Prescription Drugs

CLINICAL PHARMACOLOGY PROMETRIUM Capsules are an oral dosage form of micronized progesterone which is chemically identical to progesterone of ovarian origin. The oral bioavailability of progesterone is increased through micronization. Pharmacokinetics Absorption After oral administration of progesterone as a micronized soft-gelatin capsule formulation, maximum serum concentrations were attained within 3 hours. The absolute bioavailability of micronized progesterone is not known. Table 1 summarizes the mean pharmacokinetic parameters in postmenopausal women after five oral daily doses of PROMETRIUM Capsules 100 mg as a micronized soft-gelatin capsule formulation. TABLE 1. Pharmacokinetic Parameters of PROMETRIUM Capsules Parameter PROMETRIUM Capsules Daily Dose 100 mg 200 mg 300 mg Cmax (ng/mL) 17.3 ± 21.9a 38.1 ± 37.8 60.6 ± 72.5 Tmax (hr) 1.5 ± 0.8 2.3 ± 1.4 1.7 ± 0.6 AUC(0-10) (ng x hr/mL) 43.3 ± 30.8 101.2 ± 66.0 175.7 ± 170.3 aMean ± S.D. Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of PROMETRIUM Capsules 100 mg over the dose range 100 mg per day to 300 mg per day in postmenopausal women. Although doses greater than 300 mg per day were not studied in females, serum concentrations from a study in male volunteers appeared linear and dose proportional between 100 mg per day and 400 mg per day. The pharmacokinetic parameters in male volunteers were generally consistent with those seen in postmenopausal women. Distribution Progesterone is approximately 96 percent to 99 percent bound to serum proteins, primarily to serum albumin (50 to 54 percent) and transcortin (43 to 48 percent). Metabolism Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites which are excreted in the bile may be deconjugated and may be further metabolized in the intestine via reduction, dehydroxylation, and epimerization. Excretion The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites are eliminated mainly by the kidneys. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces. Special Populations The pharmacokinetics of PROMETRIUM Capsules have not been assessed in low body weight or obese patients. Hepatic Insufficiency The effect of hepatic impairment on the pharmacokinetics of PROMETRIUM Capsules has not been studied. Renal Insufficiency The effect of renal impairment on the pharmacokinetics of PROMETRIUM Capsules has not been studied. Food–Drug Interaction Concomitant food ingestion increased the bioavailability of PROMETRIUM Capsules relative to a fasting state when administered to postmenopausal women at a dose of 200 mg. Drug Interactions The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC50 < 0.1 μM). Ketoconazole is a known inhibitor of cytochrome P450 3A4, hence these data suggest that ketoconazole or other known inhibitors of this enzyme may increase the bioavailability of progesterone. The clinical relevance of the in vitro findings is unknown. Coadministration of conjugated estrogens and PROMETRIUM Capsules to 29 postmenopausal women over a 12-day period resulted in an increase in total estrone concentrations (Cmax 3.68 ng/mL to 4.93 ng/mL) and total equilin concentrations (Cmax 2.27 ng/mL to 3.22 ng/mL) and a decrease in circulating 17β estradiol concentrations (Cmax 0.037 ng/mL to 0.030 ng/mL). The half-life of the conjugated estrogens was similar with coadministration of PROMETRIUM Capsules. Table 2 summarizes the pharmacokinetic parameters. TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women Conjugated Estrogens Conjugated Estrogens plus PROMETRIUM Capsules Drug Cmax(ng/mL) Tmax(hr) AUC(0-24h) (ng × h/mL) Cmax(ng/mL) Tmax(hr) AUC(0-24h) (ng × h/mL) Estradiol 0.037 ± 0.048 12.7 ± 9.1 0.676 ± 0.737 0.030 ± 0.032 17.32 ± 1.21 0.561 ± 0.572 Estrone3.6810.661.34.937.585.9 Tota1a ± 1.55± 6.8± 26.36± 2.07± 3.8± 41.2 EQBrlin2.276.028.83.225.338.1 Totala ± 0.95 ± 4.0 ± 13.0 ± 1.13 ± 2.6 ± 20.2 aTotal estrogens is the sum of conjugated and unconjugated estrogen. Clinical Studies Effects On The Endometrium In a randomized, double-blind clinical trial, 358 postmenopausal women, each with an intact uterus, received treatment for up to 36 months. The treatment groups were: PROMETRIUM Capsules at the dose of 200 mg per day for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg per day (n=120); conjugated estrogens 0.625 mg per day only (n=119); or placebo (n=119). The subjects in all three treatment groups were primarily Caucasian women (87 percent or more of each group). The results for the incidence of endometrial hyperplasia in women receiving up to 3 years of treatment are shown in Table 3. A comparison of the PROMETRIUM Capsules plus conjugated estrogens treatment group to the conjugated estrogens only group showed a significantly lower rate of hyperplasia (6 percent combination product versus 64 percent estrogen alone) in the PROMETRIUM Capsules plus conjugated estrogens treatment group throughout 36 months of treatment. TABLE 3. Incidence of Endometrial Hyperplasia in Women Receiving 3 Years of Treatment Endometrial Diagnosis Treatment Group Conjugated Estrogens 0.625 mg + PROMETRIUM Capsules 200 mg (cyclical) Conjugated Estrogens 0.625 mg (alone) Placebo Number of patients % of patients Number of patients % of patients Number of patients % of patients n=117 n=115 n=116 HYPERPLASIA a 7 6 74 64 3 3 Adenocarcinoma 0 0 0 0 1 1 Atypical hyperplasia 1 1 14 12 0 0 Complex hyperplasia 0 0 27 23 1 1 Simple hyperplasia 6 5 33 29 1 1 aMost advanced result to least advanced result: Adenocarcinoma > atypical hyperplasia > complex hyperplasia > simple hyperplasia The times to diagnosis of endometrial hyperplasia over 36 months of treatment are shown in Figure 1. This figure illustrates graphically that the proportion of patients with hyperplasia was significantly greater for the conjugated estrogens group (64 percent) compared to the conjugated estrogens plus PROMETRIUM Capsules group (6 percent). Figure 1. Time to Hyperplasia in Women Receiving up to 36 Months of Treatment The discontinuation rates due to hyperplasia over the 36 months of treatment are as shown in Table 4. For any degree of hyperplasia, the discontinuation rate for patients who received conjugated estrogens plus PROMETRIUM Capsules was similar to that of the placebo only group, while the discontinuation rate for patients who received conjugated estrogens alone was significantly higher. Women who permanently discontinued treatment due to hyperplasia were similar in demographics to the overall study population. TABLE 4. Discontinuation Rate Due to Hyperplasia Over 36 Months of Treatment Most Advanced Biopsy Result Through 36 Months of Treatment Treatment Group Conjugated Estrogens + PROMETRIUM Capsules (cyclical) Conjugated Estrogens (alone) Placebo n=120 n=119 n=119 Number of patients % of patients Number of patients % of patients Number of patients % of patients Adenocarcinoma 0 0 0 0 1 1 Atypical hyperplasia 1 1 10 8 0 0 Complex hyperplasia 0 0 21 18 1 1 Simple hyperplasia 1 1 13 11 0 0 Effects On Secondary Amenorrhea In a single-center, randomized, double-blind clinical study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of PROMETRIUM Capsules therapy resulted in 80 percent of women experiencing withdrawal bleeding within 7 days of the last dose of PROMETRIUM Capsules, 300 mg per day (n=20), compared to 10 percent of women experiencing withdrawal bleeding in the placebo group (n=21). In a multicenter, parallel-group, open label, postmarketing dosing study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of PROMETRIUM Capsules during two 28-day treatment cycles, 300 mg per day (n=107) or 400 mg per day (n=99), resulted in 73.8 percent and 76.8 percent of women, respectively, experiencing withdrawal bleeding. The rate of secretory transformation was evaluated in a multicenter, randomized, double-blind clinical study in estrogen-primed postmenopausal women. PROMETRIUM Capsules administered orally for 10 days at 400 mg per day (n=22) induced complete secretory changes in the endometrium in 45 percent of women compared to 0 percent in the placebo group (n=23). A second multicenter, parallel-group, open label postmarketing dosing study in premenopausal women with secondary amenorrhea for at least 90 days also evaluated the rate of secretory transformation. All subjects received daily oral conjugated estrogens over 3 consecutive 28-day treatment cycles and PROMETRIUM Capsules, 300 mg per day (n=107) or 400 mg per day (n=99) for 10 days of each treatment cycle. The rate of complete secretory transformation was 21.5 percent and 28.3 percent, respectively. Women's Health Initiative Studies The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral conjugated estrogens (CE) [0.625 mg]-alone or in combination with medroxyprogesterone acetate (MPA) [2.5 mg] compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease [(CHD) defined as nonfatal myocardial infarction (MI), silent MI and CHD death], with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These sub studies did not evaluate the effects of CE–alone or CE plus MPA on menopausal symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. TABLE 5. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a, b Events Relative Risk CE/MPA versus Placebo (95% nCIc) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00-1.63) 31 25 CHD death 1.10 (0.70-1.75) 8 8 All stroke 1.31 (1.03-1.88) 33 25 Ischemic Stroke 1.44 (1.09-1.90) 26 18 Deepvein thrombosisd 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer e 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer d 0.81 (0.48-1.36) 6 7 Cervical cancer d 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures d 0.65 (0.46-0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59-0.85) 44 62 Total fractures d 0.76 (0.69-0.83) 152 199 Overall mortality f 1.00 (0.83-1.19) 52 52 Global Index g 1.13 (1.02-1.25) 184 165 aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. bResults are based on centrally adjudicated data. cNominal confidence intervals unadjusted for multiple looks and multiple comparisons. dNot included in Global Index. eIncludes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer. fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. gA subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified for age showed in women 50 to 59 years of age a non-significant trend toward reducing risk of overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)]. Women's Health Initiative Memory Study The estrogen plus progestin Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA 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 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable dementia and PRECAUTIONS, Geriatric Use.)

CLINICAL PHARMACOLOGY Mechanism of Action Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain a pregnancy. Pharmacokinetics Absorption Progesterone serum concentrations increased following the administration of the Endometrin Vaginal Insert in 12 healthy pre-menopausal females. On single dosing, the mean Cmax was 17.0 ng/Ml in the Endometrin twice daily group and 19.8 ng/mL in the Endometrin three times daily group. On multiple dosing, steady-state concentrations were attained within approximately 1 day after initiation of treatment with Endometrin. Both Endometrin regimens provided average serum concentrations of progesterone exceeding 10 ng/mL on Day 5. The pharmacokinetic results are summarized in Table 2. Table 2: Mean (±Standard Deviation) Serum Progesterone Pharmacokinetic Parameters Pharmacokinetic Parameter (unit) Endometrin 100 mg twice daily (N=6) Endometrin 100 mg three times daily (N=6) Single Dosing Cmax (ng/mL) 17.0 ± 6.5 19.8 ± 7.2 Tmax (hr) 24.0 ± 0.0 17.3 ± 7.4 AUC0-24 (ng•hr/mL) 217±113 284 ± 143 Day 5 of Multiple Dosing Cmax (ng/mL) 18.5 ± 5.5 24.1 ±5.6 Tmax (hr) 18.0 ± 9.4 18.0 ± 9.4 Cmin (ng/mL) 8.9 ±4.5 10.9 ± 6.7 Cavg (ng/mL) 14.0 ±4.8 15.9 ±4.3 AUC0-24 (ng•hr/mL) 327±127 436 ± 106 Cmax Maximum progesterone serum concentration. Tmax Time to maximum progesterone serum concentration. Cavg Average progesterone serum concentration. AUC0-24 Area under the drug concentration versus time curve from 0-24 hours post dose. Cmin Minimum progesterone serum concentration. Distribution Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin. Metabolism Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites that are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization. Excretion Progesterone undergoes renal and biliary elimination. Following injection of labeled progesterone, 50-60% of the excretion of metabolites occurs via the kidney; approximately 10% occurs via the bile and feces. Overall recovery of the labeled material accounts for 70% of an administered dose. Only a small portion of unchanged progesterone is excreted in the bile. Clinical Studies Luteal Supplementation During Assisted Reproductive Treatment Study A randomized, open-label, active-controlled study evaluated the efficacy of 10 weeks of treatment with two different daily dosing regimens of Endometrin (100 mg twice daily and 100 mg three times daily) for support of implantation and early pregnancy in infertile women participating in an Assisted Reproductive Technology treatment program. Efficacy was assessed on the endpoint of ongoing pregnancies, defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks post-embryo transfer. The study randomized to Endometrin 808 infertile women (74.9% White; 10.3% Hispanic, 5.4% Black, 5% Asian, and 4.6% Other) between 19 and 42 years of age (mean age 33) who had a body mass index < 34 kg/m² at screening. The ongoing pregnancy rates for subjects treated with both dosing regimens of Endometrin were noninferior (lower bounds of the 95% confidence interval of the difference between Endometrin and the active comparator excluded a difference greater than 10%) to the ongoing pregnancy rate for subjects treated with the active comparator. The results of this study are shown in Table 3. Table 3: Ongoing Pregnancy Rates* in Patients Receiving Endometrin for Luteal Supplementation and Early Pregnancy While in an Assisted Reproductive Technology Treatment Program Endometrin 100 mg twice daily Endometrin 100 mg three times daily Number of subjects 404 404 Ongoing pregnancy: n (%) 156 (39%) 171 (42%) 95% Confidence Interval of pregnancy rate [33.8, 43.6] [37.5, 47.3] Pregnancy rate percentage difference between Endometrin and comparator -3.6% 0.1% 95% Confidence Interval for difference vs comparator [-10.3, 3.2] [-6.7, 6.9] * Ongoing pregnancy defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks post-embryo transfer. Subjects participating in the study were stratified at randomization by age and ovarian reserve (as measured by serum FSH levels). The ongoing pregnancy rates for these subgroups are shown in Table 4. Table 4: Ongoing Pregnancy Rates in Age- and Ovarian Reserve-Defined Subgroups Receiving Endometrin for Luteal Supplementation and Early Pregnancy While in an Assisted Reproductive Technology Treatment Program Endometrin 100 mg twice daily Endometrin 100 mg three times daily Subjects age < 35 years (N) 247 247 Ongoing pregnancy: n (%) 111 (45%) 117(47%) Pregnancy rate percentage difference between Endometrin and comparator 0.5% 2.9% 95% Confidence Interval for difference vs. comparator [-8.3, 9.3] [-5.9, 11.7] Subjects 35-42 years of age (N) 157 157 Ongoing pregnancy: n (%) 45 (28%) 54 (34%) Pregnancy rate percentage difference between Endometrin and comparator -10.1% -4.4% 95% Confidence Interval for difference vs. comparator [-20.3, 0.3] [-14.9, 6.3] Subjects with FSH < 10IU/L (N) 350 347 Ongoing pregnancy: n (%) 140 (40%) 150(43%) Pregnancy rate percentage difference between Endometrin and comparator -2.0% 1.2% 95% Confidence Interval for difference vs. comparator [-9.3, 5.3] [-6.1, 8.5] Subjects with FSH between 10 and 15 IU/L (N) 46 51 Ongoing pregnancy: n (%) 16(35%) 20 (39%) Pregnancy rate percentage difference between Endometrin and comparator -12.2% -7.7% 95% Confidence Interval for difference vs. comparator [-31.0, 7.7] [-26.6, 11.6] In subjects under the age of 35 or with serum FSH levels less than 10 IU/L, results from both dosing regimens were non-inferior to the results from the comparator with respect to ongoing pregnancy rates. In women age 35 and older and in women with serum FSH levels between 10 and 15 IU/L, the results with respect to ongoing pregnancy rates for both dosing regimens of Endometrin did not reach the criteria for non-inferiority. Subjects who became pregnant received study medication for a total of 10 weeks. Patients over 34 kg/m² were not studied. The efficacy of Endometrin in this patient group is unknown.

Find Lowest Prices on PROMETRIUM® (progesterone, USP) Capsules 100 mg Capsules 200 mg WARNING CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY Cardiovascular Disorders and Probable Dementia Estrogens plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See Clinical Studies and WARNINGS, Cardiovascular disorders and Probable dementia.) The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See Clinical Studies and WARNINGS, Cardiovascular disorders.) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See Clinical Studies and WARNINGS, Probable dementia and PRECAUTIONS, Geriatric Use.) Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer. (See Clinical Studies and WARNINGS, Malignant neoplasms, Breast Cancer.) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION PROMETRIUM (progesterone, USP) Capsules contain micronized progesterone for oral administration. Progesterone has a molecular weight of 314.47 and a molecular formula of C21H30O2. Progesterone (pregn-4-ene-3, 20-dione) is a white or creamy white, odorless, crystalline powder practically insoluble in water, soluble in alcohol, acetone and dioxane and sparingly soluble in vegetable oils, stable in air, melting between 126° and 131°C. The structural formula is: Progesterone is synthesized from a starting material from a plant source and is chemically identical to progesterone of human ovarian origin. PROMETRIUM Capsules are available in multiple strengths to afford dosage flexibility for optimum management. PROMETRIUM Capsules contain 100 mg or 200 mg micronized progesterone. The inactive ingredients for PROMETRIUM Capsules 100 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, FD&C Red No. 40, and D&C Yellow No. 10. The inactive ingredients for PROMETRIUM Capsules 200 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Yellow No. 6.

Find Lowest Prices on Endometrin® (progesterone) Vaginal Insert DESCRIPTION Endometrin (progesterone) vaginal insert contains micronized progesterone. Endometrin is supplied with polyethylene vaginal applicators. The active ingredient, progesterone, is present in 100 mg amount along with other excipients. The chemical name for progesterone is pregn-4-ene-3,20-dione. It has an empirical formula of C21H30O2 and a molecular weight of 314.5. Progesterone exists in two polymorphic forms. The form used in Endometrin, the alpha-form, has a melting point of 127-131°C. The structural formula is: Each Endometrin Vaginal Insert delivers 100 mg of progesterone in a base containing lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicon dioxide.

INDICATIONS PROMETRIUM Capsules are indicated for use in the prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving conjugated estrogens tablets. They are also indicated for use in secondary amenorrhea. DOSAGE AND ADMINISTRATION Prevention Of Endometrial Hyperplasia PROMETRIUM 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 a uterus who is receiving daily conjugated estrogens tablets. Treatment Of Secondary Amenorrhea PROMETRIUM Capsules may be given as a single daily dose of 400 mg at bedtime for 10 days. Some women may experience difficulty swallowing PROMETRIUM Capsules. For these women, PROMETRIUM Capsules should be taken with a glass of water while in the standing position. HOW SUPPLIED PROMETRIUM (progesterone, USP) Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.” NDC 0032-1708-01 (Bottle of 100) PROMETRIUM (progesterone, USP) Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.” NDC 0032-1711-01 (Bottle of 100) Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from excessive moisture. Dispense in tight, light-resistant container as defined in USP/NF, accompanied by a Patient Insert. Keep out of reach of children. Manufactured by: Catalent Pharma Solutions, St. Petersburg, FL 33716. Revised: Sep 2013

INDICATIONS Endometrin 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. DOSAGE AND ADMINISTRATION General Dosing Information The dose of Endometrin is 100 mg administered vaginally two or three times daily starting the day after oocyte retrieval and continuing for up to 10 weeks total duration. Efficacy in women 35 years of age and older has not been clearly established. The appropriate dose of Endometrin in this age group has not been determined. HOW SUPPLIED Dosage Forms And Strengths 100 mg vaginal insert is a white to off-white oblong-shaped tablet debossed with “FPI” on one side and “100” on the other side. Storage And Handling Each Endometrin Vaginal Insert is a white to off-white oblong-shaped insert debossed with “FPI” on one side and “100” on the other side. Each Endometrin® (progesterone) Vaginal Insert, 100 mg, is packed individually in a sealed foil pouch. These pouches are available in cartons packed: 21 vaginal inserts with 21 disposable vaginal applicators (NDC 55566-6500-3) Store at 20 - 25°C (68 - 77°F); excursions permitted between 15 - 30°C (59 - 86°F). Manufactured For: Ferring Pharmaceuticals Inc. Parsippany, NJ 07054. Revised: 04/2012

PATIENT INFORMATION PROMETRIUM® (progesterone, USP) Capsules 100 mg & 200 mg Read this PATIENT INFORMATION before you start taking PROMETRIUM Capsules and read what you get each time you refill your PROMETRIUM Capsules prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT PROMETRIUM CAPSULES (A Progesterone Hormone)? Progestins with estrogens should not be used to prevent heart disease, heart attacks, strokes, or dementia. Using progestins with estrogens may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. Using progestins with estrogens may increase your chance of getting dementia, based on a study of women age 65 and older. You and your healthcare provider should talk regularly about whether you still need treatment with PROMETRIUM Capsules. THIS PRODUCT CONTAINS PEANUT OIL AND SHOULD NOT BE USED IF YOU ARE ALLERGIC TO PEANUTS. What is PROMETRIUM Capsules? PROMETRIUM Capsules contain the female hormone called progesterone. What is PROMETRIUM Capsules used for? Treatment of Menstrual Irregularities PROMETRIUM Capsules are used for the treatment of secondary amenorrhea (absence of menstrual periods in women who have previously had a menstrual period) due to a decrease in progesterone. When you do not produce enough progesterone, menstrual irregularities can occur. If your healthcare provider has determined your body does not produce enough progesterone on its own, PROMETRIUM Capsules may be prescribed to provide the progesterone you need. Protection of the Endometrium (Lining of the Uterus) PROMETRIUM Capsules are used in combination with estrogen-containing medications in a postmenopausal woman with a uterus (womb). Taking estrogen-alone increases the chance of developing a condition called endometrial hyperplasia that may lead to cancer of the lining of the uterus (womb). The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb). Who should not take PROMETRIUM Capsules? Do not start taking PROMETRIUM Capsules if you: Are allergic to peanuts Have unusual vaginal bleeding Currently have or have had certain cancers Estrogen plus progestin treatment may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should take PROMETRIUM Capsules. Had a stroke or heart attack Currently have or have had blood clots Currently have or have had liver problems Are allergic to PROMETRIUM Capsules or any of its ingredients See the list of ingredients in PROMETRIUM Capsules at the end of this leaflet. Think you may be pregnant Tell your healthcare provider: If you are breastfeeding. The hormone in PROMETRIUM Capsules can pass into your breast milk. About all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, or kidneys, or have high calcium levels in your blood. About all the medicines you take. This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PROMETRIUM Capsules work. PROMETRIUM Capsules may also affect how your other medicines work. How should I take PROMETRIUM Capsules? Prevention of Endometrial Hyperplasia: A postmenopausal woman with a uterus who is taking estrogens should take a single daily dose of 200 mg PROMETRIUM Capsules at bedtime for 12 continuous days per 28-day cycle. Secondary Amenorrhea: PROMETRIUM Capsules may be given as a single daily dose of 400 mg at bedtime for 10 days. PROMETRIUM Caps ules are to be taken at bedtime as s ome women become very drows y and/or dizzy after taking PROMETRIUM Caps ules . In a few cas es , s ymptoms may include blurred vis ion, difficulty s peaking, difficulty with walking, and feeling abnormal. If you experience thes e s ymptoms , dis cus s them with your healthcare provider right away. If you experience difficulty in swallowing PROMETRIUM Capsules, it is recommended that you take your daily dose at bedtime with a glass of water while in the standing position. What are the possible side effects of PROMETRIUM Capsules? Side effects are grouped by how serious they are and how often they happen when you are treated: Serious, but less common side effects include: Risk to the Fetus: Cases of cleft palate, cleft lip, hypospadias, ventricular septal defect, patent ductus arteriosus, and other congenital heart defects. Abnormal Blood Clotting: Stroke, heart attack, pulmonary embolus, visual loss or blindness. Some of the warning signs of serious side effects include: Changes in vision or speech Sudden new severe headaches Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue Dizziness and faintness Vomiting Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptoms that concern you. Less serious, but common side effects include: Headaches Breast pain Irregular vaginal bleeding or spotting Stomach or abdominal cramps, bloating Nausea and vomiting Hair loss Fluid retention Vaginal yeast infection These are not all the possible side effects of PROMETRIUM Capsules. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to AbbVie Inc. at 1-800-633-9110 or to FDA at 1-800-FDA-1088. What can I do to lower my chances of getting a serious side effect with PROMETRIUM Capsules? Talk with your healthcare provider regularly about whether you should continue taking PROMETRIUM Capsules. See your healthcare provider right away if you get unusual vaginal bleeding while taking PROMETRIUM Capsules. Have a pelvic exam, breast exam, and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease. General information about safe and effective use of PROMETRIUM Capsules Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take PROMETRIUM Capsules for conditions for which it was not prescribed. Your healthcare provider has prescribed this drug for you and you alone. Do not give PROMETRIUM Capsules to other people, even if they have the same symptoms you have. It may harm them. PROMETRIUM Capsules should be taken as a single daily dose at bedtime. Some women may experience extreme dizziness and/or drowsiness during initial therapy. In a few cases, symptoms may include blurred vision, difficulty speaking, difficulty with walking, and feeling abnormal. If you experience these symptoms, discuss them with your healthcare provider right away. Use caution when driving a motor vehicle or operating machinery as dizziness or drowsiness may occur. Keep PROMETRIUM Capsules out of the reach of children. This leaflet provides a summary of the most important information about PROMETRIUM Capsules. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about PROMETRIUM Capsules that is written for health professionals. You can get more information by calling the toll free number 1-800-633-9110. What are the ingredients in PROMETRIUM Capsules? Active ingredient: 100 mg or 200 mg micronized progesterone The inactive ingredients for PROMETRIUM Capsules 100 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, FD&C Red No. 40, and D&C Yellow No. 10. The inactive ingredients for PROMETRIUM Capsules 200 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Yellow No. 6. HOW SUPPLIED PROMETRIUM Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.” PROMETRIUM Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.” Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

PATIENT INFORMATION IMPORTANT: For Vaginal Use Only. Read the patient information that comes with Endometrin before you start to use it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. Your doctor may do a physical exam before prescribing Endometrin. What is Endometrin? Endometrin is a vaginal insert that contains the hormone progesterone. Endometrin is for women who need extra progesterone while undergoing treatment in an Assisted Reproductive Technology (ART) program. Progesterone is one of the hormones essential for helping you to become and to stay pregnant. If you are undergoing ART treatment, your doctor may prescribe Endometrin to provide the progesterone your body needs. Who should not use Endometrin? Do not use Endometrin if you: Are allergic to anything in Endometrin. See the end of this leaflet for a complete list of ingredients. Have unusual vaginal bleeding that has not been evaluated by a doctor. Currently have or have had liver problems. Have or have had blood clots in the legs, lungs, eyes, or elsewhere in your body. Endometrin may not be right for you. Before starting Endometrin, tell your doctor about all your health problems. Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vaginal products, vitamins, herbal supplements. Some medicines may affect Endometrin. Know what medicines you take. Keep a list of your medicines to show to the doctor and pharmacist. How should I use Endometrin? Use Endometrin exactly as prescribed. The usual dose of Endometrin is one insert placed in your vagina 2 to 3 times a day for up to a total of 10 weeks, unless your healthcare provider advises otherwise. Place an Endometrin insert in your vagina with the disposable applicator provided. Follow the steps below: Unwrap the applicator. Put one insert in the space provided at the end of the applicator. The insert should fit snugly and not fall out. Place applicator with the insert into the vagina while you are standing, sitting, or when lying on your back with your knees bent. Gently place the thin end of the applicator well into the vagina. Push the plunger to release the insert. Remove the applicator and throw it away in the trash. Other information for using Endometrin If you forget a dose of Endometrin, take the dose as soon as you remember, but do not use more than your daily dose. Call your doctor if you use too much Endometrin. Do not use any other vaginal products when you are using Endometrin. What are the possible side effects of Endometrin? Common side effects seen with ART and Endometrin included pelvic pain after surgery, abdominal pain, nausea, and swollen ovaries (ovarian hyperstimulation syndrome). Other reported side effects included abdominal bloating, headache, urinary infections, uterine cramping, constipation, vomiting, tiredness, and vaginal bleeding. Vaginal products with progesterone may also cause vaginal irritation, burning, and discharge. Serious Risks of Progesterone Progesterone can increase your chance of getting blood clots. Blood clots can be serious and lead to death. Serious blood clots include those in the: legs (thrombophlebitis) lungs (pulmonary embolus) eyes (blindness) heart (heart attack) brain (stroke) Call your doctor or get medical help right away if you have: persistent pain in the lower leg (calf) sudden shortness of breath coughing up blood sudden blindness, partial or complete severe chest pain sudden, severe headache, vomiting, dizziness, or fainting weakness in an arm or leg, or trouble speaking yellowing of the skin and/or white of the eyes indicating possible liver problem Other risks of progesterone use include: headache breast tenderness bloating or fluid retention mood swings and depression irritability drowsiness Call your doctor immediately if you have abnormal vaginal bleeding. These are not all the side effects with Endometrin. Ask your doctor or pharmacist for more information. How should I store Endometrin? Store Endometrin at room temperature, 20 - 25°C (68 - 77°F); excursions permitted between 15 - 30°C (59 - 86°F) Do not use Endometrin after the expiration date that is printed on the carton. Keep Endometrin and all medicines out of the reach of children. General information about Endometrin Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use Endometrin for a condition for which it was not prescribed. Do not give Endometrin to other women, even if they have the same condition as you do. It may harm them. This leaflet summarizes the most important information about Endometrin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Endometrin that was written for healthcare professionals. For more information call Ferring Pharmaceuticals at 1-(888)-FERRING or 1- (888)-337-7464. What are the ingredients in Endometrin? Active Ingredient: progesterone Inactive Ingredients: lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicon dioxide

SIDE EFFECTS Clinical Studies Experience 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. The safety data reflect exposure to Endometrin in 808 infertile women (74.9% White, 10.3% Hispanic, 5.4% Black, 5% Asian, and 4.6% Other) in a single Assisted Reproductive Technology 10 week clinical study conducted in the U.S. Endometrin was studied at doses of 100 mg twice daily and 100 mg three times daily. The adverse reactions that occurred at a rate greater than or equal to 2% in either Endometrin group are summarized in Table 1. Table 1: Number and Frequency of Reported Adverse Reactions in Women Treated with Endometrin in an Assisted Reproductive Technology Study Body System Preferred Term Endometrin 100 mg twice daily (N=404) Endometrin 100 mg three times daily (N=404) Gastrointestinal Disorders Abdominal pain 50 (12%) 50 (12%) Nausea 32 (8%) 29 (7%) Abdominal distension 18(4%) 17(4%) Constipation 9(2%) 14 (3%) Vomiting 13(3%) 9(2%) General Disorders and Administration Site Conditions Fatigue 7(2%) 12 (3%) Infections and Infestations Urinary tract infection 9(2%) 4 (1%) Injury, Poisoning and Procedural Complications Post-ooctye retrieval pain 115(28%) 102 (25%) Nervous System Disorders Headache 15(4%) 13(3%) Reproductive System and Breast Disorders Ovarian hyperstimulation syndrome 30 (7%) 27 (7%) Uterine spasm 15(4%) 11 (3%) Vaginal bleeding 13(3%) 14 (3%) Other less common reported adverse reactions included vaginal irritation, itching, burning, discomfort, urticaria, and peripheral edema. Expected Adverse Reaction Profile Seen with Progesterone Endometrin is also expected to have adverse reactions similar to other drugs containing progesterone that may include breast tenderness, bloating, mood swings, irritability, and drowsiness. DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted for Endometrin. 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 Endometrin has not been assessed. Endometrin 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].

WARNINGS See BOX WARNING. Cardiovasular 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. 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. 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 twentyone (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. 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. Malignantneoplasms 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 invasive 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 CE plus MPA 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. (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. 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. 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. 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 – 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. 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, 1.21-3.48). 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.) 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 General 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. 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. Dizziness And Drowsiness PROMETRIUM Capsules may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery. PROMETRIUM Capsules should be taken as a single daily dose at bedtime. Patient Information General This product contains peanut oil and s hould not be us ed if you are allergic to peanuts . Physicians are advised to discuss the contents of the Patient Information leaflet with patients for whom they prescribe PROMETRIUM Capsules. 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. Pregnancy PROMETRIUM 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. Nursing Women Detectable amounts of progestin have been identified in the milk of nursing women receiving progestins. Caution should be exercised when PROMETRIUM Capsules are administered to a nursing woman. Pediatric Use PROMETRIUM 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 PROMETRIUM Capsules to determine whether those over 65 years of age differ from younger subjects in their response to PROMETRIUM 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.)

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Cardiovascular or Cerebrovascular Disorders The physician should be alert to earliest signs of myocardial infarction, cerebrovascular disorders, arterial or venous thromboembolism (venous thromboembolism or pulmonary embolism), thrombophlebitis, or retinal thrombosis. Endometrin should be discontinued if any of these are suspected. Depression Patients with a history of depression need to be closely observed. Consider discontinuation if symptoms worsen. Use of Other Vaginal Products Endometrin should not be recommended for use with other vaginal products (such as antifungal products as this may alter progesterone release and absorption from the vaginal insert [see DRUG INTERACTIONS]. Patient Counseling Information See FDA-Approved Patient Labeling Vaginal Bleeding Inform patients of the importance of reporting irregular vaginal bleeding to their doctor as soon as possible. Common Adverse Reactions with Progesterone Inform patients of the possible side effects of progesterone therapy such as headaches, breast tenderness, bloating, mood swings, irritability, and drowsiness. Coadministration of Vaginal Products Inform patients that Endometrin is not recommended for use with other vaginal products. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Nonclinical toxicity studies to determine the potential of Endometrin to cause carcinogenicity or mutagenicity have not been performed. The effect of Endometrin on fertility has not been evaluated in animals. Use In Specific Populations Pregnancy Endometrin has been used to support embryo implantation and maintain clinical pregnancy in one clinical study. The livebirth outcomes of these pregnancies were as follows: Among the 404 subjects treated with Endometrin twice daily, 143 subjects had livebirths consisting of 85 singletons, 56 twins, and 2 triplets. In this treatment group, 13 subjects had a spontaneous abortion, 1 subject had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.4% based on 203 livebirths). Among the 404 subjects treated with Endometrin three times daily, 155 subjects had livebirths consisting of 91 singletons, 60 twins, and 4 triplets. In this treatment group, 22 subjects had a spontaneous abortion, 4 subjects had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.1% based on 223 livebirths). Birth defects reported in the Endometrin twice daily group included: one fetus with a cleft palate and intrauterine growth retardation, one fetus with spina bifida, three fetuses with congenital heart defects, one fetus with an umbilical hernia, and one fetus with an intestinal anomaly. Birth defects reported in the Endometrin three times daily group included: one fetus with an esophageal fistula, one fetus with hypospadias and an underdeveloped right ear, one fetus with Down's and an atrial septal defect, one fetus with congenital heart anomalies, one fetus with DiGeorge's syndrome, one fetus with a hand deformity, and one fetus with cleft palate. For additional information on the pharmacology of Endometrin and pregnancy outcome information [see CLINICAL PHARMACOLOGY and Clinical Studies Sections]. Nursing Mothers Detectable amounts of progesterone have been identified in the milk of nursing mothers. The effect of this on the nursing infant has not been determined. Pediatric Use This drug is not intended for pediatric use and no clinical data have been collected in children. Therefore, the safety and effectiveness of Endometrin in pediatric patients have not been established. Geriatric Use No clinical data have been collected in patients over age 65.