Reluren Tablet 40 mg+1 mg+0.5 mg
Reluren Tablet 40 mg+1 mg+0.5 mg Uses, Dosage, Side Effects, Food Interaction and all others data.
Estradiol is a naturally occurring oestrogen. Oestrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. They modulate the pituitary secretion of gonadotrophins, LH and FSH through a negative feedback system.
Estradiol acts on the on the estrogen receptors to relieve vasomotor systems (such as hot flashes) and urogenital symptoms (such as vaginal dryness and dyspareunia).
Estradiol has also been shown to exert favorable effects on bone density by inhibiting bone resorption. Estrogen appears to inhibit bone resorption and may have beneficial effects on the plasma lipid profile. Estrogens cause an increase in hepatic synthesis of various proteins, which include sex hormone binding globulin (SHBG), and thyroid-binding globulin (TBG). Estrogens are known to suppress the formation of follicle-stimulating hormone (FSH) in the anterior pituitary gland.
A note on hyper-coagulable state, cardiovascular health, and blood pressure
Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist used in the treatment of several hormone-responsive conditions. It was first approved in Japan in 2019, under the brand name Relumina, for the symptomatic treatment of uterine fibroids, and more recently by the United States' FDA in 2020, under the brand name Orgovyx, for the treatment of advanced prostate cancer. Relugolix has also been studied in the symptomatic treatment of endometriosis.
Relugolix is the first (and currently only) orally-administered GnRH receptor antagonist approved for the treatment of prostate cancer - similar therapies such as degarelix require subcutaneous administration - and therefore provides a less burdensome therapeutic option for patients who might otherwise require clinic visits for administration by healthcare professionals. In addition to its relative ease-of-use, relugolix was shown to be superior in the depression of testosterone levels when compared to leuprolide, another androgen deprivation therapy used in the treatment of prostate cancer. In May 2021, the FDA approved the combination product made up of relugolix, estradiol, and norethindrone under the market name Myfembree for the first once-daily treatment for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women.
Approximately 56% of patients achieved castrate-level testosterone concentrations (9 Relugolix requires once-daily oral administration to maintain the desired testosterone concentrations.
| Trade Name | Reluren Tablet 40 mg+1 mg+0.5 mg |
| Generic | Relugolix + Estradiol + Norethindrone |
| Weight | 40 mg+1 mg+0.5 mg |
| Type | Tablet |
| Therapeutic Class | Gonadotropin-releasing hormone (GnRH) antagonist |
| Manufacturer | Renata Limited |
| Available Country | Bangladesh |
| Last Updated: | October 19, 2023 at 6:27 am |
Uses
This is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.Reluren Tablet 40 mg+1 mg+0.5 mg is also used to associated treatment for these conditions: Atrophic Vaginitis, Breast Cancer, Breast engorgement caused by Postpartum state, Hypogonadism female, Kraurosis Vulvae, Metastatic Breast Cancer, Osteoporosis, Postmenopausal Osteoporosis, Premature Ovarian Failure (POF), Prostate Cancer, Urogenital atrophy, Vasomotor Symptoms Associated With Menopause, Vulvovaginal Atrophy, Advanced androgen dependent Prostate cancer, Female castration, Hypoestrogenism, Contraception, Hormone Replacement Therapy, PalliationAdvanced Prostate Cancer, Heavy Menstrual Bleeding
How Reluren Tablet 40 mg+1 mg+0.5 mg works
Estrogen is found in the the breast, uterine, ovarian, skin, prostate, bone, fat, and brain tissues. The main source of estrogen in adult women during the reproductive period of life is the ovarian follicle, which secretes 70 to 500 mcg of estradiol each day. After menopause, however, the majority of endogenous estrogen is produced by transformation of androstenedione (which is secreted by the adrenal cortex) to estrone in the peripheral tissues. Both estrone and its sulphate conjugated form, estrone sulphate, represent the most abundant estrogens found in postmenopausal women.
Estradiol, however, is considerably more potent than estrone and estriol at the estrogen receptor (ER). As a result, the higher estrone concentration in postmenopausal population, can cause various undesirable effects. These effects may include hot flashes, chills, vaginal dryness, mood swings, irregular menstruation, and chills, in addition to sleep problems.
Estradiol workings by binding to subtypes of the estrogen receptor: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). It also exerts potent agonism of G Protein-coupled estrogen receptor (GPER), which is recognized an important regulator of this drug's rapid effects. Once the estrogen receptor has bound to its ligand, it enters the nucleus of the target cell, regulating gene transcription and formation of of messenger RNA. This mRNA makes contact with ribosomes producing specific proteins that express the effect of estradiol upon the target cell. Agonism of estrogen receptors increases pro-estrogenic effects, leading to the relief of vasomotor and urogenital symptoms of a postmenopausal or low estradiol state.
The pathogenesis and progression of prostate cancer appear driven, at least in part, by the effects of testosterone. Androgen deprivation has been demonstrated to result in cell death and tumor regression in many well-differentiated prostate cancer cell lines - for this reason, androgen deprivation therapy (ADT) has become a standard in the treatment of prostate cancer, particularly in advanced disease.
Testosterone production in males is carried out in the Leydig cells of testes and is stimulated by luteinizing hormone (LH), which itself is produced in the pituitary gland following the binding of gonadotropin-releasing hormone (GnRH) to corresponding GnRH receptors. Relugolix is a competitive antagonist of these GnRH receptors, thereby decreasing the release of LH and, ultimately, testosterone.
Dosage
Reluren Tablet 40 mg+1 mg+0.5 mg dosage
Exclude pregnancy and discontinue hormonal contraceptives prior to this initiation. Orally one tablet once daily. In case of missed dose, need to take as soon as possible the same day and then resume regular dosing the next day at the usual time. If concomitant use of oral P-gp inhibitors is unavoidable, need to take this tablet at least 6 hours before taking the P-gp inhibitor.Safety and effectiveness of in pediatric patients have not been established.Side Effects
Most common adverse reactions (incidence >3%) are: Hot flush, Hyperhidrosis or night sweats, Uterine bleeding, Alopecia, Decreased libido.Toxicity
The NOAEL (no-observed-adverse-effect-level) oral toxicity of estradiol after 90 day in rats was 0.003 mg/kg/day for blood, female reproductive, and male reproductive, endocrine, and liver toxicity. Oral TDLO of ethinyl estradiol is 21 mg/kg/21D intermittent, woman) with an oral LD50 of 960 mg/kg in the rat.
There is limited information in the literature regarding estrogen overdose. Estradiol overdose likely leads to the occurrence of estrogen-associated adverse effects, including nausea, vomiting, abdominal pain, breast tenderness, venous thrombosis, and vaginal bleeding. It is generally recommend to discontinue estradiol treatment and offer supportive care in the case of an overdose.
Data regarding overdose of relugolix are unavailable.
Precaution
Thromboembolic disorders and vascular events: Discontinue this tablet, if an arterial or venous thrombotic, cardiovascular or cerebrovascular event occurs. Bone Loss: Decreases in Bone Mineral Density (BMD) that may not be completely reversible. Depression, mood disorders and suicidal ideation: Advise patients to seek medical attention for new onset or worsening depression, anxiety or other mood changes. Risk of early pregnancy loss: Can cause early pregnancy loss. Advise women to use effective non-hormonal contraception.Interaction
With medicine: P-gp Inhibitors: Co-administration of this tablet with P-gp inhibitors increases the AUC and maximum concentration (Cmax) of relugolix and may increase the risk of adverse reactions associated with this tablet.Combined P-gp and Strong CYP3A Inducers: Use of this tablet with combined P-gp and strong CYP3A inducers decreases the AUC and Cmax of relugolix, estradiol and/or norethindrone and may decrease the therapeutic effects of this tablet.With food and others: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme.Volume of Distribution
Estrogens administered exogenously distribute in a similar fashion to endogenous estrogens. They can be found throughout the body, especially in the sex hormone target organs, such as the breast, ovaries and uterus.
Elimination Route
The absorption of several formulations of estradiol is described below:
Oral tablets and injections
First-pass metabolism in the gastrointestinal tract rapidly breaks down estradiol tablets before entering the systemic circulation. The bioavailability of oral estrogens is said to be 2-10% due to significant first-pass effects. The esterification of estradiol improves the administration (such as with estradiol valerate) or to sustain release from intramuscular depot injections (including estradiol cypionate) via higher lipophilicity. After absorption, the esters are cleaved, which leads to the release of endogenous estradiol, or 17β-estradiol.
Transdermal preparations
The transdermal preparations slowly release estradiol through intact skin, which sustains circulating levels of estradiol during a 1 week period of time. Notably, the bioavailability of estradiol after transdermal administration is about 20 times higher than after oral administration. Transdermal estradiol avoids first pass metabolism effects that reduce bioavailability. Administration via the buttock leads to a Cmax of about 174 pg/mL compared to 147 pg/mL via the abdomen.
Spray preparations
After daily administration, the spray formulations of estradiol reach steady state within 7-8 days. After 3 sprays daily, Cmax is about 54 pg/mL with a Tmax of 20 hours. AUC is about 471 pg•hr/mL.
Vaginal ring and cream preparations
Estradiol is efficiently absorbed through the mucous membranes of the vagina. The vaginal administration of estrogens evades first-pass metabolism. Tmax after vaginal ring delivery ranges from 0.5 to 1 hour. Cmax is about 63 pg/mL. The vaginal cream preparation has a Cmax of estradiol (a component of Premarin vaginal estrogen conjugate cream) was a Cmax of 12.8 ± 16.6 pg/mL, Tmax of 8.5 ± 6.2 hours, with an AUC of 231 ± 285 pg•hr/mL.
The Cmax and AUC of orally-administered relugolix increase proportionally following single doses - in contrast, with repeat dosing the AUC remains proportional to the dose while the Cmax increases greater than proportionally to the dose. Following the administration of 120mg once daily, the steady-state AUC and Cmax of relugolix were 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively.
The absolute oral bioavailability of relugolix is approximately 12% and the median Tmax following oral administration is 2.25 hours.
Half Life
The terminal half-lives for various estrogen products post oral or intravenous administration has been reported to range from 1-12 hours. One pharmacokinetic study of oral estradiol valerate administration in postmenopausal women revealed a terminal elimination half-life of 16.9 ± 6.0 h. A pharmacokinetic study of intravenous estradiol administration in postmenopausal women showed an elimination half-life of 27.45 ± 5.65 minutes. The half-life of estradiol appears to vary by route of administration.
The average effective half-life of relugolix is 25 hours, while the average terminal elimination half-life is 60.8 hours.
Clearance
In one pharmacokinetic study, the clearance of orally administered micronized estradiol in postmenopausal women was 29.9±15.5 mL/min/kg. Another study revealed a clearance of intravenously administered estradiol was 1.3 mL/min/kg.
The average renal clearance of relugolix is 8 L/h with a total clearance of 26.4 L/h.
Elimination Route
Estradiol is excreted in the urine with both glucuronide and sulfate conjugates.
Approximately 81% of an orally administered dose was recovered in the feces, of which 4.2% was unchanged parent drug, while 4.1% of the dose was recovered in the urine, of which 2.2% remained unchanged.
Pregnancy & Breastfeeding use
Based on findings from animal studies and its mechanism of action, this may cause early pregnancy loss. Discontinue this tablet, if pregnancy occurs during treatment. There is no data on the presence of relugolix or its metabolites in human milk, the effects on the breastfed child or the effects on milk production. Relugolix was detected in milk in lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.Contraindication
High risk of arterial, venous thrombotic or thromboembolic disorder. Pregnancy. Known osteoporosis. Current or history of breast cancer or other hormone sensitive malignancies. Known hepatic impairment or disease. Undiagnosed abnormal uterine bleeding. Known hypersensitivity to relugolix, estradiol or norethindrone acetate.Acute Overdose
Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness, fatigue and withdrawal bleeding. Supportive care is recommended if an overdose occurs. The amount of relugolix, estradiol or norethindrone removed by hemodialysis is unknown.Storage Condition
Store in a cool (below 30°C) and dry place, away from light & moisture. Keep all medicines out of reach of children.Innovators Monograph
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