Adjunctive lacosamide for focal epilepsy: an open‐label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes

Aims. To evaluate the safety and effectiveness of lacosamide in a real‐life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Methods. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open‐label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12‐week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12‐week maintenance period. Primary outcomes were incidence of treatment‐emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. Results. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure‐free. Conclusion. Flexible lacosamide dosing in this open‐label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control.     

Intravenous lacosamide as short‐term replacement for oral lacosamide in partial‐onset seizures

Purpose : Lacosamide is a new antiepileptic drug effective for adjunctive treatment of partial‐onset seizures. We evaluated the safety and tolerability of an intravenous (i.v.) formulation of lacosamide (200–800 mg/day) infused over 10, 15, and 30 min as short‐term replacement for oral lacosamide in patients with partial‐onset seizures. Methods : This multicenter, open‐label, inpatient trial enrolled 160 patients from ongoing open‐label, long‐term trials who were taking stable doses of oral lacosamide and up to three concomitant antiepileptic drugs (AEDs). Serial cohorts of patients were converted from oral lacosamide treatment to the same intravenous doses infused over progressively shorter infusion durations: 30, 15, and 10 min for 2–5 days. A data monitoring committee (DMC) reviewed safety data for each cohort. The safety of intravenous lacosamide was assessed from adverse events (AEs), laboratory variables, electrocardiography findings, and physical/neurologic examinations. Results : A total of 160 patients received lacosamide 200–800 mg/day, i.v., for 2–5 days, of which 69% received 400–800 mg/day doses. The most common AEs (reported by ≤10% of patients) were headache, dizziness, and somnolence. There was no increase in frequency or severity of AEs with shorter durations of infusion or increased days of exposure. AEs were similar, but more frequent, with higher doses (≥400 mg/day). Injection‐site events were rare and did not appear to be linked to infusion doses or rates. Lacosamide plasma concentrations were linearly related to dose across the cohorts. Discussion : This comprehensive evaluation supports the safety of an intravenous lacosamide infusion duration as short as 15 min for short‐term (2–5 days) replacement for patients temporarily unable to take oral lacosamide.     

Lacosamide as adjunctive therapy for partial‐onset seizures: A randomized controlled trial

Purpose: To evaluate the efficacy and safety of lacosamide (400 and 600 mg/day) as adjunctive treatment in patients with uncontrolled partial‐onset seizures taking one to three concomitant antiepileptic drugs (AEDs). Methods: This multicenter, double‐blind, placebo‐controlled trial randomized patients 1:2:1 to placebo, lacosamide 400 mg, or lacosamide 600 mg/day. After an 8‐week baseline period, patients began treatment with placebo or lacosamide 100 mg/day, were force‐titrated weekly (100 mg/day increments) to the target dose, and entered a 12‐week maintenance period. Results: A total of 405 patients were randomized and received trial medication. Most (82.1%) were taking two to three concomitant AEDs. Median percent reductions in seizure frequency per 28 days from baseline to maintenance (intention‐to‐treat, ITT) were 37.3% for lacosamide 400 mg/day (p = 0.008) and 37.8% for lacosamide 600 mg/day (p = 0.006) compared to 20.8% for placebo, with responder rates of 38.3% and 41.2%, respectively, compared to placebo (18.3%, p < 0.001; ITT). Patients randomized to lacosamide showed large reductions in secondarily generalized tonic–clonic seizures, with median percent reductions in seizure frequency of 59.4% for lacosamide 400 mg/day and 93.0% for lacosamide 600 mg/day compared to 14.3% for placebo, and responder rates of 56.0% and 70.2% compared to placebo (33.3%). Dose‐related adverse events included dizziness, nausea, and vomiting. Discussion: Adjunctive treatment with lacosamide 400 and 600 mg/day reduced seizure frequency for patients with uncontrolled partial‐onset seizures. Lacosamide 400 mg/day provided a good balance of efficacy and tolerability; lacosamide 600 mg/day may provide additional benefit for some patients as suggested by secondary efficacy analyses, including response in patients with secondarily generalized tonic–clonic seizures.     

Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide: results from a Phase III open-label extension trial

Purpose: To evaluate the long‐term (up to 5 years exposure) safety and efficacy of lacosamide as adjunctive therapy in patients with uncontrolled partial‐onset seizures taking one to three concomitant antiepileptic drugs (AEDs) in open‐label extension trial SP756 (NCT00522275). Methods: Patients who completed the double‐blind trial SP754 (NCT00136019) were eligible to participate in this open‐label extension trial (SP756). At the conclusion of trial SP754, patients had transitioned to lacosamide 200 mg/day. Subsequent dosage adjustments of lacosamide (100–800 mg/day) and/or concomitant AEDs were allowed to optimize tolerability and seizure reduction. Treatment‐emergent adverse events (TEAEs), vital signs, body weight, clinical laboratory data, electrocardiography studies, and seizure frequency were evaluated. Key Findings: A total of 308 patients received open‐label lacosamide and 138 patients (44.8%) completed the long‐term trial. The median modal dose (defined as the daily lacosamide dose a patient received for the longest duration during the treatment period) was 500 mg/day. The percentages of patients with lacosamide exposure >1, >2, >3, or >4 years were 75%, 63%, 54%, and 29%, respectively. Primary reasons for discontinuation were lack of efficacy (26%) and adverse events (11%). Common TEAEs (≥15%) were dizziness, headache, contusion, nausea, convulsion, nasopharyngitis, fall, vomiting, and diplopia. TEAEs that led to discontinuation in ≥1.0% of patients were dizziness (1.6%) and convulsion (1.0%). The median percent reductions from baseline of trial SP754 in 28‐day seizure frequency were 53.4%, 55.2%, 58.1%, and 62.5%, respectively, for 1‐, 2‐, 3‐, and 4‐year completers. The ≥50% responder rates were 52.8%, 56.5%, 58.7%, and 62.5% for 1‐, 2‐, 3‐, and 4‐year completers, respectively. Seven of eight patients on lacosamide monotherapy for ≥12 months were deemed 50% responders. Of patients exposed to lacosamide ≥2 years, 3.1% remained seizure‐free for a period ≥2 years. Significance: Long‐term (up to 5 years) lacosamide treatment was generally well tolerated. The safety profile of lacosamide observed in this trial is consistent with that established in previous double‐blind, placebo‐controlled trials. Although the open‐label trial design limits the analysis of efficacy, long‐term reduction in seizure frequency and maintenance of efficacy was observed.     

A long-term noninterventional safety study of adjunctive lacosamide therapy in patients with epilepsy and uncontrolled partial-onset seizures

This noninterventional, observational, postauthorization safety study (SP0942, NCT00771927) evaluated the incidence of predefined cardiovascular- (CV) and psychiatric-related treatment-emergent adverse events (TEAEs), in patients with epilepsy and uncontrolled partial-onset seizures, when initiating adjunctive therapy with lacosamide or another approved antiepileptic drug (AED) according to standard medical practice. Active recording of predefined TEAEs of interest took place at three-monthly recommended visits for up to 12 months. Of 1004 patients who received at least one dose of adjunctive AEDs, 511 initially added lacosamide therapy, 493 added another AED, 69 were ≥ 65 years of age, and 72 took concomitant antiarrhythmic drugs. Patients in the lacosamide cohort had a higher median frequency of partial-onset seizures (6.0 versus 3.5 per 28 days) despite taking more concomitant AEDs (84.9% versus 66.9% took ≥ 2) at baseline. Patients who added lacosamide took a modal dose of 200 mg/day over the treatment period (n = 501), and 50.1% (256/511) completed 12 months of treatment. Fifty-one point nine percent (256/493) of patients who added another AED completed the study, with the most commonly added AED being levetiracetam (28.4%). Four patients (0.8%) in each cohort, all < 65 years of age, reported predefined CV-related TEAEs. None were considered serious or led to discontinuation. One event each of sinus bradycardia (lacosamide), atrioventricular block first degree (lacosamide), and syncope (other AED) were judged to be treatment-related. Another patient in the other AED cohort reported bradycardia while taking concomitant antiarrhythmic drugs. Predefined psychiatric-related TEAEs were reported by 21 patients (4.1%) in the lacosamide cohort and 27 patients (5.5%) in the other AED cohort. Depression was the most common to be treatment-related (7/11 and 12/18 of patients reporting treatment-related psychiatric TEAEs, respectively). Serious psychiatric-related TEAEs were reported by four patients who added lacosamide (two cases of depression, two of suicide attempt) and one who added another AED (depression). Seven deaths occurred, all of which were considered unrelated/unlikely related to study medication. This thorough evaluation revealed a low incidence of predefined CV- and psychiatric-related TEAEs in patients taking adjunctive AED therapy according to standard medical practice. No specific safety concerns related to adjunctive lacosamide therapy were noted.     

Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures

PURPOSE: To evaluate the efficacy and safety of lacosamide when added to 1 or 2 antiepileptic drugs (AEDs) in adults with uncontrolled partial-onset seizures, and assess plasma concentrations of concomitant AEDs to determine any potential for drug interactions. METHODS: During this multicenter, double-blind, placebo-controlled trial, patients were randomized to placebo or lacosamide 200, 400, or 600 mg/day after an 8-week baseline period. Lacosamide was titrated in weekly increments of 100 mg/day over 6 weeks and maintained for 12 weeks. Results were analyzed on an intention-to-treat basis. RESULTS: Four hundred eighteen patients were randomized and received trial medication; 312 completed the trial. The median percent reduction in seizure frequency per 28 days was 10%, 26%, 39%, and 40% in the placebo, lacosamide 200, 400, and 600 mg/day treatment groups, respectively. The median percent reduction in seizure frequency over placebo was significant for lacosamide 400 mg/day (p=0.0023) and 600 mg/day (p=0.0084). The 50% responder rates were 22%, 33%, 41%, and 38% for placebo, lacosamide 200, 400, and 600 mg/day, respectively. The 50% responder rate over placebo was significant for lacosamide 400 mg/day (p=0.0038) and 600 mg/day (p=0.0141). Adverse events that appeared dose-related included dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, and nystagmus. Lacosamide did not affect mean plasma concentrations of concomitantly administered AEDs. CONCLUSIONS: In this trial, adjunctive lacosamide significantly reduced seizure frequency in patients with uncontrolled partial-onset seizures. Along with favorable pharmacokinetic and tolerability profiles, these results support further development of lacosamide as an AED.     

Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial

Purpose:   To evaluate the efficacy and safety of lacosamide (200 and 400 mg/day) when added to one to three concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures.
Methods:   This multicenter, double-blind, placebo-controlled trial randomized patients (age 16–70 years) with partial-onset seizures with or without secondary generalization to placebo, lacosamide 200, or lacosamide 400 mg/day. The trial consisted of an 8-week baseline, a 4-week titration, and a 12-week maintenance period.
Results:   Four hundred eighty-five patients were randomized and received trial medication. Among these, 87% were taking two or more concomitant AEDs. Median percent reduction in seizure frequency per 28 days from baseline to maintenance period (intent-to-treat, ITT) was 20.5% for placebo, 35.3% for lacosamide 200 mg/day (p   =   0.02), and 36.4% for 400 mg/day (p   =   0.03). In the per protocol population, the reductions were 35.3% for lacosamide 200 mg/day (p   =   0.04) and 44.9% for 400 mg/day (p   =   0.01) compared to placebo (25.4%). The 50% responder rate for lacosamide 400 mg/day (40.5%) was significant (p   =   0.01) over placebo (25.8%), but was not for 200 mg/day (35.0%). In the per protocol population, the 50% responder rate for lacosamide 400 mg/day (46.3%) was significant (p   <   0.01) compared with the placebo responder rate (27.5%). Dose-related adverse events (AEs) included dizziness, nausea, and vomiting. Clinically relevant changes in the mean plasma concentrations of commonly used AEDs were not observed.
Discussion:   Results of this trial demonstrated the efficacy and tolerability of adjunctive lacosamide 200 and 400 mg/day and support that lacosamide may be an advantageous option for the treatment of partial-onset seizures in patients with epilepsy.     

Intravenous Lacosamide in Pediatric Status Epilepticus: An Open-Label Efficacy and Safety Study

IntroductionLacosamide is an antiepilepsy drug approved by the Food and Drug Administration for patients aged 17 years and older for partial-onset seizures as monotherapy or adjunctive therapy. We reviewed the use of intravenous lacosamide in children aged less than 17 years with status epilepticus.MethodsChildren who received at least one dose of intravenous lacosamide for status epilepticus at our tertiary care children's hospital from December 2011 to March 2014 were studied. Status epilepticus was defined as continuous seizure activity for longer than 20 minutes or two or more recurrent seizures without regaining baseline level of awareness. Efficacy was defined as seizure freedom or more than 50% reduction of seizures within 24 hours of administering lacosamide.ResultsNine children with a mean age of 5.7 years (range: three months to 16 years) were included. The mean initial or loading dose was 8.7 mg/kg, with seven of nine patients receiving a dose of 10 mg/kg. The average total amount of intravenous lacosamide administered within the initial 24 hours was 13.8 mg/kg. Lacosamide was found to be efficacious in seven of nine (77.8%) patients. Four patients (44.4%) became seizure free. Two patients continued to have status epilepticus within 24 hours of lacosamide administration. Bradycardia was observed in one patient.ConclusionIn children with status epilepticus, intravenous lacosamide was efficacious in 78% of the patients and 44% become seizure free. In addition, no significant adverse reactions were observed. An appropriate safe, effective initial, or loading dose may be 10 mg/kg.     

Lacosamide

Lacosamide is a new chemical entity being investigated as an adjunctive treatment for epilepsy, as well as monotherapy for diabetic neuropathic pain. Lacosamide appears to have a dual mode of action: selective enhancement of sodium channel inactivation and modulation of collapsin response mediator protein-2. Rapidly and completely absorbed after oral administration, lacosamide has an elimination half-life of approximately 13 hours and a low potential for drug interactions. Additionally, lacosamide exhibits linear, dose-proportional pharmacokinetics with low intra- and interpatient variability. Randomized controlled trials of adjunctive lacosamide (200, 400, and 600 mg/day) have demonstrated statistically significant reduction in median seizure frequency compared with placebo. In addition, 50% responder rates for lacosamide (400 and 600 mg/day) were statistically superior to placebo. The most frequently reported adverse events (≥10% of lacosamide-treated patients) included dizziness, headache, and nausea. A double-blind, double-dummy randomized trial of intravenous lacosamide (30- and 60-minute infusion) as replacement for oral lacosamide showed that the safety and tolerability profiles were comparable for intravenous and oral lacosamide. The efficacy and safety results from completed clinical trials, as well as the favorable pharmacokinetic profile, suggest that lacosamide may represent a significant advance in antiepileptic drug therapy.     

Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years

Long-term (up to 8 years of exposure) safety and efficacy of the antiepileptic drug lacosamide was evaluated in this open-label extension trial (SP615 [ClinicalTrials.gov identifier: NCT00552305]). Patients were enrolled following participation in a double-blind trial or one of two open-label trials of adjunctive lacosamide for partial-onset seizures. Dosage adjustments of lacosamide (100–800 mg/day) and/or concomitant antiepileptic drugs were allowed to optimize tolerability and seizure reduction. Of the 370 enrolled patients, 77%, 51%, and 39% had > 1, > 3, or > 5 years of lacosamide exposure, respectively. Median lacosamide modal dose was 400 mg/day. Common treatment-emergent adverse events (TEAEs) were dizziness (39.7%), headache (20.8%), nausea (17.3%), diplopia (17.0%), fatigue (16.5%), upper respiratory tract infection (16.5%), nasopharyngitis (16.2%), and contusion (15.4%). Dizziness (2.2%) was the only TEAE that led to discontinuation in > 2% of patients. Ranges for median percent reductions in seizure frequency were 47–65%, and those for ≥ 50% responder rates were 49–63% for 1-, 3-, and 5-year completer cohorts. Exposure to lacosamide for up to 8 years was generally well tolerated, with a safety profile similar to previous double-blind trials, and efficacy was maintained.     

Long‐term efficacy and safety of eslicarbazepine acetate: Results of a 1‐year open‐label extension study in partial‐onset seizures in adults with epilepsy

Purpose: To evaluate the long‐term efficacy and safety of once daily eslicarbazepine acetate (ESL) as adjunctive therapy for partial‐onset seizures in adults with epilepsy. Methods: One‐year open‐label treatment extension with ESL in patients who completed a placebo‐controlled pivotal study (Epilepsia 2009; 50: 454–463). Starting dose was 800 mg once daily, for 4 weeks; thereafter, dose could be titrated up or down. Doses of concomitant antiepileptic drugs were to be kept stable. Results: Overall, 314 patients were enrolled. The intent‐to‐treat population consisted of 312 patients, and 239 (76.6%) completed 1 year of treatment. ESL median dose was 800 mg once daily. Compared to baseline, median seizure frequency decreased by 39% during the first 4 weeks and between 48% and 56% thereafter. The responder rate (≥50% seizure reduction) was 41% during weeks 1–4 and, thereafter ranged between 48% and 53%. The proportion of seizure‐free patients per 12‐week interval ranged between 8.7% and 12.5%. Quality of life, as measured by the Quality of Life in Epilepsy Inventory‐31 (QOLIE‐31), and depressive symptoms, as measured by the Montgomery Asberg Depression Rating Scale (MADRS), improved significantly compared to baseline. Treatment‐emergent adverse events (TEAEs) were reported by 51% of patients. The most frequent TEAEs were headache (10%), dizziness (10%), diplopia (5%), and nasopharyngitis (5%). TEAEs were mostly (97%) of mild to moderate intensity. Eleven patients (3.5%) discontinued due to TEAEs. There were no results of laboratory tests raising safety concerns. Discussion: Sustained therapeutic effect, favorable tolerability and safety, and an improvement in quality of life and depressive symptoms were observed during long‐term add‐on treatment of partial‐onset seizures in adults with once daily ESL.     

Rapid loading of intravenous lacosamide: Efficacy and practicability during presurgical video‐EEG monitoring

Purpose: This study investigates immediate efficacy and safety of intravenous application of de novo lacosamide (LCM) as add‐on therapy in patients with pharmacoresistant focal epilepsy. Methods: During presurgical video–electroencephalography (EEG) monitoring, 17 adult inpatients received LCM infusion (200 mg every 12 h for 2–3 days) followed by oral formulation with the same regimen. Before and after intravenous application of LCM, seizures and interictal epileptiform discharges (IEDs) recorded with continuous video‐EEG monitoring were analyzed, and an assessment of adverse events (AEs) was performed daily. To evaluate the midterm tolerability and efficacy, follow‐up visits were conducted 1 and 3 months after discharge from hospital. Key Findings: In the acute phase, intravenous initiation of LCM was well tolerated with few mild or moderate AEs (3 of 17, 17.6%). A significant reduction of seizure frequency in the treatment phase as compared to mean seizure frequency in the 2‐day baseline phase was achieved (p < 0.05 for the first treatment day, and p < 0.005 for the second treatment day). On the first treatment day, 61.5% of the patients were seizure free, and 84.6% on the second treatment day. IED reduction after intravenous application of LCM was not significant. After 1 month, the 50% responder rate was 46.6% and after the 3‐month period, 42.8%. Significance: Our data suggest that rapid intravenous initiation of de novo LCM is safe and may protect against seizures in a rapid and midterm time window.     

Intravenous lacosamide for treatment of status epilepticus

Kellinghaus C, Berning S, Immisch I, Larch J, Rosenow F, Rossetti AO, Tilz C, Trinka E. Intravenous lacosamide for treatment of status epilepticus.
Acta Neurol Scand: 2011: 123: 137–141.
© 2010 John Wiley & Sons A/S. Objectives – Treatment of established status epilepticus (SE) requires immediate intravenous anticonvulsant therapy. Currently used first‐line drugs may cause potentially hazardous side effects. We aimed to assess the efficacy and safety of intravenous lacosamide (LCM) in SE after failure of standard treatment. Methods – We retrospectively analyzed 39 patients (21 women, 18 men, median age 62 years) from the hospital databases of five neurological departments in Germany, Austria and Switzerland between September 2008 and January 2010 who were admitted in SE and received at least one dose of intravenous LCM. Results – Types of SE were generalized convulsive (n = 6), complex partial (n = 17) and simple partial (n = 16). LCM was administered after failure of benzodiazepins or other standard drugs in all but one case. Median bolus dose of LCM was 400 mg (range 200–400 mg), which was administered at 40–80 mg/min in those patients where infusion rate was documented. SE stopped after LCM in 17 patients, while 22 patients needed further anticonvulsant treatment. The success rate in patients receiving LCM as first or second drug was 3/5, as third drug 11/19, and as fourth or later drug 3/15. In five subjects, SE could not be terminated at all. No serious adverse events attributed to LCM were documented. Conclusions – Intravenous LCM may be an alternative treatment for established SE after failure of standard therapy, or when standard agents are considered unsuitable.     

Zonisamide for essential tremor: An evaluator‐blinded study

In this evaluator‐blinded open‐treatment trial, subjects with moderate/severe upper limb essential tremor were titrated to 300 mg/day zonisamide, or adjusted to a lesser dose if symptoms warranted, as monotherapy or as adjunct to stable antitremor medication, followed by a 12‐week extension phase. The primary efficacy outcome variables were blinded rater videotaped/drawing tremor score changes at the Treatment and Extension visits compared to Baseline, based on Fahn‐Tolosa‐Marin and Postural Tremor Scales. Subjects also rated Functional Disabilities. Primary outcomes showed reduced tremor scores at the Treatment (P < 0.00001, n = 25) and Extension (n = 16) visits, at mean doses of 252 and 225 mg/day, respectively. Subject ratings indicated 200 mg/day was superior to 100 mg/day, whereas 300 mg/day produced no additional benefit, but instead was associated with more adverse symptoms, most commonly somnolence, poor energy, imbalance, and altered taste. Future double‐blind placebo‐controlled trials are warranted. © 2008 Movement Disorders Society     

Lacosamide as a new treatment option in status epilepticus

Status epilepticus is among the most common neurologic emergencies, with a mortality rate of up to 20%. The most important therapeutic goal is fast, effective, and well‐tolerated cessation of status epilepticus. Intravenous phenytoin/fosphenytoin, phenobarbital, or valproate is the current standard treatment after failure of benzodiazepines. Lacosamide as a new antiepileptic drug has been available as an intravenous solution since 2009. To date, PubMed lists 19 studies (10 single case reports and 9 case series), reporting a total of 136 episodes of refractory status epilepticus (50% nonconvulsive status epilepticus, 31% focal status epilepticus, and 19% convulsive status epilepticus) treated with lacosamide. The most often used bolus dose was 200–400 mg over 3–5 min. The overall success rate was 56% (76/136). Adverse events (AEs) were reported in 25% (34/136) of patients: mild sedation in 25 cases, 1 patient with possible angioedema, 2 with allergic skin reaction, 4 with hypotension, and 1 with pruritus. One patient developed a third‐degree atrioventricular (AV) block and paroxysmal asystole. Overall, the rate of AEs was low. Current evidence on the use of intravenous lacosamide in acute seizures and status epilepticus is restricted to retrospective case reports and case series (class IV). Further prospective studies to inform clinicians are necessary.     

Minimizing pharmacodynamic interactions of high doses of lacosamide

Edwards HB, Cole AG, Griffiths AS, Lin B, Bean A, Krauss GL. Minimizing pharmacodynamic interactions of high doses of lacosamide.
Acta Neurol Scand: 2012: 125: 228–233.
© 2011 John Wiley & Sons A/S. Objectives – To determine whether pharmacodynamic interactions between high doses of lacosamide (400–800 mg/day) and concomitant sodium channel antiepilepsy drugs (AEDs) can be minimized in patients with drug‐resistant partial‐onset seizures. Materials and methods – Patients were rapidly initiated with high‐dose lacosamide (100 mg/week; increases to 400 to 800 mg/day), while simultaneously tapering concomitant sodium channel AEDs. Seizure frequency and side effects were evaluated at six time points: baseline, titration, 3, 6, 9 and 12 months. Results – Twenty‐three patients had a baseline median of 4 seizures/month with persisting partial‐onset seizures, despite previous treatment with an average of 6.8 AEDs. Mean decreases in monthly seizure frequency were as follows: 3 months 49.9% (P = 0.011), 6 months 55.4% (P = 0.010), 9 months 60.8% (P = 0.002) and 12 months 58.2% (P = 0.011). Most adverse events were mild CNS‐related symptoms and occurred transiently only during titration – there was no significant relationship (χ² < 1.5, P > 0.1) between lacosamide dose and the presence of side effects at 3, 6, 9 or 12 months. Conclusion – s – Drug‐resistant patients rapidly titrated to high doses of lacosamide with simultaneous tapering of traditional sodium channel AEDs had marked reduction in CNS‐related adverse events compared with patients treated in three previous pivotal trials that used fixed doses of concomitant AEDs.     

Successful treatment for refractory convulsive status epilepticus by non‐parenteral lacosamide

Lacosamide (Vimpat) is a newly licensed novel antiepileptic drug. We report a case of refractory convulsive status epilepticus (CSE) that was successfully controlled with lacosamide. The 38‐year‐old male patient was admitted for a series of complex partial seizures with secondary generalization leading to refractory CSE. During the transport to the hospital the patient was given 22.5 mg diazepam, 12.5 mg etomidate, and 5 mg midazolam without success. An additional dose of 4 mg lorazepam and a dose of 1,500 mg levetiracetam after admission were yet without clinical effect. A further treatment with lacosamide (300 mg via percutaneous gastric fistula) resulted in complete clinical remission of the epileptic activity within 30 min. The application of lacosamide resulted in cessation of CSE and was well tolerated. To our knowledge, this is the first case of successful treatment of refractory CSE with lacosamide. Further studies are needed to evaluate the safety and efficacy of lacosamide in treatment of SE.     

Intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures

PURPOSE: This multicenter, double-blind, double-dummy, randomized, inpatient trial evaluated the safety, tolerability, and pharmacokinetics of intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. METHODS: Patients were enrolled from an ongoing open-label extension trial of oral lacosamide and randomized (2:1) to either intravenous lacosamide and oral placebo or intravenous placebo and oral lacosamide. During the 2-day inpatient treatment period, patients received twice-daily doses of lacosamide equivalent to their current daily dose of oral lacosamide. The first 30 patients enrolled received infusions with 60-min durations and the next 30 received infusions with 30-min durations. RESULTS: Of 60 patients randomized, 59 completed the trial. Treatment-emergent adverse events (AEs) were reported by 16 patients and included dizziness, headache, back pain, somnolence, and injection site pain. The tolerability profile of intravenous lacosamide was consistent with that of oral lacosamide. All AEs were considered mild or moderate in intensity, and no serious AEs or AEs leading to withdrawal were reported. CONCLUSIONS: Intravenous lacosamide, administered as 60- or 30-min twice-daily infusions, showed a similar safety and tolerability profile to oral lacosamide when used as replacement therapy. Results from this trial support further investigation of intravenous lacosamide at shorter infusion durations.     

Wednesday July 5, 200617:30–19:00Hall 1Schwarz Pharma & Valeant Pharmaceuticals International Satellite SymposiumWhat's around the corner: AEDs in late development

¹ E. Ben-Menachem (   ¹ Neurologkliniken, Sahlgrenska Universitetssjukhuset, Goteberg, Sweden )
Lacosamide is in Phase 3 of clinical development for the adjunctive treatment of epilepsy and neuropathic pain. Currently the mode of action (MOA) is under investigation since it has been previously demonstrated that lacosamide does not share a MOA with other currently marketed antiepileptic drugs (AEDs). The drug can be administered orally or intravenously. Results from pharmacokinetic studies suggest that lacosamide has a low potential for drug-drug interactions, and it appears that lacosamide has a minimal risk for affecting the pharmacokinetics of commonly prescribed concomitant AEDs for the treatment of epilepsy.
In a double-blind, randomized, placebo-controlled, multicenter trial for the treatment of partial seizures (SP667), lacosamide was administered orally in doses of 200 mg, 400 mg and 600 mg divided in 2 daily doses. In this trial, lacosamide demonstrated a statistically significant reduction in seizure frequency over placebo. Moreover, the 50% responder rate (defined as patients with at least a 50% reduction in seizure frequency) was statistically significant.
A further trial (SP616) investigated the safety, tolerability and pharmacokinetics of IV lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. The nature of AEs reported following 60- and 30 minute infusions of lacosamide was consistent with AEs reported following oral administration of lacosamide.
Dose-related adverse events include dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, and nystagmus.
The currently available results justify the further development of lacosamide for the treatment of epilepsy.     

Pharmacokinetics and safety of adjunctive topiramate in infants (1–24 months) with refractory partial‐onset seizures: A randomized,multicenter, open‐label phase 1 study

Purpose: To characterize the pharmacokinetics of adjunctive topiramate in infants (1–24 months) with refractory partial‐onset seizures (POS); also to evaluate safety and tolerability of topiramate in the dose range of 3–25 mg/kg/day. Methods: In this open‐label phase 1 study, infants (N = 55) with refractory POS receiving at least one concurrent antiepileptic drug (AED) were enrolled. Infants were stratified by age and randomly assigned to one of four topiramate target dose groups (3‐, 5‐, 15‐, or 25 mg/kg/day). Treatment was initiated at 3 mg/kg/day with titration to the target dose by weekly dose escalation. Topiramate was administered daily in two divided doses as oral liquid (5 mg/ml for infants <9 kg or those who could not tolerate solid foods) or sprinkle capsule (25 mg) formulations. Following seven consecutive days of topiramate administration at the target dose, four blood samples were collected from each infant for pharmacokinetic assessments (predose, 1–3, 4–6, and 8–10 h postdose). Key Findings: Fifty‐five infants (mean [SD] age in months: 11.4 [5.79]) with POS were enrolled, of whom 33% had seizures with or without secondary generalization. Complete pharmacokinetic profiles were obtained in 35 infants in whom mean plasma topiramate concentration–time profiles demonstrated linear pharmacokinetics (predose topiramate concentrations [C_trough] and area under the plasma concentration–time curve from time 0 through 12 h [AUC_{12 h}]) of topiramate over the dose range studied). Apparent steady state oral clearance (CL_ss/F) remained similar across all topiramate target dose groups and was independent of creatinine clearance, age, and weight. Mean values for CL_ss/F were approximately twofold greater in infants receiving concomitant enzyme‐inducing AEDs versus enzyme‐inhibiting AEDs. Topiramate was well tolerated and safety findings were consistent with previous reports in children and adults. Most common treatment emergent adverse events (≥10%) were upper respiratory tract infection, fever, vomiting, somnolence, and anorexia. Significance: In infants (1–24 months), topiramate exhibited linear steady state pharmacokinetics over the dose range 3–25 mg/kg/day, and CL_ss/F of topiramate was independent of dose. Moreover, the concomitant enzyme‐inducing AEDs doubled the clearance of topiramate. Topiramate was generally well tolerated as adjunctive therapy at doses up to 25 mg/kg/day.