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.

ENDOMETRIN (NDA-022057)

(PROGESTERONE)

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

Download Data

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07/15/2026 (SUPPL-12)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

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

Previous hypersensitivity reactions to progesterone or any of the ingredients of ENDOMETRIN [see Description (11)]
Abnormal vaginal bleeding that has an undiagnosed etiology
Known missed abortion or ectopic pregnancy
Hepatic adenoma, hepatocellular carcinoma, acute hepatitis, or severe (decompensated) cirrhosis
Current diagnosis of, or history of, a hormone-sensitive malignancy (e.g., breast cancer)
Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events

5 Warnings and Precautions

5.1 Cardiovascular or Cerebrovascular Disorders

Additions and/or revisions underlined:

Life-threatening arterial or venous thromboembolic disorders may occur during hormone treatment, including treatment with ENDOMETRIN.

The healthcare provider should be alert to earliest signs of myocardial infarction, cerebrovascular disorders, arterial or venous thromboembolism (venous thromboembolism or pulmonary embolism), thrombophlebitis, or retinal thrombosis. ENDOMETRIN should be discontinued if any of these are suspected.

5.2 Depression

Additions and/or revisions underlined:

ENDOMETRIN-treated women with a history of depression should be closely observed. Consider ENDOMETRIN discontinuation if symptoms worsen.

6 Adverse Reactions

6.1 Clinical Study Experience

Additions and/or revisions underlined:

. . .

The safety data reflect exposure to ENDOMETRIN in 808 infertile women in a single Assisted Reproductive Technology 10 week clinical study conducted in the U.S. [see Clinical Studies (14)]. ENDOMETRIN was studied at vaginally administered doses of 100 mg twice daily and 100 mg three times daily for 10 weeks and compared to a vaginally administered active comparator. The adverse reactions that occurred at a rate greater than or equal to 2% in either ENDOMETRIN group are summarized in Table 1.

Other less common reported adverse reactions in ENDOMETRIN-treated women included vaginal irritation, itching, burning, discomfort, urticaria, and peripheral edema.

Table 1: Number and Frequency of Reported Adverse Reactions in Infertile Women Treated with ENDOMETRIN in an Assisted Reproductive Technology Study

. . .

Adverse Reactions from Other Progesterone Products

Adverse reactions from other progesterone products included breast tenderness, bloating, mood swings, irritability, and drowsiness.

7 Drug Interactions

Additions and/or revisions underlined:

Drugs known to induce the hepatic cytochrome-P450-3A4 system may increase the elimination of progesterone, lower progesterone exposure in ENDOMETRIN-treated women, and reduce the efficacy of ENDOMETRIN.

. . .

8 Use in Specific Populations

8.1 Pregnancy

PLLR Conversion:

Risk Summary

ENDOMETRIN is indicated, as part of an Assisted Reproductive Technology (ART) treatment program, to support embryo implantation in infertile women less than 35 years of age by supplementation of corpus luteal function and to maintain pregnancy after implantation up to 10 weeks.

Maternal risks of ENDOMETRIN use during pregnancy are discussed throughout the labeling.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data: In one clinical study [see Clinical Studies (14)], ENDOMETRIN was vaginally administered to support embryo implantation during the first trimester of pregnancy and to maintain clinical pregnancy through week 10 of pregnancy when the placenta takes over production of progesterone. The live birth outcomes of these pregnancies were as follows:

Among the 404 women treated with ENDOMETRIN twice daily, 143 (35%) women had live births consisting of 85 (59%) singletons, 56 (39%) twins, and 2 (1%) triplets. In this treatment group, 13 (3%) women had a spontaneous abortion, 1 (0.2%) woman had an ectopic pregnancy, and neonatal birth defects were reported in 7 infants (3% based on 203 live births).
Among the 404 women treated with ENDOMETRIN three times daily, 155 (38%) women had live births consisting of 91 (59%) singletons, 60 (39%) twins, and 4 (3%) triplets. In this treatment group, 22 (5%) women had a spontaneous abortion, 4 (1%) women had an ectopic pregnancy, and neonatal birth defects were reported in 7 infants (3% based on 223 live births).

Birth defects reported in the ENDOMETRIN:

Twice daily group included one neonate with a cleft palate and intrauterine growth retardation, one with spina bifida, three with congenital heart defects, one with an umbilical hernia, and one with an intestinal anomaly.
Three times daily group included one neonate with an esophageal fistula, one with hypospadias and an underdeveloped right ear, one with Down Syndrome and an atrial septal defect, one with congenital heart anomalies, one with DiGeorge’s syndrome, one fetus with a hand deformity, and one with cleft palate.

For additional information on the pharmacology of ENDOMETRIN and pregnancy outcome information [see Clinical Pharmacology (12) and Clinical Studies (14)].

8.2 Lactation

PLLR Conversion:

Risk Summary

Detectable amounts of progesterone have been identified in the milk of nursing mothers. The effect of this on the nursing infant has not been determined. A published study reported no adverse effects of progesterone on milk production or infant growth during the first postpartum year.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENDOMETRIN and any potential adverse effects on the breastfed child from ENDOMETRIN or from the underlying maternal condition.

8.5 Geriatric Use

Additions and/or revisions underlined:

Clinical studies of ENDOMETRIN did not include women 65 years of age and older. ENDOMETRIN is not indicated for use in this population.

8.6 Body Mass Index

Newly added subsection

The safety and efficacy of ENDOMETRIN in women with a body mass index (BMI) >34 kg/m2 has not been studied.

8.7 Hepatic Impairment

Newly added subsection

ENDOMETRIN is contraindicated in women with hepatic adenoma, hepatocellular carcinoma, acute hepatitis, or severe (decompensated) cirrhosis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-Approved patient labeling (Patient Information).

Vaginal Bleeding

Inform patients of the importance of reporting irregular vaginal bleeding to their health care provider as soon as possible.

Common Adverse Reactions with Progesterone

Inform patients of the possible adverse reactions of ENDOMETRIN therapy such as headaches, breast tenderness, bloating, mood swings, irritability, and drowsiness.

Coadministration of Other Vaginal Products

Inform patients that ENDOMETRIN is not recommended for use with other vaginal products.

PATIENT INFORMATION

Additions and/or revisions underlined

. . .

What is ENDOMETRIN?

ENDOMETRIN is a prescription medicine vaginal insert that contains the hormone progesterone and is used to support embryo implantation in women less than 35 years of age while undergoing treatment for infertility (an Assisted Reproductive Technology (ART) program) and to maintain pregnancy for up to 10 weeks.
It is not known if ENDOMETRIN is safe and effective in children.
Important: For Vaginal Use Only.

Who should not use ENDOMETRIN?

Do not use ENDOMETRIN if you:

are allergic to progesterone or any of the ingredients in ENDOMETRIN. See the end of this leaflet for a complete list of ingredients in ENDOMETRIN.
have abnormal, undiagnosed vaginal bleeding.
have a known missed abortion or ectopic pregnancy.
currently have or have had certain liver problems.
currently have or have had cancer that is hormone sensitivity such as breast cancer.
currently have or have had blood clots.

Before using ENDOMETRIN, tell your healthcare provider about all of your medical conditions, including if you:

have a history of a heart attack, stroke (cerebrovascular disorders), or blood clots.
have a history of depression.
are currently using any other vaginal products (such as antifungal products).
are pregnant.
are breastfeeding or plan to breastfeed. Talk to your healthcare provider about the best way to feed your baby while using ENDOMETRIN.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. You should not use ENDOMETRIN while using other vaginal products. Using ENDOMETRIN with certain other medicines may affect how ENDOMETRIN works.

Know what medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use ENDOMETRIN?

Use ENDOMETRIN exactly as your healthcare provider tells you to.
ENDOMETRIN is placed in your vagina 2 to 3 times a day for up to a total of 10 weeks.

Do not use any other vaginal products while using ENDOMETRIN.

Follow the steps below:

1. Unwrap the applicator. Do not use if the contents or packaging are visibly damaged.

2. Put one vaginal insert in the space provided at the end of the applicator. The insert should fit snugly and not fall out.

. . .

What are the possible side effects of ENDOMETRIN? ENDOMETRIN may cause serious side effects, including:

Risk of heart attack, stroke, or blood clots. Your healthcare provider may stop ENDOMETRIN if you have signs of heart attack, stroke, or blood clots. Symptoms of heart attack or blood clots may include:

. . .

Depressed mood. Your healthcare provider may stop ENDOMETRIN if symptoms of depressed mood worsen.

The most common side effects of ENDOMETRIN include:

. . .

fatigue

. . .

Call your healthcare provider right away if you have irregular vaginal bleeding.

. . .

How should I store ENDOMETRIN?

Store ENDOMETRIN at room temperature between 68°F to 77°F (20°C to 25°C).
Keep ENDOMETRIN and all medicines out of the reach of children.

. . .