Duavive^® Femin (Tablets) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Pfizer Ireland Pharmaceuticals (Ireland)

ATC Code

G03CC07 (Conjugated estrogens in combination with bazedoxifene)

Active Substances

Bazedoxifene (Rec.INN registered by WHO)

Estrogens conjugated (USP United States Pharmacopeia)

Dosage Form

Duavive® Femin

Modified-release film-coated tablets 20 mg+0.45 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Modified-release film-coated tablets light pink in color, oval, biconvex, marked with black ink “0.45/20” on one side.

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose 2208 (100000 cP), magnesium stearate, sucrose, hyprolose, hypromellose 2910 (6 cP), hypromellose 2910 (15 cP), macrogol (polyethylene glycol) 400, hypromellose 2910 (3 cP), sucrose monopalmitate, ascorbic acid; film coating Opadry pink: hypromellose 2910 (6 cP), titanium dioxide, macrogol (polyethylene glycol) 400, iron oxide red dye; film coating Opaglos 2 clear: hyetellose, povidone, polydextrose, maltitol solution, poloxamer.

28 pcs. – blisters (1) – laminated aluminum foil bags (1) – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Anticlimacteric drug

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system, estrogens, combinations with other drugs

Pharmacological Action

The combination of Bazedoxifene + Conjugated estrogens is a tissue-selective estrogen complex (TSEC).

The action of conjugated estrogens is realized mainly through sulfate esters of estrone, equilin sulfates, and 17α/β-estradiol. They are responsible for replenishing estrogen deficiency in women during menopause and alleviating menopausal symptoms.

Since estrogens promote endometrial growth, the use of estrogens as monotherapy increases the risk of endometrial hyperplasia and cancer.

The addition of bazedoxifene, acting as an estrogen receptor antagonist in the uterus, significantly reduces the estrogen-mediated risk of endometrial hyperplasia in women with an intact uterus.

Pharmacokinetics

After a single dose of the Bazedoxifene combination and baseline-adjusted total estrone were absorbed with a T_max of approximately 2 h and 8.5 h, respectively.

The absolute bioavailability of bazedoxifene is approximately 6%.

Conjugated estrogens are water-soluble and well absorbed from the gastrointestinal tract after release from the dosage form. After administration of conjugated estrogens in the dose range from 0.3 mg to 0.625 mg, a dose-proportional increase in AUC and C_max of total (conjugated and unconjugated) equilin, baseline-adjusted total estrone, and baseline-adjusted unconjugated estrone was observed.

After intravenous administration of a single 3 mg dose of bazedoxifene, its V_d was 14.7±3.9 L/kg. Bazedoxifene is highly bound to plasma proteins (98-99%) in vitro, but does not bind to sex hormone-binding globulin (SHBG).

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are usually found in high concentrations in organs affected by sex hormones. Estrogens circulate in the blood predominantly bound to SHBG and albumin.

Estrogens in the bloodstream exist in a dynamic equilibrium of metabolic interconversions. 17β-estradiol undergoes reversible conversion to estrone, and both can be converted to estriol, which is the main metabolite in urine.

In postmenopausal women, a significant proportion of estrogens in the blood are present as sulfate conjugates, particularly estrone sulfate, which serves as a source for the formation of more active estrogens.

The metabolic profile of bazedoxifene in postmenopausal women was established after oral administration of 20 mg of radiolabeled bazedoxifene. Bazedoxifene undergoes extensive metabolism in women. The main metabolic pathway is glucuronidation. Cytochrome P450 enzymes are involved to a minor extent or not at all. Bazedoxifene-5-glucuronide is the main circulating metabolite. Concentrations of this glucuronide metabolite are approximately 10 times higher than the concentrations of unchanged bazedoxifene in plasma.

After a single dose of this combination, the estimated T_1/2 of baseline-adjusted total estrone (representing Conjugated estrogens) is approximately 17 h. The T_1/2 of bazedoxifene is approximately 30 h. Steady-state concentrations are reached by the second week with once-daily administration of this combination.

The components of conjugated estrogens are excreted in the urine along with glucuronide and sulfate conjugates.

The clearance of bazedoxifene after intravenous administration is 0.4 L/h/kg ± 0.1 L/h/kg. Radiolabeled Bazedoxifene is excreted primarily in the feces, with less than 1% of the substance excreted in the urine.

Indications

Treatment of symptoms of estrogen deficiency in postmenopausal women with an intact uterus (at least 12 months since last menstruation) for whom treatment with progestogen therapy is not suitable.

ICD codes

Dosage Regimen

Administer orally, once daily, as one tablet containing 20 mg bazedoxifene and 0.45 mg conjugated estrogens.

Initiate treatment for postmenopausal symptoms at the lowest effective dose for the shortest possible duration consistent with treatment goals and risks for the individual woman.

Take the tablet at approximately the same time each day, with or without food. Swallow the tablet whole; do not crush or chew.

Re-evaluate the need for continued therapy at regular intervals, at least annually. Discontinue treatment if the risk-benefit assessment is no longer favorable.

Do not co-administer with other estrogens, progestins, or other selective estrogen receptor modulators (SERMs).

If a dose is missed, take it as soon as remembered unless it is almost time for the next dose. Do not take a double dose to make up for a forgotten tablet.

Adverse Reactions

Infections and infestations Common – vulvovaginal candidiasis.

Cardiac system Rare – venous thromboembolism events (including pulmonary embolism, retinal vein thrombosis, deep vein thrombosis, and thrombophlebitis).

Gastrointestinal side effects Very common – abdominal pain; Common – constipation, diarrhea, nausea.

Hepatobiliary disorders Uncommon – cholecystitis.

Musculoskeletal and connective tissue disorders Common – muscle spasms

Laboratory and instrumental data Common – increased blood triglyceride levels.

Contraindications

Hypersensitivity to bazedoxifene and/or conjugated estrogens; confirmed, suspected, or history of breast cancer; confirmed, history of, or suspected estrogen-dependent malignancies (e.g., endometrial cancer); undiagnosed genital bleeding; endometrial hyperplasia not treated; venous thromboembolism at the time of treatment or in history (e.g., deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis); confirmed thrombophilic conditions (e.g., protein C, protein S, or antithrombin deficiency); arterial thromboembolic disease at the time of treatment or in history (e.g., myocardial infarction, stroke); liver disease at the time of treatment or in history, as well as failure to normalize liver function biochemical parameters; porphyria; women of childbearing potential, pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

The combination is intended for use only in postmenopausal women and is contraindicated in probable or established pregnancy.

Contraindicated for use during breastfeeding.

Use in Hepatic Impairment

The safety and efficacy of this combination in patients with impaired liver function have not been studied. Use in this category of patients is contraindicated.

Use in Renal Impairment

Patients with end-stage renal failure should be closely monitored, as they are expected to have increased blood levels of the estrogen components of this combination. Use in this category of patients is not recommended.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Dosage adjustment in elderly patients is not required. Experience with the drug in women over 65 years of age is limited.

Special Precautions

For the treatment of symptoms associated with postmenopause, this combination should be used only if these symptoms adversely affect quality of life. In all cases, the risks and benefits associated with the use of the drug should be carefully assessed at least annually, and treatment should be continued only if the benefit outweighs the risks.

Women taking this combination should not take progestins, other estrogens, or selective estrogen receptor modulators (SERMs).

If any of the following conditions are present at the time of treatment, have occurred in the past, and/or worsened during pregnancy or previous hormonal therapy, the patient should be closely monitored; it should be considered that a relapse or worsening of these conditions may occur during treatment with this combination. These conditions include: leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic disorders; risk factors for estrogen-dependent tumors, e.g., first-degree relative with breast cancer; arterial hypertension; liver disease (e.g., hepatic adenoma); diabetes mellitus with or without vascular involvement; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus; history of endometrial hyperplasia; epilepsy; bronchial asthma; otosclerosis.

Therapy should be discontinued in case of contraindications for its continuation (e.g., venous thromboembolism, stroke, or pregnancy) and in the following cases: jaundice or worsening liver function; significant increase in blood pressure; newly occurring migraine headache.

In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma increases with long-term estrogen monotherapy. According to available data, the risk of endometrial malignancy in women receiving estrogen monotherapy is 2-12 times higher than in women not receiving estrogens, with the degree of risk increase depending on the duration of treatment and estrogen dose. After discontinuation of treatment, the risk may remain increased for at least 10 years. Women taking this combination should not take other estrogens, as this may increase the risk of endometrial hyperplasia and endometrial carcinoma.

The presence of bazedoxifene in the combination reduces the risk of endometrial hyperplasia, which may precede the development of endometrial cancer.

If breakthrough bleeding or spotting occurs after some time of treatment or persists after treatment ends, the cause of these conditions should be determined, including by endometrial biopsy to rule out endometrial cancer.

Cumulative data indicate an increased risk of breast cancer in women receiving estrogen-only hormone replacement therapy (HRT), which depends on the duration of HRT. The results of a large meta-analysis showed that after treatment cessation, the increased risk decreases over time, and the time to return to baseline depends on the duration of HRT. When HRT lasted more than 5 years, the risk may persist for 10 years or longer. The long-term effect of this combination on the risk of breast cancer remains unknown.

The effect of this combination on the risk of ovarian cancer is unknown.

If VTE develops or is suspected, the use of this combination should be discontinued immediately.

SERMs (including Bazedoxifene) and estrogens individually increase the risk of VTE.

Hormone therapy increases the risk of VTE by 1.3-3 times. The occurrence of VTE is more likely during the first year of HRT than later.

If planned surgery will be accompanied by prolonged immobilization of the patient, it is recommended to temporarily discontinue this combination 4-6 weeks before this intervention. Treatment can be resumed only after the woman has fully regained her ability to move. In addition, women taking this combination should be advised to move periodically during travel involving prolonged immobility.

In women already receiving continuous anticoagulant therapy, a careful assessment of the benefits and risks of hormonal therapy is required.

If VTE occurs or is suspected after initiation of therapy with this combination, its use should be discontinued immediately. Women should be informed to contact their doctor immediately after experiencing symptoms of thromboembolism (such as leg swelling accompanied by pain, sudden chest pain, shortness of breath).

Estrogens can cause fluid retention, and therefore patients with impaired heart or kidney function should be closely monitored during treatment with this combination.

Patients with end-stage renal failure should be closely monitored, as they are expected to have increased blood levels of the estrogen components of this combination. Use of the drug in this category of patients is not recommended.

Serum triglyceride levels should be determined annually in patients.

In women with impaired liver function, estrogens may be poorly metabolized. In women with a history of cholestatic jaundice associated with past estrogen use or pregnancy, treatment with this combination should be conducted with caution, and in case of recurrence of jaundice, the drug should be discontinued.

Patients receiving this combination should be closely monitored for signs of gallbladder disease development.

Estrogens increase the level of thyroxine-binding globulin (TBG), leading to an increase in the total blood levels of thyroid hormones as determined by protein-bound iodine (PBI), T4 levels (determined by column chromatography or radioimmunoassay) or T3 levels (determined by radioimmunoassay). T3 resin uptake decreases, reflecting the increased TBG level. Free T4 and free T3 concentrations are unchanged. Levels of other binding proteins in serum may be increased, e.g., corticosteroid-binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased blood levels of corticosteroids and sex steroids, respectively. Concentrations of free or biologically active hormones are unchanged. Levels of other plasma proteins (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin) may increase.

Effect on ability to drive vehicles and operate machinery

This combination has a negligible effect on the ability to drive vehicles and operate machinery.

In clinical studies of bazedoxifene monotherapy, drowsiness was reported as an adverse reaction, so patients should be informed about the possible effect of this agent on the ability to drive vehicles and operate machinery.

In patients receiving bazedoxifene monotherapy, post-marketing reports included visual symptoms such as impaired visual acuity or blurred vision. If such symptoms occur, patients should refrain from driving vehicles or operating machinery requiring clear visual perception until these symptoms resolve.

Drug Interactions

In vitro and in vivo studies have shown that estrogens are partially metabolized by cytochrome P450 enzymes, including CYP3A4. However, in a clinical drug interaction study, itraconazole, a strong CYP3A4 inhibitor, at a dose of 200 mg with multiple administration had a minimal effect on the pharmacokinetics of conjugated estrogens (based on estrone and equilin levels) and bazedoxifene after a single dose of this combination at the therapeutic dose.

The metabolism of estrogens may be increased with the concomitant use of substances capable of inducing drug-metabolizing enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g., rifampicin, rifabutin, nevirapine, efavirenz). In contrast, ritonavir and nelfinavir, known strong inhibitors, exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St. John’s wort (Hypericum perforatum) may induce the metabolism of estrogens. Clinically, increased estrogen metabolism may lead to a reduction in their effect and changes in the pattern of uterine bleeding.

The metabolism of bazedoxifene may be enhanced with the concomitant use of substances known to induce UGT, such as rifampicin, phenobarbital, carbamazepine, and phenytoin, which may lead to reduced systemic concentrations of bazedoxifene. Reduced systemic concentrations of bazedoxifene may be associated with an increased risk of endometrial hyperplasia.

Bazedoxifene is metabolized by cytochrome P450 enzymes to a minor extent or not at all. Bazedoxifene does not induce or inhibit the activity of major CYP isoenzymes, and its interaction with concomitantly administered drugs via CYP-mediated metabolism is unlikely.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.