 mg/day were used as add-on
`therapy in patients with partial epilepsy. The dis-
`continuation rate due to AEs from tiagabine
`ranged from 8% to 20% in patients on drug,
`compared to 8 to 9% for patients on placebo
`[French et al. 2004]. The five most frequent
`AEs were dizziness, tremor, abnormal thinking,
`nervousness, and abdominal pain [French et al.
`2004].
`
`Other studies not included in the original QSS
`and TTA meta-analysis have compared
`tiagabine more directly with other AEDs. A
`head-to-head trial assessing the effects of tiaga-
`carbamazepine
`bine (8-80 mg/day)
`versus
`(200-2000 mg/day) and phenytoin (60-1000 mg/
`day) on mood and cognition was performed by
`Dodrill and colleagues; there were no significant
`differences among the three agents [Dodrill et al.
`2000]. A separate multicenter, open-label, ran-
`domized, parallel group study compared the effi-
`cacy, tolerability, and safety of two dosing
`regimens (target dose of 40 mg/day divided into
`either two or three doses) of tiagabine as adjunc-
`tive therapy in patients with partial seizures.
`A total of 77 patients (44%) on twice-daily tiaga-
`bine and 58 (33.7%) on thrice-daily tiagabine
`withdrew from the study [Biraben et al. 2001].
`Of these, 46 (26.3%) and 37 (21.5%) withdrew
`due to AEs; somnolence, dizziness, asthenia, and
`tremor were the most frequent [Biraben et al.
`2001]. Five patients in the twice-daily group
`and two patients in the thrice-daily group had a
`serious AE (confusion in two patients, psychosis,
`depression and dysarthria, and amblyopia and
`paranoia) [Biraben et al. 2001]. There were no
`notable changes in mean clinical chemistry
`values from baseline for both treatment groups,
`and no clinically significant changes in
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`hematology values or vital signs were observed
`during the study [Biraben et al. 2001].
`
`While other idiosyncratic AEs are uncommon
`with tiagabine, as noted above the serious idio-
`syncratic adverse event associated with its use has
`been nonconvulsive status epilepticus [Koepp
`et aL 2005].
`
`Oxcarbazepine
`Three class I studies and one class II study
`were found which compared oxcarbazepine
`with older AEDs; the first study [Bill et aL
`1997] compared oxcarbazepine (600-2100 mg/
`day) with phenytoin (100-560 mg/day); the
`second study [Christe et al. 1997] compared
`oxcarbazepine (600-2400 mg/day) with valpro-
`ate (600-2700 mg/day); the third study [Dam
`et al. 1989] compared oxcarbazepine
`(300-1800 mg/day) with immediate-release car-
`bamazepine (300-1400 mg/day); and the fourth
`study [Guerreiro et al. 1997] compared oxcar-
`bazepine (100-1350 mg/day) with phenytoin
`(100-400 mg/day) in children and adolescents.
`In both studies comparing oxcarbazepine with
`phenytoin, and in the oxcarbazepine versus
`immediate-release carbamazepine study, oxcar-
`bazepine was better tolerated with lower discon-
`tinuation rates among the oxcarbazepine-treated
`groups. There were no differences in discontin-
`uation due to AEs, however, in the oxcarbaze-
`pine versus valproate study.
`
`Some of the more common AEs associated with
`oxcarbazepine include fatigue, headache, dizzi-
`ness, ataxia, diplopia, nausea, vomiting, rash,
`and others [Guerreiro and Guerreiro, 2011;
`Bill et al. 1997; Christe et al. 1997; Guerreiro
`et al. 1997; Dam et al. 1989]. Oxcarbazepine
`use has also been associated with several safety
`issues, including hyponatremia (with 2.7% of
`patients having a serum sodium of <125 mmol/L)
`[Harden, 2000], allergic rash, and Stevens Johnson
`syndrome.
`
`Zonisamide
`Two class I placebo-controlled studies [Faught
`et al. 2001; Schmidt et al. 1993] which compared
`zonisamide (at doses of 20 mg/kg in the Schmidt
`and colleagues study, and doses of 100, 200, and
`400 mg/day in the study by Faught and col-
`leagues) with placebo were reviewed. The discon-
`tinuation rates were 10% for both placebo and
`zonisamide-treated patients. Fatigue, dizziness,
`somnolence, anorexia, and abnormal thinking
`
`were the five most common AEs reported;
`others included renal calculi, rash, and depres-
`sion [French et al. 2004].
`
`A more recent study by Zaccara and Specchio,
`not included in the initial TTA and QQS report,
`reviewed nine open-label studies in which
`patients received zonisamide (doses ranging
`between 50 and 1100 mg/day) for at least
`6 months as either add-on or monotherapy
`[Zaccara and Specchio, 2009]. Between 4% and
`24% of patients discontinued the experimental
`drug due to AEs (most commonly somnolence
`and dizziness); anorexia, headache, nausea, and
`irritability were also commonly noted [Zaccara
`and Specchio, 2009]. Oligohydrosis, rash, and
`weight loss have been documented, with renal
`stones a rare occurrence [Kothare and Kaleyias,
`2008]. Pooled safety data from all US/European
`clinical trials identified 15/1296 (1.2%) patients
`with symptomatic renal calculi [Kothare and
`Kaleyias, 2008]. Across all placebo-controlled
`studies with zonisamide, treatment-related AEs
`were reported for 61% and 49% of zonisamide
`versus placebo, respectively [Brodie and
`Mansbach, 2008]. However, these AEs were gen-
`erally of mild-to-moderate severity. Zonisamide
`tolerability is improved with slower drug titration
`[Baulac and Leppick, 2007]. Postmarketing data
`from the United States and Japan, which includes
`information from over 1 million patients and
`2 million patient-years of exposure, supports a
`relatively benign safety profile of zonisamide
`[Brodie a al. 2005].
`
`Levetiracetam
`Three class I studies (two add-on studies and one
`monotherapy study) were included in the meta-
`analysis [Ben-Menachem and Flater, 2000;
`Cereghino et al. 2000; Shorvon et al. 2000].
`Discontinuation of levetiracetam (doses ranging
`from 1000 to 3000 mg/day) due to AEs ranged
`between 7% and 13% (compared with placebo
`discontinuation of 5-8%), but the rate of discon-
`tinuation was unrelated to levetiracetam dose
`[French et aL 2004]. However, in a separate
`study which initiated levetiracetam at high
`doses (2000 or 4000 mg/day) without titration,
`higher rates of somnolence and asthenia were
`noted on the higher dose of drug [Betts et al.
`2000]. Overall, dizziness, somnolence, asthenia,
`headache, and infection were the most frequently
`reported AEs [French et al. 2004], with behav-
`ioral problems, depression, and psychosis also
`noted.
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`Therapeutic Advances in Drug Safety 2 (4)
`
`A second 1-year follow-up study of
`levetiracetam used as add-on therapy at doses of
`250-3000 mg/day, not included in the initial TTA
`and QQS report, also found levetiracetam to be
`well tolerated, with AEs leading to 17 discontinu-
`ations (N= 98) [Ben-Menachem and Gilland,
`2003]. Tiredness was the primary AE, with low
`numbers of patients also reporting irritation,
`pruritis, increased seizures, and psychosis
`[Ben-Menachem and Gilland, 2003]. When com-
`pared with phenytoin (dosed at 200-800 mg/day)
`in a separate study assessing efficacy and
`tolerability in patients who had undergone supra-
`tentorial neurosurgery, levetiracetam (dosed at
`500-3000 mg/day) was associated with signifi-
`cantly fewer early AEs than phenytoin, and had
`a higher 1