Interactions : אינטראקציות

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.

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.

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 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 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 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).