Progesterone

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. ENDOMETRIN is a progesterone 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.

Vaginal insert: 100 mg – white to off-white oblong-shaped debossed with “FPI” on one side and “100” on the other side. Vaginal insert: 100 mg ( 3 )

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 ENDOMETRIN is contraindicated in patients with ( 4 ): Previous hypersensitivity reactions to progesterone or any of the ingredients in ENDOMETRIN 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

Cardiovascular or Cerebrovascular Disorders: Life-threatening arterial or venous thromboembolic disorders may occur during hormone treatment, including treatment with ENDOMETRIN. Discontinue ENDOMETRIN if any of these are suspected. ( 5.1 ) Depression: Closely observe ENDOMETRIN-treated women with a history of depression. Consider ENDOMETRIN discontinuation if symptoms worsen. (5.2)

5.1 Cardiovascular or Cerebrovascular Disorders 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 ENDOMETRIN-treated women with a history of depression should be closely observed. Consider ENDOMETRIN discontinuation if symptoms worsen.

The most common adverse reactions reported (greater than 2%) were post-oocyte retrieval pain, abdominal pain, nausea, and ovarian hyperstimulation syndrome. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals Inc. at 1-888-FERRING (1-888-337-7464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Studies Experience 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. 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 ENDOMETRIN 100 mg twice daily (N=404) ENDOMETRIN 100 mg three times daily (N=404) Post-oocyte retrieval pain 115 (28%) 102 (25%) Abdominal pain 50 (12%) 50 (12%) Nausea 32 (8%) 29 (7%) Ovarian hyperstimulation syndrome 30 (7%) 27 (7%) Abdominal distension 18 (4%) 17 (4%) Headache 15 (4%) 13 (3%) Uterine spasm 15 (4%) 11 (3%) Vaginal bleeding 13 (3%) 14 (3%) Vomiting 13 (3%) 9 (2%) Urinary tract infection 9 (2%) 4 (1%) Constipation 9 (2%) 14 (3%) Fatigue 7 (2%) 12 (3%) Adverse Reactions from Other Progesterone Products Adverse reactions from other progesterone products included breast tenderness, bloating, mood swings, irritability, and drowsiness.

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. The effect of concomitant vaginal products on the exposure of progesterone from ENDOMETRIN has not been assessed. ENDOMETRIN is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the ENDOMETRIN vaginal insert. CYP3A4 Inducers: May increase the elimination of progesterone and may reduce the efficacy of ENDOMETRIN. ( 7 ) Other Vaginal Products: Avoid use of ENDOMETRIN with other vaginal products. ( 7 )

Pediatric Use: ENDOMETRIN is not for pediatric use. ( 8.4 ) Geriatric Use: ENDOMETRIN is not for use in women 65 years of age and older. ( 8.5 )

8.1 Pregnancy 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 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.

8.4 Pediatric Use The safety and effectiveness of ENDOMETRIN in pediatric patients have not been established.

8.5 Geriatric Use 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 The safety and efficacy of ENDOMETRIN in women with a body mass index (BMI) >34 kg/m 2 has not been studied.

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

Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain a pregnancy.