PROGESTERONE VAGINAL INSERT

Progesterone vaginal insert contains micronized progesterone. Progesterone vaginal insert is supplied with polyethylene vaginal applicators. The active ingredient, progesterone, is present in 100 mg amount along with other excipients. The chemical name for progesterone is pregn-4-ene-3,20-dione. It has a molecular formula of C 21 H 30 O 2 and a molecular weight of 314.5. Progesterone exists in two polymorphic forms. The form used in progesterone vaginal insert, the alpha-form, has a melting point of 127 to 131°C. The structural formula is: Each progesterone vaginal insert delivers 100 mg of progesterone in a base containing adipic acid, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, polyvinylpyrrolidone, pregelatinized starch, sodium bicarbonate, and sodium lauryl sulfate. Chemical Structure

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 )

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.

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 )

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.

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) ].