Prometrium What to Expect, Week-by-Week First Month

What the first month involves

Prometrium is an oral capsule of micronized progesterone. The approved uses are prevention of endometrial hyperplasia in postmenopausal women with a uterus who take conjugated estrogens tablets, and secondary amenorrhea [1]. For endometrial protection, the label dose is 200 mg at bedtime for 12 days sequentially per 28-day cycle [1]. For secondary amenorrhea, it is 400 mg at bedtime for 10 days [1].

After oral dosing, maximum serum concentrations are reached within 3 hours [2]. The label directs the single daily dose at bedtime and says Prometrium may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery [1]. The patient leaflet says to take it at bedtime because some women become very drowsy or dizzy [2]. During initial therapy, a few women had extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk, and shortness of breath [1][2]. That is the label's own list, not a prediction for every person.

Food matters for absorption. The label says food increased the bioavailability of Prometrium relative to fasting in postmenopausal women at a 200 mg dose [2]. The patient leaflet also says to take the capsule with a glass of water while standing if swallowing is difficult [2].

What side effects are listed

The label's 3-year adverse-reaction table compared cyclic Prometrium 200 mg for 12 days per month plus conjugated estrogens 0.625 mg (178 women) with placebo, meaning no hormones (174 women) [2]. Headache was reported by 31% versus 27%, breast tenderness by 27% versus 6%, dizziness by 15% versus 9%, abdominal bloating by 12% versus 5%, and nausea or vomiting by 8% versus 7% [2]. The active arm also took estrogen, so these rates cannot be assigned to progesterone alone [2]. They are 3-year rates.

In the label's shorter trial in estrogen-primed postmenopausal women with secondary amenorrhea, Prometrium 400 mg per day (25 women) was compared with placebo (24 women). Dizziness was reported by 24% versus 4%, abdominal cramping by 20% versus 13%, and headache by 16% versus 8% [2].

The label also warns that progesterone may cause some degree of fluid retention, and that women with cardiac or renal dysfunction warrant careful observation [1]. The capsules contain peanut oil, and peanut allergy is a contraindication [1].

What about bleeding in the first cycle

The label's bleeding data come from a different use. In a single-center study of premenopausal women with secondary amenorrhea for at least 90 days, 10 days of Prometrium 300 mg per day produced withdrawal bleeding within 7 days of the last dose in 80% of women (20 women), compared with 10% with placebo (21 women) [1]. The endometrial-protection schedule uses 200 mg for 12 days with conjugated estrogens [1].

Does one month establish endometrial protection?

The label's endometrial trial followed 358 postmenopausal women with a uterus for up to 36 months. Hyperplasia occurred in 6% (7 of 117) with Prometrium 200 mg for 12 days per 28-day cycle plus conjugated estrogens, 64% (74 of 115) with conjugated estrogens alone, and 3% (3 of 116) with placebo [1]. The first 28-day cycle is the start of the schedule; the measured outcome came at 36 months.

What the PEPI trial adds

PEPI was a 3-year randomized trial of 875 healthy postmenopausal women. The estrogen was conjugated equine estrogen, not estradiol, and the micronized progesterone arm took 200 mg per day for 12 days a month [4]. The placebo group received placebo pills and no hormones [4]. In the PEPI endometrial analysis, all three estrogen-plus-progestin regimens, including CEE plus cyclic micronized progesterone, had hyperplasia rates similar to placebo (P=.16) [5].

Label warnings and contraindications

The current Revision 02/2026 label has no boxed warning [3]. FDA approved updated labeling for six menopausal hormone products on 2026-02-12, removing cardiovascular, breast cancer and probable dementia language from the boxed warning; Prometrium was one of the products updated [3][6]. The WHI estrogen-plus-progestin data remain in the label's Warnings and Clinical Studies sections, and the progestin studied in WHI was medroxyprogesterone, not micronized progesterone [2][7].

The label says to stop Prometrium immediately if a pulmonary embolism, deep vein thrombosis, stroke or myocardial infarction occurs or is suspected [1]. If feasible, it says to stop at least 4 to 6 weeks before surgery with increased clot risk or during prolonged immobilization [1]. It says to discontinue if a hormone-sensitive malignancy is diagnosed [2]. With estrogen, retinal vascular thrombosis has been reported; the label says to stop pending examination if there is sudden vision loss, proptosis, diplopia or migraine [2].

The label contraindicates Prometrium in peanut allergy, unexplained abnormal genital bleeding, known or suspected breast cancer or a history of breast cancer, active or prior deep vein thrombosis or pulmonary embolism, active or prior arterial thromboembolic disease, and known liver dysfunction or disease [1].