Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

PROMETRIUM (NDA-019781)

(PROGESTERONE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/12/2026 (SUPPL-26)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

PROMETRIUM is contraindicated in women with any of the following conditions:

…

Hypersensitivity to its ingredients. PROMETRIUM Capsules contain peanut oil and is contraindicated in patients allergic to peanuts.
Abnormal genital bleeding of unknown etiology.

5 Warnings and Precautions

WARNINGS

Additions and/or revisions underlined:

1.Cardiovascular disorders

PROMETRIUM 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 PROMETRIUM if a PE, DVT stroke, or MI occurs or is suspected.

If feasible, PROMETRIUM 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 CHD events in the CE plus MPA-treated group than placebo; however, rates of CHD events were comparable among both groups for the remainder of the duration of the studies (average total follow-up of 6.8 years).

2. Malignant neoplasms

a. Breast Cancer

Prometrium is contraindicated in women with breast cancer, a history of breast cancer, or estrogen-dependent neoplasia.

(See CONTRAINDICATIONS).

Discontinue Prometrium if a hormone-sensitive malignancy is diagnosed. The use of estrogen plus progestin therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation.

Only daily oral CE 0.625 mg and MPA 2.5 mg were studied in the estrogen-alone trial of the WHI. Therefore, the relevance of the WHI findings regarding breast cancer 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.

In women 50-59 years of age, the WHI estrogen plus progestin trial reported a relative risk for invasive breast cancer of

1.21 (95% CI, 0.81, 1.80) for CE/MPA compared to placebo, with a risk difference of 6 per 10,000 WYs (33 versus 27).

In this age group, among those who reported no prior use of hormone therapy, the relative risk was 1.06 (95% CI, 0.67, 1.67) for CE/MPA compared to placebo, with a risk difference of 2 per 10,000 WYs (33 versus 31).

In the overall study population of women aged 50-79 years (average 63.4 years), the WHI estrogen plus progestin trial reported a relative risk for invasive breast cancer of 1.24 (95% CI, 1.01, 1.53) for CE/MPA compared to placebo, with a risk difference of 9 per 10,000 WYs (43 versus 35). In the overall study population, among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.85, (95% CI 1.18, 2.90) for CE/MPA compared to placebo, with a risk difference of 21 per 10,000 WYs (46 versus 25). Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, (95% CI 0.86, 1.39), with a risk difference of 4 per 10,000 WYs (40 versus 36). Invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups. (See CLINICAL STUDIES.) Extension of the WHI trial also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy.

Consistent with the WHI trial, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy. A large meta-analysis including 24 prospective studies of postmenopausal women comparing current use of estrogen plus progestin products with use duration of 5 to 14 years (average of 9 years) versus never use reported a relative risk for breast cancer of 2.08 (95% CI, 2.02 to 2.15). These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

Regarding breast cancer mortality, the WHI estrogen plus progestin trial did not show a statistically significant difference between CE/MPA and placebo. The trial reported a relative risk of 1.35 (95% CI, 0.94 to 1.95) for CE/MPA compared to placebo, with a risk difference of 1 per 10,000 WYs (5 versus 4) after a median of 19 years of cumulative follow-up.

b.Ovarian Cancer

In the overall WHI study population of women aged 50 to 79 years (average 63.4 years), the estrogen plus progestin trial reported a relative risk for ovarian cancer of 1.41 (95% CI, 0.75 to 2.66) for CE/MPA versus placebo after an average follow-up of 5.6 years. The risk difference was 1 per 10,000 WYs (5 versus 4). Comparing CE/MPA to placebo, women 50 to 59 years of age had a relative risk for ovarian cancer of 0.30 (95% CI 0.06, 1.47) and the risk difference was -3 per 10,000 WYs (1 versus 4).

A large meta-analysis including 17 prospective studies of postmenopausal women compared current use of estrogen plus progestin products versus never use and reported a relative risk for ovarian cancer of 1.37 (95% CI, 1.26 to 1.48). The duration of hormone therapy use that was associated with

…

02/15/2024 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

2. Malignant neoplasms

Additions and/or revisions underlined:

a. Breast Cancer

Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy.