Breaking the cycle: Lamotrigine and hormonal contraceptive interactions

Lamotrigine, a widely used medication for mood and seizure disorders, undergoes hepatic metabolism via uridine 5’-diphospho (UDP)-glucuronosyltransferases (UGTs).1,2 Estrogens in combined oral contraceptives (COCs) can increase the clearance of lamotrigine through enzymatic induction of the N-2-glucuronide pathway, leading to reduced serum levels of the drug.1,2 This interaction places patients at risk of subtherapeutic lamotrigine levels and consequentially breakthrough seizures or mood episodes (e.g., depression).2Females of reproductive age on lamotrigine do not exhibit significant variations in lamotrigine clearance during the menstrual cycle.3 However, in those taking COCs, lamotrigine serum levels have been found to decrease by 49% (range 41%–64%) within a week of COC initiation.4 During the hormone-free (“pill-free”) interval of COC use, lamotrigine serum levels can double (range 29%–129% higher than baseline levels) leading to toxicity.3 Furthermore, a double-blind, placebo-controlled study evaluating the effect of COCs on lamotrigine serum levels and urine excretion of lamotrigine metabolites in patients with epilepsy found that cessation of COCs leads to an 84% increase in lamotrigine serum levels.5 This change in lamotrigine concentrations occurred within one week of COC cessation, suggesting a rapid reversal of the enhancing effect of COCs on lamotrigine glucuronidation.5Adding another layer of complexity to lamotrigine and COC interactions, researchers identified that lamotrigine causes a 19% decrease in levonorgestrel plasma concentrations without corresponding hormonal evidence of ovulation.6 A more recent study suggested that lamotrigine had no effect on the levels of several oral progestins, but that specific progestins (i.e., drospirenone and levonorgestrel) appear to reduce lamotrigine serum levels.7Despite these documented interactions, real-world prescribing data show that it is rare for clinicians to adjust lamotrigine doses following initiation of exogenous estrogen therapy.8 Alarmingly, a qualitative study found that 51% of women taking lamotrigine were unaware of the interaction with their COCs.9Managing the interactionFemales with epilepsy or mood disorders on lamotrigine require careful monitoring when initiating or discontinuing COCs.10,11 Table 1 provides advice on how to manage various interaction scenarios between lamotrigine and COCs.Alternate contraceptive optionsPharmacists can help patients explore alternate contraceptive methods in patients requiring concurrent lamotrigine therapy:Extended-cycle COC or off-label continuous COC: If a COC is the preferred contraceptive method, an extended-cycle or continuous COC should be considered to minimize or avoid fluctuations in lamotrigine levels. The lamotrigine dose may need to be titrated higher compared to individuals not using a COC.Other estrogen-containing contraceptives: Vaginal rings and transdermal patches may also decrease lamotrigine levels. A retrospective chart review found that the vaginal ring decreased lamotrigine concentrations by 36%–70%, and a single patient on the transdermal patch experienced a 37% decrease in lamotrigine concentrations.13 Overall, this is not an ideal option with concurrent lamotrigine.Progestin-only intrauterine system: A pilot study suggests that levonorgestrel-releasing intrauterine systems are a safe long-acting contraceptive choice for women with epilepsy on lamotrigine.14 However, the study did find a median lamotrigine concentration reduction of 9% at day 21, which may suggest the need for increased lamotrigine doses in some patients.14 Additionally progestins may negatively impact mood, which could be a concern for some patients.15Nonhormonal methods: Barrier methods and copper intrauterine devices (IUDs) do not interact with lamotrigine and may be preferable over hormonal contraceptive methods.2,10,12Case studyPatient profile: Sarah, a 27-year-old female with epilepsy, has been seizure-free on lamotrigine (200 mg bid) for two years. She visits the pharmacy for a refill of her lamotrigine and presents a new prescription for a levonorgestrel–ethinyl estradiol COC.Pharmacist intervention: The pharmacist educates Sarah on the interaction, offers alternate contraceptive means (which Sarah declines), and advises her to monitor for increased seizure frequency after initiating the COC. The pharmacist also contacts Sarah’s neurologist to discuss increasing her lamotrigine dose. Additionally, Sarah is advised to use her COC continuously to avoid lamotrigine fluctuations during the pill-free week.Outcome: After titrating lamotrigine up by 50 mg po bid every seven days for four weeks to a new maintenance dose of 400 mg po bid, Sarah remains seizure-free. She experienced mild nausea from the COC during the first week, but has had no breakthrough bleeding and is now tolerating the combination well.SummaryPharmacists play a crucial role in identifying and managing the interaction between lamotrigine and hormonal contraceptives. By educating patients, coordinating lamotrigine dose adjustments with prescribers, and considering alternate contraceptive options, pharmacists can help females maintain seizure and/or psychiatric stability, as well as effective contraception.Katelyn Halpape is a clinical pharmacist at the Dube Centre for Mental Health in Saskatoon, SK, and an associate professor in the College of Pharmacy and Nutrition at the University of Saskatchewan.References:Öhman I, Luef G, Tomson T. Effects of pregnancy and contraception on lamotrigine disposition: new insights through analysis of lamotrigine metabolites. Seizure 2008;17(2):199-202.GlaxoSmithKline Inc. Lamictal (lamotrigine product monograph). Mississauga, ON; March 7, 2024. (accessed January 29, 2025).Wegner I, Edelbroek PM, Bulk S, et al. Lamotrigine kinetics within the menstrual cycle, after menopause, and with oral contraceptives. Neurology 2009;73(17):1388-93.Sabers A, Buchholt JM, Uldall P, et al. 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