英文药名：Briviact（brivaracetam oral solution）

中文药名：布瓦西坦口服溶液

生产厂家：优时比制药
药品介绍
UCB的新一代抗癫痫药物Briviact（brivaracetam，布瓦西坦）将成为目前治疗癫痫发作患者提供一种新的选择
2016年1月26日，癫痫新药Briviact被欧盟批准。Briviact（brivaracetam）将为使用目前治疗药物后仍经历癫痫发作的患者提供一种新的治疗选择。
这款药物作为一种辅助治疗药物被欧盟委员会批准用于16岁及以上年龄的部分性癫痫发作（有或无继发全身性）患者。试验中，Brivaraceta与安慰剂相比明显降低了癫痫发作的频次，在使用优时比药物治疗的患者中，高达40%的患者其癫痫发作频次降低50%。
据优时比称，与目前的许多癫痫治疗药物不一样，Brivaracetam不需要剂量调整，所以患者可以完整的治疗剂量来帮助控制一天的癫痫发作。患者对于能够有效控制癫痫发作并有良好耐受性的癫痫药物有未满足的需求，Toledo表示，他是巴塞罗那Vall d'Hebron医院的一名癫痫专家，并参与了Briviact试验项目。
一款新的治疗药物从最初开始就不需要调整其治疗剂量，这代表了一个巨大的进步，可以进一步帮助到癫痫患者，他补充称。这款新的药物可与实触泡蛋白 2A 连接，  左乙拉西坦也以该蛋白为靶点，所以这种蛋白在癫痫中是一个成熟的治疗靶点。这款药物将以三种剂型上市，即薄膜衣片、口服溶液及一种注射液 / 输液。
Briviact 10mg/ml oral solution
1. Name of the medicinal product
Briviact 10 mg/ml oral solution
2. Qualitative and quantitative composition
Each ml contains 10 mg brivaracetam.
Excipient(s) with known effect:
Each ml of oral solution contains 239.8 mg sorbitol (E420), 1mg methyl parahydroxybenzoate (E218) and 1.16 mg sodium.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Oral solution
Slightly viscous, clear colourless to yellowish liquid.
4. Clinical particulars
4.1 Therapeutic indications
Briviact 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.
4.2 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 (see section 5.2).
The clinical experience in patients ≥ 65 years is limited.
Renal impairment
No dose adjustment is needed in patients with impaired renal function (see section 5.2). 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 impairement (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of brivaracetam in children aged less than 16 years have not yet been established.
Currently available data are described in section 4.8, 5.1, and 5.2 but no recommendation on a posology can be made.
Method of administration
Brivaracetam oral solution can be diluted in water or juice shortly before swallowing and may be taken with or without food (see section 5.2). A nasogastric tube or a gastrostomy tube may be used when administering brivaracetam oral solution.
4.3 Contraindications
Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients listed in section 6.1.
4.4 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 impairement (see section 4.2).
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).
4.5 Interaction with other medicinal products and other forms of interaction
Formal interaction studies have only been performed in adults.
Pharmacodynamic interactions
Concomitant treatment with levetiracetam
In the clinical studies, although the numbers were limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently. No additional safety or tolerability concern was observed (see section 5.1).
Interaction with alcohol
In a pharmacokinetic and pharmacodynamic interaction study between brivaracetam 200 mg single dose and ethanol 0.6 g/L continuous infusion in healthy subjects, there was no pharmacokinetic interaction but brivaracetam approximately doubled the effect of alcohol on psychomotor function, attention and memory. Intake of brivaracetam with alcohol is not recommended.
Pharmacokinetic interactions
Effects of other agents on the pharmacokinetics of brivaracetam
In vitro data suggest that brivaracetam has a low interaction potential. The main disposition pathway of brivaracetam is by CYP-independent hydrolysis. A second disposition pathway involves hydroxylation mediated by CYP2C19 (see section 5.2).
Brivaracetam plasma concentrations may increase when coadministered with CYP2C19 strong inhibitors (e.g. fluconazole, fluvoxamine), but the risk of a clinically relevant CYP2C19-mediated inteaction is considered to be low.
Rifampicin
In healthy subjects, coadministration with the strong enzyme inducer rifampicin (600 mg/day for 5 days), decreased brivaracetam area under the plasma concentration curve (AUC) by 45 %. Prescribers should consider adjusting the brivaracetam dose in patients starting or ending treatment with rifampicin.
Strong enzyme inducing AEDs
Brivaracetam plasma concentrations are decreased when coadministered with strong enzyme inducing AEDs (carbamazepine, phenobarbital, phenytoin) but no dose adjustment is required (see table 1).
Other enzyme inducers
Other strong enzyme inducers (such as St John´s wort (Hypericum perforatum)) may also decrease the systemic exposure of brivaracetam. Therefore, starting or ending treatment with St John's wort should be done with caution.
Effects of brivaracetam on other medicinal products
Brivaracetam given 50 or 150 mg/day did not affect the AUC of midazolam (metabolised by CYP3A4). The risk of clinically relevant CYP3A4 interactions is considered to be low.
In vitro studies have shown that brivaracetam exhibits little or no inhibition of CYP450 isoforms except for CYP2C19. Brivaracetam may increase plasma concentrations of medicinal products metabolised by CYP2C19 (e.g. lanzoprazole, omeprazole, diazepam). When tested in vitro brivaracetam did not induce CYP1A1/2 but induced CYP3A4 and CYP2B6. No CYP3A4 induction was found in vivo (see midazolam above). CYP2B6 induction has not been investigated in vivo and brivaracetam may decrease plasma concentrations of medicinal products metabolised by CYP2B6 (e.g. efavirenz). In vitro, interaction studies to determine the potential inhibitory effects on transporters concluded that there were no clinically relevant effects, except for OAT3. In vitro, brivaracetam inhibits OAT3 with a half maximal inhibitory concentration 42-fold higher than the Cmax at the highest clinical dose. Brivaracetam 200mg/day may increase plasma concentrations of medicinal products transported by OAT3.
Antiepileptic drugs
Potential interactions between brivaracetam (50 mg/day to 200 mg/day) and other AEDs were investigated in a pooled analysis of plasma drug concentrations from all phase 2-3 studies in a population pharmacokinetic analysis of placebo-controlled phase 2-3 studies, and in dedicated drug-drug interaction studies (for the following AEDs: carbamazepine, lamotrigine, phenytoin and topiramate). The effect of the interactions on the plasma concentration is summarised in table 1 (increase is indicated as “↑” and decrease as “↓”, area under the plasma concentration versus time curve as “AUC”, maximum observed concentration as Cmax).
Table 1: Pharmacokinetic interactions between brivaracetam and other AEDs

AED coadministered	Influence of AED on brivaracetam plasma concentration	Influence of brivaracetam on AED plasma concentration
Carbamazepine	AUC 29 % ↓ Cmax 13 % ↓ No dose adjustment required	Carbamazepine - None Carbamazepine-epoxide ↑ (See below) No dose adjustment required.
Clobazam	No data available	None
Clonazepam	No data available	None
Lacosamide	No data available	None
Lamotrigine	None	None
Levetiracetam	None	None
Oxcarbazepine	None	None (monohydroxy derivative, MHD)
Phenobarbital	AUC 19 % ↓ No dose adjustment required	None
Phenytoin	AUC 21 % ↓ No dose adjustment required	None a AUC 20% ↑ a Cmax 20% ↑
Pregabalin	No data available	None
Topiramate	None	None
Valproic acid	None	None
Zonisamide	No data available	None

a based on a study involving the administration of a supratherapeutic dose of 400 mg/day brivaracetam
Carbamazepine
Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. In controlled studies, the carbamazepine epoxide plasma concentration increased by a mean of 37 %, 62 % and 98 % with little variability at brivaracetam doses of 50 mg/day, 100 mg/day and 200 mg/day respectively. No safety risks were observed. There was no additive effect of brivaracetam and valproate on the AUC of carbamazepine epoxide.
Oral contraceptives
Co-administration of brivaracetam (100 mg/day) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) did not influence the pharmacokinetics of either substance. When brivaracetam was coadministered at a dose of 400 mg/day (twice the recommended maximum daily dose) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg), a reduction in estrogen and progestin AUCs of 27 % and 23 %, respectively, was observed without impact on suppression of ovulation. There was generally no change in the concentration-time profiles of the endogenous markers estradiol, progesterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG).
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Physicians should discuss family planning and contraception with women of childbearing potential taking brivaracetam (see Pregnancy).
If a woman decides to become pregnant, the use of brivaracetam should be carefully re-evaluated.
Pregnancy
Risk related to epilepsy and antiepileptic medicinal products in general
For all anti-epileptic drugs, it has been shown that in the offspring of treated women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3 % in the general population. In the treated population, an increase in malformations has been noted with polytherapy; however, the extent to which the treatment and/or the underlying condition is responsible has not been elucidated. Discontinuation of anti-epileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.
Risk related to brivaracetam
There is a limited amount of data from the use of brivaracetam in pregnant women. There is no data on placental transfer in humans, but brivaracetam was shown to readily cross the placenta in rats (see section 5.3). The potential risk for humans is unknown. Animal studies did not detect any teratogenic potential of brivaracetam (see section 5.3).
In clinical studies, brivaracetam was used as adjunctive therapy and when it was used with carbamazepine, it induced a dose-related increase in the concentration of the active metabolite, carbamazepine-epoxide (see section 4.5). There is insufficient data to determine the clinical significance of this effect in pregnancy.
As a precautionary measure, brivaracetam should not be used during pregnancy unless clinically necessary i.e. (if the benefit to the mother clearly outweighs the potential risk to the foetus).
Breast-feeding
It is unknown whether brivaracetam is excreted in human breast milk. Studies in rats have shown excretion of brivaracetam in breast milk (see section 5.3). A decision should be made whether to discontinue breastfeeding or to discontinue brivaracetam, taking into account the benefit of the medicinal product to the mother. In case of co-administration of brivaracetam and carbamazepine, the amount of carbamazepine-epoxide excreted in breast milk could increase. There is insufficient data to determine the clinical significance.
Fertility
No human data on the effect of brivaracetam on fertility are available. In rats, there was no effect on fertility with brivaracetam (see section 5.3).
4.7 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.
4.8 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 reaction 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.

System organ class	Frequency	Adverse reactions from clinical trials
Infections and infestations	Common	Influenza
Blood and lymphatic system disorders	Uncommon	Neutropenia
Metabolism and nutrition disorders	Common	Decreased appetite
Psychiatric disorders	Common	Depression, anxiety, insomnia, irritability
	Uncommon	Suicidal ideation, psychotic disorder, aggression, agitation
Nervous system disorders	Very common	Dizziness, somnolence
	Common	Convulsion, vertigo
Respiratory, thoracic and mediastinal disorders	Common	Upper respiratory tract infections, cough
Gastrointestinal disorders	Common	Nausea, vomiting, constipation
General disorders and administration site conditions	Common	Fatigue

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 (see section 4.4).
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
Pharmacovigilance Section
Irish Medicines Board
Kevin O'Malley House
Earlsfort Centre
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie
4.9 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 (see section 5.2).
5. Pharmacological properties
5.1 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

Study	Placebo	Brivaracetam * Statistically significant (p-value)
		50 mg/day	100 mg/day	200 mg/day
Study N01253(1)
	n= 96	n= 101
50 % Responder rate	16.7	32.7* (p=0.008)	~	~
Percent reduction over placebo (%)	NA	22.0* (p=0.0040)	~	~
Study N01252(1)
	n = 100	n = 99	n = 100
50 % Responder rate	20.0	27.3 (p=0.372)	36.0(2) (p=0.023)	~
Percent reduction over placebo (%)	NA	9.2 (p=0.0274)	20.5(2) (p=0.0097)	~
Study N01358
	n = 259		n = 252	n = 249
50% Responder rate	21.6	~	38.9 (p<0.001)	37.8 (p<0.001)
Percent reduction over placebo (%)	NA	~	22.8* (p<0.001)	23.2* (p<0.001)

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 (see section 4.2). 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 (see section 5.2).
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.
5.2 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. 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). (see section 4.2).
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 (see section 4.2).
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. (see section 4.2)
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.
5.3 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 exposuresimilar 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.
6. Pharmaceutical particulars
6.1 List of excipients
Sodium citrate
Citric acid anhydrous (for pH-adjustement)
Methyl parahydroxybenzoate (E218)
Carmellose sodium
Sucralose
Sorbitol liquid
Glycerol (E422)
Raspberry flavour (propylene glycol 90 % - 98 %)
Purified water.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years.
After first opening: 5 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
300 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a box also containing a 10 ml graduated oral dosing syringe (polypropylene, polyethylene) and an adaptor for the syringe (polyethylene).
6.6 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.
7. Marketing authorisation holder
UCB Pharma S.A.
Allée de la Recherche 60
B-1070 Bruxelles
Belgium
8. Marketing authorisation number(s)
EU/1/15/1073/021
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 14 January 2016
10. Date of revision of the text
14 January 2016
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.