Ferring Pharmaceuticals Inc. (Page 2 of 4)

8.2 Lactation

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 MILPROSA and any potential adverse effects on the breastfed child from MILPROSA or from the underlying maternal condition.

8.4 Pediatric Use

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

8.5 Geriatric Use

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

8.6 Body Mass Index (BMI)

The safety and efficacy of MILPROSA in women with a BMI >38 kg/m2 has not been studied.

8.7 Hepatic Impairment

MILPROSA has not been studied in women with hepatic impairment.


MILPROSA (progesterone) vaginal system is a white to off-white, flexible, non-biodegradable silicone ring (toroidal-shaped) containing 1.78 grams of progesterone. MILPROSA has a cross-sectional diameter of approximately 8.5 mm, and an outer and inner diameter of approximately 55 mm and 38 mm, respectively.

The chemical name for progesterone is pregn-4-ene-3,20-dione. It has an empirical formula of C21 H30 O2 and a molecular weight of 314.5. Progesterone has a melting point of 126-131°C.

The structural formula is:

Chemical Structure
(click image for full-size original)

When placed in the vagina, each vaginal system is estimated to provide an average release rate of 11 mg/day of progesterone over 7 days.

The inactive components of the vaginal system are light mineral oil and silicone elastomer.


12.1 Mechanism of Action

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.

12.3 Pharmacokinetics


Progesterone plasma concentrations increased following the administration of MILPROSA vaginal system to 30 healthy postmenopausal females (inserted once a week for two weeks) (MILPROSA is not indicated in postmenopausal females). The 30 subjects were pre-treated with 1 mg oral estradiol tablets once a day for 28 days prior to MILPROSA treatment and during MILPROSA treatment to manage postmenopausal vaginal atrophy. Steady state concentrations were attained 96 hours after initiation of treatment with MILPROSA. After reaching steady state, MILPROSA provided average baseline-adjusted plasma concentrations of progesterone exceeding 8 ng/mL. The pharmacokinetic results are summarized in Table 2.

Table 2: Mean (± Standard Deviation) Baseline-Adjusted Plasma Progesterone Pharmacokinetic Parameters
Pharmacokinetic Parameters MILPROSA
Cmax Maximum progesterone concentration. Tmax Time to maximum progesterone concentration. Cavg Average progesterone concentration at steady state. AUC0-168hr Area under the drug concentration versus time curve from 0-168 hours post dose. AUC168-336 hr Area under the drug concentration versus time curve from 168 hours to 336 hours after initiation of treatment AUC168-inf Area under the drug concentration versus time curve from 168 hours after initiation of treatment to infinite time Kel Elimination rate constant T1/2 Terminal elimination half-life Cmin Minimum progesterone concentration.
First MILPROSA Vaginal System (n=30), 0 to 168 hours
Cmax (ng/mL)Tmax (hr)AUC0-168 hr (ng∙hr/mL)Cavg,ss 96-168hr (ng/mL) 9.33 ± 2.80134.80 ± 49.171188.41 ± 374.258.05 ± 2.50
Second MILPROSA Vaginal System (n=27, *n=22), 168 to 336 hours
Cmax (ng/mL)Tmax (hr)Cmin (ng/mL)Cavg,ss 168-336hr (ng/mL)AUC168-336 hr (ng∙hr/mL)AUC168inf (ng∙hr/mL)Kel (hr-1)T1/2 (hr) 10.66 ± 2.72206.15 ± 56.336.33 ± 1.808.20 ± 2.151377.59 ± 362.001382.62 ± 387.810.07 ± 0.0210.82 ± 4.27


Progesterone is approximately 95% to 98% bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin.


The mean (± standard deviation) elimination half-life of progesterone delivered by MILPROSA is 10.82 ± 4.27 hours.


Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones, which are conjugated to glucuronide and sulfate metabolites [See Contraindications (4)].


Progesterone undergoes both biliary and renal elimination. Following an intravenous 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 0.1% of unchanged progesterone is excreted in the bile.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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


14.1 Luteal Supplementation During Assisted Reproductive Treatment Trial

A single prospective, randomized, assessor-blind, active concurrently-controlled trial evaluated the efficacy of 10 weeks of treatment with MILPROSA for support of implantation and early pregnancy in infertile women participating in an Assisted Reproductive Technology treatment program. Women were eligible for the trial if there was tubal, idiopathic, male factor, ovulatory dysfunction or endometriosis-linked infertility, documentation of a normal uterine cavity within 1 year of screening, and a source of fresh or frozen sperm meeting standard criteria. Women were not included in the trial if they had conditions which contraindicated the use of progesterone; hypersensitivity or intolerance to silicone; history of pelvic irradiation, endometrial cancer, toxic shock syndrome, more than one failed fresh in vitro fertilization (IVF) cycle, more than two consecutive clinically recognized miscarriages, or HIV/AIDS; uncontrolled hypertension, hyperprolactinemia, or hypothyroidism; body mass index (BMI) greater than 38 kg/m2 , clinically significant endometrial pathology or a communicating hydrosalpinx; and a male partner with non-obstructive azoospermia for couples using fresh sperm.

Prior to IVF with or without intracytoplasmic sperm injection (ICSI), eligible women were started on an ovarian down-regulation protocol which begin during the cycle immediately prior to the embryo transfer cycle. Ovarian stimulation with gonadotropins products was begun once down-regulation was achieved. The length of stimulation was individualized per the trial investigational site’s standard protocol(s), and/or the trial investigator’s clinical judgment. During stimulation, the participating woman was monitored to determine when to trigger ovulation with human chorionic gonadotropin (hCG). Egg retrieval occurred approximately 35 to 37 hours after hCG administration. On the day after egg retrieval, at the time of consent, eligible women were stratified by age and randomized in a 1:1 ratio to MILPROSA, one vaginal insert every week, or the active comparator once daily. Embryo transfer occurred 3 to 5 days after egg retrieval. A serum pregnancy test was conducted 2 weeks after egg retrieval. Women whose serum ß-hCG was less than 5 mIU were discontinued from the study. Those with a serum ß-hCG greater than 5 continued dosing with MILPROSA or active comparator for up to a total of 10 weeks (i.e., through 12 weeks of pregnancy).

Efficacy was assessed by the co-primary endpoints of clinically recognized pregnancy rate, defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks and at 10 weeks post-embryo transfer. The trial randomized 646 infertile women to the MILPROSA vaginal system arm and 651 infertile women to the active control arm. Women receiving MILPROSA were 80% Caucasian, 8% African-American, 5% Hispanic, 5% Asian and between 20 and 42 years of age (mean age 31.7) with a body mass index of 38 kg/m2 or less at screening. Women in the active control arm demonstrated similar demographics.

The primary efficacy analysis set was the modified intent-to-treat population (MITT), which included all women having successful egg retrieval and having at least one dose of progesterone. Women who terminated the study prior to 6 weeks after egg retrieval were considered treatment failures at both 6 and 10 weeks. The clinical pregnancy rates at Weeks 6 and 10 were compared between the MILPROSA arm and the active comparator arm at a one-sided alpha of 0.025. The 95% confidence interval (CI) for the difference in pregnancy rate was calculated using the normal approximation method. Treatment with MILPROSA was declared non-inferior to the active comparator if the lower bound of the 95% CI for the difference in pregnancy rate was greater than -10% based on MITT population. The results with the MILPROSA treatment are shown in Table 3.

Table 3: Clinical Pregnancy Rates in Patients Receiving MILPROSA for Luteal Supplementation and Early Pregnancy While in an Assisted Reproductive Technology Treatment Program (NCT00615251).
6 weeks post-embryo transfer
Clinical Pregnancy: n (%) 310 (48.0%)
Pregnancy rate percentage difference between MILPROSA and comparator 0.8%
95% Confidence Interval for difference vs. comparator (-4.6%, 6.3%)
10 weeks post-embryo transfer
Clinical Pregnancy: n (%) 300 (46.4%)
Pregnancy rate percentage difference between MILPROSA and comparator 1.3%
95% Confidence Interval for difference vs. comparator (-4.1%, 6.7%)

The pregnancy rates at Week 6 and Week 10 post embryo transfer for women treated with MILPROSA were non-inferior to those for women treated with the active comparator.

Women participating in the trial were stratified at randomization by age. The co-primary endpoints of the clinical pregnancy rate at Weeks 6 and 10 post embryo transfer were also evaluated by age groups 18-34 and 35-42.

In women under the age of 35, the pregnancy rates with MILPROSA were 49.3% and 48.2% respectively at Weeks 6 and 10 post embryo transfer and these rates were non-inferior to the rates for women treated with the active comparator and evaluated at the same time points. The trial was insufficiently powered to provide meaningful comparisons for women age 35 and older.

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