Levetiracetam in the treatment of epilepsy
`
`E X P E RT O P I N I O N
`
`Bassel Abou-Khalil
`Department of Neurology, Vanderbilt
`University Medical Center, Nashville,
`Tennessee, USA
`
`Correspondence: Bassel Abou-Khalil
`Vanderbilt University Department of
`Neurology, A-0118 Medical Center
`North, Nashville, TN 37232-2551, USA
`Tel +1 615 936 0060
`Fax +1 615 936 0223
`Email bassel.abou-khalil@vanderbilt.edu
`
`Abstract: Epilepsy is a common chronic disorder that requires long-term antiepileptic drug
`therapy. Approximately one half of patients fail the initial antiepileptic drug and about 35%
`are refractory to medical therapy, highlighting the continued need for more effective and
`better tolerated drugs. Levetiracetam is an antiepileptic drug marketed since 2000. Its novel
`mechanism of action is modulation of synaptic neurotransmitter release through binding to
`the synaptic vesicle protein SV2A in the brain. Its pharmacokinetic advantages include rapid
`and almost complete absorption, minimal insignifi cant binding to plasma protein, absence of
`enzyme induction, absence of interactions with other drugs, and partial metabolism outside
`the liver. The availability of an intravenous preparation is yet another advantage. It has been
`demonstrated effective as adjunctive therapy for refractory partial-onset seizures, primary
`generalized tonic-clonic seizures, and myoclonic seizures of juvenile myoclonic epilepsy. In
`addition, it was found equivalent to controlled release carbamazepine as fi rst-line therapy for
`partial-onset seizures, both in effi cacy and tolerability. Its main adverse effects in randomized
`adjunctive trials in adults have been somnolence, asthenia, infection, and dizziness. In children,
`the behavioral adverse effects of hostility and nervousness were also noted. Levetiracetam is
`an important addition to the treatment of epilepsy.
`Keywords: epilepsy, seizures, antiepileptic drugs, long-term therapy, effi cacy, safety, leve-
`tiracetam
`
`Introduction – long-term management
`considerations in epilepsy
`Epilepsy is a chronic condition characterized by recurrent unprovoked epileptic seizures.
`Epileptic seizures are the clinical manifestations including symptoms and signs of an
`abnormal, excessive, and hypersynchronous electrical discharge of neurons in the
`brain. Thus, a seizure is a symptom. Epilepsy is a condition; it cannot be considered a
`disease because it can be caused by many etiologies. Epilepsy may be genetic or could
`be the result of a variety of insults to the brain, including head trauma, stroke, vascular
`malformations, or congenital brain malformations (Engel 2001). Because seizures
`and epilepsy are very heterogeneous they have to be classifi ed. The most widely used
`classifi cation is that proposed by the International League Against Epilepsy in 1981,
`dividing seizures into those that are partial and those that are generalized (Commission
`1981). Partial seizures are ones in which the fi rst clinical and electrographic changes
`suggest initial activation limited to part of one cerebral hemisphere. Partial seizures
`are further subdivided into simple partial, complex partial and partial becoming
`generalized. Simple partial seizures are those in which awareness and responsiveness
`are completely preserved. Complex partial seizures involve at least an alteration of
`responsiveness or awareness. Secondarily generalized seizures can start either as simple
`partial or complex partial, but then spread to the whole brain and most often manifest
`towards their later part with generalized tonic and then clonic activity. Generalized
`seizures are those in which the fi rst clinical changes indicate initial involvement of
`both hemispheres. Consciousness is usually impaired at onset, except for myoclonic
`ARGENTUM Exhibit 1157
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
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`Neuropsychiatric Disease and Treatment 2008:4(3) 507–523
`© 2008 Dove Medical Press Limited. All rights reserved
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`Abou-Khalil
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`seizures which are too brief for altered consciousness to be
`appreciated. Motor manifestations are bilateral if they occur.
`The initial electrographic ictal patterns are bilateral. General-
`ized seizure types include generalized absence, generalized
`myoclonic, generalized tonic, generalized clonic, generalized
`tonic clonic, and generalized atonic seizures.
`In addition to the classifi cation of epileptic seizures, the
`International League Against Epilepsy proposed a classifi -
`cation of epilepsies and epileptic syndromes (Commission
`1981, 1989). Since most patients have either partial seizure
`types or generalized seizure types, the two main subdivisions
`in the classifi cation are partial (focal, local, or localization-
`related) epilepsies, and generalized epilepsies. Each of these
`major categories is sub-classifi ed into those epilepsies that
`are idiopathic and presumed genetic or symptomatic/cryp-
`togenic (probably symptomatic), related to a brain insult. In
`general, idiopathic epilepsies respond better to treatment than
`symptomatic epilepsies. Within this epilepsy classifi cation
`are epileptic syndromes that are characterized by a specifi c
`range of age at onset, specifi c seizure types, specifi c natural
`history or course, and specifi c response to treatment. For
`example, juvenile myoclonic epilepsy is a type of idiopathic
`generalized epilepsy in which patients have generalized
`myoclonic seizures, particularly after awakening, general-
`ized tonic clonic seizures (in about 90%), and generalized
`absence seizures (in about 30% of cases). In this syndrome,
`the electroencephalogram (EEG) shows generalized
`4–6 Hz spike-and-wave discharges in between seizures.
`These patients respond well to treatment but their epilepsy is
`a lifelong condition (Renganathan and Delanty 2003). Some
`forms of epilepsy are known to have a limited course, with
`remission expected. For example, benign childhood epilepsy
`with centrotemporal spikes, also called benign rolandic epi-
`lepsy, is an epileptic syndrome in which seizures are usually
`infrequent, easily controlled, and remit at puberty (Wirrell
`1998). However, most epilepsies are chronic and require
`long-term therapy.
`The treatment of epilepsy will depend on appropriate
`classifi cation of the seizure type and the epileptic syndrome,
`then the choice of an antiepileptic drug (AED) that is most
`appropriate for the seizure type and epileptic syndrome
`and also the safest and most appropriate for the patient’s
`particular medical background. The treatment of epilepsy
`should always begin with monotherapy, using a low initial
`dose and titrating slowly. Among the more than sixteen
`marketed antiepileptic drugs approximately one half are
`older agents marketed before 1980, while the rest were
`marketed after 1990 (Table 1) (Schachter 2007). The older
`
`AEDs were generally approved for marketing and even
`used as fi rst-line agents without undergoing the rigorous
`clinical trials now required of the newer antiepileptic drugs.
`Regulatory approval for the new AEDs is restricted to the
`specifi c epilepsy patient populations in whom the drug has
`demonstrated effi cacy and to the specifi c mode of use in the
`relevant clinical trial. For example, a new AED will receive
`approval for fi rst-line monotherapy use only if demonstrated
`effective as fi rst-line monotherapy in a sound clinical trial.
`If the new AED is not started as fi rst-line monotherapy,
`but monotherapy is achieved after removal of an existing
`AED, then the regulatory approval will be for conversion to
`monotherapy only. Among the newer AEDs, the vast major-
`ity were initially tested and approved for use as adjunctive
`therapy. Monotherapy trials typically followed later. Such
`trials have earned several AEDs approval for monotherapy
`use. However, the regulatory agencies are not uniform in
`their criteria for approval of AED indications: some agents
`have been approved for monotherapy in Europe but not in
`the US.
`If seizures continue despite maximum tolerated doses
`of the fi rst AED, a change in therapy is indicated. Although
`an alternative monotherapy is usually recommended at this
`point, there is no scientifi c evidence to support the strategy
`of alternative monotherapy over adjunctive therapy (Kwan
`and Brodie 2000b; Beghi et al 2003). In general, common
`sense would decree that if the fi rst drug is not tolerated or
`if it is totally ineffective, alternative monotherapy is the
`best approach. If the fi rst drug was well tolerated and was
`at least partially effective, adjunctive therapy could be
`considered. The choice of fi rst alternative monotherapy or
`add-on therapy depends on several factors, including safety,
`tolerability, effi cacy in clinical trials, ease of use, potential
`for rapid titration, pharmacokinetic interactions, effi cacy in
`co-morbidities, and less prominently mechanism of action. If
`adjunctive therapy is chosen, potential interactions between
`the fi rst and the second AED are important factors in the
`choice of AED (Patsalos and Perucca 2003). Patients who
`fail a second AED are much less likely to become seizure
`free with the third next AED than those who have failed
`only one AED (Kwan and Brodie 2000a). After failure of
`two or three AEDs, patients with partial epilepsy should be
`considered for epilepsy surgery, which is highly effective
`in certain “surgically remediable” epileptic syndromes such
`as temporal lobe epilepsy with hippocampal sclerosis or
`focal epilepsy associated with certain benign brain lesions.
`Patients who are not excellent candidates for epilepsy
`surgery can undergo additional AED trials, including AED
`
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`
`Table 1 Spectrum of effi cacy of standard (A), and new AEDs (B). The new AEDs are listed in the order of their marketing in the US,
`following approval by the US Food and Drug Administration
`Partial
`+
`+
`+
`+
`+
`-
`+
`+
`+b
`+b
`+b
`+b
`+b
`+b
`+*
`+b
`+b
`
`Levetiracetam safety and effi cacy
`
`G absence
`-
`-
`+
`-
`-
`+
`+
`+
`
`?
`-
`+b
`?
`-
`-
`?
`?
`-
`
`A
`
`B
`
`Phenytoin
`Carbamazepine
`Valproate
`Phenobarbital
`Primidone
`Ethosuximide
`Methsuximide
`Clonazepam
`
`Felbamate
`Gabapentina
`Lamotriginea
`Topiramatea
`Tiagabine
`Oxcarbazepinea
`Levetiracetama
`Zonisamide
`Pregabalin
`
`1ary GTC
`+
`+
`+
`+
`+
`-
`?
`+
`+
`-
`+b
`+b
`?
`+?
`+b
`+
`?
`
`G myoclonic
`-
`-
`+
`-
`+
`-
`?
`+
`
`?
`-
`?
`?
`-
`-
`+b
`+
`-
`
`aNew AED with positive initial monotherapy trials.
`bNew AED effi cacy indication supported by blinded trials.
`
`combinations. In general it is advisable to avoid combinations
`of more than three AEDs because of the risk of interactions
`and additive adverse effects. Non-pharmacological therapies
`such as vagus nerve stimulation and the ketogenic diet or
`modifi ed Atkins diet can also be considered in patients who
`fail to respond to or are unable to tolerate antiepileptic drugs.
`However, vagus nerve stimulation is unlikely to produce
`seizure freedom, and compliance with the ketogenic or Atkins
`diet can be a major challenge.
`Even though the landmark study of Kwan and Brodie
`suggested that the chances of seizure freedom with a new
`AED decrease with the failure of each additional AED, one
`survey of patients who failed epilepsy surgery evaluation
`found that 21% had achieved seizure remission at follow
`up, most often due to the addition of one of the new AEDs
`(Selwa et al 2003). Levetiracetam, the focus of this review
`is one of these new AEDs.
`
`Levetiracetam
`Levetiracetam (LEV) is one of the newest AEDs, marketed
`worldwide only since 2000. It was initially approved in the
`US only as adjunctive therapy for partial-onset seizures.
`However, more recent trials earned it approval as adjunctive
`therapy for primary generalized tonic-clonic seizures and
`myoclonic seizures of juvenile myoclonic epilepsy, and a
`recent comparative monotherapy trial earned it approval for
`use as initial monotherapy in the European Union, though
`not in the US. In addition, the recent approval and marketing
`
`of an intravenous preparation has added to the versatility
`of this AED.
`
`Levetiracetam pharmacology
`LEV is rapidly and almost completely absorbed after oral
`intake, with peak plasma concentrations approximately one
`hour after oral administration. Food reduces the peak plasma
`concentration by 20% and delays it by 1.5 hours, but does not
`reduce LEV bioavailability (Patsalos 2000, 2003). There is a
`linear relationship between LEV dose and LEV serum level
`over a dose range of 500–5000 mg (Radtke 2001). LEV pro-
`tein binding, at less than 10%, is not clinically relevant. LEV
`metabolism is not dependent on the liver cytochrome P450
`enzyme system. LEV is predominantly excreted unchanged
`through the kidneys, with only about 27% metabolized.
`The main metabolic pathway is hydrolysis of the acetamide
`group in the blood (Radtke 2001). The resultant metabolite
`generated is inactive. LEV plasma half-life is 7 ± 1 hours
`in adults, but can be prolonged by an average of 2.5 hours
`in the elderly, most likely due to decreased creatinine clear-
`ance with age (French 2001; Hirsch et al 2007). In patients
`with impaired renal function, a dose adjustment is needed,
`dependent on the creatinine clearance (French 2001). The
`absence of hepatic metabolism and of protein binding predict
`absence of pharmacokinetic interactions (Nicolas et al 1999).
`Indeed, no pharmacokinetic interactions were observed
`with phenytoin, warfarin, digoxin, or oral contraceptives
`(Browne et al 2000; Levy et al 2001; Patsalos 2000, 2003;
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`Abou-Khalil
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`Ragueneau-Majlessi et al 2001, 2002; Abou-Khalil et al
`2003; Coupez et al 2003). However, some studies have sug-
`gested lower LEV levels or higher LEV clearance in patients
`taking enzyme-inducing AEDs (May et al 2003; Perucca
`et al 2003; Hirsch et al 2007). Autoinduction probably does
`not occur with LEV, but one study involving short intensive
`monitoring suggested a drop in serum levels after the fi fth
`day of administration (Stefan et al 2006).
`
`Westin et al 2008). Both studies found plasma concentrations
`to be signifi cantly lower during the third trimester in com-
`parison with baseline. The mean concentration-to-dose ratio
`in the third trimester was 50%–30% of that at baseline. This
`suggested that the elimination of LEV may be enhanced dur-
`ing pregnancy. However, there was great variability between
`patients, such that the change in serum concentration could
`not be accurately predicted.
`
`Intravenous levetiracetam
`The intravenous formulation of LEV was demonstrated
`bioequivalent to the oral formulation (Ramael et al 2006b).
`In the initial study 1,500 mg of LEV were injected over
`15 minutes (Ramael et al 2006b). The infusion was well toler-
`ated and adverse effects were similar to those with oral LEV,
`though somnolence was more common with the intravenous
`administration. In a second study, higher doses and faster
`infusion rates were used (2,000, 3,000, and 4,000 mg over
`15 min; 1,500, 2,000, and 2,500 mg over 5 min) (Ramael et al
`2006a). The most common adverse experiences, dizziness
`and somnolence, were not clearly related to dose or infusion
`rate. As expected, the peak plasma level was reached at
`5 or 15 minutes, corresponding to the end of the infusion, but
`otherwise the pharmacokinetic profi le was similar to that of
`oral LEV. LEV infusion over 15 minutes was demonstrated
`to be a practical alternative in epilepsy patients unable to
`take the oral medication (Baulac et al 2007).
`
`Pharmacology in children, infants, and neonates
`Pharmacokinetics in children were studied in 15 boys and
`nine girls 6–12 years old who received a single dose of LEV,
`20 mg/kg as an adjunct to their stable regimen of a single
`concomitant AED (Pellock et al 2001). The half-life was
`6 ± 1.1 hours. The C-max and area under the curve were lower
`in children than in adults and renal clearance was higher.
`The apparent body clearance was 1.43 ± 0.36 mL/min/kg,
`30%–40% higher in children than in adults. In another study
`in younger children and infants, the same dose/Kg was
`administered as a 10% oral solution to thirteen subjects aged
`2.3–46.2 months. The mean half-life was 5.3 ± 1.3 hours
`in this younger group (Glauser et al 2007). The half-life is
`likely longer in neonates. Two studies estimated LEV half-
`life in the neonate at 18 hours (Allegaert et al 2006; Tomson
`et al 2007).
`
`Pharmacokinetics during pregnancy
`Maternal plasma concentrations measured during the third
`trimester were compared to a “baseline” before pregnancy
`or after delivery in two small studies (Tomson et al 2007;
`
`Serum levels
`LEV has linear kinetics, such that in any individual the
`serum concentration is proportional to the dose (Patsalos
`2004). However, the effective serum level for LEV is not
`known. One study in 69 patients taking 500–3000 mg/day
`found that the trough plasma concentration ranged from 1.1
`to 33.5 µg/mL (Lancelin et al 2007). Similar mean concen-
`trations were found in patients experiencing adverse effects
`and those without adverse effects (11.2 vs 10.9 µg/mL).
`The mean plasma concentrations in responders and non-
`responders were 12.9 and 9.5 µg/mL. The difference was not
`signifi cant, but the authors suggested that 11 µg/mL could
`be a threshold concentration for a therapeutic response. The
`vast majority of patients in this study had refractory epilepsy,
`making it diffi cult to study the effective plasma concentration
`of LEV. Such a study is best conducted in patients with new
`onset epilepsy. A trial comparing LEV and carbamazepine
`in newly diagnosed patients did not report plasma concentra-
`tions (Brodie et al 2007). However, it found that most patients
`were seizure-free at the lowest LEV dose of 1000 mg/day. In
`the therapeutic drug monitoring study mentioned earlier, a
`daily dose of 1000 mg/day was associated with a mean trough
`level of 6.5 ± 2.4 µg/mL (Lancelin et al 2007). Even though
`a therapeutic and toxic LEV concentration are not defi ned,
`measuring the serum concentration is helpful to assess
`compliance. In addition, if a baseline serum concentration is
`obtained during a period of good seizure control, the serum
`concentration can be repeated with breakthrough seizures to
`assess if a drop in concentration played a role. Finally, moni-
`toring serum concentration through the course of pregnancy
`can help with calculating the recommended dose adjustments
`needed to correct for increased clearance.
`
`Putative mechanism of action
`LEV is different in its mechanism from that of other AEDs,
`because it is not effective in the standard animal models used
`to screen for anticonvulsant activity, while it is effective
`in the chronic kindling model (Loscher and Honack 1993;
`Klitgaard et al 1998). It was recently established that the
`
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`
`most relevant LEV mechanism of action is through binding
`to the synaptic vesicle protein SV2A (Lynch et al 2004). The
`SV2A binding affi nity of LEV derivatives correlated strongly
`with their binding affi nity in the brain, as well as with their
`ability to protect against seizures in the audiogenic mouse
`model (Lynch et al 2004). Similar fi ndings were noted in the
`mouse corneal kindling model and the GAERS rat model
`of generalized absence epilepsy (Kaminski et al 2008). The
`specifi c effect of LEV binding to SV2A appears to be a reduc-
`tion in the rate of vesicle release (Yang et al 2007). LEV has
`other mechanisms of action that likely play a comparatively
`smaller role: reversing the inhibition of neuronal GABA- and
`glycine-gated currents by the negative allosteric modulators
`zinc and ß-carbolines (Rigo et al 2002), and partial depression
`of the N calcium current (Niespodziany et al 2001; Lukyanetz
`et al 2002). At present, the mechanisms of action have not yet
`helped identify a specifi c clinical effi cacy profi le for LEV.
`
`Levetiracetam effi cacy – pivotal double-
`blinded randomized controlled trials
`Adjunctive therapy in refractory partial epilepsy
`in adults
`LEV was found effi cacious in 3 pivotal placebo-controlled
`randomized blinded clinical trials in adults with refrac-
`tory partial epilepsy. These trials investigated three doses,
`1000, 2000, and 3000 mg/day. All three doses were found
`to be effective. The US trial compared 1000 mg/day and
`3000 mg/day (in two divided doses) with placebo (Cereghino
`et al 2000). The study randomized 294 patients, 268 of whom
`completed the 14 weeks of treatment. After a 12-week single-
`blind baseline, LEV was titrated over 4 weeks. Patients
`in the 1000 mg/day group fi rst received 333 mg/day for
`2 weeks, then 666 mg/day for 2 weeks, while patients in
`the 3000 mg/day group received 1000 mg/day for 2 weeks
`and then 2000 mg/day for 2 weeks. The median percentage
`reduction in seizures over baseline was 32.5% for LEV
`1000 mg/day and 37.1% for LEV 3000 mg/day as compared
`with 6.8% for placebo. The 50% responder rates were 33%
`for 1000 mg/day and 39.8% for 3000 mg/day, compared
`with 10.8% for placebo. Seizure freedom was noted in 3% of
`patients in the 1000 mg group and 8% of the 3000 mg group.
`No patients were seizure-free in the placebo group. Maximum
`effi cacy was already present in the fi rst visit 2 weeks after
`initiating titration.
`The European placebo-controlled randomized double-
`blind trial compared 2000 mg/day, 1000 mg/day, and placebo
`as add-on treatment (Shorvon et al 2000). Patients random-
`ized to 2000 mg/day received 500 mg bid for 2 weeks, then
`
`Levetiracetam safety and effi cacy
`
`1000 mg bid while patients randomized to 1000 mg/day
`received placebo for 2 weeks, then 500 mg bid. The 4-week
`titration period was followed by a 12-week maintenance
`phase. Out of 324 randomized patients, 278 completed the
`study. There was a 26.5% median seizure reduction from
`baseline for the 2000 mg/day group, 17.7% for the 1000
`mg/day group, and 6.1% for the placebo group. The 50%
`responder rate was 31.6% for the 2000 mg/day group, 22.8%
`for the 1000 mg/day group, and 10.4% for the placebo
`group. Two percent of the 2000 mg patients, 5% of the 1000
`mg patients, and 1% of the 112 mg placebo patients were
`seizure free. In both the US and European trials, both doses
`tested were more effi cacious than the placebo, but were not
`signifi cantly different from each other.
`A third pivotal trial, also conducted in Europe, only com-
`pared 3000 mg per day to a placebo (Ben-Menachem and
`Falter 2000). After the baseline phase, patients randomized to
`LEV received 1000 mg/day for 2 weeks, then 2000 mg/day
`for 2 weeks before receiving 3000 mg/day for the remainder
`of the trial. The median reduction in seizure frequency from
`baseline was 39.9% for LEV compared with 7.2% for pla-
`cebo. The responder rate was 50% for LEV compared with
`16.7% for placebo. Seizure freedom was reported in 8.2% of
`LEV patients compared with 1% of placebo patients.
`The fi ndings from the above trials were confi rmed in
`a smaller blinded trial (94 patients) conducted in Taiwan,
`comparing adjunctive 2000 mg/day of LEV to placebo (Tsai
`et al 2006). The responder rate in the LEV group was 53.5%
`compared with 10.6% in the placebo group. Seizure freedom
`was observed in 8.7% of LEV patients, but none of the
`placebo patients.
`The three main pivotal trials received a number of post
`hoc analyses. Two of these analyses addressed the latency
`for onset of action of LEV. In one study, it was found that the
`increase in proportion of seizure-free patients over baseline
`was 15% for the fi rst day of treatment and 17% for second
`and third days of treatment for 1000 mg/day, all statistically
`signifi cant (French and Arrigo 2005). However the increases
`for 333 mg/day were 7% for Day 1 and 9% for the second
`and third days. These were not signifi cant. There were no
`major changes in the placebo group. In a second analysis,
`the mean proportion of seizure-free days were as computed
`during each week after initiation of treatment (French et al
`2005). The mean proportion of seizure-free days was greater
`in the LEV than the placebo group and the difference was
`observed as early as the fi rst week after initiation of treat-
`ment. Interestingly, it was also greatest at that point in time,
`after which it dropped but remained fairly stable. A similar
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`Abou-Khalil
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`observation was made in the Taiwanese study, with initial
`69% reduction in seizure frequency at the 2-week visit after
`starting LEV, compared with only 37.5% reduction at the
`end of the study (Tsai et al 2006).
`Another post hoc analysis addressed the number of
`seizure-free days (Leppik et al 2003a). Addition of LEV
`increased the number of days without seizures by 5.19 per
`quarter. An additional analysis addressed the affect of LEV
`on subtypes of partial seizures in the pooled data from the
`three major pivotal trials (Leppik et al 2003b). A statistically
`signifi cant reduction in the frequency of all partial seizures
`subtypes was observed. In addition, there was an independent
`reduction of secondarily generalized seizures over and above
`the reduction of partial seizures.
`
`Add-on treatment for refractory partial
`seizures in children
`One pediatric double-blind, placebo-controlled, randomized
`trial was performed in the US (Glauser et al 2006), in which
`216 patients were randomized, but 198 patients provided
`evaluable data. The target dose of LEV was 60 mg/kg/day
`in 2 divided doses. Patients fi rst received 20 mg/kg/day for
`2 weeks, then 40 mg/kg/day for 2 weeks before reaching the
`fi nal target dose. Patients unable to tolerate 60 mg/kg/day
`could be reduced to 40 mg/kg/day. The median percent-
`age seizure reduction from baseline was 43.8% for LEV
`compared with 23.3% for placebo. For the whole treatment
`period, the median reduction was 43.3% for LEV compared
`with 16.3% for placebo. The 50% responder rate was 44.6%
`for LEV and 19.6% for placebo. The above results were all
`statistically signifi cant in favor of LEV. Seizure freedom
`was reported in 6.9% of LEV patients compared to 1% of
`placebo patients.
`
`Monotherapy in new onset epilepsy
`LEV was compared to controlled release carbamazepine in
`patients with newly diagnosed epilepsy in a double-blind
`trial (Brodie et al 2007). Patients enrolled in the study were
`adults with 2 or more partial or generalized tonic-clonic
`seizures in the previous year. The initial dose assigned was
`either LEV 500 mg twice a day or controlled-release carba-
`mazepine (CBZ-CR) 200 mg twice a day. The dose could
`then be increased if a seizure occurred within 26 weeks of
`stabilization, with a maximum of 1,500 mg bid of LEV or
`600 mg bid of CBZ-CR. Patients who were seizure free for
`6 months continued on treatment for another 6 months. The
`intent to treat population included 285 patients randomly
`assigned to LEV and 291 patients assigned to CBZ-CR.
`
`The per protocol population (no major protocol deviations
`affecting effi cacy) included 237 and 235 patients at 6 months
`and 228 and 224 patients at 1 year for LEV and CBZ-CR. At
`6 months, 73% of LEV and 72.8% of CBZ-CR patients were
`seizure free, and at 1 year 56.6% of LEV and 58.5% of CBZ-
`CR patients were seizure free, based on the per protocol
`population. Withdrawal rates for adverse events were 14.4%
`with LEV and 19.2% with CBZ-CR, based on the intent to
`treat population. The difference was not signifi cant.
`Approximately 80% of patients experienced at least one
`adverse event in both groups. There was not much difference
`between the two groups with respect to the adverse events
`reported, except that more patients in the LEV group reported
`depression and insomnia while more patients in the CBZ-
`CR group reported back pain. This study was unique among
`comparative newly diagnosed epilepsy trials in that it used a
`controlled-release preparation of carbamazepine. It also had
`a fl exibility in dosing that gave each agent the best chances
`of success with limited adverse experiences. The lowest dose
`levels produced seizure freedom at 6 months in the major-
`ity of patients in both groups (59.1% of LEV patients and
`62.1% of CBZ-CR patients). Thus, 80.1% of LEV patients
`who were seizure free at 6 months did become seizure free
`at the starting dose (Brodie et al 2007).
`This adequately powered study showed that LEV was
`not inferior to CBZ-CR in the treatment of newly diagnosed
`patients with epilepsy. Based on the results LEV was granted
`an indication for monotherapy in newly diagnosed patients
`in the European Union. However, this trial did not satisfy
`US Federal Drug Administration (FDA) requirements for
`monotherapy indications.
`
`Adjunctive therapy in patients with idiopathic
`generalized epilepsy and generalized
`tonic-clonic seizures
`LEV was compared with placebo as add-on therapy in a
`double-blind study in patients with idiopathic generalized
`epilepsy (Berkovic et al 2007). Patients were required to
`have at least 3 generalized tonic-clonic seizures during
`an 8-week (4-week retrospective and 4-week prospective)
`baseline. The study allowed enrollment of patients aged
`4–65 years. However, only about 10% of patients were
`under 16 years of age. Patients were receiving one or two
`baseline antiepileptic drugs. The dose of LEV used was
`3,000 mg/day or 60 mg/kg/day for children younger than
`16 years and weighing less than 50 kg. At the end of the base-
`line period patients were started on LEV 1,000 mg/day for
`2 weeks, then 2,000 mg/day for 2 weeks, then 3,000 mg/day.
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`The corresponding doses for children were 20 mg/kg/day, 40
`mg/kg/day, then 60 mg/kg/day. Patients unable to tolerate
`the fi nal target dose were allowed to reduce their dose back
`to the previous value of 2,000 mg/day or 40 mg/kg/day. The
`primary effi cacy parameter was reduction in generalized
`tonic-clonic seizure frequency from baseline. A total of 164
`patients were randomized, 80 to LEV, and 84 to placebo. In
`each group 70 patients completed the evaluation. The primary
`effi cacy variable was signifi cant in favor of the LEV-treated
`group: the mean percentage reduction in weekly frequency
`was 56.5% for LEV and 28.2% for placebo (p = 0.004), and
`the median percentage reduction was 77.6% for LEV and
`44.6% for placebo (p ⬍ 0.001). The 50% responder rate
`was 72.2% for LEV and 45.2% for placebo (p ⬍ 0.001). As
`previously noted in the add-on trials for partial epilepsy, there
`was a rapid onset of action with 64.6% of patients classifi ed
`as responders at the lowest dose of 1,000 mg/day. There was
`no evidence of seizure exacerbation; fewer patients in the
`LEV than in the placebo group experienced a 25% or greater
`increase in GTC frequency. The percentage of GTC seizure-
`free patients was 34.2% in the LEV and 10.7% in the placebo
`groups (p ⬍ 0.001). A slightly smaller percentage of patients
`were free of all seizure types (24.1 vs 8.3%; p = 2.009). LEV
`was well tolerated in this trial, with only 1.3% of LEV and
`4.8% of placebo patients discontinuing treatment due to an
`adverse experience. The proportion of patients with at least
`one adverse experience was comparable in the two groups.
`Fatigue, somnolence, headache, and irritability were the only
`adverse experiences considered drug-related and reported in
`more than 5% of patients. This trial earned LEV approval
`for adjunctive therapy in the treatment of generalized tonic-
`clonic seizures in idiopathic generalized epilepsy.
`
`Adjunctive therapy in patients with refractory
`myoclonic seizures
`LEV was recently studied in a double-blind multicenter
`randomized placebo-controlled study trial in adolescents and
`adults with idiopathic generalized epilepsy with myoclonic
`seizures (Noachtar et al 2008). Patients had to be 12 years or
`older and had to be experiencing at least 8 days with myo-
`clonic seizures during the 8-week baseline period. The study
`design included a single-blind baseline period of 8 weeks, a
`4-week titration period, and a 12-week maintenance period.
`Patients were started on 1,000 mg/day of LEV for 2 weeks,
`then 2,000 mg/day for 2 weeks, then 3,000 mg/day for the
`maintenance period. Patients unable to tolerate this dose
`were allowed to reduce their dose to the previous level
`of 2,000 mg/day. The primary effi cacy endpoint was the
`
`Levetiracetam safety and effi cacy
`
`responder rate with respect to the number of days with
`myoclonic seizures. Of the 122 patients randomized, the vast
`majority had a diagnosis of juvenile myoclonic epilepsy.
`Sixty p