Crinone Gel

Generic Name:

Progesterone Gel

Brand Name Equivalent:

Crinone®

Overview of Crinone Gel

Dosage Strength of Crinone Gel

8% 1.125 g Vaginal Applicator

General Information

Progesterone is a naturally occurring progestin. In the body, it is synthesized in the ovaries, testes, placenta, and adrenal cortex. Progesterone may be given orally, parenterally, or vaginally. The hormone is primarily used to treat amenorrhea and abnormal uterine bleeding, and also to prevent endometrial hyperplasia in postmenopausal women taking estrogen therapy. The drug is sometimes used off-label for premenstrual dysphoric disorder (PMDD), and has historically been used as a contraceptive. Progesterone is also used to prevent early pregnancy failure in women with corpus luteum insufficiency, including women undergoing assisted reproductive technology (ART).123Progesterone also helps reduce the risk for preterm birth in selected patients. In women with single gestation pregnancy and a history of spontaneous preterm delivery, antenatal progesterone therapy effectively decreases the risk of a recurrent preterm delivery. Progesterone supplementation is beneficial in these women starting at 16 to 24 weeks gestation and continuing through 34 weeks gestation. It is not yet clear if the drug is beneficial at reducing risk for preterm birth in multiple gestation pregnancies.456 Progesterone was first marketed medicinally in 1939, which was prior to the modern FDA drug approval process; the injection and various bulk products for extemporaneous compounding of vaginal suppositories and other dosage forms have long been available. A progesterone-containing intrauterine device was available for contraception, but is no longer marketed. In May 1998, oral micronized progesterone capsules were first FDA-approved. In May 1997, a progesterone vaginal gel was FDA-approved for use in an Assisted Reproductive Technology (ART) program; a progesterone vaginal insert used for this purpose was FDA-approved in June 2007.

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 essential for the development of decidual tissue, and the effect of progesterone on the differentiation of glandular epithelia and stroma has been extensively studied. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain the pregnancy. Normal or near-normal endometrial responses to oral estradiol and intramuscular progesterone have been noted in functionally agonadal women through the sixth decade of life. Progesterone administration decreases the circulatory levels of gonadotropins.32

Progesterone can be used to achieve normalized progesterone levels in women with secondary amenorrhea. When a woman does not produce enough progesterone, menstrual irregularities may occur. Progesterone can thus help re-establish normal menstrual cycles in pre-menopausal women with such irregularities.27

The primary role of progesterone when used in the menopausal woman is for a protective effect that reductes the risk of endometrial hyperplasia when used with estrogen in the woman with an intact uterus. Micronized oral progesterone does not appear to have adverse effects on serum lipid profiles when used in regimens for hormone replacement therapy (HRT).7

Progesterone has also been used historically as a contraceptive, including in intrauterine contraceptive devices (IUDs). The primary contraceptive effect of exogenous progestins involves the suppression of the midcycle surge of luteinizing hormone (LH). The exact mechanism of action, however, is unknown. At the cellular level, progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge, thereby preventing follicular maturation and ovulation. Additional mechanisms may be involved in the contraceptive effect. Other actions of progestins include alterations in the endometrium that can impair implantation and an increase in cervical mucus viscosity which inhibits sperm migration into the uterus.

Pharmacokinetics

Progesterone is administered intravaginally (Crinone gel). Once in the systemic circulation, progesterone is extensively (96—99%) bound to cortisol binding globulin, sex hormone binding globulin, and albumin. The drug is metabolized hepatically to pregnanediol and conjugated with glucuronic acid. The plasma elimination half-life ranges 5—20 minutes. The metabolites are excreted primarily in the urine (50—60%). About 10% is eliminated via the bile and feces.

Route-Specific Pharmacokinetics:

Vaginal Route: Following intravaginal administration of progesterone gel, absorption is prolonged with an absorption half-life of approximately 25—50 hours.

Indications

For the treatment of amenorrhea:

Intravaginal dosage (micronized gel): Adult females: Administer the 4% or 8% gel PV every other day up to a total of 6 doses. Use the 8% gel for women who fail to respond to the 4% gel. Note that dosage increases from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed.

For the treatment of infertility or for the prevention of early pregnancy failure† (e.g., miscarriage) in women with corpus luteum insufficiency†: NOTE: The optimal dose and route of progesterone administration has not been determined. Vaginal progesterone is often used preferentially over the intramuscular formulation secondary to comparable efficacy and decreased side effects (e.g., pain at the injection site, sterile abscess formation).8

Vaginal dosage (micronized gel): Adult females: 90 mg (8% gel) PV once daily. In women with partial or complete ovarian failure, a dose of 90 mg intravaginally twice daily is recommended. If pregnancy occurs, treatment may be continued until placental autonomy is achieved, up to 10 to 12 weeks of gestation.

For preterm delivery prophylaxis†:

Vaginal dosage (progesterone 8% vaginal gel): Adult females: 1 applicator (each applicator delivers 1.125 grams gel containing 90 mg progesterone) vaginally once daily at bedtime starting at 16 to 24 weeks gestation and continuing through 34 weeks gestation. Progesterone helps reduce the risk for preterm birth in selected patients. In women with single gestation pregnancy and a history of spontaneous preterm delivery, antenatal progesterone therapy effectively decreases the risk of a recurrent preterm delivery. In one study, vaginal progesterone gel was also associated with a significant reduction in the rate of preterm birth before 28 weeks and 35 weeks, and a significant reduction in the incidence of neonatal respiratory distress syndrome, any neonatal morbidity or mortality event, and birth weight less than 1500 grams.9 It is not yet clear if the drug is routinely beneficial at reducing risk for preterm birth in multiple gestation pregnancies.45106

† Off-label indication

Contraindications/Precautions

Progesterone is contraindicated in patients with pre-existing breast cancer or cancer of reproductive organs, such as cervical cancer, endometrial cancer, ovarian cancer, uterine cancer, or vaginal cancer. Likewise, progesterone formulations should not be used in patients with undiagnosed vaginal bleeding. Progesterone, like other hormones, can influence hormonally-dependent cancers.132711 HORMONE REPLACEMENT THERAPY (HRT): Oral progesterone labeling contains a boxed warning regarding the potential risk for breast cancer (new primary malignancy) in post-menopausal women receiving estrogen and progestin hormonal replacement therapy (HRT).7 The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of estrogen plus progestin.1213 After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups.12 Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.7 Adding a progestin such as progesterone to estrogen HRT has been shown to reduce, but not completely eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen plus progestin HRT is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.7 The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.7

Progesterone products are contraindicated in patients with hepatic disease or known hepatic dysfunction.132711

Progesterone injections are formulated in oil and are for intramuscular use only. Never administer via intravenous administration.11 Oil microembolization, such as pulmonary oil microembolism, may occur if inadvertently administered intravenously, which may result in serious reactions. Some injection formulations are made from sesame oil and are not for use in patients with sesame oil hypersensitivity. Benzyl alcohol is also contained in some injection formulas, so use with caution in patients with benzyl alcohol hypersensitivity.

Progesterone at high doses is an antifertility drug and high doses of progesterone injection would be expected to impair fertility until the cessation of treatment. Women of childbearing age may expect some degree of infertility during treatment with progesterone injection at high doses.11

Select progesterone products are specifically labeled for use to provide luteal support during early pregnancy.132 Animal studies involving oral, vaginal, or in utero administration of progesterone have not indicated evidence of fetal harm. Progesterone vaginal gel may be used to support early pregnancy as part of an Assisted Reproductive Technology (ART) program; if pregnancy occurs, the gel is typically continued for 10 to 12 weeks until placental production of progesterone is adequate to support the pregnancy. Similarly, progesterone vaginal inserts are used for up to 10 weeks in ART. Progesterone should only be used during early pregnancy under the observation of an ART specialist.132 Data suggest that vaginal progesterone is effective in preventing preterm delivery and associated neonatal complications, especially during high-risk singleton pregnancy; administration usually is initiated at 16 to 24 weeks gestation and continues through 34 weeks gestation.451069 Progesterone should not be used if there is ectopic pregnancy, missed/ incomplete abortion, or during diagnostic tests for pregnancy.13211 Progesterone capsules are only indicated in postmenopausal women, and thus this dosage form is specifically contraindicated for use during pregnancy.7

Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the breast-feeding infant has not been determined.132711 In general, use of progestins has not had adverse effects on lactation.14 Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for progesterone and the potential adverse effects on the breast-fed infant.

The safety and effectiveness of progesterone formulations have not been established in children or infants. The safety and efficacy of progesterone have only been established in females of reproductive age. Use of progesterone in female children before menarche is not usually indicated. In neonates, inadvertent exposure to progesterone injections, which may contain benzyl alcohol, can result in a "gasping syndrome".

Progesterone is contraindicated in patients with a history of thrombophlebitis, active or previous history of thromboembolism or thromboembolic disease (including stroke and myocardial infarction). Patients with risk factors for heart disease, thromboembolism, and stroke (e.g., known cerebrovascular disease, hypertension, diabetes mellitus, tobacco smoking, hypercholesterolemia, obesity, etc.) should be monitored closely and managed appropriately. During use of progesterone in patients without a history of thrombosis, the provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, heart attack, cerebrovascular disorder such as stroke or focal headache with symptoms consistent with cerebral ischemia, pulmonary embolism, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, progesterone therapy should be discontinued immediately.132711 HORMONAL REPLACEMENT THERAPY (HRT): Progesterone, when used with estrogen therapy for postmenopausal hormone replacement, is associated with cardiovascular and thromboembolic risks, which are highlighted in the oral progesterone boxed warnings. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with estrogen-progestin therapy, relative to placebo.7 In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT vs. women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.1513 Estrogens with or without a progestin such as progesterone should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease) in postmenopausal women. In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.13 16 Studies have also shown no cardiovascular benefit to the use of estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.1718 In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke.19137

Progesterone should be used cautiously in patients with diabetes mellitus. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. There are possible risks which may be associated with the use of progestin treatment, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects. Use with caution in patients with known hyperlipidemia.

Progesterone should be prescribed cautiously in patients with asthma, congestive heart failure, nephrotic syndrome or other renal disease, or cardiac disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions.

Progesterone should be used cautiously in patients with a history of major depression, migraine, or seizure disorder. Progestins may exacerbate these conditions in some patients. If a patient receiving progesterone develops changes in migraine patterns, or a focal migraine with symptoms consistent with cerebral ischemia, or a severe headache pattern that may indicate a cerebrovascular disorder, consider discontinuation of the drug. Some cases of seizures following administration of progestins have been reported.

An intrauterine device containing progesterone should not be used if there is any infection or inflammation in the female reproductive tract. There is a risk of infection progressing to pelvic inflammatory disease. Exposure to sexually transmitted disease also increases this risk.

Progesterone may cause transient dizziness in some patients. Use caution when driving or operating machinery.

Estrogen/progestin combination therapy has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).207

Pregnancy

Select progesterone products are specifically labeled for use to provide luteal support during early pregnancy.132 Animal studies involving oral, vaginal, or in utero administration of progesterone have not indicated evidence of fetal harm. Progesterone vaginal gel may be used to support early pregnancy as part of an Assisted Reproductive Technology (ART) program; if pregnancy occurs, the gel is typically continued for 10 to 12 weeks until placental production of progesterone is adequate to support the pregnancy. Similarly, progesterone vaginal inserts are used for up to 10 weeks in ART. Progesterone should only be used during early pregnancy under the observation of an ART specialist.132 Data suggest that vaginal progesterone is effective in preventing preterm delivery and associated neonatal complications, especially during high-risk singleton pregnancy; administration usually is initiated at 16 to 24 weeks gestation and continues through 34 weeks gestation.451069 Progesterone should not be used if there is ectopic pregnancy, missed/ incomplete abortion, or during diagnostic tests for pregnancy.13211

Breast-feeding

Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the breast-feeding infant has not been determined.132711 In general, use of progestins has not had adverse effects on lactation.14 Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for progesterone and the potential adverse effects on the breast-fed infant.

Adverse Reactions/Side Effects

The most common adverse reactions occurring during therapy with progesterone include menstrual irregularity, menstrual flow changes, and dysmenorrhea or amenorrhea. These effects may be indistinguishable from pregnancy. Progesterone also causes spotting, breakthrough bleeding, weight gain, nausea, vomiting, breast tenderness or mastalgia, and mild headache. These adverse effects occur less frequently with progestin-only OCs compared to combination OCs. Other reported adverse reactions during therapy include melasma, chloasma, libido decrease, libido increase, breast discharge, cervicitis, galactorrhea, hirsutism, leukorrhea, unusual weakness, and vaginitis. Post-marketing experiences with oral progesterone include endometrial carcinoma, hypospadia, intra-uterine death, menorrhagia, menstrual disorder, metorrhagia, ovarian cyst, and spontaneous fetal abortion.21Additional adverse reactions associated with the intravaginal gel include breast enlargement, dyspareunia, nocturia, perineal pain, dysmenorrhea, premenstrual tension, vaginal dryness, and vaginal discharge.2 Adverse reactions associated with vaginal inserts include vaginal irritation, vaginal itching, vaginal burning, and vaginal pain/discomfort.1

Fluid retention and/or edema may occur in patients receiving progesterone. Patients with heart failure and/or renal disease may experience an exacerbation of their condition. Post-marketing reports of adverse reactions with oral progesterone include facial edema, circulatory collapse, congenital heart disease, hypertension, hypotension, and sinus tachycardia.21

Patients receiving progesterone or other hormonal contraceptives can experience emotional lability. This adverse effect may be manifest as mental depression, anxiety, frustration, irritability, anger, or other emotional outbursts. Additional CNS and psychiatric adverse events reported include insomnia, aggression, forgetfulness, migraine, tremor, headache, dizziness, drowsiness, and fatigue. Post-marketing experience reports include convulsions, depersonalization, disorientation, dysarthria, loss of consciousness, paresthesias, sedation, stupor, difficulty walking, syncope, transient ischemic attack, suicidal ideation, and feeling drunk.21

The insertion of an intrauterine device (IUD) containing progesterone may result in infection. The risk of infection is greatest within the first 20 days after insertion. Untreated infection may lead to pelvic inflammatory disease, which requires removal of the system and appropriate antibiotic treatment. The patient's partner may also require antibiotic treatment. Uterine pain may follow initial insertion of the progesterone IUD and usually responds to analgesic therapy. Pain should not persist for more than a few hours after IUD insertion.1

During use of progesterone, the provider should be alert to the earliest manifestations of a thrombotic disorder (e.g., thrombophlebitis, deep vein thrombosis, migraine /headache or other neurologic event with focal symptoms that suggest cerebral ischemia, pulmonary embolism, heart attack, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, progesterone therapy should be discontinued immediately.713211HORMONAL REPLACEMENT THERAPY (HRT): Progesterone, when used with estrogen therapy for postmenopausal hormone replacement, is associated with cardiovascular and thromboembolism risks in postmenopausal women, which are highlighted in the oral progesterone boxed warnings. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with estrogen-progestin therapy, relative to placebo.7 In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT vs. women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.1513 Estrogens with or without a progestin such as progesterone should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease) in postmenopausal women. In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.13 16 Studies have also shown no cardiovascular benefit to the use of estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.1718 In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke.19137

Intramuscular administration of progesterone often causes an injection site reaction. Adverse local reactions include erythema, irritation, pain, and swelling at the site of injection. More general dermatological events have been reported and include alopecia, pruritus, urticaria, acne vulgaris, rash (unspecified), seborrhea, skin discoloration, fever, and hot flashes. Anaphylactoid reactions and hypersensitivity, including dyspnea, rhinitis, asthma, hyperventilation, and throat tightness have been reported.212

Gastrointestinal (GI) adverse reactions reported with progesterone use include abdominal pain, bloating, nausea, vomiting, dyspepsia, eructation, flatulence, diarrhea, constipation, anorexia, appetite stimulation, and weight loss.713211 Gastritis and dysphagia have been reported with oral progesterone capsules and acute pancreatitis, hepatic failure, hepatic necrosis, hepatitis, and swollen tongue (glossitis) were reported postmarketing.7

Adverse reactions reported with progesterone use include abnormal gait, arthralgia, choking (with oral formulations), cleft lip, cleft palate, tinnitus, vertigo, cystitis, dysuria, increased urinary frequency, leg pain, musculoskeletal pain, flu-like symptoms, xerophthalmia, benign cyst, purpura, anemia, infection, pharyngitis, sinusitis, urinary tract infection, and conjunctivitis.212

Estrogen/progestin combination hormone replacement therapy (HRT) has been found to fail to prevent mild impaired cognition (memory loss) and to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).207

The issue of hormonal influences on the development of cancers (new primary malignancy) has been widely researched for many decades. The risks of various cancers for progestins used for infertility or for short term treatment of irregular uterine bleeding are expected to differ from the risks associated with postmenopausal hormone replacement therapy (HRT). Undiagnosed vaginal bleeding should be evaluated in any patient using progesterone as is clinically appropriate, since female genital cancers may be influenced by hormonal therapy. HORMONE REPLACEMENT THERAPY POSTMENOPAUSE: Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. The Women's Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. Due to breast cancer and other cancer risks, combined HRT should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.713222324 There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Among combined estrogen/progestin HRT users, roughly 10% will have some endometrial thickening. Postmarketing reports of endometrial hyperplasia have been reported in women receiving combined estrogen/progestin HRT; however, the incidence of endometrial hyperplasia is estimated to be 1% or less in these patients.7242513 Women who used HRT for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use. The contraindications and precautions sections for progesterone HRT product labels more fully discuss the data and what is known about HRT use with respect to risks for various cancers.713222324

Storage

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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