Drug Evaluation

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Lacosamide for the treatment of epilepsy Stefano de Biase, Gian Luigi Gigli, Mariarosaria Valente & Giovanni Merlino†

1.

Introduction

2.

Introduction to the compound

3.

Conclusion

4.

Expert opinion

†

“ S. Maria della Misericordia” University Hospital, Department of Neurosciences, Udine, Italy

Introduction: Epilepsy is one of the most common neurological disorders. Despite the development of new antiepileptic drugs (AEDs), ~ 30% of epilepsy patients experience recurrent seizures and even more experience side effects. Therefore, there is still need for new AEDs with enhanced effectiveness and tolerability. Areas covered: The article is based on a search using PubMed, including articles published between 1999 and 2013. It is focused on the pharmacokinetic, pharmacological and clinical data of lacosamide (LCM) for the treatment of epilepsy. Expert opinion: Along with favorable tolerability and pharmacokinetic profiles, LCM has been demonstrated to significantly reduce seizure frequency in patients with partial-onset seizures when prescribed as adjunctive treatment at doses of 200 and 400 mg/day. LCM has a unique mechanism of action, selectively enhancing slow inactivation of voltage-gated sodium channels. Its mechanism of action could be exploited to reduce the percentage of pharmacoresistant patients. Although LCM is not FDA approved for treatment of status epilepticus, it has demonstrated promising preliminary results. Large prospective studies are needed to verify these. In addition, the results of ongoing trials will help to confirm if LCM could be used as a monotherapy regimen in the treatment of partial-onset seizures and generalized tonic--clonic seizures. Keywords: absorption, distribution, elimination, lacosamide, partial-onset seizures, pharmacokinetic, status epilepticus, toxicology Expert Opin. Drug Metab. Toxicol. (2014) 10(3):459-468

1.

Introduction

Epilepsy is a condition defined by the occurrence of at least two unprovoked epileptic seizures, which is the clinical manifestation of an abnormal and excessive discharge of a set of neurons in the brain [1]. Epilepsy affects up to 2% of the population worldwide, with annual incidence rates of ~ 40 -- 70/100,000/year [2]. The prevalence is estimated as 5 -- 10/1000, excluding epilepsy in remission, febrile convulsions and single seizures [3]. Overall prevalence and incidence of epilepsy tend to be lower in developed regions (USA and Europe) in comparison with developing regions (Latin America and Africa). Increased prevalence and incidence may be related to factors such as low socioeconomic status, limited access to healthcare and environmental exposures. In developing countries, prevalence of epilepsy generally peaks in adolescence and early adulthood. On the other hand, in developed countries, incidence and prevalence is higher among the elderly [4]. Seizures can be classified as being generalized (with synchronized discharges involving both hemispheres from onset to termination) or partial (paroxysmal discharge localized to part of the cerebral cortex).

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Box 1. Drug summary.

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Drug name Phase Indication

Lacosamide Launched Adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged > 16 years (EMEA) and 17 years (FDA) Mechanism of action Dual mode of action: slow inactivation of VGSCs and binding to CRMP-2 Route of Oral, intravenous administration O Chemical structure H N

H3C

N H O

2.

O CH3

Pivotal trial(s)

C13H18N2O3 LCM showed a dose-dependent increase in efficacy and decrease in retention rate. LCM 200 mg/day failed to show a statistically significant effect compared to placebo in some trials, whereas the efficacy of LCM 600 mg/day was not markedly better than LCM 400 mg/day which showed the most favorable tradeoff between efficacy and tolerability [36-38]

CRMP2: Collapsing-response mediator protein-2; EMEA: European Medicines Agency; FDA: Food and Drug Administration; LCM: Lacosamide; VGSC: Voltage-gated sodium channels.

The goal of pharmacologic therapy with antiepileptic drugs (AEDs) is to reduce the frequency of seizures and achieve a seizure-free state with minimal side effects [5]. In the past decades, several new options for the medical treatment of epilepsy have been introduced. However, only half of patients achieve seizure freedom with the first administered AED, and ~ 30% of patients treated with available AEDs continue to experience uncontrolled seizures [6]. In addition, ~ 20 -- 30% of patients will discontinue therapy because of intolerable adverse drug effects [7]. One of the greatest unmet needs in treatment of epilepsy is a better seizure-free efficacy. Uncontrolled seizures may have debilitating psychosocial consequences and carry a significant risk of injury and/or death. Therefore, there is still need for the development of effective and well-tolerated new AEDs. Furthermore, a better understanding of epileptic syndromes and their pathophysiology as well as the development of valid biomarkers to predict epilepsy and its severity after an insult or an indentified genetic defect is required [8,9]. Clinical guidelines suggest that the use of AEDs should be personalized and the choice of AEDs should be based on factors, including the patient’s epilepsy syndrome, seizure type and lifestyle [10,11]. 460

In recent years, a third-generation class of AEDs was introduced in the market with presumed good efficacy and favorable tolerability profile, increasing the AEDs armamentarium. Several of them had novel mechanism of action (i.e., retigabine, perampanel and lacosamide [LCM]), offering opportunity to improve both seizure control and treatment tolerability. LCM is a novel AED licensed in 2008 by the European Medicines Agency (EMEA) and by the US FDA as adjunctive therapy for partial-onset seizures in patients with epilepsy aged > 16 years (EMEA) and 17 years (FDA) [12,13]. This article summarizes the pharmacological and clinical data of this drug (Box 1).

Introduction to the compound

LCM (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide) is a unique functionalized amino acid that was specifically synthesized as an anticonvulsive drug candidate. Its empirical formula is C13H18N2O3. It is a white-to-yellow crystalline powder with a molecular weight of 250.30 Da and a melting point of 143 C to 144 C that has high water solubility [14,15]. Oral LCM is available in 50, 100, 150 and 200-mg tablets [13]. In addition, an intravenous formulation is being developed for short-term replacement of oral LCM in patients with partial-onset seizures but is not currently approved for the treatment of status epilepticus (SE). LCM solution for infusion (10 mg/ml) is isotonic, stable at room temperature, has a pH of 3.5 -- 5 and does not require dilution prior to intravenous administration. However, it can also be diluted in sodium chloride 0.9%, dextrose 5% or lactated Ringer’s solution, if needed [13]. Additionally, LCM is available as oral syrup (15 mg/ml) in Europe. LCM oral solution contains aspartame and should be used with caution in patients with phenylketonuria [12]. Pharmacodynamics LCM demonstrated broad anticonvulsant effects in murine seizure models for generalized seizures, complex partial-onset seizures and SE [15,16]. LCM is believed to have a dual mode of action. It has been postulated that LCM has an effect on the voltage-gated sodium channels (VGSCs). Unlike other AEDs, such as carbamazepine, phenytoin and lamotrigine, LCM selectively enhances the slow inactivation of VGSCs with no effects on fast inactivation, making its mechanism of action unique [17]. This results in the stabilization of hyperexcitable neuronal membranes and the inhibition of repetitive neuronal firing, thus controlling neuronal hyperexcitability [18]. LCM also binds to collapsing-response mediator protein-2 (CRMP2), a phosphoprotein that is expressed mainly in the nervous system [15]. However, this binding has recently been challenged [19]. The CRMP family of proteins is implicated in developmental processes of the nervous system, since most of the five CRMP proteins are highly expressed during early 2.1

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Lacosamide

development and mainly in the CNS [20]. A study examining the hippocampus of patients with drug-resistant mesial temporal lobe epilepsy found reduced levels of CRMP-2 expressed compared to the control patients without epilepsy [21]. LCM does not affect AMPA, kainate, NMDA, GABA or a variety of dopaminergic, serotonergic, histaminergic, adrenergic, muscarinic or cannabinoid receptors [15,17]. Therefore, LCM with its specific mechanism of action did not influence receptors used by other AEDs for their antiepileptic properties (e.g., AMPA and GABA) that might give LCM an even higher efficacy. At the same time, LCM does not interfere with receptors that might cause additional side effects (i.e., histaminergic and muscarinic receptors). Pharmacokinetics and metabolism LCM is available in three different formulations: tablet, syrup and intravenous solution. LCM met bioequivalence criteria for 30- and 60-min infusions compared to oral LCM (200 mg) in healthy volunteers [22]. A placebo-controlled trial showed that patients with partial-onset seizures could switch from oral to intravenous LCM for 2 days using 60- and 30-min infusions at doses of 200 -- 600 mg/day [23]. In another trial, 15-min infusions were bioequivalent to oral LCM for AUC; however, the Cmax was slightly above the bioequivalence range raising the possibility that a higher Cmax might reduce tolerability [24]. Bioequivalence between the tablet and the syrup formulations of LCM has been established [25]. LCM is rapidly and completely absorbed following oral administration, with negligible first-pass effect. The bioavailability of LCM is ~ 100% [18,26]. On 24 healthy volunteers, it was demonstrated that administration of food did not alter the rate or extent of gastrointestinal absorption [27]. Peak plasma concentration occurs 1 -- 4 h after oral administration and immediately after intravenous infusion. In rats, LCM showed linear pharmacokinetics at an intravenous dose of 1 -- 30 mg/kg and an oral dose of 1 -- 10 mg/kg but nonlinear pharmacokinetics at a 30 mg/kg oral dose; this appeared to result from absorption saturation [28]. In humans, LCM displayed a linear pharmacokinetics; plasma concentrations increase proportionally with dose in the therapeutic range (50 -- 300 mg intravenous and 100 -- 800 mg oral), with low intrapatient and interpatient variability [17]. Healthy elderly subjects (> 65 years) exhibited slightly higher values of Cmax and AUC than young subjects (18 -- 45 years) but without clinical relevance. The difference is mainly due to the reduced total body water in elderly subjects resulting in higher drug concentrations. Similarly, females exhibited slightly higher Cmax and AUC values than males, without clinical relevance, most likely explained by a lower body weight [29]. The elimination half-life of LCM is about 13 h, allowing convenient twice-daily dosing [14]. Following twice-daily administration of oral LCM, steady-state plasma concentrations is reached after 3 days [30]. The volume of distribution 2.1.1

is ~ 0.6 l/kg and LCM is bound < 15% to plasma protein [25]. Greenaway et al., based on saliva data, found that LCM has high protein binding [31]. However, these results were not confirmed in other studies. Cawello et al. reported a low difference for saliva and total plasma concentration ratio (£ 10%), which is indicative of low protein binding [25]. Recently, Fountain et al. evaluated plasma protein binding by equilibrium dialysis confirming that LCM has a low protein binding (< 15%) [32]. LCM is eliminated mainly by renal excretion. After oral and intravenous administration of radiolabeled LCM, ~ 95% of the radioactivity was recovered in the urine and < 0.5% in the feces [13]. LCM was eliminated in the urine unchanged (~ 40% of the administered dose) and as O-desmethyl metabolite (< 30%). A polar fraction accounted for ~ 20% of the radioactivity in the urine [13]. Although CYP2C19 is mainly responsible for the formation of the O-desmethyl metabolite, no clinically relevant effects on plasma concentrations were found when LCM was given to poor or extensive metabolizers of CYP2C19, indicating that the metabolic pathway involving CYP2C19 is minor [33]. Main properties and pharmacokinetic parameters of LCM are summarized in Table 1. Special populations LCM is eliminated predominantly via the kidneys. AUC is increased by 25% in patients with mild-to-moderate renal impairment (creatinine clearance 30 -- 80 ml/min) and 60% in severely renally impaired patients (creatinine clearance < 30 ml/min). No dose adjustment is necessary in mild and moderately renally impaired subjects. A maximum dose of 250 mg/day (EU) [12] and 300 mg/day (USA) [13] is recommended for patients with severe renal impairment and in patients with end-stage renal disease. Hemodialysis removes ~ 50% of LCM from plasma; therefore, dose supplementation following hemodialysis should be considered [13]. In patients with moderate hepatic impairment (Child-Pugh class B), the AUC of LCM is increased by ~ 50 to 60% and a maximum dose of 300 mg/day is recommended. LCM has not been studied in patients with severe hepatic impairment and is not recommended in these patients (Table 2). Given its possible interaction with CRMP-2, it has been suggested that LCM has the potential to adversely affect CNS development. CRMP-2 is known to be highly expressed during gestation and early in life [34]. There are no adequate and well-controlled studies in pregnant women. LCM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 2.1.2

Interactions LCM has low potential for pharmacokinetic interactions with other AEDs or other drugs. The low protein binding of LCM minimizes the potential for displacement of other drugs [35]. Furthermore, there is no indication that LCM acts as an inducer or inhibitor of the CYP450 isoenzymes, except for the inhibition of CYP2C19 in vitro at concentrations 2.1.3

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Table 1. Main properties and pharmacokinetic parameters of lacosamide.

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Starting dose Therapeutic dose Dosing schedule Bioavailability Influence of concomitant food Pharmacokinetic

Time to Cmax (h) Elimination half-life (h) Distribution volume Protein binding Induction/inhibition of CYP450 system Relevant interaction with anticonvulsants Relevant interaction with digoxin, warfarin, metformin, omeprazole, estradiol, levonorgestrel Elimination route Most common adverse events

100 mg/day 200 -- 400/day b.i.d. ~ 100% No Linear, with linear increase of plasma concentration with dose 200 mg: Cmax 5.1 ± 1.4 µg/ml; AUC 80.9 ± 17.5 µg  h/ml; 400 mg: Cmax 8.7 ± 0.8 µg/ml; AUC 143 ± 27 µg  h/ml; 600 mg: Cmax 14.3 ± 2.3 µg/ml; AUC 231 ± 49 µg  h/ml; 800 mg: Cmax 19.0 ± 4.8 µg/ml; AUC 302 ± 79 µg  h/ml [17,22] 1 -- 4 h after oral dosing and at the end of infusion after intravenous administration 13 0.6 l/kg < 15% No No No

Renal Dizziness, headache, nausea, diplopia

AUC: Area under the curve; b.i.d.: Twice a day; Cmax: Maximum plasma concentration; CYP450: Cytochrome P450.

Table 2. Lacosamide in special populations. Renal impairment

Hepatic impairment

Cardiac disease

Pregnancy Pediatric population Geriatric population

No dose adjustment in mild and moderate renal impairment (ClCr > 30 ml/min). A maximum dose of 250 mg/day (EU) and 300 mg/day (USA) is recommended for patients with severe renal impairment and with end-stage renal disease. In patients with moderate hepatic impairment (Child-Pugh class B) a maximum dose of 300 mg/day is recommended. LCM has not been studied in patients with severe hepatic impairment and is not recommended. Caution should be used in adults with cardiac conduction problems or severe cardiac disease (e.g., first-degree AV block or higher, sick sinus syndrome, myocardial ischemia, heart failure). In those patients, an ECG should be obtained prior to starting therapy and at the end of dose titration. In EU, LCM is contraindicated in patients with second- or third-degree AV block. There are no adequate and well-controlled studies in pregnant women. LCM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The safety and effectiveness of LCM in pediatric patients have not been established. No dose adjustment based on age is considered necessary. Caution should be exercised for dose titration in elderly patients.

AV: Atrioventricular; ClCr: Creatinine clearance; EU: Europe; LCM: Lacosamide; USA: United States.

> 15-fold higher than therapeutic plasma levels. During in vivo studies, the enzyme CYP2C19 was not induced or inhibited by LCM [15]. LCM did not show effect on the serum levels of other AEDs, including carbamazepine, levetiracetam, lamotrigine, topiramate, valproate, zonisamide, gabapentin and phenytoin [36-38], with the exception of a mild decrease of the monohydroxy-derivative of oxcarbazepine without clinical relevance in one Phase III trial [24]. However, a population pharmacokinetic analysis estimated that concomitant administration of LCM and AEDs that were enzyme inducers (e.g., carbamazepine, phenytoin, phenobarbital) reduced the overall systemic exposure of LCM by 15 -- 25% [13]. Other drug interaction studies have also found no effect on the pharmacokinetics of metformin, digoxin, warfarin, oral contraceptives and omeprazole [13,39-41]. 462

Clinical efficacy The therapeutic efficacy of adjunctive oral LCM in adult patients with partial-onset seizures has been evaluated in three large, Phase II/III, randomized, double-blind, placebocontrolled trials [36-38]. The main results are summarized in Table 3. In summary, LCM showed a dose-dependent increase in efficacy and decrease in retention rate. LCM 200 mg/day failed to show a statistically significant effect compared to placebo in some of the trials and primary outcome parameters but had the best retention rates, whereas LCM 600 mg/day had the lowest retention rates with the efficacy not markedly better than LCM 400 mg/day. Therefore, doses about 400 mg seem to show the most favorable tradeoff between efficacy and tolerability [18]. Three open-label, extension trials of the Phase II/III studies confirmed the long-term 2.2

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35.0% p = 0.07 (n = 160) 35.3% p = 0.02 (n = 160) Halasz et al. [37]

20.8% (n = 104) 20.5% (n = 159)

Median percentage reduction in seizure frequency per 28 days: p values are based on log-transformed seizure frequency from pairwise treatment analysis of covariance models performed on the intent-to-treat population; 50% responder rate: p values are based on the pairwise treatment logistic regression models performed on the intent-to-treat population.

38.1% p = 0.0141 (n = 105) 37.8% p < 0.001 (n = 97) -41.1% p = 0.0038 (n = 107) 38.3% p < 0.001 (n = 201) 40.5% p = 0.01 (n = 158) 32.7% p = 0.0899 (n = 107) --

21.9% (n = 96) 18.3% (n = 1e04) 25.8% (n = 159) 40% p = 0.0084 (n = 105) 37.8% p = 0.006 (n = 97) -39% p = 0.0023 (n = 107) 37.3% p = 0.008 (n = 201) 36.4% p = 158) 26% p = 0.1010 (n = 107) -10% (n = 96)

Ben-Menachem et al. [36] Chung et al. [38]

LCM 400 mg/day LCM 200 mg/day Placebo

LCM 200 mg/day

LCM 400 mg/day

LCM 600 mg/day

Placebo

50% responder rate Median percentage reduction in seizure frequency per 28 days Trial

Table 3. Main results of the Phase IIb/III trials.

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LCM 600 mg/day

Lacosamide

efficacy and tolerability of adjunctive LCM in patients with partial seizures [42-44]. In postmarketing studies, LCM has confirmed to be efficacious and well tolerated [45-47]. In particular, Garcı´a-Morales et al. and Harden et al. found that the 50% responder rate was even higher than the clinical trials [46,47]. The authors assumed that it may be due to the higher refractory epilepsy population in clinical efficacy studies. LCM showed favorable antiepileptic activity when given in combination with levetiracetam, a second-generation AED. Combination of these two AEDs produces very robust synergistic effects in the 6-Hz electrical stimulation model, and a pharmaceutical composition comprising LCM and levetiracetam has been patented by UCB Pharma (EP 2462990 A1) [48]. In addition, clinical trials have been started based on this favorable AED combination (NCT01484977, NCT01345058) [49]. Although LCM is not approved for the treatment of SE, multiple case reports and case series have documented that LCM administration led to termination of SE episodes in patients not responding to standard therapies [50-52]. In a recent review, H€ofler and Trinka reported that in the literature, on a total of 136 episodes (50% nonconvulsive SE, 31% focal SE and 19% convulsive SE) treated with LCM, the overall success rate was 56% (76/136). The most often used bolus dose was 200 -- 400 mg over 3 -- 5 min [53]. In addition, Kellinghaus et al., in a study of 39 patients with SE, reported that the earlier the LCM was administered, the higher was the possibility of success. A clear order effect of intravenous LCM was found, with decreasing success rates as SE progresses [52]. A decreasing efficacy with increasing duration of SE has been demonstrated experimentally [54]. In a recent study, Belcastro et al. reported that LCM exhibited safety and efficacy profiles making it an optimal candidate as a first-choice drug against post-stroke nonconvulsive SE [55]. Intravenous formulation may also be helpful for patients who need a rapid effective protection against seizures. In a recent study, Fountain et al. have demonstrated the efficacy and tolerability of rapid initiation of LCM using a single intravenous loading dose (200 and 300 mg) administered over 15 min in LCM-naı¨ve patients [56]. At the moment, LCM is approved as an add-on treatment of partial-onset seizures. There is an ongoing trial with the objective of demonstrating the efficacy and safety of LCM monotherapy in subjects with partial-onset seizures (NCT00520741) [49]. Another ongoing trial has the objective of comparing efficacy and safety of LCM with carbamazepine controlled release (CBZ-CR) as monotherapy in subjects with epilepsy experiencing partial-onset or generalized tonic--clonic seizures (NCT01243177) [49]. LCM is currently approved in patients with epilepsy aged > 16 years (EMEA) and 17 years (FDA). However, based on the already published case series, LCM appears to be useful and safe as adjunctive therapy also in children with refractory seizures [57-59]. Clinical trials currently in progress will help to

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obtain more definitive information on the efficacy and tolerability of LCM in children (NCT01969851; NCT01964560; NCT00938431; NCT01921205; NCT00938912) [49]. Safety and tolerability Studies suggest that LCM is generally well tolerated with just mild or moderate side effects. From the Phase II/III, the most common treatment-emergent adverse events, reported in > 10% of patients, involved the nervous or gastrointestinal systems and included dizziness, headache, nausea and diplopia. The rate of discontinuation as a result of an adverse event was 8 and 17% in patients randomized to receive LCM at the recommended doses of 200 and 400 mg/day, respectively, 29% at 600 mg/day and 5% in patients randomized to receive placebo [36-38]. The long-term open-label extension trials showed a similar profile of mainly mild-to-moderate CNS and gastrointestinal effects [42-44]. Patients should be counseled that LCM may cause dizziness and ataxia and they should be advised not to drive or operate other complex machinery until they are familiar with the effects of LCM [13]. Post-hoc exploratory analysis of pooled Phase II/III LCM data showed a dose relationship for discontinuations because of adverse events for patients taking concomitant sodium channel AEDs [58]. Otherwise, patients receiving LCM added to AEDs with non-sodium channel mechanisms had marked seizure reduction and few discontinued treatment because of treatment-emergent adverse events [60]. It has been suggested that poorer tolerability observed with LCM plus other sodium channel blockers may be due to a pharmacodynamic interaction rather than pharmacokinetic interaction [61-63]. Edwards et al. observed that patients rapidly titrated to high doses of LCM with simultaneous tapering of traditional sodium channel AEDs had marked reduction in CNS-related adverse events compared with patients who used fixed doses of concomitant AEDs [64]. Sodium channel blocking drugs cause slowing of conduction velocity in cardiac tissues. ECG data of the large randomized trials showed a mild increase in mean PR interval compared to baseline that seemed to be dose-related (4.2 to 12.3 ms at a dose of 400 mg/day) [36-38]. LCM should be used with caution in adults with cardiac conduction problems or severe cardiac disease (e.g., first-degree atrioventricular (AV) block or higher, sick sinus syndrome, myocardial ischemia, heart failure). In those patients, an ECG should be obtained prior to starting therapy and at the end of dose titration. In Europe, LCM is contraindicated in patients with second- or third-degree AV block [13]. Elevations of ALT greater than or equal to three times the upper limit have been reported in the Phase II/III trials: it occurred in 0.7% of the 935 LCM recipients and 0% in the 356 placebo recipients [36-38]. Suicidal thoughts have been described in patients taking LCM. Patients, their caregivers and families should be advised about this possible increased risk. They should also be aware that large doses of LCM (300 -800 mg in adults) can produce a mild euphoria [13]. Although

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euphoria has been reported in < 1% of patients enrolled in clinical trials, LCM is a schedule V controlled substance in the USA. Regulatory affairs LCM was given approval in 2008 by the EMEA and by the FDA as adjunctive therapy for partial-onset seizures with or without secondary generalization in patients with epilepsy aged > 16 years (EMEA) and 17 years (FDA) [12,13]. LCM is supplied as a tablet designed for oral administration or as a solution designed for intravenous administration. In Europe, LCM is available also as oral syrup. It has been demonstrated that the tablet and syrup formulations of LCM 200 mg were bioequivalent and well tolerated [25]. The recommended initial dose is 50 mg twice daily. LCM can be increased at weekly intervals by 100 mg/day given as two divided doses up to the recommended maintenance dose of 200 to 400 mg/day. Furthermore, LCM injection for intravenous use is indicated as adjunctive therapy in the treatment of partial-onset seizures when oral administration is temporarily not feasible. When switching from oral LCM, the initial total daily intravenous dosage should be equivalent to the total daily dosage and frequency of oral LCM and should be infused intravenously over a period of 30 to 60 min [13]. There is experience with twice daily intravenous infusion for up to 5 days [65]. At the end of the intravenous treatment period, the patient may be switched to LCM oral administration at the equivalent daily dosage and frequency of the intravenous administration [13]. At the beginning of 2013, LCM has been approved in the European Union for initiation as a single-loading dose of 200 mg followed ~ 12 h later by a 100 mg twice daily maintenance dose regimen [12]. The single-loading dose is approved for all formulation of LCM (tablet, syrup and solution for infusion) and allows for the rapid attainment of LCM steady-state plasma concentration. This approval supports the feasibility of rapid initiation of adjunctive LCM treatment for some patients with partial-onset seizures not controlled with their current therapy. It should be noted that the incidence of CNS adverse reaction, such as dizziness, may be higher after a loading dose and its administration requires medical supervision [12]. 2.4

3.

Conclusion

The introduction of LCM as an option for the treatment of partial-onset seizures has increased the AEDs armamentarium available for clinicians. Several clinical trials have demonstrated that LCM is a well-tolerated and effective option for the treatment of partial-onset seizures, as an adjunctive agent, at a daily dose of 200 -- 400 mg/day. LCM has a unique mechanism of action, unlike traditional sodium channel AEDs, selectively enhancing slow inactivation of VGSCs.

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In addition to its efficacy and tolerability, LCM meets most of the properties of an ideal AED. It provides high oral bioavailability unaffected by food, linear pharmacokinetics, good tolerability and minimal drug--drug interactions. The low protein binding (< 15%) and the absence of indications that LCM acts as an inducer or inhibitor of the CYP450 isoenzymes at therapeutic doses, justifies the low potential for drug interactions. Such an absence of interaction may allow for ease of LCM use as adjunctive therapy. Dizziness is the most common reported adverse event, followed by headache, nausea and diplopia. The proportion of side effects and withdrawals increased with dose. Combining LCM with AEDs that act on sodium channels may be more likely to produce adverse events. 4.

Expert opinion

Epilepsy is one of the most common neurological disorders. Almost one-third of patients treated with available AEDs suffer of uncontrolled seizures and ~ 20 -- 30% of epileptic patients will discontinue therapy because of intolerable adverse drug effects. Therefore there is still need for new AEDs with enhanced effectiveness and tolerability. LCM has a unique mechanism of action, selectively enhancing slow inactivation of VGSCs. Bearing in mind its unique mechanism of action, LCM could be exploited in combination with AEDs carrying different pharmacodynamic properties to reduce the percentage of pharmacoresistant patients. In particular, the combination between LCM and levetiracetam shows very robust synergistic effects and there are ongoing trials with the objective of demonstrating the efficacy and tolerability of this combination. If the results are confirmed, the combination of LCM and levetiracetam could be one of the most widely used for the treatment of partial-onset seizures in the coming years. The availability of multiple LCM formulations is distinctive among AEDs, allowing flexibility of administration. Intravenous formulation is easy to handle and has shown to be bioequivalent to oral formulation. It is advantageous for patients who are unable to take oral medications: when patients undergo surgery, are hospitalized, have swallowing difficulties or experience acute gastrointestinal disorders.

This reduces the likelihood of seizure exacerbation and avoids unexpected side effects from using an alternative AED. LCM is not FDA-approved for treatment of SE and current evidence on the use of intravenous LCM in SE is restricted to retrospective case reports and case series. Large prospective studies are needed to assess optimal timing, dosing as well as the safety and efficacy of LCM in SE. However, LCM could be an alternative treatment, for this life-threatening neurological disorder, if other more established drugs fail or are considered unsuitable. The management of patients with SE is challenging and there is a paucity of data to guide the treatment. Clinical trials are evaluating the efficacy and safety of LCM monotherapy in subjects with partial-onset seizures. Current literature supports a well-definite role of LCM as adjunctive therapy for partial-onset seizures; however, its role as a monotherapy needs to be established. In addition, there is a clinical trial evaluating, in a head-to-head study with CBZ-CR, the efficacy and safety of LCM as a monotherapy in the treatment of partial-onset seizures and generalized tonic--clonic seizures. If the efficacy of LCM will be confirmed in the treatment of both seizures types, this could markedly increase the use of LCM in the treatment of epilepsy in the next years. LCM is currently approved in patients with epilepsy aged > 16 years (EMEA) and 17 years (FDA); however, based on the case series published, LCM appears to be useful as adjunctive therapy also in children with refractory seizures. Clinical trials currently in progress will help in obtaining more definitive information on the efficacy and tolerability of LCM in children. In addition, the availability of an oral solution (EU) that facilitates the administration of the drug in children could encourage the use of LCM in the pediatric population. To date, LCM represents a reliable therapeutic option for the clinician as an add-on treatment of partial-onset seizures in adults; however, it is possible that LCM will increase its field of use in the treatment of epilepsy in the coming years.

Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.

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Affiliation Stefano de Biase1,2 MD, Gian Luigi Gigli1,2 MD, Mariarosaria Valente1,2 MD & Giovanni Merlino†2 MD PhD † Author for correspondence 1 University of Udine Medical School, Department of Experimental and Clinical Medical Sciences, Neurology Unit, Piazza Santa Maria della Misercordia, 15 33100 Udine, Italy 2 “S. Maria della Misericordia” University Hospital, Department of Neurosciences, Piazza Santa Maria della Misericordia, 15 33100 Udine, Italy Tel: +39 0432552720; E-mail: [email protected]