Drug Interactions between conjugated estrogens / medroxyprogesterone and nelfinavir

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations and pharmacologic effects of medroxyprogesterone, which is primarily metabolized by the isoenzyme. Aminoglutethimide, a CYP450 3A4 inducer, has been shown to significantly decrease the serum levels of medroxyprogesterone by 50% or more when administered at 250 mg two to four times daily to women with breast cancer receiving high-dose medroxyprogesterone orally. The decrease was accompanied by an increase in serum cortisol level, which suggests diminished adrenal suppressive effect of medroxyprogesterone. The interaction has not been studied with depot formulations of medroxyprogesterone. Because the clearance of medroxyprogesterone is approximately equal to the rate of hepatic blood flow, drugs that induce CYP450 3A4 are not expected to significantly affect the pharmacokinetics of medroxyprogesterone administered parenterally. In one study, no interaction was reported when medroxyprogesterone was administered intravenously with aminoglutethimide.

MANAGEMENT: Pharmacologic response to medroxyprogesterone should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the dosage adjusted as necessary. When administered as the depot formulation for contraception, no dosage adjustment for medroxyprogesterone is currently recommended during coadministration with CYP450 3A4 inducers. However, consideration may be given to decreasing the dosing interval (e.g., from one injection every 12 weeks to every 10 weeks) if an interaction is suspected.

MONITOR: Coadministration of conjugated estrogens with ritonavir or nelfinavir may lead to decreased plasma concentrations of conjugated estrogens. The proposed mechanism may involve induction of the CYP450 3A4-mediated metabolism of conjugated estrogens by ritonavir and nelfinavir. Increased metabolism of estrogens may lead to decreased efficacy of the hormone replacement therapy. Ritonavir is a known CYP450 3A4 substrate and inhibitor; however, it has also been shown to reduce plasma concentrations of contraceptive hormones via a possible mechanism involving induction of glucuronosyltransferase and/or CYP450 hydroxylation. In addition, along with being a strong CYP450 3A4 inhibitor, nelfinavir has also been shown to possess CYP450 3A4-inducing properties.

MANAGEMENT: Dosage adjustments as well as increased clinical and laboratory monitoring should be considered whenever ritonavir or nelfinavir is added to or withdrawn from therapy with conjugated estrogens.