4 CLINICAL PARTICULARS 4.1 Therapeutic Indications Trimetazidine is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies. 4.2 Posology and method of administration Oral administration. Posology The dose is one tablet of 35mg of trimetazidine twice daily during meals. Special populations Renal impairment In patients with moderate renal impairment (creatinine clearance [30-60] ml/min) (see sections 4.4 and 5.2), the recommended dose is 1 tablet of 35mg in the morning during breakfast. Elderly Elderly patients may have increased trimetazidine exposure due to age-related decrease in renal function (see section 5.2). In patients with moderate renal impairment (creatinine clearance [30-60] ml/min), the recommended dose is 1 tablet of 35mg in the morning during breakfast. Dose titration in elderly patients should be exercised with caution (see section 4.4). Health Products Regulatory Authority

Summary of product characteristics

Summary Background Further options for monotherapy are needed to treat newly diagnosed epilepsy in adults. We assessed the efficacy, safety, and tolerability of lacosamide as a first-line monotherapy option for these patients. Methods In this phase 3, randomised, double-blind, non-inferiority trial, patients from 185 epilepsy or general neurology centres in Europe, North America, and the Asia Pacific region, aged 16 years or older and with newly diagnosed epilepsy were randomly assigned in a 1:1 ratio, via a computer-generated code, to receive lacosamide monotherapy or controlled-release carbamazepine (carbamazepine-CR) twice daily. Patients, investigators, and trial personnel were masked to treatment allocation. From starting doses of 100 mg/day lacosamide or 200 mg/day carbamazepine-CR, uptitration to the first target level of 200 mg/day and 400 mg/day, respectively, took place over 2 weeks. After a 1-week stabilisation period, patients entered a 6-month assessment period. If a seizure occurred, the dose was titrated to the next target level (400 or 600 mg/day for lacosamide and 800 or 1200 mg/day for carbamazepine-CR) over 2 weeks with a 1-week stabilisation period, and the 6-month assessment period began again. Patients who completed 6 months of treatment and remained seizure-free entered a 6-month maintenance period on the same dose. The primary efficacy outcome was the proportion of patients remaining free from seizures for 6 consecutive months after stabilisation at the last assessed dose. The predefined non-inferiority criteria were −12% absolute and −20% relative difference between treatment groups. This trial is registered with ClinicalTrials.gov, number NCT01243177. Findings The trial was done between April 27, 2011, and Aug 7, 2015. 888 patients were randomly assigned treatment. 444 patients taking lacosamide and 442 taking carbamazepine-CR were included in the full analysis set (took at least one dose of study treatment), and 408 and 397, respectively, were included in the per-protocol set. In the full analysis set, 327 (74%) patients in the lacosamide group and 308 (70%) in the carbamazepine-CR group completed 6 months of treatment without seizures. The proportion of patients in the full analysis set predicted by the Kaplan-Meier method to be seizure-free at 6 months was 90% taking lacosamide and 91% taking carbamazepine-CR (absolute treatment-difference: −1·3%, 95% CI −5·5 to 2·8 relative treatment difference: −6·0%). Kaplan-Meier estimates results were similar in the per-protocol set (92% and 93%; −1·3%, −5·3 to 2·7; −5·7%). Treatment-emergent adverse events were reported in 328 (74%) patients receiving lacosamide and 332 (75%) receiving carbamazepine-CR. 32 (7%) patients taking lacosamide and 43 (10%) taking carbamazepine-CR had serious treatment-emergent adverse events, and 47 (11%) and 69 (16%), respectively, had treatment-emergent adverse events that led to withdrawal. Interpretation Treatment with lacosamide met the predefined non-inferiority criteria when compared with carbamazepine-CR. Therefore, it might be useful as first-line monotherapy for adults with newly diagnosed epilepsy. Funding UCB Pharma.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(16)30292-7.pdf

Efficacy, safety, and tolerability of lacosamide monotherapy versus controlled-release carbamazepine in patients with newly diagnosed epilepsy: a phase 3, randomised, double-blind, non-inferiority trial

Sodium channel blockers have been the mainstay of the pharmacological management of focal and generalised tonic–clonic seizures for more than 70 years The focus of this paper will be on phenytoin, carbamazepine, lamotrigine, oxcarbazepine, rufinamide, lacosamide and eslicarbazepine acetate All these antiepileptic drugs have similar efficacy and share similar dose-dependent, adverse effect profiles, although phenytoin, carbamazepine and oxcarbazepine are more likely to cause idiosyncratic reactions than the others With the exception of lamotrigine, rufinamide and lacosamide, all are enzyme inducers and most are minor teratogens; although data on teratogenicity are sparse with lacosamide and eslicarbazepine acetate There is increasing evidence that these drugs differ mechanistically, with the newer agents, lacosamide and eslicarbazepine acetate, having their major pharmacological effect on the slow inactivation state of the sodium channel, which may be associated with better tolerability at higher dosage, although hard evidence in support of this observation is currently not available Rufinamide is licensed only for Lennox-Gastaut syndrome in children aged 4 years and above There is a move away from using enzyme inducers, particularly phenytoin and carbamazepine, in everyday clinical practice There seems little doubt, however, that some sodium channel blockers will have an enduring place in the management of epilepsy well into the 21st century

Sodium Channel Blockers in the Treatment of Epilepsy

Eslicarbazepine acetate is a new anti-epileptic drug belonging to the dibenzazepine carboxamide family that is currently approved as adjunctive therapy and monotherapy for partial-onset (focal) seizures. The drug enhances slow inactivation of voltage-gated sodium channels and subsequently reduces the activity of rapidly firing neurons. Eslicarbazepine acetate has few, but some, drug–drug interactions. It is a weak enzyme inducer and it inhibits cytochrome P450 2C19, but it affects a smaller assortment of enzymes than carbamazepine. Clinical studies using eslicarbazepine acetate as adjunctive treatment or monotherapy have demonstrated its efficacy in patients with refractory or newly diagnosed focal seizures. The drug is generally well tolerated, and the most common side effects include dizziness, headache, and diplopia. One of the greatest strengths of eslicarbazepine acetate is its ability to be administered only once per day. Eslicarbazepine acetate has many advantages over older anti-epileptic drugs, and it should be strongly considered when treating patients with partial-onset epilepsy.

/pdf/eslicarbazepine-acetate-a-new-improvement-on-a-classic-drug-16j4dqxabe.pdf

Eslicarbazepine Acetate: A New Improvement on a Classic Drug Family for the Treatment of Partial-Onset Seizures.

Background This is an updated version of the original Cochrane Review published in 2017. Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer‐term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first‐line treatment for focal onset seizures and sodium valproate for generalised onset seizures; however, a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. Objectives To compare the time to treatment failure, remission and first seizure of 12 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide, eslicarbazepine acetate, lacosamide) currently used as monotherapy in children and adults with focal onset seizures (simple focal, complex focal or secondary generalised) or generalised tonic‐clonic seizures with or without other generalised seizure types (absence, myoclonus). Search methods For the latest update, we searched the following databases on 12 April 2021: the Cochrane Register of Studies (CRS Web), which includes PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Epilepsy Group Specialised Register and MEDLINE (Ovid, 1946 to April 09, 2021). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators and experts in the field. Selection criteria We included randomised controlled trials of a monotherapy design in adults or children with focal onset seizures or generalised onset tonic‐clonic seizures (with or without other generalised seizure types). Data collection and analysis This was an individual participant data (IPD) and network meta‐analysis (NMA) review. Our primary outcome was 'time to treatment failure', and our secondary outcomes were 'time to achieve 12‐month remission', 'time to achieve six‐month remission', and 'time to first seizure post‐randomisation'. We performed frequentist NMA to combine direct evidence with indirect evidence across the treatment network of 12 drugs. We investigated inconsistency between direct 'pairwise' estimates and NMA results via node splitting. Results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs) and we assessed the certainty of the evidence using the CiNeMA approach, based on the GRADE framework. We have also provided a narrative summary of the most commonly reported adverse events. Main results IPD were provided for at least one outcome of this review for 14,789 out of a total of 22,049 eligible participants (67% of total data) from 39 out of the 89 eligible trials (43% of total trials). We could not include IPD from the remaining 50 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country‐specific restrictions. No IPD were available from a single trial of eslicarbazepine acetate, so this AED could not be included in the NMA. Network meta‐analysis showed high‐certainty evidence that for our primary outcome, ‘time to treatment failure’, for individuals with focal seizures; lamotrigine performs better than most other treatments in terms of treatment failure for any reason and due to adverse events, including the other first‐line treatment carbamazepine; HRs (95% CIs) for treatment failure for any reason for lamotrigine versus: levetiracetam 1.01 (0.88 to 1.20), zonisamide 1.18 (0.96 to 1.44), lacosamide 1.19 (0.90 to 1.58), carbamazepine 1.26 (1.10 to 1.44), oxcarbazepine 1.30 (1.02 to 1.66), sodium valproate 1.35 (1.09 to 1.69), phenytoin 1.44 (1.11 to 1.85), topiramate 1.50 (1.23 to 1.81), gabapentin 1.53 (1.26 to 1.85), phenobarbitone 1.97 (1.45 to 2.67). No significant difference between lamotrigine and levetiracetam was shown for any treatment failure outcome, and both AEDs seemed to perform better than all other AEDs. For people with generalised onset seizures, evidence was more limited and of moderate certainty; no other treatment performed better than first‐line treatment sodium valproate, but there were no differences between sodium valproate, lamotrigine or levetiracetam in terms of treatment failure; HRs (95% CIs) for treatment failure for any reason for sodium valproate versus: lamotrigine 1.06 (0.81 to 1.37), levetiracetam 1.13 (0.89 to 1.42), gabapentin 1.13 (0.61 to 2.11), phenytoin 1.17 (0.80 to 1.73), oxcarbazepine 1.24 (0.72 to 2.14), topiramate 1.37 (1.06 to 1.77), carbamazepine 1.52 (1.18 to 1.96), phenobarbitone 2.13 (1.20 to 3.79), lacosamide 2.64 (1.14 to 6.09). Network meta‐analysis also showed high‐certainty evidence that for secondary remission outcomes, few notable differences were shown for either seizure type; for individuals with focal seizures, carbamazepine performed better than gabapentin (12‐month remission) and sodium valproate (six‐month remission). No differences between lamotrigine and any AED were shown for individuals with focal seizures, or between sodium valproate and other AEDs for individuals with generalised onset seizures. Network meta‐analysis also showed high‐ to moderate‐certainty evidence that, for ‘time to first seizure,’ in general, the earliest licensed treatments (phenytoin and phenobarbitone) performed better than the other treatments for individuals with focal seizures; phenobarbitone performed better than both first‐line treatments carbamazepine and lamotrigine. There were no notable differences between the newer drugs (oxcarbazepine, topiramate, gabapentin, levetiracetam, zonisamide and lacosamide) for either seizure type. Generally, direct evidence (where available) and network meta‐analysis estimates were numerically similar and consistent with confidence intervals of effect sizes overlapping. There was no important indication of inconsistency between direct and network meta‐analysis results. The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders; however, reporting of adverse events was highly variable across AEDs and across studies. Authors' conclusions High‐certainty evidence demonstrates that for people with focal onset seizures, current first‐line treatment options carbamazepine and lamotrigine, as well as newer drug levetiracetam, show the best profile in terms of treatment failure and seizure control as first‐line treatments. For people with generalised tonic‐clonic seizures (with or without other seizure types), current first‐line treatment sodium valproate has the best profile compared to all other treatments, but lamotrigine and levetiracetam would be the most suitable alternative first‐line treatments, particularly for those for whom sodium valproate may not be an appropriate treatment option. Further evidence from randomised controlled trials recruiting individuals with generalised tonic‐clonic seizures (with or without other seizure types) is needed. 

Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data

Purpose This phase-III, randomised, double-blind, active-controlled, non-inferiority study aimed to demonstrate the efficacy and safety of once-daily (QD) ESL as monotherapy treatment for newly diagnosed adults with POS in comparison to twice-daily (BID) controlled-release carbamazepine (CBZ-CR). Method Patients (≥18 years) were randomised (1:1) to receive ESL or CBZ-CR in a 3-step dose-level design. Each dose-level was maintained through a 26 week Evaluation-Period (EP). Subjects who remained seizure-free at any dose-level continued through subsequent periods/phases. Primary-endpoint was proportion of patients with 26 week seizure freedom in the per-protocol (PP) population. Results 815 patients were randomised (PP population; ESL n=388; CBZ-CR n=397). In the PP population, the proportion of subjects classified as seizure-free for the entire 26 week Evaluation Period at the last evaluated dose was comparable between the ESL group (71.1%) and the CBZ-CR group (75.6%) and ESL was shown to be non-inferior to CBZ-CR. Results from the sensitivity analyses were consistent with the primary analysis results. ESL was non-inferior to CBZ-CR during 1 year of treatment, as the 1 year seizure-free rate at the last evaluated dose (PP population) was 64.7% on ESL group and 70.3% on CBZ-CR group. Conclusion ESL QD was non-inferior to CBZ-CR BID for seizure freedom rates in patients with newly diagnosed epilepsy. Sponsored by BIAL-Portela and Ca S.A.

https://jnnp.bmj.com/content/jnnp/88/Suppl_1/A23.1.full.pdf

PO043 Efficacy of eslicarbazepine acetate versus controlled-release carbamazepine as monotherapy in patients with newly diagnosed partial-onset seizures

Incidence of treatment-emergent adverse events in Parkinson's disease patients according to baseline dopamine agonist use: Post-hoc analysis from double-blind combined BIPARK-I and II data

Switching entacapone or placebo to opicapone Open-label: Efficacy results of the BIPARK-I 1-year extension study

Objective: To evaluate the effect of ESL on plasma sodium levels and hyponatremia treatment-emergent adverse events (TEAEs) in children aged 4–17 years with partial-onset (focal) seizures (POS). Background: ESL is a once-daily oral antiepileptic drug (AED) for POS. Reductions in sodium levels and clinically significant hyponatremia have previously been reported in adults taking ESL. Design/Methods: This post-hoc analysis evaluated safety and tolerability data pooled from two randomized, double-blind, placebo-controlled trials (2093–208 and -305) of adjunctive ESL in pediatric patients (4–17 years) with POS refractory to treatment with 1–2 AEDs. In study 208-Part 1, patients (6–16 years) received ESL (target dose, 30 mg/kg/day) for 12 weeks. In study 305-Part 1, patients (2–17 years) received ESL (target dose 20 mg/kg/day) for 18 weeks. All patients could continue into uncontrolled, open-label extension (OLE) studies of ESL. Plasma sodium levels and TEAEs were assessed. Results: The safety populations (4–17 years of age; ≥1 dose of study drug) of the pooled controlled studies, 1-year OLEs, and post–1-year OLEs comprised 362 (ESL, n=202; placebo, n=160), 337, and 177 patients, respectively. Potentially clinically significant (PCS) decreases (>10 mEq/L) in plasma sodium level from baseline occurred in 1.5%, 1.5%, and 0.8% of ESL patients during the controlled, 1-year OLE, and post–1-year OLE periods, respectively, and PCS (≤125 mEq/L) minimum post-dose sodium levels occurred in 0.5%, 0, and 0.8% of ESL patients, respectively. Minimum post-dose sodium levels were >135 mEq/L in >90% of patients in all periods. No hyponatremia-related TEAEs were reported during the controlled or post–1-year OLE periods. Hyponatremia was reported in one patient (0.3%) during the 1-year OLE period. Conclusions: Clinically meaningful minimum post-dose sodium levels/reductions in sodium level from baseline, and hyponatremia-related TEAEs, were infrequent in children (aged 4–17 years) taking ESL. Study Supported by: BIAL and Sunovion Pharmaceuticals Inc. Disclosure: Dr. Vaisleib has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sunovion Pharmaceuticals Inc; Greenwich Biosciences. Dr. Duchowny holds stock and/or stock options in Angel Medical Systems. Dr. Grinnell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employment: Sunovion Pharmaceuticals Inc. Dr. Cantu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employment: Sunovion Pharmaceuticals Inc. Dr. Vieira has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employment: BIAL — Portela & Ca., S.A. Dr. Ikedo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employment: BIAL — Portela & Ca., S.A. Dr. Li has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sunovion Pharmaceuticals Inc. Dr. Blum has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employment: Sunovion Pharmaceuticals Inc.

Analysis of Sodium Levels and Hyponatremia Events in Trials of Eslicarbazepine Acetate (ESL) in Pediatric Patients (Aged 4–17 years) (P5.268)

Influence of demographic characteristics in the efficacy response of Parkinson’s disease patients with motor fluctuations: Post-hoc analysis from combined BIPARK-I and II

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