PROGESTERONE: 5,509 Adverse Event Reports & Safety Profile

DESCRIPTION Crinone ® (progesterone gel) is a bioadhesive vaginal gel containing micronized progesterone in an emulsion system, which is contained in single use, polypropylene vaginal applicators. The carrier vehicle is an oil in water emulsion containing the water swellable, but insoluble polymer, polycarbophil. The progesterone is partially soluble in both the oil and water phase of the vehicle, with the majority of the progesterone existing as a suspension. Physically, Crinone has the appearance of a soft, white to off-white gel. The active ingredient, progesterone, is present in either a 4% or an 8% concentration (w/w). The chemical name for progesterone is pregn-4-ene-3,20-dione. It has an empirical formula of C 21 H 30 O 2 and a molecular weight of 314.5. The structural formula is: Progesterone exists in two polymorphic forms.

Form

1, which is the form used in Crinone, exists as white orthorhombic prisms with a melting point of 127-131°C. Each applicator delivers 1.125 grams of Crinone gel containing either 45 mg (4% gel) or 90 mg (8% gel) of progesterone in a base containing glycerin, light mineral oil, polycarbophil, carbomer homopolymer Type B, hydrogenated palm oil glyceride, sorbic acid, purified water and may contain sodium hydroxide. The structural formula

DIRECTIONS: Apply once or twice a day. Massage into inner arms, thighs, chest or apply to inner forearm and rub arms together or use as directed by your Physician.

This Container

Yields approximately 70 full pumps or 75 mg of bio-identical Progesterone USP (7.5%) per pump. It also contains Retinol, Vitamin E, Coconut Oil, Shea Butter, and other ingredients to support transdermal bioavailability and overall skin tone. This is an All Natural product. Application is intended for external cosmetic use.

DOSAGE AND ADMINISTRATION: Progesterone is administered by intramuscular injection. It differs from other commonly used steroids in that it is irritating at the place of injection.

Amenorrhea

Five to 10 mg are given for six to eight consecutive days. If there has been sufficient ovarian activity to produce a proliferative endometrium, one can expect withdrawal bleeding 48 to 72 hours after the last injection. This may be followed by spontaneous normal cycles.

Functional Uterine Bleeding

Five to 10 mg are given daily for six doses. Bleeding may be expected to cease within six days. When estrogen is given as well, the administration of progesterone is begun after two weeks of estrogen therapy. If menstrual flow begins during the course of injections of progesterone, they are discontinued. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit.

Amenorrhea

Five to 10 mg are given for six to eight consecutive days. If there has been sufficient ovarian activity to produce a proliferative endometrium, one can expect withdrawal bleeding 48 to 72 hours after the last injection. This may be followed by spontaneous normal cycles.

Functional Uterine Bleeding

Five to 10 mg are given daily for six doses. Bleeding may be expected to cease within six days. When estrogen is given as well, the administration of progesterone is begun after two weeks of estrogen therapy. If menstrual flow begins during the course of injections of progesterone, they are discontinued. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit.

ENDOMETRIN is contraindicated in individuals with any of the following conditions: Previous allergic reactions to progesterone or any of the ingredients of ENDOMETRIN [ see Description (11) ] Undiagnosed vaginal bleeding Known missed abortion or ectopic pregnancy Liver disease Known or suspected malignancy of the breast or genital organs Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events Previous allergic reactions to progesterone or any of the ingredients of ENDOMETRIN Vaginal Insert ( 4 ) Undiagnosed vaginal bleeding ( 4 ) Known missed abortion or ectopic pregnancy ( 4 ) Liver disease ( 4 ) Known or suspected malignancy of the breast or genital organs ( 4 ) Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events ( 4 )

ADVERSE REACTIONS See BOXED WARNING , WARNINGS and PRECAUTIONS . 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. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the effects of progesterone capsules on the endometrium was studied in a total of 875 postmenopausal women.

Table

6 lists adverse reactions greater than or equal to 2 percent of women who received cyclic progesterone capsules 200 mg daily (12 days per calendar month cycle) with 0.625 mg conjugated estrogens or placebo. TABLE 6.

Adverse

Reactions (≥ 2%) Reported in an 875 Patient Placebo-Controlled Trial in Postmenopausal Women Over a 3-Year Period [Percentage (%) of Patients Reporting]

Progesterone Capsules

200 mg with Conjugated Estrogens 0.625 mg Placebo (n=178) (n=174)

Headache

31 27 Breast Tenderness 27 6 Joint Pain 20 29 Depression 19 12 Dizziness 15 9 Abdominal Bloating 12 5 Hot Flashes 11 35 Urinary Problems 11 9 Abdominal Pain 10 10 Vaginal Discharge 10 3 Nausea / Vomiting 8 7 Worry 8 4 Chest Pain 7 5 Diarrhea 7 4 Night Sweats 7 17 Breast Pain 6 2 Swelling of Hands and Feet 6 9 Vaginal Dryness 6 10 Constipation 3 2 Breast Carcinoma 2 <1 Breast Excisional Biopsy 2 <1 Cholecystectomy 2 <1 Effects on Secondary Amenorrhea In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the effects of progesterone capsules on secondary amenorrhea was studied in 49 estrogen-primed postmenopausal women.

Table

7 lists adverse reactions greater than or equal to 5 percent of women who received progesterone capsules or placebo. TABLE 7.

Adverse

Reactions (≥ 5%) Reported in Patients Using 400 mg/day in a Placebo-Controlled Trial in Estrogen-Primed Postmenopausal Women Adverse Experience Progesterone Capsules 400 mg Placebo n=25 n=24 Percentage (%) of Patients Fatigue 8 4 Headache 16 8 Dizziness 24 4 Abdominal Distention (Bloating) 8 8 Abdominal Pain (Cramping) 20 13 Diarrhea 8 4 Nausea 8 0 Back Pain 8 8 Musculoskeletal Pain 12 4 Irritability 8 4 Breast Pain 16 8 Infection Viral 12 0 Coughing 8 0 In a multicenter, parallel-group, open label postmarketing dosing study consisting of three consecutive 28­-day treatment cycles, 220 premenopausal women with secondary amenorrhea were randomized to receive daily conjugated estrogens therapy (0.625 mg conjugated estrogens) and progesterone capsules, 300 mg per day (n=113) or progesterone capsules, 400 mg per day (n=107) for 10 days of each treatment cycle. Overall, the most frequently reported treatment-emergent adverse reactions, reported in greater than or equal to 5 percent of subjects, were nausea, fatigue, vaginal mycosis, nasopharyngitis, upper respiratory tract infection, headache, dizziness, breast tenderness, abdominal distension, acne, dysmenorrhea, mood swing and urinary tract infection.

Postmarketing

Experience: The following additional adverse reactions have been reported with progesterone capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Genitourinary

System: endometrial carcinoma, hypospadia, intra-uterine death, menorrhagia, menstrual disorder, metrorrhagia, ovarian cyst, spontaneous abortion. Cardiovascular: circulatory collapse, congenital heart disease (including ventricular septal defect and patent ductus arteriosus), hypertension, hypotension, tachycardia. Gastrointestinal: acute pancreatitis, cholestasis, cholestatic hepatitis, dysphagia, hepatic failure, hepatic necrosis, hepatitis, increased liver function tests (including alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased), jaundice, swollen tongue. Skin: alopecia, pruritus, urticaria. Eyes: blurred vision, diplopia, visual disturbance.

Central Nervous

System: aggression, convulsion, depersonalization, depressed consciousness, disorientation, dysarthria, loss of consciousness, paresthesia, sedation, stupor, syncope (with and without hypotension), transient ischemic attack, suicidal ideation. During initial therapy, a few women have experienced a constellation of many or all of the following symptoms: extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk and shortness of breath. Miscellaneous: abnormal gait, anaphylactic reaction, arthralgia, blood glucose increased, choking, cleft lip, cleft palate, difficulty walking, dyspnea, face edema, feeling abnormal, feeling drunk, hypersensitivity, asthma, muscle cramp, throat tightness, tinnitus, vertigo, weight decreased, weight increased. To report SUSPECTED ADVERSE REACTIONS, contact AvkARE at 1-855-361-3993; email [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNINGS See BOXED 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 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted (see CLINICAL STUDIES ). 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 1 and a trend toward decreasing relative risk was reported in years 2 through 5 (see CLINICAL STUDIES ). 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 (2,321) 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). 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 demonstrated during the first year and persisted (see CLINICAL STUDIES ). 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 4 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 WHI substudy of daily CE (0.625 mg)- alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average of follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] compared to placebo (see CLINICAL STUDIES ). 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, 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 CE plus MPA compared with placebo. In the 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 (see CLINICAL STUDIES ). 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. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. 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.

Endometrial

Cancer 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 2 to 12 times greater than in non-users, 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 5 to 10 years or more and this risk has been shown to persist for at least 8 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.

Ovarian Cancer

The 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 to 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 plus progestin and 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 65 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 to 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 (see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use ). 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.

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 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted (see CLINICAL STUDIES ). 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 1 and a trend toward decreasing relative risk was reported in years 2 through 5 (see CLINICAL STUDIES ). 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 (2,321) 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). 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 demonstrated during the first year and persisted (see CLINICAL STUDIES ). 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 4 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 WHI substudy of daily CE (0.625 mg)- alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average of follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] compared to placebo (see CLINICAL STUDIES ). 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, 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 CE plus MPA compared with placebo. In the 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 (see CLINICAL STUDIES ). 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. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. 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.

Endometrial

Cancer 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 2 to 12 times greater than in non-users, 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 5 to 10 years or more and this risk has been shown to persist for at least 8 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.

Ovarian Cancer

The 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 to 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 plus progestin and 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 65 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 to 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 (see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use ). 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.

PRECAUTIONS A.

General

1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared with estrogen-alone regimens. These include an increased risk of breast cancer. 2.

Fluid Retention

Progesterone may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation. 3. Dizziness and Drowsiness Progesterone capsules may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery. Progesterone capsules should be taken as a single daily dose at bedtime. B.

Patient Information

General: This product contains peanut oil and should not be used if you are allergic to peanuts. Physicians are advised to discuss the contents of the Patient Information leaflet with patients for whom they prescribe progesterone capsules. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 C. Drug-Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy: Increased sulfobromophthalein retention and other hepatic function tests. Coagulation tests: increase in prothrombin factors VII, VIII, IX and X. Pregnanediol determination. Thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values. D. Carcinogenesis, Mutagenesis, Impairment of Fertility Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumors and endometrial stromal sarcomas. In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumors. Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumors in rats previously treated with a chemical carcinogen. Progesterone did not show evidence of genotoxicity in in vitro studies for point mutations or for chromosomal damage. In vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Exogenously administered progesterone has been shown to inhibit ovulation in a number of species and it is expected that high doses given for an extended duration would impair fertility until the cessation of treatment. E.

Pregnancy

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. F.

Nursing Women

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. G.

Pediatric Use

Progesterone capsules are not indicated in children. Clinical studies have not been conducted in the pediatric population. H.

Geriatric Use

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.

The

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 CLINICAL STUDIES and 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 65 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. (See CLINICAL STUDIES and WARNINGS , Probable dementia . )

INTERACTIONS No formal drug-drug interaction studies have been conducted for progesterone vaginal insert. Drugs known to induce the hepatic cytochrome-P450-3A4 system (such as rifampin, carbamazepine) may increase the elimination of progesterone. The effect of concomitant vaginal products on the exposure of progesterone from progesterone vaginal insert has not been assessed. Progesterone vaginal insert is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal insert [ see Warnings and Precautions (5.3) ].

Active Ingredient Micronized Progesterone USP, (Wild Yam) 2%

DISCLAIMER Disclaimer: This drug has not been found by FDA to be safe and effective, and this labeling has not been approved by FDA. For further information about unapproved drugs For further information about unapproved drugs, https://www.fda.gov/drugs/enforcement-activities-fda/unapproved-drugs

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