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

Absorption

Progesterone serum concentrations increased following the administration of the ENDOMETRIN Vaginal Insert in 12 healthy pre-menopausal females. On single dosing, the mean C_max was 17.0 ng/mL in the ENDOMETRIN twice daily group and 19.8 ng/mL in the ENDOMETRIN three times daily group. On multiple dosing, steady-state concentrations were attained within approximately 1 day after initiation of treatment with ENDOMETRIN. Both ENDOMETRIN regimens provided average serum concentrations of progesterone exceeding 10 ng/mL on Day 5. The pharmacokinetic results are summarized in Table 2.

Table 2. Mean (±Standard Deviation) Serum Progesterone Pharmacokinetic Parameters:

C_max Maximum progesterone serum concentration.
T_max Time to maximum progesterone serum concentration
C_avg Average progesterone serum concentration.
AUC_0-24 Area under the drug concentration versus time curve from 0-24 hours post dose.
C_min Minimum progesterone serum concentration.

Distribution

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

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.

14.1 Luteal Supplementation During Assisted Reproductive Treatment Study

A randomized, open-label, active-controlled study evaluated the efficacy of 10 weeks of treatment with two different daily dosing regimens of ENDOMETRIN (100 mg twice daily and 100 mg three times daily) for support of implantation and early pregnancy in infertile women participating in an Assisted Reproductive Technology treatment program. Efficacy was assessed on the endpoint of ongoing pregnancies, defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks post-embryo transfer. The study randomized to ENDOMETRIN 808 infertile women (74.9% White; 10.3% Hispanic, 5.4% Black, 5% Asian, and 4.6% Other) between 19 and 42 years of age (mean age 33) who had a body mass index <34 kg/m² at screening.

The ongoing pregnancy rates for subjects treated with both dosing regimens of ENDOMETRIN were non-inferior (lower bounds of the 95% confidence interval of the difference between ENDOMETRIN and the active comparator excluded a difference greater than 10%) to the ongoing pregnancy rate for subjects treated with the active comparator. The results of this study are shown in Table 3.

Table 3. Ongoing Pregnancy Rates^* in Patients Receiving ENDOMETRIN for Luteal Supplementation and Early Pregnancy While in an Assisted Reproductive Technology Treatment Program:

^* Ongoing pregnancy defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks postembryo transfer.

Subjects participating in the study were stratified at randomization by age and ovarian reserve (as measured by serum FSH levels). The ongoing pregnancy rates for these subgroups are shown in Table 4.

Table 4. Ongoing Pregnancy Rates in Age- and Ovarian Reserve-Defined Subgroups Receiving ENDOMETRIN for Luteal Supplementation and Early Pregnancy While in an Assisted Reproductive Technology Treatment Program:

In subjects under the age of 35 or with serum FSH levels less than 10 IU/L, results from both dosing regimens were non-inferior to the results from the comparator with respect to ongoing pregnancy rates. In women age 35 and older and in women with serum FSH levels between 10 and 15 IU/L, the results with respect to ongoing pregnancy rates for both dosing regimens of ENDOMETRIN did not reach the criteria for non-inferiority.

Subjects who became pregnant received study medication for a total of 10 weeks. Patients over 34 kg/m² were not studied. The efficacy of ENDOMETRIN in this patient group is unknown.