Oral Micronized Progesterone FDA Approval History

When was oral micronized progesterone approved?

Drugs@FDA records the original approval of NDA 019781 for Prometrium on May 14, 1998, as a Type 3 new dosage form [1]. The NDA covers oral micronized progesterone in 100 mg and 200 mg capsules [2]. Drugs@FDA lists ACERTIS PHARMS as the current company on the application [1]. The label states that micronization increases oral bioavailability and describes the progesterone as chemically identical to progesterone of ovarian origin [2].

What did FDA approve it for?

The labeled indications are only two: prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving conjugated estrogens tablets, and secondary amenorrhea [2]. For endometrial protection, the label gives 200 mg orally at bedtime for 12 days sequentially per 28-day cycle, with daily conjugated estrogens [2]. For secondary amenorrhea, the label gives 400 mg at bedtime for 10 days [2]. The labeled estrogen is conjugated estrogens, not estradiol [2]. The label also places the dose at bedtime and warns that progesterone may cause transient dizziness and drowsiness [2][5].

What trial supported endometrial safety?

The label describes a randomized, double-blind trial of 358 postmenopausal women with an intact uterus who were treated for up to 36 months [2]. The arms were Prometrium 200 mg for 12 days per 28-day cycle plus conjugated estrogens 0.625 mg (n=120), conjugated estrogens alone (n=119), or placebo (n=119) [2]. By 36 months, endometrial hyperplasia occurred in 6% (7 of 117) with the combination, 64% (74 of 115) with estrogen alone, and 3% (3 of 116) with placebo; atypical hyperplasia occurred in 1%, 12%, and 0%, respectively [2].

The separate PEPI trial was a 3-year, multicenter, randomized, double-blind, placebo-controlled trial of 875 healthy postmenopausal women aged 45 to 64 [6]. Its five arms were placebo, conjugated equine estrogen 0.625 mg/day alone, and three estrogen-plus-progestin regimens, including conjugated equine estrogen plus cyclic micronized progesterone 200 mg/day for 12 days a month [6]. The endometrial histology analysis included 596 women; all three estrogen-plus-progestin regimens had hyperplasia rates similar to placebo (P=.16), while estrogen alone had higher rates [7]. In PEPI, HDL cholesterol rose by 0.11 mmol/L with conjugated equine estrogen plus cyclic micronized progesterone and by 0.14 mmol/L with estrogen alone, compared with 0.03 to 0.04 mmol/L with the medroxyprogesterone regimens and a 0.03 mmol/L fall with placebo [6].

How has the label changed?

The current Prometrium label is Revision 02/2026 [2][5]. FDA approved labeling changes for six menopausal hormone therapy products on February 12, 2026, removing risk statements about cardiovascular disease, breast cancer and probable dementia from the boxed warning [3]. Prometrium was among the six products whose prescribing information was updated [4]. The current label has no boxed warning [5][3][4]. Older labels had one [3][5]. The WHI estrogen-plus-progestin data remain in the Warnings and Clinical Studies sections [5].

The WHI trial that produced those data used conjugated estrogens 0.625 mg plus medroxyprogesterone 2.5 mg, not micronized progesterone, in 16,608 women aged 50 to 79 [8]. The label summarizes 5.6 years of treatment and reports invasive breast cancer relative risk 1.24 (95% CI 1.01 to 1.53), deep vein thrombosis relative risk 1.87, pulmonary embolism relative risk 1.98 and stroke relative risk 1.37 for that regimen [2][8]. On pregnancy, the label says Prometrium capsules should not be used during pregnancy, although its text still contains a Pregnancy Category B paragraph [5].

Are generic progesterone capsules available?

Generic progesterone capsules exist [1]. Drugs@FDA lists 100 mg progesterone capsules from Amneal and Bionpharma with therapeutic equivalence code AB [1]. Compounded progesterone is not FDA-approved, and FDA does not verify the safety, effectiveness or quality of compounded drugs before they are marketed [9].

What did post-market studies show?

The ESTHER case-control study in France recruited 271 women with a first documented idiopathic venous thromboembolism and 610 controls [10]. Current use of micronized progesterone was not significantly associated with venous thromboembolism (odds ratio 0.7, 95% CI 0.3 to 1.9), while norpregnane derivatives had an odds ratio of 3.9 (95% CI 1.5 to 10.0) [10]. The E3N cohort followed 80,377 postmenopausal women and identified 2,354 invasive breast cancers over a mean of 8.1 postmenopausal years [11]. Compared with never-use, estrogen-progesterone had a relative risk of 1.00 (95% CI 0.83 to 1.22), while estrogen plus other progestagens had a relative risk of 1.69 (95% CI 1.50 to 1.91) [11]. Both are observational studies [10][11].

What does the current label warn about?

The label lists six contraindications: (1) hypersensitivity to its ingredients, including peanut allergy because the capsules contain peanut oil; (2) abnormal genital bleeding of unknown cause; (3) known, suspected or history of breast cancer; (4) active or prior deep vein thrombosis or pulmonary embolism; (5) active or prior arterial thromboembolic disease; and (6) known liver dysfunction or disease [2]. The label warns about transient dizziness and drowsiness and says to use caution when driving a motor vehicle or operating machinery [2]. It also notes that progesterone may cause some degree of fluid retention [2].