REVIEW ARTICLE
`
`Newer Anti-epileptic Drugs
`
`SATINDER ANEJA AND SUVASINI SHARMA
`From Department of Pediatrics, Lady Hardinge Medical College and associated Kalawati Saran Childrens Hospital, New Delhi,
`India.
`Correspondence to: Dr Satinder Aneja, Director Professor and Head, Department of Pediatrics, Lady Hardinge Medical College
`and associated Kalawati Saran Children's Hospital, New Delhi, India. drsaneja@gmail.com
`
`Need and Purpose of review:A number of newer anti-epileptic drugs have been developed in the last few years to improve the treatment
`outcomes in epilepsy. In this review, we discuss the use of newer anti-epileptic drugs in children.
`Methods used for locating, selecting, extracting and synthesizing data: MEDLINE search (1966-2013) was performed using terms
`"newer anti-epileptic drugs", "Oxcarbazepine", vigabatrin", topiramate", "zonisamide", "levetiracetam", "lacosamide", "rufinamide",
`"stiripentol", "retigabine", "eslicarbazepine", "brivaracetam", "ganaxolone" and "perampanel" for reports on use in children. Review
`articles, practice parameters, guidelines, systematic reviews, meta-analyses, randomized controlled trials, cohort studies, and case
`series were included. The main data extracted included indications, efficacy and adverse effects in children.
`Main conclusions: Oxcarbazepine is established as effective initial monotherapy for children with partial-onset seizures. Vigabatrin is
`the drug of choice for infantile spasms associated with tuberous sclerosis. Lamotrigine , levetiracetam and lacosamide are good add-on
`drugs for patients with partial seizures. Lamotrigine may be considered as monotherapy in adolescent females with idiopathic generalized
`epilepsy. Levetiracetam is a good option as monotherapy for females with juvenile myoclonic epilepsy. Topiramate is a good add-on drug
`in patients with epileptic encephalopathies such as Lennox-Gastaut syndrome and myoclonic astatic epilepsy.
`Keywords: Refractory epilepsy; Epileptic encephalopathies; Oxcarbazepine; Vigabatrin; Lamotrigine; Levetiracetam.
`
`About 65% of children with newly diagnosed
`
`epilepsy achieve sustained freedom from
`seizures with the initially prescribed
`ntiepileptic drug (AED). An additional 15-
`20% become seizure free with subsequently prescribed
`AEDs, while the remainder cannot achieve seizure
`control with available medications. There is an unmet
`need for efficacious AED with good safety profile in this
`group, and there is a continued research in this field for
`an ideal AED. After the introduction of sodium
`valproate in 1967, there was hiatus of two decades after
`which ten new AEDs were launched during the so called
`"decade of Brains". These expanded the armamentarium
`of therapeutics for intractable epilepsy.
`These newer AEDs are used as an adjunct to
`conventional AEDs in children with intractable epilepsy.
`However, more studies are required to evaluate their use as
`first line AED for children with epilepsy. These newer
`drugs are more efficacious and have a better safety as
`compared to conventional AED. However, caution must
`be exercised for possible drug interactions with
`conventional AEDs before using them as an adjunct.
`Moreover, many of these newer AEDs have been recently
`launched in Indian market and cost of some them are
`largely prohibitive.
`
`Intractable epilepsy refractory to appropriate
`conventional AED is an indication for the newer drugs.
`Among children presenting with refractory epilepsy, one
`must always look for causes of psuedointractability
`including possibility of non epileptic event, misdiagnosis
`of seizure type, and wrong choice of conventional AEDs.
`These causes must always be thought before using newer
`AEDs as an adjunct.
`
`These medications should be prescribed by
`pediatricians with an in-depth knowledge of the
`pharmacokinetics of the drug, its indications, dosage, side
`effects and possible drug interactions. The present review
`intends to provide an insight to these aspects of use of
`antiepileptic drugs. We discuss the pediatric use of newer
`anti-epileptic drugs, both the ones which are already in the
`market (lamotrigine, topiramate, levetiracetam,
`oxcarbazepine, zonisamide, vigabatrin, lacosamide,
`eslicarbazepine), and the newer ones in development and
`which are likely to be available soon (rufmamide,
`stiripentol, retigabine, brivaracetam, ganaxolone, and
`perampanel). The use of gabapentin and pregabalin will
`not be discussed in this review as these are used
`predominantly for the management of neuropathic pain,
`and not epilepsy.
`
`INDIAN PEDIATRICS
`
`1033 (cid:9)
`
`VOLUME 50—NOVEMBER 15, 2013
`
`ARGENTUM Exhibit 1058
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`Page 00001
`
`

`
`ANEJA AND SHARMA (cid:9)
`
`NEWER ANTI-EPILEPTIC DRUGS
`
`THE NEWER ANTI-EPILEPTIC DRUGS
`
`consider stopping the drug after 6 months.
`
`Vigabatrin
`
`Levetiracetam
`
`Vigabatrin is a structural analogue of gamma-
`aminobutyric acid (GABA), which irreversibly inhibits
`the enzyme GABA transaminase.
`Indications: It is used as a first line drug for treatment of
`infantile spasms in children with tuberous sclerosis [1].
`As there is insufficient evidence for the use of other AEDs
`in infantile spasms [2], it may be considered as a first line
`treatment in other patients with infantile spasms in whom
`the use of hormonal treatment (corticosteroids, ACTH) is
`contraindicated.
`Efficacy: Clinical trials have shown that spasm cessation
`is greatest in patients with tuberous sclerosis complex
`(74%) compared with other symptomatic etiologies
`(50%) [3]. In a large randomized controlled trial, it was
`shown that hormonal treatment (ACTH and
`prednisolone) was associated with better outcome at 2
`weeks (73%) when compared to vigabatrin (54%) [4].
`Advantages: It has good oral bioavailablity and the drug
`is excreted unchanged by kidney. Drug interactions are
`minimal with conventional AEDs.
`Side effects: The major concern with the use of vigabatrin
`is the development of bilateral concentric peripheral
`visual field constriction, which has been seen in one third
`of adults and 20% of children treated with vigabatrin [5].
`Because of the difficulties and inconsistencies with
`formal visual field testing in young infants and children,
`visual fields in children have been tested using highly
`sensitive electroretinograms. The earliest finding of the
`first abnormal field examination in adults was after 9
`months of treatment; in children, the earliest sustained
`onset of the vigabatrin induced retinal defect in infants
`was 3.1 months [6]. Most patients with abnormalities
`received treatment for at least 6 months, and even those
`treated for more than 2 years have been reported to have
`stable visual fields [7]. As infantile spasms comprise a
`severe epileptic encephalopathy with poor develop-
`mental outcome if uncontrolled, the risks and benefits
`should be weighed before starting vigabatrin treatment.
`Myoclonic seizures and abscence seizures are known to
`be precipitated by vigabatrin.
`Dosage: Pediatric doses range from 50 mg/kg/day to 150
`mg/ kg/day [8]. The dose may be increased by 30-40 mg/
`kg/day every 4-5 days till the maximum dose is reached.
`The time to response with vigabatrin is quite short,
`usually within 2 weeks. If the infant has not shown
`improvement in spasms within 2 weeks, vigabatrin
`should be discontinued [9]. In infants with good response
`
`Levetiracetam is a broad spectrum AED which
`selectively inhibits high-voltage-activated calcium
`channels and reduces calcium release from intraneuronal
`stores [10]. It also binds to a specific target in the brain,
`the synaptic vesicle protein 2A (SV2A), an integral
`membrane glycoprotein, which is involved in the control
`of vesicle fusion and exocytosis.
`Indications: Levetiracetam is effective as adjunctive
`therapy in pediatric patients with partial onset seizures
`and in primary generalized tonic-clonic seizures [II].
`Intravenous preparation has recently shown efficacy in
`neonatal seizures [12] and status epilepticus [13].
`Efficacy: In a randomized, double-blind, placebo-
`controlled, multicenter trial in 101 children with
`refractory partial seizures, >50% seizure reductions was
`seen in 44.6% receiving levetiracetam and 19.6% in
`patients receiving placebo [14]. Levetiracetam has been
`evaluated in childhood epilepsy syndromes including
`rolandic epilepsy [15], electrical status epilepticus in
`slow sleep, myoclonic and tonic clonic seizures of
`Lennox Gastaut syndrome [16] and as an alternative to
`valproate in juvenile myoclonic epilepsy in adolescent
`girls [17]. Beneficial effects on language development
`have been reported [18].
`
`Advantages: Levetiracetam has a favourable
`pharmacokinetic profile in terms of safety inpatients with
`liver disease and minimal drug interaction with other
`AEDs.
`Side effect: Levetiracetam is well tolerated in children
`with minor adverse events like headache, anorexia, and
`somnolence. However, there are concerns of behavioural
`side effects like aggression, emotional lability,
`oppositional behavior, and psychosis in children [19].
`Dosage: Pediatric dose start from 10 mg/kg/day (divided
`tweice daily) to be hiked by 10-20 mg/kg every two
`weeks to a maximum dose of 40-60 mg/kg/day.
`
`Topiramate
`
`Topiramate is a sulphamate substituted monosaccharide,
`a broad spectrum AED acting on voltage dependent
`sodium channels, enhancement of GABA, decrease in
`glutamate and inhibition of carbonic anhydrase.
`Indications: Topiramate is a useful adjunct in refractory
`partial or generalized epilepsy and other epileptic
`syndromes.
`Efficacy: Topiramate has demonstrated efficacy as an
`
`INDIAN PEDIATRICS
`
`1034 (cid:9)
`
`VOLUME 50—NOVEMBER 15, 2013
`
`Page 00002
`
`(cid:9)
`

`
`ANEJA AND SHARMA (cid:9)
`
`NEWER ANTI-EPILEPTIC DRUGS
`
`adjuctive therapy in partial epilepsy [20], intractable
`epilepsy [21], Lennox Gastaut syndrome [22], infantile
`spasms [23], generalized epilepsy of infancy and
`myoclonic—astatic epilepsy [24]. Pooled data from two
`randomized, double-blind studies found that topiramate
`adjunctive therapy may be efficacious for juvenile
`myoclonic seizures in adults and children [25].
`
`Side effects: Topiramate has good safety with no evidence
`of life threatening adverse effects or organ toxicity. The
`most frequently reported side effects are dizziness,
`mental slowing, somnolence, ataxia, impaired
`concentration and confusion [24]. Most of these are
`transient and observed during the initial weeks of therapy
`and can be reduced by slow titration of the dose. Anorexia
`and mild weight loss has been observed during the
`therapy. Other reported side effects include metabolic
`acidosis, nephrolithiasis, decreased sweating and
`resultant hyperthennia [26]. Children on combination of
`topiramate and valproate should be monitored for signs
`of encephalopathy resulting from hyperammonemia [27].
`
`Dosage: Pediatric dosage is 1-3 mg/kg/day (divided
`twice daily) hiked bi-weekly to 3-8 mg/kg/day.
`
`Lamotrigine
`
`Lamotrigine is another broad spectrum AED which acts
`by blocking the voltage dependent sodium channels and
`thus blocks the release of glutamate through stabilization
`of presynaptic membrane. Enzyme inducing drugs like
`phenytoin and carbamazepine may shorten the half life of
`Lamotrigine.
`
`Indications and efficacy: It is an effective adjunct to
`refractory partial and generalized epilepsy [28]. It is
`particularly useful in typical and atypical absence seizure
`in Lennox Gastaut syndrome and in children with
`myoclonic-astatic epilepsy [22, 29]. It is also useful as a
`first line agent in children with idiopathic generalized
`epilepsy.
`
`Side effects: Common dose related side effectsinclude
`somnolence, sleep disturbances, dizziness, diplopia,
`ataxia, nausea and vomiting. Serious side effects of
`lamotrigine which often require drug withdrawls include
`skin rash and rarely Steven Johnson syndrome and toxic
`epidermal necrolysis [30]. The neurotoxicity and skin
`rash is more often seen when lamotrigine is administered
`with valproate or when the dose is titrated rapidly.
`Lamotrigine may exacerbate myoclonic seizures in
`patients with Dravet syndrome [31].
`
`valproate as the latter prolongs the half life of
`lamotrigine.
`
`Oxcarbazepine
`
`Oxcarbazepine is the 10-keto analogue of carbamazepine
`which blocks high frequency voltage dependent
`repetitive firing of sodium channels.
`
`Indications and efficacy: Oxcarbazepine is used as first
`line drug for partial and secondarily generalized seizures
`[32]. Amongst the newer AED, oxcarbazepine is
`established as evidence-based effective initial
`monotherapy for children with partial-onset seizures and
`focal epilepsy.
`
`Side effects: Unlike carbamazepine, oxcarbazepine is not
`metabolized to epoxide derivative thus minimizing side
`effects like skin rash encountered with carbamazepine.
`Reported side effects of oxcarbazepine include
`hyponatremia, headache, dizziness, and ataxia [33]. The
`advantage of oxcarbazepine over carbamazepine is that it
`does not cause hepatic induction nor does it undergo
`auto-induction [33].
`
`Dosage: Oxcarbazepine can be started with initial dose of
`5 to 8 mg/kg/day in 2 divided doses increasing by 5 to 8
`mg/kg after 5 to 7 days up to a maximum of 30 mg/kg.
`The usual effective dose ranges from 10 to 30 mg/kg/day.
`Zonisamide
`
`Zonisamide is a sulphonamide derivative, a broad
`spectrum AED that acts through multiple actions:
`facilitation of dopaminergic and serotoninergic
`neurotransmission through the blockade of T-type
`calcium channels, prolongation of sodium channel
`inactivation and as a weak inhibitor of carbonic
`anhydrase.
`
`Indications: Zonisamide has also been found useful in
`progressive myoclonic epilepsy syndromes such as
`Unverricht-Lundborg disease and Lafora body disease
`[36]. Useful as a second-line agent for infantile spasms,
`Lennox-Gastaut syndrome, and juvenile myoclonic
`epilepsy [35].
`
`Side effects: Somnolence, poor appetite, weight loss,
`headache, pruritus, and skin rash are commonly observed
`adverse effects [37]. Other rare side effects include
`kidney stones, oligohydrosis and hyperthennia [38].
`Higher doses (6-8 mg/kg) has been associated with
`problems of language development like vocabulary
`acquisition [39].
`
`Dosage: Lamotrgine is started at 1-2 mg/kg followed by
`slow hiking biweekly to 3-8 mg/kg/day. The drug dosage
`is reduced to half when used in combination with
`
`Dosage: The usual starting dose is 2-4 mg/kg/day, and
`the maintenance dose is 4-8 mg/kg/day;divided once or
`twice daily.
`
`INDIAN PEDIATRICS (cid:9)
`
`1035 (cid:9)
`
`VOLUME 50—NOVEMBER 15, 2013
`
`Page 00003
`
`

`
`ANEJA AND SHARMA
`
`Lacosamide
`
`Lacosamide is a functionalized amino acid that
`selectively enhances slow inactivation of voltage-gated
`sodium channels, increasing the proportion of sodium
`channels unavailable for depolarization.
`Indication: Lacosamide is used in children with
`refractory epilepsy with 30-50% of children having more
`than 50% reduction in seizure frequency [40].
`Efficacy: Lacosamide is available in both oral and as an
`injection for intravenous preparation, which may have a
`role in status epilepticus. Pediatric experience with
`lacosamide has been limited [40]. Most of the available
`literature are retrospective data on small number of
`patients with an efficacy rate of 30-50% [41-43].
`Side effect: Lacosamide is generally well tolerated with
`reports of irritability, oral tics, and prolonged crying as
`adverse effects in children [40].
`
`Rufinamide
`
`Rufinamide is a triazole derivative that was approved by
`FDA in 2008 for adjunctive use in the treatment of
`seizures associated with Lennox—Gastaut syndrome in
`children aged above 4 years [44]. Its mechanism of action
`is not completely understood but it is believed to work by
`prolonging the inactive state of sodium channels and
`therefore limiting excessive firing of sodium-dependent
`action potentials.
`Indication: The only approved indication in children (>4
`yrs) is with refractory Lennox Gastaut syndrome].
`Efficacy: In Lennox-Gastaut syndrome, rufinamide was
`studied in a randomized, double-blind, parallel-group,
`placebo-controlled, multicenter trial in patients aged 4 to
`37 years with multiple seizure types [45]. At the end of 12
`weeks of therapy, median total seizure frequency was
`decreased by 32.7% in the rufinamide group compared to
`11.7% in the placebo group. Rufinamide has
`demonstrated efficacy in partial onset seizures in older
`adolescents and adults [46]. Rufinamide has also been
`evaluated in a prospective study for the treatment of
`refractory partial onset seizure and childhood onset
`refractory epileptic encephalopathy [47, 48].
`Side effect: The most commonly observed adverse are
`headache, dizziness, fatigue, somnolence, and nausea.
`
`Stiripentol
`
`Stiripentol is an AED used as an adjunctive to clobazam
`and valproate in the treatment of refractory generalized
`tonic-clonic seizures in patients with severe myoclonic
`epilepsy in infancy i.e., Dravet syndrome [49]. It
`
`NEWER ANTI-EPILEPTIC DRUGS
`
`enhances central gamma-aminobutyric acid transmission
`and inhibits the metabolism of concurrently administered
`anticonvulsants that are substrates for various
`cytochrome P450 isoenzymes, such as clobazam [50]. In
`a randomized, double-blind, placebo controlled trial
`conducted in France, stiripentol was used as an
`adjunctive therapy in children with Dravet syndrome who
`failed to respond to valproate and clobazam and was
`shown to have better response rate (71%) as compared to
`placebo (5%) [51] .
`Other Newer AEDs
`Retigabine (ezogabine) is a novel investigational AED
`developed as an adjunctive treatment for partial epilepsy.
`Retigabine opens voltage-gated KCNQ2/3 and
`KCNQ3/5 potassium channels leading to cellular
`membrane hyperpolarization (52). In a pooled analysis of
`three randomized controlled trials, 1240 patients were
`included, with 813 patients randomized to retigabine and
`427 to placebo (53). Responder rates (>50% reduction in
`seizure frequency) were 35% and 45% for retigabine
`dose at 600 and 900 mg/day, respectively. There is no
`pediatric experience so far, but retigabine may potentially
`be a useful agent in the treatment of benign familial
`neonatal convulsions which is caused by loss of function
`mutations involving the KCNQ2/3 genes [54].
`Brivaracetam is an analogue of levetiracetam, which has
`been found useful in adults with photosensitive epilepsy,
`and as an adjunctive treatment in refractory partial-onset
`epilepsy. There is no pediatric experience till now.
`Ganaxolone is a synthetic analogue of allopregnenolone,
`a neurosteroid, which is an allosteric modulator of the
`GABA-A receptor complex. In a 3-month pediatric add-
`on study, 20 subjects aged 6 months to 7 years with
`refractory infantile spasms, or with continuing seizures
`after a prior history of infantile spasms were titrated up to
`12 mg/kg. Sixteen patients completed the study; 25%
`showed a > 50% reduction in seizures, and one patient
`was seizure free (55). Ganaxolone may also have efficacy
`for catamenial seizures.
`Eslicarbazepine actetate is structurally related to
`carbamazepine and oxcarbazepine and has been used as
`adjunctive therapy for adults with partial seizures. There
`is no pediatric experience so far.
`Perampanel is a selective, non-competitive antagonist of
`a-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid
`(AMPA) -type glutamate receptors, currently in clinical
`development as adjunctive therapy for the treatment of
`refractory partial-onset seizures [56]. Efficacy and
`tolerability of adjunctive perampanel in patients aged
`>12 years with refractory partial-onset seizures has been
`
`INDIAN PEDIATRICS
`
`1036 (cid:9)
`
`VOLUME 50—NOVEMBER 15, 2013
`
`Page 00004
`
`(cid:9)
`(cid:9)
`

`
`ANEJA AND SHARMA
`
`NEWER ANTI-EPILEPTIC DRUGS
`
`demonstrated in three phase III, randomized, double-
`blind, placebo-controlled trials.
`
`CURRENT STATUS OF THE NEWER AEDs
`
`The dosages and adverse effects of the newer AED
`currently available in India are summarized in Table I.
`Amongst the newer AED, oxcarbazepine is established as
`effective as initial monotherapy for children with partial-
`onset seizures. Vigabatrin is the drug of choice for
`infantile spasms associated with Tuberous sclerosis.
`Lamotrigine may be considered as monotherapy in
`adolescent females with idiopathic generalized epilepsy.
`Certain newer AEDs such as lamotrigine and vigabatrin
`are known to worsen myoclonic seizures. There is paucity
`of data on the use of newer AEDs in children from India.
`Indian Guidelines for diagnosis and management of
`childhood epilepsy were recently published [57]. As per
`these guidelines, the only newer AED which are
`recommended for use as monotherapy in new-onset
`epilepsy are lamotrigine in partial and generalized
`seizures, and oxcarbazepine in partial seizures. The
`others are recommended as adjunctive treatment in
`children who have failed conventional AED.
`
`Levetiracetam is a good option as monotherapy for
`females with juvenile myoclonic epilepsy. Topiramate and
`
`zonisamide are good options in patients with infantile
`spasms who have failed hormonal therapy and vigabatrin.
`Topiramate is a good add-on drug in patients with epileptic
`encephalopathies such as Lennox-Gastaut syndrome and
`Myoclonic astatic epilepsy. Lamotrigine, levetiracetam
`and lacosamide are good add-on drugs for patients with
`refractory partial seizures. Lamotrigine is also effective in
`tonic seizures seen in children with Lennox-Gastaut
`syndrome.
`
`Rare but serious side effects must always be borne in
`mind while prescribing newer AEDs: irreversible
`peripheral field defect with vigabatrin, allergic rash/Steven
`Johnson syndrome with lamotrigine, arrhythmias with
`rufinamide (short QT interval) and lacosamide (prolonged
`PR interval) and fatal hyperammonemic encephalopathy
`with topiramate. Role of monitoring serum levels of newer
`AEDs are limited as the recommended levels are not well
`defined.
`
`CONCLUSION
`
`Most of these newer AED have been tested as add-on
`therapy in drug resistant epilepsy and are not superior to
`the first generation AEDs in efficacy. The main
`advantage of some of the newer agents was their better
`tolerability and pharmacokinetic profiles compared to
`
`Drug
`
`Lamotrigine
`Monotherapy
`
`TABLE I CHARACTERISTICS OF THE NEW ANTIEPILEPTIC DRUGS
`
`Initial dose
`(mg/kg/day)
`
`Maintenance (cid:9) Daily (cid:9)
`(mg/kg/day) (cid:9)
`doses no
`
`Side effects (cid:9)
`
`Formulation
`
`0.5
`
`2-10
`
`2
`
`Skin rash, somnolence, dizziness, (cid:9) Tab 5 mg; 25 mg, 50 mg
`nausea, diplopia
`
`With enzyme
`inducing AEDs
`With valproate
`Vigabatrin
`
`2
`0.2
`20-50
`
`Oxcarbazepine
`
`Topiramate
`
`Zonisamide
`
`Levetiracetam
`
`Lacosamide
`
`5-8
`
`1
`
`1-2
`
`10
`
`1-2
`
`5-15
`1-5
`50-150
`
`10-30
`
`6-9
`
`8-12
`
`20-60
`
`6-9
`
`2
`1-2
`2
`
`2
`
`2
`
`2
`
`2
`
`2
`
`Tab 150 mg, 300 mg,
`Syrup 300 mg/5 mL
`Tab 25 mg, 50 mg, 100 mg
`
`Cap 25mg, 50 mg, 100 mg
`
`Tab 500 mg
`
`Hyperkinesia, weight gain, (cid:9)
`insomnia, visual field defects
`Dizziness, ataxia, somnolence (cid:9)
`hyponatremia (cid:9)
`Wt. loss, lethargy, anorexia, (cid:9)
`hyperpyrexia, renal calculi
`Ataxia, renal (cid:9)
`calculi hyperpyrexia
`Headache, anorexia, somnolence, (cid:9) Tab 250 mg, 500 mg,
`behavioral problems (cid:9)
`Syrup 500 mg/5 mL
`Dizziness, headache, diplopia, (cid:9)
`Tab 50 mg, 100 mg
`nausea
`
`INDIAN PEDIATRICS
`
`1037 (cid:9)
`
`VOLUME 50—NOVEMBER 15, 2013
`
`Page 00005
`
`(cid:9)
`

`
`ANEJA AND SHARMA (cid:9)
`
`NEWER ANTI-EPILEPTIC DRUGS
`
`TABLE H PHARMACOKINETIC PROPERTIES OF NEWER ANTIEPILEPTIC DRUGS
`
`Drug
`
`Oral bioavailability Elimination t1/2
`
`Protein binding
`
`Metabolism
`
`Vigabatrin
`Levetiracetam
`Topiramate
`Lamotrigine
`Oxcarbazepine
`Zonisamide
`Lacosamide
`Rufinamide
`Stiripentol
`
`80-100%
`100%
`>80%
`<100%
`>95%
`100%
`100%
`Dose dependent
`Quick absorption
`
`5-8 hrs
`6-8 hrs
`21 hours
`29 hours
`8-10 hours
`60 hours
`13 hours
`6-10 hours
`4.5 hours
`
`Nil
`<10%
`15-40%
`55%
`38%
`40-60%
`<15%
`34%
`99%
`
`Renal
`2/3° renal1/3° enzymatic hydrolysis
`30% metabolised70% excreted unchanged
`Metabolized in liver
`Metabolized in liver to active metabolite
`Metabolized in liver
`Metabolized in liver
`Metabolized in liver
`Metabolized in liver
`
`TABLE HI MECHANISM OF ACTION, INDICATIONS AND MAIN ADVERSE EFFECTS OF NEWER ANTIEPILEPTIC DRUGS
`
`Principal mechanism (cid:9)
`of action (cid:9)
`
`Indications in pediatric (cid:9)
`epilepsy
`
`Main adverse effect (cid:9)
`
`Remarks
`
`Drug
`
`Vigabatrin (cid:9)
`
`Inhibition of GABA (cid:9)
`transaminase (cid:9)
`
`Levetiracetam (cid:9)
`
`Inhibition of N- type (cid:9)
`calcium channel (cid:9)
`
`Topiramate (cid:9)
`
`Lamotrigine (cid:9)
`
`Blockage of voltage
`dependent Na+
`channel, inhibition
`ofGABA
`Inhibition of voltage
`gated sodium channel
`
`Oxcarbazepine Inhibition of voltage
`sensitive sodium
`channel
`
`Zonisamide
`
`Lacosamide
`
`Rufinamide
`
`Stiripentol
`level
`
`Acts on sodium and
`voltage dependent
`calcium channel
`Enhances slow inacti-
`vation of voltgage gated
`sodium channel
`Reduces recovery
`capacity of sodium
`channel inactivation
`Increase in GABA (cid:9)
`refractory seizures in (cid:9)
`
`Visual field defects (cid:9)
`
`Behavioural
`disturbances
`
`Monotherapy in infantile (cid:9)
`spasm (tuberous sclerosis); (cid:9)
`adjuctive therapy in
`resistant partial epilepsy
`Adjunctive therapy in
`partial onset seizure;
`Myoclonic seizure 'AIME;
`GTCS in IGE
`Behavioural and
`Adjunctive therapy
`(>2 yrs) in refractory (cid:9)
`cognitive problem;
`weight loss; metabolic
`partial, generalized and
`seizures associated with LGS acidosis; nephrolithiasis
`Allergic rash/Steven
`Adjunctive treatment for (cid:9)
`focal or generalized seizures Johnson syndrome
`and seizures of LGS
`
`Monotherapy or adjunctive CNS side effects,
`therapy (>4 yr) for focal (cid:9)
`hyponatremia
`seizure with or without
`secondary generalization
`Adjunctive therapy in (cid:9)
`refractory focal seizures (cid:9)
`
`CNS side effects,
`cognitive effect,
`weight loss
`Frequent CNS effects,
`prolongation of PR
`interval
`Occasional CNS side
`effects
`
`Few minor CNS effects (cid:9)
`of drug interaction
`
`Adjunctive therapy in (cid:9)
`refractory focal and (cid:9)
`generalized epilepsy (cid:9)
`Adjunctive treatment in (cid:9)
`refractory seizures in LGS (cid:9)
`
`Adjunctive therapy for (cid:9)
`
`dravet syndrome
`
`It can aggravate absence
`and Myoclonic seizure
`
`No drug interaction;
`good safety profile; safe
`in liver disease
`
`Slow titration mandatory;
`never withdraw drug
`abruptly
`
`Slow titration; half dose
`when used with valpraote;
`can precipitate
`Myoclonic seizures
`Can worsen absence and
`Myoclonic seizure,
`
`Drug interactions with
`otherAEDs
`
`Limited experience in
`children; more studies
`required
`Avoid in patients with
`familial short QT
`syndrome
`Limited experience;
`
`(GABA- Gamma amino butyric acid, CNS-Central nervous system, IGE- idiopathic generalized epilepsy, JME- juvenile myoclonic epilepsy, GTCS-
`generalized tonic clonic seizure, LGS- Lennox Gastaut syndrome).
`
`INDIAN PEDIATRICS (cid:9)
`
`1038 (cid:9)
`
`VOLUME 50—NOVEMBER 15, 2013
`
`Page 00006
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`ANEJA AND SHARMA
`
`NEWER ANTI-EPILEPTIC DRUGS
`
`the earlier AED. Other than Oxcarbazepine for partial
`epilepsy, there is no evidence for the use of the newer
`AED as monotherapy in new-onset epilepsy in children.
`Some of the newer AEDs have proven efficacy for some
`childhood epileptic syndrome e.g. vigabatrin for infantile
`spasms, levetiracetam for juvenile myoclonic epilepsy,
`rufinamide for Lennox-Gastaut syndrome and stiripentol
`for Dravet syndrome. The current choice of available
`AEDs also allows for options for children with
`concomitant systemic illnesses and co-morbidities based
`on the pharmacokinetic profiles of these drugs.
`
`However, the cost of these drugs increases the cost of
`therapy and limits their use in low and middle income
`countries.
`
`REFERENCES
`
`1. Mackay MT, Weiss SK, Adams-Webber T, Ashwal
`S, Stephens D, Ballaban-Gill K, et al.Practice parameter:
`medical treatment of infantile spasms: report of the
`American Academy of Neurology and the Child Neurology
`Society. Neurology. 2004; 62:1668-81.
`2. Go CY, Mackay MT, Weiss SK, Stephens D, Adams-
`Webber T, Ashwal S, et al. Evidence-based guideline
`update: medical treatment of infantile spasms. Report of the
`Guideline Development Subcommittee of the American
`Academy of Neurology and the Practice Committee of the
`Child Neurology Society. Neurology. 2012;78:1974-80.
`3. Elterman RD, Shields WD, Mansfield KA, Nakagawa J.
`Randomized trial of vigabatrin in patients with infantile
`spasms. Neurology. 2001;57:1416-21.
`4. Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy
`CR, Newton RW, et al. The United Kingdom Infantile
`Spasms Study (UKISS) comparing hormone treatment
`with vigabatrin on developmental and epilepsy outcomes to
`age 14 months: a multicentre randomised trial. Lancet
`Neurol. 2005;4:712-7.
`5. Plant GT, Sergott RC. Understanding and interpreting
`vision safety issues with vigabatrin therapy. Acta Neurol
`Scand Suppl. 2011:57-71.
`6. Willmore LI, Abelson MB, Ben-Menachem E, Pellock JM,
`Shields WD. Vigabatrin: 2008 update. Epilepsia.
`2009;50:163-73.
`7. Krauss GL. Evaluating risks for vigabatrin treatment.
`Epilepsy Curr. 2009;9:125-9.
`8. Cannant L. Vigabatrin therapy for infantile spasms: review
`of major trials in Europe, Canada, and the United States;
`and recommendations for dosing. Acta Neurol Scand
`Suppl. 2011:36-47.
`9. Pellock JM, Hrachovy R, Shinnar S, Baram TZ, Bettis D,
`Dlugos DJ, etal. Infantile spasms: a U.S. consensus report.
`Epilepsia. 2010;51:2175-89.
`10. Lukyanetz EA, Shkryl VM, Kostyuk PG. Selective
`blockade of N-type calcium channels by levetiracetam.
`Epilepsia. 2002;43:9-18.
`11. Verrotti A, D'Adamo E, Parisi P, Chiarelli F, Curatolo P.
`Levetiracetam in childhood epilepsy. Paediatr Drugs.
`
`2010;12:177-86.
`12 . Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger
`J. Levetiracetam: safety and efficacy in neonatal seizures.
`Eur J Pediatr Neurol. 2011;15:1-7.
`13. McTaque A, Kneen R, Kumar R, Spinty S, Appleton R.
`Intravenous levetiracetam in acute repitive seizures and
`status epilepticus in children: experience from a children's
`hospital. Seizure. 2012;21:529-34.
`14. Kossoff EH, Bergey GK, Freeman JM, Vining EP.
`Levetiracetam psychosis in children with epilepsy.
`Epilepsia. 2001;42:1611-3.
`15. Verrotti A, Coppola G, Manco R, Ciambra G, lannetti P,
`Grosso S, et al. Levetiracetam monotherapy for children
`and adolescents with benign rolandic seizures. Seizure.
`2007;16:271-5.
`16. De Los Reyes EC, Sharp GB, Williams JP, Hale SE.
`Levetiracetam in the treatment of Lennox-Gastaut
`syndrome. Pediatr Neurol. 2004;30:254-6.
`17. Verrotti A, Cerminara C, Coppola G, Franzoni E, Parisi P,
`'anneal P, et al. Levetiracetam in juvenile myoclonic
`epilepsy: long-term efficacy in newly diagnosed
`adolescents. Dev Med Child Neurol. 2008;50:29-32.
`18. Kossoff EH, Los JG, Boatman DF. A pilot study
`transitioning children onto levetiracetam monotherapy to
`improve language dysfunction associated with benign
`rolandic epilepsy. Epilepsy Behay. 2007;11:514-7.
`19. Kossoff EH, Bergey GK, Freeman JM, Vining EP.
`Levetiracetam psychosis in children with epilepsy.
`Epilepsia. 2001;42:1611-3.
`20. Coppola G, Caliendo G, Terracciano MM, Buono S,
`Pellegrino L, Pascotto A. Topiramate in refractory partial-
`onset seizures in children, adolescents and young adults: a
`multicentric open trial. Epilepsy Res. 2001;43:255-60.
`21. Sreenivasan P, Kunju PA. Efficacy of Topiramate as an
`add-on drug in seizures in Indian children-an
`observational study. Indian J Pediatr. 2011;78:1221-4.
`22. Hancock EC, Cross JH. Treatment of Lennox-Gastaut
`syndrome. (cid:9)
`Cochrane (cid:9)
`Database (cid:9)
`Syst (cid:9)
`Rev.
`2013;2:CD003277.
`23. Zou LP, Lin Q, Qin J, Cai FC, Liu ZS, Mix E. Evaluation of
`open-label topiramate as primary or adjunctive therapy in
`infantile spasms. Clin Neuropharmacol. 2008;31:86-92.
`24. Mikaeloff Y, de Saint-Martin A, Mancini J, Peudenier S,
`Pedespan JM, Vallee L, et al. Topiramate: efficacy and
`tolerability in children according to epilepsy syndromes.
`Epilepsy Res. 2003;53:225-32.
`25. Biton V, Bourgeois BF. Topiramate in patients with
`juvenile myoclonic epilepsy. Arch Neurol. 2005;62:1705-
`1708.
`26. Ben-Zeev B, Watemberg N, Augarten A, Brand N, Yahav
`Y, Efrati 0, et al. Oligohydrosis and hyperthermia: pilot
`study of a novel topiramate adverse effect. J Child Neurol.
`2003;18:254-7.
`27. Yamamoto Y, Takahashi