Progesterone vaginal insert

1 INDICATIONS AND USAGE Progesterone vaginal insert is indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women. Progesterone vaginal insert is a progesterone indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women. ( 1 )

2 DOSAGE AND ADMINISTRATION The dose of progesterone vaginal insert 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. Efficacy in women 35 years of age and older has not been clearly established. The appropriate dose of progesterone vaginal insert in this age group has not been determined. ( 2.1 ) 2.1 General Dosing Information The dose of progesterone vaginal insert 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. Efficacy in women 35 years of age and older has not been clearly established. The appropriate dose of progesterone vaginal insert in this age group has not been determined.

4 CONTRAINDICATIONS Progesterone vaginal insert should not be used in individuals with any of the following conditions: Previous allergic reactions to progesterone or any of the ingredients of progesterone vaginal insert [ see Description (11) ] Known missed abortion or ectopic pregnancy Liver disease Known or suspected breast cancer Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events Previous allergic reactions to progesterone or any of the ingredients of progesterone vaginal insert ( 4 ) Known missed abortion or ectopic pregnancy ( 4 ) Liver disease ( 4 ) Known or suspected breast cancer ( 4 ) Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events ( 4 )

5 WARNINGS AND PRECAUTIONS Life-threatening arterial or venous thromboembolic disorders may occur during hormone treatment, including treatment with progesterone vaginal insert. Discontinue progesterone vaginal insert if any of these are suspected. ( 5.1 ) Observe patients with a history of depression closely. Consider discontinuation if symptoms worsen. ( 5.2 ) Progesterone vaginal insert is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal insert. ( 5.3 ) 5.1 Cardiovascular or Cerebrovascular Disorders The physician should be alert to earliest signs of myocardial infarction, cerebrovascular disorders, arterial or venous thromboembolism (venous thromboembolism or pulmonary embolism), thrombophlebitis, or retinal thrombosis. Progesterone vaginal insert should be discontinued if any of these are suspected. 5.2 Depression Patients with a history of depression need to be closely observed. Consider discontinuation if symptoms worsen. 5.3 Use of Other Vaginal Products Progesterone vaginal insert is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal insert [ see Drug Interactions (7) ].

7 DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted for progesterone vaginal insert. Drugs known to induce the hepatic cytochrome-P450-3A4 system (such as rifampin, carbamazepine) may increase the elimination of progesterone. The effect of concomitant vaginal products on the exposure of progesterone from progesterone vaginal insert has not been assessed. Progesterone vaginal insert is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal insert [ see Warnings and Precautions (5.3) ].

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 Xiromed, LLC at 1-844-XIROMED (1-844-947-6633) 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 progesterone vaginal insert in 808 infertile women (74.9% White, 10.3% Hispanic, 5.4% Black, 5% Asian, and 4.6% Other) in a single Assisted Reproductive Technology 10 week clinical study conducted in the U.S. Progesterone vaginal insert was studied at doses of 100 mg twice daily and 100 mg three times daily. The adverse reactions that occurred at a rate greater than or equal to 2% in either progesterone vaginal insert group are summarized in Table 1. Table 1: Number and Frequency of Reported Adverse Reactions in Women Treated with Progesterone Vaginal Insert in an Assisted Reproductive Technology Study Body System Progesterone vaginal insert 100 mg twice daily (N=404) Progesterone vaginal insert 100 mg three times daily (N=404) Preferred Term Gastrointestinal Disorders Abdominal pain 50 (12%) 50 (12%) Nausea 32 (8%) 29 (7%) Abdominal distension 18 (4%) 17 (4%) Constipation 9 (2%) 14 (3%) Vomiting 13 (3%) 9 (2%) General Disorders and Administration Site Conditions Fatigue 7 (2%) 12 (3%) Infections and Infestations Urinary tract infection 9 (2%) 4 (1%) Injury, Poisoning and Procedural Complications Post-oocyte retrieval pain 115 (28%) 102 (25%) Nervous System Disorders Headache 15 (4%) 13 (3%) Reproductive System and Breast Disorders Ovarian hyperstimulation syndrome 30 (7%) 27 (7%) Uterine spasm 15 (4%) 11 (3%) Vaginal bleeding 13 (3%) 14 (3%) Other less common reported adverse reactions included vaginal irritation, itching, burning, discomfort, urticaria, and peripheral edema. 6.2 Expected Adverse Reaction Profile Seen with Progesterone Progesterone vaginal insert is also expected to have adverse reactions similar to other drugs containing progesterone that may include breast tenderness, bloating, mood swings, irritability, and drowsiness.

8.1 Pregnancy Progesterone vaginal insert has been used to support embryo implantation and maintain clinical pregnancy in one clinical study. The live birth outcomes of these pregnancies were as follows: Among the 404 subjects treated with progesterone vaginal insert twice daily, 143 subjects had live births consisting of 85 singletons, 56 twins, and 2 triplets. In this treatment group, 13 subjects had a spontaneous abortion, 1 subject had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.4% based on 203 livebirths). Among the 404 subjects treated with progesterone vaginal insert three times daily, 155 subjects had livebirths consisting of 91 singletons, 60 twins, and 4 triplets. In this treatment group, 22 subjects had a spontaneous abortion, 4 subjects had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.1% based on 223 livebirths). Birth defects reported in the progesterone vaginal insert twice daily group included: one fetus with a cleft palate and intrauterine growth retardation, one fetus with spina bifida, three fetuses with congenital heart defects, one fetus with an umbilical hernia, and one fetus with an intestinal anomaly. Birth defects reported in the progesterone vaginal insert three times daily group included: one fetus with an esophageal fistula, one fetus with hypospadias and an underdeveloped right ear, one fetus with Down Syndrome and an atrial septal defect, one fetus with congenital heart anomalies, one fetus with DiGeorge's syndrome, one fetus with a hand deformity, and one fetus with cleft palate. For additional information on the pharmacology of progesterone vaginal insert and pregnancy outcome information [ see Clinical Pharmacology (12) and Clinical Studies Sections (14) ].