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`Acta Neural Scand 2013: 127: 149-153 DOl: 10.1 111jj.1600-0404.2012.01704.x
`
`© 2012 John Wiley & Sons A/S
`ACT A NEUROLOGICA
`SCANDINA VICA
`
`Clinical experience with using lacosamide
`for the treatment of epilepsy in a tertiary
`centre
`
`Kamel JT, DeGruyter MA, D'Souza WJ, Cook MJ. Clinical
`experience with using lacosamide for the treatment of epilepsy in a
`tertiary centre.
`Acta Neurol Scand: 2013: 127: 149-153.
`© 2012 John Wiley & Sons A/S.
`
`J. T. Kamel, M. A. DeGruyter,
`W. J. D'Souza, M. J. Cook
`The Department of Medicine, St. Vincent's Hospital
`Melbourne, The University of Melbourne, Fitzroy,
`Melbourne, Australia
`
`Objective - Lacosamide is approved for the adjunctive treatment of
`partial-onset seizures in adults. Phase II/III clinical trials suggest that
`it is a safe, effective and well-tolerated medication. However, there is
`little post-marketing information available about this medication.
`Methods We report our clinical experience from a tertiary referral
`epilepsy centre, which has been using lacosamide for the past
`18 months, with 128 patients treated during this time. Results- Fifty(cid:173)
`three patients (41 %) achieved at least a 50% reduction in seizure
`frequency, with 14 patients (11 %) achieving seizure freedom for a
`mean time of 35 weeks. This 50% responder rate matches, and the
`seizure free rate outperforms that seen in previous pooled trials. The
`efficacy of lacosamide did not vary with concurrent sodium channel
`blocking agent (SCB) use, and a statistically significant dose(cid:173)
`dependent response was not shown, which is in contrast to previous
`trials. Treatment emergent adverse effects (TEAEs) were noted in 52
`patients (41 %), with 24 patients (19%) discontinuing the medication.
`TEAEs were more frequent in patients on concurrent SCBs, affecting
`51% vs. 28 °/o of patients not on other SCBs. This increased risk of
`TEAEs from concurrent SCB use was of statistical significance
`0.01). The most frequently noted TEAEs from lacosamide were
`-(P
`dizziness, sedation and diplopia, which all appeared to be dose(cid:173)
`related. Conclusion- This post-marketing analysis suggests that
`lacosamide in clinical practice at least mirrors, and possibly
`outperforms the results seen in previous phase II/III trials.
`
`Key words: antiepileptic drugs; lacosamide;
`lamotrigine; sodium channel blocking agent
`
`J. T. Kamel. The Department of Neurology and
`Neurological Research, The Department of Medicine,
`St. Vincent's Hospital Melbourne, PO Box 2900, Fitzroy,
`Melbourne, Vic 3065, Australia
`Tel.: +61 3 9288 2211
`Fax: +61 39 288 4871
`e-mail: jordan.kamel@svhm.org.au
`
`Accepted for publication June 20, 2012
`
`Introduction
`
`Lacosamide is a new antiepileptic drug (AED),
`which is approved for the adjunctive treatment of
`in adults. It selectively
`partial-onset seizures
`inactivation of voltage-gated
`enhances
`slow
`sodium channels without affecting fast inactiva(cid:173)
`tion. This may make it more selective than older
`generation AEDs, such as phenytoin and carba(cid:173)
`mazepine, for repeatedly depolarizing neurons of
`seizure activity (1). Other favourable aspects of
`lacosamide include its pharmacokinetic profile,
`with high oral bioavailability of approximately
`lOOo/o, twice-daily dosing with a relatively long
`
`elimination half-life of 13 h, linear pharmacoki(cid:173)
`netics and renal elimination (2). It has minimal
`binding
`to plasma proteins, has no known
`clinically
`relevant drug-drug
`interactions
`(3),
`and does not induce or inhibit enzymes of the
`cytochrome P450 system ( 4). In addition, cost
`utility results have shown that lacosamide is a
`cost-effective treatment for uncontrolled partial(cid:173)
`onset seizures ( 5).
`Although there are no pharmacokinetic interac(cid:173)
`tions with the more traditional voltage-gated
`sodium channel blockers (SCBs), such as carba(cid:173)
`mazepine and phenytoin (6), it has been suggested
`that neurotoxicity with lacosamide may be more
`
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`Kamel et al.
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`likely with concomitant use through pharmacody(cid:173)
`namic effects. The central adverse effects of
`drowsiness, dizziness and diplopia may be amelio(cid:173)
`rated by dose reduction of the other SCB (7).
`Previous phase II/III clinical
`trials suggest
`that lacosamide is a safe, effective and well-toler(cid:173)
`ated medication (8). However, there is very little
`post-marketing experience available in the current
`literature, with only a handful of such analyses
`reported to date (9, 10). Our tertiary epilepsy
`centre has been using lacosamide for the past
`18 months, with 128 patients treated during this
`time. We report our experiences with efficacy, tol(cid:173)
`erability and side effects of this medication.
`
`Methods
`
`At a tertiary epilepsy centre, a total of 128
`patients were commenced on lacosamide between
`December 2009 and April 2011. The dose was
`started at 50 mg twice daily and titrated up as
`guided by the treating epileptologist. The data of
`this group of consecutive patients were collected
`and analysed retrospectively, primarily through
`access to patient notes and medical records.
`The efficacy on seizure frequency reduction
`once a maintenance dose was reached was catego(cid:173)
`rized as 100% response, >50o/o response, <50%
`but >Oo/o response, no effect, or worsening of sei(cid:173)
`zure frequency. This was
`routinely enquired
`about by the treating epileptologist and recorded
`in
`the patient's medical notes.
`In addition,
`patients were encouraged to keep seizure diaries.
`Efficacy of lacosamide
`:::; 200 mgjday was com(cid:173)
`pared to >200 mgjday for statistical significance,
`using Fisher's exact test. Doses higher than
`200 mg/day were grouped together in assessment
`of efficacy, because of the low sample size in
`patients on these doses.
`The tolerability of lacosamide was assessed by
`routinely asking patients of any potential treat(cid:173)
`ment emergent adverse effects (TEAEs) that were
`noted after commencing the medication. Concur(cid:173)
`rent AEDs were noted, and patients were
`grouped according to those that were taking at
`least one traditional SCB (which included phenyt(cid:173)
`oin, primidone, carbamazepine and oxcarbaze(cid:173)
`pine), and
`those
`that were not. Although
`lamotrigine does exert a
`therapeutic effect
`through inhibiting sodium channels, for all inten(cid:173)
`sive purposes regarding
`its pharmacodynamic
`actions through other pathways and side effect
`profile
`in general,
`it was considered by the
`authors to be considered as a non-SCB. The sta(cid:173)
`tistical significance of TEAE incidence between
`patient groups according to concurrent SCB use,
`
`150
`
`as well as differences in efficacy, was analysed
`using Fisher's exact test.
`
`Results
`
`A total of 128 patients were commenced on lacosa(cid:173)
`mide. About119 had symptomatic focal epilepsies.
`Surgical candidates were not excluded. There were
`also nine patients that had idiopathic generalized
`epilepsies; in several of these cases, the patients in
`this group were commenced on lacosamide when
`their epilepsies were thought to be of a focal nat(cid:173)
`ure, but later proven to be generalized. Given this
`small sample size, patients with IGE were unable
`to be analysed separately. The 71
`(55%) of
`patients were on at least one traditional SCB. The
`dosage of lacosamide ranged from 100 to 500 mg
`daily. The baseline characteristics of our patients
`and lacosamide usage are outlined in Table 1.
`Fifty-three patients (41 o/o) achieved at least a
`50% reduction in seizure frequency (50% respon(cid:173)
`der rate), with 14 patients (11 o/o) achieving com(cid:173)
`plete seizure remission. The average time our
`patients have been seizure free on lacosamide is
`35 weeks, which _is
`longer
`than the 12-week_
`Maintenance Phase used to assess patients in past
`phase II/III clinical trials. There were 44 patients
`(34o/o) that did not note any reduction in their
`seizure frequency. This is represented in Fig. 1.
`No patients noted worsening of their seizures
`after commencement of lacosamide. Fig. 1 also
`includes efficacy data according to lacosamide
`dose and concurrent SCB use.
`Higher dosages of lacosamide were not superior
`to lower dosages in our cohort of patients.
`Although there was a slightly higher percentage of
`patients who experienced seizure freedom (12o/o vs
`
`Table 1 Baseline characteristics of patients on lacosamide
`
`Age (mean, years)
`Female
`Duration on lacosamide (mean)
`Dosage
`::; 200 mg/day
`>200 and ::; 300 mg/day
`>300 and ::; 400 mg/day
`>400 mg/day
`Mean dose
`Patients on concomitant SCBs
`No. of concomitant AEDs
`0
`
`2
`3
`4
`5
`
`39 (range 18--72)
`64 (50%)
`7 months (range 1-17)
`
`79 (61.7%)
`29 (22.6%)
`19 (14.8%)
`1 (0.8%)
`250 mg/day
`71 (55%)
`
`1 (1%)
`9 (7%)
`35 (27%)
`52 (41%)
`26 (20%)
`5 (4%)
`
`AEDs, antiepileptic drugs; SCBs, sodium channel blockers.
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`T
`
`I
`
`All patients (n = 128)
`
`Dose s200 mg/day (n = 79)
`
`Dose > 200 mg/day (n = 49)
`
`Concurrent SCB (n = 57)
`
`No concurrent SCB (n = 71)
`
`Efficacy of lacosamide
`
`Seizure reduction
`
`0%
`
`>0 to :550% >50 to :5100%
`
`100%
`
`Figure 1. Efficacy of lacosamide.
`
`lOo/o), this was offset by fewer patients achieving
`>50% seizure reduction (39% vs 43%); overall,
`there was no statistical significance between the
`two groups (P = 0.71; Fisher's exact test).
`The subgroup taking concurrent sodium chan(cid:173)
`nel blocking agents had a higher percentage of
`patients achieving a >50°/o seizure reduction
`(45o/o vs 37°/o). However, this association did not
`reach statistical significance (P 0.37; Fisher's
`exact test).
`Treatment emergent adverse effects were noted
`in 52 patients (41 o/o), with 24 patients (19%) dis(cid:173)
`continuing the medication, at least in part due to
`these side effects. TEAEs were more frequent in
`patients on concurrent SCBs, affecting 51 o/o of
`patients in this group, compared with those not
`on other SCBs, affecting 28o/o of these patients
`(Table 2). This association between concurrent
`SCB use and increased risk of adverse effects was
`of statistical significance (P = 0.01; Fisher's exact
`test).
`Treatment emergent adverse effects were
`reported in 20 of 61 patients (33%) on lamotri(cid:173)
`gine and 7 of 37 patients (19o/o) on lamotrigine
`
`Table 2 Comparison of adverse effects (AEs) between patients on concurrent
`sodium channel blocking agents (SCB) and those that were not
`
`SCB
`No SCB
`Total
`
`AEs (%)
`
`36 (51)
`16 (28)
`52 (41)
`
`No AEs (%)
`
`35 (49)
`41 (72)
`76 (59)
`
`Total
`
`71
`57
`128
`
`P = 0.01; Fisher's exact test.
`
`Table 3 Comparison of adverse effects (AEs) between patients on lamotrigine
`(LTG) and those on concurrent sodium channel blockers (SCB) with lamotrigine
`excluded
`
`LTG
`SCB
`Total
`
`AEs (%)
`
`7 (19)
`23 (49)
`30 (36)
`
`No AEs (%)
`
`30 (81)
`24 (51)
`54 (64)
`
`Total
`
`37
`47
`84
`
`P < 0.01; Fisher's exact test.
`
`Clinical experience with lacosamide
`
`after excluding those on other concurrent SCBs.
`Compared to patients on concurrent SCBs and
`not on lamotrigine, where 23 of 47 patients
`(49o/o) experienced TEAEs (Table 3), this differ(cid:173)
`ence in risk is of statistical significance (P < 0.01;
`Fisher's exact test). This supports the notion
`discussed earlier that the pharmacodynamic effect
`of lamotrigine differs to that of the more tradi(cid:173)
`tional SCBs and behaves clinically more like a
`non-SCB.
`frequently noted TEAEs were
`The most
`dizziness/ataxia in 26 patients (20o/o), sedation in
`18 patients (14o/o) and diplopia in 6 patients (5o/o;
`see Fig. 2 for all adverse effects noted).
`
`Discussion
`
`The baseline characteristics of age and gender
`were very similar to those seen in the populations
`from pooled analyses of phase II/III clinical trials
`(11). In these trials, 82°/o of patients were on at
`least one other 'traditional' SCB. In our patient
`group, only 55o/o were on another SCB. However,
`it should be noted that these trials included lamo(cid:173)
`trigine as a SCB, and when accounting for this,
`the range of concurrent AEDs used is similar.
`The number of concurrent AEDs used was higher
`in our group of patients, with significantly more
`patients taking three or more other AEDs in both
`SCB and non-SCB groups (Table 1), in compari(cid:173)
`son with the phase II/III clinical trials patients.
`The reason for this is unclear, but perhaps reflects
`the cohort of patients with particular refractory
`disease being referred to our epilepsy centre.
`The 50o/o responder rate amongst our patients
`was 41 o/o, which was similar to the pooled
`analysis results for lacosamide 200 mgjday (50%
`intent-to-treat and
`responder rate of 34.1 °/o
`34.8°/o modified
`ITT), and
`for
`lacosamide
`400 mgjday (50% responder rate of 39.7% ITT
`and 44.3 o/o miTT) (8). This suggests that these
`results from phase II/III trials are at least repro(cid:173)
`ducible in our post-marketing experience.
`Interestingly, the 50% responder rate was not
`significantly
`different
`between
`lower-dose
`( ~ 200 mgjday) and higher-dose (>200 mgjday)
`lacosamide. This is in contrast to previous pooled
`analysis results discussed, which demonstrate a
`dose-related treatment response, with 400 mgjday
`more effective than 200 mgjday (8). Although we
`had 128 patients in our cohort, when subdivided
`according to dose, our sample sizes decrease to
`significantly <200+ patients enrolled in each dos(cid:173)
`age arm of previous phase II/III trials. This lack
`of power could potentially account for not find(cid:173)
`ing this dose-related response.
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`Kamel et al.
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`"'Incidence (%)
`25
`
`Adverse effects associated with lacosamide
`
`20
`
`15
`
`10
`
`Dizziness/
`ataxia
`
`Sedation
`
`Blurred Gastrointestinal Headache Depression/
`vision/diplopia
`upset
`anxiety
`
`Facial
`swelling
`
`Weight loss
`
`Rash
`
`Figure 2. Adverse effects associated with lacosamide.
`
`The 50o/o responder rate also did not differ
`according to whether patients were taking con(cid:173)
`current SCBs or not, and this relationship did
`not show any meaningful statistical significance.
`Similar findings have been reached by another
`post-marketing study by Stephen et al. (10).
`Of note, 14 of our patients (II%) became
`seizure free after commencing lacosamide,
`in
`comparison with the 2.7% of patients taking
`lacosamide 200 mgjday and 3.3% of patients tak(cid:173)
`ing 400 mgjday in the phase II/III trials who
`completed the 12-week Maintenance Phase (8).
`As mentioned in the results section, this is a con(cid:173)
`siderable shorter period than that of our patients.
`The increased TEAEs seen in patients on con(cid:173)
`current SCBs compared with those on AEDs
`with other mechanisms were statistically signifi(cid:173)
`cant (51 o/o vs 28%, P
`0.01). This is in contrast
`to the study by Stephen et al. (1 0), which con(cid:173)
`cluded that lacosamide is as well tolerated in
`patients on traditional SCBs. Our findings are,
`however, concordant with suggestions by the post
`hoc analysis of pooled clinical trial data by Sake
`et al., which suggest
`that there may be an
`improved tolerability for lacosamide in patients
`not on other SCBs.
`Despite our patients generally taking more con(cid:173)
`current AEDs, the side effect noted from lacosa(cid:173)
`mide was overall less than that seen in previous
`trials. One possible reason is that the dosages of
`lacosamide used in our patients were overall
`lower than those used in the trials (11), and doses
`in these trials were more rapidly titrated up in a
`forced schedule, in comparison with the physi(cid:173)
`cian-guided approach used in everyday clinical
`practice.
`
`152
`
`Conclusions
`
`treated 128
`Our tertiary epilepsy centre has
`patients with lacosamide. The 50o/o responder
`rate was 41%, which includes II% of patients
`who became seizure free. This post-marketing
`experience suggests that lacosamide in clinical
`practice at least mirrors and possibly outperforms
`the results seen in previous phase II/III trials.
`Our study did not demonstrate a dose-dependent
`efficacy. TEAEs were more frequent in patients
`on concurrent sodium channel blocking agents.
`
`Acknowledgements
`
`We confirm that we have read the Journal's position on
`issues involved in ethical publication and affirm that this
`report is consistent with those guidelines.
`
`Conflicts of interest
`
`The preparation of this article was not supported by any
`external funding. J.T. Kamel has received previous educa(cid:173)
`tional support from UCB Pharma. M.A. DeGruyter has no
`conflict of interest to disclose. W.J. D'Souza has received
`travel,
`investigator-initiated and speaker honoraria from
`UCB Pharma. He has received educational, travel and fellow(cid:173)
`ship grants from GSK neurology Australia. He has received
`educational grants from Novartis Pharmaceuticals and Pfizer
`Pharmaceuticals. He has received honoraria from Scigen
`Pharmaceuticals. M.J. Cook has received travel and speaker
`honoraria from UCB Pharma, Scigen Pharmaceuticals and
`Sanofi.
`
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