ENDOMETRIN Vaginal insert Ref.[10804] Active ingredients: Progesterone

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. ENDOMETRIN 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

ENDOMETRIN should not be 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)].

6.2 Expected Adverse Reaction Profile Seen with Progesterone

ENDOMETRIN is also expected to have adverse reactions similar to other drugs containing progesterone that may include breast tenderness, bloating, mood swings, irritability, and drowsiness.

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 (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. ENDOMETRIN 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 ENDOMETRIN group are summarized in Table 1.

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

Other less common reported adverse reactions included vaginal irritation, itching, burning, discomfort, urticaria, and peripheral edema.

No formal drug-drug interaction studies have been conducted for ENDOMETRIN. 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 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 vaginal insert [see Warnings and Precautions (5.3)].

ENDOMETRIN 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 ENDOMETRIN 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 ENDOMETRIN 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 ENDOMETRIN 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 ENDOMETRIN 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 ENDOMETRIN and pregnancy outcome information [see Clinical Pharmacology (12) and Clinical Studies Sections (14)].

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.

This drug is not intended for pediatric use and no clinical data have been collected in children. Therefore, the safety and effectiveness of ENDOMETRIN in pediatric patients have not been established.

No clinical data have been collected in patients over age 65.