Concomitant Antiepileptic Drugs Research Articles

Efficacy and tolerability of perampanel in pediatric patients with Dravet syndrome

PurposeIn the present study, we aimed to investigate the efficacy and tolerability of perampanel in patients with Dravet syndrome. MethodsWe retrospectively reviewed data regarding seizure frequency and adverse effects in 10 patients (four boys, six girls) with Dravet syndrome following treatment with perampanel. Perampanel treatment was considered effective when seizure frequency had been reduced by more than 50%. ResultsThe mean age of patients at perampanel introduction was 11.5 ± 2.2 years. Seizure types were as follows: generalized tonic-clonic seizure (n = 8), unilateral clonic seizure (n = 6), myoclonic seizure (n = 3), atypical absence seizure (n = 3), and focal impaired awareness seizure (n = 1). The average number of concomitant anti-epileptic drugs (AEDs) was 3 ± 0.9. The mean duration of perampanel use was 11.1 ± 3.8 months. Seizure frequency was reduced by more than 50% in five patients (50%). The efficacy of perampanel for each seizure type was as follows: generalized tonic-clonic seizure: 50% (4/8), unilateral clonic seizure: 50% (3/6), myoclonic seizure: 33% (1/3), atypical absence seizure: 33% (1/3), and focal impaired awareness seizure: 100% (1/1). The effects of perampanel in each patient occurred between 3 and 6 months following the initiation of treatment. Seizure reduction was observed beginning at perampanel doses of 0.1 ± 0.07 mg/kg/day. Adverse events were observed in seven of 10 patients. Although somnolence was noted in 50% of patients, most events were mild. ConclusionsThe results of this retrospective observational study indicate that perampanel treatment may be promising in some patients with Dravet syndrome. Additional studies are necessary to verify the actual efficacy of perampanel for Dravet syndrome.

Effect of Concomitant Enzyme-Inducing Antiepileptic Drugs (EIAEDs) on the Safety and Efficacy of Adjunctive Perampanel in Patients Aged 4 to <12 years with Partial-Onset Seizures (POS): Final Results from the 311 Core Study (P3.5-007)

Effect of Concomitant Enzyme-Inducing Antiepileptic Drugs (EIAEDs) on the Safety and Efficacy of Adjunctive Perampanel in Patients Aged 4 to <12 years with Partial-Onset Seizures (POS): Final Results from the 311 Core Study (P3.5-007)

Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results

BackgroundSince 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016. MethodsChildren and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex®; 100 mg/mL) in oral solution at 2–10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25–50 mg/kg/day. Patient visits were every 2–4 weeks. The percentage change from baseline in median monthly convulsive (ie, major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had ≥50%, ≥75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks. ResultsOf the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0–10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1–146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥50%, ≥75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%). ConclusionsResults from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.

Clinical profiles associated with serum perampanel concentrations in children with refractory epilepsy

BackgroundPerampanel (PER) is a new antiepileptic drug (AED) with a novel mechanism of action. Investigations of the efficacy and safety of PER in pediatric and adult patients have increased recently. Although the clinical usefulness and pharmacokinetics of PER have been investigated in adolescent and adult populations, similar studies have not been performed in children. Patients and methodsWe retrospectively reviewed the medical records of patients treated with PER for more than 6 months in the Department of Pediatrics, Hiroshima University Hospital, between September 2016 and November 2018. We obtained demographic and clinical data including age, sex, epilepsy type, seizure type, seizure frequency before and after treatment initiation, adverse events, reasons for discontinuing PER treatment, doses at evaluation points, serum concentrations, concomitant AEDs, intellectual status, and epilepsy etiology. Seizure types and epilepsy syndromes were classified according to the criteria of the International League Against Epilepsy. ResultsThe study included 44 patients (22 males) between the ages of 6 months and 16 years. Of those, 10 patients discontinued PER therapy. The 50% response rate was 52.3% in patients treated with PER, and four patients achieved complete seizure control. Perampanel was highly effective in patients with generalized and focal epilepsy (50% responder rates, 52.9% and 50.0%, respectively). Favorable response rates were observed for tonic–clonic, focal nonmotor, and absence seizures with 50% response rates of 54.5%, 50.0%, and 66.7%, respectively. The 50% responder rate was 31.3 for epileptic spasms (ES). Treatment-emergent adverse events (TEAEs) included somnolence (n = 8), irritability (n = 2), ataxia (n = 2), and one case each of dizziness, compulsiveness, and enuresis. Serum concentrations of PER were compared in patients taking concomitant enzyme-inducing antiepileptic drugs (EIAEDs; carbamazepine, phenytoin, and phenobarbital) and those taking concomitant non-EIAEDs. Serum PER concentrations were correlated with dose per body weight in both groups (EIAED: r = 0.765, p = 0.00000212; non-EIAED: r = 0.71, p = 0.0000158). The mean concentration-to-dose (CD) ratio was 2398.4 ng mL−1 mg−1 kg−1 (range: 800–4524.7) in the non-EIAED group and 693.7 ng mL−1 mg−1 kg−1 (range: 344–1309.7) in the EIAED group. Serum PER levels were lower in the EIAED group than in the non-EIAED group. All patients with serum PER concentrations above 400 ng/mL experienced somnolence. ConclusionsPerampanel is effective against various types of seizures, including ES, in pediatric patients with refractory epilepsy. Furthermore, PER has good tolerability when the dose is adjusted based on serum concentrations. The PER CD ratio was lower in pediatric patients than in adolescents and adults; therefore, clinicians must consider the CD ratio when treating children with PER.

Don't Fear the Reefer-Evidence Mounts for Plant-Based Cannabidiol as Treatment for Epilepsy.

[Box: see text]

The effect of perampanel on aggression and depression in patients with epilepsy: A short-term prospective study

PurposeUsing specialized tools, we assessed patients receiving perampanel (PER) to investigate its effects on aggression and depression, as well as the impact of other concomitant antiepileptic drugs (AEDs) on those conditions. MethodSeventy-seven patients with epilepsy were initially enrolled, then examined at entry and 12 weeks later (endpoint). At both examinations, assessments were performed with the Buss Perry Aggression Questionnaire (BAQ) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Ultimately, 59 patients completed the study. ResultsTotal BAQ (p = 0.013) and NDDI-E (p = 0.000) scores at the endpoint were significantly increased in comparison with those at entry. Analysis with 4 subscales showed increases in both verbal and physical aggression, while multivariate analysis revealed that concomitant AED administration did not have a significant impact on the increase of BAQ or NDDI-E score. A dose-dependent effect of PER was confirmed in BAQ, but not NDDI-E results. PER was discontinued due to adverse psychiatric effects in 3.9% of the patients. ConclusionsThe present findings indicate that PER increases assessment scores indicative of aggression as well as depression. No additional aggression-augmenting effect was seen with concomitant AED administration.

The influence of concomitant antiepileptic drugs on lamotrigine serum concentrations in Northwest Chinese Han population with epilepsy

ObjectiveThe aims of this study were to identify the influencing factors such as gender, age, dose and combinations of other antiepileptic drugs (AEDs), especially in triple combinations on the pharmacokinetic of Lamotrigine (LTG) in epilepsy patients of Northwest Chinese Han population.MethodsData of the LTG concentration and clinical information were analyzed retrospectively from a therapeutic drug monitoring (TDM) database at the Clinical Pharmacy Laboratory of Xi’an Central Hospital between January 1, 2016 and January 1, 2018. The independent-sample t-test, one-way ANOVA analysis and Bonferroni and Tamhane T3 post-hoc test, the stepwise multivariate regression analysis were adopted by IBM SPSS, version 22.0.Results226 serum samples met the inclusion criteria and were evaluated. The mean LTG serum concentration was 5.48±3.83 μg/mL. There were no gender differences (P = 0.64), and there were no significant effects by age on LTG serum concentration after age stratification (3–14 years old, 14-45 years old, 45–59 years old) (P = 0.05). Multiple regression analysis showed that the daily LTG dose and co-administration of other AEDs significantly affected LTG serum concentrations. Combination with enzyme-inducer AEDs, the mean steady-state LTG concentration could be decreased by 30.73% compared with LTG monotherapy. Among enzyme-inducer AEDs, particularly strong inducer Carbamazepine (CBZ) could decrease the mean LTG concentration by 53.65%, but weak inducer AEDs such as Oxcarbazepine (OXC) and Topiramate (TPM) had no effect, Valproic acid (VPA) could increase the mean LTG concentration by 93.95%, and the inducer only partially compensated for the inhibitory effect of VPA in triple combination.ConclusionsThere were no significant gender and age effects, but the LTG daily dose and co-administration of other AEDs significantly affected LTG serum concentration. Combination with enzyme-inducer AEDs, especially CBZ could significantly decrease LTG serum concentrations, VPA could significantly increase LTG serum concentrations, and the inducer only partially compensated for the inhibitory effect of VPA in triple combination. In the clinical setting, these findings can help to estimate LTG concentrations and adjust dosage and evaluate adverse drug reactions.

Perampanel in patients with brain tumor-related epilepsy in real-life clinical practice: a retrospective analysis

Introduction: Epilepsy occurs in 35–70% of patients with gliomas; glutamate plays a central role via AMPA-receptor activation, which is involved both in seizure activity and tumor growth. We conducted a retrospective study on brain tumor-related epilepsy patients (BTRE) treated with perampanel in add-on (PER) for 12 months, to evaluate efficacy and tollerability, according to real-life clinical practice.Materials and methods: Medical records of eleven patients (9 males, mean age 54 years) with glioma and epilepsy treated with PER in add-on, for inadequate seizure control or adverse events (AEs) from previous antiepileptic drugs (AEDs) therapy, were reviewed. Data collected included: tumor history, molecular factors, systemic therapy, type and number of seizures and concomitant AEDs, and AEs.Results: After 12 months of PER therapy, five patients were seizure-free, 4 had a seizure reduction ≥50% and the seizure frequency was unchanged in 2 patients. Responder rate was 81.8%. Two patients reported AEs; PER dose was reduced only in the one case. The final median dose of PER was 7.3 mg/day. We didn’t find statistically significant differences in the comparison between mean values pre, mean values post and the average of decreasing number of seizures related to: histology, presence/absence of chemotherapy, radiotherapy, progression disease, KPS, IDH1, MGMT.Discussion: Despite the limitations due to small number of patients in a retrospective study, the high rate of responder and seizure-free patients suggest that PER could be a therapeutic option in BTRE. Prospective controlled studies are needed to confirm our data.

Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US.

Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16weeks. The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy. Patients aged 1-17years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3months, and every 3months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15days of treatment, at 1month, at 3months, and every 3months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures. Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53months (mean 21months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6months and more gradually thereafter. At 24months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained> 50% reduction in motor seizures, including three (11.5%) who remain seizure free. Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment.

Efficacy, tolerability, and blood concentration of zonisamide in daily clinical practice

We aimed to evaluate the efficacy, tolerability, and blood concentration of zonisamide (ZNS) used in daily clinical practice. This was a retrospective study performed at a single epilepsy center and included 149 patients with epilepsy. The efficacy and retention of ZNS for 52 weeks, percentage of patients who were seizure free for 26 weeks, and the 5-year retention rate were analyzed. The tolerability was assessed based on treatment-emergent adverse effects (AEs) and the adverse effect profile (AEP). More than 70% (105/149) of patients were on ZNS polytherapy. The mean dose of ZNS was 300 ± 170.6 mg/day, and the antiepileptic drug (AED) load was 2.0 ± 1.1 (median 1.8, range 0.2–5.3). The retention rate for 52 weeks and the percentage of patients who were seizure-free for 26 weeks were 73% and 42%, respectively. The retention rate decreased with time and reached 43% in 5 years. Younger age of onset was a significant variable affecting retention rate for 52 weeks (p = 0.044), whereas fewer concomitant AEDs were significantly associated with being seizure free for 26 weeks (p = 0.0006). AEs were reported in 24% (36/147) of patients. The number, mechanism of action, or drug load of the AEDs did not predict the development of AEs; however, blood concentration of ZNS was significantly higher in patients with AEs (p = 0.0011) than in those without AEs. ZNS is a well-tolerated and effective AED in daily clinical practice, and several clinical factors may predict the efficacy and tolerability of ZNS.

Zonisamide add-on therapy for focal epilepsy.

The majority of people with epilepsy have a good prognosis, and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCT) of zonisamide, used as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant antiepileptic drug. This is an updated version of the Cochrane review previously published in 2013. To evaluate the efficacy and tolerability of zonisamide, when used as an add-on treatment for people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs. For this update, on 4 September 2017, we searched the Cochrane Epilepsy Group Specialised Register, Cochrane Register of Studies Online, MEDLINE Ovid, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform ICTRP. We searched SCOPUS on 13 February 2013, but this is no longer necessary, because RCTs and quasi-RCTs in Embase are now included in CENTRAL. In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing or unpublished studies. Randomised controlled trials, in which add-on zonisamide was compared with placebo or another antiepileptic drug in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs. Two review authors independently selected trials for inclusion, extracted data, assessed for risk of bias using the Cochrane 'Risk of bias' tool, and assessed the quality of the evidence, using the GRADE approach. The primary outcome was at least a 50% reduction in total seizure frequency; the secondary outcomes were (1) tolerability; and (2) adverse effects. We used an intention-to-treat approach for our primary analyses. We estimated summary risk ratios (RRs) for each outcome. We displayed a summary of the estimates of effects and quality of the evidence for each outcome in a 'Summary of findings' table. We included eight studies (1636 participants). The overall RR with 95% confidence interval (CI) for at least a 50% reduction in seizure frequency compared to placebo for 300 mg to 500 mg/day of zonisamide was 1.90 (95% CI 1.63 to 2.22; 7 trials, 1371 participants; moderate-quality evidence). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 mg to 500 mg/day) was 1.86 (95% CI 1.60 to 2.17; 7 trials, 1429 participants; moderate-quality evidence). The number needed to treat for an additional beneficial outcome was six (95% CI 4.1 to 6.8) for this outcome. Two trials provided evidence of a dose-response relationship for this outcome. The RR for treatment withdrawal for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.59 (95% CI 1.18 to 2.13; 6 trials, 1099 participants; moderate-quality evidence), and for 100 mg to 500 mg/day was 1.44 (95% CI 1.08 to 1.93; 6 trials, 1156 participants; moderate-quality evidence). The number needed to treat for an additional harmful outcome was 15 (95% CI 9.3 to 36.7). The CIs of the following adverse effects indicated that they were significantly associated with zonisamide: ataxia RR 3.85 (99% CI 1.36 to 10.93; 4 trials, 734 participants; low-quality evidence); somnolence RR 1.52 (99% CI 1.00 to 2.31; 8 trials, 1636 participants; moderate-quality evidence); agitation RR 2.35 (99% CI 1.05 to 5.27; 4 trials, 598 participants; low-quality evidence); and anorexia RR 2.74 (99% CI 1.64 to 4.60; 6 trials, 1181 participants; low-quality evidence).Across the eight studies, we rated risk of bias domains at low or unclear risk of bias apart from two studies which we rated at high risk of attrition bias. Five of the eight studies were sponsored by the drug companies that produced zonisamide. When used as an add-on treatment in people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs, moderate-quality evidence found that zonisamide was more successful than placebo at reducing the frequency of seizures by at least 50%. We were unable to identify minimum effective and maximum tolerated doses. The included trials evaluated a maximum stable-dose phase of 18 weeks, so results cannot be used to confirm longer periods of efficacy in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

Safety and Efficacy of Perampanel as Adjunctive Therapy in Patients with Refractory Focal Epilepsy Over 12 Months: Clinical Experience in a Real-World Setting

Abstract Background The main purpose of this study is to assess efficacy and tolerability of perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, as an add-on treatment in adult patients with refractory focal-onset seizures. Patients and Methods A prospective, open label, observational study was conducted in patients with refractory focal-onset seizures treated with PER at our Epilepsy Unit, from May 2015 to February 2016. Patients were followed up for 1 year. Frequency of seizure and tolerability was assessed every 3 months. Patients were under a polytherapy, and the mean number of concomitant antiepileptic drugs (AEDs) at PER initiation was 2.9. Results We consecutively enrolled 52 patients (M/F = 18/34). Three were lost on follow-up. Mean age was 38.7 years, with a mean duration of disease of 28.1 years. After 1 year of treatment, 57.14% reported a 50% or greater reduction in seizure frequency; five (10.21%) were seizure free. Six (12.25%) patients reported a reduction lower than 50%. Mean dosage of PER was 7.57 mg. Thirty-one patients were taking enzyme-inducing AEDs (carbamazepine, oxcarbazepine, phenytoin). In this subgroup, the responder rate was 45.2%. Twenty-one patients reported side-effects, most frequently somnolence (11), vertigo/ataxia (6), and aggressiveness (5). Eleven (22.4%) patients reduced or discontinued at least one concomitant AED, while the electroencephalography improved in four (8.16%). Sixteen (32.65%) patients withdrew PER, after a mean duration of 163 days, the mean dosage being 6.4 mg (range 4–12). Conclusions Adjunctive PER can achieve clinically meaningful improvement, or even seizure freedom, in almost two-thirds of patients suffering from refractory focal-onset epilepsies. It seems similarly safe and well-tolerated. Enzyme-inducing AEDs may limit the efficacy of PER.

Influence of Dose and Antiepileptic Comedication on Lacosamide Serum Concentrations in Patients With Epilepsy of Different Ages.

Lacosamide (LCM) is a new antiepileptic drug (AED). The purpose of the study was to investigate the effects of LCM dose, body weight, height, sex, age, and concomitant AEDs on LCM trough serum concentrations (at a steady state) in patients with epilepsy. A total number of 3154 blood samples of 973 consecutive patients of the Mara Hospital (Bethel Epilepsy Centre) were evaluated. Generalized estimating equation (GEE) models were used for statistical analyses. GEE analyses showed that LCM trough serum concentrations were significantly correlated with the body weight-normalized LCM dose (range: 0.44-25.7 mg/kg; 45-1050 mg) and significantly dependent on comedication and age. Compared with adults (18-60 years), the LCM trough serum concentrations of children aged 6-12 years and children younger than 6 years were significantly lower (-21% to -38%, respectively) and those of elderly patients (>60 years) were significantly higher (+20%). Sex had no significant influence. Carbamazepine, phenytoin, primidone, phenobarbital, and methsuximide decreased LCM trough serum concentrations significantly by 30%, 32%, 34%, 39%, and 41%, respectively, whereas other AEDs (eg, oxcarbazepine, eslicarbazepine acetate, valproate) had no significant or only a minor impact (zonisamide) on LCM trough concentrations. In children, the effect of enzyme-inducing AEDs was more marked. Of note, the number of blood samples (n = 151) of patients younger than 12 (n = 78) was comparatively low. Alternative GEE models confirmed the effect of comedication, whereas the effect of age, especially in children, depended on adjustment of LCM dosage to body weight, body surface area, or approximated volume of distribution. In accordance with previous therapeutic drug monitoring studies, our results confirmed that enzyme inducers reduce the LCM trough serum concentrations by 30%-40%. In children, the effects of comedication are more pronounced but should be confirmed by further studies.

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month GENERAL study.

To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE). This multicenter, retrospective, 1-year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ≥12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included. The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic-clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure-free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add-on (after ≤2 prior AEDs) than late (≥3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent. In routine clinical care of patients with IGE, perampanel improved seizure outcomes for GTCS, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real-world evidence with perampanel across different seizure types in IGE.

Perampanel in routine clinical use across Europe: Pooled, multicenter, observational data.

To pool observational data on the routine use of perampanel to obtain information on real-world outcomes and data in populations typically underrepresented in clinical trials. Individual-level data of people with epilepsy treated with perampanel at 45 European centers were merged into a single dataset. Prespecified outcomes were: 1-year retention rate, 1-year seizure freedom rate (duration≥6months), and incidence of treatment-emergent adverse events (TEAEs). In addition, relationships were explored with logistic regression analyses. The full analysis set comprised 2396 people: 95% had focal seizures; median epilepsy duration was 27years; median number of concomitant antiepileptic drugs (AEDs) was 2; and median prior AEDs was 6. One-year retention rate was 48% (1117/2332; 95% confidence interval [CI] 46-50%), and 1-year seizure-free rate (≥6-month duration) was 9.2% (74/803; 95% CI 7-11%). Median treatment duration was 11.3months (1832 patient-years); median dose was 8mg. In 388 individuals with available data at 3, 6, and 12months, responder rates were 42%, 46%, and 39%, respectively. During the first year, TEAEs were reported in 68% of participants (1317/1497; 95% CI 66-70%). Logistic regression found higher age at perampanel initiation was associated with higher seizure-free rate, and higher number of prior AEDs with lower seizure-free rate and lower rates of somatic TEAEs. In 135 individuals aged ≥65years, 1-year retention rate was 48% and seizure-free rate was 28%. Across a large, treatment-resistant population, add-on perampanel was retained for ≥1year by 48% of individuals, and 9% were seizure-free for ≥6months. TEAEs were in line with previous reports in routine clinical use, and less frequent than in the clinical trial setting. No new or unexpected TEAEs were seen. Despite the limitations of observational studies, our data indicate that some individuals may derive a marked benefit from the use of perampanel.

Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

SummaryObjectiveSince 2014, cannabidiol (CBD) has been administered to patients with treatment‐resistant epilepsies (TREs) in an ongoing expanded‐access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.MethodsTwenty‐five US‐based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4‐week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2‐10 mg/kg/d, titrated to a maximum dose of 25‐50 mg/kg/d. Patient visits were every 2‐4 weeks through 16 weeks and every 2‐12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last‐observation‐carried‐forward method to account for missing data. Adverse events (AEs) were documented at each visit.ResultsOf 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4‐62). Median number of concomitant AEDs was 3 (range, 0‐10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add‐on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%).SignificanceResults from this ongoing EAP support previous observational and clinical trial data showing that add‐on CBD may be an efficacious long‐term treatment option for TRE.

055 Effect of common concomitant antiepileptic drugs during adjunctive treatment with perampanel: post hoc analysis from the open-label extension of a phase III study in patients with idiopathic generalised epilepsy

IntroductionPerampanel is approved for adjunctive treatment of partial seizures, with or without secondarily generalised seizures, and primary generalised tonic-clonic (PGTC) seizures in epilepsy patients aged ≥12 years. Perampanel is also approved for monotherapy use for partial seizures in the US. This post hoc analysis assessed the effects of the most common concomitant Baseline antiepileptic drugs (AEDs) on discontinuation rates and treatment-emergent adverse event (TEAE) incidence during adjunctive treatment with perampanel in patients (aged ≥12 years) with idiopathic generalised epilepsy (IGE) and PGTC seizures in the open-label extension (OLEx) Phase of Study 332 (NCT02307578).MethodsPatients completing the double-blind study could receive perampanel (≤12 mg/day) during the OLEx (6 week blinded Conversion Period;≤136 weeks’ Maintenance). Here, we report results for perampanel >4–8 mg/day and >8–12 mg/day.ResultsMost common concomitant Baseline AEDs were valproic acid (n=55), lamotrigine (n=53), levetiracetam (n=37), topiramate (n=21) and zonisamide (n=12); patients may have received >1 of these Baseline AEDs. The most common reasons for discontinuing were adverse event(s) (AE), ‘other’ and patient choice. Lamotrigine: patient choice, n=6/34 (>4–8 mg/day); AE/‘other’, both n=3/19 (>8–12 mg/day). Levetiracetam: patient choice, n=5/27 (>4–8 mg/day); AE, n=2/10 (>8–12 mg/day). Topiramate: ‘other’, n=3/15 (>4–8 mg/day); AE/‘other’, both n=1/6 (>8–12 mg/day). Valproic acid: patient choice, n=6/38 (>4–8 mg/day); ‘other’, n=4/17 (>8–12 mg/day). Zonisamide: patient choice/‘other’, both n=2/10 (>4–8 mg/day); no discontinuations (>8–12 mg/day). Patient-reported TEAEs ranged from: 88.2% (lamotrigine) to 93.3% (topiramate) for perampanel >4–8 mg/day, and 70.6% (valproic acid) to 100.0% (topiramate and zonisamide) for perampanel >8–12 mg/day. The most common TEAE was dizziness.ConclusionIn this post hoc analysis, primary reasons for discontinuation and TEAE incidence differed between the most common Baseline AED subgroups and perampanel dose range, although TEAE types were similar. These data provide additional information on the safety of adjunctive perampanel in patients with IGE.Study supportEisai Inc.

Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacy

BackgroundSome studies suggest higher efficacy of lacosamide (LCM) in status epilepticus (SE) with higher loading doses; however, this weight-adjusted dose has not been evaluated. ObjectiveThe objective was to evaluate the relationship between loading weight-adjusted dose and efficacy of LCM in SE. MethodsA group of patients with SE treated with LCM from Spanish hospitals was examined retrospectively. Demographic data, type of SE, etiology, response rate, last antiepileptic drug (AED) used, treatment line in which LCM was used, total loading dose, and weight-adjusted dose were collected. ResultsOne hundred sixty-five cases of SE were collected; 87 (52.7%) patients had nonconvulsive SE. Mean age was 64.2 ± 17.2 and 60.6% (n = 100) were men. Regarding etiology, SE was considered as acute symptomatic in 85 (51.5%), remote symptomatic in 51 (30.9%), progressive symptomatic in 10 (6.1%), and cryptogenic in 19 (11.5%). Lacosamide was used as the third drug in 46.1%, and as a second option in 28%. In 115 patients, clonazepam had been used as the first option, and no benzodiazepines had been administered in the remaining 50. The median loading dose was 400 mg (100–600 mg), and the weight-adjusted dose was 5 mg/kg (3–6 mg/kg). The response rate was 63.3%, and 55.1% responded within the first 12 h.Efficacy was significantly higher in patients who had taken benzodiazepines at LCM loading doses >5.3 mg/kg (p = 0.006). This relationship was maintained independent of using other concomitant AEDs. However, if benzodiazepines were not taken, this relationship was not found. ConclusionsIn adults with benzodiazepine-resistant SE, the response rate to LCM was higher, with weight-adjusted doses above 5.3 mg/kg.

Efficacy and Safety of Everolimus Based on Prior and Concomitant Antiepileptic Drugs in Patients with Tuberous Sclerosis Complex (TSC)-Associated Treatment-Refractory Seizures: A Subanalysis of the Phase 3 EXIST-3 Study (S9.007)

Efficacy and Safety of Everolimus Based on Prior and Concomitant Antiepileptic Drugs in Patients with Tuberous Sclerosis Complex (TSC)-Associated Treatment-Refractory Seizures: A Subanalysis of the Phase 3 EXIST-3 Study (S9.007)

Sodium and Thyroid Hormone Levels During Phase III Trials of Adjunctive Eslicarbazepine Acetate (ESL), According to Concomitant Antiepileptic Drug (AED) Use (P5.271)

Sodium and Thyroid Hormone Levels During Phase III Trials of Adjunctive Eslicarbazepine Acetate (ESL), According to Concomitant Antiepileptic Drug (AED) Use (P5.271)