Endometrin (progesterone) Vaginal Insert contains micronized progesterone. Endometrin is supplied with polyethylene vaginal applicators.

The active ingredient, progesterone, 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 C₂₁H₃₀O₂ and a molecular weight of 314.5. Progesterone exists in two polymorphic forms. The form used in Endometrin, the alpha-form, has a melting point of 127-131°C.

The structural formula is:

Each Endometrin Vaginal Insert delivers 100 mg of progesterone in a base containing lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide.

Endometrin 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.

General Dosing Information

The dose of Endometrin 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 Endometrin 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 “FPI” on one side and “100” on the other side.

Storage And Handling

Each Endometrin Vaginal Insert is a white to off-white oblong-shaped insert debossed with “FPI” on one side and “100” on the other side. Each Endometrin® (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 55566-6500-3)

Store at 25°C (77°F); excursions permitted between 15-30°C (59-86°F).

Manufactured by: Pharmaceutics International Inc., Hunt Valley, MD 21031, Manufactured for: Ferring Pharmaceuticals Inc., Parsippany, NJ 07054. FDA revision date: 2/26/2008

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 Endometrin 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. Endometrin 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 Endometrin group are summarized in Table 1.

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

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

Expected Adverse Reaction Profile Seen with Progesterone

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

No formal drug-drug interaction studies have been conducted for Endometrin. 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 Endometrin has not been assessed. Endometrin 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].

Included as part of the PRECAUTIONS section.

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. Endometrin should be discontinued if any of these are suspected.

Depression

Patients with a history of depression need to be closely observed. Consider discontinuation if symptoms worsen.

Use of Other Vaginal Products

Endometrin 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].

Patient Counseling Information

See FDA-Approved Patient Labeling

Vaginal Bleeding

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

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.

Coadministration of Vaginal Products

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

Nonclinical 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.

Use In Specific Populations

Pregnancy

Endometrin has been used to support embryo implantation and maintain clinical pregnancy in one clinical study. The livebirth outcomes of these pregnancies were as follows:

• Among the 404 subjects treated with Endometrin 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 Endometrin 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 Endometrin 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 Endometrin 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 Endometrin and pregnancy outcome information [see CLINICAL PHARMACOLOGY and Clinical Studies Sections ].

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.

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 Endometrin in pediatric patients have not been established.

Geriatric Use

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

Treatment of overdosage consists of discontinuation of Endometrin together with institution of appropriate symptomatic and supportive care.

Endometrin should not be used in individuals with any of the following conditions:

• Previous allergic reactions to progesterone or any of the ingredients of Endometrin [see DESCRIPTION]
• 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

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.

Pharmacokinetics

Absorption

Progesterone serum concentrations increased following the administration of the Endometrin Vaginal Insert in 12 healthy pre-menopausal females. On single dosing, the mean Cmax 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

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.

Clinical Studies

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

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 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.

FDA-Approved Patient Labeling

IMPORTANT: For Vaginal Use Only.

Read the patient information that comes with Endometrin before you start to use it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. Your doctor may do a physical exam before prescribing Endometrin.

What is Endometrin?

Endometrin is a vaginal insert that contains the hormone progesterone. Endometrin is for women who need extra progesterone while undergoing treatment in an Assisted Reproductive Technology (ART) program. Progesterone is one of the hormones essential for helping you to become and to stay pregnant. If you are undergoing ART treatment, your doctor may prescribe Endometrin to provide the progesterone your body needs.

Who should not use Endometrin?

Do not use Endometrin if you:

• Are allergic to anything in Endometrin. See the end of this leaflet for a complete list of ingredients.
• Have unusual vaginal bleeding that has not been evaluated by a doctor.
• Currently have or have had liver problems.
• Have or have had blood clots in the legs, lungs, eyes, or elsewhere in your body.

Endometrin may not be right for you. Before starting Endometrin, tell your doctor about all your health problems.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vaginal products, vitamins, herbal supplements. Some medicines may affect Endometrin.

Know what medicines you take. Keep a list of your medicines to show to the doctor and pharmacist.

How should I use Endometrin?

• Use Endometrin exactly as prescribed. The usual dose of Endometrin is one insert placed in your vagina 2 to 3 times a day for up to a total of 10 weeks, unless your healthcare provider advises otherwise.
• Place an Endometrin insert in your vagina with the disposable applicator provided.

Follow the steps below:

1. Unwrap the applicator.
2. Put one insert in the space provided at the end of the applicator. The insert should fit snugly and not fall out.
3. Place applicator with the insert into the vagina while you are standing, sitting, or when lying on your back with your knees bent. Gently place the thin end of the applicator well into the vagina.
4. Push the plunger to release the insert.
5. Remove the applicator and throw it away in the trash.

Other information for using Endometrin

• If you forget a dose of Endometrin, take the dose as soon as you remember, but do not use more than your daily dose.
• Call your doctor if you use too much Endometrin.
• Do not use any other vaginal products when you are using Endometrin.

What are the possible side effects of Endometrin?

Common side effects seen with ART and Endometrin included pelvic pain after surgery, abdominal pain, nausea, and swollen ovaries (ovarian hyperstimulation syndrome).

Other reported side effects included abdominal bloating, headache, urinary infections, uterine cramping, constipation, vomiting, tiredness, and vaginal bleeding.

Vaginal products with progesterone may also cause vaginal irritation, burning, and discharge.

Serious Risks of Progesterone

Progesterone can increase your chance of getting blood clots. Blood clots can be serious and lead to death.

Serious blood clots include those in the:

• legs (thrombophlebitis)
• lungs (pulmonary embolus)
• eyes (blindness)
• heart (heart attack)
• brain (stroke)

Call your doctor or get medical help right away if you have:

• persistent pain in the lower leg (calf)
• sudden shortness of breath
• coughing up blood
• sudden blindness, partial or complete
• severe chest pain
• sudden, severe headache, vomiting, dizziness, or fainting
• weakness in an arm or leg, or trouble speaking
• yellowing of the skin and/or white of the eyes indicating possible liver problem

Other risks of progesterone use include:

• headache
• breast tenderness
• bloating or fluid retention
• mood swings and depression
• irritability
• drowsiness

Call your doctor immediately if you have abnormal vaginal bleeding

These are not all the side effects with Endometrin. Ask your doctor or pharmacist for more information.

How should I store Endometrin?

• Store Endometrin at room temperature, 25°C (77°F); excursions permitted between 15 to 30°C (59 to 86°F).
• Do not use Endometrin after the expiration date that is printed on the carton.
• Keep Endometrin and all medicines out of the reach of children.

General information about Endometrin

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use Endometrin for a condition for which it was not prescribed. Do not give Endometrin to other women, even if they have the same condition as you do. It may harm them.

This leaflet summarizes the most important information about Endometrin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Endometrin that was written for healthcare professionals. For more information call Ferring Pharmaceuticals at 1-800-822-8214.

What are the ingredients in Endometrin?

Active Ingredient: progesterone

Inactive Ingredients: lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PROGESTERONE SUPPOSITORY - VAGINAL

(pro-JESS-ter-own)

COMMON BRAND NAME(S): Endometrin

USES: This medication contains a female hormone called progesterone. Progesterone is needed to prepare the lining of the uterus so it can receive a fertilized egg. Progesterone and other hormones help you become and stay pregnant. This medication is used to increase the level of progesterone in women taking fertility treatments because these treatments tend to decrease progesterone levels.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using this drug and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

This medication is for vaginal use only. Unwrap the suppository. Following the instructions, use the applicator to insert this medication into the vagina, usually 2 or 3 times a day as directed by your doctor. If you become pregnant, continue to use this medication for up to a total of 10 weeks or as directed by your doctor.

Dosage is based on your medical condition and response to treatment.

To get the most benefit from this medication, use it regularly at evenly spaced intervals. To help you remember, use it at the same times each day.

SIDE EFFECTS: Bloating, stomach/abdominal pain, nausea, breast tenderness, headache, drowsiness, mood swings, irritability, or vaginal discomfort may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual vaginal bleeding, severe mental/mood changes (e.g., depression), swelling ankles/feet, yellowing eyes/skin, breast lumps.

This medication may rarely cause very serious problems from blood clots (e.g., heart attack, stroke, blood clots in the lungs/legs, blindness). Seek immediate medical attention if you have any of the following symptoms: chest/jaw/left arm pain, weakness on one side of the body, slurred speech, difficulty walking, sudden vision/eye changes (e.g., blurred/double vision, loss of vision, bulging eyes), confusion, sudden severe headache, severe dizziness, fainting, trouble breathing, coughing up blood, pain/redness/swelling/weakness of the arms/legs, calf pain/swelling that is warm to the touch.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the tongue/lips/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using progesterone, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: history of blood clots, recent stroke or heart attack (within 1 year), liver disease, cancer of the breast or other female organs, vaginal bleeding of unknown cause, a loss of pregnancy with some tissue remaining in the uterus ("missed abortion"), an abnormal pregnancy where the fertilized egg is outside of the uterus (ectopic pregnancy).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, heart disease (e.g., past heart attacks, congestive heart failure), high blood pressure, seizures, migraine headaches, asthma, depression, diabetes, strokes, high level of fats in the blood (high cholesterol/triglycerides).

This drug may make you drowsy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcohol because it may worsen this side effect. In general, alcohol is not recommended if you are pregnant or think you are pregnant because it can harm the baby.

Although unlikely, blood clots may occur with this medication. Your risk is increased if you have surgery or if you stay in a chair or bed for a long time (e.g., a long plane flight). Tell your doctor beforehand of any of these events because you may need special precautions.

This medication may be used during pregnancy, but only as directed by your doctor. Discuss the risks and benefits with your doctor.

This drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs affecting liver enzymes that remove progesterone from your body (such as rifampin, St. John's wort, azole antifungals including itraconazole, certain anti-seizure medicines including carbamazepine/phenobarbital/phenytoin).

Do not use other vaginal products during treatment with this medication unless otherwise directed by your doctor. Doing so may affect how well the drug is absorbed by your body.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: This medicine may be harmful if swallowed. If swallowing or overdose is suspected, contact your poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Keep all medical and laboratory appointments.

MISSED DOSE: If you miss a dose, use it as soon as you remember. However, do not use more doses in a day than prescribed. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C). Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.