BRIVIACT 10mg / ml injection / infusion solution medication leaflet

Briviact 10 mg/ml solution for injection/infusion

Each ml contains 10mg brivaracetam

Each 5 ml vial contains 50 mg brivaracetam

Each ml of solution for injection/infusion contains 3.8 mg sodium.

For the full list of excipients, see section 6.1.

Solution for injection/infusion (injection/infusion)

Clear, colourless, solution.

Briviact is indicated as adjunctive therapy in the treatment of partial onset seizures with or withoutsecondary generalisation in adults, adolescents and children from 2 years of age with epilepsy.

Brivaracetam solution for injection/infusion is an alternative route of administration for patients whenoral administration is temporarily not feasible. There is no experience with twice daily intravenousadministration of brivaracetam for a period longer than 4 days.

The recommended posology for adults, adolescents and children from 2 years of age is summarised inthe following table. The dose should be administered in two equally divided doses, approximately12 hours apart.

Recommended starting dose Recommended maintenance Therapeutic dose range*dose

Adolescents and children weighing 50 kg or more, and adults50 mg/day (or 100 mg/day)** 100 mg/day 50 - 200 mg/day

Adolescents and children weighing from 20 kg to less than 50 kg1 mg/kg/day (up to 2 mg/kg/day)** 2 mg/kg/day 1 - 4 mg/kg/day

Children weighing from 10 kg to less than 20 kg1 mg/kg/day (up to 2.5 mg/kg/day)** 2.5 mg/kg/day 1 - 5 mg/kg/day

* Based on individual patient response, the dose may be adjusted between this effective dose range.

** Based on physician’s assessment of need for seizure control

Brivaracetam may be initiated with either intravenous or oral administration. When converting fromoral to intravenous administration or vice versa, the total daily dose and frequency of administrationshould be maintained.

The recommended starting dose is either 50 mg/day or 100 mg/day based on physician’s assessment ofrequired seizure reduction versus potential side effects. Based on individual patient response andtolerability, the dose may be adjusted in the effective dose range of 50 mg/day to 200 mg/day.

Adolescents and children weighing 50 kg or more

The recommended starting dose is 50 mg/day. Brivaracetam may also be initiated at 100 mg/day basedon physician’s assessment of need for seizure control. The recommended maintenance dose is100 mg/day. Based on individual patient response, the dose may be adjusted in the effective doserange of 50 mg/day to 200 mg/day.

Adolescents and children weighing from 20 kg to less than 50 kg

The recommended starting dose is 1 mg/kg/day. Brivaracetam may also be initiated at doses up to2 mg/kg/day based on physician’s assessment of need for seizure control. The recommendedmaintenance dose is 2 mg/kg/day. Based on individual patient response, the dose may be adjusted inthe effective dose range of 1 mg/kg/day to 4 mg/kg/day.

Children weighing from 10 kg to less than 20 kg

The recommended starting dose is 1 mg/kg/day. Brivaracetam may also be initiated at doses up to2.5 mg/kg/day based on physician’s assessment of need for seizure control. The recommendedmaintenance dose is 2.5 mg/kg/day. Based on individual patient response, the dose may be adjusted inthe effective dose range of 1 mg/kg/day to 5 mg/kg/day.

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

For patients from 16 years of age, if brivaracetam has to be discontinued, it is recommended that thedose is reduced gradually by 50 mg/day on a weekly basis.

For patients below the age of 16 years, if brivaracetam has to be discontinued, it is recommended thatthe dose is reduced by a maximum of half the dose every week until a dose of 1 mg/kg/day (forpatients with a body weight less than 50 kg) or 50 mg/day (for patients with body weight of 50 kg ormore) is reached.

After 1 week of treatment at 50 mg/day, a final week of treatment at the dose of 20 mg/day isrecommended.

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.

No dose adjustment is needed in patients with impaired renal function (see section 5.2). Brivaracetamis not recommended in end-stage renal disease patients undergoing dialysis due to lack of data.

Based on data in adults, no dose adjustment is necessary in paediatric patients with impaired renalfunction. No clinical data are available in paediatric patients with renal impairment.

Exposure to brivaracetam was increased in adult patients with chronic liver disease.

In patients with hepatic impairment, the following adjusted doses, administered in 2 divided doses,approximately 12 hours apart, are recommended for all stages of hepatic impairment (see sections 4.4and 5.2). No clinical data are available in paediatric patients with hepatic impairment.

Age and body weight Recommended starting Recommendeddose maximum daily dose

Adolescents and children weighing 50 kg or 50 mg/day 150 mg/daymore, and adults

Adolescents and children weighing from 20 kg to 1 mg/kg/day 3 mg/kg/dayless than 50 kg

Children weighing from 10 kg to less than 20 kg 1 mg/kg/day 4 mg/kg/day

Paediatric patients less than 2 years of age

The efficacy of brivaracetam in paediatric patients aged less than 2 years has not yet been established.

Currently available data are described in section 4.8, 5.1, and 5.2 but no recommendation on aposology can be made.

- Intravenous bolus: brivaracetam may be administered as an intravenous bolus without dilution.

- Intravenous infusion: brivaracetam may be diluted in a compatible diluent and administered as a15-minute intravenous infusion (see section 6.6). This medicinal product must not be mixedwith other medicinal products.

Brivaracetam bolus injection or intravenous infusion has not been studied in acute conditions; e.g.status epilepticus and is therefore not recommended for such conditions.

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipientslisted in section 6.1.

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 clinical studiesof AEDs has also shown a small increased risk of suicidal ideation andbehaviour. The mechanism of this risk is not known and the available data do not exclude thepossibility of an increased risk for brivaracetam.

Patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatmentshould be considered. Patients (and caregivers of patients) should be advised to seek medical adviceshould any signs of suicidal ideation or behaviour emerge. See also section 4.8, paediatric data.

There are limited clinical data on the use of brivaracetam in patients with pre-existing hepaticimpairment. Dose adjustments are recommended for patients with hepatic impairment (see section4.2).

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), which canbe life-threatening or fatal, have been reported in association with brivaracetam treatment. At the timeof the prescription patients should be advised of the signs and symptoms and monitored closely forskin reactions. If signs and symptoms suggestive of these reactions appear, brivaracetam should bewithdrawn immediately and an alternative treatment should be considered.

This medicinal product contains 19.1 mg sodium per vial, equivalent to 1 % of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Formal interaction studies have only been performed in adults.

Concomitant treatment with levetiracetam

In the clinical studies, although the numbers were limited, there was no observed benefit ofbrivaracetam versus placebo in patients taking levetiracetam concurrently. No additional safety ortolerability concern was observed (see section 5.1).

Interaction with alcohol

In a pharmacokinetic and pharmacodynamic interaction study between brivaracetam 200 mg singledose and ethanol 0.6 g/L continuous infusion in healthy subjects, there was no pharmacokineticinteraction, but brivaracetam approximately doubled the effect of alcohol on psychomotor function,attention and memory. Intake of brivaracetam with alcohol is not recommended.

Effects of other medicinal products on the pharmacokinetics of brivaracetam

In vitro data suggest that brivaracetam has a low interaction potential. The main disposition pathwayof brivaracetam is by CYP-independent hydrolysis. A second disposition pathway involveshydroxylation mediated by CYP2C19 (see section 5.2).

Brivaracetam plasma concentrations may increase when coadministered with CYP2C19 stronginhibitors (e.g. fluconazole, fluvoxamine), but the risk of a clinically relevant CYP2C19-mediatedinteraction is considered to be low. Limited clinical data are available implying that coadministrationof cannabidiol may increase the plasma exposure of brivaracetam, possibly through CYP2C19inhibition, but the clinical relevance is uncertain.

In healthy subjects, coadministration with the strong enzyme inducer rifampicin (600 mg/day for5 days), decreased brivaracetam area under the plasma concentration curve (AUC) by45 %. Prescribers should consider adjusting the brivaracetam dose in patients starting or endingtreatment 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 thesystemic exposure of brivaracetam. Therefore, starting or ending treatment with St John’s wort shouldbe 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 isoformsexcept for CYP2C19. Brivaracetam may increase plasma concentrations of medicinal productsmetabolised by CYP2C19 (e.g. lanzoprazole, omeprazole, diazepam). When tested in vitrobrivaracetam did not induce CYP1A1/2 but induced CYP3A4 and CYP2B6. No CYP3A4 inductionwas found in vivo (see midazolam above). CYP2B6 induction has not been investigated in vivo andbrivaracetam may decrease plasma concentrations of medicinal products metabolised by CYP2B6(e.g. efavirenz). In vitro, interaction studies to determine the potential inhibitory effects on transportersconcluded that there were no clinically relevant effects, except for OAT3. In vitro, brivaracetaminhibits OAT3 with a half maximal inhibitory concentration 42-fold higher than the Cmax at the highestclinical dose. Brivaracetam 200mg/day may increase plasma concentrations of medicinal productstransported by OAT3.

Antiepileptic drugs

Potential interactions between brivaracetam (50 mg/day to 200 mg/day) and other AEDs wereinvestigated in a pooled analysis of plasma drug concentrations from all phase 2-3 studies in apopulation pharmacokinetic analysis of placebo-controlled phase 2-3 clinical studies, and in dedicateddrug-drug interaction studies (for the following AEDs: carbamazepine, lamotrigine, phenytoin andtopiramate). 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 timecurve as “AUC”, maximum observed concentration as Cmax).

Table 1: Pharmacokinetic interactions between brivaracetam and other AEDs

AED coadministered Influence of AED on brivaracetam Influence of brivaracetam onplasma concentration AED plasma concentration

Carbamazepine AUC 29 % ↓ Carbamazepine - None

Cmax 13 % ↓ Carbamazepine-epoxide ↑

No dose adjustment required (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 % ↓ None

No dose adjustment required

Phenytoin AUC 21 % ↓ None

No dose adjustment required a AUC 20% ↑a Cmax 20% ↑

Pregabalin No data available None

Topiramate None None

Valproic acid None None

Zonisamide No data available Nonea 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 increasedconcentration of carbamazepine epoxide, an active metabolite of carbamazepine. In controlled clinicalstudies, the carbamazepine epoxide plasma concentration increased by a mean of 37 %, 62 % and98 % with little variability at brivaracetam doses of 50 mg/day, 100 mg/day and 200 mg/dayrespectively. No safety risks were observed. There was no additive effect of brivaracetam andvalproate on the AUC of carbamazepine epoxide.

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 maximumdaily dose) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel(0.15 mg), a reduction in oestrogen and progestin AUCs of 27 % and 23 %, respectively, was observedwithout impact on suppression of ovulation. There was generally no change in the concentration-timeprofiles of the endogenous markers estradiol, progesterone, luteinizing hormone (LH), folliclestimulating hormone (FSH), and sex hormone binding globulin (SHBG).

Physicians should discuss family planning and contraception with women of childbearing potentialtaking brivaracetam (see Pregnancy).

If a woman decides to become pregnant, the use of brivaracetam should be carefully re-evaluated.

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, theprevalence of malformations is two to three times greater than the rate of approximately 3 % in thegeneral population. In the treated population, an increase in malformations has been noted withpolytherapy; however, the extent to which the treatment and/or the underlying condition is responsiblehas not been elucidated. Discontinuation of anti-epileptic treatments may result in exacerbation of thedisease 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 onplacental transfer in humans, but brivaracetam was shown to readily cross the placenta in rats (seesection 5.3). The potential risk for humans is unknown. Animal studies did not detect any teratogenicpotential of brivaracetam (see section 5.3).

In clinical studies, brivaracetam was used as adjunctive therapy and when it was used withcarbamazepine, 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 clinicalsignificance of this effect in pregnancy.

As a precautionary measure, brivaracetam should not be used during pregnancy unless clinicallynecessary i.e. (if the benefit to the mother clearly outweighs the potential risk to the foetus).

Brivaracetam is excreted in human breast milk. A decision should be made whether to discontinuebreastfeeding or to discontinue brivaracetam, taking into account the benefit of the medicinal productto the mother. In case of co-administration of brivaracetam and carbamazepine, the amount ofcarbamazepine-epoxide excreted in breast milk could increase. There is insufficient data to determinethe clinical significance.

No human data on the effect of brivaracetam on fertility are available. In rats, there was no effect onfertility with brivaracetam (see section 5.3).

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 todrive a car or to operate other potentially hazardous machines until they are familiar with the effects ofbrivaracetam on their ability to perform such activities.

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 andfatigue were reported at a higher incidence with increasing dose.

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

In the table below, adverse reactions, which were identified based on review of the three placebo-controlled, fixed-dose studies safety database in subjects ≥ 16 years of age and from post-marketingexperience, 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) and not known (frequency cannot be estimated from available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class Frequency Adverse reactions

Infections and Common Influenzainfestations

Blood and lymphatic Uncommon Neutropeniasystem disorders

Immune system disorders Uncommon Type I hypersensitivity

Metabolism and nutrition Common Decreased appetitedisorders

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 Common Upper respiratory tract infections, coughmediastinal disorders

Gastrointestinal Common Nausea, vomiting, constipationdisorders

Skin and subcutaneous Not known Stevens-Johnson syndrome(1)tissue disorders

General disorders and Common Fatigueadministration siteconditions(1) Adverse reactions reported in post marketing experience.

Neutropenia has been reported in 0.5 % (6/1,099) brivaracetam patients and 0 % (0/459) placebopatients. Four of these subjects had decreased neutrophil counts at baseline, and experiencedadditional decrease in neutrophil counts after initiation of brivaracetam treatment. None of the 6 casesof neutropenia were severe, required any specific treatment or led to discontinuation of brivaracetamand 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 nocases of completed suicide and suicide attempt, however both have been reported in open-labelextension studies(see section 4.4).

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

Adverse reactions with intravenous administration generally appeared to be similar to those observedwith oral administration. Intravenous administration was associated with infusion site pain in 2.8 % ofthe patients.

The safety profile of brivaracetam observed in children from 1 month of age was consistent with thesafety profile observed in adults. In the open label, uncontrolled, long-term studies suicidal ideationwas reported in 4.7 % of paediatric patients (assessed from 6 years onwards, more common inadolescents) compared with 2.4 % of adults and behavioural disorders were reported in 24.8 % ofpaediatric patients compared with 15.1 % of adults. The majority of events were mild or moderate inintensity, were non-serious, and did not lead to discontinuation of study drug. An additional adversereaction reported in children was psychomotor hyperactivity (4.7 %).

No specific pattern of adverse event (AE) was identified in children from 1◦month to < 4◦years of agewhen compared to older paediatric age groups. No significant safety information was identifiedindicating the increasing incidence of a particular AE in this age group. As data available in childrenyounger than 2 years of age is limited, brivaracetam is not indicated in this age range. Limited clinicaldata are available in neonates.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

The following adverse reactions were reported with brivaracetam overdose: nausea, vertigo, balancedisorder, anxiety, fatigue, irritability, aggression, insomnia, depression, and suicidal ideation in thepost-marketing experience. In general, the adverse reactions associated with brivaracetam overdosewere consistent with the known adverse reactions.

There is no specific antidote for overdose with brivaracetam. Treatment of an overdose should includegeneral supportive measures. Since less than 10 % of brivaracetam is excreted in urine, haemodialysisis not expected to significantly enhance brivaracetam clearance (see section 5.2).

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

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

The efficacy of brivaracetam for the adjunctive therapy of partial onset seizures (POS) was establishedin 3 randomized, double-blind, placebo-controlled, fixed-dose, multi-center clinical studies in subjects16 years of age and older. The daily dose of brivaracetam ranged from 5 to 200 mg/day across thesestudies. 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 enrollmentcriteria 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 endpointsin 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 %) andlevetiracetam (9.8 %). The median baseline seizure frequency across the 3 studies was 9 seizures per28 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 theadjunctive treatment of partial onset seizures in patients 16 years of age and older between 50 mg/dayand 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= 10150 % Responder rate 16.7 32.7* ~ ~(p=0.008)

Percent reduction over placebo (%) NA 22.0* ~ ~(p=0.004)

Study N01252(1)n = 100 n = 99 n = 10050 % Responder rate 20.0 27.3 36.0(2) ~(p=0.372) (p=0.023)

Percent reduction over placebo (%) NA 9.2 20.5(2) ~(p=0.274) (p=0.010)

Study N01358n = 259 n = 252 n = 24950% Responder rate 21.6 ~ 38.9* 37.8*(p<0.001) (p<0.001)

Percent reduction over placebo (%) NA ~ 22.8* 23.2*(p<0.001) (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 sequentialtesting procedure, The 100 mg/day dose was nominally significant.

In clinical studies, a reduction in seizure frequency over placebo was higher with the dose of100 mg/day than with 50 mg/day. Apart from dose-dependent increases in incidences of somnolenceand 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) bycategory of reduction from baseline in POS frequency per 28 days in all 3 studies. Patients with morethan a 25 % increase in POS are shown at left as “worse”. Patients with an improvement in percentreduction in baseline POS frequency are shown in the 4 right-most categories. The percentages ofpatients 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 over12 weeks across all three double-blind pivotal clinical studies

In a pooled analysis of the three pivotal clinical studies, 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 iscombined with inducing or non-inducing AEDs. In clinical studies 2.5 % (4/161), 5.1 % (17/332) and4.0% (10/249) of the patients on brivaracetam 50 mg/day, 100 mg/day and 200 mg/day respectivelybecame 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 inpatients with type IC seizure (secondary generalized tonic-clonic seizures) at baseline treated withbrivaracetam (66.6 % (n=62), 61.2 % (n=100) and 82.1 % (n=75) of the patients on brivaracetam50 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 notrecommended for use in monotherapy.

Treatment with levetiracetam

In two phase 3 randomised placebo-controlled clinical studies, levetiracetam was administered asconcomitant AED in about 20 % of the patients. Although the number of subjects is limited, there wasno observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrentlywhich may reflect competition at the SV2A binding site. No additional safety or tolerability concernswere observed.

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

Elderly (65 years of age and above)

The three pivotal double-blind placebo-controlled clinical studies included 38 elderly patients agedbetween 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 thelong-term open-label extension studies. From entry into the randomized studies,5.3 % of the subjectsexposed to brivaracetam for 6 months (n=1,500) were seizure free compared to 4.6 % and 3.7 % forsubjects exposed for 12 months (n=1,188) and 24 months (n=847), respectively. However, as a highproportion of subjects (26%) discontinued from the open-label studies due to lack of efficacy, aselection bias may have occurred, as the subjects who stayed in the study responded better than thosewho have terminated prematurely.

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

In children aged 2 years and older, partial onset seizures have a similar pathophysiology to those inadolescents and adults. Experience with epilepsy medicines suggests that the results of efficacy studiesperformed in adults can be extrapolated to children down to the age of 2 years provided the paediatricdose adaptations are established and safety has been demonstrated (see sections 5.2 and 4.8). Doses inpatients from 2 years of age were defined by weight-based dose adaptations which have beenestablished to achieve similar plasma concentrations to the ones observed in adults taking efficaciousdoses (section 5.2).

A long-term, uncontrolled, open-label safety study included children (from 1 month of age to less than16 years) who continued treatment after completing the PK study (see section 5.2), children whocontinued treatment after completing the i.v. (intravenous) safety study and children directly enrolledinto the safety study. Children who directly enrolled received a brivaracetam starting dose of1 mg/kg/day and depending on response and tolerability, the dose was increased up to 5 mg/kg/day bydoubling the dose at weekly intervals. No child received a dose greater than 200 mg/day. For childrenweighing 50 kg or greater the brivaracetam starting dose was 50 mg/day and depending on responseand tolerability, the dose was increased up to a maximum of 200 mg/day by weekly increments of50 mg/day.

From the pooled open-label safety and PK studies in adjunctive therapy, 186 children with POS in theage range of 1 month < 16 years of age have received brivaracetam, of whom 149 have been treatedfor ≥ 3 months, 138 for ≥ 6 months, 123 for ≥ 12 months, 107 for ≥ 24 months, and 90 for≥ 36 months.

The European Medicines Agency has deferred the obligation to submit the results of studies withbrivaracetam in one or more subsets of the paediatric population in epilepsy with partial onset seizures(see section 4.2 for information on paediatric use).

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-subjectvariability, and features complete absorption, very low protein binding, renal excretion followingextensive biotransformation, and pharmacologically inactive metabolites.

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

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

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

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

Brivaracetam is primarily metabolized by hydrolysis of the amide moiety to form the correspondingcarboxylic acid (approximately 60 % the elimination), and secondarily by hydroxylation on the propylside chain (approximately 30 % the elimination). The hydrolysis of the amide moiety leading to thecarboxylic acid metabolite (34 % of the dose in urine) is supported by hepatic and extra-hepaticamidase. In vitro, the hydroxylation of brivaracetam is mediated primarily by CYP2C19. Bothmetabolites, are further metabolised forming a common hydroxylated acid formed predominantly byhydroxylation 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 hydroxymetabolite is decreased 10-fold while brivaracetam itself is increased by 22 % or 42 % in individualswith one or both mutated alleles. The three metabolites are not pharmacologically active.

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

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

Brivaracetam is cleared by multiple pathways including renal excretion, non-CYP-mediatedhydrolysis 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 aniontransporter polypeptide 1B1 (OATP1B1) and OATP1B3.

In vitro assays showed that brivaracetam disposition should not be significantly affected by CYP (eg.

CYP1A, CYP2C8, CYP2C9, CYP2D6 and CYP3A4) inhibitors.

In vitro, brivaracetam was not an inhibitor of the CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,

CYP2D6, CYP3A4, 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 notinduce CYP1A2.

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 was7.9 hours and 9.3 hours in the 65 to 75 and >75 years groups, respectively. The steady-state plasmaclearance of brivaracetam was similar (0.76 ml/min/kg) to young healthy male subjects(0.83 ml/min/kg). (see section 4.2).

A study in subjects with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m² and notrequiring 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 wereincreased 3-, 4-, and 21-fold, respectively. The renal clearance of these non active metabolites wasdecreased 10-fold. The hydroxyacid metabolite did not reveal any safety concerns in non clinicalstudies. Brivaracetam has not been studied in patients undergoing hemodialysis (see section 4.2).

A pharmacokinetic study in subjects with hepatic cirrhosis (Child-Pugh classes A, B, and C) showedsimilar increases in exposure to brivaracetam irrespective of disease severity (50 %, 57 % and 59 %),relative to matched healthy controls. (see section 4.2).

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

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

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

Pharmacokinetic/pharmacodynamics relationship

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

In a pharmacokinetic study with a 3-week evaluation period and weekly fixed 3-step up-titration usingthe brivaracetam oral solution, 99 subjects aged 1 month to < 16 years were evaluated. Brivaracetamwas administered at weekly increasing doses of approximately 1 mg/kg/day, 2 mg/kg/day, and4 mg/kg/day. All doses were adjusted by body weight, and did not exceed a maximum of 50 mg/day,100 mg/day, and 200 mg/day. At the end of the evaluation period, subjects may have been eligible forentry into a long-term follow-up study continuing on their last received dose (see section 4.8). Plasmaconcentrations were shown to be dose-proportional in all age groups. Population pharmacokineticsmodeling was performed based on sparse plasma concentration data collected in the 3-week PK studyand the ongoing long-term follow-up study. 232 paediatric patients with epilepsy, aged 2 months to17 years, were included in the analysis. The analysis indicated that doses of 5.0 (body weights 10-20 kg) and 4.0 mg/kg/day (body weights 20-50 kg) provide the same steady-state average plasmaconcentration as in adults receiving 200 mg/day. The estimated plasma clearance was 0.96 L/h, 1.61

L/h, 2.18 L/h and 3.19 L/h for children weighing 10 kg, 20 kg, 30 kg and 50 kg, respectively. Incomparison, plasma clearance was estimated at 3.58 L/h in adult patients (70 kg body weight).

Currently, no clinical data are available in neonates.

In safety pharmacology studies, the predominant effects were CNS related (mainly transient CNSdepression and decreased spontaneous locomotor activity) seen at multiples (greater than 50 fold) ofthe pharmacologically active dose of brivaracetam, 2 mg/kg. Learning and memory function were notaffected.

Findings not observed in clinical studies, but seen in the repeated-dose toxicology dog studies atexposure similar to the clinical plasma AUC, were hepatotoxic effects (mainly porphyria). However,toxicological data accumulated on brivaracetam and on a structurally-related compound indicate thatthe dog liver changes have developed through mechanisms not relevant for humans. No adverse liverchanges 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, clumsymovements) 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 studiesdid not indicate any oncogenic potential in rats, whereas increased incidences of hepatocellular tumorsin 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 ineither rat or rabbit. Embryotoxicity was observed in rabbits at a maternal toxic dose of brivaracetamwith 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 withconcentrations similar to maternal plasma levels.

Brivaracetam did not show any dependence potential in rats.

In juvenile rats, brivaracetam exposure levels 6- to 15-fold the clinical AUC exposure at the maximumrecommended dose induced developmental adverse effects (i.e. mortality, clinical signs, decreasedbody weight and lower brain weight). There were no adverse effects on CNS function,neuropathological and brain histopathological examination. In juvenile dogs, the brivaracetam-inducedchanges 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.

Sodium acetate (trihydrate)

Acetic acid, glacial (for pH-adjustment)

Sodium chloride

Water for injections

This medicinal product must not be mixed with other medicinal products.

4 years.

Following dilution, brivaracetam solution for injection/infusion was found to be physically compatibleand chemically stable when mixed with the diluents listed in the section 6.6 for 24 hours and stored in

PVC or polyolefin bags at temperature up to 25°C. From a microbiological point of view, the productshould be used immediately after dilution. If not used immediately, in-use storage time and conditionsprior to use are the responsibility of the user.

This medicinal product does not require any special storage conditions.

For storage conditions after dilution of the medicinal product, see section 6.3.

6 ml nominal capacity glass vials (type I) with siliconized bromobutyl rubber stoppers and sealed withan aluminium/polypropylene tear off cap. Each single use vial contains an extractable volume of notless than 5 ml of solution for injection/infusion.

Each carton contains 10 vials.

This medicinal product is for single use only, any unused solution should be discarded.

Product with particulate matter or discoloration should not be used.

Brivaracetam solution for injection/infusion is physically compatible and chemically stable whenmixed with the following diluents

Diluents

- Sodium chloride 9 mg/ml (0.9 %) solution for injection

- Glucose 50 mg/ml (5 %) solution for injection

- Lactated Ringer’s solution for injection.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

UCB Pharma S.A.

Allée de la Recherche 60

B-1070 Bruxelles

Belgium

EU/1/15/1073/022

Date of first authorisation: 14 January 2016

Date of latest renewal: 9 October 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.