Oral contraceptives reduce lamotrigine plasma levels
Sabers A, Ohman I, Christensen J and Tomson T;
Commented by , 25 Sep 2003
Background
Many antiepileptic drugs (AEDs) stimulate the metabolism of oral contraceptive steroids, thereby reducing contraceptive efficacy. A small case series suggested that a reverse interaction occurs with lamotrigine, i.e. that oral contraceptives may lower plasma lamotrigine levels markedly (1).
Aim
To assess the influence of steroid contraceptive steroids on plasma lamotrigine levels in women receiving stable lamotrigine therapy.
Methods
Retrospective assessment of plasma lamotrigine levels within a therapeutic drug monitoring service.
Women aged 15 to 30 years, stabilized on lamotrigine alone or combined with non-interacting drugs, were included.
When information was not available from medical records, women were sent a questionnaire enquiring whether they were using a combined oral contraceptive (ethinylestradiol and levonorgestrel/desogestrel) at the time of sampling.
Plasma lamotrigine levels in women on oral contraceptives were compared with those in women not on contraceptives (controls).
Results
Data were available for 22 women taking oral contraceptives and 30 controls.
Mean steady-state plasma lamotrigine levels in women on oral contraceptives were less than one-half those found in controls (13 vs 28 mmol/L, p<0.0001), despite similar lamotrigine dosages in the two groups (349 vs 327 mg/day).
The ratio of lamotrigine dose/body weight/plasma concentration in women on oral contraceptives was more than twice as high that found in controls (2.1 L/kg/day vs 0.8 L/kg/day, p<0.0001).
Discussion
Despite the methodological limitations of the retrospective design, this study demonstrates that women taking oral contraceptives show markedly reduced plasma lamotrigine levels.
This is probably due to induction of lamotrigine glucuronidation. Oral contraceptives steroids have been found to induce the metabolism of other glucuronidated drugs such as paracetamol (2) and clofibrate (3).
The interaction is likely to have clinical relevance, as suggested by an earlier report describing seizure deterioration after oral contraceptives had been added, or adverse effects following withdrawal of oral contraceptives, in a small group of women taking lamotrigine (4). Interestingly, lamotrigine levels decline markedly also during pregnancy (5).
It is striking that such a prominent effect escaped detection until now, despite the fact that lamotrigine is actively promoted as a treatment of choice in women. Failure to recognize the interaction may be due to the fact that monitoring lamotrigine concentrations is generally discouraged, an approach that has been criticized (6).
Some questions remain unanswered:
- does the magnitude of interaction change during the 7-day pill-free cycle, leading to fluctuations in lamotrigine levels?
- does the pattern of interaction change in women taking valproic acid, a powerful inhibitor of lamotrigine metabolism?
- does a similar interaction occur with contraceptive implants, or with the progesterone pill?
Physicians should be aware of this interaction. Careful observation of clinical response and, whenever possible, serial measurements of lamotrigine concentrations are recommended when oral contraceptives are added or withdrawn in women stabilized on lamotrigine.
References
- Sabers A, Bucholt JM, Uldall P et al. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Research 2001; 47; 151-154
- Miners JO, Attwood J, Birkett DJ. Influence of sex and oral contraceptives steroids on paracetamol metabolism. British Journal of Clinical Pharmacology 1983; 16; 503-509
- Miners JO, Robson RA, Birkett DJ. Gender and oral contraceptive steroids as determinants of drug glucuronidation: effects on clofibric acid elimination. British Journal of Clinical Pharmacology 1984; 18; 240-243
- Sabers A, Bucholt JM, Uldall P et al. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Research 2001; 47; 151-154
- Tran TA, Leppik IE, Blesi K et al. Lamotrigine clearance during pregnancy. Neurology 2002; 59; 251-255
- Perucca E. Is there a role for therapeutic drug monitoring of new anticonvulsants? Clinical Pharmacokinetics 2000; 38; 191-204