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Lamotrigine is an anticonvulsant drug for the treatment of partial seizures and primary and secondary generalized tonic-clonic seizures in adults and children . It can be used either as monotherapy or in combination with other drugs. In addition, lamotrigine is approved in some countries for the treatment of bipolar I disorder in adults.
Lamotrigine may be a desirable treatment option for women with epilepsy because it is not associated with weight gain and does not disrupt the menstrual cycle . However, the co-administration of anticonvulsants and oral contraceptives may be associated with drug interactions . Many anticonvulsants have hepatic enzyme-inducing properties , and effects that increase clearance or decrease absorption of the active components may lessen the efficacy of oral contraceptives. Similarly, the use of the latter may increase the metabolism of drugs like lamotrigine, whose major route of elimination is by glucuronidation [5–7]. Recent case reports of increased seizure frequency or recurrence of seizures following treatment with, and adverse events after withdrawal of oral contraceptives, were associated with decreased lamotrigine concentrations [8, 9].
Therefore, a study was conducted to examine the effect of co-administration of a combined oral contraceptive (ethinyloestradiol plus levonorgestrel) on the pharmacokinetics of lamotrigine, and also the effect of lamotrigine on the pharmacokinetics of the oral contraceptive.
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Of the 22 subjects enrolled, 16 completed the study. Six subjects (27%) were prematurely withdrawn due to dizziness in association with ataxia (3 subjects), diplopia (1 subject), visual hallucinations (1 subject), or nausea (1 subject). Originally, lamotrigine was to have been titrated to 500 mg day−1 but, following the occurrence of central nervous system adverse events at 400 mg day−1 and the consequent withdrawal of 5 subjects, the maximum lamotrigine dose was decreased to 300 mg day−1. One other subject, receiving 200 mg day−1 of lamotrigine, was also withdrawn. All 16 subjects who completed the study received 300 mg lamotrigine for at least 3 weeks prior to blood sampling on day 105.
Median serum concentration-time profiles for lamotrigine in the presence and absence of the combined oral contraceptive are displayed in Figure 1. Lamotrigine tmax was between 0.5 and 4 h postdose, irrespective of the drug regimen. The mean ratios of lamotrigine Cmax and AUC(0,24 h) for the comparison of lamotrigine + combined oral contraceptive : lamotrigine alone were 0.61 (a 39% decrease) and 0.48 (a 52% decrease), respectively, with the 90% CIs of these ratios being outside of the acceptance range (0.75–1.33) (Table 1). The observed decrease in lamotrigine AUC(0,24 h) translates to an approximate 2.1-fold increase in apparent lamotrigine oral clearance in the presence of the combined oral contraceptive.
Figure 1. Median (n = 16) serum lamotrigine concentration-time profiles after oral administration of lamotrigine (300 mg) alone or with the combined oral contraceptive. Lamotrigine + combined oral contraceptive (day 105) (•), lamotrigine alone (day 126) (○)
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Table 1. Geometric mean (SD) pharmacokinetic parameters (n = 16) and statistical comparisons (ratios [90% CI]) for lamotrigine (LTG), ethinyloestradiol and levonorgestrel after administration of lamotrigine (300 mg) alone and with the combined oral contraceptive (COC)
| ||LTG + COC||Effect of COC on lamotrigine (LTG)|
|LTG||Ratio LTG + COC : LTG [90% CI]|
| Cmax (µg ml−1)||6.33 (1.43)||10.3 (1.91)||0.61 [0.57, 0.66]|
| AUC(0,24 h) (µg ml−1 h)||78.8 (31.0)||163 (42.7)||0.48 [0.44, 0.53]|
| ||LTG + COC||Effect of lamotrigine (LTG) on COC|
|COC||Ratio LTG + COC : COC [90% CI]|
| Cmax (pg ml−1)|| 91.7 (37.1)|| 89.5 (35.1)||1.02 [0.95, 1.10]|
| AUC(0,24 h) (pg ml−1 h)|| 785 (267)|| 849 (265)||0.93 [0.88, 0.97]|
| Cmax (pg ml−1)|| 6886 (1797)|| 7858 (2393)||0.88 [0.82, 0.93]|
| AUC(0,24 h) (pg ml−1 h)||79981 (21605)||98653 (33157)||0.81 [0.76, 0.86]|
Statistical analyses of predose serum lamotrigine concentrations indicated attainment of steady state on day 105 and on day 126. A stepped and marked rise in predose serum lamotrigine concentrations was observed during the pill-free week (days 106–112), with concentrations by day 112 being approximately 2-fold higher than during the combined oral contraceptive co-administration period (Table 2). Normalisation of lamotrigine clearance was incomplete by the end of the pill-free week, with predose concentrations on day 112 being approximately 80% of those achieved during the lamotrigine monotherapy period (Table 2).
Table 2. Mean (range) of predose serum lamotrigine concentrations and of individual ratios of predose concentrations during the pill-free week relative to combined oral contraceptive co-administration (days 103–105) or lamotrigine monotherapy (days 124–126)
| ||Predose concentration (µg ml−1)||Ratio relative to co-administration period||Ratio relative to monotherapy period|
|Days 103–105||2.02 (0.64–5.50),||–||–|
|Day 108||2.78 (0.99–7.12),||1.27 (0.92–1.63),||0.47 (0.21–0.84)|
|Day 110||3.15 (0.91–7.52),||1.63 (2.58–2.17),||0.60 (0.16–0.88)|
|Day 112||4.05 (1.79–8.02),||2.16 (1.39–2.94),||0.77 (0.47–0.98)|
|Days 124–126||5.30 (2.44–8.98)|| || |
The median plasma concentration-time profiles of ethinyloestradiol and levonorgestrel administered with and without lamotrigine are shown in Figure 2. Peak concentrations were observed between 1.0 and 3 h postdose for ethinyloestradiol and 0.5 and 3 h postdose for levonorgestrel, irrespective of the drug regimen. All 90% CIs for ethinyloestradiol and levonorgestrel Cmax and AUC(0,24 h) for the ratio lamotrigine + combined oral contraceptive : combined oral contraceptive alone were inside the acceptance range 0.70–1.43 (Table 1). However, there was a mean 12% decrease in Cmax and 19% decrease in AUC(0,24 h) for levonorgestrel when the combined oral contraceptive was co-administered with lamotrigine. Statistical analysis of predose ethinyloestradiol and levonorgestrel concentrations indicated that steady-state conditions had been attained for each compound prior to the pharmacokinetic profiling.
Figure 2. Median (n = 16) plasma ethinyloestradiol alone (day 21) (○), ethinyloestradiol + LTG (day 105) (•) (A) and levonorgestrel alone (day 21) (○), levonorgestrel + LTG (day 105) (B) concentration-time profiles after oral administration of the combined oral contraceptive alone (n = 16) or with lamotrigine
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During co-administration of lamotrigine with the combined oral contraceptive there was, on average, a 4.7-fold increase in serum FSH, a 3.4-fold increase in serum LH and a relatively small increase in serum oestradiol, compared with combined oral contraceptive therapy alone (Table 3a). Individual values for serum FSH and LH increased in most subjects, whereas individual values for serum oestradiol remained below 73 pmol l−1 in 9 of the 16 subjects during lamotrigine co-administration. There was a marginal increase in serum oestradiol in 6 subjects, to a maximum of 118 pmol l−1, and, in one subject, there was a larger increase, to 279 pmol l−1. There was a poor correlation between changes in LH, FSH, oestradiol and changes in levonorgestrel exposure (data not shown). During co-administration of lamotrigine and the combined oral contraceptive there was, on average, a slight decrease in serum progesterone (Table 3b). There was no clear pattern to individual changes in serum progesterone.
Table 3. Serum hormone concentrations following administration of the combined oral contraceptive (COC) alone or with lamotrigine (300 mg)
|(a) FSH, LH, oestradiol and SHBG|
|Hormone||Day 5 to day 7 (COC alone) (n = 22)||Day 89 to day 91 (COC + lamotrigine 300 mg) (n = 16)|
|Geometric mean||Range||Geometric mean||Range|
|FSH (IU l−1)a||1.02||<0.50–5.20||4.80||0.94–12.5|
|LH (MIU l−1)a||0.70||<0.50–3.20||2.40||<0.5–8.90|
|Oestradiol (pmol l−1)b||<73.0c||<73.0c||86.8||<73.0–279|
|SHBG (nmol l−1)||158||50.0–375||115||57.0–242|
|Hormone||Day 20 to day 22 (COC alone) (n = 22)||Day 104 to day 106 (COC + lamotrigine 300 mg) (n = 16)|
|Geometric mean||Range||Geometric mean||Range|
|Progesterone (nmol l−1)a||1.47||<1.00–2.90||1.28||<1.00–2.20|
There was, also, a slight decrease in the geometric mean and maximum values for serum SHBG, during co-administration of lamotrigine with the combined oral contraceptive, compared with administration of the combined oral contraceptive alone (Table 3a). However, there was no detectable change in the minimum values for serum SHBG.
Data are reported from the 22 subjects who initially enrolled in the study. The most frequently reported adverse events (>2 subjects) were headache, dizziness, skin rash, nausea, upper respiratory tract infection, fatigue, metrorrhagia, diplopia, ataxia, insomnia and gastroenteritis. None of the rashes was severe, and no subjects discontinued the study medication for this reason. Dizziness, diplopia and ataxia occurred primarily in subjects who received lamotrigine 400 mg day−1. Intermenstrual bleeding (metrorrhagia or vaginal haemorrhage), which was only observed during the period of co-administration of lamotrigine and the combined oral contraceptive, was reported by 7/22 (32%) of subjects; there was no clear relationship between the dose of lamotrigine, or the increase in FSH and LH serum concentrations, and the observed episodes of intermenstrual bleeding.
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Serum concentrations of lamotrigine decreased (by, an average, 39% in Cmax and 52% in AUC(0,24 h)) during co-administration with the combined oral contraceptive. We consider that this halving of systemic exposure is clinically important with direct implications for the dosing of lamotrigine in women who start or stop a combined oral contraceptive. Thus, a dosage adjustment for lamotrigine may be necessary when these agents are co-administered.
The effect of the combined oral contraceptive on lamotrigine disposition in the present prospective study is in close agreement with the earlier findings of Sabers et al.[8, 9]. In a retrospective report of 7 patients in whom plasma lamotrigine concentrations were decreased (by a mean of 49%), it was concluded that the interaction between oral contraceptives and lamotrigine was clinically relevant and associated with changes in seizure frequency/recurrence upon addition, or adverse effects following withdrawal, of an oral contraceptive . Subsequently, Sabers et al. reported that the mean plasma lamotrigine concentration was 13 µmol l−1 (≈ 3.3 µg ml−1) in 22 women taking lamotrigine plus an oral contraceptive, compared with 28 µmol l−1 in 30 women on lamotrigine alone .
The two-fold increase in lamotrigine clearance in the presence of the combined oral contraceptive is similar to the effects of known hepatic enzyme-inducing drugs  and is consistent with reports that oral contraceptives can increase the metabolism of glucuronidated drugs by induction of the uridine diphosphate glucuronosyltransferase system [5–7].
Predose serum lamotrigine concentrations increased in a fairly rapid and linear manner during the ‘pill-free’ week, with concentrations at the end of that week being, on average, approximately two-fold higher than during co-administration of the combined oral contraceptive. However, complete normalization of lamotrigine clearance was not attained by the end of the ‘pill-free’ week.
A previous study has shown no effect of lamotrigine on the disposition of the components of a combined oral contraceptive. However, no formal pharmacokinetic evaluation was undertaken and only the 12 h postdose concentrations were compared . In the present study the Cmax and AUC(0,24 h) of ethinyloestradiol were found to be comparable when administered with and without lamotrigine. However, those of levonorgestrel were 12% and 19% lower, respectively, during lamotrigine co-administration. The magnitude of these changes did not meet the predefined criteria for clinical relevance. Levonorgestrel AUC has been shown to be decreased by 42% by phenytoin , 40% by carbamazepine  and 32% by oxcarbazepine . In another report, the anticonvulsant agent felbamate was shown to cause a 42% decrease in the AUC(0,24 h) of gestodene but did not have a clinically relevant effect on exposure to ethinyloestradiol .
Although the mechanism of the selective effect of lamotrigine on levonorgestrel is unknown, a modest induction of clearance appears to be the most plausible explanation. Direct glucuronidation of levonorgestrel is a relatively minor route of its metabolism . Thus, the present findings would indicate that direct glucuronidation of levonorgestrel is either greater than has been previously established or that lamotrigine has an effect on the hydroxylation and sulphation of levonorgestrel. Based on results of drug interaction studies conducted with lamotrigine , a lack of effect on urinary 6β-hydroxycortisol excretion , and on the relatively minor effect of lamotrigine on ethinyloestradiol exposure (present study), lamotrigine is probably not an inducer of cytochrome P450 enzymes.
A small decrease in mean serum progesterone was observed on co-administration of lamotrigine (300 mg) with the combined oral contraceptive, compared with administration of the combined oral contraceptive alone. Serum progesterone values exceeding 5.1 nmol l−1 would have indicated that ovulation had probably occurred. For all subjects studied, and in both pill cycles, serum progesterone values remained well below 5.1 nmol l−1, indicating maintenance of contraceptive efficacy during the period of co-administration.
Large increases in serum FSH and LH were observed on co-administration of lamotrigine (300 mg) with the combined oral contraceptive. A relatively small increase in serum oestradiol was also observed. These changes may have occurred as a consequence of the lower plasma concentrations of levonorgestrel observed during the period of coadministration of lamotrigine and the combined oral contraceptive, although there was a poor correlation between changes in LH, FSH and oestradiol and those in levonorgestrel exposure. Taken together, the observed changes in serum FSH, LH and oestradiol may indicate the potential for some loss of suppression of the hypothalamic-pituitary-ovarian axis during the period of co-administration of lamotrigine and the combined oral contraceptive. However, complete suppression of ovarian follicular activity does not necessarily occur with oral contraceptive use [18, 19].
Intermenstrual bleeding was reported by 32% of subjects during the period of co-administration of lamotrigine and combined oral contraceptive, which may indicate some loss of cycle control. However, there was no clear pattern to the intermenstrual bleeding with respect to the day of the pill cycle on which it started, or the duration of the bleeding. The absence of the any clear relationship between the dose of lamotrigine at which episodes of intermenstrual bleeding occurred, and the lack of a placebo control group with which to compare the incidence of intermenstrual bleeding, makes it difficult to draw conclusions about this observation. Furthermore, there appears to be no direct evidence to relate less effective cycle control to increased ovarian activity  or impaired contraceptive efficacy . Any future evaluation of these hormonal findings would benefit from a more extensive temporal evaluation of the pharmacodynamic parameters, and a closer examination of changes in menstrual pattern by using a placebo group.
In general, lamotrigine was well-tolerated at doses of up to 300 mg day−1 when co-administered with the combined oral contraceptive, and the observed adverse events were typical of previous studies of lamotrigine conducted in healthy subjects. An increased incidence of central nervous system adverse events was observed when the dose was increased from 300 mg to 400 mg, characterized primarily by dizziness. The effects of lamotrigine on the central nervous system are well-recognized, and typically occur when the dose is being increased. The severity of symptoms experienced by some subjects may have been the consequence of increasing the dose of lamotrigine to 400 mg on the same day as starting a pill-free week, when the normalization of lamotrigine clearance is occurring.
In conclusion, a clinically relevant effect of a combined oral contraceptive on the pharmacokinetics of lamotrigine was observed, and a dosage adjustment for lamotrigine may be necessary when this combination is administered. Lamotrigine had a modest effect on the pharmacokinetics of levonorgestrel and, although there may have been some loss of suppression of ovarian activity during co-administration, no subjects showed hormonal evidence of ovulation.