Progesterone

INDICATIONS AND USAGE Progesterone 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 Progesterone 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 Progesterone capsules may be given as a single daily dose of 400 mg at bedtime for 10 days. Some women may experience difficulty swallowing progesterone capsules. For these women, progesterone capsules should be taken with a glass of water while in the standing position.

CONTRAINDICATIONS Progesterone capsules should not be used in women with any of the following conditions: 1. Progesterone capsules should not be used in patients with known hypersensitivity to its ingredients. Progesterone capsules contain peanut oil and should never be used by patients allergic to peanuts. 2. Undiagnosed abnormal genital bleeding. 3. Known, suspected, or history of breast cancer. 4. Active deep vein thrombosis, pulmonary embolism or history of these conditions. 5. Active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. 6. Known liver dysfunction or disease. 7. Known or suspected pregnancy.

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. …

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.

DESCRIPTION Progesterone Capsules contain micronized progesterone for oral administration. Progesterone has a molecular weight of 314.47 and a molecular formula of C 21 H 30 O 2 . Progesterone (pregn-4-ene-3, 20-dione) is a white to creamy white, odorless, crystalline powder practically insoluble in water, soluble in alcohol, in acetone, and in dioxane and sparingly soluble in vegetable oils, melting between 126° and 131°C. The structural formula is: Progesterone, USP is synthesized from a starting material from a plant source and is chemically identical to progesterone of human ovarian origin. Progesterone capsules are available in multiple strengths to afford dosage flexibility for optimum management. Progesterone capsules contain 100 mg or 200 mg micronized progesterone. The inactive ingredients for progesterone capsules 100 mg include: D&C Yellow No. 10, FD&C Red No. 40, gelatin, glycerin, lecithin, peanut oil, and titanium dioxide. The inactive ingredients for progesterone capsules 200 mg include: D&C Yellow No. 10, gelatin, glycerin, lecithin, peanut oil, and titanium dioxide. The imprinting Opacode ® S-1-277002 Black contains, ammonium hydroxide, black iron oxide, propylene glycol and shellac (100 mg and 200 mg)

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

HOW SUPPLIED Progesterone capsules, 100 mg are off-white, ovoid, capsules with " PR1 " marked. NDC 76420-267-10, Bottle of 10 capsules (repackaged from NDC 16714-157-01) NDC 76420-267-30, Bottle of 30 capsules (repackaged from NDC 16714-157-01) NDC 76420-267-60, Bottle of 60 capsules (repackaged from NDC 16714-157-01) NDC 76420-267-90, Bottle of 90 capsules (repackaged from NDC 16714-157-01) NDC 76420-267-01, Bottle of 100 capsules (relabeled from NDC 16714-157-01) Progesterone capsules, 200 mg are off-white, ovoid, capsules with " PR2 " marked. NDC 76420-574-10, Bottle of 10 capsules (repackaged from NDC 16714-158-01) NDC 76420-574-30, Bottle of 30 capsules (repackaged from NDC 16714-158-01) NDC 76420-574-60, Bottle of 60 capsules (repackaged from NDC 16714-158-01) NDC 76420-574-90, Bottle of 90 capsules (repackaged from NDC 16714-158-01) NDC 76420-574-01, Bottle of 100 capsules (relabeled from NDC 16714-158-01) 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.