Prefest (Estradiol,Norgestimate)

Uses

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.

Norgestimate is a progesterone used as a contraceptive and to treat acne vulgaris.

Norgestimate is formulated with ethinylestradiol as a combined oral contraceptive. It can also be given with low dose ethinylestradiol for contraception as well as the treatment of moderate acne vulgaris in women ≥15 years old.

Prefest (Estradiol,Norgestimate) 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, PalliationHypermenorrhea, Idiopathic Hirsutism, Menstrual Distress (Dysmenorrhea), Postmenopausal Osteoporosis, Moderate Acne vulgaris, Moderate Menopausal Vasomotor Symptoms, Moderate Vulvovaginal atrophy, Severe Vasomotor Symptoms Associated With Menopause, Severe menopausal vulvovaginal atrophy, Oral Contraceptives

How Prefest (Estradiol,Norgestimate) 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.

Progesterone analogs like norgestimate decrease the frequency of gonadotropin releasing hormone pulses from the hypothalamus, decreasing follicle stimulating hormone and luteinizing hormone. These actions prevent ovulation.

Norgestimate suppresses the hypothalamo-pituitary-axis, reducing androgen synthesis. It also induces production of sex hormone binding globulin, which decreases free testosterone. These actions together result in less testosterone being available to stimulate sebaceous glands, resulting in effective treatment of some forms of acne.

Dosage

Prefest (Estradiol,Norgestimate) dosage

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

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 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 overdoses of norgestimate are rare. However, the majority of patients overdosing on oral contraceptives do not become seriously ill. Treat overdoses with symptomatic and supportive care.

Precaution

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

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

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.

Data regarding the volume of distribution of norgestimate are not readily available.

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.

Oral norgestimate has a T_max of 0.5-2h.

On day 21 of cycle 3, 17-desacetylnorgestimate reaches a C_max of 1.82ng/mL, with a T_max of 1.5h, and an AUC of 16.1h*ng/mL. At the same time, norgestrel reaches a C_max of 2.79ng/mL, with a T_max of 1.7h, and an AUC of 49.9h*ng/mL.

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.

Norgestimate is rapidly deacetylated. The active metabolites of norgestimate, 17-desacetyl norgestimate, has a half life of 12-30h, while norgestrel has a half life of 36.4±10.2h.

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.

Data regarding the clearance of norgestimate is not readily available.

Elimination Route

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

Norgestimate is 45-49% eliminated in urine and 16-49% eliminated in feces. Unchanged norgestimate is not detected in urine.

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

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 at room temperature.

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