Brivaracetam

Strong enzyme inducers such as St John’s wort (Hypericum perforatum) may decrease the systemic exposure of brivaracetam. Therefore, starting or ending treatment with St John’s wort should be done with caution.

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. No clinical data are available in paediatric patients with hepatic impairment.

Brivaracetam is not recommended in end-stage renal disease patients undergoing dialysis due to lack of data.

Brivaracetam plasma concentrations are decreased when coadministered with strong enzyme inducing AEDs (carbamazepine, phenobarbital, phenytoin) but no dose adjustment is required.

^a based on a study involving the administration of a supratherapeutic dose of 400 mg/day brivaracetam.

Carbamazepine

Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. In controlled studies, the carbamazepine epoxide plasma concentration increased by a mean of 37%, 62% and 98% with little variability at brivaracetam doses of 50 mg/day, 100 mg/day and 200 mg/day respectively. No safety risks were observed. There was no additive effect of brivaracetam and valproate on the AUC of carbamazepine epoxide.

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.

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).

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.

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.

Fertility

No human data on the effect of brivaracetam on fertility are available. In rats, there was no effect on fertility with brivaracetam.

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.

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 placebocontrolled, fixed-dose studies safety database in subjects ≥16 years of age, are listed by System Organ Class and frequency. The frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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.

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. No clinical data are available in neonates.

Elderly

Of the 130 elderly subjects enrolled in the brivaracetam phase ⅔ 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.