Lupigestrone

Uses

Lupigestrone capsules are used for use in the prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving conjugated estrogens tablets. They are also used for use in secondary amenorrhea.

Lupigestrone is also used to associated treatment for these conditions: Abnormal Uterine Bleeding, Amenorrhea, Endometrial hyperplasia caused by conjugated estrogen, Female Infertility, Pregnant State, Secondary Amenorrhea, Recurrent spontaneous preterm birth, Assisted Reproductive Techniques (ART), Assisted Reproductive Technology therapy

How Lupigestrone works

Lupigestrone binds and activates its nuclear receptor, PR, which plays an important part in the signaling of stimuli that maintain the endometrium during its preparation for pregnancy.

Lupigestrone receptor (PR) is a member of the nuclear/steroid hormone receptor (SHR) family of ligand-dependent transcription factors that is expressed primarily in female reproductive tissue as well as the central nervous system. As a result of its binding its associated steroid hormone, progesterone, the progesterone receptor (PR) modulates the expression of genes that regulate the development, differentiation, and proliferation of target tissues . In humans, PR is found to be highly expressed in the stromal (connective tissue) cells during the secretory phase and during pregnancy .

Lupigestrone may prevent pregnancy by changing the consistency of cervical mucus to be unfavorable for sperm penetration, and by inhibiting follicle-stimulating hormone (FSH), which normally causes ovulation. With perfect use, the first-year failure rate for progestin-only oral contraceptives is approximately 0.5%. The typical failure rate, however, is estimated to be approximately 5%, due to late or missed pills .

Dosage

Lupigestrone dosage

Oral administration:

Prevention Of Endometrial Hyperplasia: Lupigestrone Capsules should be given as a single daily dose at bedtime, 200 mg orally for 12 days sequentially per 28-day cycle, to a postmenopausal woman with auteruswho is receiving daily conjugated estrogens tablets.

Treatment Of Secondary Amenorrhea: Lupigestrone Capsules may be given as a single daily dose of 400 mg at bedtime for 10 days. Some women may experience difficulty swallowing Lupigestrone Capsules. For these women, Lupigestrone Capsules should be taken with a glass of water while in the standing position.

Vaginal or rectal insertion:

For women undergoing Assisted Reproductive Technology (ART) programme: The recommended dose is 400 mg twice a day byvaginal insertion.Start using Cyclogest 400 mg on the day of egg retrieval. The administration of Cyclogest should be continued for 38 days if pregnancy has been confirmed.

For the treatment of premenstrual syndrome and post-natal depression: The recommended dose is 200 mg once a day or 400 mg twice a day byvaginal or rectal insertion.

The pessary may be inserted into either the vagina or rectum (back passage) depending upon the following certain other conditions.

Side Effects

Common side effects are Headache, Breast T enderness, Joint Pain, Depression, Dizziness, Urinary Problems, Abdominal Pain, Vaginal Discharge, Nausea / Vomiting, Worry, Chest Pain, Diarrhea, Night Sweats, Breast Pain, Swelling of Hands and Feet, Vaginal Dryness, Constipation, Breast Carcinoma, Breast Excisional Biopsy, Cholecystectomy

Toxicity

Intraperitoneal LD50 (rat): 327 mg/kg .

Use in pregnancy

Only forms of progesterone that are indicated on product labeling for pregnancy should be used. Some forms of progesterone should not be used in pregnancy , . Refer to individual product monographs for information regarding use in pregnancy. Many studies have found no effects on fetal development associated with long-term use of contraceptive doses of oral progestins. Studies of infant growth and development that have been conducted have not demonstrated significant adverse effects, however, these studies are few in number. It is therefore advisable to rule out suspected pregnancy before starting any hormonal contraceptive .

Effects on fertility

Lupigestrone at high doses is an antifertility drug and high doses would be expected to impair fertility until cessation . The progesterone contraceptive should not be used during pregnancy.

Carcinogenicity

Lupigestrone has been shown to induce or promote the formation of ovarian, uterine, mammary, and genital tract tumors in animals. The clinical relevance of these findings is unknown . Certain epidemiological studies of patients using oral contraceptives have reported an increased relative risk of developing breast cancer, especially at a younger age and associated with a longer duration of use. These studies have mainly involved combined oral contraceptives, and therefore, it is unknown whether this risk is attributable to progestins, estrogens, or a combination of both. At this time, there is insufficient data to determine whether the use of progestin-only contraceptives increases the risk in a similar way to combined contraceptives. A meta-analysis of 54 studies showed a small increase in the frequency of breast cancer diagnosis for women who were currently using combined oral contraceptives, or had used them within the past 10 years. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of hormone use. Women with breast cancer should not use oral contraceptives, as there is no sufficient data to fully establish or negate the risk of cancer with hormonal contraceptive use .

Use in breastfeeding

Lupigestrone has been detected in the milk of nursing mothers , . No adverse effects, in general, have been found on breastfeeding ability or on the health, growth, or development of the growing infant. Despite this, isolated post-marketing cases of decreased milk production have been reported .

Precaution

Discontinue medications if there is sudden partial or complete loss of vision, proptosis or diplopia; migraine and embolic disorders; epilepsy, migraine, asthma, cardiac or renal dysfunction. History of depression, glucose tolerance and diabetic patients. May impair ability to drive or operate machinery. Avoid sudden withdrawal of progesterone; lactation.

Interaction

Enhanced clearance with enzyme-inducing drugs eg, carbamazepine, griseofulvin, phenobarbital, phenytoin and rifampicin. Ketoconazole may increase serum levels of progesterone. May inhibit ciclosporin metabolism.

Food Interaction

• Administer vitamin supplements.
• Avoid alcohol.
• Limit caffeine intake.
• Take at the same time every day.
• Take with food.

[Moderate] MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4.

Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

Orange juice is not expected to interact with these drugs.

Lupigestrone Cholesterol interaction

[Moderate] Some progestogenic agents may elevate plasma LDL levels and

Patients with preexisting hyperlipidemia may require closer monitoring during progestogen therapy, and adjustments made accordingly in their lipid-lowering regimen.

Lupigestrone Hypertension interaction

[Moderate] Estrogens and progestogens may cause fluid retention, particularly when given in high dosages or for prolonged periods.

Therapy with these agents should be administered cautiously in patients who have preexisting problems with excess fluid.

In addition, patients with conditions that may be adversely affected by fluid accumulation, such as asthma, epilepsy, migraine, and cardiovascular or renal dysfunction, should be observed for exacerbation of their condition during estrogen and

Lupigestrone Drug Interaction

Unknown: amphetamine / dextroamphetamine, thyroid desiccated, diphenhydramine, ubiquinone, duloxetine, dehydroepiandrosterone, estradiol, omega-3 polyunsaturated fatty acids, fluticasone nasal, escitalopram, montelukast, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, lisdexamfetamine, bupropion, alprazolam, cetirizine

Lupigestrone Disease Interaction

Major: breast malignancy, liver disease, thromboembolismModerate: depression, fluid retention, glucose intolerance, retinal thrombosis, thyroid function tests, hyperlipidemiaMinor: weight gain

Volume of Distribution

When administered vaginally, progesterone is well absorbed by uterine endometrial tissue, and a small percentage is distributed into the systemic circulation. The amount of progesterone in the systemic circulation appears to be of minimal importance, especially when implantation, pregnancy, and live birth outcomes appear similar for intramuscular and vaginal administration of progesterone .

Elimination Route

Oral micronized capsules

Following oral administration of progesterone in the micronized soft-gelatin capsule formulation, peak serum concentration was achieved in the first 3 hours. The absolute bioavailability of micronized progesterone is unknown at this time. In postmenopausal women, serum progesterone concentration increased in a dose-proportional and linear fashion after multiple doses of progesterone capsules, ranging from 100 mg/day to 300 mg/day .

IM administration

After intramuscular (IM) administration of 10 mg of progesterone in oil, the maximum plasma concentrations were achieved in about 8 hours post-injection and plasma concentrations stayed above baseline for approximately 24 hours post-injection. Injections of 10, 25, and 50 mg lead to geometric mean values for maximum plasma concentration (CMAX) of 7, 28, and 50 ng/mL, respectively . Lupigestrone administered by the intramuscular (IM) route avoids significant first-pass hepatic metabolism. As a result, endometrial tissue concentrations of progesterone achieved with IM administration are higher when compared with oral administration. Despite this, the highest concentrations of progesterone in endometrial tissue are reached with vaginal administration .

Note on oral contraceptive tablet absorption

Serum progestin levels peak about 2 hours after oral administration of progesterone-only contraceptive tablets, followed by rapid distribution and elimination. By 24 hours after drug administration, serum levels remain near the baseline, making efficacy dependent upon strict adherence to the dosing schedule. Large variations in serum progesterone levels occur among individuals. Progestin-only administration leads to lower steady-state serum progestin levels and a shorter elimination half-life than concurrent administration with estrogens .

Half Life

Absorption half-life is approximately 25-50 hours and an elimination half-life of 5-20 minutes (progesterone gel) .

Lupigestrone, administered orally, has a short serum half-life (approximately 5 minutes). It is rapidly metabolized to 17-hydroxyprogesterone during its first pass through the liver .

Clearance

Apparent clearance

1367 ± 348 (50mg of progesterone administered by vaginal insert once daily) .

106 ± 15 L/h (50mg/mL IM injection once daily) .

Elimination Route

Lupigestrone metabolites are excreted mainly by the kidneys. Urinary elimination is observed for 95% of patients in the form of glycuroconjugated metabolites, primarily 3 a, 5 ß–pregnanediol (pregnandiol) . The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the urine and bile. Lupigestrone metabolites, excreted in the bile, may undergo enterohepatic recycling or may be found excreted in the feces.

Pregnancy & Breastfeeding use

Pregnancy Category B. Reproductive studies have been performed in mice at doses up to 9 times the human oral dose, in rats at doses up to 44 times the human oral dose, in rabbits at a dose of 10 mcg/day delivered locally within the uterus by an implanted device, in guinea pigs at doses of approximately one-half the human oral dose and in rhesus monkeys at doses approximately the human dose, all based on body surface area, and have revealed little or no evidence of impaired fertility or harm to the fetus due to progesterone.

Nursing Women: Detectable amounts of progestin have been identified in the milk of nursing women receiving progestins. Caution should be exercised when Lupigestrone Capsules are administered to a nursing woman.

Contraindication

Lupigestrone Capsules should not be used in women with any of the following conditions:

• Lupigestrone Capsules should not be used in patients with known hypersensitivity to its ingredients. Lupigestrone Capsules contain peanut oil and should never be used by patients allergic to peanuts.
• Undiagnosed abnormal genital bleeding.
• Known, suspected, or history of breast cancer.
• Active deep vein thrombosis, pulmonary embolism or history of these conditions.
• Active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions.
• Known liver dysfunction or disease.
• Known or suspected pregnancy.

Special Warning

Pediatric Use: Lupigestrone Capsules are not indicated in children. Clinical studies have not been conducted in the pediatric population.

Geriatric Use: There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Lupigestrone Capsules to determine whether those over 65 years of age differ from younger subjects in their response to Lupigestrone Capsules.

Hepatic Insufficiency: The effect of hepatic impairment on the pharmacokinetics of Lupigestrone Capsules has not been studied.

Renal Insufficiency: The effect of renal impairment on the pharmacokinetics of Lupigestrone Capsules has not been studied.

Acute Overdose

No studies on overdosage have been conducted in humans. In the case of overdosage, Lupigestrone Capsules should be discontinued and the patient should be treated symptomatically.

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