Premphase Prempro
Premphase Prempro Uses, Dosage, Side Effects, Food Interaction and all others data.
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.
Medroxyprogesterone is a synthetic progestogen which converts the proliferative phase of the endometrium into secretory phase. It has some androgenic and anabolic activities but no oestrogenic effects. Parenteral use leads to inhibition of pituitary gonadotropins, thus preventing follicular maturation and ovulation.
Medroxyprogesterone acetate (MPA) inhibits gonadotropin production, reduces nuclear estrogen receptors and DNA synthesis in epithelial cells of the endometrium, and induces p53 dependant apoptosis in cancer cell lines. MPA oral tablets have a half life of 40-60 hours and other formulations can have half lives that are considerably longer, so the duration of action is long. The therapeutic window is wide as patients may take doses ranging from 5mg orally daily to 1000mg as a depo injection weekly. Long term use of MPA is associated with a reduction in bone density and patients who taking MPA during adolescence may have lower peak bone mass than untreated patients, which can also increase the risk of osteoporosis and fractures in the future.
| Trade Name | Premphase Prempro |
| Generic | Conjugated estrogens + medroxyprogesterone acetate |
| Type | Tablets |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
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.
Medroxy Progesterone Acetate tablets are used for the treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. They are also used for use in the prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving daily oral conjugated estrogens 0.625 mg tablets.
Premphase Prempro is also used to associated treatment for these conditions: Atrophic 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 DyspareuniaAbnormal Uterine Bleeding, Amenorrhea, Endometrial Hyperplasia, Endometriosis related pain, Metastatic Renal Cell Carcinoma, Osteoporosis, Pain, Postmenopausal Osteoporosis, Pregnant State, Vasomotor Symptoms Associated With Menopause, Vulvovaginal Atrophy, Metastatic Endometrial carcinoma, Contraception, Estrogen Replacement Therapy, Hormonal Contraception
How Premphase Prempro works
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.
Medroxyprogesterone acetate (MPA) inhibits the production of gonadotropin, preventing follicular maturation and ovulation, which is responsible for it’s ability to prevent pregnancy. This action also thins the endometrium. MPA reduces nuclear estrogen receptors and DNA synthesis in epithelial cells of the endometrium. MPA can also induce p53 dependant apoptosis in certain cancer cell lines, and inhibit GABA-A receptors.
Dosage
Premphase Prempro 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.
Oral-
- Palliative treatment of endometrial and renal carcinoma: 200-600 mg daily.
- Mild to moderate endometriosis: 10 mg tid.
- Breast cancer: 0.4-1.5 g daily. Max: 2 g daily.
- Progestogen component in menopausal hormonal replacement therapy: Dosage dependant on oestrogen component of therapy, several regimens are used: 1.5 mg, 2.5 mg or 5 mg daily; 5 or 10 mg daily for 12-14 days of a 28-day cycle; 20 mg daily for 14 days of a 91-day cycle.
- Menorrhagia: 2.5-10 mg daily for 5-10 days starting on the 16th-21st day of the menstrual cycle. Repeat for 2 cycles.
- Palliative treatment of prostatic carcinoma: 100-600 mg daily.
- Secondary amenorrhoea: 2.5-10 mg daily for 5-10 days. Repeated for 3 cycles.
Intramuscular:
- Endometriosis: 50 mg wkly or 100 mg every 2 wk.
- Contraception: 150 mg every 12 wk.
- Palliative treatment of endometrial and renal carcinoma: Initially 0.4-1 g wkly. Reduce as necessary, maintenance may be as low as 0.4 g mthly.
- Palliative treatment of prostatic carcinoma: 0.5 g twice wkly for first 3 mth. Maintenance 0.5 g wkly.
- Breast cancer: 0.5-1 g daily for first 4 wk. Maintenance 0.5 g twice wkly.
Subcutaneous:
- Contraception, Endometriosis: 104 mg every 12-14 wk.
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.
Depression, fluid retention. Fatigue, insomnia, dizziness, headache, nausea; breast tenderness; wt gain/loss, anorexia; cholestatic jaundice; pain at Inj site.
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.
The oral LD50 in rats is >6400mg/kg and in mice is >16g/kg. The intraperitoneal LD50 in rats is >900mg/kg and in mice is >1500mg/kg. The subcutaneous LD50 in rats is >900mg/kg and in mice is>1500mg/kg.
Patients experiencing and overdose or oral medroxyprogesterone acetate (MPA) may present with nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding. Treat patients by stopping MPA and beginning symptomatic treatment. Patients who have been given too much of a MPA depo injection should contact a healthcare professional, hospital emergency department, or local poison control immediately.
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
Patients with depression, DM, epilepsy, asthma, migraine, hypertension, renal or cardiac dysfunction. Monitor patient closely for loss of vision, proptosis, diplopia and thromboembolic disorders. Lactation.
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.
Aminoglutethimide and enzyme-inducing drugs (e.g. carbamazepine, griseofulvin, phenobarbital, rifampicin, phenytoin) may reduce plasma concentrations leading to reduced efficacy. Additional measures required when medroxyprogesterone is used for contraception during coadministration with these drugs.
Volume of Distribution
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.
The volume of distribution of medroxyprogesterone acetate is 20±3L.
Elimination Route
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.
Absorption of oral medroxyprogesterone acetate (MPA) varies considerably between formulations. A 1000mg oral dose reaches an average Cmax of 145-315nmol/L while a 500mg oral dose reaches an average Cmax of 33-178nmol/L with a Tmax of 1-3 hours and a lag time of half an hour. The AUC of a 500mg oral dose of MPA was 543.4-1981.1nmol*L/h depending on formulation.
Intramuscular MPA reaches a Cmax of 4.69±1.52nmol/L with a Tmax of 4.75±2.09 days and an AUC of 81.58±27.64days*nmol/L. Subcutaneous MPA reaches a Cmax of 3.83±1.56nmol/L with a T±max of 6.52±2.07 days and an AUC of 72.26±38.73days*nmol/L. However, the pharmacokinetics of MPA may also vary depending on injection site.
Half Life
The median half-life of the conjugated estrogens is reported to be of 17 hours.
Oral medroxyprogesterone acetate (MPA) has an absorption half life of 15-30min and a biological half life of 40-60 hours. Intramuscular MPA has an absorption half life of 0.86±0.30 days and an elimination half life of 24.03±21.74 days. Subcutaneous MPA has an absorption half life of 1.05±0.56 days and an elimination half life of 30.90±15.11 days.
Clearance
The reported normal clearance rate for estrogens is of approximately 615 L/m2.
The mean clearance of medroxyprogesterone acetate (MPA) is 1668±146L/day or 21.9±4.3L/kg/day. Due to the high inter patient variability in MPA pharmacokinetics, clearance has been reported to be 1600-4000L/day.
Elimination Route
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.
The majority of medroxyprogesterone acetate (MPA) is eliminated in the urine as glucuronide conjugates and a minority of sulphate conjugates. Glucuronide conjugates are also detected in the feces. Determining the exact ratio of metabolites and parent compound eliminated in the urine and feces is difficult as the metabolite profile in the urine is not significantly different and radio labelling studies are not readily available.
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.
Pregnancy Category X. Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Nursing Mothers: Medroxy Progesterone Acetate should not be used during lactation. Detectable amounts of progestin have been identified in the breast milk of nursing mothers receiving progestins.
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.
Thromboembolic disorders; cerebral apoplexy; severe hepatic dysfunction; undiagnosed vaginal bleeding, incomplete abortion, hormone-dependent carcinoma; pregnancy.
Special Warning
Pediatric Use: Medroxy Progesterone Acetate tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population.
Geriatric Use: There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Medroxy Progesterone Acetate alone to determine whether those over 65 years of age differ from younger subjects in their response to Medroxy Progesterone Acetate alone.
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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