Brivaracetam MSN 50 mg film-coated tablets

4.1. Therapeutic indications

Brivaracetam MSN 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. 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 dose Therapeutic dose range* 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. 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 dose Recommended maximum daily dose Adolescents and children weighing 50 kg or more, and adults 50 mg/day 150 mg/day Adolescents and children weighing from 20 kg to less than 50 kg 1 mg/kg/day 3 mg/kg/day 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 Brivaracetam MSN 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. 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 This medicine 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 co-administered 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. 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 C max 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 C max ). Table 1: Pharmacokinetic interactions between brivaracetam and other AEDs AED coadministered Influence of AED on brivaracetam plasma concentration Influence of brivaracetam on AED plasma concentration Carbamazepine AUC 29 % ↓ C max 13 % ↓ No dose adjustment required Carbamazepine - None Carbamazepine-epoxide ↑ (See below) No dose adjustment required. Clobazam No data available None Clonazepam No data available None Lacosamide No data available None Lamotrigine None None Levetiracetam None None Oxcarbazepine None None (monohydroxy derivative, MHD) Phenobarbital AUC 19 % ↓ No dose adjustment required None Phenytoin AUC 21 % ↓ No dose adjustment required None a AUC 20% ↑ a C max 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. 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 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 infestations Common Influenza Blood and lymphatic system disorders Uncommon Neutropenia Immune system disorders Uncommon Type I hypersensitivity Metabolism and nutrition disorders Common Decreased appetite Psychiatric disorders Common Depression, anxiety, insomnia, irritability Uncommon Suicidal ideation, psychotic disorder, aggression, agitation Nervous system disorders Very common Dizziness, somnolence Common Convulsion, vertigo Respiratory, thoracic and mediastinal disorders Common Upper respiratory tract infections, cough Gastrointestinal disorders Common Nausea, vomiting, constipation Skin and subcutaneous tissue disorders Not known Stevens-Johnson syndrome (1) General disorders and administration site conditions Common Fatigue (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 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 1month 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 Yellow Card Scheme at http://www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

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).