Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: BIAL-Portela & Ca SA, À Av. da Siderurgia Nacional, 4745-457, S. Mamede do Coronado, Portugal, tel: +351 22 986 61 00, fax: +351 22 986 61 99, e-mail: info@bial.com
Pharmacotherapeutic group: Antiepileptics, carboxamide derivatives
ATC code: N03AF04
The precise mechanisms of action of eslicarbazepine acetate are unknown. However, in vitro electrophysiological studies indicate that both eslicarbazepine acetate and its metabolites stabilise the inactivated state of voltage-gated sodium channels, precluding their return to the activated state and thereby preventing repetitive neuronal firing.
Eslicarbazepine acetate and its active metabolites prevented the development of seizures in nonclinical models predictive of anticonvulsant efficacy in man. In humans, the pharmacological activity of eslicarbazepine acetate is primarily exerted through the active metabolite eslicarbazepine.
The efficacy of eslicarbazepine acetate as adjunctive therapy has been demonstrated in four phase III double-blind placebo-controlled studies in 1,703 randomized adult patients with partial epilepsy refractory to treatment with one to three concomitant antiepileptic medicinal products. Oxcarbazepine and felbamate were not allowed as concomitant medicinal products in these studies. Eslicarbazepine acetate was tested at doses of 400 mg (in -301 and -302 studies only), 800 mg and 1,200 mg, once daily. Eslicarbazepine acetate 800 mg once daily and 1,200 mg once daily were significantly more effective than placebo in reducing seizure frequency over a 12-week maintenance period. The percentage of subjects with ≥50% reduction (1581 analyzed) in seizure frequency in the phase III studies was 19.3% for placebo, 20.8% for eslicarbazepine acetate 400 mg, 30.5% for eslicarbazepine acetate 800 mg and 35.3% for eslicarbazepine acetate 1,200 mg daily.
The efficacy of eslicarbazepine acetate as monotherapy has been demonstrated in a double-blind, active controlled (carbamazepine controlled release) study, involving 815 randomized adult patients with newly diagnosed partial-onset seizures. Eslicarbazepine acetate was tested at once-daily doses of 800 mg, 1,200 mg and 1,600 mg. The doses of the active comparator, carbamazepine controlled release, were 200 mg, 400 mg and 600 mg, twice-daily. All subjects were randomized to the lowest dose level and only if a seizure occurred subjects were to be escalated to the next dose level. From the 815 randomized patients, 401 patients were treated with eslicarbazepine acetate once-daily [271 patients (67.6%) remained at dose of 800 mg, 70 patients (17.5%) remained at dose of 1,200 mg and 60 patients (15.0%) were treated with 1,600 mg]. In the primary efficacy analysis, in which drop-outs were considered as non-responders, 71.1% subjects were classified as seizure free in the eslicarbazepine acetate group and 75.6% in the carbamazepine controlled release group during the 26 week evaluation period (average risk difference -4.28%, 95% confidence interval: [-10,30; 1,74]. The treatment effect observed during the 26-week evaluation period was maintained over 1 year of treatment with 64.7 % eslicarbazepine acetate subjects and 70.3 % carbamazepine controlled release subjects classified as seizure free (average risk difference -5.46%, 95% confidence interval: [-11.88; 0.97]. In the analysis of treatment failure (seizure risk) based on time to event analysis (Kaplan-Meier analysis and Cox regression), the Kaplan-Meier estimates of seizure risk at the end of the evaluation period was 0.06 with carbamazepine and 0.12 with eslicarbazepine acetate and by the end of 1 year with an additional increased risk to 0.11 with carbamazepine and 0.19 with eslicarbazepine acetate (p=0.0002).
At 1 year, the probability for subjects to withdraw due to either adverse reactions or lack of efficacy was 0.26 for eslicarbazepine acetate and 0.21 for carbamazepine controlled release.
The efficacy of eslicarbazepine acetate as conversion to monotherapy was evaluated in 2 double-blind, randomized controlled studies in 365 adult patients with partial-onset seizures. Eslicarbazepine acetate was tested at doses of 1,200 mg and 1,600 mg once-daily. Seizure-free rates during the entire 10-week monotherapy period were 7.6% (1,600 mg) and 8.3 % (1,200 mg) in one study and 10.0% (1,600 mg) and 7.4 % (1,200 mg) in the other study, respectively.
The safety and efficacy of eslicarbazepine acetate as adjunctive therapy for partial seizures in elderly patients were evaluated in one non-controlled study, with a duration of 26 weeks, in 72 elderly (aged ≥ 65 years). The data shows that the incidence of adverse reactions in this population (65.3 ) is similar to the general population enrolled in the double-blind epilepsy studies (66.8). The most frequent individual adverse reactions were dizziness (12.5% of subjects), somnolence (9.7%), fatigue, convulsion and hyponatraemia (8.3%, each), nasopharyngitis (6.9%) and upper respiratory tract infection (5.6%). A total of 50 of the 72 subjects starting the study completed the 26-week treatment period that corresponds to a retention rate of 69.4% (see section 4.2 for information on elderly use).
There is limited data on monotherapy regimen available in the erldely population. Only a few subjects (N=27) aged above 65 years were treated with eslicarbazepine acetate in monotherapy study.
The efficacy and safety of eslicarbazepine acetate as adjunctive therapy for partial-onset seizures in children was evaluated in one phase II study in children aged from 6 to 16 years (N=123) and one phase III study in children aged from 2 to 18 years (N=304). Both studies were double-blind and placebo controlled with a duration of maintenance of 8 weeks (study 208) and 12 weeks (study 305), respectively. Study 208 included 2 additional subsequent long-term, open-label extensions (1 year in part II and 2 years in part III) and Study 305 included 4 subsequent long-term, open-label extension periods (1 year in Parts II, III and IV and 2 years in Part V). Eslicarbazepine acetate was tested at doses of 20 and 30 mg/kg/day, up to a maximum of 1,200 mg/day. The target dose was 30 mg/kg/day in study 208 and 20 mg/kg/day in study 305. Doses could be adjusted based on tolerability and treatment response.
In the double-blind period of the phase II study, evaluation of efficacy was a secondary objective. The least square mean reduction in standardised seizure frequency from baseline to maintenance period was significantly (p<0.001) higher with eslicarbazepine acetate (34.8%) compared to placebo ( 13.8%). Forty-two patients (50.6%) in the eslicarbazepine acetate group compared to 10 patients (25.0%) in the placebo group were responders (≥50% reduction of standardised seizure frequency), resulting in a significant difference (p=0.009).
In the double-blind period of the phase III study, the least square mean reduction in standardised seizure frequency with eslicarbazepine acetate (18.1% versus baseline) was different to placebo ( 8.6% versus baseline) but not statistically significant (p=0.2490). Forty-one patients (30.6%) in the eslicarbazepine acetate group compared to 40 patients (31.0%) in the placebo group were responders (≥50% reduction of standardised seizure frequency), resulting in a non-significant difference (p=0.9017). Post-hoc subgroup analyses for the phase III study were conducted by age strata and above 6 years, as well as by dose. In children above 6 years, 36 patients (35.0%) in the eslicarbazepine acetate group compared to 29 patients (30.2%) in the placebo group were responders (p=0.4759) and the least square mean reduction in standardised seizure frequency was higher in the eslicarbazepine acetate group compared to placebo (-24.4% versus -10.5%); however, the difference of 13.9% was not statistically significant (p=0.1040). A total of 39% patients in study 305 were up titrated to the maximum possible dose (30 mg/kg/day). Amongst these, when excluding patients aged 6 years and younger, 14 (48.3%) and 11 (30.6%) of patients in the eslicarbazepine acetate and placebo group, respectively, were responders (p=0.1514). Although the robustness of these post-hoc subgroup analyses is limited, the data suggest an age and dose dependent increase in effect size.
In the subsequent 1-year open-label extension (Part II) of the phase III study (ITT set N=225) the total responder rate was 46.7% (steadily increasing from 44.9% (weeks 1-4) to 57.5% (weeks > 40)). The total median standardised seizure frequency was 6.1 (decreasing from 7.0 (weeks 1-4) to 4.0 (weeks > 40), resulting in a median relative change compared to the baseline period of -46.7%). The median relative change was larger in the previous placebo group (51.4%) than in the previous ESL group ( 40.4%). The proportion of patients with exacerbation (increase of ≥25%) compared to the baseline period was 14.2%.
In the subsequent 3 open-label extensions (ITT set N=148), the overall responder rate was 26.6% when compared to baseline Parts III–V (i.e. the last 4 weeks in part II). The total median standardised seizure frequency was 2.4 (resulting in a median relative change from Baseline Part III–V of -22.9%). The overall median relative decrease in Part I was greater in patients treated with ESL (-25.8%) than in patients treated with placebo (-16.4%). The overall proportion of patients with exacerbation (increase of ≥25%) compared to Baseline Parts III–V was 25.7%.
Of the 183 patients who completed parts I and II of the study, 152 patients were enrolled into part III. Of these, 65 patients had received ESL and 87 patients had received placebo during the double-blind part of the study. 14 patients (9.2%) completed open-label treatment with ESL through Part V. The most common reason for withdrawal during any part of the study was sponsor request (30 patients in part III [19.7% of the patients who entered part III], 9 in part IV [9.6% of the patients who entered part IV], and 43 in part V [64.2% of the patients who entered Part V]).
Taking into consideration the limitations of open label uncontrolled data, the long-term response to eslicarbazepine acetate in the open-label parts of the study was overall maintained.
The European Medicines Agency has deferred the obligation to submit the results of studies with Zebinix in one or more subsets of the paediatric population in the treatment of epilepsy with partial onset seizures (see section 4.2 for information on paediatric use).
Eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of eslicarbazepine acetate usually remain below the limit of quantification, following oral administration. Eslicarbazepine Cmax is attained at 2 to 3 hours post-dose (tmax). Bioavailability may be assumed as high because the amount of metabolites recovered in urine corresponded to more than 90% of an eslicarbazepine acetate dose.
The binding of eslicarbazepine to plasma proteins is relatively low (<40%) and independent from concentration. In vitro studies have shown that plasma protein binding was not relevantly affected by the presence of warfarin, diazepam, digoxin, phenytoin and tolbutamide. The binding of warfarin, diazepam, digoxin, phenytoin and tolbutamide was not significantly affected by the presence of eslicarbazepine.
Eslicarbazepine acetate is rapidly and extensively biotransformed to its major active metabolite eslicarbazepine by hydrolytic first-pass metabolism. The steady state plasma concentrations are attained after 4 to 5 days of once daily dosing, consistent with an effective half-life in the order of 20-24 hours. In studies in healthy subjects and epileptic adult patients, the apparent half-life of eslicarbazepine was 10-20 hours and 13-20 hours, respectively. Minor metabolites in plasma are Rlicarbazepine and oxcarbazepine, which were shown to be active, and the glucuronic acid conjugates of eslicarbazepine acetate, eslicarbazepine, R-licarbazepine and oxcarbazepine.
Eslicarbazepine acetate does not affect its own metabolism or clearance.
Eslicarbazepine is a weak inducer of CYP3A4 and has inhibiting properties with respect to CYP2C19 (as stated in section 4.5).
In studies with eslicarbazepine in fresh human hepatocytes a mild induction of UGT1A1 mediated glucuronidation was observed.
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion, in the unchanged and glucuronide conjugate forms. In total, eslicarbazepine and its glucuronide correspond to more than 90% of total metabolites excreted in urine, approximately two thirds in the unchanged form and one third as glucuronide conjugate.
The pharmacokinetics of eslicarbazepine acetate is linear and dose-proportional in the range 400-1,200 mg both in healthy subjects and patients.
The pharmacokinetic profile of eslicarbazepine acetate is unaffected in the elderly patients with creatinine clearance >60 ml/min (see section 4.2).
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion. A study in adult patients with mild to severe renal impairment showed that clearance is dependent on renal function. During treatment with Zebinix dose adjustment is recommended in patients, adult and children above 6 years of age with creatinine clearance <60 ml/min (see section 4.2).
In children from 2 to 6 years of age, the use of eslicarbazepine acetate is not recommended. At this age the intrinsic activity of the elimination process has not yet reached maturation.
Haemodialysis removes eslicarbazepine acetate metabolites from plasma.
The pharmacokinetics and metabolism of eslicarbazepine acetate were evaluated in healthy subjects and moderately liver-impaired patients after multiple oral doses. Moderate hepatic impairment did not affect the pharmacokinetics of eslicarbazepine acetate. No dose adjustment is recommended in patients with mild to moderate liver impairment (see section 4.2). The pharmacokinetics of eslicarbazepine acetate has not been evaluated in patients with severe hepatic impairment.
Studies in healthy subjects and patients showed that pharmacokinetics of eslicarbazepine acetate were not affected by gender.
Similar to adults, eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of eslicarbazepine acetate usually remain below the limit of quantification, following oral administration. Eslicarbazepine Cmax is attained at 2 to 3 hours post-dose (tmax). Body weight was shown to have an effect on volume of distribution and clearance. Furthermore, a role of age independently of weight with regards to clearance of eslicarbazepine acetate could not be excluded, in particular for the youngest age group (2-6 years).
Population pharmacokinetics indicate that in the subgroup of children aged from 2 to 6 years, doses of 27.5 mg/kg/day and 40 mg/kg/day are required in order to achieve exposures that are equivalent to the therapeutic doses of 20 and 30 mg/kg/day in children above 6 years of age.
Population pharmacokinetics indicate that comparable eslicarbazepine exposure is observed between 20 and 30 mg/kg/day in children above 6 years old and adults with 800 and 1200 mg of eslicarbazepine acetate once-daily, respectively (see section 4.2).
Adverse reactions observed in animal studies occurred at exposure levels appreciably lower than the clinical exposure levels to eslicarbazepine (the principal and pharmacologically active metabolite of eslicarbazepine acetate). Safety margins based on comparative exposure have thus not been established.
Evidence of nephrotoxicity was observed in repeated dose-toxicity studies in the rat, but was not seen in studies in mice or dogs, and is consistent with an exacerbation of spontaneous chronic progressive nephropathy in this species.
Liver centrilobular hypertrophy was seen in repeated-dose toxicity studies in mice and rats and an increased incidence of liver tumours was observed in the carcinogenicity study in mice; these findings are consistent with an induction of hepatic microsomal enzymes, an effect which has not been observed in patients receiving eslicarbazepine acetate.
In repeat-dose studies in juvenile dogs, the toxicity profile was comparable to that observed in adult animals. In the 10-month study decreases in bone mineral content, bone area and/or bone mineral density in lumbar vertebrae and/or femur were observed in high-dose female animals at exposure levels lower than the clinical exposure levels to eslicarbazepine in children.
Genotoxicity studies with eslicarbazepine acetate indicate no special hazards for humans.
Impairment of fertility was observed in female rats; decreases in implantations and live embryos seen in the mouse fertility study may also indicate effects on female fertility, however, corpora lutea counts were not evaluated. Eslicarbazepine acetate was not teratogenic in the rat or rabbit, but did induce skeletal abnormalities in the mouse. Ossification delays, reduced foetal weights, an increase in minor skeletal and visceral anomalies were observed at maternal toxic doses in embryotoxicity studies in mice, rats and rabbits. A delay in the sexual development of the F1 generation was observed in peri/postnatal studies in mice and rats.
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