lacosamide and Drug-Related-Side-Effects-and-Adverse-Reactions

Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

Topics: Acetamides; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Follow-Up Studies; Humans; Lacosamide; Longitudinal Studies; Medication Adherence; Nitriles; Product Surveillance, Postmarketing; Pyridones; Pyrrolidinones; Seizures

To evaluate safety and tolerability of adjunctive lacosamide in children with focal seizures.. Patients were eligible for this open-label, fixed-titration trial (SP0847; NCT00938431) if aged 1 month-17 years with focal seizures taking 1-3 antiepileptic drugs. Findings from Cohort 1, aged 5-11 years, who received lacosamide ≤8 mg/kg/day, informed dosing for age-based cohorts 2-5, who then received ≤12 mg/kg/day (≤600 mg/day). Oral lacosamide was initiated at 2 mg/kg/day (1 mg/kg bid) and uptitrated by 2 mg/kg/day/week to the maximum cohort-defined dose (maximum trial duration: 13 weeks). Patients who did not achieve the maximum cohort-defined dose were discontinued.. Forty-seven patients (aged 6 months-≤17 years) enrolled (≥1 month-<4 years: n = 15; ≥4-<12 years: n = 23; ≥12-≤17 years: n = 9). 24/47 (51.1%) patients completed the trial at the maximum cohort-defined dose and 40/47 (85.1%) continued lacosamide in the extension trial. Treatment-emergent adverse events (TEAEs) were reported by 42/47 (89.4%) patients. The most common TEAEs (≥10% of patients) were vomiting (21.3%), diarrhea (14.9%), somnolence (12.8%), irritability, dizziness, and pyrexia (10.6% each). Twenty (42.6%) patients discontinued due to TEAEs, most commonly vomiting (8.5%), gait disturbance, dizziness, and somnolence (6.4% each). Six (12.8%) patients reported serious TEAEs, most commonly status epilepticus (3/47; 6.4%).. This fixed-titration trial supports the safety of adjunctive lacosamide in children (aged 6 months-≤17 years) with focal seizures. The TEAE profile was generally consistent with that observed in trials in adults, and no new safety concerns were identified.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Epilepsies, Partial; Female; Humans; Infant; Lacosamide; Male

The purpose of this study was to compare the efficacy and safety of lacosamide (LCM) and sodium valproate (SVA) in lorazepam (LOR)-resistant SE.. Patients with LOR-resistant SE were randomized to intravenous LCM 400mg at the rate of 60mg/kg/min or SVA 30mg/kg at the rate of 100mg/min. The SE severity score (STESS), duration of SE and its etiology, and MRI findings were noted. Primary outcome was seizure cessation for 1h, and secondary outcomes were 24h seizure remission, in-hospital death, and severe adverse events (SAE).. Sixty-six patients were included, and their median age was 40 (range 18-90) years. Thirty-three patients each received LCM and SVA. Their demographic, clinical, STESS, etiology, and MRI findings were not significantly different. One-hour seizure remission was not significantly different between LCM and SVA groups (66.7% vs 69.7%; P=0.79). Twenty-four-hour seizure freedom was insignificantly higher in SVA (20, 66.6%) compared with LCM group (15, 45.5%). Death (10 vs 12) and composite side effects (4 vs 6) were also not significantly different in LCM and SVA groups. LCM was associated with hypotension and bradycardia (1 patient), and SVA with liver dysfunction (6).. In patients with LOR-resistant SE, both LCM and SVA have comparable efficacy and safety.

Topics: Acetamides; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lacosamide; Lorazepam; Male; Middle Aged; Pilot Projects; Seizures; Status Epilepticus; Treatment Outcome; Valproic Acid; Young Adult

This phase 1, randomized, double-blind, placebo- and active comparator-controlled crossover study assessed the abuse potential of the antiepileptic drug, lacosamide.. After a qualification phase, 38 healthy, recreational central nervous system-depressant users were randomized to treatment sequences comprising single oral therapeutic (200 mg) and supratherapeutic (800 mg) doses of lacosamide, alprazolam (1.5 and 3 mg), and placebo. Subjective effects were assessed for 24 hours following each dose using a range of scales, with a 5- to 9-day washout between treatments.. Mean subjective effects for 200 mg lacosamide were statistically similar to placebo and significantly lower than with alprazolam for most end points. Lacosamide 800 mg elicited transient, statistically significant positive effects compared with placebo, but also persistent Bad Drug Effects including statistically greater maximum effect (Emax) scores for Nausea and Dysphoria compared with other treatments (P < 0.0002). Consistent with this, the 800 mg lacosamide dose showed a significantly lower "at this moment" Drug Liking visual analog scale (VAS) Emax compared with 3 mg alprazolam, but was not different from 1.5 mg alprazolam (73.1/100, 85.4/100, and 78.9/100, respectively, where 50 is neutral). Overall Drug Liking VAS and Take Drug Again VAS Emax for 800 mg lacosamide were not significantly different from placebo and were lower than those for both alprazolam doses (P < 0.0001).. These results suggest that in recreational central nervous system-depressant users, lacosamide has detectable abuse-related subjective effects, but a relatively low potential for abuse compared with alprazolam. These findings contributed toward placement of lacosamide into Schedule V of the US Controlled Substances Act.

Topics: Acetamides; Adult; Alprazolam; Anticonvulsants; Central Nervous System Depressants; Cross-Over Studies; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lacosamide; Male; Middle Aged; Substance-Related Disorders; Young Adult

The antiepileptic drug lacosamide has a low potential for drug-drug interactions, but is a substrate and moderate inhibitor of the cytochrome P450 (CYP) enzyme CYP2C19.. This phase I, randomized, open-label, two-way crossover trial evaluated the pharmacokinetic effects of lacosamide and omeprazole coadministration.. Healthy, White, male volunteers (n = 36) who were not poor metabolizers of CYP2C19 were randomized to treatment A (single-dose 40 mg omeprazole on days 1 and 8 together with 6 days of multiple-dose lacosamide [200-600 mg/day] on days 3-8) and treatment B (single doses of 300 mg lacosamide on days 1 and 8 with 7 days of 40 mg/day omeprazole on days 3-9) in pseudorandom order, separated by a ≥ 7-day washout period. Area under the concentration-time curve (AUC) and peak concentration (C(max)) were the primary pharmacokinetic parameters measured for lacosamide or omeprazole administered alone (reference) or in combination (test). Bioequivalence was determined if the 90 % confidence interval (CI) of the ratio (test/reference) fell within the acceptance range of 0.8-1.25.. The point estimates (90 % CI) of the ratio of omeprazole + lacosamide coadministered versus omeprazole alone for AUC (1.098 [0.996-1.209]) and C(max) (1.105 [0.979-1.247]) fell within the acceptance range for bioequivalence. The point estimates (90 % CI) of the ratio of lacosamide + omeprazole coadministration versus lacosamide alone also fell within the acceptance range for bioequivalence (AUC 1.133 [1.102-1.165]); C(max) 0.996 (0.947-1.047).. Steady-state lacosamide did not influence omeprazole single-dose pharmacokinetics, and multiple-dose omeprazole did not influence lacosamide single-dose pharmacokinetics.

Topics: Acetamides; Administration, Oral; Adolescent; Adult; Cross-Over Studies; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Healthy Volunteers; Humans; Lacosamide; Male; Middle Aged; Omeprazole; Therapeutic Equivalency; Young Adult

Recent data suggest that P-glycoprotein may be involved in cellular transport of lacosamide.. To investigate potential drug-drug interactions (DDIs) between lacosamide and digoxin, this phase I, multiple-dose, randomised, double-blind, placebo-controlled, crossover trial assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of digoxin administered in combination with lacosamide or placebo.. Twenty healthy White male volunteers were randomised. After receiving digoxin 0.25 mg three times daily on day 1 (loading dose), participants received digoxin 0.25 mg once daily on days 2-22. Participants received either lacosamide (200 mg twice daily) or placebo on days 8-11 and vice versa on days 18-21, after a 6-day washout. The steady-state area under concentration-time curve over the dosing interval (AUC(24,ss)) and maximum steady-state plasma concentration (C(max,ss)) of digoxin were measured; ratios of these parameters for co-administration of digoxin + lacosamide versus digoxin alone were used to evaluate potential DDIs. Interaction was excluded if the 90 % confidence interval (CI) for the geometric mean ratio of AUC24,ss and C max,ss fell within the acceptance range for bioequivalence (0.8-1.25).. The point estimates (90 % CI) of the geometric mean ratios for co-administration of digoxin with lacosamide versus digoxin alone for AUC(24,ss) [1.024 (0.979-1.071)] and C(max,ss) [1.049 (0.959-1.147)] were within the acceptance range for bioequivalence. Digoxin and lacosamide co-administration was generally well-tolerated. A small numerical increase in the mean PR interval following co-administered digoxin + lacosamide was observed versus digoxin alone and versus pre-treatment baseline values (178.5 vs. 170.4 or 166.8 ms, respectively). The RR interval increased in parallel. The change was not considered clinically relevant.. Co-administration of steady-state digoxin (0.25 mg/day) with multiple-dose lacosamide (400 mg/day) versus digoxin alone revealed no differences in digoxin disposition.

Topics: Acetamides; Adolescent; Adult; Cross-Over Studies; Digoxin; Double-Blind Method; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Healthy Volunteers; Humans; Lacosamide; Male; Middle Aged; Placebos; Young Adult

The aims of this multicenter, randomized, placebo-controlled, double-blind trial were to confirm the efficacy of lacosamide at a daily dose of 400 mg/d and to explore the efficacy, safety, and tolerability of lacosamide 200 mg/d and 600 mg/d in the treatment of painful diabetic neuropathy.. The trial consisted of a 2-week run-in period, a 6-week titration phase, and a 12-week maintenance phase, during which patients received placebo or fixed doses of lacosamide 200, 400, or 600 mg/d. No back titration was allowed during the trial. The primary efficacy criterion was the change in Likert pain score from baseline to the average over the last 4 weeks of the maintenance phase in the intent-to-treat population.. The lacosamide 400 mg/d group demonstrated statistically significant improvement in Likert pain score over placebo for the primary efficacy measure. At the end of treatment, 58% of patients in the lacosamide 400 mg/d treatment group achieved at least a 2-point or 30% reduction in Likert pain score, compared with 46% of placebo-treated patients. The lacosamide 200 mg/d group separated from placebo, but failed to show statistical significance for any of the primary or secondary outcome measures. The lacosamide 600 mg/d group was significantly more efficacious than placebo in the observed cases but not in the intent-to-treat population. This was probably secondary to a relatively high-premature withdrawal rate due to adverse events that occurred during the titration phase in that group. Overall lacosamide at daily doses of 200 to 400 mg was well tolerated, with 8% of patients discontinuing due to an adverse event from the 200 mg/d group and 23% from the 400 mg/d group compared with 9% in the placebo group. Discontinuations due to adverse events were highest in the 600 mg/d group (40%). The most common adverse events consisted of dizziness, nausea, tremor, headache, and fatigue. Somnolence, cognitive and behavioral side effects, weight change, and edema were notably low.. Safety and efficacy analyses indicated that lacosamide 400 mg/d provided an optimal balance between efficacy and side effects in patients with painful diabetic neuropathy.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Analgesics; Comorbidity; Diabetic Neuropathies; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Fibromyalgia; Humans; Incidence; Lacosamide; Male; Middle Aged; Pain Measurement; Placebo Effect; Treatment Outcome; United States

Lacosamide is licensed for the treatment of focal seizures in both adults and children, however there is little information available on its adverse reactions. Using the FDA Adverse Event Reporting System (FAERS), we seek to assess adverse occurrences that may be related to Lacosamide.. On the basis of the FAERS database from the fourth quarter of 2008 to the second quarter of 2022, disproportionality analysis was carried out using the reporting odds ratio (ROR) method, the United Kingdom Medicines and Healthcare Products Regulatory Agency omnbius standard (MHRA) method, and the bayesian confidence propagation neural network (BCPNN) method. We extracted valuable positive signals for designated medical event (DME) screening, focused on the evaluation and comparison of safety signals appearing in DME with system organ classification (SOC) analysis.. A total of 10,226 adverse reaction reports with Lacosamide as the primary suspect drug were obtained, with 30,960 reported cases, detecting 232 valuable positive signals, involving a total of 20 SOCs, of which the most frequently reported SOCs were nervous system disorders (6537 cases, 55.21%), psychiatric disorders (1530 cases, 12.92%), injury poisoning and procedural complications (1059 cases, 8.94%). According to 232 valuable positive signals with DME screening results, two signals of stevens-johnson syndrome and ventricular fibrillation were consistent with PT signals on the DME list, with the two SOCs focusing on skin and subcutaneous tissue disorders and cardiac disorders, respectively.. Our research demonstrates that the clinical use of Lacosamide should be noticed and avoided in relation to ADRs since it raises the risk of cardiac arrest, ventricular fibrillation, stevens-johnson syndrome, and rhabdomyolysis.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Bayes Theorem; Child; Drug-Related Side Effects and Adverse Reactions; Humans; Lacosamide; Pharmacovigilance; Stevens-Johnson Syndrome; United States; Ventricular Fibrillation

Lacosamide (LCM) is a new-generation anti-seizure medication approved for monotherapy and add-on therapy for focal-onset epilepsy. It has novel pharmacodynamics and favorable pharmacokinetic qualities with good clinical response. This study aims to evaluate the effectiveness and tolerability of LCM when used in the immediate switch from sodium channel blockers in patients with focal-onset and generalized-onset epilepsies. This retrospective, multicenter observational study was conducted with adult patients who received LCM as mono- or polytherapy through immediate switch with 6 to 52 months follow-up. The clinical data obtained during the follow-up period were analyzed to assess retention rate, seizure freedom, more than 50% seizure reduction, and adverse effects. A total of 32 patients (eight females, 24 males) with a median age of 49.75 (range, 23-86) years, median age at epilepsy onset of 32.58 (range, 0.5-85) years, and median epilepsy duration of 17.17 (range, 1-46) years were included in this study. Seizure frequency was between 1 and 90 in the past 6 months. Seven (21.9%) of the patients had structural brain lesions and 27 (84.4%) of the patients had EEG abnormalities. The adverse effects leading to switching were hyponatremia, rash, elevated liver enzymes, pain, and erectile dysfunction. At 14.34 (range, 6-52) months follow-up, 30 (93.75%) patients in total retained LCM, 20 (66.7%) of them were seizure-free, and 13 were on LCM monotherapy. Responder rate was 81.25%. Eight (25%) of the patients experienced adverse effects after the immediate switch. One patient with generalized-onset epilepsy needed to quit LCM due to an increase in seizures. Seizure frequency did not change in three patients in the focal-onset group. Immediate switch to LCM showed favorable outcomes with a significant reduction in seizure frequency, high retention rates, and tolerable adverse effect profiles in both focal-onset and generalized-onset seizures.

Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Epilepsies, Partial; Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Sodium Channel Blockers; Treatment Outcome; Young Adult

Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients.. We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints).. Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence.. This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

Topics: Acetamides; Anticonvulsants; Brain Neoplasms; Drug-Related Side Effects and Adverse Reactions; Epilepsies, Partial; Epilepsy; Humans; Lacosamide; Quality of Life; Retrospective Studies; Seizures; Treatment Outcome

To describe an 'unexpected' case of abrupt personality following the introduction of lacosamide.. A description of an 82-year-old male receiving neurological follow-up since 2010 due to epilepsy secondary to haemorrhagic stroke. We report a case of abrupt personality change in an 82-year-old male following the introduction of lacosamide with a return to the previous state after its discontinuation. We explored possible mechanisms and pharmacokinetic concerns explaining this personality change.. In fact, a few days after introducing lacosamide, the patient was described as 'gentle', 'calm' and apologetic for his past aggressions against his family and caregivers which was in complete contrast to his usual personality. There was also marked insistence and the use of sexualised language towards women in his close circle, especially his home nurses. In view of his insistent behaviour towards his nurses and unusual sexualised language, lacosamide was withdrawn. A few days later, the patient displayed his usual, vindictive, aggressive and forceful character. He no longer made any sexualised remarks to his home nurses.. To our knowledge, this is the first case of a sudden behavioural and personality change reported by family, friends and carers following the introduction of lacosamide.

Topics: Aged, 80 and over; Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lacosamide; Male; Personality

To compare the efficacy and safety of lacosamide versus phenytoin for seizure prophylaxis following TBI.. All TBI patients who received prophylaxis with either phenytoin or lacosamide were retrospectively identified. The incidence of seizures within the first 7 days of injury were compared along with adverse effects requiring drug discontinuation. A planned sub-group analysis was performed for patients with severe TBI (GCS < 9).. There were 481 patients (phenytoin, n = 116; lacosamide, n = 365). Demographics were similar but age (50 ± 21 vs 58 ± 22 years, P < .001) and initial GCS (11.3 ± 4.3 vs 12.5 ± 3.8, P = .010) were lower in the phenytoin group. The need for mechanical ventilation was higher (53% vs 38%, P = .004). Seizures occurred in 0.9% of the phenytoin group and 1.4% of the lacosamide group (P = 1.00). ADEs were significantly higher with phenytoin (5.2% vs 0.5%, P = .003). This difference remained significant upon multivariate analysis [OR(95% CI) = 9.4(1.8-48.9)]. Subgroup analysis for patients with severe TBI revealed no difference in seizures (phenytoin, 0% vs lacosamide, 1.5%; P = 1.00) but more ADEs with phenytoin (12.5% vs 0%, P = .010).. There was no difference between lacosamide and phenytoin in the prevention of early post traumatic seizures in patients following TBI. Lacosamide may have a more tolerable side effect profile.

Topics: Adult; Aged; Anticonvulsants; Brain Injuries, Traumatic; Drug-Related Side Effects and Adverse Reactions; Epilepsy, Post-Traumatic; Female; Humans; Incidence; Lacosamide; Male; Middle Aged; Phenytoin; Retrospective Studies

Intravenous (IV) lacosamide use for status epilepticus has increased in recent years and is recommended for refractory status epilepticus by current guidelines. Per the lacosamide package labeling, the preferred route of administration is diluted and infused over 30-60 min; however, administration undiluted is also acceptable and recent literature demonstrated safety at a maximum rate of 80 mg per minute (Kellinghaus et al. in Acta Neurol Scand 123:137-141, 2011). Undiluted administration as an IV push has potential to increase efficiency of administration to patients needing urgent seizure control since it may be dispensed from automatic dispensing cabinets in patient care areas. This study aims to compare safety outcomes and efficiency of administration in patients receiving lacosamide IV push compared to IV piggyback.. We present a single-center, retrospective cohort study of patients receiving lacosamide via IV piggyback or IV push from June 2016 to July 2017. Baseline characteristics, data related to potential safety concerns and timing of ordering, verification, and administration were collected. The primary safety outcomes were incidence of infusion site reactions, hypotension (systolic blood pressure [SBP] < 90 mm Hg), and bradycardia (heart rate [HR] < 50 beats per minute) documented within 2 h of each lacosamide dose. Secondary safety outcomes included the incidence of PR interval prolongation in patients with at least one electrocardiogram measured. The primary efficiency outcome was the time between order verification and administration.. Patients in the IV piggyback (n = 88) and IV push (n = 78) groups had similar baseline characteristics, initial dose, SBP, and HR. Hypotension (8 vs. 10.3%) and bradycardia (2.3 vs. 2.6%) rates were similar among both groups (p > 0.05). Only one patient in each group had documented PR prolongation, and no documented infusion reactions occurred. Median time from order verification to administration was significantly reduced in the IV push group (35 min vs. 1 h 49 min; p < 0.001).. Administration of lacosamide via IV push results in similar adverse effect rates to IV piggyback preparations with more efficient time to administration.

Topics: Aged; Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infusions, Intravenous; Lacosamide; Male; Middle Aged; Retrospective Studies; Status Epilepticus

Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Fructose; Humans; Lacosamide; Levetiracetam; Male; Medical Audit; Mental Disorders; Middle Aged; Nitriles; Piracetam; Pregabalin; Prospective Studies; Pyridones; Retrospective Studies; Seizures; Sodium Channel Blockers; Topiramate; Young Adult

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

To obtain better understanding of the effect of lacosamide (LCM) in clinical practice, laboratory and clinical data of 17 patients under treatment with LCM as an add-on antiepileptic drug (AED) were retrospectively evaluated.. Total LCM serum concentrations were obtained at hourly intervals for up to 5h and 8h after morning dose. Adverse drug reactions (ADR) were assessed.. LCM serum concentrations showed high fluctuations during the day with a steep increase within the first 3h after intake (mean 87.8%; range: 44.4-149.0%) under b.i.d. Mean trough and peak concentrations of LCM were 5.0 μg/ml (range: 1.8-9.5 μg/ml) and 9.7 μg/ml (range: 4.0-18.3 μg/ml), respectively; mean dose 353 mg/d (range: 200-600mg/d). Twelve patients showed ADRs. After conversion to t.i.d. or dose reduction LCM serum concentration showed lower fluctuations during the day and a lower increase after intake (mean: 50.0%, range: 27.1-66.7%); peak LCM was 9.4 μg/ml (range: 4.7-11.6 μg/ml), mean dose 388 mg/d (range: 300-500 mg/d). These interventions led to amelioration of the ADR.. Changing the dose regimen from two to three times daily could reduce fluctuations of LCM during the day and improve tolerability of LCM in patients with ADR.

Topics: Acetamides; Adult; Anticonvulsants; Chromatography, Liquid; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Time Factors; Young Adult

Topics: Acetamides; Antibodies, Monoclonal; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Azepines; Benzazepines; Benzhydryl Compounds; Benzyl Alcohol; Benzylamines; Cyclams; Cyclopropanes; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Everolimus; Febuxostat; Fluorenes; Fluoroquinolones; Gout Suppressants; Heterocyclic Compounds; Humans; Immunosuppressive Agents; Indoles; Lacosamide; Milnacipran; Oligopeptides; Phenols; Selective Serotonin Reuptake Inhibitors; Sirolimus; Tapentadol; Thiazoles; Tolvaptan; Triazoles