And Norethindrone

Uses

Elagolix is used for the management of moderate to severe pain associated with endometriosis.

• No dose adjustment of Elagolix is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis)
• No dosage adjustment of Elagolix is required in women with mild hepatic impairment.
• Safety and effectiveness of Elagolix in patients less than 18 years of age have not been established.

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.

And Norethindrone is also used to associated treatment for these conditions: Heavy Menstrual Bleeding, Moderate Endometriosis related pain, Severe Endometriosis related painAtrophic 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 And Norethindrone works

Endometriosis develops when tissue that is similar to the kind that is normally located in the uterus starts to grow outside of the uterus . Such growth leads to various symptoms like pain during periods, pelvic pain between periods, and pain during sexual intercourse . The growths themselves are referred to as lesions and frequently develop on the ovaries, fallopian tubes, and other areas around the uterus, including the bowel or bladder . The growth of these lesions is dependent upon the estrogen hormone .

Elagolix is an orally-administered, nonpeptide small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland . Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.

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

And Norethindrone dosage

Exclude pregnancy before starting Elagolix or start Elagolix within 7 days from the onset of menses. Take Elagolix at approximately the same time each day, with or without food.

Initiate treatment with Elagolix 150 mg once daily-

• Maximum Treatment Duration: 24 months
• Coexisting Condition: None

• Maximum Treatment Duration: 6 months
• Coexisting Condition: Dyspareunia

• Maximum Treatment Duration: 6 months
• Coexisting Condition: Moderate hepatic impairment (Child-Pugh Class B)

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

Most common adverse reactions (>5%) in clinical trials included hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions and mood changes.

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

In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed . Common adverse reactions of elagolix include hot flush, headache, nausea, insomnia, mood alterations, amenorrhea, depression, anxiety, arthralgia, bone loss, changes in menstrual bleeding patterns, suicidal ideation and behavior, exacerbation of existing mood disorders, and/or hepatic transaminase elevations .

The recommended duration of use for elagolix is up to 24 months for the 150 mg once daily dose and up to six months for the 200 mg twice daily dose, as it causes a dose-dependent decrease in bone mineral density (BMD) . BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment . For women with moderate hepatic impairment, the recommended dosage is 150 mg once daily for up to six months .

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

• Bone Loss: Dose- and duration-dependent decreases in bone mineral density (BMD) that may not be completely reversible. Assess BMD in women with additional risk factors for bone loss
• Reduced Ability to Recognize Pregnancy: Elagolix may alter menstrual bleeding, which may reduce the ability to recognize pregnancy. Perform testing if pregnancy is suspected. Discontinue if pregnancy is confirmed
• Suicidal Ideation and Mood Disorders: Advise patients to seek medical attention for suicidal ideation, suicidal behavior, new onset or worsening depression, anxiety, or other mood changes
• Hepatic Transaminase Elevations: Dose-dependent elevations in serum alanine aminotransferase (ALT). Counsel patients on signs and symptoms of liver injury
• Potential for Reduced Efficacy with Estrogen-Containing Contraceptives: Use non-hormonal contraception during treatment and for one week after discontinuing Elagolix.

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

The apparent volume of distribution at steady state (Vdss/F) of elagolix is reported to be 1674 for a 150 mg daily regimen and 881 for a 200 mg twice daily regimen .

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 Tmax of elagolix is reported as being 1.0 hours . The effect of a high-fat meal (relative to fasting) can result in a reduction of the AUC and Cmax by as much as 24% and 36%, respectively .

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 terminal phase elimination half-life of elagolix is recorded as being 4 to 6 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

The oral clearance (CL/F) of elagolix is 123 L/hr for a 150 mg once daily regimen and 144 L/hr for a 200 mg twice daily regimen .

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

The primary route of elimination of elagolix is via hepatic metabolism .

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

Pregnancy & Breastfeeding use

Exposure to Elagolix early in pregnancy may increase the risk of early pregnancy loss. Use of Elagolix is contraindicated in pregnant women. Discontinue Elagolix if pregnancy occurs during treatment. The limited human data with the use of Elagolix in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with Elagolix, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups. There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production.

There are no adequate animal data on the excretion of Elagolix in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Elagolix and any potential adverse effects on the breastfed child from Elagolix.

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

Elagolix is contraindicated in women:

• Who are pregnant
• Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss.
• With known osteoporosis because of the risk of further bone loss
• With severe hepatic impairment because of the risk of bone loss
• With concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil)

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

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Store at room temperature.

Innovators Monograph

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