Drospirenone And Estradiol

Uses

Drospirenone is used for oral contraception.

Treatment of moderate to severe vasomotor symptoms associated with the menopause.

Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.

Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.

Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).

Prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.

Drospirenone And Estradiol is also used to associated treatment for these conditions: Abnormal Uterine Bleeding, Acne Vulgaris, Endometriosis, Hypermenorrhea, Idiopathic Hirsutism, Menstrual Distress (Dysmenorrhea), Menstrual Irregularities, Osteoporotic Fractures, Pregnant State, Premenstrual Dysphoric Disorder, Vasomotor Symptoms Associated With Menopause, Vulvovaginal Atrophy, Hypoestrogenism, Folate supplementation therapy, Hormone Replacement Therapy, Oral ContraceptivesAtrophic 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, Palliation

How Drospirenone And Estradiol works

Drospirenone and ethinyl estradiol in combination suppress the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH), preventing ovulation. Other changes induced by this drug which may aid in the prevention of pregnancy include alterations in cervical mucus consistency, hindering sperm movement, and lowering the chance of embryo implantation.

Drospirenone is an analog of the diuretic spironolactone, which exerts anti-mineralocorticoid activity, blocking aldosterone receptors, which increases sodium and water excretion. Studies in animals have demonstrated that drospirenone administration leads to antiandrogenic activity. This activity helps to oppose the effects of naturally occurring androgens, inhibiting the binding of dihydrotestosterone (DHT) to its receptor, and preventing androgen synthesis in the ovaries, helping to treat acne and hirsutism. Drospirenone may also decrease the level of edema in sebaceous follicle during the second half of the menstrual cycle, when acne often appears.

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.

Dosage

Drospirenone And Estradiol dosage

Drospirenone (white active and light pink inert tablets) is swallowed whole once a day. Take one tablet daily for 28 consecutive days; one white active tablet daily during the first 24 days and one light pink inert tablet daily during the 4 following days. Tablets must be taken every day at about the same time of the day so that the interval between two tablets is always 24 hours.

Oral:

• Prostate cancer: 10 mg 3 times/day for at least 3 month.
• Menopausal vasomotor symptoms: 1-2 mg/day on a cyclical or continuous regimen
• Prevention of postmenopausal osteoporosis: 0.5 mg/day in cyclical regimen.
• Hypogonadism: 1-2 mg/day in a cyclic regimen.

Vaginal:

• Vulvular and vag atrophy: Insert 2-4 g/day for 2 wk. Maintenance: 1 g 1-3 times/wk.
• Postmenopausal vag atrophy; Urogenital symptoms: Insert a ring and keep in place for 90 days.
• Atrophic vaginitis: Insert 1 tab once daily for 2 wk. Maintenance: 1 tab twice wkly. Attempt to discontinue or taper medication at 3-6 monthly intervals.

Side Effects

The following clinically significant Side Effects are described elsewhere in other sections of the labeling:

• Hyperkalemia
• Bleeding Irregularities and Amenorrhea
• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

GI disturbances, genitourinary changes, haematologic disorders, CV and CNS effects, endocrine and metabolic disorders, cholestatic jaundice, local skin reactions, chorea, contact lens intolerance, steeping of corneal curvature, pulmonary thromboembolism, carbohydrate intolerance.

Toxicity

The oral LD50 of drospirenone in rats is >2000 mg/kg.

Overdose information An overdose of drospirenone, like other oral contraceptives, may lead to cause nausea or withdrawal bleeding. For drospirenone in particular, as an analog of spironolactone, may affect the levels of serum sodium and potassium. Their concentrations should be monitored in cases of overdose in addition to monitoring from metabolic acidosis and hyperkalemia, which may also result.

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.

Precaution

Before you take Drospirenone, do not take this medicine and tell your doctor if you are already taking the following medicines: efavirenz, phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, rifabutin, rufinamide, aprepitant, products containing St. John's wort. Take special care while taking Drospirenone Hyperkalemia Thromboembolic Disorders, Bone Loss, Liver Disease Ectopic Pregnancy, Risk of Hyperglycemia in Patients with Diabetes, Bleeding Irregularities, and Amenorrhea, Depression.

Conditions exacerbated by fluid retention; hypercalcaemia, cerebrovascular diorders, coronary artery disease, gall bladder diseases; lipid effects; familial defects of lipoprotein metabolism. May increase BP, risk of venous thromboembolism, breast cancer, benign hepatic adenoma, endometrial cancer and size of preexisting uterine leiomyomata. Dosage should be reduced in hepatic impairment. Lactation. Child.

Interaction

Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of Drospirenone or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with Drospirenone.

CYP1A2 and CYP3A4 inducers e.g. aminoglutethimide, carbamazepine, phenobarbital, and rifampin may decrease the effects of estradiol. May enhance the effects of hydrocortisone and prednisolone when used together.

Volume of Distribution

The volume of distribution of drospirenone is estimated to be 4 L/kg, according to the FDA label for Yaz. Prescribing information from a combination of estradiol and drospirenone estimates the volume of distribution to range from 3.7- 4.2 L/kg.

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 absolute bioavailability of drospirenone is approximately 76% due to first-pass effects. The maximum plasma concentration of drospirenone occurs within 1 to 2 hours after oral administration and is estimated to range between 60 and 87 ng/mL. A European prescribing monograph for the combination product of estradiol and drospirenone indicates that drospirenone is both completely and rapidly absorbed. It reports a Cmax of 21.9 ng/ml, achieved approximately 1-hour post-administration. The absolute bioavailability is reported to range between 76 to 85%.

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.

Half Life

The serum half-life of drospirenone is estimated to be 30 hours. The half-life of drospirenone metabolite excretion in the urine and feces is approximately 40 hours.

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.

Clearance

Drospirenone is rapidly cleared, typically within 2-3 days of administration of the last active tablet. The rate of clearance of drospirenone calculated in the serum ranges from 1.2-1.5 ml/min/kg, however, this value can vary by up to 25% according to the patient.

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.

Elimination Route

Various metabolites of drospirenone are measured in the urine and feces. Drospirenone elimination from the body is almost after 10 days post-administration when negligible amounts of drospirenone are found unchanged in both the urine and feces. Between 38% to 47% of the metabolites are identified as glucuronide and sulfate conjugates in the urine. In the feces, approximately 17% to 20% of identifiable metabolites are found to be excreted as glucuronides and sulfates.

Estradiol is excreted in the urine with both glucuronide and sulfate conjugates.

Pregnancy & Breastfeeding use

Pregnancy Category X. Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal 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.

Contraindication

• Renal impairment
• Adrenal insufficiency
• Presence or history of progestin sensitive cancers
• Liver tumors, benign or malignant, or hepatic impairment
• Undiagnosed abnormal uterine bleeding

Hypersensitivity; undiagnosed vag bleeding; thrombophloebitis or thromboembolic disorders; breast carcinoma except in selected patients being treated for metastatic disease; oestrogen-dependent tumor; porphyria; pregnancy.

Storage Condition

Store below 30°C and dry place. Keep away from light. Keep out of the reach of children.

Store at room temperature.

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