ENDOMETRIN

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION The recommended ENDOMETRIN dose is 100 mg administered vaginally two or three times daily starting the day after oocyte retrieval and continuing for up to 10 weeks total duration. The recommended ENDOMETRIN dose is 100 mg administered vaginally two or three times daily starting the day after oocyte retrieval and continuing for up to 10 weeks total duration. ( 2 ) Efficacy in women 35 years of age and older has not been clearly established. The appropriate dose of ENDOMETRIN in this age group has not been determined. ( 2 )

4 CONTRAINDICATIONS 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

5 WARNINGS AND PRECAUTIONS 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.

7 DRUG INTERACTIONS 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 )

6 ADVERSE REACTIONS 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.

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) ] .