ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

Briviact 10 mg film-coated tablets

Briviact 25 mg film-coated tablets
Briviact 50 mg film-coated tablets
Briviact 75 mg film-coated tablets
Briviact 100 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Briviact 10 mg film-coated tablets

Each film-coated tablet contains 10 mg brivaracetam.

Briviact 25 mg film-coated tablets

Each film-coated tablet contains 25 mg brivaracetam.

Briviact 50 mg film-coated tablets

Each film-coated tablet contains 50 mg brivaracetam.

Briviact 75 mg film-coated tablets

Each film-coated tablet contains 75 mg brivaracetam.

Briviact 100 mg film-coated tablets

Each film-coated tablet contains 100 mg brivaracetam.

Excipient(s) with known effect:

Briviact 10 mg film-coated tablets

Each 10 mg film-coated tablet contains 88 mg lactose.

Briviact 25 mg film-coated tablets

Each 25 mg film-coated tablet contains 94 mg lactose.

Briviact 50 mg film-coated tablets

Each 50 mg film-coated tablet contains 189 mg lactose.

Briviact 75 mg film-coated tablets

Each 75 mg film-coated tablet contains 283 mg lactose.

Briviact 100 mg film-coated tablets

Each 100 mg film-coated tablet contains 377 mg lactose.

For the full list of excipients, see section 6.1.

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3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Briviact 10 mg film-coated tablets

White to off-white, round film-coated tablets of 6.5 mm in diameter and debossed with ‘u10’ on one
side.

Briviact 25 mg film-coated tablets

Grey, oval film-coated tablets with dimensions of 8.9 mm x 5.0 mm and debossed with ‘u25’ on one
side.

Briviact 50 mg film-coated tablets

Yellow, oval film-coated tablets with dimensions of 11.7 mm x 6.6 mm and debossed with ‘u50’ on
one side.

Briviact 75 mg film-coated tablets

Purple, oval film-coated tablets with dimensions of 13.0 mm x 7.3 mm debossed with ‘u75’ on one
side.

Briviact 100 mg film-coated tablets

Green-grey, oval film-coated tablets with dimensions of 14.5 mm x 8.1 mm and debossed with ‘u100’
on one side.

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 adults, adolescents and children from 2 years of age with epilepsy.

4.2 Posology and method of administration

Posology

The physician should prescribe the most appropriate formulation and strength according to weight and
dose.

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

Recommended starting dose Recommended maintenance Therapeutic dose range*

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

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

1 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 kg

1 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 within this effective dose range.
** Based on physician’s assessment of need for seizure control

Adults
The recommended starting dose is either 50 mg/day or 100 mg/day based on physician’s assessment of
required seizure reduction versus potential side effects. Based on individual patient response and
tolerability, 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 based
on physician’s assessment of need for seizure control. The recommended maintenance dose is
100 mg/day. Based on individual patient response, the dose may be adjusted in the effective dose
range 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 to
2 mg/kg/day based on physician’s assessment of need for seizure control. The recommended
maintenance dose is 2 mg/kg/day. Based on individual patient response, the dose may be adjusted in
the 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 to
2.5 mg/kg/day based on physician’s assessment of need for seizure control. The recommended
maintenance dose is 2.5 mg/kg/day. Based on individual patient response, the dose may be adjusted in
the effective dose range of 1 mg/kg/day to 5 mg/kg/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
For patients from 16 years of age, if brivaracetam has to be discontinued, it is recommended that the
dose 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 that
the dose is reduced by a maximum of half the dose every week until a dose of 1 mg/kg/day (for
patients with a body weight less than 50 kg) or 50 mg/day (for patients with body weight of 50 kg or
more) is reached.
After 1 week of treatment at 50 mg/day, a final week of treatment at the dose of 20 mg/day is
recommended.

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

Hepatic 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 4.4
and 5.2). No clinical data are available in paediatric patients with hepatic impairment.

Age and body weight Recommended starting Recommended

dose maximum daily dose
Adolescents and children weighing 50 kg or 50 mg/day 150 mg/day
more, and adults
Adolescents and children weighing from 20 kg to 1 mg/kg/day 3 mg/kg/day
less 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 a
posology can be made.

Method of administration

Brivaracetam film-coated tablets must be taken orally and swallowed in whole with liquid and may be
taken with or without food (see section 5.2). Patients not being able to swallow tablets in whole or
patients for whom the dose can not be met with the use of whole tablets should use Briviact 10 mg/ml
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 clinical studies 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. See also section 4.8, paediatric data.

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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 (see section
4.2).

Severe cutaneous adverse reactions (SCARs)

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

Excipients

Lactose intolerance
Brivaracetam film-coated tablets contain lactose. Patients with rare hereditary problems of galactose
intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium content
Brivaracetam film-coated tablets contain less than 1 mmol sodium (23mg) per tablet, that is to say
essentially ‘sodium free’.

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 medicinal products 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
interaction is considered to be low. Limited clinical data are available implying that coadministration
of cannabidiol may increase the plasma exposure of brivaracetam, possibly through CYP2C19
inhibition, but the clinical relevance is uncertain.

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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 clinical 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).

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Table 1: Pharmacokinetic interactions between brivaracetam and other AEDs
AED coadministered Influence of AED on brivaracetam Influence of brivaracetam on
plasma 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 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 clinical
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 oestrogen 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.

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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

Brivaracetam is excreted in human breast milk. 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

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 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 randomized
to brivaracetam at respectively the dose of 50 mg/day, 100 mg/day and 200 mg/day and 1.7 % for

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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 three placebo-
controlled, fixed-dose studies safety database in subjects ≥ 16 years of age and from post-marketing
experience, 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 Influenza
infestations
Blood and lymphatic Uncommon Neutropenia
system disorders
Immune system disorders Uncommon Type I hypersensitivity
Metabolism and nutrition Common Decreased appetite
disorders
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, cough
mediastinal disorders
Gastrointestinal Common Nausea, vomiting, constipation
disorders
Skin and subcutaneous Not known Stevens-Johnson syndrome(1)
tissue disorders
General disorders and Common Fatigue
administration site
conditions
(1)
Adverse reactions reported in post marketing experience.

Description of selected adverse reactions

Neutropenia has been reported in 0.5 % (6/1099) 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 % (3/1099) 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).

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

Paediatric population

The safety profile of brivaracetam observed in children from 1 month of age was consistent with the
safety profile observed in adults. In the open label, uncontrolled, long-term studies suicidal ideation
was reported in 4.7 % of paediatric patients assessed from 6 years onwards (more common in
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adolescents) compared with 2.4 % of adults and behavioural disorders were reported in 24.8 % of
paediatric patients compared with 15.1 % of adults. The majority of events were mild or moderate in
intensity, were non-serious, and did not lead to discontinuation of study drug. An additional adverse
reaction 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 age
when compared to older paediatric age groups. No significant safety information was identified
indicating the increasing incidence of a particular AE in this age group. As data available in children
younger than 2 years of age is limited, brivaracetam is not indicated in this age range. Limited 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
listed in Appendix V.

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

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.

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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 clinical 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=0.004)

Study N01252(1)
n = 100 n = 99 n = 100
50 % 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 N01358
n = 259 n = 252 n = 249
50% 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 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
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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 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 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 clinical 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 clinical studies included 38 elderly patients aged
between 65 and 80 years. Although data are limited, the efficacy was comparable to younger subjects.

13
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.
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

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

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

From the pooled open-label safety and PK studies in adjunctive therapy, 186 children with POS in the
age range of 1 month < 16 years of age have received brivaracetam, of whom 149 have been treated
for ≥ 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 with
brivaracetam in one or more subsets of the paediatric population in epilepsy with partial onset seizures
(see section 4.2 for information on paediatric use).

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.

14
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, 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 not
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).

15
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 classes 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).

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.

Paediatric population

In a pharmacokinetic study with a 3-week evaluation period and weekly fixed 3-step up-titration using
the brivaracetam oral solution, 99 subjects aged 1 month to < 16 years were evaluated. Brivaracetam
was administered at weekly increasing doses of approximately 1 mg/kg/day, 2 mg/kg/day, and
4 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 for
entry into a long-term follow-up study continuing on their last received dose (see section 4.8). Plasma
concentrations were shown to be dose-proportional in all age groups. Population pharmacokinetics
modeling was performed based on sparse plasma concentration data collected in the 3-week PK study
and the ongoing long-term follow-up study. 232 paediatric patients with epilepsy, aged 2 months to
17 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 plasma
concentration 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. In
comparison, plasma clearance was estimated at 3.58 L/h in adult patients (70 kg body weight).
Currently, no clinical data are available in neonates.

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.

16
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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core

Croscarmellose sodium,
Lactose monohydrate
Betadex
Lactose anhydrous
Magnesium stearate

Coating

Briviact 10 mg film-coated tablets

Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol (3350)
Talc

Briviact 25 mg film-coated tablets

Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol (3350)
Talc
Iron oxide yellow (E172)

17
Iron oxide black (E172)

Briviact 50 mg film-coated tablets

Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol (3350)
Talc
Iron oxide yellow (E172)
Iron oxide red (E172)

Briviact 75 mg film-coated tablets

Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol (3350)
Talc
Iron oxide yellow (E172)
Iron oxide red (E172)
Iron oxide black (E172)

Briviact 100 mg film-coated tablets

Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol (3350)
Talc
Iron oxide yellow (E172)
Iron oxide black (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Briviact 10 mg film-coated tablets

• Packs of 14, 56 film-coated tablets and multipacks containing 168 (3 packs of 56) film-coated
tablets in PVC/PCTFE - Aluminium blisters
• Packs of 14 x 1 and 100 x 1 film-coated tablets in PVC/PCTFE - Aluminium blisters

Briviact 25 mg film-coated tablets

• Packs of 14, 56 film-coated tablets and multipacks containing 168 (3 packs of 56) film-coated
tablets in PVC/PCTFE - Aluminium blisters
• Packs of 14 x 1 and 100 x 1 film-coated tablets in PVC/PCTFE - Aluminium blisters

Briviact 50 mg film-coated tablets

• Packs of 14, 56 film-coated tablets and multipacks containing 168 (3 packs of 56) film-coated
tablets in PVC/PCTFE - Aluminium blisters
• Packs of 14 x 1 and 100 x 1 film-coated tablets in PVC/PCTFE - Aluminium blisters

18
Briviact 75 mg film-coated tablets
• Packs of 14, 56 film-coated tablets and multipacks containing 168 (3 packs of 56) film-coated
tablets in PVC/PCTFE - Aluminium blisters
• Packs of 14 x 1 and 100 x 1 film-coated tablets in PVC/PCTFE - Aluminium blisters

Briviact 100 mg film-coated tablets

• Packs of 14, 56 film-coated tablets and multipacks containing 168 (3 packs of 56) film-coated
tablets in PVC/PCTFE - Aluminium blisters
• Packs of 14 x 1 and 100 x 1 film-coated tablets in PVC/PCTFE - Aluminium blisters

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

Any unused medicinal product 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/1/15/1073/001
EU/1/15/1073/002
EU/1/15/1073/003
EU/1/15/1073/004
EU/1/15/1073/005
EU/1/15/1073/006
EU/1/15/1073/007
EU/1/15/1073/008
EU/1/15/1073/009
EU/1/15/1073/010
EU/1/15/1073/011
EU/1/15/1073/012
EU/1/15/1073/013
EU/1/15/1073/014
EU/1/15/1073/015
EU/1/15/1073/016
EU/1/15/1073/017
EU/1/15/1073/018
EU/1/15/1073/019
EU/1/15/1073/020
EU/1/15/1073/023
EU/1/15/1073/024
EU/1/15/1073/025
EU/1/15/1073/026
EU/1/15/1073/027

19
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 January 2016

Date of latest renewal: 9 October 2020

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

20
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 168 mg sorbitol (E420), 1 mg methyl parahydroxybenzoate (E218)
and maximum 5.5 mg propylene glycol (E1520).

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 adults, adolescents and children from 2 years of age with epilepsy.

4.2 Posology and method of administration

Posology

The physician should prescribe the most appropriate formulation and strength according to weight and
dose. It is recommended to parent and care giver to administer Briviact oral solution with the
measuring device (10 ml or 5 ml oral dosing syringe) provided in the carton box.

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

Recommended starting dose Recommended maintenance Therapeutic dose range*

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

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

1 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 kg

1 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 within this effective dose range.
** Based on physician’s assessment of need for seizure control

21
Adults
The recommended starting dose is either 50 mg/day or 100 mg/day based on physician’s assessment of
required seizure reduction versus potential side effects. Based on individual patient response and
tolerability, 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 based
on physician’s assessment of need for seizure control. The recommended maintenance dose is
100 mg/day. Based on individual patient response, the dose may be adjusted in the effective dose
range 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 1mg/kg/day. Brivaracetam may also be initiated at doses up to
2 mg/kg/day based on physician’s assessment of need for seizure control. The recommended
maintenance dose is 2 mg/kg/day. Based on individual patient response, the dose may be adjusted in
the 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 to
2.5 mg/kg/day based on physician’s assessment of need for seizure control. The recommended
maintenance dose is 2.5 mg/kg/day. Based on individual patient response, the dose may be adjusted in
the effective dose range of 1 mg/kg/day to 5 mg/kg/day.

The dose per intake for each patient should be calculated using the following formula:

Volume per administration (ml) = [weight (kg) x daily dose (mg/kg/day) ] x 0.05

Briviact oral solution is provided with:

- a 5 ml syringe (blue graduation marks) graduated every 0.1 ml increments (each 0.1 ml
increment corresponds to 1 mg of brivaracetam). Additional graduations at 0.25 ml and
0.75 ml starting at 0.25 ml up to 5 ml are shown.
- a 10 ml syringe (black graduation marks) graduated in 0.25 ml increments (each 0.25 ml
increment corresponds to 2.5 mg of brivaracetam).

The physician should instruct the patient on the appropriate syringe to use.

If the calculated dose per intake is 5 mg (0.5 ml) or more and up to 50 mg (5 ml), the 5 ml oral syringe
should be used.
If the calculated dose per intake is more than 50 mg (5 ml), the larger 10 ml oral syringe should be
used.
The calculated dose should be rounded to the nearest graduated increment. If the calculated dose is
equidistant between two graduated increments, the larger graduated increment should be used.

The table below provides examples of volumes of oral solution per intake depending on prescribed
dose and body weight. The precise volume of oral solution is to be calculated according to the exact
body weight of the child.
Note that the dosage is limited to the available graduations of the syringes. For example, for a patient
that needs a dose of 2.15 ml, the applied volume needs to be rounded up to 2.2 ml as the 5 ml syringe
can only deliver 2.1 ml or 2.2 ml. Likewise a volume of 1.13 ml would need to be rounded down to a
delivered volume of 1.1 ml.

22
 Volumes of oral solution to be taken per administration for adolescents and
children weighing 50 kg or more, and adults
Prescribed
For a dose of For a dose of For a dose of For a dose of
dose
50 mg/day 100 mg/day 150 mg/day 200 mg/day

25 mg/intake 50 mg/intake 75 mg/intake 100 mg/intake

Recommended
5 ml 10 ml
syringe
Weight
Volume administered Volume administered
50 kg or more 2.5 ml 5 ml 7.5 ml 10 ml
(25 mg) (50 mg) (75 mg) (100 mg)

Volumes of oral solution to be taken per administration for adolescents and

children weighing from 20 kg to less than 50 kg
Prescribed
For a dose of For a dose of For a dose of For a dose of
dose
1 mg/kg/day 2 mg/kg/day 3 mg/kg/day 4 mg/kg/day

0.05 ml/kg/intake 0.1 ml/kg/intake 0.15 ml/kg/intake 0.2 ml/kg/intake

(corresponding to (corresponding to (corresponding to (corresponding to

0.5 mg/kg/intake) 1 mg/kg/intake) 1.5 mg/kg/intake) 2 mg/kg/intake)
Recommended
5 ml 5 ml or 10 ml*
syringe
Weight
Volume administered Volume administered
20 kg 1 ml 2 ml 3 ml 4 ml
(10 mg) (20 mg) (30 mg) (40 mg)
25 kg 1.25 ml 2.5 ml 3.75 ml 5 ml
(12.5 mg) (25 mg) (37.5 mg) (50 mg)
30 kg 1.5 ml 3 ml 4.5 ml 6 ml*
(15 mg) (30 mg) (45 mg) (60 mg)
35 kg 1.75 ml 3.5 ml 5.25 ml* 7 ml*
(17.5 mg) (35 mg) (52.5 mg) (70 mg)
40 kg 2 ml 4 ml 6 ml* 8 ml*
(20 mg) (40 mg) (60 mg) (80 mg)
45 kg 2.25 ml 4.5 ml 6.75 ml* 9 ml*
(22.5 mg) (45mg) (67.5 mg) (90 mg)
* For volume above 5 ml and up to 10 ml, the patient should be instructed to use the 10 ml oral
syringe

23
 Volumes of oral solution to be taken per administration for children weighing from 10 kg to less
than 20 kg
Prescribed
For a dose of For a dose of For a dose of For a dose of For a dose of
dose
1 mg/kg/day 2.5 mg/kg/day 3 mg/kg/day 4 mg/kg/day 5 mg/kg/day

0.05 ml/kg/intake 0.125 ml/kg/intake 0.15 ml/kg/intake 0.2 ml/kg/intake 0.25 ml/kg/intake

(corresponding to (corresponding to (corresponding to (corresponding (corresponding to

0.5 mg/kg/intake) 1.25 mg/kg/intake) 1.5 mg/kg/intake) to 2.5 mg/kg/intake)
2 mg/kg/intake)
Recommended syringe: 5 ml
Weight
Volume administered

10 kg 0.5 ml 1.25 ml 1.5 ml 2 ml 2.5 ml

(5 mg) (12.5 mg) (15 mg) (20 mg) (25 mg)
12 kg 0.6 ml 1.5 ml 1.8 ml 2.4 ml 3.0 ml
(6 mg) (15 mg) (18 mg) (24 mg) (30 mg)
14 kg 0.7 ml 1.75 ml 2.1 ml 2.8 ml 3.5 ml
(7 mg) (17.5 mg) (21 mg) (28 mg) (35 mg)
15 kg 0.75 ml 1.9 ml 2.25 ml 3 ml 3.75 ml
(7.5 mg) (19.0 mg) (22.5 mg) (30 mg) (37.5 mg)

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
For patients from 16 years of age, if brivaracetam has to be discontinued, it is recommended that the
dose 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 that
the dose is reduced by a maximum of half the dose every week until a dose of 1 mg/kg/day (for
patients with a body weight less than 50 kg) or 50 mg/day (for patients with body weight of 50 kg or
more) is reached.
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.
Based on data in adults, no dose adjustment is necessary in paediatric patients with impaired renal
function. No clinical data are available in paediatric patients with renal impairment.

Hepatic 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 4.4
and 5.2). No clinical data are available in paediatric patients with hepatic impairment.

24
Age and body weight Recommended starting Recommended
dose maximum daily dose
Adolescents and children weighing 50 kg or 50 mg/day 150 mg/day
more, and adults
Adolescents and children weighing from 20 kg to 1 mg/kg/day 3 mg/kg/day
less 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 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.

Briviact oral solution is provided with a 5 ml and a 10 ml oral dosing syringe with their adaptor.

Instructions for use are provided in the package leaflet.

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 clinical studies 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. See also section 4.8, paediatric data.

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 (see section
4.2).

Severe cutaneous adverse reactions (SCARs)

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

25
Excipients

Sodium content
Brivaracetam oral solution contains less than 1 mmol sodium (23mg) per ml, that is to say essentially
‘sodium free’.

Fructose intolerance
This medicine contains 168 mg sorbitol (E420) in each ml. Patients with hereditary fructose
intolerance (HFI) should not take this medicinal product.

Excipients which may cause intolerance

The oral solution contains methyl parahydroxybenzoate (E218), which may cause allergic reactions
(possibly delayed).
Brivaracetam oral solution contains propylene glycol (E1520).

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 medicinal products 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
interaction is considered to be low. Limited clinical data are available implying that coadministration
of cannabidiol may increase the plasma exposure of brivaracetam, possibly through CYP2C19
inhibition, but the clinical relevance is uncertain.

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).

26
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 clinical 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 Influence of brivaracetam on
plasma 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 None
a
based on a study involving the administration of a supratherapeutic dose of 400 mg/day brivaracetam

27
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 clinical
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 oestrogen 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

Brivaracetam is excreted in human breast milk. 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

28
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

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 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 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 three placebo-
controlled, fixed-dose studies safety database in subjects ≥ 16 years of age and from post-marketing
experience, 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 Influenza
infestations
Blood and lymphatic Uncommon Neutropenia
system disorders
Immune system disorders Uncommon Type I hypersensitivity
Metabolism and nutrition Common Decreased appetite
disorders
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, cough
mediastinal disorders
Gastrointestinal Common Nausea, vomiting, constipation
disorders

29
 System organ class Frequency Adverse reactions
Skin and subcutaneous Not known Stevens-Johnson syndrome(1)
tissue disorders
General disorders and Common Fatigue
administration site
conditions
(1)
Adverse reactions reported in post marketing experience.

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).

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

Paediatric population

The safety profile of brivaracetam observed in children from 1 month of age was consistent with the
safety profile observed in adults. In the open label, uncontrolled, long-term studies suicidal ideation
was reported in 4.7 % of paediatric patients (assessed from 6 years onwards, more common in
adolescents) compared with 2.4 % of adults and behavioural disorders were reported in 24.8 % of
paediatric patients compared with 15.1 % of adults. The majority of events were mild or moderate in
intensity, were non-serious, and did not lead to discontinuation of study drug. An additional adverse
reaction 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 age
when compared to older paediatric age groups. No significant safety information was identified
indicating the increasing incidence of a particular AE in this age group. As data available in children
younger than 2 years of age is limited, brivaracetam is not indicated in this age range. Limited 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
listed in Appendix V.

30
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.
The following adverse reactions were reported with brivaracetam overdose: nausea, vertigo, balance
disorder, anxiety, fatigue, irritability, aggression, insomnia, depression, and suicidal ideation in the
post-marketing experience. In general, the adverse reactions associated with brivaracetam overdose
were consistent with the known adverse reactions.

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 clinical 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.

31
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=0.004)

Study N01252(1)
n = 100 n = 99 n = 100
50 % 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 N01358
n = 259 n = 252 n = 249
50% 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 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.

32
Figure 1: Proportion of patients by category of seizure response for brivaracetam and placebo over
12 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 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 clinical 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 clinical 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

33
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.
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 clinical studies.

Paediatric population

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

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

From the pooled open-label safety and PK studies in adjunctive therapy, 186 children with POS in the
age range of 1 month < 16 years of age have received brivaracetam, of whom 149 have been treated
for ≥ 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 with
brivaracetam in one or more subsets of the paediatric population in epilepsy with partial onset seizures
(see section 4.2 for information on paediatric use).

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.

34
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, 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 not
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).

35
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 classes 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).

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.

Paediatric population

In a pharmacokinetic study with a 3-week evaluation period and weekly fixed 3-step up-titration using
the brivaracetam oral solution, 99 subjects aged 1 month to < 16 years were evaluated. Brivaracetam
was administered at weekly increasing doses of approximately 1 mg/kg/day, 2 mg/kg/day, and
4 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 for
entry into a long-term follow-up study continuing on their last received dose (see section 4.8). Plasma
concentrations were shown to be dose-proportional in all age groups. Population pharmacokinetics
modeling was performed based on sparse plasma concentration data collected in the 3-week PK study
and the ongoing long-term follow-up study. 232 paediatric patients with epilepsy, aged 2 months to
17 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 plasma
concentration 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. In
comparison, plasma clearance was estimated at 3.58 L/h in adult patients (70 kg body weight).
Currently, no clinical data are available in neonates.

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.

36
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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium citrate
Citric acid anhydrous (for pH-adjustment)
Methyl parahydroxybenzoate (E218)
Carmellose sodium
Sucralose
Sorbitol liquid (E420)
Glycerol (E422)
Raspberry flavour (propylene glycol (E1520) 90 % - 98 %)
Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

4 years.
After first opening: 8 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

37
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 5 ml (blue graduation marks) and a 10 ml (black graduation marks) graduated oral dosing
syringe (polypropylene, polyethylene) and an adaptor for the syringe (polyethylene).

6.6 Special precautions for disposal

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

Date of latest renewal: 9 October 2020

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

38
1. NAME OF THE MEDICINAL PRODUCT

Briviact 10 mg/ml solution for injection/infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 10mg brivaracetam

Each 5 ml vial contains 50 mg brivaracetam

Excipient(s) with known effect:

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection/infusion (injection/infusion)

Clear, colourless, solution.

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 adults, adolescents and children from 2 years of age with epilepsy.

4.2 Posology and method of administration

Posology

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

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

Recommended starting dose Recommended maintenance Therapeutic dose range*

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

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

1 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 kg

1 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

39
Adults
Brivaracetam may be initiated with either intravenous or oral administration. When converting from
oral to intravenous administration or vice versa, the total daily dose and frequency of administration
should be maintained.
The recommended starting dose is either 50 mg/day or 100 mg/day based on physician’s assessment of
required seizure reduction versus potential side effects. Based on individual patient response and
tolerability, 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 based
on physician’s assessment of need for seizure control. The recommended maintenance dose is
100 mg/day. Based on individual patient response, the dose may be adjusted in the effective dose
range 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 to
2 mg/kg/day based on physician’s assessment of need for seizure control. The recommended
maintenance dose is 2 mg/kg/day. Based on individual patient response, the dose may be adjusted in
the 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 to
2.5 mg/kg/day based on physician’s assessment of need for seizure control. The recommended
maintenance dose is 2.5 mg/kg/day. Based on individual patient response, the dose may be adjusted in
the effective dose range of 1 mg/kg/day to 5 mg/kg/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
For patients from 16 years of age, if brivaracetam has to be discontinued, it is recommended that the
dose 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 that
the dose is reduced by a maximum of half the dose every week until a dose of 1 mg/kg/day (for
patients with a body weight less than 50 kg) or 50 mg/day (for patients with body weight of 50 kg or
more) is reached.
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.
Based on data in adults, no dose adjustment is necessary in paediatric patients with impaired renal
function. No clinical data are available in paediatric patients with renal impairment.

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

40
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 4.4
and 5.2). No clinical data are available in paediatric patients with hepatic impairment.

Age and body weight Recommended starting Recommended

dose maximum daily dose
Adolescents and children weighing 50 kg or 50 mg/day 150 mg/day
more, and adults
Adolescents and children weighing from 20 kg to 1 mg/kg/day 3 mg/kg/day
less 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 a
posology can be made.

Method of administration

- 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 a
15-minute intravenous infusion (see section 6.6). This medicinal product must not be mixed
with 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.

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 clinical studiesof 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. See also section 4.8, paediatric data.

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 (see section
4.2).

41
Severe cutaneous adverse reactions (SCARs)

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

Excipients

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

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 medicinal products 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
interaction is considered to be low. Limited clinical data are available implying that coadministration
of cannabidiol may increase the plasma exposure of brivaracetam, possibly through CYP2C19
inhibition, but the clinical relevance is uncertain.

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.

42
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 clinical 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 Influence of brivaracetam on
plasma 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 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 clinical
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
43
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 oestrogen 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

Brivaracetam is excreted in human breast milk. 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.

44
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

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 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 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 three placebo-
controlled, fixed-dose studies safety database in subjects ≥ 16 years of age and from post-marketing
experience, 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.

45
System organ class Frequency Adverse reactions
Infections and Common Influenza
infestations
Blood and lymphatic Uncommon Neutropenia
system disorders
Immune system disorders Uncommon Type I hypersensitivity
Metabolism and nutrition Common Decreased appetite
disorders
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, cough
mediastinal disorders
Gastrointestinal Common Nausea, vomiting, constipation
disorders
Skin and subcutaneous Not known Stevens-Johnson syndrome(1)
tissue disorders
General disorders and Common Fatigue
administration site
conditions
(1)
Adverse reactions reported in post marketing experience.

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).

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

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

Paediatric population

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

46
No specific pattern of adverse event (AE) was identified in children from 1◦month to < 4◦years of age
when compared to older paediatric age groups. No significant safety information was identified
indicating the increasing incidence of a particular AE in this age group. As data available in children
younger than 2 years of age is limited, brivaracetam is not indicated in this age range. Limited 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
listed in Appendix V.

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

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.

47
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 clinical 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=0.004)

Study N01252(1)
n = 100 n = 99 n = 100
50 % 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 N01358
n = 259 n = 252 n = 249
50% 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 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
48
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 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 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 clinical 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 clinical studies included 38 elderly patients aged
between 65 and 80 years. Although data are limited, the efficacy was comparable to younger subjects.

49
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.
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 clinical studies.

Paediatric population

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

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

From the pooled open-label safety and PK studies in adjunctive therapy, 186 children with POS in the
age range of 1 month < 16 years of age have received brivaracetam, of whom 149 have been treated
for ≥ 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 with
brivaracetam in one or more subsets of the paediatric population in epilepsy with partial onset seizures
(see section 4.2 for information on paediatric use).

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.

50
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, 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 not
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).

51
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 classes 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).

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.

Paediatric population

In a pharmacokinetic study with a 3-week evaluation period and weekly fixed 3-step up-titration using
the brivaracetam oral solution, 99 subjects aged 1 month to < 16 years were evaluated. Brivaracetam
was administered at weekly increasing doses of approximately 1 mg/kg/day, 2 mg/kg/day, and
4 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 for
entry into a long-term follow-up study continuing on their last received dose (see section 4.8). Plasma
concentrations were shown to be dose-proportional in all age groups. Population pharmacokinetics
modeling was performed based on sparse plasma concentration data collected in the 3-week PK study
and the ongoing long-term follow-up study. 232 paediatric patients with epilepsy, aged 2 months to
17 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 plasma
concentration 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. In
comparison, plasma clearance was estimated at 3.58 L/h in adult patients (70 kg body weight).
Currently, no clinical data are available in neonates.

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.

52
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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium acetate (trihydrate)

Acetic acid, glacial (for pH-adjustment)
Sodium chloride
Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

4 years.
Following dilution, brivaracetam solution for injection/infusion was found to be physically compatible
and 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 product
should be used immediately after dilution. If not used immediately, in-use storage time and conditions
prior to use are the responsibility of the user.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

53
For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

6 ml nominal capacity glass vials (type I) with siliconized bromobutyl rubber stoppers and sealed with
an aluminium/polypropylene tear off cap. Each single use vial contains an extractable volume of not
less than 5 ml of solution for injection/infusion.

Each carton contains 10 vials.

6.6 Special precautions for disposal and other handling

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 when
mixed 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 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/1/15/1073/022

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 January 2016

Date of latest renewal: 9 October 2020

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

54
 ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH

RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY

AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE

MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL
PRODUCT

55
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

UCB Pharma S.A.

Chemin du Foriest
B-1420 Braine l'Alleud
Belgium

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION

• Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and
any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing
authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;

• Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile or
as the result of an important (pharmacovigilance or risk minimisation) milestone being
reached.

56
 ANNEX III

LABELLING AND PACKAGE LEAFLET

57
A. LABELLING

58
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Briviact 10 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 10 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
56 film-coated tablets
100 x 1 film-coated tablets
14 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

59
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/001 14 film-coated tablets

EU/1/15/1073/002 56 film-coated tablets
EU/1/15/1073/003 100 x 1 film-coated tablets
EU/1/15/1073/023 14 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 10 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

60
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON OF MULTIPACK (WITH BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 10 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 10 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack: 168 (3 packs of 56) film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

61
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/004 168 (3 packs of 56) film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 10 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

62
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

INTERMEDIATE CARTON WITHIN MULTIPACK (3 PACKS OF 56 FILM-COATED

TABLETS) (WITHOUT BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 10 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 10 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

56 film-coated tablets. Component of a multipack, can’t be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

63
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 10 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

64
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Briviact 10 mg tablets
brivaracetam

2. NAME OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A. (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Calendar days: Mon., Tue.,Wed., Thu., Fri., Sat., Sun.

(not for packsizes 14 x1 and 100 x 1 film-coated tablet)

65
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Briviact 25 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 25 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
56 film-coated tablets
100 x 1 film-coated tablets
14 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

66
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/005 14 film-coated tablets

EU/1/15/1073/006 56 film-coated tablets
EU/1/15/1073/007 100 x 1 film-coated tablets
EU/1/15/1073/024 14 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 25 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

67
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON OF MULTIPACK (WITH BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 25 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 25 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack: 168 (3 packs of 56) film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

68
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/008 168 (3 packs of 56) film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 25 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

69
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

INTERMEDIATE CARTON WITHIN MULTIPACK (3 PACKS OF 56 FILM-COATED

TABLETS) (WITHOUT BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 25 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 25 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

56 film-coated tablets. Component of a multipack, can’t be sold separatly.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

70
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 25 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

71
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Briviact 25 mg tablets
brivaracetam

2. NAME OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A. (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Calendar days: Mon., Tue.,Wed., Thu., Fri., Sat., Sun.

(not for packsizes 14 x1 and 100 x 1 film-coated tablet)

72
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Briviact 50 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 50 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
56 film-coated tablets
100 x 1 film-coated tablets
14 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

73
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/009 14 film-coated tablets

EU/1/15/1073/010 56 film-coated tablets
EU/1/15/1073/011 100 x 1 film-coated tablets
EU/1/15/1073/025 14 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 50 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

74
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON of MULTIPACK (WITH BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 50 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 50 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack: 168 (3 packs of 56) film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

75
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/012 168 (3 packs of 56) film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 50 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

76
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

INTERMEDIATE CARTON WITHIN MULTIPACK (3 PACKS OF 56 FILM-COATED

TABLETS)
(WITHOUT BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 50 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 50 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

56 film-coated tablets. Component of a multipack, can’t be sold separatly.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

77
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 50 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

78
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Briviact 50 mg tablets
brivaracetam

2. NAME OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A. (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Calendar days: Mon., Tue.,Wed., Thu., Fri., Sat., Sun.

(not for packsizes 14 x1 and 100 x 1 film-coated tablet)

79
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Briviact 75 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 75 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
56 film-coated tablets
100 x 1 film-coated tablets
14 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

80
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/013 14 film-coated tablets

EU/1/15/1073/014 56 film-coated tablets
EU/1/15/1073/015 100 x 1 film-coated tablets
EU/1/15/1073/026 14 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 75 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

81
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON of MULTIPACK (WITH BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 75 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 75 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack: 168 (3 packs of 56) film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

82
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/016 168 (3 packs of 56) film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 75 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

83
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

INTERMEDIATE CARTON WITHIN MULTIPACK (3 PACKS OF 56 FILM-COATED

TABLETS)
(WITHOUT BLUEBOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 75 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 75 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

56 film-coated tablets. Component of a multipack, can’t be sold separatly.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

84
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 75 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

85
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Briviact 75 mg tablets
brivaracetam

2. NAME OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A. (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Calendar days: Mon., Tue.,Wed., Thu., Fri., Sat., Sun.

(not for packsizes 14 x1 and 100 x 1 film-coated tablet)

86
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Briviact 100 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 100 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
56 film-coated tablets
100 x 1 film-coated tablets
14 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

87
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/017 14 film-coated tablets

EU/1/15/1073/018 56 film-coated tablets
EU/1/15/1073/019 100 x 1 film-coated tablets
EU/1/15/1073/027 14 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

88
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON OF MULTIPACK (WITH BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 100 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 100 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack: 168 (3 packs of 56) film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

89
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/020 168 (3 packs of 56) film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

90
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

INTERMEDIATE CARTON WITHIN MULTIPACK (3 PACKS OF 56 FILM-COATED

TABLETS)
(WITHOUT BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Briviact 100 mg film-coated tablets

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 100 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate and lactose anhydrous.

See leaflet for further information. (Omitted from cartons of 14 film-coated tablets)

4. PHARMACEUTICAL FORM AND CONTENTS

56 film-coated tablets. Component of a multipack, can be sold separatly.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

91
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

92
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Briviact 100 mg tablets

brivaracetam

2. NAME OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A. (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Calendar days: Mon., Tue.,Wed., Thu., Fri., Sat., Sun.

(not for packsizes 14 x1 and 100 x 1 film-coated tablet)

93
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE
PACKAGING

OUTER CARTON / BOTTLE

1. NAME OF THE MEDICINAL PRODUCT

Briviact 10 mg/ml oral solution

brivaracetam

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each ml of oral solution contains 10 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains sorbitol liquid (E420), propylene glycol (E1520) and methyl parahydroxybenzoate (E218).
See leaflet for further information. (Only for outer carton)

4. PHARMACEUTICAL FORM AND CONTENTS

300 ml
Two oral syringes (5 ml and 10 ml) with 2 adaptors are included in the carton. Check with your doctor
which one you should use.
Syringes 10 ml and 5ml (as colored symbols - only for the outer carton)

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
After first opening of the bottle, use within 8 months.
Opening date (Only for outer carton)

9. SPECIAL STORAGE CONDITIONS

94
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60 (address only for outer carton)
B-1070 Bruxelles
Belgium (name and address only for outer carton, logo on carton and etiquette)

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/021

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

briviact 10 mg/ml (Only for outer carton)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included. (Only for outer carton)

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

(Only for outer carton)

95
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Briviact 10 mg/ml solution for injection/infusion

brivaracetam

2. STATEMENT OF ACTIVE SUB STANCE(S)

Each ml of solution for injection/infusion contains 10 mg brivaracetam.

One vial of 5 ml contains 50 mg brivaracetam.

3. LIST OF EXCIPIENTS

Contains sodium acetate (trihydrate), glacial acetic acid, sodium chloride, water for injections.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

50 mg/5 ml
10 vials solution for injection/infusion

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Intravenous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

96
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60
B-1070 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1073/022

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

97
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Briviact 10 mg/ml injection/infusion

brivaracetam
IV

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

50 mg/5 ml

6. OTHER

98
B. PACKAGE LEAFLET

99
 Package leaflet: Information for the patient

Briviact 10 mg film-coated tablets

Briviact 25 mg film-coated tablets
Briviact 50 mg film-coated tablets
Briviact 75 mg film-coated tablets
Briviact 100 mg film-coated tablets
brivaracetam

Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Briviact is and what it is used for
2. What you need to know before you take Briviact
3. How to take Briviact
4. Possible side effects
5. How to store Briviact
6. Contents of the pack and other information

1. What Briviact is and what it is used for

What Briviact is
Briviact contains the active substance brivaracetam. It belongs to a group of medicines called
‘anti-epileptics’. These medicines are used to treat epilepsy.

What Briviact is used for

• Briviact is used in adults, adolescents and children from 2 years of age.
• It is used to treat a type of epilepsy that has partial seizures with or without a secondary
generalisation.
• Partial seizures are fits that start by only affecting one side of the brain. These partial seizures
can spread and extend to larger areas on both sides of the brain – this is called a ‘secondary
generalisation’.
• You have been given this medicine to lower the number of fits (seizures) you have.
• Briviact is used together with other medicines for epilepsy.

2. What you need to know before you take Briviact

Do not take Briviact if:

- you are allergic to brivaracetam, other similar chemical compounds as levetiracetam or
piracetam or any of the other ingredients of this medicine (listed in section 6). If you are not
sure, talk to your doctor or pharmacist before taking Briviact.
- you have ever developed as severe skin rash or skin peeling, blistering and/or mouth sores after
taking Briviact.
Serious skin reactions including Stevens-Johnson syndrome have been reported in association
with Briviact treatment. Stop using Briviact and seek medical attention immediately if you
notice any of the symptoms related to these serious skin reactions described in section 4.

100
Warnings and precautions
Talk to your doctor or pharmacist before taking Briviact if:
- You have thoughts of harming or killing yourself. A small number of people being treated with
anti-epileptic medicines such as Briviact have had thoughts of harming or killing themselves. If
you have any of these thoughts at any time, contact your doctor immediately.
- You have liver problems - your doctor may need to adjust your dose.

Children
Briviact is not recommended for use in children under 2 years of age.

Other medicines and Briviact

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines.

In particular, tell your doctor if you are taking any of the following medicines – this is because your
doctor may need to adjust your Briviact dose:
- Rifampicin - a medicine used to treat bacterial infections.
- St John’s wort (also known as Hypericum perforatum) - a herbal medicine used to treat
depression and anxiety as well as other conditions.

Briviact with alcohol

- Combining this medicine with alcohol is not recommended.
- If you drink alcohol while taking Briviact the negative effects of alcohol may be increased.

Pregnancy and breast-feeding

Fertile women should discuss the use of contraceptives with the doctor.

If you are pregnant or breast-feeding, think you may be pregnant or planning to have a baby, ask your
doctor or pharmacist for advice before taking this medicine.

It is not recommended to take Briviact if you are pregnant, as the effects of Briviact on pregnancy and
the unborn baby are not known.
It is not recommended to breast-feed your baby while taking Briviact, as Briviact passes into breast
milk.

Do not stop treatment without talking to your doctor first. Stopping treatment could increase your
seizures and harm your baby.

Driving and using machines

- You may feel sleepy, dizzy or tired while taking Briviact.
- These effects are more likely at the start of the treatment or after a dose increase.
- Do not drive, cycle or use any tools or machines until you know how the medicine affects you.

Briviact contains lactose and sodium

Briviact film-coated tablets contain:
- lactose (a type of sugar) - If you have been told by your doctor that you have an intolerance to
some sugars, contact your doctor before taking this medicine.
- sodium – This medecine contains less than 1 mmol sodium (23mg) per tablet, that is to say
essentially ‘sodium free’.

3. How to take Briviact

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure. Other form(s) of this medicine may be more suitable for certain patients e.g.
children (if tablets can not be swallowed in whole, for example); ask your doctor or pharmacist.

101
You will take Briviact together with other medicines for epilepsy.

How much to take

Your doctor will work out the right daily dose for [Link] the daily dose in two equal divided doses,
approximately 12 hours apart.

Adolescents and children weighing 50 kg or more, and adults

- The recommended dose is from 25 mg to 100 mg taken twice a day . Your doctor may then
decide to adjust your dose to find the best dose for you.

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

- The recommended dose is from 0.5 mg to 2 mg for each kg of bodyweight, taken twice a day.
Your doctor may then decide to adjust your dose to find the best dose for you.

Children weighing from 10 kg to less than 20 kg

- The recommended dose is from 0.5 mg to 2.5 mg for each kg of bodyweight, taken twice a day.
Your child’s doctor may then decide to adjust your child’s dose to find the best dose for your
child.

People with liver problems

If you have problems with your liver:
- As an adolescent or child weighing 50 kg or more, or as an adult, the maximum dose you will
take is 75 mg twice a day.
- As an adolescent or child weighing from 20 kg to less than 50 kg, the maximum dose you will
take is 1.5 mg for each kg of bodyweight twice a day.
- As a child weighing from 10 kg to less than 20 kg, the maximum dose your child will take is
2 mg for each kg of bodyweight twice a day.

How to take Briviact tablets

- Swallow the tablets whole with a glass of liquid.
- The medicine may be taken with or without food.

How long to take Briviact for

Briviact is a long term treatment – keep taking Briviact until your doctor tells you to stop.

If you take more Briviact than you should

If you have taken more Briviact than you should, talk to your doctor. You may feel dizzy and sleepy.
You may also have any of the following symptoms: feeling sick, a feeling of ‘spinning’, problems of
keeping your balance, anxiety, feeling very tired, irritability, being aggressive, not being able to sleep,
depression, thoughts or attempts of harming or killing yourself.

If you forget to take Briviact

- If you miss a dose take it as soon as you remember.
- Then take your next dose at the time you would normally take it.
- Do not take a double dose to make up for a forgotten dose.
- If you are not sure what to do, ask your doctor or pharmacist.

If you stop taking Briviact

- Do not stop taking this medicine unless your doctor tells you to. This is because stopping
treatment could increase the number of fits you have.
- If your doctor asks you to stop taking this medicine they will lower your dose gradually. This
helps to stop your fits coming back or getting worse

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

102
4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common: may affect more than 1 in 10 people

- feeling sleepy or dizzy

Common: may affect up to 1 in 10 people

- flu
- feeling very tired (fatigue)
- convulsion, a feeling of ‘spinning’ (vertigo)
- feeling and being sick, constipation
- depression, anxiety, not being able to sleep (insomnia), irritability
- infections of the nose and throat (such as the ‘common cold’), cough
- decreased appetite

Uncommon: may affect up to 1 in 100 people

- allergic reactions
- abnormal thinking and/or loss of touch with reality (psychotic disorder), being aggressive,
nervous excitement (agitation)
- thoughts or attempts of harming or killing yourself: tell your doctor straight away
- a decrease in white blood cells (called ‘neutropenia’) - shown in blood tests

Not known: frequency cannot be estimated from the available data

- a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and
genitals (Stevens-Johnson syndrome)

Additional side effects in children

Common: may affect up to 1 in 10 people

- restlessness and hyperactivity (psychomotor hyperactivity)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V. By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store Briviact

- Keep this medicine out of the sight and reach of children.

- Do not use this medicine after the expiry date which is stated on the carton and blister after
EXP. The expiry date refers to the last day of that month.
- This medicinal product does not require any special storage conditions.
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how
to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Briviact contains

The active substance is brivaracetam.
Each film-coated tablet contains 10 mg, 25 mg, 50 mg, 75 mg, or 100 mg brivaracetam.

103
The other ingredients are:
Core
Croscarmellose sodium, lactose monohydrate, betadex, lactose anhydrous, magnesium stearate

Coating
- 10 mg film-coated tablets: poly(vinyl alcohol), titanium dioxide (E171), macrogol (3350), talc.
- 25 mg film-coated tablets: poly(vinyl alcohol), titanium dioxide (E171), macrogol (3350), talc, iron
oxide yellow (E172), iron oxide black (E172).
- 50 mg film-coated tablets: poly(vinyl alcohol), titanium dioxide (E171), macrogol (3350), talc, iron
oxide yellow (E172), iron oxide red (E172).
- 75 mg film-coated tablets: poly(vinyl alcohol), titanium dioxide (E171), macrogol (3350), talc, iron
oxide yellow (E172), iron oxide red (E172), iron oxide black (E172).
- 100 mg film-coated tablets: poly(vinyl alcohol), titanium dioxide (E171), macrogol (3350), talc, iron
oxide yellow (E172), iron oxide black (E172).

What Briviact looks like and contents of the pack

Briviact 10 mg are white to off-white, round, film-coated tablets of 6.5 mm in diameter and debossed
with ‘u10’ on one side.
Briviact 25 mg are grey, oval, film-coated tablets of 8.9 mm x 5.0 mm and debossed with ‘u25’ on one
side.
Briviact 50 mg are yellow, oval, film-coated tablets of 11.7 mm x 6.6 mm and debossed with ‘u50’ on
one side.
Briviact 75 mg are purple, oval, film-coated tablets of 13.0 mm x 7.3 mm and debossed with ‘u75’ on
one side.
Briviact 100 mg are green-grey, oval, film-coated tablets of 14.5 mm x 8.1 mm and debossed with
‘u100’ on one side.

Briviact tablets are packaged in blister packs supplied in cardboard boxes containing either 14, 56,
14 x 1 or 100 x 1 film-coated tablets or in multipacks containing 168 (3 packs of 56) film-coated
tablets.
All packs are available in PVC/PCTFE - Aluminium blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

UCB Pharma S.A., Allée de la Recherche 60, B-1070 Bruxelles, Belgium.

Manufacturer
UCB Pharma S.A., Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

België/Belgique/Belgien Lietuva
UCB Pharma SA/NV UCB Pharma Oy Finland
Tél/Tel: + 32 / (0)2 559 92 00 Tel: + 358 9 2514 4221 (Suomija)

България Luxembourg/Luxemburg
Ю СИ БИ България ЕООД UCB Pharma SA/NV
Teл.: + 359 (0) 2 962 30 49 Tél/Tel: + 32 / (0)2 559 92 00 (Belgique/Belgien)

Česká republika Magyarország

UCB s.r.o. UCB Magyarország Kft.
Tel: + 420 221 773 411 Tel.: + 36-(1) 391 0060

Danmark Malta
UCB Nordic A/S Pharmasud Ltd.
Tlf.: + 45 / 32 46 24 00 Tel: + 356 / 21 37 64 36

104
Deutschland Nederland
UCB Pharma GmbH UCB Pharma B.V.
Tel: + 49 /(0) 2173 48 4848 Tel.: + 31 / (0)76-573 11 40

Eesti Norge
UCB Pharma Oy Finland UCB Nordic A/S
Tel: + 358 9 2514 4221 (Soome) Tlf: + 47 / 67 16 5880

Ελλάδα Österreich
UCB Α.Ε. UCB Pharma GmbH
Τηλ: + 30 / 2109974000 Tel: + 43-(0)1 291 80 00

España Polska
UCB Pharma, S.A. UCB Pharma Sp. z o.o. / VEDIM Sp. z o.o.
Tel: + 34 / 91 570 34 44 Tel: + 48 22 696 99 20

France Portugal
UCB Pharma S.A. UCB Pharma (Produtos Farmacêuticos), Lda
Tél: + 33 / (0)1 47 29 44 35 Tel: + 351 / 21 302 5300

Hrvatska România
Medis Adria d.o.o. UCB Pharma Romania S.R.L.
Tel: +385 (0) 1 230 34 46 Tel: + 40 21 300 29 04

Ireland Slovenija
UCB (Pharma) Ireland Ltd. Medis, d.o.o.
Tel: + 353 / (0)1-46 37 395 Tel: + 386 1 589 69 00

Ísland Slovenská republika

Vistor hf. UCB s.r.o., organizačná zložka
Simi: + 354 535 7000 Tel: + 421 (0) 2 5920 2020

Italia Suomi/Finland
UCB Pharma S.p.A. UCB Pharma Oy Finland
Tel: + 39 / 02 300 791 Puh/Tel: + 358 9 2514 4221

Κύπρος Sverige
Lifepharma (Z.A.M.) Ltd UCB Nordic A/S
Τηλ: + 357 22 05 63 00 Tel: + 46 / (0) 40 29 49 00

Latvija
UCB Pharma Oy Finland
Tel: + 358 9 2514 4221 (Somija)

This leaflet was last revised in {month YYYY}.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
[Link]

105
 Package leaflet: Information for the patient

Briviact 10mg/ml oral solution

brivaracetam

Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Briviact is and what it is used for
2. What you need to know before you take Briviact
3. How to take Briviact
4. Possible side effects
5. How to store Briviact
6. Contents of the pack and other information

1. What Briviact is and what it is used for

What Briviact is
Briviact contains the active substance brivaracetam. It belongs to a group of medicines called
‘anti-epileptics’. These medicines are used to treat epilepsy.

What Briviact is used for

• Briviact is used in adults, adolescents and children from 2 years of age.
• It is used to treat a type of epilepsy that has partial seizures with or without a secondary
generalisation.
• Partial seizures are fits that start by only affecting one side of the brain. These partial seizures
can spread and extend to larger areas on both sides of the brain – this is called a ‘secondary
generalisation’.
• You have been given this medicine to lower the number of fits (seizures) you have.
• Briviact is used together with other medicines for epilepsy.

2. What you need to know before you take Briviact

Do not take Briviact if:

- you are allergic to brivaracetam, other similar chemical compounds as levetiracetam or
piracetam or any of the other ingredients of this medicine (listed in section 6). If you are not
sure, talk to your doctor or pharmacist before taking Briviact.
- you have ever developed as severe skin rash or skin peeling, blistering and/or mouth sores after
taking Briviact.
Serious skin reactions including Stevens-Johnson syndrome have been reported in association
with Briviact treatment. Stop using Briviact and seek medical attention immediately if you
notice any of the symptoms related to these serious skin reactions described in section 4.

106
Warnings and precautions
Talk to your doctor or pharmacist before taking Briviact if:
- You have thoughts of harming or killing yourself. A small number of people being treated with
anti-epileptic medicines such as Briviact have had thoughts of harming or killing themselves. If
you have any of these thoughts at any time, contact your doctor immediately.
- You have liver problems - your doctor may need to adjust your dose.

Children
Briviact is not recommended for use in children under 2 years of age.

Other medicines and Briviact

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines.

In particular, tell your doctor if you are taking any of the following medicines – this is because your
doctor may need to adjust your Briviact dose:
- Rifampicin - a medicine used to treat bacterial infections.
- St John’s wort (also known as Hypericum perforatum) - a herbal medicine used to treat
depression and anxiety as well as other conditions.

Briviact with alcohol

- Combining this medicine with alcohol is not recommended.
- If you drink alcohol while taking Briviact the negative effects of alcohol may be increased.

Pregnancy and breast-feeding

Fertile women should discuss the use of contraceptives with the doctor.

If you are pregnant or breast-feeding, think you may be pregnant or planning to have a baby, ask your
doctor or pharmacist for advice before taking this medicine.

It is not recommended to take Briviact if you are pregnant, as the effects of Briviact on pregnancy and
the unborn baby are not known.
It is not recommended to breast-feed your baby while taking Briviact, as Briviact passes into breast
milk.

Do not stop treatment without talking to your doctor first. Stopping treatment could increase your
seizures and harm your baby.

Driving and using machines

- You may feel sleepy, dizzy or tired while taking Briviact.
- These effects are more likely at the start of the treatment or after a dose increase.
- Do not drive, cycle or use any tools or machines until you know how the medicine affects you.

Briviact oral solution contains methyl parahydroxybenzoate, sodium, sorbitol and propylene
glycol
- Methyl parahydroxybenzoate (E218): This may cause allergic reactions (possibly delayed).
- Sodium: This medicine contains less than 1 mmol sodium (23mg) per millilitre, that is to say
essentially ‘sodium free
- Sorbitol (E420) (a type of sugar): This medicine contains 168 mg sorbitol in each ml. Sorbitol is
a source of fructose. If your doctor has told you that you (or your child) have an intolerance to
some sugars or if you have been diagnosed with hereditary fructose intolerance (HFI), a rare
genetic disorder in which a person cannot break down fructose, talk to your doctor before you
(or your child) take or receive this medicine.
- Propylene glycol (E1520): This medicine contains maximum 5.5 mg propylene glycol in each
millilitre.

107
 3. How to take Briviact

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.

You will take Briviact together with other medicines for epilepsy.

How much to take

Your doctor will work out the right daily dose for you. Take the daily dose in two equal divided doses,
approximately 12 hours apart.

Adolescents and children weighing 50 kg or more, and adults

- The recommended dose is from 25 mg to 100 mg taken twice a day. Your doctor may then
decide to adjust your dose to find the best dose for you.

The table below only shows examples of doses to take and which syringe to use. Your doctor will
work out the right dose for you and which syringe to use, depending on your weight.

Dose in ml to be taken twice daily and which syringe to use - for adolescents and children
weighing 50 kg or more, and adults:
Dose in ml Dose in ml Dose in ml Dose in ml
Weight (corresponding to (corresponding (corresponding (corresponding
25 mg) to 50 mg) to 75 mg) to 100 mg)
50 kg or more 2.5 ml 5 ml 7.5 ml 10 ml
Use the 5 ml syringe Use the 10 ml syringe
(blue graduation marks) (black graduation marks)

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

- The recommended dose is from 0.5 mg to 2 mg for each kg of bodyweight, taken twice a day.
Your doctor may then decide to adjust your dose to find the best dose for you.

The table below only shows examples of doses to take and which syringe to use. Your doctor will
work out the right dose for you and which syringe to use, depending on your weight.

Dose in ml to be taken twice daily and which syringe to use - for adolescents and children weighing from
20 kg to less than 50 kg:
Dose in ml Dose in ml Dose in ml Dose in ml
(corresponding to (corresponding to (corresponding to (corresponding to
Weight
0.5 mg/kg 1 mg/kg 1.5 mg/kg 2 mg/kg
= 0.05 ml/kg) = 0.1 ml/kg) = 0.15 ml/kg) = 0.2 ml/kg)
20 kg 1 ml 2 ml 3 ml 4 ml
25 kg 1.25 ml 2.5 ml 3.75 ml 5 ml
30 kg 1.5 ml 3 ml 4.5 ml 6 ml*
35 kg 1.75 ml 3.5 ml 5.25 ml* 7 ml*
40 kg 2 ml 4 ml 6 ml* 8 ml*
45 kg 2.25 ml 4.5 ml 6.75 ml* 9 ml*
For volume between 0.5 ml and 5 ml,
use the 5 ml oral syringe (blue
graduation marks)
Use the 5 ml syringe
(blue graduation marks) * For volume above 5 ml and up to 10
ml, use the 10 ml oral syringe (black
graduation marks)

108
 Children weighing from 10 kg to less than 20 kg
- The recommended dose is from 0.5 mg to 2.5 mg for each kg of bodyweight, taken twice a day.
Your child’s doctor may then decide to adjust your child’s dose to find the best dose for your
child.

The table below only shows examples of doses to take and which syringe to use. Your doctor will
work out the right dose for you and which syringe to use, depending on your weight.

Dose in ml to be taken twice daily and which syringe to use - for children weighing from 10 kg to less than
20 kg:
Dose in ml Dose in ml Dose in ml Dose in ml Dose in ml
(corresponding to (corresponding (corresponding (corresponding (corresponding
Weight
0.5 mg/kg to 1.25 mg/kg to 1.5 mg/kg to 2 mg/kg to 2.5 mg/kg
= 0.05 ml/kg) = 0.125 ml/kg) = 0.15 ml/kg) = 0.2 ml/kg) = 0.25 ml/kg)
10 kg 0.5 ml 1.25 ml 1.5 ml 2 ml 2.5 ml
12 kg 0.6 ml 1.5 ml 1.8 ml 2.4 ml 3.0 ml
14 kg 0.7 ml 1.75 ml 2.1 ml 2.8 ml 3.5 ml
15 kg 0.75 ml 1.9 ml 2.25 ml 3 ml 3.75 ml
Use the 5 ml syringe
(blue graduation marks)

People with liver problems

If you have problems with your liver:
- As an adolescent or child weighing 50 kg or more, or as an adult,the maximum dose you will
take is 75 mg twice a day.
- As an adolescent or child weighing from 20 kg to less than 50 kg, the maximum dose you will
take is 1.5 mg for each kg of bodyweight twice a day.
- As a child weighing from 10 kg to less than 20 kg, the maximum dose your child will take is
2 mg for each kg of bodyweight twice a day.

How to take Briviact oral solution

- You can take Briviact oral solution on its own, or dilute it in water or juice shortly before
swallowing.
- The medicine may be taken with or without food.

Instructions for use for patients or carers:

Two oral syringes will be provided in the carton. Check with your doctor which one you should use.
- For volume between 0.5 ml and 5 ml, you should use the 5 ml oral syringe (blue graduation
marks) provided in the carton to ensure accurate dosing.
- For volume above 5 ml and up to 10 ml, you should use the 10 ml oral syringe (black
graduation marks) provided in the carton to ensure accurate dosing.

5 ml oral dosing syringe 10 ml oral dosing syringe

The 5 ml oral syringe has 2 overlapping blue The 10 ml oral syringe has black graduation
graduation marks: in steps of 0.25 ml and in marks in steps of 0.25 ml.
steps of 0.1 ml.

109
- Open the bottle: press the cap and turn it anti-clockwise (figure 1).

Follow these steps the first time you take Briviact:

- Take off the adaptor from the oral syringe (figure 2).
- Put the adaptor into the top of the bottle (figure 3). Make sure it is fixed well in place. You do
not need to remove the adaptor after use.

Follow these steps each time you take Briviact:

- Put the oral syringe into the adaptor opening (figure 4).
- Turn the bottle upside down (figure 5).

- Hold the bottle upside down in one hand and use the other hand to fill the oral syringe.
- Pull the plunger down to fill the oral syringe with a small amount of solution (figure 6).
- Then push the plunger up to remove any possible air bubbles (figure 7).
- Pull the plunger down to the millilitre (ml) dose marker on the oral syringe prescribed by your
doctor (figure 8). The plunger may rise back up the barrel on the first dosage. Therefore,
ensure that the plunger is kept in position until the oral syringe is disconnected from the bottle.

110
 - Turn the bottle the right way up (figure 9).
- Take the oral syringe out of the adaptor (figure 10).

There are two ways in which you can choose to drink the medicine:
- empty the contents of the syringe into water (or juice) by pushing the plunger to the bottom of
the oral syringe (figure 11) – you will then need to drink all of the water (add just enough to
make it easy to drink) or
- drink the solution directly from the oral syringe without water – drink the whole contents of
the syringe (figure 12).

- Close the bottle with the plastic screw cap (you do not need to remove the adaptor).
- To clean the oral syringe, rinse with cold water only, moving the plunger several times up and
down to take up and expel the water, without separating the two components of the syringe
(figure 13).

- Keep the bottle, the oral syringe, and the leaflet in the carton.

How long to take Briviact for

Briviact is a long term treatment – keep taking Briviact until your doctor tells you to stop.

If you take more Briviact than you should

If you have taken more Briviact than you should, talk to your doctor. You may feel dizzy and sleepy.

111
You may also have any of the following symptoms: feeling sick, a feeling of ‘spinning’, problems of
keeping your balance, anxiety, feeling very tired, irritability, being aggressive, not being able to sleep,
depression, thoughts or attempts of harming or killing yourself.

If you forget to take Briviact

- If you miss a dose take it as soon as you remember.
- Then take your next dose at the time you would normally take it.
- Do not take a double dose to make up for a forgotten dose.
- If you are not sure what to do, ask your doctor or pharmacist.

If you stop taking Briviact

- Do not stop taking this medicine unless your doctor tells you to. This is because stopping
treatment could increase the number of fits you have.
- If your doctor asks you to stop taking this medicine they will lower your dose gradually. This
helps to stop your fits coming back or getting worse.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common: may affect more than 1 in 10 people

- feeling sleepy or dizzy

Common: may affect up to 1 in 10 people

- flu
- feeling very tired (fatigue)
- convulsion, a feeling of ‘spinning’ (vertigo)
- feeling and being sick, constipation
- depression, anxiety, not being able to sleep (insomnia), irritability
- infections of the nose and throat (such as the ‘common cold’), cough
- decreased appetite

Uncommon: may affect up to 1 in 100 people

- allergic reactions
- abnormal thinking and/or loss of touch with reality (psychotic disorder), being aggressive,
nervous excitement (agitation)
- thoughts or attempts of harming or killing yourself: tell your doctor straight away
- a decrease in white blood cells (called ‘neutropenia’) - shown in blood tests
Not known: frequency cannot be estimated from the available data
- a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and
genitals (Stevens-Johnson syndrome)

Additional side effects in children

Common: may affect up to 1 in 10 people

- restlessness and hyperactivity (psychomotor hyperactivity)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V. By reporting side effects you can help provide more information on the safety of
this medicine.

112
5. How to store Briviact

- Keep this medicine out of the sight and reach of children.

- Do not use this medicine after the expiry date which is stated on the cardboard box and bottle
after EXP. The expiry date refers to the last day of that month.
- This medicinal product does not require any special storage conditions.
- After first opening of the bottle, use within 8 months.
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how
to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Briviact contains

The active substance is brivaracetam.
Each millilitre (ml) contains 10 milligrams (mg) brivaracetam.

The other ingredients are: sodium citrate, citric acid anhydrous, methyl parahydroxybenzoate (E218),
carmellose sodium, sucralose, sorbitol liquid (E420), glycerol (E422), raspberry flavour (propylene
glycol (E1520) 90 % - 98 %), purified water.

What Briviact looks like and contents of the pack

Briviact 10 mg/ml oral solution is slightly viscous, clear, colourless to yellowish liquid.

The 300 ml glass bottle of Briviact is packed in a cardboard box containing a 10 ml oral
polypropylene/polyethylene syringe (black graduation marks), a 5 ml oral polypropylene/polyethylene
syringe (blue graduation marks), and polyethylene adaptors for the syringes.

Marketing Authorisation Holder

UCB Pharma S.A., Allée de la Recherche 60, B-1070 Bruxelles, Belgium.

Manufacturer
UCB Pharma S.A., Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium.

For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

België/Belgique/Belgien Lietuva
UCB Pharma SA/NV UCB Pharma Oy Finland
Tél/Tel: + 32 / (0)2 559 92 00 Tel: + 358 9 2514 4221 (Suomija)

България Luxembourg/Luxemburg
Ю СИ БИ България ЕООД UCB Pharma SA/NV
Teл.: + 359 (0) 2 962 30 49 Tél/Tel: + 32 / (0)2 559 92 00 (Belgique/Belgien)

Česká republika Magyarország

UCB s.r.o. UCB Magyarország Kft.
Tel: + 420 221 773 411 Tel.: + 36-(1) 391 0060

Danmark Malta
UCB Nordic A/S Pharmasud Ltd.
Tlf.: + 45 / 32 46 24 00 Tel: + 356 / 21 37 64 36

Deutschland Nederland
UCB Pharma GmbH UCB Pharma B.V.
Tel: + 49 /(0) 2173 48 4848 Tel.: + 31 / (0)76-573 11 40

113
Eesti Norge
UCB Pharma Oy Finland UCB Nordic A/S
Tel: + 358 9 2514 4221 (Soome) Tlf: + 47 / 67 16 5880

Ελλάδα Österreich
UCB Α.Ε. UCB Pharma GmbH
Τηλ: + 30 / 2109974000 Tel: + 43-(0)1 291 80 00

España Polska
UCB Pharma, S.A. UCB Pharma Sp. z o.o. / VEDIM Sp. z o.o.
Tel: + 34 / 91 570 34 44 Tel: + 48 22 696 99 20

France Portugal
UCB Pharma S.A. UCB Pharma (Produtos Farmacêuticos), Lda
Tél: + 33 / (0)1 47 29 44 35 Tel: + 351 / 21 302 5300

Hrvatska România
Medis Adria d.o.o. UCB Pharma Romania S.R.L.
Tel: +385 (0) 1 230 34 46 Tel: + 40 21 300 29 04

Ireland Slovenija
UCB (Pharma) Ireland Ltd. Medis, d.o.o.
Tel: + 353 / (0)1-46 37 395 Tel: + 386 1 589 69 00

Ísland Slovenská republika

Vistor hf. UCB s.r.o., organizačná zložka
Simi: + 354 535 7000 Tel: + 421 (0) 2 5920 2020

Italia Suomi/Finland
UCB Pharma S.p.A. UCB Pharma Oy Finland
Tel: + 39 / 02 300 791 Puh/Tel: + 358 9 2514 4221

Κύπρος Sverige
Lifepharma (Z.A.M.) Ltd UCB Nordic A/S
Τηλ: + 357 22 05 63 00 Tel: + 46 / (0) 40 29 49 00

Latvija
UCB Pharma Oy Finland
Tel: + 358 9 2514 4221 (Somija)

This leaflet was last revised in {month YYYY}.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency website:
[Link]

114
 Package leaflet: Information for the patient

Briviact 10mg/ml solution for injection/infusion

brivaracetam

Read all of this leaflet carefully before you start using this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Briviact is and what it is used for
2. What you need to know before you use Briviact
3. How to use Briviact
4. Possible side effects
5. How to store Briviact
6. Contents of the pack and other information

1. What Briviact is and what it is used for

What Briviact is
Briviact contains the active substance brivaracetam. It belongs to a group of medicines called
‘anti-epileptics’. These medicines are used to treat epilepsy.

What Briviact is used for

• Briviact is used in adults, adolescents and children from 2 years of age.
• It is used to treat a type of epilepsy that has partial seizures with or without a secondary
generalisation.
• Partial seizures are fits that start by only affecting one side of the brain. These partial seizures
can spread and extend to larger areas on both sides of the brain – this is called a ‘secondary
generalisation’.
• You have been given this medicine to lower the number of fits (seizures) you have.
• Briviact is used together with other medicines for epilepsy.

2. What you need to know before you take Briviact

Do not use Briviact if:

- you are allergic to brivaracetam, other similar chemical compounds as levetiracetam or
piracetam or any of the other ingredients of this medicine (listed in section 6). If you are not
sure, talk to your doctor or pharmacist before taking Briviact.
- you have ever developed as severe skin rash or skin peeling, blistering and/or mouth sores after
taking Briviact.
Serious skin reactions including Stevens-Johnson syndrome have been reported in association
with Briviact treatment. Stop using Briviact and seek medical attention immediately if you
notice any of the symptoms related to these serious skin reactions described in section 4.

115
Warnings and precautions
Talk to your doctor or pharmacist before using Briviact if:
- You have thoughts of harming or killing yourself. A small number of people being treated with
anti-epileptic medicines such as Briviact have had thoughts of harming or killing themselves. If
you have any of these thoughts at any time, contact your doctor immediately.
- You have liver problems - your doctor may need to adjust your dose.

Children
Briviact is not recommended for use in children under 2 years of age.

Other medicines and Briviact

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines.

In particular, tell your doctor if you are taking any of the following medicines – this is because your
doctor may need to adjust your Briviact dose:
- Rifampicin - a medicine used to treat bacterial infections.
- St John’s wort (also known as Hypericum perforatum) - a herbal medicine used to treat
depression and anxiety as well as other conditions.

Briviact with alcohol

- Combining this medicine with alcohol is not recommended.
- If you drink alcohol while taking Briviact the negative effects of alcohol may be increased.

Pregnancy and breast-feeding

Fertile women should discuss the use of contraceptives with the doctor.

If you are pregnant or breast-feeding, think you may be pregnant or planning to have a baby, ask your
doctor or pharmacist for advice before taking this medicine.

It is not recommended to take Briviact if you are pregnant, as the effects of Briviact on pregnancy and
the unborn baby are not known.
It is not recommended to breast-feed your baby while taking Briviact, as Briviact passes into breast
milk.

Do not stop treatment without talking to your doctor first. Stopping treatment could increase your
seizures and harm your baby.

Driving and using machines

- You may feel sleepy, dizzy or tired while using Briviact.
- These effects are more likely at the start of the treatment or after a dose increase.
- Do not drive, cycle or use any tools or machines until you know how the medicine affects you.

Briviact contains sodium

This medicine contains 19.1 mg sodium (main component of cooking/table salt) in each vial. This is
equivalent to 1 % of the recommended maximum daily dietary intake of sodium for an adult.

3. How to use Briviact

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if
you are not sure.

You will use Briviact together with other medicines for epilepsy.

- When you start taking this medicine you will take Briviact orally (as tablets or an oral solution)
or be given it as an injection or infusion.

116
- Briviact solution for injection/infusion is used for a short amount of time when you cannot take
Briviact orally.
- You can switch between taking Briviact orally to the solution for injection/infusion, and the
other way around.

How much you will be given

Your doctor will work out the right daily dose for [Link] the daily dose in two equal divided doses,
approximately 12 hours apart.

Adolescents and children weighing 50 kg or more, and adults

- The recommended dose is from 25 mg to 100 mg taken twice a day. Your doctor may then
decide to adjust your dose to find the best dose for you.

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

- Your doctor may prescribe the injection only for a few days if you cannot take your medicine by
mouth.
- The recommended dose is from 0.5 mg to 2 mg for each kg of bodyweight, taken twice a day.
Your doctor may then decide to adjust your dose to find the best dose for you.

Children weighing from 10 kg to less than 20 kg

- Your child’s doctor may prescribe the injection only for a few days if your child cannot take the
medicine by mouth.
- The recommended dose is from 0.5 mg to 2.5 mg for each kg of bodyweight, taken twice a day.
Your child’s doctor may then decide to adjust your child’s dose to find the best dose for your
child.

People with liver problems

If you have problems with your liver:
- As an adolescent or child weighing 50 kg or more, or as an adult, the maximum dose you will
take is 75 mg twice a day.
- As an adolescent or child weighing from 20 kg to less than 50 kg, the maximum dose you will
take is 1.5 mg for each kg of bodyweight twice a day.
- As a child weighing from 10 kg to less than 20 kg, the maximum dose your child will take is
2 mg for each kg of bodyweight twice a day.

How Briviact is given

Briviact is administered as an injection or infusion into a vein by a doctor or a nurse. The medicine is
injected slowly into your vein or given as an infusion (drip) over 15 minutes.

How long to use Briviact for

- Your doctor will decide for how many days you will be given the injections or infusion.
- For the long term treatment with Briviact, your doctor will ask to you to take Briviact tablets or
oral solution.

If you have more Briviact than you should

If you think you have been given too much Briviact, tell your doctor straight away.

If you stop using Briviact

- Do not stop taking this medicine unless your doctor tells you to. This is because stopping
treatment could increase the number of fits you have.
- If your doctor asks you to stop taking this medicine they will lower your dose gradually. This
helps to stop your fits coming back or getting worse.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

117
4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common: may affect more than 1 in 10 people

- feeling sleepy or dizzy

Common: may affect up to 1 in 10 people

- flu
- feeling very tired (fatigue)
- convulsion, a feeling of ‘spinning’ (vertigo)
- feeling and being sick, constipation
- pain or discomfort at the injection or infusion site
- depression, anxiety, not being able to sleep (insomnia), irritability
- infections of the nose and throat (such as the ‘common cold’), cough
- decrease appetite

Uncommon: may affect up to 1 in 100 people

- allergic reactions
- abnormal thinking and/or loss of touch with reality (psychotic disorder), being aggressive,
nervous excitement (agitation)
- thoughts or attempts of harming or killing yourself: tell your doctor straight away
- a decrease in white blood cells (called ‘neutropenia’) - shown in blood tests

Not known: frequency cannot be estimated from the available data

- a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and
genitals (Stevens-Johnson syndrome)

Additional side effects in children

Common: may affect up to 1 in 10 people

- restlessness and hyperactivity (psychomotor hyperactivity)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V. By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store Briviact

- Keep this medicine out of the sight and reach of children.

- Do not use this medicine after the expiry date which is stated on the carton and vial after EXP.
The expiry date refers to the last day of that month.
- Briviact may be diluted before it is injected by your doctor or nurse. In such cases, it should be
used straight after dilution.
- This medicinal product does not require any special storage conditions.
- Each vial of Briviact solution for injection/infusion must be used only once (single use). Any
unused solution should be discarded.
- Only clear solution free from particles and discoloration should be used.
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how
to throw away medicines you no longer use. These measures will help protect the environment.

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6. Contents of the pack and other information

What Briviact contains

The active substance is brivaracetam.
- Each ml contains 10 mg brivaracetam
- Each 5 ml vial contains 50 mg brivaracetam

The other ingredients are: sodium acetate (trihydrate), glacial acetic acid , sodium chloride, water for
injections.

What Briviact looks like and contents of the pack

Briviact 10 mg/ml solution for injection/infusion is a clear, colourless, sterile solution.
Briviact 10 mg/ml solution for injection/infusion 5 ml vial is packed in a carton box of 10 vials.

Marketing Authorisation Holder

UCB Pharma S.A., Allée de la Recherche 60, B-1070 Bruxelles, Belgium.

Manufacturer
UCB Pharma S.A., Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium.

For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

België/Belgique/Belgien Lietuva
UCB Pharma SA/NV UCB Pharma Oy Finland
Tél/Tel: + 32 / (0)2 559 92 00 Tel: + 358 9 2514 4221 (Suomija)

България Luxembourg/Luxemburg
Ю СИ БИ България ЕООД UCB Pharma SA/NV
Teл.: + 359 (0) 2 962 30 49 Tél/Tel: + 32 / (0)2 559 92 00 (Belgique/Belgien)

Česká republika Magyarország

UCB s.r.o. UCB Magyarország Kft.
Tel: + 420 221 773 411 Tel.: + 36-(1) 391 0060

Danmark Malta
UCB Nordic A/S Pharmasud Ltd.
Tlf.: + 45 / 32 46 24 00 Tel: + 356 / 21 37 64 36

Deutschland Nederland
UCB Pharma GmbH UCB Pharma B.V.
Tel: + 49 /(0) 2173 48 4848 Tel.: + 31 / (0)76-573 11 40

Eesti Norge
UCB Pharma Oy Finland UCB Nordic A/S
Tel: + 358 9 2514 4221 (Soome) Tlf: + 47 / 67 16 5880

Ελλάδα Österreich
UCB Α.Ε. UCB Pharma GmbH
Τηλ: + 30 / 2109974000 Tel: + 43-(0)1 291 80 00

España Polska
UCB Pharma, S.A. UCB Pharma Sp. z o.o. / VEDIM Sp. z o.o.
Tel: + 34 / 91 570 34 44 Tel: + 48 22 696 99 20

119
France Portugal
UCB Pharma S.A. UCB Pharma (Produtos Farmacêuticos), Lda
Tél: + 33 / (0)1 47 29 44 35 Tel: + 351 / 21 302 5300

Hrvatska România
Medis Adria d.o.o. UCB Pharma Romania S.R.L.
Tel: +385 (0) 1 230 34 46 Tel: + 40 21 300 29 04

Ireland Slovenija
UCB (Pharma) Ireland Ltd. Medis, d.o.o.
Tel: + 353 / (0)1-46 37 395 Tel: + 386 1 589 69 00

Ísland Slovenská republika

Vistor hf. UCB s.r.o., organizačná zložka
Simi: + 354 535 7000 Tel: + 421 (0) 2 5920 2020

Italia Suomi/Finland
UCB Pharma S.p.A. UCB Pharma Oy Finland
Tel: + 39 / 02 300 791 Puh/Tel: + 358 9 2514 4221

Κύπρος Sverige
Lifepharma (Z.A.M.) Ltd UCB Nordic A/S
Τηλ: + 357 22 05 63 00 Tel: + 46 / (0) 40 29 49 00

Latvija
UCB Pharma Oy Finland
Tel: + 358 9 2514 4221 (Somija)

This leaflet was last revised in {month YYYY}.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
[Link]

The following information is intended for medical or healthcare professionals only

Briviact solution for injection/infusion can be administered as a bolus injection or as an infusion:

• Intravenous bolus: may be administered directly without dilution

• Intravenous infusion: may be administered over 15 minutes in a compatible diluent

Briviact may be diluted with the following solutions: sodium chloride 9 mg/ml (0.9 %), glucose
50 mg/ml (5 %) solution for injection or lactated Ringer’s solution.
Each vial of Briviact solution for injection/infusion must be used only once (single use). Any unused
solution should be discarded (see section 3).

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 ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS
OF THE MARKETING AUTHORISATION(S)

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Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for brivaracetam, the scientific
conclusions of PRAC are as follows:
In view of available data on Stevens-Johnson syndrome from spontaneous reports, including in 4
cases with close temporal relationship and positive dechallenge, and in view of a plausible
mechanism of action, the PRAC considers a causal relationship between brivaracetam and Stevens-
Johnson syndrome is at least a reasonable possibility. The PRAC concluded that the product
information of products containing brivaracetam should be amended accordingly.
Having reviewed the PRAC recommendation, the CHMP agrees with the PRAC overall
conclusions and grounds for recommendation.

Grounds for the variation to the terms of the marketing authorisation(s)

On the basis of the scientific conclusions for brivaracetam the CHMP is of the opinion that the
benefit-risk balance of the medicinal product(s) containing brivaracetam is unchanged subject to the
proposed changes to the product information
The CHMP recommends that the terms of the marketing authorisation(s) should be varied.

122