PROGEVA

Progesterone is a hormone that occurs naturally in females, and is essential for endometrial receptivity, embryo implantation, and the successful establishment of pregnancy.

A low progesterone concentration or an insufficient response to progesterone can cause infertility and pregnancy loss 7.

Progesterone is used in various contraceptive preparations to prevent ovulation and fertilization 15, 8 as well as in other formulations to promote and support pregnancy.

Please see

Medroxyprogesterone acetate, Megestrol acetate, Dydrogesterone and Hydroxyprogesterone entries for information on various other forms of progesterone.

Pharmaceutical progesterone is made from a plant source as a starting material and is chemically identical to progesterone of human ovarian origin Label.

Progesterone is available in gelatinized capsule form, vaginal gel form, tablet form, vaginal insert form, and injection form, all used for various purposes Label, 20, 22, 21, 23.

Gelatinized capsules

The gelatinized capsules are indicated for use in the prevention of endometrial hyperplasia in non-hysterectomized postmenopausal women who are receiving conjugated estrogens tablets.

They are also indicated for use in secondary amenorrhea Label.

Vaginal gel

Progesterone gel (8%) is indicated as progesterone supplementation or replacement as part of an Assisted Reproductive Technology (“ART”) treatment for infertile women with progesterone deficiency.

The lower concentration progesterone gel (4%) is used in the treatment of secondary amenorrhea, with the use of the 8% concentration if there is no therapeutic response to the 4% gel 20.

Vaginal insert

This form is indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women 21.

Injection (intramuscular) This drug is indicated in amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer 23.

Tablets, contraceptive The tablet form of progesterone in contraceptive formulations is indicated for the prevention of pregnancy 22.

Progesterone, depending on concentration and dosage form, and timing of exposure may have several pharmacodynamic effects.

These actions, according, to various preparations, are listed below: General effects Progesterone is the main hormone of the corpus luteum and the placenta.

It acts on the uterus by changing the proliferative phase to the secretory phase of the endometrium (inner mucous lining of the uterus).

This hormone, stimulated by a hormone called luteinizing hormone (LH) is the main hormone during the secretory phase to prepare the corpus luteum and the endometrium for implantation of a fertilized ovum.

As the luteal phase concludes, the progesterone hormone sends negative feedback to the anterior pituitary gland in the brain to decrease FSH (follicle stimulating hormone) and LH (luteinizing hormone) levels.

This prevents ovulation and maturation of oocytes (immature egg cells).

The endometrium then prepares for pregnancy by increasing its vascularity (blood vessels) and stimulating mucous secretion.

This process occurs by progesterone stimulating the endometrium to decrease endometrial proliferation, leading to a decreased uterine lining thickness, developing more complex uterine glands, collecting energy in the form of glycogen, and providing more uterine blood vessel surface area suitable for supporting a growing embryo.

As opposed to cervical mucous changes observed during the proliferative phase and ovulation, progesterone decreases and thickens the cervical mucus, rendering it less elastic.

This change occurs because the fertilization time period has passed, and a specific consistency of mucous amenable to sperm entry is no longer required 16.

Gelatinized capsules

Progesterone capsules are an oral dosage form of micronized progesterone which, chemically identical to progesterone of ovarian origin.

Progesterone capsules have all the properties of endogenous progesterone with induction of a secretory phase endometrium with gestagenic, antiestrogenic, slightly antiandrogenic and anti-aldosterone effects 24.

Progesterone opposes the effects of estrogen on the uterus, and is beneficial in women with unopposed estrogen exposure, which carries an increased risk of malignancy 24.

Vaginal gel and vaginal insert

The gel preparation mimics the effects of naturally occurring progesterone.

In the presence of adequate levels of estrogen, progesterone converts a proliferative endometrium into secretory endometrium.

This means that the endometrium changes from a growing and thickening stage into a subsequent preparation stage for pregnancy, which involves further preparatory changes.

Progesterone is necessary for the development of decidual tissue (specialized tissue amenable to supporting a possible pregnancy).

Progesterone is required to increase endometrial receptivity for the implantation of a fertilized embryo.

Once an embryo is implanted, progesterone helps to maintain the pregnancy 20.

Injection (intramuscular) Intramuscular injected progesterone increases serum progesterone and aids in the prevention of endometrial tissue overgrowth due to unopposed estrogen (which leads to abnormal uterine bleeding and sometimes uterine cancer) 18, 25.

In the absence or deficiency of progesterone, the endometrium continually proliferates, eventually outgrowing its limited blood supply, shedding incompletely, and leading to abnormal and/or profuse bleeding as well as malignancy 18.

Tablets, contraceptive Progesterone-only contraceptive tablets prevent conception by suppressing ovulation in about half of users, causing a thickening of cervical mucus to inhibit sperm movement, lowering the midcycle LH and FSH hormone peaks, slowing the movement of the ovum through the fallopian tubes, and causing secretory changes in the endometrium as described above 22.

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 Label.

Intramuscular administration

After intramuscular (Intramuscular) 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 25.

Progesterone administered by the intramuscular (Intramuscular) route avoids significant first-pass hepatic metabolism.

As a result, endometrial tissue concentrations of progesterone achieved with Intramuscular administration are higher when compared with oral administration.

Despite this, the highest concentrations of progesterone in endometrial tissue are reached with vaginal administration 11.

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 22.

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 11.

Progesterone is mainly metabolized by the liver.

After oral administration, the major plasma metabolites found are 20 a hydroxy-Δ4 a-prenolone and 5 a-dihydroprogesterone.

Some progesterone metabolites are found excreted in the bile and these metabolites may be deconjugated and subsequently metabolized in the gut by reduction, dehydroxylation, and epimerization Label.

The major plasma and urinary metabolites are comparable to those found during the physiological progesterone secretion of the corpus luteum 24.

Hover over products below to view reaction partners Progesterone 6β-Hydroxyprogesterone deoxycorticosterone 11-deoxycorticosterone 21-OH-progesterone 17-OH progesterone 5 a-dihydroprogesterone 20 a hydroxy.

• prenolone Pregnanolone + pregnanediol + pregnanetriol.

Progesterone 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 ) 24.

The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the urine and bile.

Progesterone metabolites, excreted in the bile, may undergo enterohepatic recycling or may be found excreted in the feces.

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

Progesterone, administered Oral, has a short serum half-life (approximately 5 minutes).

It is rapidly metabolized to 17-hydroxyprogesterone during its first pass through the liver 11.

Apparent clearance 1367 ± 348 (50 mg of progesterone administered by vaginal insert once daily) 11. 106 ± 15 L/h (50 mg/mL Intramuscular injection once daily) 11.

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LD50 (rat): 327 mg/kg MSDS.

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 Label, 22.

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 22.

Effects on fertility

Progesterone at high doses is an antifertility drug and high doses would be expected to impair fertility until cessation 25.

The progesterone contraceptive should not be used during pregnancy.

Progesterone 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 24.

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 22.

Use in breastfeeding

Progesterone has been detected in the milk of nursing mothers 21, 22.

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 22.

WARNING. 1.

Cardiovascular disorders

An increased risk of pulmonary embolism, deep vein thrombosis (DVT), stroke, and myocardial infarction has been reported with estrogen plus progestin therapy.

Should any of these occur or be suspected, estrogen with progestin therapy should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (for example, personal history or family history of venous thromboembolism [VTE], obesity, and systemic lupus erythematosus) should be managed appropriately. a.

Stroke In the

Women’s Health Initiative (WHI) estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same receiving placebo (33 versus 25 per 10,000 women-years).

The increase in risk was demonstrated after the first year and persisted.

Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. b.

Coronary Heart Disease In the

WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).

An increase in relative risk was demonstrated in year and a trend toward decreasing relative risk was reported in years 2 through 5.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit.

During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease.

There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years.

Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II.

Average follow-up in HERS

II was an additional 2.7 years, for a total of 6.8 years overall.

Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. c.

Venous thromboembolism In the

WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and pulmonary embolism [PE]) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years) and PE.

Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated.

The increase in

VTE risk was observed during the first year and persisted.

Should a

VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

If feasible, estrogens with progestins should be discontinued at least to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2.

Malignant neoplasms a.

Breast cancer

The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the Women’s Health Initiative (WHI) substudy of daily CE (0.625 mg) plus MPA (2.5 mg).

After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of breast cancer in women who took daily CE plus MPA.

In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women.

The relative risk of invasive breast cancer was 1.24 (95 percent nCI 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo.

Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for estrogen plus progestin compared with placebo.

Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo.

In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group.

Metastatic disease was rare, with no apparent difference between the two groups.

Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

Consistent with the

WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use.

The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping).

Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy.

However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations.

In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. b.

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus.

The reported endometrial cancer risk among unopposed estrogen users is about to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose.

Most studies show no significant increased risk associated with the use of estrogens for less than 1 year.

The greatest risk appears associated with prolonged use, with increased risks of 15.

• to 24-fold for to 10 years or more and this risk has been shown to persist for at least to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen plus progestin therapy is important.

Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.

There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.

Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. c.

WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer.

After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent nCI 0.77-3.24).

The absolute risk for CE plus

MPA versus placebo was 4 versus 3 cases per 10,000 women-years.

In some epidemiologic studies, the use of estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer.

However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. 3.

Probable Dementia In the estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4,532 postmenopausal women to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

In the

WHIMS estrogen plus progestin ancillary study, after an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia.

The relative risk of probable dementia for estrogen plus progestin versus placebo was 2.05 (95 percent CI 1.21– 3.48).

The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years.

It is unknown whether these findings apply to younger postmenopausal women. 4.

Vision abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogen.

Discontinue estrogen plus progestin therapy pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine.

If examination reveals papilledema or retinal vascular lesions, estrogen plus progestin therapy should be permanently discontinued.

Progesterone capsules should not be used in women with any of the following conditions: Progesterone capsules should not be used in patients with known hypersensitivity to its ingredients.

Progesterone 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.

Progesterone capsules should be given as a single daily dose at bedtime, 200 mg orally for 12 days sequentially per 28-day cycle, to postmenopausal women with a uterus who are receiving daily conjugated estrogens tablets.

Progesterone capsules may be given as a single daily dose of 400 mg at bedtime for 10 days.

Some women may experience difficulty swallowing progesterone capsules.

For these women, progesterone capsules should be taken with a glass of water while in the standing position.

Progesterone, capsules 100 mg are available as an oval yellow, opaque, capsule imprinted with P-3 in black ink.

NDC 71335-9739-7: 12 Capsules in a BOTTLE NDC 71335-9739-1: 30 Capsules in a BOTTLE NDC 71335-9739-2: 8 Capsules in a BOTTLE NDC 71335-9739-3: 100 Capsules in a BOTTLE NDC 71335-9739-4: 10 Capsules in a BOTTLE NDC 71335-9739-5: 90 Capsules in a BOTTLE NDC 71335-9739-6: 60 Capsules in a BOTTLE NDC 71335-9739-8: 180 Capsules in a BOTTLE Store at 20-25°C (68-77°F).

Protect from excessive moisture

Keep out of reach of children.

Dispense in tight, light-resistant container as defined in USP/NF, accompanied by a Patient Insert.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

Progesterone capsules should not be used during pregnancy. See CONTRAINDICATIONS. 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.

Detectable amounts of progestin have been identified in the milk of nursing women receiving progestins.

Caution should be exercised when progesterone capsules are administered to a nursing woman.

Progesterone capsules are not indicated in children.

Clinical studies have not been conducted in the pediatric population.

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

Women’s Health Initiative Study In the Women’s Health Initiative (WHI) estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. See WARNINGS, Cardiovascular **Disorders** and Malignant Neoplasms. The Women’s Health Initiative Memory Study In the Women’s Health Initiative Memory Study (WHIMS) of postmenopausal women to 79 years of age, there was an increased risk of developing probable dementia in the estrogen plus progestin ancillary study when compared to placebo.