Drug interactions between CombiPatch and fosphenytoin

estradiol ↔ fosphenytoin

Applies to:CombiPatch (estradiol/norethindrone) and fosphenytoin

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of estrogens and progestins. Estrogens have been shown in in vitro and in vivo studies to be partially metabolized by CYP450 3A4, and other steroids including progestins are also believed to undergo metabolism by this isoenzyme. The interaction has been reported primarily with oral contraceptives. There have been case reports of menstrual breakthrough bleeding or unwanted pregnancy in women receiving low-dose oral contraceptives following the addition of known CYP450 3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort. Inadequate response to estrogen replacement therapy has also been reported in a patient treated with phenytoin. Aminoglutethimide, a CYP450 3A4 inducer, has been shown to decrease medroxyprogesterone and megestrol serum levels by 74% in six patients stabilized on their progestin regimen.

MANAGEMENT: Pharmacologic response to estrogens and progestins should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the hormone dosage adjusted as necessary. Patients should be advised to notify their physician if they experience inadequate control of symptoms associated with estrogen deficiency (e.g., nocturnal sweating, vasomotor disturbances, atrophic vaginitis) or changes in the uterine bleeding profile.

norethindrone ↔ fosphenytoin

Applies to:CombiPatch (estradiol/norethindrone) and fosphenytoin

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with certain anticonvulsants such as carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and primidone may reduce the efficacy of contraceptive hormones. There have been numerous case reports of menstrual abnormalities (e.g., breakthrough bleeding, amenorrhea, irregular menses) and unintended pregnancy occurring in women who received oral contraceptives with anticonvulsants. The incidence of menstrual irregularities associated with this combination has been reported to be as high as 65% in some studies. The interaction stems from accelerated clearance of contraceptive hormones as well as decreased plasma concentrations of unbound (active) hormones due to induction of hepatic CYP450 enzymatic activity and hormone-binding globulin capacity by some anticonvulsants. Pharmacokinetic studies have found that normally recommended dosages of carbamazepine, phenobarbital, oxcarbazepine, and phenytoin can individually reduce the systemic exposure (AUC) of ethinyl estradiol and levonorgestrel by a third or more.

MANAGEMENT: Women using hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant therapy with enzyme-inducing anticonvulsants. Alternative or additional methods of birth control should be used during and for at least two weeks after short-term and 4 weeks after long-term (greater than 4 weeks) anticonvulsant therapy. If a combination oral contraceptive pill is used, a regimen containing at least 50 mcg of ethinyl estradiol per day or equivalent should be selected. Although breakthrough bleeding is not necessarily indicative of low ethinyl estradiol serum levels or increased risk of ovulation, some clinicians suggest that women who experience breakthrough bleeding during enzyme-inducing therapy may be prescribed an increased dose of ethinyl estradiol above 50 mcg daily by combining more than one formulation of contraceptive pill if necessary. For levonorgestrel emergency contraception in patients receiving enzyme-inducing therapy, a regimen consisting of a 1.5 mg dose as soon as possible (within 72 hours of unprotected intercourse) followed by a 0.75 mg or 1.5 mg dose twelve hours later has been recommended by some clinicians. An alternative is a single 2.25 mg dose as soon as possible following unprotected intercourse. However, there are no data on efficacy, compliance, or side effects with any of these regimens. No precautions or recommendations are available for women using hormone-releasing intrauterine systems, but a significant interaction with these systems is thought to be unlikely due to their local action. Injectable progestin-only contraceptives are also thought to be unaffected by enzyme-inducing drugs.