бривиак

Overdose

Symptoms

There is limited clinical experience with brivaracetam overdose in humans. Somnolence and dizziness have been reported in a healthy subject taking a single dose of 1,400 mg of brivaracetam.

Management of overdose

There is no specific antidote for overdose with brivaracetam. Treatment of an overdose should include general supportive measures. Since less than 10 % of brivaracetam is excreted in urine, haemodialysis is not expected to significantly enhance brivaracetam clearance.

Contraindications

Incompatibilities

Not applicable

Undesirable effects

Summary of the safety profile

In all controlled and uncontrolled trials in patients with epilepsy, 2,388 subjects have received brivaracetam, of whom 1,740 have been treated for > 6 months, 1,363 for > 12 months, 923 for > 24 months and 569 for > 60 months (5 years).

The most frequently reported adverse reactions (>10 %) with brivaracetam treatment were: somnolence (14.3 %) and dizziness (11.0 %). They were usually mild to moderate in intensity. Somnolence and fatigue (8.2 %) were reported at a higher incidence with increasing dose. The types of adverse reactions reported during the first 7 days of treatment were similar to those reported for the overall treatment period.

The discontinuation rate due to adverse reactions was 3.5 %, 3.4 % and 4.0 % for patients randomized to brivaracetam at respectively the dose of 50 mg/day, 100 mg/day and 200 mg/day and 1.7% for patients randomized to placebo. The adverse reactions most frequently resulting in discontinuation of brivaracetam therapy were dizziness (0.8 %) and convulsion (0.8 %).

Tabulated list of adverse reactions

In the table below, adverse reactions, which were identified based on review of the full brivaracetam clinical studies safety database, are listed by System Organ Class and frequency.

The frequencies are defined as follows: very common (>1/10), common (>1/100 to <1/10), uncommon (> 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Description of selected adverse reactions

Neutropenia has been reported in 0.5 % (6/1,099) brivaracetam patients and 0 % (0/459) placebo patients. Four of these subjects had decreased neutrophil counts at baseline, and experienced additional decrease in neutrophil counts after initiation of brivaracetam treatment. None of the 6 cases of neutropenia were severe, required any specific treatment or led to discontinuation of brivaracetam and none had associated infections.

Suicidal ideation has been reported in 0.3 % (3/1,099) brivaracetam patients and 0.7 % (3/459) placebo patients. In the short-term clinical studies of brivaracetam in epilepsy patients, there were no cases of completed suicide and suicide attempt, however both have been reported in open-label extension studies.

Reactions suggestive of immediate (Type I) hypersensitivity have been reported in a small number of brivaracetam patients (9/3022) during clinical development.

Open-label extension studies

In patients who were followed up in the open-label extension studies for up to 8 years, the safety profile was similar to that observed in the short-term, placebo-controlled studies.

Paediatric population

There are limited safety data from open-label studies in children from 1 month to <16 years of age. A total of 152 children (1 month to < 16 years of age) were treated with brivaracetam in a pharmacokinetic study and the related follow up study. From the limited available data, the most frequently reported TEAEs considered drug-related by the investigator were somnolence (10 %), decreased appetite (8 %), fatigue (5 %) and weight decreased (5 %).The safety profile appears to be consistent with that known in adults. No data are available on neurodevelopment. Currently, no clinical data are available in neonates.

Elderly

Of the 130 elderly subjects enrolled in the brivaracetam phase 2/3 development program (44 with epilepsy), 100 were 65-74 years of age and 30 were 75-84 years of age. The safety profile in elderly patients appears to be similar to that observed in younger adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:

UK

The Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Preclinical safety data

In safety pharmacology studies, the predominant effects were CNS related (mainly transient CNS depression and decreased spontaneous locomotor activity) seen at multiples (greater than 50 fold) of the pharmacologically active dose of brivaracetam, 2 mg/kg. Learning and memory function were not affected.

Findings not observed in clinical studies, but seen in the repeated-dose toxicology dog studies at exposure similar to the clinical plasma AUC, were hepatotoxic effects (mainly porphyria). However, toxicological data accumulated on brivaracetam and on a structurally-related compound indicate that the dog liver changes have developed through mechanisms not relevant for humans. No adverse liver changes were seen in rats and monkeys following chronic administration of brivaracetam at 5- and 42-fold the clinical AUC exposure. In monkeys, CNS signs (prostrate, loss of balance, clumsy movements) occurred at 64 fold the clinical Cmax, these effects being less apparent over time.

Genotoxicity studies have not detected any mutagenic or clastogenic activity. Carcinogenicity studies did not indicate any oncogenic potential in rats, whereas increased incidences of hepatocellular tumors in male mice are considered to result of a non-genotoxic, mode of action linked to a phenobarbitone-like liver enzyme induction, which is a known rodent specific phenomenon.

Brivaracetam did not affect male or female fertility and has demonstrated no teratogenic potential in either rat or rabbit. Embryotoxicity was observed in rabbits at a maternal toxic dose of brivaracetam with an exposure level 8-fold the clinical AUC exposure at the maximum recommended dose. In rats, brivaracetam was shown to readily cross the placenta and to be excreted in milk of lactating rats with concentrations similar to maternal plasma levels.

Brivaracetam did not show any dependence potential in rats.

Juvenile animals studies

In juvenile rats, brivaracetam exposure levels 6- to 15-fold the clinical AUC exposure at the maximum recommended dose induced developmental adverse effects (i.e. mortality, clinical signs, decreased body weight and lower brain weight). There were no adverse effects on CNS function, neuropathological and brain histopathological examination. In juvenile dogs, the brivaracetam-induced changes at the exposure level 6- fold the clinical AUC were similar to those observed in adult animals. There were no adverse effects in any of the standard developmental or maturation endpoints.

Therapeutic indications

БРИВИАК is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in adult and adolescent patients from 16 years of age with epilepsy.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX23

Mechanism of action

Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A), a transmembrane glycoprotein found at presynaptic level in neurons and in endocrine cells. Although the exact role of this protein remains to be elucidated it has been shown to modulate exocytosis of neurotransmitters. Binding to SV2A is believed to be the primary mechanism for brivaracetam anticonvulsant activity.

Clinical efficacy and safety

The efficacy of brivaracetam for the adjunctive therapy of partial-onset seizures (POS) was established in 3 randomized, double-blind, placebo-controlled, fixed-dose, multi-center studies in subjects 16 years of age and older. The daily dose of brivaracetam ranged from 5 to 200 mg/day across these studies. All studies had an 8-week baseline period followed by a 12-week treatment period with no up-titration. 1,558 patients received study drug of which 1,099 received brivaracetam. Study enrollment criteria required that patients have uncontrolled POS despite treatment with either 1 or 2 concomitant AEDs. Patients were required to have at least 8 POS during the baseline period. The primary endpoints in the phase 3 studies were the percent reduction in POS frequency over placebo and the 50 % responder rate based on 50 % reduction in POS frequency from baseline.

The most commonly taken AEDs at the time of study entry were carbamazepine (40.6 %), lamotrigine (25.2 %), valproate (20.5 %), oxcarbazepine (16.0 %), topiramate (13.5 %), phenytoin (10.2 %) and levetiracetam (9.8 %). The median baseline seizure frequency across the 3 studies was 9 seizures per 28 days. Patients had a mean duration of epilepsy of approximately 23 years.

The efficacy outcomes are summarized in Table 2. Overall, brivaracetam was efficacious for the adjunctive treatment of partial onset seizures in patients 16 years of age and older between 50 mg/day and 200 mg/day.

Table 2: Key Efficacy Outcomes for Partial Onset Seizure Frequency per 28 Days

n = randomised patients who received at least 1 dose of study medication

~ Dose not studied

* Statistically significant

(1) Approximately 20 % of the patients were on concomitant levetiracetam

(2) The primary outcome for N01252 did not achieve statistical significance based on the sequential testing procedure. The 100 mg/day dose was nominally significant.

In clinical studies, a reduction in seizure frequency over placebo was higher with the dose of 100 mg/day than with 50 mg/day. Apart from dose-dependent increases in incidences of somnolence and fatigue brivaracetam 50 mg/day and 100 mg/day had a similar safety profile including CNS-related AEs and with long-term use.

Figure 1 shows the percentage of patients (excluding patients with concomitant levetiracetam) by category of reduction from baseline in POS frequency per 28 days in all 3 studies. Patients with more than a 25 % increase in POS are shown at left as “worse”. Patients with an improvement in percent reduction in baseline POS frequency are shown in the 4 right-most categories. The percentages of patients with at least a 50 % reduction in seizure frequency were 20.3 %, 34.2 %, 39.5 %, and 37.8 % for placebo, 50 mg/day, 100 mg/day, and 200 mg/day, respectively.

Figure 1: Proportion of patients by category of seizure response for brivaracetam and placebo over 12 weeks across all three double-blind pivotal trials

In a pooled analysis of the three pivotal trials, no differences in efficacy (measured as 50 % responder rate) was observed within the dose range of 50 mg/day to 200 mg/day when brivaracetam is combined with inducing or non-inducing AEDs. In clinical studies 2.5 % (4/161), 5.1 % (17/332) and 4.0% (10/249) of the patients on brivaracetam 50 mg/day, 100 mg/day and 200 mg/day respectively became seizure free during the 12-week treatment period compared with 0.5 % (2/418) on placebo.

Improvement in the median percent reduction in seizure frequency per 28 days has been observed in patients with type IC seizure (secondary generalized tonic-clonic seizures) at baseline treated with brivaracetam (66.6 % (n=62), 61.2 % (n=100) and 82.1 % (n=75) of the patients on brivaracetam 50 mg/day, 100 mg/day and 200 mg/day respectively as compared to placebo 33.3 % (n=115)).

The efficacy of brivaracetam in monotherapy has not been established. Brivaracetam is not recommended for use in monotherapy.

Treatment with levetiracetam

In two phase 3 randomised placebo-controlled studies, levetiracetam was administered as concomitant AED in about 20 % of the patients. Although the number of subjects is limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently which may reflect competition at the SV2A binding site. No additional safety or tolerability concerns were observed.

In a third study, a pre-specified analysis demonstrated efficacy over placebo for 100 mg/day and 200 mg/day in patients with prior exposure to levetiracetam. The lower efficacy observed in these patients compared to the leveticacetam-naïve patients was likely due to the higher number of prior AEDs used and higher baseline seizure frequency.

Elderly (65 years of age and above)

The three pivotal double-blind placebo-controlled studies included 38 elderly patients aged between 65 and 80 years. Although data are limited, the efficacy was comparable to younger subjects.

Open label extension studies

Across all studies, 81.7 % of the patients who completed randomized studies were enrolled in the long-term open-label extension studies. From entry into the randomized studies,5.3 % of the subjects exposed to brivaracetam for 6 months (n=1,500) were seizure free compared to 4.6 % and 3.7 % for subjects exposed for 12 months (n=1,188) and 24 months (n=847), respectively. However, as a high proportion of subjects (26%) discontinued from the open-label studies due to lack of efficacy, a selection bias may have occurred, as the subjects who stayed in the study responded better than those who have terminated prematurely.

Paediatric population

The efficacy and tolerability of brivaracetam in paediatric patients have not been established. Brivaracetam was evaluated in these patients in short term open-label pharmacokinetic study and an ongoing open-label extension study, in 152 subjects from 1 month to 16 years of age.

The European Medicines Agency has deferred the obligation to submit the results of studies with brivaracetam in one or more subsets of the paediatric population in epilepsy with partial-onset seizures.

Pharmacokinetic properties

Brivaracetam film-coated tablets, oral solution and solution for intravenous injection show the same AUC, while the maximum plasma concentration is slightly higher after intravenous administration. Brivaracetam exhibits linear and time-independent pharmacokinetics with low intra- and inter-subject variability, and features complete absorption, very low protein binding, renal excretion following extensive biotransformation, and pharmacologically inactive metabolites.

Absorption

Brivaracetam is rapidly and completely absorbed after oral administration and the absolute bioavailablity is approximately 100 %. The median tmax for tablets taken without food is 1 hour (tmax range is 0.25 to 3 h).

Coadministration with a high-fat meal slowed down the absorption rate (median tmax 3 h) and decreased the maximum plasma concentration (37 % lower) of brivaracetam, while the extent of absorption remained unchanged.

Distribution

Brivaracetam is weakly bound (≤ 20 %) to plasma proteins. The volume of distribution is 0.5 L/kg, a value close to that of the total body water.

Due to its lipophylicity (Log P) brivaracetam has high cell membrane permeability.

Biotransformation

Brivaracetam is primarily metabolized by hydrolysis of the amide moiety to form the corresponding carboxylic acid (approximately 60 % the elimination), and secondarily by hydroxylation on the propyl side chain (approximately 30 % the elimination). The hydrolysis of the amide moiety leading to the carboxylic acid metabolite (34 % of the dose in urine) is supported by hepatic and extra-hepatic amidase. In vitro, the hydroxylation of brivaracetam is mediated primarily by CYP2C19. Both metabolites, are further metabolised forming a common hydroxylated acid formed predominantly by hydroxylation of the propyl side chain on the carboxylic acid metabolite (mainly by CYP2C9). In vivo, in human subjects possessing ineffective mutations of CYP2C19, production of the hydroxy metabolite is decreased 10-fold while brivaracetam itself is increased by 22 % or 42 % in individuals with one or both mutated alleles. The three metabolites are not pharmacologically active.

Elimination

Brivaracetam is eliminated primarily by metabolism and by excretion in the urine. More than 95 % of the dose, including metabolites, is excreted in the urine within 72 hours after intake. Less than 1 % of the dose is excreted in faeces and less than 10 % of brivaracetam is excreted unchanged in urine. The terminal plasma half-life (t1/2) is approximately 9 hours. The total plasma clearance in patients was estimated to 3.6 L/h.

Linearity

Pharmacokinetics is dose-proportional from 10 to at least 600 mg.

Interactions with medicinal products

Brivaracetam is cleared by multiple pathways including renal excretion, non-CYP-mediated hydrolysis and CYP-mediated oxidations. In vitro, brivaracetam is not a substrate of human P-glycoprotein (P-gp), multidrug resistance proteins (MRP) 1 and 2, and likely not organic anion transporter polypeptide 1B1 (OATP1B1) and OATP1B3.

In vitro assays showed that brivaracetam disposition should not be significantly affected by CYP (eg. CYP1A, 2C8, 2C9, 2D6 and 3A4) inhibitors.

In vitro, brivaracetam was not an inhibitor of the CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 3A4, or the transporters P-gp, BCRP, BSEP MRP2, MATE-K, MATE-1, OATP1B1, OATP1B3, OAT1 and OCT1 at clinically relevant concentrations. In vitro, brivaracetam did ot induce CYP1A2.

Pharmacokinetics in special patient groups

Elderly (65 years of age and above)

In a study in elderly subjects (65 to79 years old; with creatinine clearance 53 to 98 ml/min/1.73 m²) receiving brivaracetam 400 mg/day in bid administration, the plasma half-life of brivaracetam was 7.9 hours and 9.3 hours in the 65 to 75 and >75 years groups, respectively. The steady-state plasma clearance of brivaracetam was similar (0.76 ml/min/kg) to young healthy male subjects (0.83 ml/min/kg)..

Renal impairment

A study in subjects with severe renal impairment (creatinine clearance <30 ml/min/1.73 m² and not requiring dialysis) revealed that the plasma AUC of brivaracetam was moderately increased (+21 %) relative to healthy controls, while the AUC of the acid, hydroxy and hydroxyacid metabolites were increased 3-, 4-, and 21-fold, respectively. The renal clearance of these non active metabolites was decreased 10-fold. The hydroxyacid metabolite did not reveal any safety concerns in non clinical studies. Brivaracetam has not been studied in patients undergoing hemodialysis.

Hepatic impairment

A pharmacokinetic study in subjects with hepatic cirrhosis (Child-Pugh grades A, B, and C) showed similar increases in exposure to brivaracetam irrespective of disease severity (50 %, 57 % and 59 %), relative to matched healthy controls.

Paediatric population

In a pharmacokinetic study in 99 subjects aged 1 month to <16 years receiving brivaracetam oral solution, plasma concentrations were shown to be dose-proportional in all age groups. Population pharmacokinetics modeling indicated that the dose of 2.0 mg/kg twice a day provides the same steady-state average plasma concentration as in adults receiving 100 mg twice daily.

Body weight

A 40 % decrease in steady-state plasma concentration has been estimated across a body weight range from 46 kg to 115 kg. However, this is not considered to be a clinically relevant difference.

Gender

There are no clinically relevant differences in the pharmacokinetics of brivaracetam by gender.

Race

The pharmacokinetics of brivaracetam was not significantly affected by race (Caucasian, , Asian) in a population pharmacokinetic modeling from epilepsy patients. The number of patients with other ethnic background was limited.

Pharmacokinetic/pharmacodynamics relationship

The EC50 (brivaracetam plasma concentration corresponding to 50 % of the maximum effect) was estimated to be 0.57 mg/L. This plasma concentration is slightly above the median exposure obtained after brivaracetam doses of 50 mg/day. Further seizure frequency reduction is obtained by increasing the dose to 100 mg/day and reaches a plateau at 200 mg/day.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic drugs (AEDs), including brivaracetam, in several indications. A meta-analysis of randomized placebo-controlled trials of AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for brivaracetam.

Patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should any signs of suicidal ideation or behaviour emerge.

Hepatic impairment

There are limited clinical data on the use of brivaracetam in patients with pre-existing hepatic impairment. Dose adjustments are recommended for patients with hepatic impairment.

Excipients

Sodium content

Brivaracetam oral solution contains sodium. To be taken into consideration by patients on a controlled sodium diet.

Fructose intolerance

The oral solution contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Excipients which may cause intolerance

The oral solution contains methyl parahydroxybenzoate (E218), which may cause allergic reactions (possibly delayed).

Effects on ability to drive and use machines

Brivaracetam has minor or moderate influence on the ability to drive and use machines.

Due to possible differences in individual sensitivity some patients might experience somnolence, dizziness, and other central nervous system (CNS) related symptoms. Patients should be advised not to drive a car or to operate other potentially hazardous machines until they are familiar with the effects of brivaracetam on their ability to perform such activities.

Dosage (Posology) and method of administration

Posology

The recommended starting dose is either 50 mg/day or 100 mg/day based on physician assessment of required seizure reduction versus potential side effects. The dose should be administered in two equally divided doses, once in the morning and once in the evening. Based on individual patient response and tolerability, the dose may be adjusted in the dose range of 50 mg/day to 200 mg/day.

Missed doses

If patients missed one dose or more, it is recommended that they take a single dose as soon as they remember and take the following dose at the usual morning or evening time. This may avoid the brivaracetam plasma concentration falling below the efficacy level and prevent breakthrough seizures from occurring.

Discontinuation

If brivaracetam has to be discontinued it is recommended to withdraw it gradually by 50 mg/day on a weekly basis. After 1 week of treatment at 50 mg/day, a final week of treatment at the dose of 20 mg/day is recommended.

Special populations

Elderly (65 years of age and above)

No dose adjustment is needed in elderly patients.

The clinical experience in patients > 65 years is limited.

Renal impairment

No dose adjustment is needed in patients with impaired renal function. Brivaracetam is not recommended in end-stage renal disease patients undergoing dialysis due to lack of data.

Hepatic impairment

Exposure to brivaracetam was increased in patients with chronic liver disease. A 50 mg/day starting dose should be considered. A maximum daily dose of 150 mg administered in 2 divided doses is recommended for all stages of hepatic impairment.

Paediatric population

The safety and efficacy of brivaracetam in children aged less than 16 years have not yet been established.

Method of administration

Brivaracetam oral solution can be diluted in water or juice shortly before swallowing and may be taken with or without food. A nasogastric tube or a gastrostomy tube may be used when administering brivaracetam oral solution.

Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product, neat or diluted, or waste material should be disposed of in accordance with local requirements.