Endometrin - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Endometrin - Scientific Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Amenorrhea, Progesterone Insufficiency
Class: Progestins
Form: Vaginal (e.g., douche, pessary, etc.), Tablets
Ingredients: Progesteronelactose, monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide.

Pharmaceutical Information

Drug Substance

Proper name:progesterone, USP
Chemical name:pregn-4-ene-3, 20-dione
Molecular formula:C21H30O2
Molecular weight:314.5
Structural formula:


C21H30O2

Physicochemical properties:
Progesterone exists in two polymorphic forms. The form used in Endometrin, the alpha-form, has a melting point of 127-131°C.
Aqueous Solubility:<1mg/mL (insoluble) at 20° C in water
pKa:18-22

Clinical Trials

Luteal Supplementation During In Vitro Fertilization 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) and progesterone gel 90 mg applied vaginally once 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 1.

Table 1: Ongoing Pregnancy Rates* in Patients Receiving Endometrin for Luteal Supplementation and Early Pregnancy While in an In Vitro Fertilization program.
Endometrin 100 mg twice dailyEndometrin 100 mg three times dailyProgesterone gel 90 mg once daily
Number of subjects404404403
Ongoing pregnancy: n (%)156 (39%)171 (42%)170 (42%)
95% Confidence Interval of pregnancy rate[33.8,43.6][37.5,47.3][37.3, 47.2]
Pregnancy rate percentage difference between Endometrin and comparator-3.6%0.1%NA
95% Confidence Interval for difference vs. comparator[-10.3, 3.2][-6.7, 6.9]NA

*Ongoing pregnancy defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks post-embryo 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 2.

Table 2: Ongoing Pregnancy Rates in Age- and Ovarian Reserve-Defined Subgroups Receiving Endometrin for Luteal Supplementation and Early Pregnancy while in an In Vitro Fertilization program.
Endometrin 100 mg twice dailyEndometrin 100 mg three times dailyProgesterone gel 90 mg once daily
Subjects age < 35 years (N)247247243
Ongoing pregnancy: n (%)111 (45%)117 (47%)108 (44%)
Pregnancy rate percentage difference between Endometrin and comparator0.5%2.9%NA
95% Confidence Interval for difference vs. comparator[-8.3, 9.3][-5.9, 11.7]NA
Subjects 35-42 years of age (N)157157160
Ongoing pregnancy: n (%)45 (28%)54 (34%)62 (38%)
Pregnancy rate percentage difference between Endometrin and comparator-10.1%-4.4%NA
95% Confidence Interval for difference vs. comparator[-20.3, 0.3][-14.9, 6.3]NA
Subjects with FSH < 10 IU/L (N)350347350
Ongoing pregnancy: n (%)140 (40%)150 (43%)147 (42%)
Pregnancy rate percentage difference between Endometrin and comparator-2.0%1.2%NA
95% Confidence Interval for difference vs. comparator[-9.3, 5.3][-6.1, 8.5]NA
Subjects with FSH between 10 and 15 IU/L (N)465149
Ongoing pregnancy: n (%)16 (35 %)20 (39%)23 (47%)
Pregnancy rate percentage difference between Endometrin and comparator-12.2%-7.7%NA
95% Confidence Interval for difference vs. comparator[-31.0, 7.7][-26.6, 11.6]NA

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 rate 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.

Detailed Pharmacology

Clinical Pharmacology

Administered vaginally, progesterone may undergo a presumptive uterine pass effect as suggested by higher uterine tissue progesterone concentrations after vaginal administration than seen in intramuscular (IM) administration.

In blood, progesterone is largely (95- 98%) bound to plasma proteins. The 3 primary progesterone- binding proteins in plasma are albumin, cortisol-binding globulin (CBG), and sex hormone-binding globulin (SHBG), with albumin being predominant progesterone- binding protein. Progesterone is primarily metabolized through reduction processes. Progesterone is metabolized hepatically to pregnanediol and conjugated with glucuronic acid. Approximately 50-60% of metabolite excretion occurs via the kidney and an additional 10% of metabolites are excreted via the bile. Progesterone metabolites excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces.

Because progesterone is primarily metabolized through reduction process, hydroxylation processes and therefore the potential role for CYP isoforms, which catalyze oxidative biotransformations, play a minor role. Drug interactions have not been identified with other progesterone vaginal products. There is no evidence that progesterone treatment, especially when given vaginally, will clinically significantly affect the metabolism of other drugs administered concomitantly. Other drugs administered concomitantly with Endometrin are not expected to affect Endometrin metabolism in a clinically significant way.

Pharmacokinetics

Endometrin pharmacokinetics was evaluated in 18 premenopausal cycling female subjects between 18 and 40 years of age with an intact uterus. The subjects were randomly assigned to Endometrim 100 mg BID, Endometrin 100 TID, or progesterone 8% gel (90 mg QD). Progesterone serum concentrations increased rapidly following the administration of the Endometrin vaginal tablets. The progesterone concentrations approximated steady-state concentration by the time the second dose was administered (12 hours after the first dose) in the BID regimen and by the time of the second dose on Day 2 (32 hours after the start of dosing) for Endometrin TID. Steady-state serum progesterone concentrations for both Endometrin regimens exceeded the physiologically significant level of 60.42 nmol/L for the entire 24 hours of Day 5 of treatment. Both Endometrin regimens produced higher peak serum concentrations (Cmax), higher minimum concentration (Cmin), and greater systemic exposure (AUC0-24) than did progesterone gel applied 90 mg vaginally once daily.

The results of a study comparing Endometrin (50 mg QD, 100 mg QD, 200 mg QD, 100 mg BID, and 200 mg BID) to progesterone IM (50 mg QD) indicted that the vaginal tablet formulation of micronized progesterone was rapidly absorbed and produced increases in systemic progesterone concentrations. Based on serum progesterone concentrations, steady-state pharmacokinetics was reached within 24 hours using vaginal tablets. Trough concentrations remained stable for 10 days with repeated dosing. The vaginal tablets resulted in substantially lower systemic concentrations of progesterone than equivalent progesterone doses administered IM. Results from three studies indicate that Endometrin 100 mg BID or 100 mg TID should be effective to develop and maintain secretory endometrim and to provide luteal support of pregnancy throughout the first trimester.

Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.