Estrogens and Lamotrigine: New Developments

Practitioners have known for almost 2 decades that oral contraceptives (OCs) consistently and substantially reduce the serum concentrations of lamotrigine and may reduce seizure control. This mechanism appears to be caused by the induction of lamotrigine glucuronidation by OCs.

Let’s look at 3 more-recent discoveries related to the interaction that provide important new insights. First, a recent case report demonstrated that the interaction may be problematic in patients with bipolar disorder as well as those with seizures. Second, there is evidence that the interaction may be mitigated by other drugs, specifically valproic acid. Finally, it appears that lamotrigine levels may also be reduced by hormone replacement therapy (HRT).

Case Report

A 23-year-old woman taking an OC (1 mg norethisterone + 0.035 mg ethinyl estradiol) was started on lamotrigine 400 mg/day for bipolar disorder.¹ After several weeks, her lamotrigine serum concentrations were quite low, and her bipolar disorder had not improved. She was then switched sequentially to lithium, valproic acid, and carbamazepine, but they were all ineffective, and some had adverse events. Her health care provider then substituted leuprorelin for her OC and restarted lamotrigine at the original dose (400 mg/day), leading to therapeutic lamotrigine concentrations and effective stabilization of her bipolar disorder. This case is consistent with the findings in patients taking lamotrigine for seizures, and the interaction is rated “probable” using the Drug Interaction Probability Scale.²

Influence of Comedication

In a prospective study in women taking lamotrigine for epilepsy, the effect of an additional antiepileptic drug on the lamotrigine—OC interaction was studied.³ In women on lamotrigine monotherapy or on lamotrigine plus carbamazepine, lamotrigine clearance fell as expected during the OC-free week. However, in patients on lamotrigine plus valproic acid, there was no change in lamotrigine clearance during the OC-free week. The study was small, and more data are needed, but it does suggest that the expected lamotrigine—OC interaction does not occur in patients also taking valproic acid.

Valproic acid is known to inhibit uridine diphosphate—glucuronyltransferase (UGT) activity, so it is possible that UGT inhibition by valproic acid interferes with the UGT induction caused by OCs. Clinically, it is important to consider that valproic acid may inhibit the lamotrigine–OC interaction because anticipatory dose adjustments of lamotrigine when starting or stopping OCs could result in lamotrigine levels that are too high, leading to adverse outcomes, or too low, leading to seizures.

Effect of HRT on Lamotrigine

In a case-control study, women taking lamotrigine with ethinyl estradiol or HRT were matched with controls taking lamotrigine without concurrent estrogen therapy. When lamotrigine serum concentration-to-dose ratios (CDRs) were calculated, both the women on ethinyl estradiol and those on HRT had significantly lower lamotrigine CDRs than women taking lamotrigine in the absence of estrogens. Given that this was a retrospective case-control study, confirmation of this effect is needed, ideally with a prospective controlled study. However, the results are consistent with a report describing 2 women on lamotrigine who developed reduced lamotrigine serum concentrations after HRT was started, one of whom had increased seizure frequency.⁴

The effect of HRT on lamotrigine is interesting because theoretically, HRT should simply restore serum estrogen concentrations to physiologic premenopausal levels. But the available evidence does suggest that HRT may reduce lamotrigine serum concentrations and efficacy.

Conclusion

The ability of OCs to substantially reduce lamotrigine serum concentrations is well documented and may necessitate adjustments in lamotrigine dosege. The interaction is also likely to occur when lamotrigine is used for bipolar disorder or other indications, and some evidence suggests that it may occur with the use of HRT as well as OCs. In patients with epilepsy, the presence of valproic acid may mitigate the interaction. This means that stopping or starting valproic acid may cause the lamotrigine—OC interaction to appear or disappear, effects that are very unlikely to be accounted for by computerized clinical decision support systems.

John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD, are professors of pharmacy at the University of Washington School of Pharmacy in Seattle.

References

• Sawagashira R, Fujii Y, Kusumi I. Clinical pharmacokinetic interactions between lamotrigine and hormonal contraceptives in bipolar I disorder. Psychiatry Clin Neurosci. 2017;71(4):290. doi: 10.1111/pcn.12512.
• Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother. 2007;41(4):674-680. doi: 10.1345/aph.1H423.
• Wegner I, Wilhelm AJ, Lambrechts DA, Sander JW, Lindhout D. Effect of oral contraceptives on lamotrigine levels depends on comedication. Acta Neurol Scand. 2014;129(6):393-398. doi: 10.1111/ane.12197.
• Harden CL, Herzog AG, Nikolov BG, et al. Hormone replacement therapy in women with epilepsy: a randomized, double-blind, placebo-controlled study. Epilepsia. 2006;47(9):1447-1551. doi: 10.1111/j.1528-1167.2006.00507.x.