Estrogens may diminish the effectiveness of anticoagulant, antidiabetic and antihypertensive agents.
Preparations inducing liver enzymes (e.g. barbiturates, hydantoins, carbamazepine, meprobamates, phenylbutazone or rifampicin) may interfere with the activity of orally administered estrogens.
No clinically important pharmacokinetic interactions were identified between conjugated estrogens and bazedoxifene (see DOSAGE AND ADMINISTRATION, Dosing Considerations).
Results from a clinical drug‑drug interaction study conducted with DUAVIVE as well as results from monotherapy trials with conjugated estrogens or bazedoxifene, the components of DUAVIVE, are noted below:
In vitro and in vivo trials have shown that estrogens are partially metabolized by cytochrome P450 3A4 (CYP3A4). Concomitant administration of itraconazole, a strong CYP3A4 inhibitor, with DUAVIVE in a clinical drug-drug interaction study, resulted in increases in bazedoxifene exposure (40%) and, to a lesser extent, conjugated estrogens exposure (9% for baseline-adjusted total estrone, 5% for total equilin), compared to DUAVIVE alone.
Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in adverse effects. Increased exposure of conjugated estrogens may increase the risk of endometrial hyperplasia, therefore, patients with undiagnosed persistent or recurring abnormal genital bleeding who are under long-term treatment with CYP3A4 inhibitors, should have adequate diagnostic measures taken to rule out malignancy, including directed or random endometrial sampling when indicated.
Inducers of CYP3A4, such as St. John's Wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, phenytoin, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile of estrogen therapy.
Bazedoxifene undergoes little or no cytochrome P450 (CYP)-mediated metabolism. Bazedoxifene does not induce or inhibit the activities of major CYP isoenzymes. BZA did not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2 in human liver microsomes at concentrations which are expected to result in clinically meaningful drug-drug interactions. There was no significant induction observed for CYP1A1/2, CYP2B, CYP2A1, CYP3A, CYP2B1, or CYP2C11 following administration of BZA to rats. In vitro data suggest that bazedoxifene is unlikely to interact with co-administered drugs via CYP-mediated metabolism.
Uridine Diphosphate Glucuronosyltransferase (UGT)
Bazedoxifene undergoes metabolism by uridine diphosphate glucuronosyltransferase (UGT) enzymes in the intestinal tract and liver. The metabolism of BZA may be increased by concomitant use of substances known to induce UGTs, such as rifampin, phenobarbital, carbamazepine, and phenytoin, potentially leading to decreased systemic concentrations of bazedoxifene. Decreased exposure of bazedoxifene may increase the risk of endometrial hyperplasia, therefore, patients with undiagnosed persistent or recurring abnormal genital bleeding who are taking UGT inducers and DUAVIVE should have adequate diagnostic measures taken to rule out malignancy, including directed or random endometrial sampling when indicated.
Inhibitors of UGT enzymes could potentially increase the systemic concentrations of bazedoxifene.
The pharmacokinetics of bazedoxifene (20 mg, single-dose) and ibuprofen (600 mg, single-dose) were not significantly altered when the drugs are co-administered in generally healthy postmenopausal women.
The drug interaction between conjugated estrogens and ibuprofen has not been evaluated.
Concomitant administration of bazedoxifene (40 mg daily) and atorvastatin (20 mg, single-dose) to healthy postmenopausal women did not affect the pharmacokinetics of bazedoxifene, atorvastatin or its active metabolites.
The drug interaction between conjugated estrogens and atorvastatin has not been evaluated.
Co-administration of a single 40 mg dose of bazedoxifene with azithromycin (500 mg loading dose followed by daily doses of 250 mg) to healthy postmenopausal women did not significantly alter the pharmacokinetics of bazedoxifene.
The drug interaction between conjugated estrogens and azithromycin has not been evaluated.
Aluminum and magnesium hydroxide
Concomitant administration of bazedoxifene (40 mg) and antacids containing aluminum and magnesium hydroxide to healthy postmenopausal women did not significantly alter the pharmacokinetics of bazedoxifene.
Drugs highly bound to plasma proteins
Bazedoxifene is highly bound to plasma proteins. In vitro trials showed the protein binding of warfarin, diazepam or digoxin was not altered by bazedoxifene. Similarly, the protein binding of bazedoxifene was not altered by these drugs. Therefore, drug-drug interactions due to alterations of protein binding between bazedoxifene and warfarin, diazepam or digoxin are unlikely.
When conjugated estrogens/bazedoxifene were administered with a high-fat meal, the absorption of bazedoxifene was increased, whereas the pharmacokinetics of conjugated estrogens were unaffected. No adjustment in dose is recommended; DUAVIVE may be given at any time of the day, without regard to meals (see DOSAGE AND ADMINISTRATION).
Inhibitors of CYP3A4, such as grapefruit juice, may increase plasma concentrations of estrogens and may result in adverse effects (see DRUGS INTERACTIONS – Cytochrome P450).
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 products (see DRUGS INTERACTIONS – Cytochrome P450).
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.
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 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 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 therapy (HT) when relevant specimens are submitted.
In clinical trials of up to 2 years duration, the following laboratory results were observed in women treated with DUAVIVE:
- Increased plasma HDL cholesterol, reduced total cholesterol and LDL cholesterol concentrations, increased triglyceride levels. Decrease in Lp (a) and increase in Apo A1 and decrease in Apo B
- Decrease in antithrombin III activity and fibrinogen
- Small increases from baseline in plasminogen activity
- No effect on partial thromboplastin time, prothrombin time, or serum concentrations of D-dimer
- No significant changes in fasting glucose, fasting insulin, or C-reactive protein levels