Bazedoxifene And Conjugated Estrogens
Bazedoxifene And Conjugated Estrogens Uses, Dosage, Side Effects, Food Interaction and all others data.
Bazedoxifene is a third generation selective estrogen receptor modulator (SERM), developed by Pfizer following the completion of their takeover of Wyeth Pharmaceuticals. In late 2013, Pfizer received approval for bazedoxifene as part of the combination drug DUAVEE in the prevention (not treatment) of postmenopausal osteoporosis. It is approved in the European Union (marketed in Italy and Spain) and Japan as monotherapy. In 2013, the combination product containing conjugated estrogens and bazedoxifene was approved by the FDA for the treatment of moderate to severe vasomotor symptoms associated with menopause, as well as the prevention of postmenopausal osteoporosis in women.
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogen in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
The binding of estrogens to the estrogen receptor produces the activation of nuclear receptors in order to bind to estrogen response elements in certain target genes. This mechanistic cascade results in histone acetylation, alteration of chromatin conformation and the initiation of transcription of certain specific drugs.
In preclinical studies, the conjugated estrogens are known to have a similar estrogenic potency than estrone and the equilin components of the conjugated estrogens have similar potency in the liver when compared to bioidentical estradiol. It has also been tested and confirmed that conjugated estrogens present a selective estrogen receptor modulator profile which allows it to have a large beneficial effect on the bone and cardiovascular system.
Clinically, the administration of conjugated estrogens is known to promote vasomotor stability, maintain genitourinary function, and normal growth and development of female sex hormones. It has also been shown to prevent accelerated bone loss by inhibiting bone resorption and restoring the balance of bone resorption. In the hormonal area, it is shown to inhibit luteinizing hormone and decrease the serum concentration of testosterone.
| Trade Name | Bazedoxifene And Conjugated Estrogens |
| Generic | Bazedoxifene + conjugated estrogens |
| Weight | 20mg + 0.45mg |
| Type | Oral tablet |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Bazedoxifene is a selective estrogen receptor modulator (SERM) used to treat moderate to severe vasomotor symptoms in menopause and osteoporosis alone or in combination with conjugated estrogens.
Indicated for following conditions alone or in combination with conjugated estrogens in women with a uterus:
Treatment of moderate to severe vasomotor symptoms associated with menopause
Prevention of postmenopausal osteoporosis
Conjugated Estrogens vaginal cream is used for the treatment of atrophic vaginitis, dyspareunia and kraurosis vulvae. Conjugated Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia.
Bazedoxifene And Conjugated Estrogens is also used to associated treatment for these conditions: Postmenopausal Osteoporosis, Moderate Menopausal Vasomotor Symptoms, Severe Vasomotor Symptoms Associated With MenopauseAtrophic Vaginitis, Atrophy of vulva, Kraurosis Vulvae caused by Menopause, Metastatic Breast Cancer, Osteoporosis, Premature Ovarian Failure (POF), Vasomotor Symptoms Associated With Menopause, Vulvovaginal Atrophy, Androgen-dependent tumor Advanced Prostate Carcinoma, Hypoestrogenism, Moderate Dyspareunia, Severe Dyspareunia
How Bazedoxifene And Conjugated Estrogens works
Bazedoxifene belongs to a class of compounds known as selective estrogen receptor modulators (SERMs). Bazedoxifene acts as both an oestrogen-receptor agonist and/or antagonist, depending upon the cell and tissue type and target genes. Bazedoxifene decreases bone resorption and reduces biochemical markers of bone turnover to the premenopausal range. These effects on bone remodelling lead to an increase in bone mineral density (BMD), which in turn contributes to a reduction in the risk of fractures. Bazedoxifene functions primarily as an oestrogen-receptor antagonist in uterine and breast tissues.
The conjugated estrogens, equally to the normal physiological estrogen, work by agonistically binding to the estrogen receptors alpha and beta. The estrogen receptors vary in quantity and proportion according to the tissues and hence, the activity of this conjugated estrogens is very variable.
The activity made by the conjugated estrogens is driven by the increase in the synthesis of DNA, RNA and various proteins in responsive tissues which in order will reduce the release of gonadotropin-releasing hormone, follicle-stimulating hormone and leuteinizing hormone.
The specific mechanism of action cannot be described only in terms of total estrogenic action as the pharmacokinetic profile, the tissue specificity and the tissue metabolism is different for each component of the product.
Dosage
Bazedoxifene And Conjugated Estrogens dosage
Menopausal vasomotor symptoms: 0.45 mg/day, up to 1.25 mg/day. Attempt to discontinue medication at 3-6-mth intervals.
Vulvular and vaginal atrophy: 0.3 mg/day.
Female hypogonadism: 0.3-0.625 mg/day in a cyclical regimen. Add progestin treatment once skeletal maturity is achieved.
Female castration, Primary ovarian failure: 1.25 mg/day in a cyclical regimen. Palliation in prostate carcinoma 1.25-2.5 mg 3 times/day.
Osteoporosis prophylaxis in postmenopausal women: Initial: 0.3 mg/day in a cyclical or continuous regimen depending on patient's condition.
Side Effects
Breast pain, tenderness or enlargement, Headache/migraine, Gut disturbances, such as nausea, abdominal pain, bloating, flatulence, indigestion, Legcramps, Fatigue, Weightchanges, Vaginalthrush, Depression, Anxiety, Dizziness, Changes in sex drive, Rise in blood pressure, Gall bladder disease, Swelling of the ankles due to to fluid retention (peripheral oedema), Skin reactions such as rash and itch, Steepening of corneal curvature which may make contact lenses uncomfortable, Premenstrual-like symptoms, Disturbance in liver function, Irregular brown patches on the skin, usually of the face (chloasma), Blood clots in the blood vessels.
Toxicity
The reported oral LD50 in the rat is of more than 5000 mg/kg. Serious overdosage symptoms have not been reported. There have been only reports of nausea, vomiting, and withdrawal in bleeding in females.
Long-term continuous administration of estrogens is correlated to increased risk on the incidence of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Precaution
Asthma, epilepsy, migraine; heart or kidney dysfunction; CV disease; cerebrovascular disorders; diabetes, hypercalcaemia; gall bladder disease; porphyria. Children. Lactation.
Lactation: Use controversial; estrogens are excreted into breast milk in small quantities; use with caution
Interaction
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Volume of Distribution
Following intravenous administration of a 3 mg dose of bazedoxifene, the volume of distribution is 14.7 ± 3.9 l/kg.
The physiological distribution of estrogens in the body is very similar to what is seen in endogenous estrogens and hence, it is widely distributed. The conjugated estrogens are mainly found in the sex hormone target organs.
Elimination Route
Bazedoxifene is rapidly absorbed with a tmax of approximately 2 hours and exhibits a linear increase in plasma concentrations for single doses from 0.5 mg up to 120 mg and multiple daily doses from 1 mg to 80 mg. The absolute bioavailability of bazedoxifene is approximately 6%.
The conjugated estrogens are well absorbed in the gastrointestinal tract and the maximum plasma concentration of the conjugated estrogens is reached after 7 hours depending on the estrone component. The maximal plasma concentration of conjugated estrogens after multiple doses of 0.45 mg is reported to be of 2.6 ng/ml with an AUC in the steady state of 35 ng.h/ml. Unconjugated estrogens are known to be cleared from the circulation at a faster rate than their ester forms.
Half Life
~30 hours.
The median half-life of the conjugated estrogens is reported to be of 17 hours.
Clearance
The apparent oral clearance of bazedoxifene is approximately 4 to 5 l/h/kg.
The reported normal clearance rate for estrogens is of approximately 615 L/m2.
Elimination Route
The major route of elimination of radio-labelled bazedoxifene is the faeces, and less than 1% of the dose is eliminated in urine.
The conjugated estrogens are eliminated mainly in the urine. In this renal elimination, it is possible to find 17 beta-estradiol, estrone, estriol, as well as the glucuronide and sulfate conjugates of the estrogens.
Pregnancy & Breastfeeding use
For women with a uterus: If pregnancy occurs during medication with Conjugated Oestrogens treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.
Lactation: Conjugated Oestrogens is not indicated during lactation.
Contraindication
Known or suspected pregnancy; undiagnosed abnormal uterine bleeding; known, suspected, or history of past breast cancer; known or suspected estrogen-dependent neoplasia (e.g., endometrial cancer, endometrial hyperplasia); active or history of arterial thromboembolic disease (e.g., stroke, myocardial infarction or venous thromboembolism (such as deep venous thrombosis, pulmonary embolism); active or chronic liver dysfunction or disease; known thrombophilic disorders (e.g., protein C, protein S, or antithrombin deficiency); hypersensitivity to any component of this medication.
Acute Overdose
Symptoms of overdosage of estrogen containing products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment if necessary should be symptomatic.
Storage Condition
Do not store above 25° C. Store at room temperature.
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