PREMARIN (conjugated estrogens) Drug Interactions

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Data from a drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both drugs are not altered when the drugs are co-administered. Other clinical drug-drug interaction studies have not been conducted with conjugated estrogens.

Estrogens may diminish the effectiveness of anticoagulant, antidiabetic and antihypertensive agents.

Drug-Drug Interactions

The following section contains information on drug interactions with ethinyl estradiol-containing products (specifically, oral contraceptives) that have been reported in the public literature. The clinical significance of these drugs is unknown; additionally, it is unknown whether such interactions occur with drug products containing other types of estrogens. Monitoring of patient response to therapy is recommended.

Hepatic metabolism
Interactions can occur with drugs that induce microsomal enzymes which can decrease ethinyl estradiol concentrations (eg., rifampin, barbiturates, phenytoin, carbamazepine, troglitazone).

Gastrointestinal wall
Sulfation of ethinyl estradiol has been shown to occur in the gastrointestinal (GI) wall. Therefore, drugs which act as competitive inhibitors for sulfation in the GI wall may increase ethinyl estradiol bioavailability (eg., ascorbic acid, acetaminophen).

Interference in the metabolism of other drugs
Ethinyl estradiol may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes or by inducing hepatic drug conjugation, particularly glucuronidation. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of certain drugs containing ethinyl estradiol (eg., oral contraceptives containing ethinyl estradiol). In addition, products containing ethinyl estradiol may induce the conjugation of other compounds.

Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with certain ethinyl estradiol-containing drug products (eg., oral contraceptives containing ethinyl estradiol).

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, phenytoin, carbamazepine, rifampicin, and dexamethasone may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects.

Other interactions with ethinyl estradiol
Coadministration of atorvastatin and certain ethinyl estradiol-containing drug products (eg., oral contraceptives) increase AUC values for ethinyl estradiol by 20 percent.

Clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

Drug-Food Interactions
CYP3A4 inhibitors such as grapefruit juice may increase plasma concentrations of 17 ß-estradiol and may result in side effects.

A single dose study in healthy, postmenopausal women was conducted to investigate any potential drug interaction when 2 x 0.625 mg PREMARIN(conjugated estrogens) and 2.5 mg medroxyprogesterone acetate (MPA) tablets were administered immediately following a high-fat breakfast. Administration with food slowed the absorption of the conjugated estrogens, thereby reducing the Cmax of the various estrogens by 25% to 30%, and increasing MPA Cmax by 89% and AUC0-∞ by 28%. Thus, food slightly lowered the Cmax, but did not affect the AUC, of the estrogens from a 0.625 mg PREMARIN tablet; food significantly increased the Cmax and AUC of MPA from a 2.5-mg tablet.

Drug-Herb Interactions
It was found that some herbal products (e.g., St. John’s wort), which are available as over-the- counter (OTC) products, might interfere with steroid metabolism, and therefore alter the efficacy and safety of estrogen/progestin products. Hot flashes and vaginal bleeding have been reported in patients taking estrogen replacement therapy (ERT) and combined estrogen plus progestin therapy (HRT) and St. John’s Wort (Hypericum perforatum) preparations. St. John’s Wort may induce hepatic microsomal enzymes, which theoretically may result in reduced efficacy of ERT and HRT.

Physicians and other health care providers should be made aware of other non-prescription products concomitantly used by the patient, including herbal and natural products, obtained from the widely spread Health Stores.

Drug-Laboratory Test Interactions
The results of certain endocrine and liver function tests may be affected by estrogen-containing products:

  • increased prothrombin time and partial thromboplastin time; increased levels of fibrinogen and fibrinogen activity, increased coagulation factors VII, VIII, IX, X; increased norepinephrine-induced platelet aggregability; decreased antithrombin III;
  • increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone (T4) as measured by column or radioimmunoassay;T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered;
  • impaired glucose tolerance;
  • increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased serum triglycerides and phospholipids concentration;
  • other binding proteins may be elevated in serum i.e., corticosteroid binding globulin (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids respectively,; free or biologically active hormone concentrations are unchanged;
  • The response to metyrapone may be reduced.

The results of the above laboratory tests should not be considered reliable unless therapy has been discontinued for two to four weeks.

The pathologist should be informed that the patient is receiving hormone replacement therapy (HRT) when relevant specimens are submitted.

Drug-lifestyle interactions
Acute alcohol ingestion during HRT may lead to elevations in circulating estradiol levels.

Drug-Food Interactions

The absorption of estrogens from the PREMARIN tablets 1.25 mg is not affected by food. PREMARIN tablets may be taken without regard to meals (see DOSAGE AND ADMINISTRATION).