PROGESTERONE (Page 5 of 7)

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– 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 a possible 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.

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 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.)

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 experiences 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 Experiences (≥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 Congugated Estrogens0.625 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

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