Dienogest + Estradiol Valerate

Dienogest + Estradiol Valerate Uses, Dosage, Side Effects, Food Interaction and all others data.

Dienogest is a nortestosterone derivative with no androgenic but rather an antiandrogenic activity of approximately 1/3 of that of cyproterone acetate. Dienogest binds to the progesterone receptor of the human uterus with only 10% of the relative affinity of progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.

Dienogest acts on endometriosis by reducing the endogenous production of estradiol and thereby suppressing the trophic effects of estradiol on both the eutopic and ectopic endometrium. When given continuously, dienogest leads to a hypoestrogenic, hypergestagenic endocrine environment causing initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions. Additional properties eg, immunologic and antiangiogenic effects, seem to contribute to the inhibitory action of dienogest on cell proliferation.

Dienogest exhibits a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use . It also mediates an antiandrogenic effect that is equivalent to approximately one third that of cyproterone acetate . A dose of 2 mg inhibits the growth of ovarian follicles at 10 mm and maintains the concentration of progesterone at a low level, but has a weak inhibitory effect on FSH and LH. 1mg/kg of dienogest also directly inhibits ovulation . In clinical trials composing of patients with endometriosis, dienogest therapy effectively reduced painful symptoms and endometriotic lesions associated with the disorder .Dienogest displays no antiestrogenic activity as it activate neither estrogen receptor (ER) α nor ERβ [A16570], and causes hypoestrogenic effects instead as it is shown to decrease the relative expressions of ERβ and ERα . It has no glucocorticoid or mineralocorticoid effects. In combined oral contraceptive pills (COCP) with ethinyloestradiol, dienogest conjuction therapy effectively reduces the symptoms of acne and hirsutism, as well as improving excessively heavy or prolonged menstrual bleeding .

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.

Dienogest + Estradiol Valerate
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	Dienogest + Estradiol Valerate
Generic	Dienogest + Estradiol Valerate
Type
Therapeutic Class	Drugs for menopausal symptoms: Hormone replacement therapy, Female Sex hormones
Manufacturer
Available Country	Bangladesh
Last Updated:	September 24, 2024 at 5:38 am

Uses

This is indicated for- Relief of post-menopausal symptoms associated with decrease of estrogen hormones including hot flushes and vaginal dryness Women who desire the complete stoppage of menstrual bleeding after its intermittent recurrence due to impending menopause Women who displayed undue obstruction of normal daily activities due to menopausal symptoms.

Dienogest + Estradiol Valerate is also used to associated treatment for these conditions: Hypermenorrhea, Pain, Contraception, Oral ContraceptivesHeavy 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 Contraceptives

How Dienogest + Estradiol Valerate works

Dienogest acts as an agonist at the progesterone receptor (PR) with weak affinity that is comparable to that of progesterone but has a very potent progestagenic effect in the endometrium, causing endometrial atrophy after prolonged use . It promotes antiproliferative, immunologic and antiangiogenic effects on endometrial tissue. Dienogest reduces the level of endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium . Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue . It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism [A16570].

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.

Dosage

Dienogest + Estradiol Valerate dosage

One tablet should be taken daily at the same time blister packet. blister packet. Each blister pack contains tablets for 28 days of treatment. This is for oral use only. The tablets are to be swallowed whole with some liquid. Treatment is continuous, which means that the next pack follows immediately without a break. The tablets should preferably be taken at the same time every day. In case a tablet is forgotten it should be taken as soon as possible. If more than 24 hours have elapsed no extra tablet needs to be taken. If several tablets are forgotten, bleeding may occur.

Side Effects

The following diseases are reported more often in women using HRT compared to women not using HRT: Breast cancer, Abnormal growth or cancer of the lining of the womb (endometrial hyperplasia or cancer), Ovarian cancer, Blood clots in the veins of the legs or lungs (venous thromboembolism), Heart disease, Stroke, Probable memory loss if hrt is started over the age of 65Most frequent side effects: unexpected menstruation-like bleeding, breast tenderness, breast pain Unexpected menstruation-like bleeding occurs during the first few months of treatment with this medicine. Usually temporary and normally disappears with continued treatment. If it does not, contact your doctor. Common side effects (between 1 and 10 in every 100 patients are likely to get these): headache, migraine, dizziness, tiredness, anxiety, depressive mood high blood pressure, worsening of high blood pressure feeling sick, abdominal pain, diarrhoea, increase in gamma gt (an enzyme) thickening of the lining of the womb, inflammation of the genitals, swollen breasts hot flushes changes in body weight, thrush Uncommon side effects (between 1 and 10 in every 1000 patients are likely to get these): sleeplessness, nervousness inflammation of the veins, venous blood clot (leg pain), painful veins constipation, swollen tummy (bloating), inflammation of the stomachincreased sweating, hair loss, a variety of skin conditions such as exanthema, eczema and acne-like Dermatitis acnechanges in vaginal secretions, lumpy breasts (fibrocystic disease) allergic reactions fluid retention in the legs, altered blood fats, increase in blood sugar, change in sex drive, muscle Cramps, anaemia Rare side effects (between 1 and 10 in every 10,000 patients are likely to get these): Depression, visual disorders, palpitations, indigestion, disturbances in liver enzymes, increase in the size of fibroids, increased appetite.

Toxicity

Oral LD50 in mouse is 4 mg/kg . In a long-term carcinogenicity study involving rats and mice, exposure of 10 times the dose of maximum recommended clinical dose of dienogest resulted in increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma . These tumors are thought to arise from marked species differences in the optimal oestrogen:progestogen ratio for reproductive function. In rat liver foci assay, dienogest did not induce tumor promotion activity . Dienogest does not display genotoxic potential.

Precaution

If you have ever had any of the following problems, before you start the treatment, as these may return or become worse during treatment with this tablet. If so, you should see your doctor more often for check-ups:Uterine Fibroids, Endometriosis, Endometrial hyperplasia, Increased risk of developing blood clots, Risk factors for estrogen-dependent tumours, e.g. 1st-degree heredity for breast cancer, High blood pressure, A liver disorder, such as a benign liver tumour, Diabetes, Gallstones, Migraine or severe headaches, Systemic Lupus, Erythematosus, Epilepsy, Asthma, Otosclerosis, A very high level of fat in your blood (triglycerides), Fluid retention due to cardiac or kidney problems, Hereditary angioedema, products containing oestrogens may cause or worsen the symptoms.You should see your doctor immediately if you experience symptoms of angioedema such as: Swollen face, tongue and/or throat and/or difficulty swallowing, or hives together with, Difficulty breathing.Stop taking this tablet and see a doctor immediately: Jaundice or deterioration in liver function, Significant increase in blood pressure, New onset of migraine-type headache, Pregnancy. If you notice signs of a blood clot, such as, Painful swelling and redness of the legs, Sudden chest pain, or difficulty breathing.HRT and cancer: Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer). Taking oestrogen-only HRT will increase the risk of excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the womb lining (endometrial cancer) The progestogen in this tablet protects you from this extra risk.Irregular bleeding: You may have irregular bleeding or drops of blood (spotting) during the first 3-6 months of taking this tablet. However, if the irregular bleeding: carries on for more than the first 6 months.Breast cancer: Evidence suggests that taking combined oestrogen-progestogen and possibly also oestrogen-only HRT increases the risk of breast cancer. This extra risk depends on how long you take HRT. The additional risk becomes clear within a few years. However, it returns to normal within a few years (at most 5) after stopping treatment.Blood clots in a vein (thrombosis): The risk of blood clots in the veins is about 1.3 to 3-times higher in HRT users than in non-users, especially during the first year of taking it. Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death. Inform your doctor if any of these situations applies to you: you are unable to walk for a long time because of major surgery, injury or illness you are seriously overweight (bmi >30 kg/m²) you have any blood clotting problem that needs long-term treatment with a medicine used to prevent blood clots if any of your close relatives has ever had a blood clot in the leg, lung or an other organ you have systemic lupus erythematosus (sle) you have cancer Heart disease (heart attack): There is no evidence that HRT will prevent a heart attack. Women over the age of 60 years who use oestrogen-progestogen HRT are slightly more likely to develop heart disease than those not taking any HRT.Stroke: The risk of getting stroke is about 1.5 times higher in HRT users than in non-users. The number of extra cases of stroke due to use of HRT will increase with age.

Interaction

Some medicines may interfere with the effect of this tablet. This might lead to irregular bleeding. This applies to the following medicines: Medicines for epilepsy (such as phenobarbital, phenytoin, carbamazepine) Medicines for tuberculosis (such as rifampicin and rifabutin) Medicines for HIV infection (e.g. nevirapine, efavirenz, ritonavir and nelfinavir) Herbal remedies containing St. John’s wort (Hypericum perforatum).

Volume of Distribution

The apparent volume of distribution (Vd/F) of dienogest is 40 L .

Elimination Route

Dienogest is rapidly absorbed following oral administration, with 91% bioavailability. The peak plasma concentration of 47 ng/mL is reached at about 1.5 hours after single ingestion of 2 mg . The stable concentrations of the drug are reached after two days of initial treatment .

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.

Half Life

Elimination half-life of dienogest is around 9-10 hours. The half-life of urinary metabolites excretion is 14 hours .

Clearance

The metabolic clearance rate from serum (Cl/F) is 64 mL/min .

Elimination Route

The ratio of renal elimination to fecal elimination of dienogest is 3:1, where dienogest is predominantly excreted in the form of inactive metabolites. Most of orally administered drug is excreted in the urine within the first 24 hours of ingestion .

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

Pregnancy & Breastfeeding use

This is for use in post-menopausal women only. If you become pregnant, stop taking and contact your doctor. If you are lactating mother, stop taking this tablet and contact your doctor.

Contraindication

Known past or suspected breast cancer Known or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer) Undiagnosed genital bleeding Untreated endometrial hyperplasia Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism) Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency) Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal Porphyria Hypersensitivity to the active substances or to any of the ingredients

Special Warning

Use in Children: Dienogest is not indicated in children prior to menarche. The safety and efficacy of Dienogest in adolescents (menarche to 18 years) has not yet been established.

Use in the Elderly: There is no relevant indication for the use of Dienogest in the geriatric population.

Acute Overdose

Acute toxicity studies indicated that, even in the case of inadvertent intake of a multiple of the therapeutic dose, no acute toxicity risk is to be expected. Overdose may cause nausea and vomiting, and withdrawal bleeding may occur in some women. There is no specific antidote.