Tridestra

Tridestra Uses, Dosage, Side Effects, Food Interaction and all others data.

Estradiol Valerate (also known as E2V) is a pro-drug ester of Estradiol, a naturally occurring hormone that circulates endogenously within the human body. Estradiol is the most potent form of all mammalian estrogenic steroids and acts as the major female sex hormone. As a pro-drug of estradiol, estradiol acetate therefore has the same downstream effects within the body through binding to the Estrogen Receptor (ER) including ERα and ERβ subtypes, which are located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain.

Estradiol is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%). First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter systemic circulation and exert its estrogenic effects . Esterification of estradiol aims to improves absorption and bioavailability after oral administration (such as with Estradiol valerate) or to sustain release from depot intramuscular injections (such as with Estradiol Cypionate) through improved lipophilicity. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol. Ester pro-drugs of estradiol are therefore considered to be bioidentical forms of estrogen .

Estradiol valerate is commercially available as an intramuscular injection as the product Delestrogen and is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding.

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.

Tridestra
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Tridestra
Generic	medroxyprogesterone acetate + estradiol valerate
Type
Therapeutic Class
Manufacturer	Orion Pharma (UK) Limited
Available Country	United Kingdom
Last Updated:	September 19, 2023 at 7:00 am

Uses

Estradiol valerate is an estradiol prodrug used to treat some effects of menopause, hypoestrogenism, androgen dependant carcinoma of the prostate, and in combination products for endometriosis and contraception.

Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding.

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.

Tridestra is also used to associated treatment for these conditions: Heavy Menstrual Bleeding, Hypogonadism, Menopausal Symptoms, Menopause, Menstrual Irregularities, Postmenopausal Osteoporosis, Primary Amenorrhoea, Secondary Amenorrhea, Advanced Hormone-dependent prostate cancer, Hypoestrogenism, Moderate Menopausal Vasomotor Symptoms, Moderate menopausal vulvovaginal atrophy, Severe Vasomotor Symptoms Associated With Menopause, Severe menopausal vulvovaginal atrophy, Hormone Replacement Therapy, Oral ContraceptivesAbnormal 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 Tridestra works

Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.

Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause, which are primarily caused by a loss of estrogenic activity.

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

Tridestra dosage

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

Depression, fluid retention. Fatigue, insomnia, dizziness, headache, nausea; breast tenderness; wt gain/loss, anorexia; cholestatic jaundice; pain at Inj site.

Toxicity

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

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

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 volume of distribution of medroxyprogesterone acetate is 20±3L.

Elimination Route

IM Injection: When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks .

Natazia: After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve [AUC(0–24h)] was 1301 pg·h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen.

Absorption of oral medroxyprogesterone acetate (MPA) varies considerably between formulations. A 1000mg oral dose reaches an average C_max of 145-315nmol/L while a 500mg oral dose reaches an average C_max of 33-178nmol/L with a T_max 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 C_max of 4.69±1.52nmol/L with a T_max of 4.75±2.09 days and an AUC of 81.58±27.64days*nmol/L. Subcutaneous MPA reaches a C_max 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

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 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

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

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

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

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.