Progesterone Vaginal Inserts (Progesterone): Uses, Dosage, Side Effects & Warnings

Uses

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. Progesterone vaginal insert is a progesterone 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( 1 ).

Dosage and administration

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 ( 2.1 ). 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.

Dosage forms and strengths

100 mg vaginal insert is a white to off-white oblong-shaped tablet debossed with “175” on one side and “G” on the other side.
• 100 mg vaginal insert ( 3 )

Contraindications

Progesterone vaginal insert should not be used 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 )]
• Known missed abortion or ectopic pregnancy
• Liver disease
• Known or suspected breast cancer
• Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events
• Previous allergic reactions to progesterone or any of the ingredients of progesterone vaginal insert ( 4 )
• Known missed abortion or ectopic pregnancy ( 4 )
• Liver disease ( 4 )
• Known or suspected breast cancer ( 4 )
• Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events ( 4 )

Warnings and precautions

• Life-threatening arterial or venous thromboembolic disorders may occur during hormone treatment, including treatment with progesterone vaginal insert. Discontinue progesterone vaginal insert if any of these are suspected ( 5.1 )
• Observe patients with a history of depression closely. Consider discontinuation if symptoms worsen ( 5.2 )
• 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 ( 5.3 ) 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 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 Drug Interactions ( 7 )].

Side effects

The most common adverse reactions reported (greater than 2 %) were post-oocyte retrieval pain, abdominal pain, nausea, and ovarian hyperstimulation syndrome ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Body System Progesterone Vaginal Insert 100 mg twice daily (N=404) Progesterone Vaginal Insert 100 mg three times daily (N=404) Preferred Term Gastrointestinal Disorders Abdominal pain 50 (12%) 50 (12%) Nausea 32 (8%) 29 (7%) Abdominal distension 18 (4%) 17 (4%) Constipation 9 (2%) 14 (3%) Vomiting 13 (3%) 9 (2%) General Disorders & Administration Site Conditions Fatigue 7 (2%) 12 (3%) Infections and Infestations Urinary tract infection 9 (2%) 4 (1%) Injury, Poisoning and Procedural Complications Post-oocyte retrieval pain 115 (28%) 102 (25%) Nervous System Disorders Headache 15 (4%) 13 (3%) Reproductive System and Breast Disorders Ovarian hyperstimulation syndrome 30 (7%) 27 (7%) Uterine spasm 15 (4%) 11 (3%) Vaginal bleeding 13 (3%) 14 (3%) 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.

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 )] .

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 livebirths 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 livebirths).
• Among the 404 subjects treated with progesterone vaginal insert three times daily, 155 subjects had livebirths 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 livebirths). 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’s 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.

Pregnancy

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 livebirths 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 livebirths).
• Among the 404 subjects treated with progesterone vaginal insert three times daily, 155 subjects had livebirths 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 livebirths). 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’s 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 )] .

Pediatric use

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.

Geriatric use

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

Overdosage

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

Description

Progesterone Vaginal Insert contains micronized progesterone. 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 empirical formula of C 21 H 30 O 2 and a molecular weight of 314.46. Progesterone exists in two polymorphic forms. The form used in progesterone vaginal insert, the alpha-form, has a melting point of 126°C to 131°C. The structural formula is: C 21 H 30 O 2 Each Progesterone Vaginal Insert delivers 100 mg of progesterone, USP in a base containing adipic acid, colloidal silicone dioxide, lactose monohydrate, magnesium stearate, povidone, pregelatinized corn starch, sodium bicarbonate and sodium lauryl sulfate. structure

Mechanism of action

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.

How supplied

Each Progesterone Vaginal Insert is a white to off-white oblong-shaped tablet debossed with “175” on one side and “G” on the other side. Each Progesterone Vaginal Insert, 100 mg, is packed individually in a blister pack. These blister packs are available in cartons packed:
• 21 vaginal inserts with 21 disposable vaginal applicators (NDC 68462-175-33) 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).

Storage

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).

Patient information

See FDA-Approved Patient Labeling ( 17.4 ) 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 Vaginal Products Inform patients that progesterone vaginal insert is not recommended for use with other vaginal products. 17.4 FDA-Approved Patient Labeling Progesterone (proe jes' ter one) Vaginal Insert

Active ingredients

Progesterone in 1 product

Progesterone Vaginal Inserts NDC products (1)

NDC	Strength & form	Labeler	Type
68462-175	Progesterone 100 mg/1 Insert	Glenmark Pharmaceuticals Inc., USA	ANDA

Frequently asked questions

What is Progesterone Vaginal Inserts used for?

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. Progesterone vaginal insert is a progesterone indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an…

What are the side effects of Progesterone Vaginal Inserts?

The most common adverse reactions reported (greater than 2 %) were post-oocyte retrieval pain, abdominal pain, nausea, and ovarian hyperstimulation syndrome ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely… See the full label for the complete list.

Who makes Progesterone Vaginal Inserts?

Progesterone Vaginal Inserts is listed by 1 labeler in the FDA NDC directory, including Glenmark Pharmaceuticals Inc., USA.