DOSAGE & ADMINISTRATION SECTION

DOSAGE AND ADMINISTRATION

Prevention of Endometrial Hyperplasia

Progesterone capsules should be given as a single daily dose at bedtime, 200 mg orally for 12 days sequentially per 28-day cycle, to a postmenopausal woman with a uterus who is receiving daily conjugated estrogens tablets.

Treatment of Secondary Amenorrhea

Progesterone capsules may be given as a single daily dose of 400 mg at bedtime for 10 days.

Some women may experience difficulty swallowing progesterone capsules. For these women, progesterone capsules should be taken with a glass of water while in the standing position.

PRECAUTIONS SECTION

PRECAUTIONS

A. General

1. Addition of a progestin when a woman has not had a hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared with estrogen-alone regimens. These include an increased risk of breast cancer.

2. Fluid Retention

Progesterone may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation.

3. Dizziness and Drowsiness

Progesterone capsules may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery. Progesterone capsules should be taken as a single daily dose at bedtime.

B. Patient Information

General: This product contains peanut oil and should not be used if you are allergic to peanuts.

Physicians are advised to discuss the contents of the Patient Information leaflet with patients for whom they prescribe progesterone capsules.

C. Drug-Laboratory Test Interactions

The following laboratory results may be altered by the use of estrogen plus progestin therapy:

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Increased sulfobromophthalein retention and other hepatic function tests. 

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Coagulation tests: increase in prothrombin factors VII, VIII, IX and X. 

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Pregnanediol determination. 

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Thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values.

D. Carcinogenesis, Mutagenesis, Impairment of Fertility

Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumors and endometrial stromal sarcomas. In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumors. Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumors in rats previously treated with a chemical carcinogen.

Progesterone did not show evidence of genotoxicity in in vitro studies for point mutations or for chromosomal damage. In vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Exogenously administered progesterone has been shown to inhibit ovulation in a number of species and it is expected that high doses given for an extended duration would impair fertility until the cessation of treatment.

E. Pregnancy

Progesterone capsules should not be used during pregnancy. (See CONTRAINDICATIONS).

Pregnancy Category B: Reproductive studies have been performed in mice at doses up to 9 times the human oral dose, in rats at doses up to 44 times the human oral dose, in rabbits at a dose of 10 mcg/day delivered locally within the uterus by an implanted device, in guinea pigs at doses of approximately one-half the human oral dose and in rhesus monkeys at doses approximately the human dose, all based on body surface area, and have revealed little or no evidence of impaired fertility or harm to the fetus due to progesterone.

F. Nursing Women

Detectable amounts of progestin have been identified in the milk of nursing women receiving progestins. Caution should be exercised when progesterone capsules are administered to a nursing woman.

G. Pediatric Use

Progesterone capsules are not indicated in children. Clinical studies have not been conducted in the pediatric population.

H. Geriatric Use

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing progesterone capsules to determine whether those over 65 years of age differ from younger subjects in their response to progesterone capsules.

The Women's Health Initiative Study

In the Women's Health Initiative (WHI) estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (SeeCLINICAL STUDIES andWARNINGS, Cardiovascular disorders andMalignant neoplasms.)

The Women's Health Initiative Memory Study

In the Women's Health Initiative Memory Study (WHIMS) of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in the estrogen plus progestin ancillary study when compared to placebo. (SeeCLINICAL STUDIES andWARNINGS, Probable dementia.)

ADVERSE REACTIONS SECTION

ADVERSE REACTIONS

SeeBOXED WARNING,WARNINGS andPRECAUTIONS.

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.

In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the effects of progesterone capsules on the endometrium was studied in a total of 875 postmenopausal women. Table 6 lists adverse reactions greater than or equal to 2 percent of women who received cyclic progesterone capsules 200 mg daily (12 days per calendar month cycle) with 0.625 mg conjugated estrogens or placebo.

Effects on Secondary Amenorrhea

In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the effects of progesterone capsules on secondary amenorrhea was studied in 49 estrogen-primed postmenopausal women. Table 7 lists adverse reactions greater than or equal to 5 percent of women who received progesterone capsules or placebo.

In a multicenter, parallel-group, open label postmarketing dosing study consisting of three consecutive 28-day treatment cycles, 220 premenopausal women with secondary amenorrhea were randomized to receive daily conjugated estrogens therapy (0.625 mg conjugated estrogens) and progesterone capsules, 300 mg per day (n=113) or progesterone capsules, 400 mg per /day (n=107) for 10 days of each treatment cycle. Overall, the most frequently reported treatment-emergent adverse reactions, reported in greater than or equal to 5 percent of subjects, were nausea, fatigue, vaginal mycosis, nasopharyngitis, upper respiratory tract infection, headache, dizziness, breast tenderness, abdominal distension, acne, dysmenorrhea, mood swing, and urinary tract infection.

Postmarketing Experience:

The following additional adverse reactions have been reported with progesterone capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Genitourinary System: endometrial carcinoma, hypospadia, intra-uterine death, menorrhagia, menstrual disorder, metrorrhagia, ovarian cyst, spontaneous abortion.

Cardiovascular: circulatory collapse, congenital heart disease (including ventricular septal defect and patent ductus arteriosus), hypertension, hypotension, tachycardia.

Gastrointestinal: acute pancreatitis, cholestasis, cholestatic hepatitis, dysphagia, hepatic failure, hepatic necrosis, hepatitis, increased liver function tests (including alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased), jaundice, swollen tongue.

Skin: alopecia, pruritus, urticaria.

Eyes: blurred vision, diplopia, visual disturbance.

Central Nervous System: aggression, convulsion, depersonalization, depressed consciousness, disorientation, dysarthria, loss of consciousness, paresthesia, sedation, stupor, syncope (with and without hypotension), transient ischemic attack, suicidal ideation.

During initial therapy, a few women have experienced a constellation of many or all of the following symptoms: extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk, and shortness of breath.

Miscellaneous: abnormal gait, anaphylactic reaction, arthralgia, blood glucose increased, choking, cleft lip, cleft palate, difficulty walking, dyspnea, face edema, feeling abnormal, feeling drunk, hypersensitivity, asthma, muscle cramp, throat tightness, tinnitus, vertigo, weight decreased, weight increased.

SPL PATIENT PACKAGE INSERT SECTION

PATIENT INFORMATION

Progesterone Capsules (proe-JES-ter-own)

Read this PATIENT INFORMATION before you start taking progesterone capsules and read what you get each time you refill your progesterone capsules prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Progestins with estrogens should not be used to prevent heart disease, heart attacks, strokes, or dementia. 

Using progestins with estrogens may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots.

Using progestins with estrogens may increase your chance of getting dementia, based on a study of women age 65 and older.

You and your healthcare provider should talk regularly about whether you still need treatment with progesterone capsules.

THIS PRODUCT CONTAINS PEANUT OIL AND SHOULD NOT BE USED IF YOU ARE ALLERGIC TO PEANUTS.

What is progesterone capsules?

Progesterone capsules contain the female hormone called progesterone.

What is progesterone capsules used for?

Treatment of Menstrual Irregularities

Progesterone capsules are used for the treatment of secondary amenorrhea (absence of menstrual periods in women who have previously had a menstrual period) due to a decrease in progesterone. When you do not produce enough progesterone, menstrual irregularities can occur. If your healthcare provider has determined your body does not produce enough progesterone on its own, progesterone capsules may be prescribed to provide the progesterone you need.

Protection of the Endometrium (Lining of the Uterus)

Progesterone capsules are used in combination with estrogen-containing medications in a postmenopausal woman with a uterus (womb). Taking estrogen- alone increases the chance of developing a condition called endometrial hyperplasia that may lead to cancer of the lining of the uterus (womb). The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb).

Who should not take progesterone capsules?

Do not start taking progesterone capsules if you:

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**Are allergic to peanuts**

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**Have unusual vaginal bleeding**

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**Currently have or have had certain cancers**   

Estrogen plus progestin treatment may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should take progesterone capsules.

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**Had a stroke or heart attack**

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**Currently have or have had blood clots**

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**Currently have or have had liver problems**

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**Are allergic to progesterone capsules or any of its ingredients**   

See the list of ingredients in progesterone capsules at the end of this leaflet.

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**Think you may be pregnant**

Tell your healthcare provider:

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**If you are breastfeeding.** The hormone in progesterone capsules can pass into your breast milk. 

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**About all of your medical problems.** Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, or kidneys, or have high calcium levels in your blood.

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**About all the medicines you take.** This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how progesterone capsules work. Progesterone capsules may also affect how your other medicines work.

How should I take progesterone capsules?

Prevention of Endometrial Hyperplasia: A post-menopausal woman with a uterus who is taking estrogens should take a single daily dose of 200 mg progesterone capsules at bedtime for 12 continuous days per 28-day cycle.

Secondary Amenorrhea: Progesterone capsules may be given as a single daily dose of 400 mg at bedtime for 10 days.

**Progesterone capsules are to be taken at bedtime as some women become very drowsy and/or dizzy after taking progesterone capsules. In a few cases, symptoms may include blurred vision, difficulty speaking, difficulty with walking, and feeling abnormal. If you experience these symptoms, discuss them with your healthcare provider right away.**

If you experience difficulty in swallowing progesterone capsules, it is recommended that you take your daily dose at bedtime with a glass of water while in the standing position.

What are the possible side effects of progesterone capsules?

Side effects are grouped by how serious they are and how often they happen when you are treated:

** Serious, but less common side effects include:**

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**Risk to the Fetus:** Cases of cleft palate, cleft lip, hypospadias, ventricular septal defect, patent ductus arteriosus, and other congenital heart defects.

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**Abnormal Blood Clotting:** Stroke, heart attack, pulmonary embolus, visual loss or blindness.

Some of the warning signs of serious side effects include:

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Changes in vision or speech

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Sudden new severe headaches

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Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

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Dizziness and faintness

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Vomiting

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptoms that concern you.

Less serious, but common side effects include:

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Headaches

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Breast pain

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Irregular vaginal bleeding or spotting

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Stomach or abdominal cramps, bloating

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Nausea and vomiting

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Hair loss

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Fluid retention

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Vaginal yeast infection

These are not all the possible side effects of progesterone capsules. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to Xiromed, LLC at 1-844-XIROMED (1-844-947-6633) or to FDA at 1-800-FDA-1088.

What can I do to lower my chances of getting a serious side effect with progesterone capsules?

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Talk with your healthcare provider regularly about whether you should continue taking progesterone capsules.

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See your healthcare provider right away if you get unusual vaginal bleeding while taking progesterone capsules.

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Have a pelvic exam, breast exam, and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.

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If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease.

General information about safe and effective use of progesterone capsules

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Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take progesterone capsules for conditions for which it was not prescribed.

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Your healthcare provider has prescribed this drug for you and you alone. Do not give progesterone capsules to other people, even if they have the same symptoms you have. It may harm them.

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Progesterone capsules should be taken as a single daily dose at bedtime. Some women may experience extreme dizziness and/or drowsiness during initial therapy. In a few cases, symptoms may include blurred vision, difficulty speaking, difficulty with walking, and feeling abnormal. If you experience these symptoms, discuss them with your healthcare provider right away.

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Use caution when driving a motor vehicle or operating machinery as dizziness or drowsiness may occur.

Keep progesterone capsules out of the reach of children.

This leaflet provides a summary of the most important information about progesterone capsules. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about progesterone capsules that is written for health professionals. You can get more information by calling the toll free number 1-844-XIROMED (1-844-947-6633).

What are the ingredients in progesterone capsules?

Active ingredient: 100 mg or 200 mg micronized progesterone

Inactive ingredients: peanut oil, gelatin, glycerin, soya lecithin, titanium dioxide, and triglycerides medium chain.

HOW SUPPLIED

Progesterone capsules, 100 mg are off-white, ovoid, capsules with "PR1" marked.

NDC 70700-162-01, Bottle of 100 capsules.

Progesterone capsules, 200 mg are off-white, ovoid, capsules with "PR2" marked.

NDC70700-163-01, Bottle of 100 capsules.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Protect from excessive moisture. Dispense in tight, light-resistant container as defined in USP.

Manufactured for:
Xiromed LLC, Florham Park, NJ 07932

Product of Spain

Rev: April 2020
PI-162-00