Drug Interactions between Demulen 1/50 and topiramate

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with topiramate, particularly at dosages above 200 mg/day, may decrease the plasma concentrations and efficacy of contraceptive hormones. The proposed mechanism is topiramate induction of CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of steroidal hormones. In 45 healthy volunteers who received a combination oral contraceptive containing 1 mg norethindrone and 35 mcg ethinyl estradiol daily for one cycle in the absence of other medications, coadministration of topiramate 50 to 200 mg/day during a subsequent cycle was not associated with statistically significant nor dose-dependent changes in mean exposure (AUC) to either component of the contraceptive. The change in 6-beta-hydroxycortisol/cortisol ratio, which is a marker for CYP450 3A induction, was also not statistically significant during topiramate administration compared with baseline. However, changes in ethinyl estradiol exposure in individual subjects receiving topiramate 200 mg/day ranged from decreases of approximately 35% to 90% in five individuals to increases of approximately 35% to 60% in three individuals. In another study, 12 women receiving stable valproic acid monotherapy for epilepsy were given the same oral contraceptive formulation for one cycle (baseline), followed by coadministration of topiramate 100, 200, and 400 mg every 12 hours for cycles 2 through 4, respectively. Compared to baseline, mean exposure (AUC) to ethinyl estradiol was statistically significantly decreased by 18%, 21% and 30%, respectively, while exposure to norethindrone was not significantly affected during topiramate treatment at any dosage. The clinical significance of the observations from these studies is unknown. Although topiramate did not demonstrate significant effects on norethindrone at dosages up to 800 mg/day and had modest, dose-dependent effects on ethinyl estradiol only at dosages greater than 200 mg/day, marked changes may occur in some patients treated with topiramate due to substantial interindividual variability in sensitivity and susceptibility to enzyme induction. In addition, some enzyme-inducing anticonvulsants such as carbamazepine, phenytoin, and phenobarbital are known to enhance the plasma levels of sex hormone-binding globulin (SHBG). Since changes to SHBG were not evaluated in these studies, the possibility that unbound/free (i.e., biologically active) norethindrone levels may be impacted by topiramate cannot be ruled out.

MANAGEMENT: The potential for decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients using hormonal contraceptives (including oral, injectable, transdermal, and implantable forms) during treatment with topiramate, particularly at dosages above 200 mg/day. Some clinicians and manufacturers recommend that patients on topiramate dosages at or above 200 mg/day who are taking oral contraceptives should receive a preparation containing no less than 30 or 35 mcg of estrogen, while others recommend at least 50 mcg. Intrauterine systems are unlikely to be significantly affected because of their local action, thus they may be preferable to other routes of administration. Patients should be advised to report any change in their bleeding patterns, although contraceptive efficacy can be decreased even in the absence of breakthrough bleeding. Because use of topiramate can cause fetal harm, it is particularly important that patients not become pregnant during treatment. Counseling should be provided regarding the use of alternative (non-hormonal) or additional (back-up) pregnancy prevention methods during and for at least 28 days after discontinuing topiramate. Input from a gynecologist or similar expert on adequate contraception, including emergency contraception, should be sought as needed. Alternative, nonenzyme-inducing anticonvulsants that are not believed to interact significantly with hormonal contraceptives include clonazepam, ethosuximide, gabapentin, levetiracetam, pregabalin, tiagabine, valproic acid, vigabatrin, and zonisamide.

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ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with topiramate, particularly at dosages above 200 mg/day, may decrease the plasma concentrations and efficacy of contraceptive hormones. The proposed mechanism is topiramate induction of CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of steroidal hormones. In 45 healthy volunteers who received a combination oral contraceptive containing 1 mg norethindrone and 35 mcg ethinyl estradiol daily for one cycle in the absence of other medications, coadministration of topiramate 50 to 200 mg/day during a subsequent cycle was not associated with statistically significant nor dose-dependent changes in mean exposure (AUC) to either component of the contraceptive. The change in 6-beta-hydroxycortisol/cortisol ratio, which is a marker for CYP450 3A induction, was also not statistically significant during topiramate administration compared with baseline. However, changes in ethinyl estradiol exposure in individual subjects receiving topiramate 200 mg/day ranged from decreases of approximately 35% to 90% in five individuals to increases of approximately 35% to 60% in three individuals. In another study, 12 women receiving stable valproic acid monotherapy for epilepsy were given the same oral contraceptive formulation for one cycle (baseline), followed by coadministration of topiramate 100, 200, and 400 mg every 12 hours for cycles 2 through 4, respectively. Compared to baseline, mean exposure (AUC) to ethinyl estradiol was statistically significantly decreased by 18%, 21% and 30%, respectively, while exposure to norethindrone was not significantly affected during topiramate treatment at any dosage. The clinical significance of the observations from these studies is unknown. Although topiramate did not demonstrate significant effects on norethindrone at dosages up to 800 mg/day and had modest, dose-dependent effects on ethinyl estradiol only at dosages greater than 200 mg/day, marked changes may occur in some patients treated with topiramate due to substantial interindividual variability in sensitivity and susceptibility to enzyme induction. In addition, some enzyme-inducing anticonvulsants such as carbamazepine, phenytoin, and phenobarbital are known to enhance the plasma levels of sex hormone-binding globulin (SHBG). Since changes to SHBG were not evaluated in these studies, the possibility that unbound/free (i.e., biologically active) norethindrone levels may be impacted by topiramate cannot be ruled out.

MANAGEMENT: The potential for decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients using hormonal contraceptives (including oral, injectable, transdermal, and implantable forms) during treatment with topiramate, particularly at dosages above 200 mg/day. Some clinicians and manufacturers recommend that patients on topiramate dosages at or above 200 mg/day who are taking oral contraceptives should receive a preparation containing no less than 30 or 35 mcg of estrogen, while others recommend at least 50 mcg. Intrauterine systems are unlikely to be significantly affected because of their local action, thus they may be preferable to other routes of administration. Patients should be advised to report any change in their bleeding patterns, although contraceptive efficacy can be decreased even in the absence of breakthrough bleeding. Because use of topiramate can cause fetal harm, it is particularly important that patients not become pregnant during treatment. Counseling should be provided regarding the use of alternative (non-hormonal) or additional (back-up) pregnancy prevention methods during and for at least 28 days after discontinuing topiramate. Input from a gynecologist or similar expert on adequate contraception, including emergency contraception, should be sought as needed. Alternative, nonenzyme-inducing anticonvulsants that are not believed to interact significantly with hormonal contraceptives include clonazepam, ethosuximide, gabapentin, levetiracetam, pregabalin, tiagabine, valproic acid, vigabatrin, and zonisamide.

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