ENDOMETRIN - Ferring Pharmaceuticals Inc.

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.

ENDOMETRIN-treated women with a history of depression should be closely observed. Consider ENDOMETRIN discontinuation if symptoms worsen.

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.

Adverse Reactions from Other Progesterone Products

Adverse reactions from other progesterone products included breast tenderness, bloating, mood swings, irritability, and drowsiness.

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)].

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.

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

Clinical studies of ENDOMETRIN did not include women 65 years of age and older. ENDOMETRIN is not indicated for use in this population.

The safety and efficacy of ENDOMETRIN in women with a body mass index (BMI) >34 kg/m² has not been studied.

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.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of ENDOMETRIN have not been fully characterized.

Absorption

Progesterone serum concentrations increased following the administration of the ENDOMETRIN vaginal insert in 12 healthy premenopausal females. After 5 days of dosing, steady-state progesterone concentrations were attained within approximately 1 day after initiation of ENDOMETRIN treatment. Both ENDOMETRIN dosing regimens provided average serum progesterone concentrations that exceeded 10 ng/mL on Day 5. The pharmacokinetic results are summarized in Table 2.

Distribution  

Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin.

Elimination

Metabolism: Progesterone is metabolized primarily by the liver, largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites that are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.

Excretion: Progesterone undergoes renal and biliary elimination. Following injection of labeled progesterone, 50-60% of the excretion of metabolites occurs via the kidney; approximately 10% occurs via the bile and feces. Overall recovery of the labeled material accounts for 70% of an administered dose. Only a small portion of unchanged progesterone is excreted in the bile.

Nonclinical toxicity studies to determine the potential of ENDOMETRIN to cause carcinogenicity or mutagenicity have not been performed. The effect of ENDOMETRIN on fertility has not been evaluated in animals.