Presentation and Status in Health Basket
Film Coated Tablets
14 X 10 mg
Film Coated Tablets
56 X 25 mg
Film Coated Tablets
56 X 50 mg
Film Coated Tablets
56 X 100 mg
Adults: The recommended starting dose is either 50 mg/day or 100 mg/day based on physician assessment of required seizure reduction versus potential side effects. The dose should be administered in two equally divided doses, once in the morning and once in the evening. Based on individual patient response and tolerability, the dose may be adjusted in the dose range of 50 mg/day to 200 mg/day.
Missed doses: If patients missed one dose or more, it is recommended that they take a single dose as soon as they remember and take the following dose at the usual morning or evening time. This may avoid the brivaracetam plasma concentration falling below the efficacy level and prevent breakthrough seizures
Discontinuation: If brivaracetam has to be discontinued it is recommended to withdraw it gradually by 50 mg/day on a weekly basis. After 1 week of treatment at 50 mg/day, a final week of treatment at the dose of 20 mg/day is recommended.
Elderly (65 years of age and above): No dose adjustment is needed in elderly patients. The clinical experience in patients ≥ 65 years is limited.
Renal impairment: No dose adjustment is needed in patients with impaired renal function. Brivaracetam is not recommended in end-stage renal disease patients undergoing dialysis due to lack of data.
Based on data in adults, no dose adjustment is necessary in paediatric patients with impaired renal function.
Hepatic impairment: Exposure to brivaracetam was increased in adult patients with chronic liver disease. In adults, a 50 mg/day starting dose should be considered. In children and adolecscents weighing 50 kg or greater, a 50 mg/day starting dose is recommended. A maximum daily dose of 150 mg administered in 2 divided doses is recommended for all stages of hepatic impairment.
In children and adolescents weighing less than 50 kg, a 1 mg/kg/day starting dose is recommended.
The maximum dose should not exceed 3 mg/kg/day. No clinical data are available in paediatric patients with hepatic impairment.
Paediatric population: The physician should prescribe the most appropriate formulation and strength according to weight and dose.
Table 1 at the attached doctor’s leaflet summarises the recommended posology for children from 4 years of age and adolescents.
Children (from 4 years of age) and adolescents weighing 50 kg or more: The recommended starting dose is 50mg/day. Brivaracetam may also be initiated at 100 mg/day based on physician assessment of need for seizure control. The dose should be administered in two equally divided doses, once in the morning and once in the evening. 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 and 200 mg/day.
Children (from 4 years of age) and adolescents weighing less than 50 kg: The recommended starting dose is 1 mg/kg/day. Brivaracetam may also be initiated at 2 mg/kg/day based on physician assessment of need for seizure control. The dose should be administered in two equally divided doses, once in the morning and once in the evening.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 and 4 mg/kg/day.
Children less than 4 years: The safety and efficacy of brivaracetam in children aged less than 4 years have not yet been established.
Currently available data are described in section 4.8, 5.1, and 5.2 at the attached doctor’s leaflet but no recommendation on a posology can be made.
Method of administration: Brivaracetam film-coated tablets must be taken orally swallowed in whole with liquid and may be taken with or without food.
Briviact is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in adults, adolescents and children from 4 years of age with epilepsy.
Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.
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 placebocontrolled trials of AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for brivaracetam.
Patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should any signs of suicidal ideation or behaviour emerge.
Hepatic impairment: There are limited clinical data on the use of brivaracetam in patients with pre-existing hepatic impairment. Dose adjustments are recommended for patients with hepatic impairment.
Lactose intolerance: Brivaracetam film-coated tablets contain lactose. Patients with rare heriditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The most frequently reported adverse reactions (>10 %) with brivaracetam treatment were: somnolence (14.3 %) and dizziness (11.0 %). They were usually mild to moderate in intensity.
Somnolence and fatigue (8.2 %) were reported at a higher incidence with increasing dose. The types of adverse reactions reported during the first 7 days of treatment were similar to those reported for the overall treatment period.
The adverse reactions most frequently resulting in discontinuation of brivaracetam therapy were dizziness (0.8 %) and convulsion (0.8 %).
See prescribing information for full details.
Formal interaction studies have only been performed in adults.
Concomitant treatment with levetiracetam: In the clinical studies, although the numbers were limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently. No additional safety or tolerability concern was observed.
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.
Effects of other agents on the pharmacokinetics of brivaracetam: In vitro data suggest that brivaracetam has a low interaction potential. The main disposition pathway of brivaracetam is by CYP-independent hydrolysis. A second disposition pathway involves hydroxylation mediated by CYP2C19.
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.
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 at the attached doctor’s leaflet).
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 200 mg/day may increase plasma concentrations of medicinal products transported by OAT3.
Potential interactions between brivaracetam (50 mg/day to 200 mg/day) and other AEDs were investigated in a pooled analysis of plasma drug concentrations from all phase 2-3 studies, in a population pharmacokinetic analysis of placebo-controlled phase 2-3 studies, and in dedicated drugdrug 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 at the attached doctor’s leaflet.
Carbamazepine: Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. In controlled studies, the carbamazepine epoxide plasma concentration increased by a mean of 37 %, 62 % and 98 % with little variability at brivaracetam doses of 50 mg/day, 100 mg/day and 200 mg/day respectively. No safety risks were observed. There was no additive effect of brivaracetam and valproate on the AUC of carbamazepine epoxide.
Co-administration of brivaracetam (100 mg/day) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) did not influence the pharmacokinetics of either substance.
When brivaracetam was coadministered at a dose of 400 mg/day (twice the recommended maximum daily dose) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg), a reduction in estrogen and progestin AUCs of 27 % and 23 %, respectively, was observed without impact on suppression of ovulation. There was generally no change in the concentration-time profiles of the endogenous markers estradiol, progesterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG).
Pregnancy and Lactation
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. The potential risk for humans is unknown. Animal studies did not detect any teratogenic potential of brivaracetam.
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. 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).
Lactation: It is unknown whether brivaracetam is excreted in human breast milk. Studies in rats have shown excretion of brivaracetam in 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.
Symptoms: There is limited clinical experience with brivaracetam overdose in humans. Somnolence and dizziness have been reported in a healthy subject taking a single dose of 1,400 mg of brivaracetam.
Management: 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.