Summary:Purpose: To study the interaction between lamotrigine (LTG) and hormonal contraception.Methods: LTG serum concentrations of female patients using either no hormonal contraception (n = 18), an ethinyl estradiol (EE)-containing (n = 11), or a progestogen (PG)-onlycontaining compound (n = 16) were analyzed. Patients were recruited prospectively, and blood samples were drawn during drug fasting and at steady-state conditions. Comedication with enzyme inducers, valproate, topiramate, or sertraline was not allowed. Some patients changed groups and thus served as their own controls. Samples were analyzed by a gas chromatography/ mass spectroscopy method. The Mann-Whitney U test was used for statistical comparison of the groups.Results: The LTG serum concentration-to-dose ratio (CDR), expressed as (mg/L)/(mg/d) was significantly lower in women using EE than in the control group (mean ± SD, 0.010 ± 0.004 vs. 0.017 ± 0.006; p = 0.003). The CDR in women using PG was 0.02 ± 0.007, which was not statistically different from controls. No difference was found in CDR between women using either oral, topical, or parenteral PG. Five women switched from the control to the EE group and experienced a considerable reduction in CDR. An increase of the CDR toward control level was seen in the two women who changed from EE to PG.Conclusions: It is the EE component of oral contraceptives that interacts with LTG. The PG-only compounds did not alter LTG serum concentrations in this study. These findings should be considered when counselling women with epilepsy in the childbearing ages.

Background and objectiveLaboratories sometimes use different reference ranges for the same antiepileptic drug (AED), particularly for new and poorly investigated drugs. This may contribute to misunderstandings, concerns or inappropriate dose changes, which in turn may affect therapeutic effect, drug safety or treatment adherence. Therefore, the Norwegian Association of Clinical Pharmacology wished to update and harmonize the reference ranges for AEDs and establish national guidelines for Norway.MethodsA working group collected information on the reference ranges used by Norwegian laboratories for all commonly used AEDs. These reference ranges were compared to recent recommendations by the International League Against Epilepsy, current literature, applicable clinical studies, reference ranges used by leading Northern European epilepsy centers outside of Norway, and routine data derived from Norwegian laboratory databases.ResultsReference ranges varied between laboratories for four of 23 available AEDs (lamotrigine, valproate, eslicarbazepine and oxcarbazepine). For four AEDs (brivaracetam, perampanel, stiripentol and sulthiame), reference ranges had not previously been established. In total, 13 reference ranges were either harmonized, updated or newly established. No changes were applied to the remaining 10 AEDs.ConclusionUpdated and harmonized reference ranges are now available for 22 of the 23 AEDs available in Norway. The exception is vigabatrin (reference range not applicable). Revision of reference ranges is an important part of pharmacovigilance of AEDs and must be a continuous process based on current literature and clinical experience.

Antiepileptic drugs (AEDs) are effective against seizures, but their use is often limited by adverse effects, among them psychiatric and behavioral ones including aggressive behavior (AB). Knowledge of the incidence, risk factors, and the underlying mechanisms of AB induced by AEDs may help to facilitate management and reduce the risk of such side effects. The exact incidence of AB as an adverse effect of AEDs is difficult to estimate, but frequencies up to 16% have been reported. Primarily, levetiracetam (LEV), perampanel (PER), and topiramate (TPM), which have diverse mechanisms of action, have been associated with AB. Currently, there is no evidence for a specific pharmacological mechanism solely explaining the increased incidence of AB with LEV, PER, and TPM. Serotonin (5-HT) and GABA, and particularly glutamate (via the AMPA receptor), seem to play key roles. Other mechanisms involve hormones, epigenetics, and “alternative psychosis” and related phenomena. Increased individual susceptibility due to an underlying neurological and/or a mental health disorder may further explain why people with epilepsy are at an increased risk of AB when using AEDs. Remarkably, AB may occur with a delay of weeks or months after start of treatment. Information to patients, relatives, and caregivers, as well as sufficient clinical follow-up, is crucial, and there is a need for further research to understand the complex relationship between AED mechanisms of action and the induction/worsening of AB.

Serum concentrations of LEV declined significantly in the third trimester of pregnancy and increased rapidly after delivery.