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Evaluation of diazepam nasal spray in patients with epilepsy concomitantly using maintenance benzodiazepines: An interim subgroup analysis from a phase 3, long-term, open-label safety study.
Segal, EB, Tarquinio, D, Miller, I, Wheless, JW, Dlugos, D, Biton, V, Cascino, GD, Desai, J, Hogan, RE, Liow, K, et al
Epilepsia. 2021;(6):1442-1450
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OBJECTIVE Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness. METHODS A long-term, phase 3, open-label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen. RESULTS Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6-65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no-benzodiazepine group. Findings were similar in a sub-analysis of patients who were (n = 44) or were not (n = 75) taking clobazam. SIGNIFICANCE This analysis of patients from a long-term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub-analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use.
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Pharmacokinetics and safety of VALTOCO (NRL-1; diazepam nasal spray) in patients with epilepsy during seizure (ictal/peri-ictal) and nonseizure (interictal) conditions: A phase 1, open-label study.
Hogan, RE, Tarquinio, D, Sperling, MR, Klein, P, Miller, I, Segal, EB, Rabinowicz, AL, Carrazana, E
Epilepsia. 2020;(5):935-943
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OBJECTIVE To assess pharmacokinetics and safety of diazepam nasal spray (NRL-1; VALTOCO®) in pediatric and adult patients with epilepsy in seizure and nonseizure states. METHODS A single dose of diazepam nasal spray (5, 10, 15, or 20 mg based on weight) was administered during each of two conditions (ictal/peri-ictal and interictal condition) to patients 6-65 years old with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness; a second dose was permitted if needed for persistent seizures. Dosing could be interictal or ictal/peri-ictal first, with a washout of ≥14 days. Blood samples for pharmacokinetic analysis were taken at prespecified time points. Treatment-emergent adverse events (TEAEs), sedation, nasal irritation, nasal mucosal pain, and olfactory changes were assessed. RESULTS Of 57 patients in the study (mean age = 28.1 years [range = 6-59], 54.4% female, 80.7% white), 49 were included in the primary pharmacokinetic analyses. Diazepam pharmacokinetic profiles were similar under both conditions, with approximately 2-hour median time to mean (SD) maximum plasma concentrations of 164 (88) and 189 (110) ng/mL for ictal/peri-ictal and interictal conditions, respectively; drug exposure during the first 6 hours postdosing was 532 (313) and 615 (368) h•ng/mL, respectively. Seventeen patients (29.8%) reported TEAEs, of whom eight (14%) had treatment-related TEAEs, with those reported in ≥2 patients being dysgeusia (n = 3, 5.3%) and nasal discomfort (n = 2, 3.5%). One patient had serious TEAEs (recurrent seizures, metabolic encephalopathy), which were deemed unrelated to study treatment. No changes in respiratory rate were observed, nor were there clinically relevant changes in sedation, olfaction, nasal irritation, or acute nasal mucosal pain. SIGNIFICANCE The epileptic conditions (ictal/peri-ictal, interictal) had minimal impact on diazepam nasal spray pharmacokinetics in patients with epilepsy. Therefore, diazepam nasal spray can be administered ictally and interictally. Diazepam nasal spray safety was consistent with the profile of diazepam.
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Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy.
Wechsler, RT, Radtke, RA, Smith, M, Vossler, DG, Strom, L, Trinka, E, Cheng, H, Grinnell, T, Blum, D, Vieira, M, et al
Epilepsia. 2019;(7):1341-1352
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OBJECTIVE To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal- (partial-) onset seizures. METHODS This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400-1200 mg once daily), two phase 3 trials of ESL monotherapy (1200-1600 mg once daily), and their open-label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+ ]), incidences of hyponatremia-related treatment-emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. RESULTS The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open-label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+ ] measurement ≤125 mEq/L, <9% had a >10 mEq/L decrease in [Na+ ] from baseline, <6% had a hyponatremia-related TEAE, and <2% discontinued the controlled trials due to a hyponatremia-related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator-reported TEAE of "hyponatremia" or "blood sodium decreased" did not have a corresponding laboratory [Na+ ] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+ ] measurement ≤125 mEq/L. SIGNIFICANCE Reductions in serum sodium concentrations and hyponatremia-related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+ ] measurements.
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Intravenous lacosamide in clinical practice-Results from an independent registry.
Lang, N, Lange, M, Schmitt, FC, Bös, M, Weber, Y, Evers, S, Burghaus, L, Kellinghaus, C, Schubert-Bast, S, Bösel, J, et al
Seizure. 2016;:5-9
Abstract
PURPOSE This non-interventional study was conducted to evaluate the efficacy and tolerability of intravenous lacosamide (LCM-iv) under routine conditions in daily clinical practice as a prospective registry. METHODS Patients with any type of seizure or epilepsy syndrome were recruited in 16 neurological and neuropediatric centers in Germany if the treating physician decided to administer LCM-iv for any reason. Observation time per patient was 10 days with daily documentation of LCM-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events. Treatment efficacy, tolerability, and handling of LCM-iv were assessed using a five-step scale. RESULTS In 119 patients treating physicians classified epilepsies as focal in 66.1% and generalized in 17.4% (16.5% unclassifiable). Most common etiologies of seizures were tumors (36.1%) and cerebrovascular diseases (21.8%). Reasons for LCM-iv treatment included preparation for surgery (25.2%), convulsive (24.4%) and non-convulsive (18.5%) status epilepticus (SE), series of seizures (16.0%), gastrointestinal causes (5.9%), and acute seizures (4.2%). The median dose of LCM-iv was 300mg per day. In 45 of 64 patients (70.3%) with SE or series of seizures, epileptic activity ceased during observation time. Five patients showed abnormalities in ECG prior to the infusion and one patient afterwards, but during infusion no abnormalities were reported. Treating physicians rated efficacy and tolerability as very good or good in 77.6% and 93.1% of patients, respectively. CONCLUSIONS This large and independent multicenter registry on the use of LCM-iv in clinical practice demonstrates that LCM-iv is well-tolerated and highly efficacious when given in emergency situations, including patients experiencing SE. It is advisable to perform an electrocardiogram prior to LCM-iv administration.
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Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: Impact of mechanism of action and pharmacokinetics on clinical outcomes.
Kwan, P, Brodie, MJ, Laurenza, A, FitzGibbon, H, Gidal, BE
Epilepsy research. 2015;:117-24
Abstract
AIM: To further explore the impact of concomitant antiepileptic drugs (AEDs) on the efficacy and tolerability of adjunctive perampanel for focal epilepsy. METHODS Data were pooled from three phase III trials of adjunctive perampanel in patients (≥12 years of age) with refractory partial-onset seizures. Concomitant AEDs were categorized according to whether or not they were enzyme-inducing AEDs (EIAEDs; known to reduce perampanel plasma concentrations) or sodium channel blockers (SCBs). Post hoc analyses assessed the impact of co-administration of non-EIAED SCBs and the overall number of concomitant AEDs on changes in seizure frequency, 50% responder rates, rates of treatment-emergent adverse events (TEAEs), and rates of discontinuation due to TEAEs, in patients randomized to receive daily placebo or perampanel 2, 4, 8, or 12mg. RESULTS Amongst 1480 randomized and treated patients, most were receiving two or more concomitant AEDs (n=1273, 86.0%), one or more EIAEDs (n=1083, 73.2%), and/or one or more SCBs (n=1203, 81.3%) at Baseline. The magnitude of seizure reduction appeared unaffected by the presence of non-EIAED SCBs, but lower in the presence of multiple AEDs. Frequency of TEAEs did not appear to be affected by the presence of non-EIAED SCBs or multiple AEDs. CONCLUSION Beyond the known interactions between perampanel and EIAEDs, perampanel efficacy appears to be unaffected by the use of concomitant non-EIAED SCBs, but may be reduced in the presence of multiple concomitant AEDs (possibly indicative of the presence of more refractory epilepsy). Nonetheless, with careful titration to balance efficacy and tolerability, perampanel may be combined with a range of AEDs, facilitating integration into treatment plans.
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Effect of switching hepatic enzyme-inducer antiepileptic drug to levetiracetam on bone mineral density, 25 hydroxyvitamin D, and parathyroid hormone in young adult patients with epilepsy.
Phabphal, K, Geater, A, Limapichat, K, Sathirapanya, P, Setthawatcharawanich, S, Leelawattana, R
Epilepsia. 2013;(6):e94-8
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We sought to determine the effect of changing phenytoin therapy on bone mineral density (BMD) and 25-hydroxyvitamin D in patients with epilepsy. Of the 90 patients, 54 patients had switched to levetiracetam, 19 patients had stopped, and 17 patients continued taking phenytoin. We proposed a 2-year period to examine 25-hydroxyvitamin D, parathyroid hormone, and BMD. The patients who switched or stopped phenytoin showed a significant increase in BMD of the lumbar spine and left femur, and in 25-hydroxyvitamin D. In contrast, those who continued phenytoin had a significant decrease in BMD at both sites and in 25-hydroxyvitamin D. Patients who were taken off phenytoin and those switching to levetiracetam did not show a significant difference in BMD, 25-hydroxyvitamin D, parathyroid, or calcium at follow-up. Compared with those who continued phenytoin, the BMD was significantly higher in patients switching to levetiracetam and those who stopped using phenytoin. Switching medications may be necessary in some cases to avoid low BMD.
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Vagus nerve stimulation increases energy expenditure: relation to brown adipose tissue activity.
Vijgen, GH, Bouvy, ND, Leenen, L, Rijkers, K, Cornips, E, Majoie, M, Brans, B, van Marken Lichtenbelt, WD
PloS one. 2013;(10):e77221
Abstract
BACKGROUND Human brown adipose tissue (BAT) activity is inversely related to obesity and positively related to energy expenditure. BAT is highly innervated and it is suggested the vagus nerve mediates peripheral signals to the central nervous system, there connecting to sympathetic nerves that innervate BAT. Vagus nerve stimulation (VNS) is used for refractory epilepsy, but is also reported to generate weight loss. We hypothesize VNS increases energy expenditure by activating BAT. METHODS AND FINDINGS Fifteen patients with stable vns therapy (age: 45 ± 10 yrs; body mass index; 25.2 ± 3.5 kg/m(2)) were included between January 2011 and June 2012. Ten subjects were measured twice, once with active and once with inactivated VNS. Five other subjects were measured twice, once with active VNS at room temperature and once with active VNS under cold exposure in order to determine maximal cold-induced BAT activity. BAT activity was assessed by 18-Fluoro-Deoxy-Glucose-Positron-Emission-Tomography-and-Computed-Tomography. Basal metabolic rate (BMR) was significantly higher when VNS was turned on (mean change; +2.2%). Mean BAT activity was not significantly different between active VNS and inactive VNS (BAT SUV(Mean); 0.55 ± 0.25 versus 0.67 ± 0.46, P = 0.619). However, the change in energy expenditure upon VNS intervention (On-Off) was significantly correlated to the change in BAT activity (r = 0.935, P<0.001). CONCLUSIONS VNS significantly increases energy expenditure. The observed change in energy expenditure was significantly related to the change in BAT activity. This suggests a role for BAT in the VNS increase in energy expenditure. Chronic VNS may have a beneficial effect on the human energy balance that has potential application for weight management therapy. TRIAL REGISTRATION The study was registered in the Clinical Trial Register under the ClinicalTrials.gov Identifier NCT01491282.
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[Eslicarbazepine acetate in clinical practice. Efficacy and safety results].
Serrano-Castro, PJ, Payán-Ortiz, M, Cimadevilla, JM, Quiroga-Subirana, P, Fernández-Pérez, J
Revista de neurologia. 2013;(6):309-14
Abstract
INTRODUCTION. Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED) licensed in Spain in February 2011 as an adjunctive therapy in adults with partial seizures with or without secondary generalization. Clinical trials with ESL have demonstrated acceptable efficacy and safety. AIM. To evaluate the results of ESL in our epilepsy unit during its first year of clinical experience with this AED. PATIENTS AND METHODS. We included all patients who started treatment with ESL at our epilepsy unit from March 2011 to May 2012. We collected the following variables: gender, aetiology of epilepsy, epileptogenic area, reason for switch to ESL, clinical response after initiation of ESL, adverse effects of ESL, refractoriness criteria and treatment discontinuation. A bivariate factor-to-factor correlation study was carried out to establish associations between the independent variables and the clinical response. RESULTS. We recruited 105 patients (51.4% male). 20,7% of patients remained seizure-free and 58.4% showed > 50% improvement after introduction of ESL. At 6 months, 18.1% had experienced some type of side effect, with cognitive disorders being the most common, and 11.5% had discontinued treatment. Combination with lacosamide proved to be significantly less effective in the control of seizures. Combination of ESL with the rest of sodium channel inhibitors was similar in efficacy to others combinations. CONCLUSIONS. ESL is a well-tolerated and effective AED when is used as adjunctive treatment with most of other AED in clinical practice.
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E-mail management of the modified Atkins Diet for adults with epilepsy is feasible and effective.
Cervenka, MC, Terao, NN, Bosarge, JL, Henry, BJ, Klees, AA, Morrison, PF, Kossoff, EH
Epilepsia. 2012;(4):728-32
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PURPOSE The modified Atkins Diet (MAD) is an effective dietary treatment for children with epilepsy. However, adults may have limited access to this therapy because of lack of availability of dietitian or nutrition support or familiarity with the diet by their treating neurologist. This study was designed to investigate the tolerability and efficacy of the MAD administered solely via e-mail to adults with pharmacoresistant epilepsy. METHODS A prospective, open-label, proof-of-principle 3-month study design was employed. Adults were enrolled, instructed on how to self-administer a 20 g carbohydrate per day MAD, and followed by the investigators only via e-mail. There were no clinic visits or dietitian contacts during the study period. KEY FINDINGS Twenty-five participants (median age 30 years [range 18-66 years], 68% female) consented and 22 started the MAD. The median prior anticonvulsants was 5 (range 2-10) and seizure frequency was 5 per week (range 1-140). Urinary ketosis was achieved in 21 participants (95%), of which 16 (76%) reported at least 40 mg/dl (moderate). Twenty-one participants (95%) remained on the MAD at 1 month and 14 (64%) at 3 months. After 1 month, 9 (41%) had >50% seizure reduction including one (5%) with >90% seizure reduction using intent-to-treat analysis. After 3 months, 6 (27%) had >50% seizure reduction including 3 (14%) with >90% seizure reduction. The mean ketogenic ratio was 1.1:1 (fat:carbohydrates and protein) for those who provided a MAD food record at follow-up. Over the study period, the median number of e-mails sent by the participants was 6 (range 1-19). The most frequent side effect was weight loss. SIGNIFICANCE E-mail administration of the MAD to adults with refractory epilepsy appears to be feasible and effective. Therefore, when dietitian or physician support is limited for adult patients with epilepsy, remote access via telemedicine could provide an alternative.
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[Experience with ketogenic diet as treatment for refractory epilepsy].
Ramírez-Camacho, A, Meavilla, S, Catalán, N, Gutiérrez, A, Campistol, J
Revista de neurologia. 2011;(9):524-30
Abstract
INTRODUCTION Epilepsy is a disease where most patients have a good control with pharmacological antiepileptic treatment. Nevertheless, 25% of the patients have a refractory epilepsy to usual antiepileptic drugs. Ketogenic diet is one of the treatment options for this type of epilepsy. In spite of the increased popularity of it as an antiepileptic treatment, it does not exist an international consensus of its indications and management. AIM: To evaluate the response, tolerance and adverse effects of the patients with refractory epilepsy at our hospital during the last 20 years. PATIENTS AND METHODS We reviewed the data of 30 patients with ketogenic diet and the follow-up at the Neurology and Nutrition Services in our Hospital. RESULTS Ten patients (35.7%) had a positive response with reduction of their seizures for more than six months; five of them had a 50-75% decrease in seizures and five of them had more than 75% of seizure reduction. The most common short term adverse effects were diarrhea, vomiting and hypoglicemia whereas long term adverse effects were constipation and weight gain. CONCLUSIONS We recommend to use ketogenic diet as treatment in refractory epilepsy since there is a positive response in seizure control in some cases. The adverse effects seen could be prevented or treated without complications. It is a preferable treatment option before using other aggressive therapeutical measures or when surgery is not feasible.