Progesterone Vaginal (Crinone, Prometrium) Package Insert

1 INDICATIONS AND USAGE

Progesterone vaginal insert is indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

The dose of progesterone vaginal insert is 100 mg administered vaginally two or three times daily starting the day after oocyte retrieval and continuing for up to 10 weeks total duration. Efficacy in women 35 years of age and older has not been clearly established. The appropriate dose of progesterone vaginal insert in this age group has not been determined.

3 DOSAGE FORMS AND STRENGTHS

100 mg vaginal insert is a white to off-white oblong-shaped tablet debossed with “FPI” on one side and “100” on the other side.

4 CONTRAINDICATIONS

Progesterone vaginal insert is contraindicated in individuals with any of the following conditions:

• Previous allergic reactions to progesterone or any of the ingredients of progesterone vaginal insert [ see Description (11) ]
• Undiagnosed vaginal bleeding
• Known missed abortion or ectopic pregnancy
• Liver disease
• Known or suspected malignancy of the breast or genital organs
• Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events

5 WARNINGS AND PRECAUTIONS

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. Progesterone vaginal insert 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

Progesterone vaginal insert 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 ADVERSE REACTIONS

6.1 Clinical Studies Experience

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 progesterone vaginal insert 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. progesterone vaginal insert 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 progesterone vaginal insert group are summarized in Table 1.

Table 1: Number and Frequency of Reported Adverse Reactions in Women Treated with Progesterone Vaginal Insert in an Assisted Reproductive Technology Study

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

6.2 Expected Adverse Reaction Profile Seen with Progesterone

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

7 DRUG INTERACTIONS

No formal drug-drug interaction studies have been conducted for progesterone vaginal insert. 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 progesterone vaginal insert has not been assessed. Progesterone vaginal insert 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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Progesterone vaginal insert 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 progesterone vaginal insert 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 live births).
• Among the 404 subjects treated with progesterone vaginal insert three times daily, 155 subjects had live births 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 live births).

Birth defects reported in the progesterone vaginal insert 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 progesterone vaginal insert 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 progesterone vaginal insert and pregnancy outcome information [see Clinical Pharmacology (12)and Clinical Studies Sections (14)] .

8.3 Nursing Mothers

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.

8.4 Pediatric Use

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

8.5 Geriatric Use

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

10 OVERDOSAGE

Treatment of overdosage consists of discontinuation of progesterone vaginal insert together with institution of appropriate symptomatic and supportive care.

11 DESCRIPTION

Progesterone vaginal insert contains micronized progesterone, USP. Progesterone vaginal insert is supplied with polyethylene vaginal applicators.

The active ingredient, progesterone, USP is present in 100 mg amount along with other excipients. The chemical name for progesterone is pregn-4-ene-3,20-dione. It has an molecular formula of C ₂₁H ₃₀O ₂and a molecular weight of 314.5. Progesterone exists in two polymorphic forms. The form used in progesterone vaginal insert, the alpha-form, has a melting point of 127°C to 131°C.

The structural formula is:

Each progesterone vaginal insert delivers 100 mg of progesterone, USP in a base containing lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicon dioxide.

12 CLINICAL PHARMACOLOGY

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

Absorption

Progesterone serum concentrations increased following the administration of the progesterone vaginal insert in 12 healthy pre-menopausal females. On single dosing, the mean Cmax was 17.0 ng/mL in the progesterone vaginal insert twice daily group and 19.8 ng/mL in the progesterone vaginal insert three times daily group. On multiple dosing, steady-state concentrations were attained within approximately 1 day after initiation of treatment with progesterone vaginal insert. Both progesterone vaginal insert 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 _maxMaximum progesterone serum concentration.

T _maxTime to maximum progesterone serum concentration.

C _avgAverage progesterone serum concentration.

AUC _0-24Area under the drug concentration versus time curve from 0 to 24 hours post dose.

C _minMinimum 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 to 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14 CLINICAL STUDIES

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 progesterone vaginal insert (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 progesterone vaginal insert 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 progesterone vaginal insert were non-inferior (lower bounds of the 95% confidence interval of the difference between progesterone vaginal insert 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 Progesterone Vaginal Insert 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 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 4.

Table 4: Ongoing Pregnancy Rates in Age- and Ovarian Reserve-Defined Subgroups Receiving Progesterone Vaginal Insert 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 progesterone vaginal insert 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 progesterone vaginal insert in this patient group is unknown.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each progesterone vaginal insert is a white to off-white oblong-shaped insert debossed with “FPI” on one side and “100” on the other side. Each progesterone vaginal insert, 100 mg, is packed individually in a sealed foil pouch. These pouches are available in cartons packed:

• 21 vaginal inserts with 21 disposable vaginal applicators (NDC 70095-136-03)

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling.

17.1 Vaginal Bleeding

Inform patients of the importance of reporting irregular vaginal bleeding to their doctor as soon as possible.

17.2 Common Adverse Reactions with Progesterone

Inform patients of the possible side effects of progesterone therapy such as headaches, breast tenderness, bloating, mood swings, irritability, and drowsiness.

17.3 Coadministration of Other Vaginal Products

Inform patients that progesterone vaginal insert is not recommended for use with other vaginal products.

MANUFACTURED FOR:

FERRING PHARMACEUTICALS INC.

PARSIPPANY, NJ 07054

DISTRIBUTED BY:

SUN PHARMACEUTICAL INDUSTRIES, INC.

CRANBURY, NJ 08512

Revised: 02/2026