Progesterone 100 mg Capsule, 100-count — NDC 0054-0829-25 (Billing 00054-0829-25)

WARNINGS 1. Cardiovascular disorders Progesterone Capsules is contraindicated in females with active DVT, PE, arterial thromboembolic disease (e.g., stroke, MI) disease, or a history of these conditions ( See CONTRAINDICATIONS ). Immediately discontinue Progesterone Capsules if a PE, DVT, stroke, or MI occurs or is suspected.

If feasible, discontinue Progesterone Capsules at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. The safety and efficacy of estrogen plus progestogen for the prevention of cardiovascular disorders has not been established. ( See CLINICAL STUDIES ) The Women’s Health Initiative (WHI) estrogen plus progestin trial reported increased risks of PE, DVT, stroke, and MI in postmenopausal women (50 to 79 years of age, average age 63.4 years) 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.

Analyses were also conducted in women aged 50-59 years, a group of women more likely to present with new onset of moderate to severe VMS compared to women in other age groups in the trial. ( See CLINICAL STUDIES .) Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin trial of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known.

Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. a. Venous Thromboembolism In women aged 50 to 59 years, the WHI estrogen plus progestin trial reported a relative risk for PE of 2.05 (95% confidence interval [CI], 0.89, 4.71) for CE/MPA compared to placebo, with a risk difference of 6 per 10,000 women-years (WYs; 11 versus 5). The relative risk for DVT was 3.01 (95% CI, 1.36, 6.66) in those receiving CE/MPA compared to placebo, with a risk difference of 10 per 10,000 WYs (15 versus 5).

( See CLINICAL STUDIES ). In the overall study population of women aged 50 to 79 years (average 63.4 years), the trial reported a relative risk for PE of 1.98 (95% CI, 1.36, 2.87) for CE/MPA compared to placebo, with a risk difference of 9 per 10,000 WYs (18 versus 9). The relative risk for DVT was 1.87 (95% CI, 1.37, 2.54) for CE/MPA compared to placebo, with a risk difference of 12 per 10,000 WYs (25 versus 14).

( See CLINICAL STUDIES ). b . Stroke In women aged 50 to 59 years, the WHI estrogen plus progestin trial reported a relative risk for stroke of 1.51 (95% CI, 0.81, 2.82) for CE/MPA compared to placebo, with a risk difference of 5 per 10,000 WYs (15 versus 10). ( See CLINICAL STUDIES ).

In the overall study population of women aged 50 to 79 years (average 63.4 years), the WHI estrogen plus progestin trial reported relative risk for stroke of 1.37 (95% CI, 1.07, 1.76) for CE/MPA compared to placebo, with a risk difference of 9 per 10,000 WYs (33 versus 24). ( See CLINICAL STUDIES ). c . Coronary Heart Disease In women 50 to 59 years of age, the WHI estrogen plus progestin trial reported a relative risk for coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) of 1.34 (95% CI, 0.82, 2.19) for CE/MPA compared placebo, with a risk difference of 5 per 10,000 WYs (23 versus 17).

In the overall study population of women aged 50 to 79 years (average 63.4 years), the trial reported a relative risk of CHD of 1.18 (95% CI, 0.95, 1.45) for CE/MPA compared to placebo, with a risk difference of 6 per 10,000 WYs (41 versus 35). ( See CLINICAL STUDIES ). In the Heart and Estrogen/Progestin Replacement Study (HERS) and open label extension (HERS II), postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) received daily CE (0.625 mg) plus MPA or placebo.

In Year 1, there were more C… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS See 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 7 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. Effects on Secondary Amenorrhea In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the effects of Progesterone on secondary amenorrhea was studied in 49 estrogen-primed postmenopausal women. Table 8 lists adverse reactions greater than or equal to 5 percent of women who received Progesterone Capsules or placebo.

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. Table 7 Table 8

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.

PRECAUTIONS A. General 1. 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. 2 . 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. 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. 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 dem… [Excerpted — this section continues on DailyMed.]