Brief Review Article
`
`JPPT
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`Use of Lacosamide in Children with Refractory Epilepsy
`
`Marcia L. Buck, PharmD1,2 and Howard P. Goodkin, MD, PhD2,3
`
`Departments of 1Pharmacy Services, 2Pediatrics, and 3Neurology, University of Virginia, Charlottesville, Virginia
`
`OBJECTIVES..Lacosamide.was.approved.by.the.US.Food.and.Drug.Administration.in.2008.for.adjunctive.
`therapy.for.focal.onset.seizures.in.patients.17.years.of.age.and.older..The.efficacy.of.this.agent.in.adults.has.
`led.clinicians.to.consider.lacosamide.for.children.with.refractory.seizures.
`METHODS..The.MEDLINE.database.(1950-June.2012).was.searched.for.abstracts.containing.lacosamide.
`as.the.key.term..Additional.references.were.obtained.from.the.manufacturer.and.the.bibliographies.of.
`the.articles.reviewed..All.available.English-language.case.reports.and.clinical.trials.were.included.in.the.
`evaluation.
`RESULTS..Several.case.series.studies.have.been.published.which.support.the.use.of.lacosamide.in.children.
`with.refractory.seizures..In.the.papers.published.to.date,.30%.to.50%.of.children.experienced.at.least.a.50%.
`reduction.in.seizure.frequency,.similar.to.results.obtained.in.clinical.trials.in.adults..Children.with.focal.on-
`set.seizures.were.most.likely.to.benefit.from.treatment,.while.results.in.children.with.generalized.seizures.
`or.multiple.seizure.types.were.mixed..Adverse.effects.in.children.were.similar.to.those.seen.in.adults,.with.
`dizziness,.headache,.and.nausea.occurring.most.frequently..Lack.of.efficacy.has.been.the.most.common.
`cause.of.discontinuation.
`CONCLUSIONS..Lacosamide.appears.to.be.a.useful.adjunct.therapy.in.children.with.refractory.seizures..
`Clinical.trials.are.under.way.that.may.provide.more.definitive.information.on.the.efficacy.and.safety.of.
`lacosamide.in.children.and.allow.clinicians.to.determine.the.appropriate.place.of.this.antiseizure.drug.in.
`pediatric.epilepsy.management.
`
`INDEX TERMS.child,.epilepsy,.lacosamide,.Lennox-Gastaut.syndrome,.partial-onset.seizures
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`J.Pediatr.Pharmacol.Ther 2012;17(3):211–219
`
`INTRODUCTION
`
`and provides preliminary recommendations for
`lacosamide use in children.
`
`Lacosamide (Vimpat, UCB, Inc., Smyrna, GA)
`was approved by the United States Food and
`Drug Administration (FDA) on October 28, 2008,
`for use as an adjunctive agent in the treatment
`of focal onset seizures in patients 17 years of age
`and older.1–3 Its unique mechanism of action, lack
`of significant drug interactions, relatively mild
`adverse effect profile, and availability in an intra-
`venous (IV) dosage form have made lacosamide
`a useful addition to treatment with traditional an-
`tiseizure drugs.3 While not yet approved for use
`in the pediatric population, preliminary reports
`suggest it may have a role in the management
`of refractory epilepsy (seizures not controlled
`with one to three antiseizure drugs). This review
`summarizes information in the current literature
`
`MECHANISM OF ACTION
`
`Lacosamide, (R)-2-acetamido-N-benzyl-3-
`methoxypropionamide (Figure 1), is a functional-
`ized amino acid that selectively enhances slow
`inactivation of voltage-gated sodium channels,
`increasing the proportion of sodium channels
`unavailable for depolarization. This enhance-
`ment of the slow inactivation of the voltage-
`gated sodium channels produces stabilization of
`neuronal membranes and inhibition of sustained
`repetitive neuronal firing (Figure 2). Unlike other
`anticonvulsants, including carbamazepine, felb-
`amate, lamotrigine, oxcarbazepine, phenytoin,
`and topiramate, lacosamide does not alter fast
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`Figure 1..Chemical.Structure.of.Lacosamide.[(R)-2-aceta-
`mido-N-benzyl-3-methoxypropionamide]
`
`inactivation of voltage-gated sodium channels.
`Lacosamide may also interact with collapsin
`response mediator protein 2 (CRMP-2);4 how-
`ever, this binding has recently been challenged.5
`CRMP-2 is part of a signal transduction cascade
`of neurotrophic factors involved in neuronal
`differentiation, regulation of gene expression,
`polarization, and axonal outgrowth. It has been
`proposed that binding at CRMP-2 could produce
`a neuroprotective effect, reducing glutamate-
`induced excitotoxicity and enhancing the clinical
`efficacy of lacosamide.
`
`FORMULATION
`
`Lacosamide is available as an injection for
`IV administration, as well as in tablet and oral
`solution forms. The 200 mg/20 mL single-dose
`vial contains sodium chloride and water as inac-
`tive ingredients. The pH is adjusted to achieve
`a pH between 3.5 and 5 with hydrochloric acid.
`Oral lacosamide is available in 50-, 100-, 150-,
`and 200-mg tablets. Inactive ingredients include
`colloidal silicon dioxide, crospovidone, hydroxy-
`propylcellulose, hypromellose, magnesium state,
`microcrystalline cellulose, polyethylene glycol,
`polyvinyl alcohol, talc, titanium dioxide, and
`red, black, or yellow iron oxide and FD&C Blue
`no. 2 or indigo carmine aluminum lake as color-
`ing agents. The 10 mg/mL strawberry-flavored
`lacosamide oral solution contains water, sorbitol,
`glycerin, polyethylene glycol, carboxymethylcel-
`lulose sodium, acesulfame potassium, methyl-
`paraben, anhydrous citric acid, sodium chloride,
`aspartame, and maltol.3
`
`PHARMACOKINETICS
`
`A study of the pharmacokinetic profile of lacos-
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`Buck ML, et al
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`amide in children is currently under way. The
`phase 2 trial (clinical trial NCT00938431) is a mul-
`ticenter study of children between 1 month and
`17 years of age.6 Patients will be randomized to
`receive lacosamide oral solution at doses ranging
`from 8 to 12 mg/kg/day. In adults, lacosamide
`is completely absorbed after oral administration,
`with a bioavailability of approximately 100%.2,3
`Food does not alter the rate or extent of absorp-
`tion. Maximum serum concentrations occur 0.5
`to 4 hours after an oral dose. The volume of dis-
`tribution of lacosamide is approximately 0.6 L/
`kg. Most studies suggest a low degree of protein
`binding (approximately 15%).
`The elimination half-life of lacosamide in
`adults ranges from 12 to 16 hours. An estimated
`40% of the lacosamide dose is excreted as un-
`changed drug; conversion to O-desmethyl-
`lacosamide, an inactive metabolite, by CYP2C19,
`CYP2C9, and CYP3A4 accounts for another 20%
`to 30%. Genetic polymorphism does not appear
`to produce clinically significant changes in lacos-
`amide pharmacokinetics, as lacosamide doses in
`extensive metabolizers and poor metabolizers
`of CYP2C19 have produced similar plasma con-
`centrations. Area under the concentration curve
`(AUC) is increased by 25% in patients with mild
`to moderate renal impairment (creatinine clear-
`
`Figure 2..Mechanism.of.Action.for.Lacosamide.
`AMPA,.α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic.
`acid.receptor;.K,.potassium;.NMDA,.N-Methyl-D-aspartic.
`acid;.VG-Ca2+,.voltage.gates.calcium.channels;.VG-Na+,.
`voltage.gates.sodium.channels
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`J Pediatr Pharmacol Ther 2012 Vol. 17 No. 3 • www.jppt.org
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`Lacosamide Use in Children
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`Table 1..Adverse.Effects.Associated.with.Lacosamide.
`Adverse Effect*
`Incidence of Effect
`Lacosamide
`Placebo
`(n=944)
`(n=364)
`31%
`8%
`Dizziness
`13%
`9%
`Headache
`11%
`2%
`Diplopia
`11%
`4%
`Nausea
`9%
`3%
`Vomiting
`9%
`6%
`Fatigue
`Blurred.vision
`8%
`3%
`8%
`2%
`Ataxia
`7%
`5%
`Somnolence
`7%
`4%
`Tremor
`5%
`4%
`Nystagmus
`* Adverse effects reported in ≥5% of patients
`
`ance, 30-80 mL/min) and by 60% in those with
`severe renal impairment (creatinine clearance,
`≤30 mL/min). In patients with moderate hepatic
`impairment (Child-Pugh class B), the AUC of
`lacosamide is increased by approximately 50% to
`60%. Lacosamide has not been studied in patients
`with severe hepatic impairment.
`
`ADVERSE EFFECTS
`
`Lacosamide is generally well tolerated. In
`pooled data from placebo-controlled clinical tri-
`als in adults, the most frequent reactions were
`dizziness, headache, diplopia, and nausea (Table
`1).3,7,8 Most adverse effects seen with lacosamide
`are dose-related and are reversible upon discon-
`tinuation or dose reduction. Discontinuation of
`therapy as the result of an adverse effect has
`been reported in 8% of adults receiving 200 mg/
`day, 17% of those taking 400 mg/day, and 29%
`of patients taking 600 mg/day.3 Intravenous ad-
`ministration of lacosamide has been associated
`with injection site pain or discomfort in 2.5% of
`patients, venous irritation in 1%, and erythema
`in 0.5%. Similar adverse effect data have been
`observed in pediatric case reports and case series,
`with dizziness and nausea being the commonly
`reported reactions (Table 2). In addition to the
`somnolence, dizziness, and headache observed
`in both children and adults, the four available
`pediatric case series have also reported central
`nervous system findings of irritability, oral tics,
`and prolonged crying.9–12
`Elevations in alanine transaminase up to three
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`times the upper limit of normal were reported in
`0.7% of adults receiving lacosamide in premar-
`keting clinical trials.3 Those changes resolved
`with discontinuation of therapy. A healthy adult
`volunteer enrolled in a clinical trial experienced
`acute hepatitis, with transaminase concentrations
`more than 20 times the upper limit of normal,
`and nephritis 10 days after stopping lacosamide,
`consistent with a delayed multiorgan hypersen-
`sitivity reaction. The patient recovered within
`a month with no apparent sequelae. Two other
`cases of rash with concurrent increased serum
`transaminase concentrations have been reported
`to the manufacturer, as well as a patient who
`developed myocarditis and hepatitis after start-
`ing lacosamide.3 Hypersensitivity to lacosamide
`has also presented as acute angioedema in adults
`being treated for refractory status epilepticus.13
`There have been no reports of abnormalities in
`serum transaminases or angioedema in children
`treated with lacosamide, but one case of facial
`edema has been documented,12 and close moni-
`toring is warranted in any patient suspected of
`having a lacosamide-induced hypersensitivity
`reaction.
`Lacosamide has been shown to produce a
`dose-related increase in the PR interval dur-
`ing electrocardiographic (ECG) monitoring
`in both healthy volunteers and patients with
`epilepsy.3,7,8,14,15 This effect is likely the result of
`lacosamide enhancement of slow inactivation
`of voltage-gated sodium channels. The change
`appears to be proportional to the lacosamide
`dose, with a maximum increase of 7.3 ms in pa-
`tients taking 400 mg/day and 11.9 ms in those
`taking 800 mg/day. Asymptomatic first-degree
`atrioventricular (AV) block was reported in 0.4%
`of adults with focal onset epilepsy and in 0.5%
`of adults with diabetic neuropathy participat-
`ing in premarketing clinical trials. Second- or
`third-degree AV block has been identified in
`only a small number of patients, with most
`cases coming from postmarketing reports in
`adults being treated for diabetic neuropathy.
`A case of second-degree AV block in a patient
`with epilepsy was recently described.15 The
`patient, a 45-year-old man, was admitted with
`palpitations, dyspnea, and exercise intolerance.
`His medications included desmopressin, hydro-
`cortisone, levothyroxine, somatropin, alfuzosin,
`risedronate, carbamazepine, oxcarbazepine, and
`lacosamide, 200 mg once daily. Lacosamide had
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`Table 2..Pediatric.Lacosamide.Case.Series.and.Retrospective.Studies8-11.
`
`Study
`
`No. of
`Patients
`Age (range)
`
`Seizure
`Type
`
`Patients
`experiencing
`≥50% reduction
`in seizure
`frequency
`
`Patients who
`discontinued
`therapy (%)
`
`Gavatha.
`et.al9
`
`14.
`(3-18.yr)
`
`Focal.onset
`
`5.(36%)
`
`Guilhoto.
`et.al10
`
`16.
`(8-21.yr)
`
`Focal.onset
`
`6.(37.5%)
`
`12.(67%).due.to.
`lack.of.efficacy.
`at.initial.
`assessment
`1.(6%).due.to.
`ADE
`2.(12.5%).
`due.to.lack.of.
`efficacy
`4.(25%).due.to.
`ADE
`
`Mean
`Effective
`Dosage (mg/
`kg/day)
`(range)
`
`6.34.
`(1.7-10)
`
`4.7.
`(0.5-8.8)
`
`Heyman.
`et.al11
`
`17.
`(1.5-16.yr)
`
`Rastogi.
`et.al12
`
`16.
`(1-16.yr)
`
`Focal.onset,.
`tonic,.
`generalized.
`tonic-clonic*
`
`Focal,.atonic,.
`tonic,.tonic,.
`clonic,.
`myolonic,.
`atypical.
`absence*
`
`6.(35%)
`
`6.(35%).due.to.
`lack.of.efficacy
`
`12.39.
`(6.7-20)
`
`8.(50%)
`
`NR
`
`9.4.
`(2.4-19.4)
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`Buck ML, et al
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`Adverse effects reported
`during treatment (%)
`
`Somnolence.(17%),.
`irritability.(11%),.sleep.
`disturbances.(6%),.
`pancytopenia.(6%)
`
`Nausea.and.vomiting.
`(12.5%),.headache.(6%),.
`blurred.vision.(6%),.tics.(6%),.
`behavioral.outbursts.(6%),.
`ataxia(6%),.and.depression.
`(6%)
`
`Nausea.(18%),.dizziness.
`(18%),.restlessness.(12%),.
`fatigue.(12%),.headache.
`(12%),.increased.appetite.
`(6%),.prolonged.crying.(6%)
`
`nausea,.vomiting,.
`gastrointestinal.intolerance,.
`dizziness,.headache,.
`somnolence,.facial.edema.
`(frequency.not.specified).
`
`ADE, adverse drug event; NR, not reported
`* Included patients with Lennox-Gastaut syndrome (LGS)
`
`been initiated 3 months earlier as a replacement
`for zonisamide. Cardiac monitoring revealed a
`prolonged PR interval (>400 ms at maximum),
`an AV block (Mobitz I/Wenckebach), and right
`bundle branch block. His rhythm disturbances
`resolved 19 hours after his last dose of lacos-
`amide. Zonisamide was restarted, and the pa-
`tient recovered without sequelae. The authors
`concluded that the patient’s carbamazepine may
`have already lengthened the PR interval to the
`upper limit of normal (200 ms) and the addition
`of lacosamide potentiated the effect. As a result of
`these reports, it is recommended that lacosamide
`be used with caution in adults with cardiac con-
`duction problems or severe cardiac disease. In
`those patients, an ECG should be obtained prior
`to starting therapy and at the end of dose titra-
`tion. Concurrent administration of other drugs
`that prolong the PR interval should be avoided.
`Although no cases of lacosamide-induced PR
`
`prolongation or AV block have been reported in
`children, the same precautions should apply. In
`addition, children with a family history of cardiac
`disease or conduction disturbances may be at
`higher risk for PR prolongation and should be
`closely monitored during treatment.
`Suicidal thoughts have been described in pa-
`tients taking antiseizure drugs. To date, a single
`child, age 17.5 years, who was being treated
`with levetiracetam, lamotrigine, clonazepam,
`and phenobarbital developed suicidal ideation
`following initiation of lacosamide that resolved
`after lacosamide was withdrawn.10 In order to
`educate patients and their families about this
`risk, the FDA has approved a Risk Evaluation
`and Mitigation Strategy (REMS) program for
`all drugs in this therapeutic class.3 A medication
`guide must be given to the patient or family at
`the time an antiseizure drug is dispensed.
`Patients and their families should also be
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`Lacosamide Use in Children
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`aware that large doses of lacosamide (300-800
`mg in adults) can produce a mild euphoria.2,3
`Although euphoria has been reported in less
`than 1% of patients enrolled in clinical trials, the
`risk for abuse resulted in lacosamide being ap-
`proved as a schedule V controlled substance in
`the United States.
`Given its possible interaction with CRMP-2,
`it has been suggested that lacosamide has the
`potential to adversely affect central nervous
`system development. CRMP-2 is known to be
`highly expressed during gestation and early in
`life.16 Studies in rats given lacosamide early in life
`resulted in decreased brain weight and long-term
`deficits in learning and memory.3 Administration
`to rats during pregnancy resulted in increased
`perinatal mortality and impaired growth. Ad-
`ditional research in this area is needed to clarify
`the risk-to-benefit ratio of using this therapy in
`infants or during pregnancy and lactation.
`Lacosamide should only be used during preg-
`nancy if no safer alternatives are available. Clini-
`cians are encouraged to enroll any pregnant wom-
`en taking lacosamide into the UCB Antiepileptic
`Drug Pregnancy Registry (phone, 1-888-233-2334,
`or website at http://www.vimpat.com).3 Women
`taking lacosamide during pregnancy should also
`be enrolled in the North American Antiepileptic
`Drug Pregnancy Registry. Information on this
`collaborative program can be obtained by calling
`1-888-233-2334 or at the website at http://www.
`aedpregnancyregistry.org.
`
`DRUG INTERACTIONS
`
`At this time, no clinically significant drug
`interactions with lacosamide have been identi-
`fied. Lacosamide does not appear to produce
`significant induction or inhibition of CYP1A2,
`2B6, 2C9, 2C19, or 3A4. A small (20%) increase
`in ethinyl estradiol has been reported in women
`taking lacosamide with oral contraceptives.
`Minor reductions in serum concentrations (<
`25%) occur in carbamazepine, phenytoin, and
`phenobarbital when given with lacosamide.3
`None of these changes in drug concentrations re-
`quire dosage adjustment. Novy and colleagues17
`recently reported a series of seven patients
`who developed neurologic adverse effects after
`lacosamide was added to a regimen containing
`other voltage-gated sodium channels-blocking
`antiseizure drugs. There was no evidence of a
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`pharmacokinetic drug interaction or elevated
`serum drug concentrations in these patients that
`might have explained the increased incidence of
`diplopia, dizziness, and drowsiness. Reduction in
`the patient’s original antiseizure drugs resulted
`in symptomatic improvement in all of the cases.
`These and other authors have proposed that ad-
`verse effects noted during lacosamide titration
`may represent a pharmacodynamic drug inter-
`action resulting from synergistic voltage-gated
`sodium channels blockade, similar to that noted
`with other combinations of antiseizure drugs
`affecting these channels such as carbamazepine
`and lamotrigine.17–19
`
`CLINICAL EXPERIENCE IN CHILDREN
`
`In randomized controlled trials conducted in
`adults, lacosamide has demonstrated significant
`benefit in treating refractory seizures, with 30% to
`40% of patients achieving a ≥50% reduction in sei-
`zure frequency at doses of 400 to 600 mg/day.2,7,8
`Since 2010, four studies have been published
`that describe similar benefits from lacosamide
`in children and young adults with refractory
`epilepsy (Table 2).9–12
`In the first prospective case series, 14 patients
`between 3 and 18 years of age with focal onset
`seizures were treated with oral lacosamide for a
`period of at least 3 months.9 All of the children
`had been treated with multiple antiseizure
`drugs prior to starting lacosamide; the average
`number of previously failed agents was seven,
`with a range from three to sixteen. Lacosamide
`was initiated at 1 mg/kg/day and increased in 1
`mg/kg/day increments on a weekly basis. Final
`doses ranged from 2 to 10 mg/kg/day. Thirty-six
`percent (5 of 14) of the children experienced a
`≥50% reduction in seizure frequency at the time
`of initial assessment, which ranged from 3 to 8
`months (mean, 5 months). Twenty percent (3 of
`14) of patients maintained this level of seizure
`control for an additional 8 to 13 months. In total,
`1 year after enrollment, only 4 of the original 18
`children were still taking the therapy. Lacosamide
`was eventually discontinued in 12 patients due
`to lack of efficacy or loss of efficacy at follow-up.
`One patient was lost to follow-up. Mild adverse
`effects were common, with 39% of children
`experiencing symptoms of somnolence or ir-
`ritability. Only 1 patient discontinued therapy
`after developing normochromic anemia with
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`thrombocytopenia and granulocytopenia while
`receiving therapy but had a similar history of
`pancytopenia prior to initiation of lacosamide.
`After a period of worsening seizure frequency,
`lacosamide was restarted without any adverse
`effect on blood counts. Although a significant re-
`duction in seizure frequency was not maintained
`in most of the patients, the authors concluded
`that lacosamide has the potential to be a useful
`adjunct therapeutic agent in children with refrac-
`tory seizures.
`A retrospective review was composed of a
`final cohort of 16 patients who were receiving
`an average of two other antiseizure drugs for
`their refractory focal onset seizures at the time
`lacosamide was initiated.10 The patients ranged
`from 8 to 21 years old, with a mean age of 14.9
`years. Two of the patients were over 17 years
`of age. Three patients had undergone epilepsy
`surgery, 9 received vagus nerve stimulation, and
`3 had been treated with the ketogenic diet. The
`average lacosamide dose at the end of titration
`was 4.7 mg/kg/day. Length of follow-up ranged
`from 1 to 13 months, with a median of 4 months.
`The median number of seizures per month for the
`total population decreased from 57 at baseline to
`12.5 at follow-up (a 39.6% reduction, p<0.01). Six
`children (37.5%) had a ≥50% reduction in seizure
`frequency. Three of these 6 patients were free of
`seizures. Seven patients had no improvement.
`Four patients discontinued therapy because
`of adverse effects, including tics, behavioral
`changes, increased seizures, or depression with
`suicidal ideation (each in 1 patient). As with the
`previous case series, the authors suggested that
`lacosamide may play a useful role in treating
`refractory seizures in children and should be
`evaluated in a prospective controlled trial.
`In a retrospective study of 17 children (ages 1.5-
`16 years) receiving oral lacosamide for refractory
`seizures, 35% (6 of 17) achieved a reduction in
`seizure frequency of ≥50%.11 The patient popu-
`lation was composed of 12 patients with focal
`seizures and 5 with both focal and generalized
`onset seizures, including 2 children diagnosed
`with Lennox-Gastaut syndrome (LGS). The mean
`number of previous antiseizure drugs used per
`child was 6.6 (range, 4 to 11). Initial doses ranged
`from 1.4 to 5 mg/kg/day (mean, 3.04 ± 1.09 mg/
`kg/day). Doses were titrated at weekly intervals,
`up to a maximum of 6.7 to 20 mg/kg/day (mean,
`12.39 ± 4.48 mg/kg/day). The mean length of
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`Buck ML, et al
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`follow-up was 9.1 ± 4.4 months. In addition to
`reduction in seizure frequency, 7 children (41%)
`had improvement in behavioral or motor func-
`tion. While a significant number of children
`initially demonstrated improvement, lacosamide
`was eventually discontinued in 6 children (35%)
`because of lack of efficacy. Both of the patients
`with LGS experienced an increase in their seizure
`frequency during treatment. Adverse effects were
`reported in 10 patients, including nausea, dizzi-
`ness, restlessness, fatigue, headache, increased
`appetite, and prolonged crying.
`Another recent prospective study described
`the use of lacosamide in 21 children (ages 1 to
`16 years) with both focal and generalized onset
`seizures.12 Sixteen patients were included in the
`final analysis, with a mean age of 8.6 years. Of the
`eight children with a generalized-onset epilepsy
`syndromes, four were diagnosed with LGS. The
`average length of follow-up was 9.8 months. The
`average number of antiseizure drugs at the time
`of lacosamide initiation was 1.8. The patients
`had failed an average of 6.6 previous treatments
`as well as the ketogenic diet and vagal nerve
`stimulation. The average initial dose was 5.8
`mg/kg/day. The average lacosamide dose at the
`end of titration was 9.4 mg/kg/day, with a range
`of 2.4 to 19.4 mg/kg/day. Eight patients (50%)
`had a reduction in seizure frequency of ≥50%.
`Three patients had a reduction of ≥90%. Children
`with focal onset seizures were the most likely to
`respond, while patients with generalized tonic-
`clonic and tonic seizures were the least likely
`to benefit from lacosamide. Of the 4 patients
`with LGS, 2 had significant improvement (≥90%
`reduction in frequency) and 2 had no response.
`Adverse effects included nausea, vomiting, diz-
`ziness, headache, somnolence, and facial edema.
`Despite the positive response in the 2 patients
`with LGS in the study described above, the role
`of lacosamide in treating children and young
`adults with this syndrome remains undefined.
`A 2010 case series of 3 young adult patients
`(24-27 years of age) with LGS described wors-
`ening of seizure frequency after initiation of
`lacosamide.18 All 3 patients had been initiated
`on the recommended adult dose of 50 mg/day
`and increased at increments of 50 mg/day each
`week. Two of the patients reached a final dose
`of 200 mg/day; 1 of these patients experienced
`increased seizures at 15 days and the other at 30
`days from the time of the last dose increase. The
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`Lacosamide Use in Children
`
`third patient developed an increase in seizure
`frequency at 4 days after reaching a dose of 100
`mg/day. All patients returned to their baseline
`seizure frequency after lacosamide was dis-
`continued. The authors hypothesized that this
`worsening of seizure frequency may reflect a
`pharmacodynamic interaction resulting from an
`additive or synergistic effect of lacosamide with
`their patient’s other antiseizure drugs that block
`voltage gates sodium channels. In a similar case
`report, a 20-year-old man with LGS, who had
`failed treatment with phenobarbital, vigabatrin,
`valproic acid, clobazam, and carbamazepine,
`was admitted for increased seizure frequency.20
`He was treated with topiramate, levetiracetam,
`phenytoin, clonazepam, and risperidone. After
`developing signs of phenytoin-induced hepa-
`totoxicity, he was given a trial of IV lacosamide
`at a dose of 200 mg/day. Within days of starting
`therapy, the patient began to experience an in-
`crease in tonic seizures, from an average of 4 per
`day to 10 per day, coinciding with a worsening
`of EEG findings. The patient returned to baseline
`within 48 hours of lacosamide discontinuation.
`In contrast to those reports of the use of lacos-
`amide in the treatment of LGS, a recent case series
`suggested benefit from lacosamide in 3 young
`adults (19-23 years of age) with juvenile myo-
`clonic epilepsy, a form of generalized epilepsy
`that typically presents in late childhood.21 One of
`the patients received lacosamide as single-agent
`therapy. The other 2 patients had lacosamide
`added to their current regimens (valproic acid
`in one and a combination of levetiracetam and
`lamotrigine in the other) for breakthrough sei-
`zures. All 3 patients became seizure-free on a
`lacosamide dose of 200 mg given twice daily.
`Two patients remained on therapy at the time of
`publication (12 and 18 months), while 1 discon-
`tinued therapy after 4 months because of fatigue,
`depression, and anxiety. That patient’s symptoms
`continued after lacosamide was stopped but later
`abated when levetiracetam was discontinued.
`Lacosamide has also been used in the manage-
`ment of refractory status epilepticus. Several
`papers describe a beneficial effect in adult pa-
`tients,22,23 but to date there have been only limited
`reports of its use in children.24,25 At this time, no
`dosing recommendations can be made for this
`use in infants or children.
`Issues of lacosamide efficacy, adverse effects,
`and dosing in children are being addressed in
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`JPPT
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`several ongoing clinical trials. Two open-label
`phase 2 clinical trials are currently enrolling
`children from 1 month to 17 years of age. The
`first (trial NCT00938431) started in October
`2009 and is a multicenter study of the safety and
`pharmacokinetics of lacosamide in children with
`focal onset seizures. Children who are still expe-
`riencing seizures on stable doses of up to three
`other antiseizure drugs are eligible to participate.
`Subjects will receive lacosamide oral solution in
`doses of 8, 10, or 12 mg/kg/day for up to 42 days.
`The estimated completion date for this study is
`March 2013. The second study, a long-term safety
`and efficacy study (trial NCT00938912) began in
`December 2009. Subjects will be treated for up to
`2 years with lacosamide oral solution at doses of
`2 to 12 mg/kg/day or tablets at doses between
`100 and 600 mg/day. All doses will be divided
`and given twice daily. The trial has an estimated
`completion date of October 2017. In both studies,
`the primary outcome measure is the frequency
`of treatment-related adverse effects. Secondary
`outcomes include change from baseline seizure
`frequency, plasma concentrations, and change
`from baseline Clinical and Caregiver Global
`Impression of Change scores. A third study (the
`NCT00832884 trial) is currently under way to
`evaluate the safety of IV lacosamide in children.
`Patients between 4 and 20 years of age with
`epilepsy who are unable to take oral medication
`are eligible for enrollment in that phase 4 study.
`Subjects are randomized to receive lacosamide
`doses of 0.7, 1.4, 2.1, or 2.9 mg/kg, up to a maxi-
`mum of 200 mg. Details for the phase 2 and IV
`lacosamide studies are available on the clinical
`trials website of the National Institutes of Health.6
`
`DOSING AND ADMINISTRATION
`
`The recommended initial dose of lacosamide in
`patients 17 years of age and older is 50 mg admin-
`istered twice daily. The dose may be increased by
`100 mg/day at weekly intervals up to the usual
`maintenance dose of 200 to 400 mg/day. Data
`from clinical trials have shown that doses above
`600 mg did not provide greater seizure control
`but were associated with a higher incidence of
`adverse effects. There are no established dosing
`recommendations for lacosamide in children at
`this time. Based on the available pediatric case
`series and retrospective reviews, a starting dose
`of 1 mg/kg/day, divided and given in two doses,
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`JPPT
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`may be considered for initiation of therapy.9–12
`Doses should be titrated at weekly intervals,
`with an incremental increase of no more than
`1 mg/kg/day. The effective pediatric doses in
`the cases and studies published to date have
`ranged from 4 to 12 mg/kg/day. A maximum
`weight-based dose for children has not yet been
`established, but doses of up to 20 mg/kg/day
`have been reported.
`No dosage adjustment is needed for mild to
`moderate renal impairment. In adults with severe
`renal impairment or end-stage renal disease, the
`manufacturer recommends a maximum daily
`dose of 300 mg/day. No dosing guidelines are
`available for pediatric patients with renal impair-
`ment. Lacosamide is removed by hemodialysis. It
`is recommended that a supplemental dose of up
`to 50% of the maintenance dose be administered
`after a 4-hour hemodialysis session. A maximum
`daily dose of 300 mg/day is also recommended
`for adults with mild to moderate hepatic impair-
`ment (Child-Pugh class B). Lacosamide is not
`recommended for use in patients with severe
`hepatic impairment.
`The IV and oral doses of lacosamide are equiva-
`lent. It is recommended by the manufacturer that
`IV doses be infused, with or without further dilu-
`tion, over 30 to 60 minutes. In a recent open-label
`trials lacosamide infusion times as short as 15
`minutes were tolerated without serious adverse
`effects, but a case of transient hypotension after a
`15 minute infusion has been reported to the man-
`ufacturer.3,23 Lacosamide injection is stable for at
`least 24 hours at room temperature when diluted
`with sodium chloride 0.9%, dextrose injection
`5%, or Lactated Ringer’s solution. Lacosamide
`tablets or solution may be taken with or without
`food. A calibrated dosing spoon or oral syringe
`should be used to prepare doses of lacosamide
`oral solution to ensure delivery of an accurate
`dose. The solution must be discarded after 7
`weeks from the date of opening. Lacosamide oral
`solution contains aspartame and should be used
`with caution in patients with phenylketonuria. A
`200-mg (20-mL) dose of the oral solution provides
`0.32 mg of phenylalanine.
`
`SUMMARY
`
`Based on the case series studies published to
`date, lacosamide appears to be a useful adjunct
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`Buck ML, et al
`
`in treatment of children with seizures refractory
`to traditional antiseizure drugs. The percentage
`of pediatric patients with focal onset seizures
`experiencing significant reductions in seizure
`frequency has been similar to results obtained in
`adults. The results of lacosamide us