These highlights do not include all the information needed to use ESTRADIOL AND PROGESTERONE CAPSULES safely and effectively. See full prescribing information for ESTRADIOL AND PROGESTERONE CAPSULES. ESTRADIOL and PROGESTERONE capsules, for oral use Initial U.S. Approval: 2018

Estradiol and Progesterone by

Drug Labeling and Warnings

Estradiol and Progesterone by is a Prescription medication manufactured, distributed, or labeled by Amneal Pharmaceuticals NY LLC, Amneal Pharmaceuticals of New York, LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

ESTRADIOL AND PROGESTERONE- estradiol and progesterone capsule 
Amneal Pharmaceuticals NY LLC

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FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause

2 DOSAGE AND ADMINISTRATION

The timing of estradiol and progesterone capsule initiation can affect the overall risk-benefit profile. Consider initiating estradiol and progesterone capsules in women < 60 years old or < 10 years from onset of menopause [see Warnings and Precautions (5), Adverse Reactions (6.1), Use in Specific Populations (8.5) and Clinical Studies (14)].

Take a single estradiol and progesterone capsule orally each evening with food. Generally, start therapy with estradiol and progesterone capsules, 0.5 mg/100 mg dosage strength. Make dosage adjustment based on the clinical response. Attempt to taper or discontinue estradiol and progesterone capsules at 3 to 6 month intervals.

3 DOSAGE FORMS AND STRENGTHS

Estradiol and progesterone capsules, 1 mg/100 mg, are oval shaped, opaque, pink soft gelatin capsules, printed with “1A1”.

4 CONTRAINDICATIONS

Estradiol and progesterone capsules are contraindicated in women with any of the following conditions:

• Abnormal genital bleeding of unknown etiology [see Warnings and Precautions (5.2)].
• Breast cancer or a history of breast cancer [see Warnings and Precautions (5.2)].
• Estrogen-dependent neoplasia [see Warnings and Precautions (5.2)].
• Active deep vein thrombosis (DVT), pulmonary embolism (PE), or history of these conditions [see Warnings and Precautions (5.1)].
• Active arterial thromboembolic disease (for example, stroke, myocardial infarction (MI)), or a history of these conditions [see Warnings and Precautions (5.1)].
• Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol and progesterone capsules or any of its ingredients.
• Hepatic impairment or disease [see Warnings and Precautions (5.8)].
• Known thrombophilic disorders, such as protein C, protein S, or antithrombin deficiency.

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Disorders

Estradiol and progesterone capsules are contraindicated in females with active DVT, PE, arterial thromboembolic disease (e.g., stroke, MI) disease, or a history of these conditions [see Contraindications (4)]. Immediately discontinue estradiol and progesterone capsules if a PE, DVT, stroke, or MI occurs or is suspected.

If feasible, discontinue estradiol and progesterone capsules at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

The safety and efficacy of estradiol and progesterone capsules for the prevention of cardiovascular disorders has not been established [see Clinical Studies (14.4)].

The Women’s Health Initiative (WHI) estrogen plus progestin trial reported increased risks of PE, DVT, stroke, and MI in postmenopausal women (50 to 79 years of age, average age 63.4 years) during the 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. Analyses were also conducted in women aged 50 to 59 years, a group of women more likely to present with new onset of moderate to severe VMS compared to women in other age groups in the trial [see Clinical Studies (14.4)].

Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin trial of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products.

Venous Thromboembolism

In women aged 50 to 59 years, the WHI estrogen plus progestin trial reported a relative risk for PE of 2.05 (95% confidence interval [CI], 0.89 to 4.71) for CE/MPA compared to placebo, with a risk difference of 6 per 10,000 women-years (WYs; 11 versus 5). The relative risk for DVT was 3.01 (95% CI, 1.36 to 6.66) in those receiving CE/MPA compared to placebo, with a risk difference of 10 per 10,000 WYs (15 versus 5) [see Clinical Studies (14.4)].

In the overall study population of women aged 50 to 79 years (average 63.4 years), the trial reported a relative risk for PE of 1.98 (95% CI, 1.36 to 2.87) for CE/MPA compared to placebo, with a risk difference of 9 per 10,000 WYs (18 versus 9). The relative risk for DVT was 1.87 (95% CI, 1.37­ to 2.54) for CE/MPA compared to placebo, with a risk difference of 12 per 10,000 WYs (25 versus 14) [see Clinical Studies (14.4)].

Stroke

In women aged 50 to 59 years, the WHI estrogen plus progestin trial reported a relative risk for stroke of 1.51 (95% CI, 0.81-2.82) for CE/MPA compared to placebo, with a risk difference of 5 per 10,000 WYs (15 versus 10) [see Clinical Studies (14.4)].

In the overall study population of women aged 50 to 79 years (average 63.4 years), the WHI estrogen plus progestin trial reported relative risk for stroke of 1.37 (95% CI, 1.07 to 1.76) for CE/MPA compared to placebo, with a risk difference of 9 per 10,000 WYs (33 versus 24) [see Clinical Studies (14.4)].

Coronary Heart Disease

In women 50 to 59 years of age, the WHI estrogen plus progestin trial reported a relative risk for coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) of 1.34 (95% CI, 0.82 to 2.19) for CE/MPA compared placebo, with a risk difference of 5 per 10,000 WYs (23 versus 17).

In the overall study population of women aged 50 to 79 years (average 63.4 years), the trial reported a relative risk of CHD of 1.18 (95% CI, 0.95-1.45) for CE/MPA compared to placebo, with a risk difference of 6 per 10,000 WYs (41 versus 35) [see Clinical Studies (14.4)].

In the Heart and Estrogen/Progestin Replacement Study (HERS) and open label extension (HERS II), postmenopausal women with documented heart disease (n=2,763, average age 66.7 years) received daily CE (0.625 mg) plus MPA or placebo. In Year 1, there were more CHD events in the CE plus MPA-treated group than placebo; however, rates of CHD events were comparable among both groups for the remainder of the duration of the studies (average total follow-up of 6.8 years).2, 3

5.2 Malignant Neoplasms

Breast Cancer

Estradiol and progesterone capsules is contraindicated in women with breast cancer, a history of breast cancer, or estrogen-dependent neoplasia [see Contraindications (4)].

Discontinue estradiol and progesterone capsules if a hormone-sensitive malignancy is diagnosed. The use of estrogen plus progestin therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation.

Only daily oral CE 0.625 mg and MPA 2.5 mg were studied in the estrogen plus progestin trial of the WHI. Therefore, the relevance of the WHI findings regarding breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products.

In women 50-59 years of age, the WHI estrogen plus progestin trial reported a relative risk for invasive breast cancer of 1.21 (95% CI, 0.81 to 1.80) for CE/MPA compared to placebo, with a risk difference of 6 per 10,000 WYs (33 versus 27). In this age group, among those who reported no prior use of hormone therapy, the relative risk was 1.06 (95% CI, 0.67 to 1.67) for CE/MPA compared to placebo, with a risk difference of 2 per 10,000 WYs (33 versus 31) [see Clinical Studies (14.4)].

In the overall study population of women aged 50 to 79 years (average 63.4 years), the WHI estrogen plus progestin trial reported a relative risk for invasive breast cancer of 1.24 (95% CI, 1.01 to 1.53) for CE/MPA compared to placebo, with a risk difference of 9 per 10,000 WYs (43 versus 35). In the overall study population, among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.85 (95% CI, 1.18 to 2.90) for CE/MPA compared to placebo, with a risk difference of 21 per 10,000 WYs (46 versus 25). Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09 (95% CI, 0.86 to 1.39), with a risk difference of 4 per 10,000 WYs (40 versus 36). Invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. Extension of the WHI trial also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy [see Clinical Studies (14.4)].1

Consistent with the WHI trial, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy. A large meta-analysis including 24 prospective studies of postmenopausal women comparing current use of estrogen plus progestin products with use duration of 5 to 14 years (average of 9 years) versus never use reported a relative risk for breast cancer of 2.08 (95% CI, 2.02 to 2.15). These studies have not generally found the risk of breast cancer to be different among the various estrogen plus progestin combinations, doses, or routes of administration.4

Regarding breast cancer mortality, the WHI estrogen plus progestin trial did not show a statistically significant difference between CE/MPA and placebo. The trial reported a relative risk of 1.35 (95% CI, 0.94 to 1.95) for CE/MPA compared to placebo, with a risk difference of 1 per 10,000 WYs (5 versus 4) after a median of 19 years of cumulative follow-up [see Clinical Studies (14.4)].

Ovarian Cancer

Comparing CE/MPA to placebo, women 50-59 years of age had a relative risk for ovarian cancer of 0.30 (95% CI, 0.06 to 1.47) and the risk difference was -3 per 10,000 WYs (1 versus 4) [see Clinical Studies (14.4)].

In the overall WHI study population of women aged 50-79 years (average 63.4 years), the WHI estrogen plus progestin trial reported a relative risk for ovarian cancer of 1.41 (95% CI, 0.75 to 2.66) for CE/MPA versus placebo after an average follow-up of 5.6 years. The risk difference was 1 per 10,000 WYs (5 versus 4) [see Clinical Studies (14.4)].

A large meta-analysis including 17 prospective studies of postmenopausal women compared current use of estrogen plus progestin products versus never use and reported a relative risk for ovarian cancer of 1.37 (95% CI, 1.26 to 1.48). The duration of hormone therapy use that was associated with an increased risk of ovarian cancer is unknown.5

5.3 Gallbladder Disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5.4 Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including estradiol and progesterone capsules if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.

5.5 Visual Abnormalities

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue estradiol and progesterone capsules pending examination if there is a sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including estradiol and progesterone capsules, if examination reveals papilledema or retinal vascular lesions.

5.6 Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.

5.7 Exacerbation of Hypertriglyceridemia

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue estradiol and progesterone capsules if pancreatitis occurs.

5.8 Hepatic Impairment and/or Past History of Cholestatic Jaundice

Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue estradiol and progesterone capsules.

5.9 Exacerbation of Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with estradiol and progesterone capsules to maintain their free thyroid hormone levels in an acceptable range.

5.10 Fluid Retention

Estrogens plus progestogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogen plus progestogen therapy, including estradiol and progesterone capsules, with evidence of medically concerning fluid retention.

5.11 Hypocalcemia

Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including estradiol and progesterone capsules, outweigh the risks in such women.

5.12 Hereditary Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including estradiol and progesterone capsules, outweigh the risks in such women.

5.13 Exacerbation of Other Conditions

Estrogen therapy, including estradiol and progesterone capsules, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in women with such conditions.

5.14 Laboratory Tests

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of postmenopausal women with moderate to severe vasomotor symptoms.

5.15 Drug Laboratory Test Interactions

• Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
• Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
• Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
• Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.
• Impaired glucose tolerance.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

• Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)].
• Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)].

6.1 Clinical Trials 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 of estradiol and progesterone capsules was assessed in a 1-year trial that included 1,835 postmenopausal women (1,684 were treated with estradiol and progesterone capsules once daily and 151 women received placebo). Most women (~70%) in the active treatment groups were treated for ≥ 326 days.

Treatment related adverse reactions with an incidence of ≥ 3% in either estradiol and progesterone capsules group and numerically greater than those reported in the placebo group are listed in Table 1.

Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥ 3% and Numerically More Common in Women Receiving Estradiol and Progesterone Capsules 1 mg/100 mg
Preferred Term	Estradiol and Progesterone Capsules; 0.5 mg/100 mg; (N=424)	Estradiol and Progesterone Capsules; 1 mg/100 mg; (N=415)	Placebo; (N=151)
Breast tenderness	17 (4.0)	43 (10.4)	1 (0.7)
Headache	17 (4.0)	14 (3.4)	1 (0.7)
Nausea	15 (3.5)	9 (2.2)	1 (0.7)
Vaginal bleeding	10 (2.4)	14 (3.4)	0
Vaginal discharge	8 (1.9)	14 (3.4)	1 (0.7)
Pelvic pain	12 (2.8)	13 (3.1)	0

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of estradiol and progesterone capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders

Abdominal pain and discomfort, abdominal distention, diarrhea, nausea, vomiting.

General disorders and administration site conditions

Fatigue, feeling abnormal, malaise.

Investigations

Weight increased.

Metabolism and nutrition disorders

Fluid retention.

Musculoskeletal and connective tissue disorders

Muscle spasms, pain in extremity.

Nervous system disorders

Dizziness, headache, somnolence.

Psychiatric disorders

Insomnia, sleep disorder.

Reproductive system and breast disorders

Breast pain, breast tenderness, uterine bleeding.

Skin and subcutaneous tissue disorders

Night sweats, pruritus.

Vascular disorders

Hot flush.

7 DRUG INTERACTIONS

In vitro and in vivo studies have shown that estrogens and progestins are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism. Inducers of CYP3A4 such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens and progestins, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of the estrogen or the progestin or both and may result in adverse reactions.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Estradiol and progesterone capsules are not indicated for use in pregnancy. There are no data with the use of estradiol and progesterone capsules in pregnant women, however, epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation

Risk Summary

Estrogens plus progestogens are present in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for estradiol and progesterone capsules and any potential adverse effects on the breastfed child from estradiol and progesterone capsules or from the underlying maternal condition.

8.4 Pediatric Use

Estradiol and progesterone capsules are not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

8.5 Geriatric Use

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

The Women’s Health Initiative Studies

In the WHI estrogen plus progestin trial (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 [see Clinical Studies (14.4)].

The Women’s Health Initiative Memory Study

In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin [see Clinical Studies (14.5)].

It is unknown whether these findings apply to younger postmenopausal women [see Clinical Studies (14.5)]. The safety and efficacy of estradiol and progesterone capsules for the prevention of dementia has not been established.

10 OVERDOSAGE

Overdosage of estrogen plus progestogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of estradiol and progesterone capsules therapy with institution of appropriate symptomatic care.

11 DESCRIPTION

Estradiol and progesterone capsules, 1 mg/100mg, are oval shaped, opaque capsules in which the estradiol, USP is solubilized and the progesterone, USP is micronized and suspended in the mixture of glyceryl monocaprylocaprate and lauroyl polyoxylglycerides. Each pink, soft gelatin capsule is printed with “1A1”.

Estradiol, USP (estra-1,3,5 (10)-triene-3,17β-diol), an estrogen, has a molecular weight of 272.38, and chemical formula C18H24O2.

Progesterone, USP (pregn-4-ene-3, 20-dione) has a molecular weight of 314.47, and chemical formula C21H30O2.

The structural formulas are as follows: 

Estradiol, USP

Progesterone, USP

Each estradiol and progesterone capsule, 1 mg/100 mg, contains the following inactive ingredients: FD&C Red #40, gelatin, glycerin, glyceryl monocaprylocaprate, lauroyl polyoxylglycerides, purified water, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Endogenous progesterone 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 enhances cellular differentiation and generally opposes the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progesterone exerts its effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system.

12.2 Pharmacodynamics

Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to estradiol and progesterone capsules nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

12.3 Pharmacokinetics

Absorption

The oral absorption of both estradiol and progesterone is subject to first-pass metabolism. After multiple doses of estradiol and progesterone capsules administered with food, the tmax (the time at which the maximum concentration is attained) for estradiol is approximately 3 to 6 hours and approximately 3 hours for progesterone (Figure 1, Figure 2, and Table 2, below). Steady-state for both estradiol and progesterone components of estradiol and progesterone capsules, as well as estradiol’s main metabolite, estrone, is achieved within seven days. A dose-dependent increase in AUC0-t and Cmax of estradiol and a slightly more than proportionality increase in AUC0-t and Cmax of estrone were observed when the dose of estradiol was increased from 0.5 mg/day to 1 mg/day (Table 2).

Figure 1: Mean Steady-State Serum Estradiol Concentrations Following Daily Oral Administration of 0.5 mg Estradiol/100mg Progesterone or 1 mg Estradiol/100 mg Progesterone with Food (Baseline Adjusted, at Day 7)

Figure 2: Mean Steady-State Serum Progesterone Concentrations Following Daily Oral Administration of 0.5 mg Estradiol/100 mg Progesterone or 1 mg Estradiol/100 mg Progesterone with Food (Baseline Adjusted, at Day 7)

Table 2: Mean (SD) Steady-State Pharmacokinetic Parameters after Administration of Capsules Containing 0.5 mg Estradiol/100 mg Progesterone or 1 mg Estradiol/100 mg Progesterone with Food in Healthy Postmenopausal Women (Baseline Adjusted, at Day 7)
Dosage Strength; (estradiol/progesterone)	Estradiol and Progesterone Capsules; 0.5 mg/100 mg; Mean (SD)		Estradiol and Progesterone Capsules; 1 mg/100 mg; Mean (SD)
Estradiol	N		N
AUC0-τ (pg·h/mL)	17	386.8 (356.6)	20	772.4 (384.1)
Cmax (pg/mL)	17	23.95 (16.86)	20	42.27 (18.60)
Cavg (pg/mL)	17	16.64 (14.50)	19	33.99 (14.53)
tmax (h)#	17	6.00 (0.00 to 12.00)	19	3.00 (0.67 to 18.03)
t1/2 (h)*	11	28.01 (9.99)	19	26.47 (14.61)
Estrone
AUC0-τ (pg·h/mL)	17	1981 (976.0)	20	4,594 (2,138)
Cmax (pg/mL)	17	108.0 (48.58)	20	238.5 (100.4)
Cavg (pg/mL)	17	82.81 (40.80)	20	192.1 (89.43)
tmax (h)#	17	11.98 (2.00 to 18.00)	20	5.00 (1.50 to 12.00)
t1/2 (h)*	17	20.46 (5.61)	19	22.37 (7.64)
Progesterone
AUC0-τ (ng·h/mL)	17	12.19 (11.01)	20	18.05 (15.58)
Cmax (ng/mL)	17	4.40 (5.72)	20	11.31 (23.10)
Cavg (ng/mL)	17	0.55 (0.45)	20	0.76 (0.65)
tmax (h)#	17	2.00 (0.67 to 8.00)	20	2.51 (0.67 to 6.00)
t1/2 (h)	13	8.77 (2.78)	18	9.98 (2.57)
#Median and range
*Effective t1/2. Calculated as 24ln(2)/ ln (accumulation ratio/(accumulation ratio-1)) for subjects with accumulation ratio >1.
Abbreviations: AUC0-τ = area under the concentration vs time curve within the dosing interval at steady-state, Cavg = average concentration at steady-state, Cmax = maximum concentration, SD = standard deviation, tmax = time to maximum concentration, t1/2 = half-life

Food Effect

Concomitant food ingestion increased the AUC and Cmax of the progesterone component of estradiol and progesterone capsules relative to a fasting state when administered at a dose of 100 mg. In a study where estradiol and progesterone capsules was administered to postmenopausal women at a dose of 1 mg estradiol/100 mg progesterone within 30 minutes of starting a high-fat meal, the Cmax and AUC of progesterone were 162% and 79% higher, respectively, relative to the fasting state and the median tmax of progesterone was delayed from 2 hours to 3 hours. Concomitant food ingestion had no effect on the AUC of the estradiol component of estradiol and progesterone capsules but decreased Cmax by approximately 54% and delayed median tmax from 1 hour to 12 hours.

Distribution

Estradiol

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulating in the blood largely are bound to SHBG and albumin.

Progesterone

Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin (50% to 54%) and transcortin (43% to 48%).

Elimination

Following repeat dosing with estradiol and progesterone capsules, 0.5 mg/100 mg or 1 mg/100 mg, the half-life of estradiol was 28 ± 10 hours and 26 ± 15 hours, respectively, and the half-life of progesterone was 9 ± 3 hours and 10 ± 3 hours, respectively (Table 2).

Metabolism

Estradiol

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Progesterone

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, which are excreted in the bile, may be deconjugated and may be further metabolized in the intestine via reduction, dehydroxylation, and epimerization.

Excretion

Estradiol

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Progesterone

The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites are eliminated mainly by the kidneys. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

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 1,000 mg/kg and 2,000 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.

14 CLINICAL STUDIES

14.1 Effects on Vasomotor Symptoms in Postmenopausal Women

The effectiveness and safety of estradiol and progesterone capsules, 0.5 mg/100 mg and 1 mg/100 mg, on moderate to severe vasomotor symptoms (hot flushes) due to menopause were examined in a 12-week randomized, double-blind, placebo-controlled substudy of a single 52-week safety study. A total of 726 postmenopausal women were randomized to multiple dose combinations of estradiol and progesterone, and placebo; these women were 40 to 65 years of age (mean 54.6 years) and had at least 50 moderate to severe vasomotor symptoms per week at baseline. The mean number of years since last menstrual period was 5.9 years, with all women undergoing natural menopause. The primary efficacy population consisted of women who self-identified their race as: White (67%), Black/African American (31%), and “Other” (2.1%). In the substudy evaluating effects on moderate to severe vasomotor symptoms, a total of 149 women received estradiol and progesterone capsules, 0.5 mg/100 mg, 141 women received estradiol and progesterone capsules, 1 mg/100 mg, and 135 women received placebo.

The evaluated co-primary efficacy endpoints included: 1) mean weekly reduction in frequency of moderate to severe vasomotor symptoms with estradiol and progesterone capsules compared to placebo at Weeks 4 and 12 and 2) mean weekly reduction in severity of moderate to severe vasomotor symptoms with estradiol and progesterone capsules compared to placebo at Weeks 4 and 12.

Overall, estradiol and progesterone capsules, 0.5 mg/100 mg and 1 mg/100 mg, statistically significantly reduced both the frequency and severity of moderate to severe vasomotor symptoms from baseline compared with placebo at Weeks 4 and 12. The change from baseline in the frequency and severity of vasomotor symptoms observed and the difference from placebo are shown in Table 3 and Table 4, respectively.

Table 3: Mean Weekly Change from Baseline and Difference from Placebo in the Frequency of Moderate to Severe Vasomotor Symptoms
	Estradiol and Progesterone Capsules; 0.5 mg/100 mg; (N=149)	Estradiol and Progesterone Capsules; 1 mg/100 mg; (N=141)	Placebo; (N=135)
Week 4	n=144	n=134	n=126
Baseline	72.3 (28.06)	72.1 (27.80)	72.3 (23.44)
Mean (SD) change from baseline	-35.1 (29.14)	-40.6 (30.59)	-26.4 (27.05)
Difference from placebo*	-8.07 (3.25)	-12.81 (3.30)	---
P-value**	0.013	< 0.001	---
Week 12	n=129	n=124	n=115
Baseline	72.8 (28.96)	72.2 (25.04)	72.2 (22.66)
Mean (SD) change from baseline	-53.7 (31.93)	-55.1 (31.36)	-40.2 (29.79)
Difference from placebo*	-15.07 (3.39)	-16.58 (3.44)	---
P-value**	<0.001	<0.001	---
*Least square mean difference (SE) from placebo
**P-value of least square mean difference from placebo using mixed model repeated measures analyses
Definitions: SD – standard deviation; SE – standard error

Table 4: Mean Weekly Change from Baseline and Difference from Placebo in the Severity of Moderate to Severe Vasomotor Symptoms
	Estradiol and Progesterone Capsules; 0.5 mg/100 mg; (N=149)	Estradiol and Progesterone Capsules; 1 mg/100 mg; (N=141)	Placebo; (N=135)
Week 4	n=144	n=134	n=126
Baseline	2.51 (0.248)	2.54 (0.325)	2.52 (0.249)
Mean (SD) change from baseline	-0.51 (0.563)	-0.48 (0.547)	-0.34 (0.386)
Difference from placebo*	-0.17 (0.060)	-0.13 (0.061)	---
P-value**	0.005	0.031	---
Week 12	n=129	n=124	n=115
Baseline	2.51 (0.248)	2.55 (0.235)	2.52 (0.245)
Mean (SD) change from baseline	-0.90 (0.783)	-1.12 (0.963)	-0.56 (0.603)
Difference from placebo*	-0.39 (0.099)	-0.57 (0.100)	---
P-value**	<0.001	<0.001	---
*Least square mean difference (SE) from placebo
** P-value of least square mean difference from placebo using mixed model repeated measures analyses
Definitions: SD – standard deviation; SE – standard error

Adjusting for potential confounders such as BMI, smoking, alcohol use, and baseline estradiol level, treatment with estradiol and progesterone capsules, 0.5 mg/100 mg or 1 mg/100 mg, did not demonstrate statistically significant reductions in both frequency and severity of moderate to severe vasomotor symptoms by Week 12 in women who self-identified as Black/African Americans (data not shown).

14.2 Effects on Endometrium in Postmenopausal Women

Effects of estradiol and progesterone capsules, 0.5 mg/100 mg and 1 mg/100 mg, on endometrial hyperplasia and endometrial malignancy were assessed in the 52-week safety trial. The Endometrial Safety population included women who had taken at least one dose of estradiol and progesterone capsules, 0.5 mg/100 mg or 1 mg/100 mg, and had baseline and post-baseline endometrial biopsies. During the trial, endometrial biopsy assessments revealed one (1) case of endometrial hyperplasia and no cases of endometrial cancer in women who received estradiol and progesterone capsules, 0.5 mg/100 mg, one (1) case of endometrial hyperplasia and no cases of endometrial cancer in women who received estradiol and progesterone capsules, 1 mg/100 mg and no cases of endometrial hyperplasia or endometrial cancer in women who received placebo (see Table 5).

Table 5: Incidence of Endometrial Hyperplasia After up to 12 Months of Treatment
	Estradiol and Progesterone Capsules; 0.5 mg/100 mg; (N=303)	Estradiol and Progesterone Capsules; 1 mg/100 mg; (N=281)	Placebo; (N=92)
Hyperplasia incidence rate % (n/N)	1/303 (0.33)	1/281 (0.36)	0/92 (0.00)
One-sided upper 95% confidence limit	1.83	1.97	3.93

Six (6) cases of disordered proliferative endometrium were reported for estradiol and progesterone capsules, 0.5 mg/100 mg, and four (4) cases of disordered proliferative endometrium were also reported for estradiol and progesterone capsules, 1 mg/100 mg, in the 52-week safety trial.

14.3 Effects on Uterine Bleeding or Spotting in Postmenopausal Women

Uterine bleeding or spotting was evaluated in the 52-week safety study by daily diary. At 52 weeks, cumulative amenorrhea was reported by 67.6% of women who received estradiol and progesterone capsules, 0.5 mg/100 mg, 56.1% of women who received estradiol and progesterone capsules, 1 mg/100 mg, and 78.9% who received placebo.

14.4 Women’s Health Initiative Estrogen Plus Progestin Trial

The WHI estrogen plus progestin trial enrolled predominantly healthy postmenopausal women to assess the risks and benefits of daily oral CE (0.625 mg) in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. This trial did not evaluate the effects of CE plus MPA on menopausal symptoms.

The WHI estrogen plus progestin trial was stopped early. After an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer crossed the predefined stopping threshold. The global index was supportive of a finding of overall harm. The absolute excess risk of events included in the global index was 19 per 10,000 women-years.

Results of the trial, which enrolled 16,608 women (average 63 years of age, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other) are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.6,7

Table 6: Relative Risk and Risk Difference Observed in the WHI Estrogen Plus Progestin Trial at an Average of 5.6 Yearsa,b
Event	Relative Ratio (95% CI)c	Risk Difference (CEMPA vs placebo/10,000 WYs)
CHD events	1.18 (0.95 to 1.45)	6 (41 vs 35)
Non-fatal MI	1.24 (0.98 to 1.56)	6 (35 vs 29)
CHD death	1.05 (0.76 to 1.45)	1 (16 vs 15)
All Strokes	1.37 (1.07 to 1.76)	9 (33 vs 24)
Deep vein thrombosisd	1.87 (1.37 to 2.54)	12 (25 vs 14)
Pulmonary embolism	1.98 (1.36 to 2.87)	9 (18 vs 9)
Invasive breast cancere	1.24 (1.01 to 1.53)	9 (43 vs 35)
Colorectal cancer	0.62 (0.43 to 0.89)	-6 (10 vs 17)
Endometrial cancerd	0.83 (0.49 to 1.40)	-1 (6 vs 7)
Hip fracture	0.67 (0.47 to 0.95)	-6 (11 vs 17)
Vertebral fractured	0.68 (0.48 to 0.96)	-6 (12 vs 17)
Total facturesd	0.76 (0.69 to 0.83)	-51 (161 vs 212)
Overall mortalityc,f	0.97 (0.81 to 1.16)	-1 (52 vs 53)
Global Indexg	1.12 (1.02 to 1.24)	20 (189 vs 168)
a Adapted from 2013 WHI substudy (CE/MPA n=8,506, placebo n=8,102). WHI publications can be viewed at www.nhlbi.nih.gov/whi.
b Results are based on centrally adjudicated data
c In the WHI studies, hazard ratios were estimated using Cox proportional hazards models comparing treatment to placebo; however, they are described here as relative risks. Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
d Not included in “global index.”
e Includes metastatic and non-metastatic breast cancer with the exception of in situ cancer.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
g A subset of the events was combined in a “global index,” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, PE, colorectal cancer, hip fracture, or death due to other causes.

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The results of the WHI estrogen plus progestin trial in women 50 to 59 years of age (N=2,837 for CE/MPA; N=2,683 for placebo) are shown in Table 7.

Table 7: Relative Risk and Risk Difference Observed Among Women 50 to 59 Years of Age in the WHI Estrogen Plus Progestin Trial at an Average of 5.8 Yearsa,b
Event	Relative Ratio (95% CI)c	Risk Difference (CEMPA vs placebo/10,000 WYs)
CHD events	1.34 (0.82 to 2.19)	5 (23 vs 17)
Non-fatal MI	1.32 (0.77 to 2.25)	4 (19 vs 15)
CHD death	0.77 (0.33 to 1.79)	-2 (6 vs 8)
All Strokes	1.51 (0.81 to 2.82)	5 (15 vs 10)
Deep vein thrombosisd	3.01 (1.36 to 6.66)	10 (15 vs 5)
Pulmonary embolism	2.05 (0.89 to 4.71)	6 (11 vs 5)
Invasive breast cancere	1.21 (0.81 to 1.80)	6 (33 vs 27)
Colorectal cancer	0.79 (0.29 to 2.18)	-1 (4 vs 5)
Endometrial cancerd	1.07 (0.33 to 3.53)	0 (4 vs 3)
Hip fracture	0.17 (0.22 to 1.45)	-3 (1 vs 3)
Vertebral fractured	0.38 (0.15 to 0.97)	-6 (4 vs 10)
Total facturesd	0.82 (0.68 to 1.00)	-25 (120 vs 145)
Overall mortalityc,f	0.67 (0.43 to 1.04)	-10 (21 vs 31)
Global Indexg	1.12 (0.89 to 1.40)	12 (103 vs 91)
a Adapted from 2013 WHI trial (CE/MPA n=2,837; placebo=2,683). WHI publications can be viewed at www.nhlbi.nih.gov/whi.
b Results are based on centrally adjudicated data.
c In the WHI studies, hazard ratios were estimated using Cox proportional hazards models comparing treatment to placebo; however, they are described here as relative risks. Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
d Not included in “global index.”
e Includes metastatic and non-metastatic breast cancer with the exception of in situ cancer.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
g A subset of the events was combined in a “global index,” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, PE, colorectal cancer, hip fracture, or death due to other causes.

14.5 Women’s Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were 65 to 69 years of age 35% were 70 to 74 years; 18% were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD), and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD.

 After an average follow-up of 4 years, the relative risk of probable dementia for CE/MPA versus placebo was 2.01 (95% CI, 1.19 to -3.42), with a risk difference of 23 per 10,000 WYs (46 versus 23). Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Use in Specific Populations (8.5)].8

15 REFERENCES

1. Manson, J. E., et al Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA, 310(13): 1353–1368 (2013). https://doi.org/10.1001/jama.2013.278040
2. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998 Aug 19;280(7):605-13. doi: 10.1001/jama.280.7.605. PMID: 9718051.
3. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N; HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study followup (HERS II). JAMA. 2002 Jul 3;288(1):49­-57. doi: 10.1001/jama.288.1.49. Erratum in: JAMA 2002 Sep 4;288(9):1064. PMID 12090862.
4. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019 Sep 28;394(10204):1159-1168. doi: 10.1016/S0140-6736(19)31709-X. Epub 2019 Aug 29. PMID: 31474332; PMCID: PMC6891893.
5. Collaborative Group On Epidemiological Studies Of Ovarian Cancer; Beral V, Gaitskell K, Hermon C, Moser K, Reeves G, Peto R. Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet. 2015 May 9;385(9980):1835-42. doi:10.1016/S0140-6736(14)61687-1. Epub 2015 Feb 13. PMID: 25684585; PMCID: PMC4427760.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Estradiol and progesterone capsules, 1 mg/100 mg, are available as oval shaped, opaque, pink soft gelatin capsules, printed with “1A1”. Estradiol and progesterone capsules, 1 mg/100 mg, are supplied as follows:

Blister package of 30 capsules:           NDC: 69238-1690-3

Keep out of reach of children. Packages are not child-resistant.

16.2 Storage and Handling

Store at 20° to 25ºC (68° to 77ºF), excursions permitted between 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise women to read the FDA-approved patient labeling (Patient Information).

Vaginal Bleeding

Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)].

Possible Serious Adverse Reactions with Estrogen Plus Progestogen Therapy

Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestogen therapy including cardiovascular disorders and malignant neoplasms [see Warnings and Precautions (5.1, 5.2)].

Possible Common Adverse Reactions with Estrogen Plus Progestogen Therapy

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestogen therapy such as breast tenderness, headache, nausea, vaginal bleeding, vaginal discharge, and pelvic pain [see Adverse Reactions (6.1)].

Missed Evening Dose of Estradiol and Progesterone Capsules

Advise the woman that if she misses her evening dose, she should take the dose with food as soon as she can, unless it is within two hours of the next evening dose.

Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

Rev. 02-2026-01

PATIENT INFORMATION 

Estradiol (esʺ tra dyeʹ ol) and Progesterone (proe jesʹ ter one); capsules, for oral use
What is the most important information I should know about estradiol and progesterone capsules (a combination of estrogen and progestogen)? Do not use estrogens with or without progestogens to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function). Using estrogens with progestogens may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots.
What is estradiol and progesterone capsules? Estradiol and progesterone capsules are a prescription medicine that contains two kinds of hormones, an estrogen and a progestogen.
What are estradiol and progesterone capsules used for? Estradiol and progesterone capsules are used after menopause to reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe.
Who should not use estradiol and progesterone capsules? Do not use estradiol and progesterone capsules if you have had your uterus (womb) removed (hysterectomy). Estradiol and progesterone capsules contains a progestogen to decrease the chance of getting cancer of the uterus. If you do not have a uterus, you do not need a progestogen and you should not use estradiol and progesterone capsules.
Do not start using estradiol and progesterone capsules if you: have any unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have been diagnosed with a bleeding disorder currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol and progesterone capsules. currently have or have had blood clots. had a stroke or heart attack. currently have or have had liver problems. are allergic to estradiol and progesterone capsules or any of its ingredients. See the list of ingredients in estradiol and progesterone capsules at the end of this leaflet.
Before you use estradiol and progesterone capsules, tell your healthcare provider about all of your medical conditions, including if you: have high levels of fat in your blood (triglycerides). have any unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. have any other medical conditions that may become worse while you are using estradiol and progesterone capsules. Your healthcare provider may need to check you more carefully if you have certain conditions, such as:
asthma (wheezing) diabetes a genetic problem called porphyria lupus hypertension (high blood pressure) have high calcium in your blood		epilepsy (seizures) migraine endometriosis angioedema (swelling of face or tongue) problems with your heart, liver, thyroid or kidneys
are going to have surgery or will be on bed rest. Your healthcare provider will let you know if you need to stop using estradiol and progesterone capsules. are pregnant or think you may be pregnant. Estradiol and progesterone capsules are not for pregnant women. are breastfeeding. The hormones in estradiol and progesterone capsules can pass into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol and progesterone capsules work. Some other medicines and food products may increase or decrease the concentrations of the hormones in estradiol and progesterone capsules in the blood. Estradiol and progesterone capsules may affect how your other medicines work, and other medicines may affect how estradiol and progesterone capsules work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.
How should I use estradiol and progesterone capsules? Take estradiol and progesterone capsules exactly as your healthcare provider tells you to take it. Take 1 capsule by mouth each evening with food. If you miss a dose of estradiol and progesterone capsules, take the missed dose as soon as possible with food, unless it is within two hours of the next evening dose of estradiol and progesterone capsules. Estrogens should be used at the lowest dose possible for your treatment and only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about whether you still need treatment with estradiol and progesterone capsules.
What are the possible side effects of estradiol and 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: heart attack stroke blood clots breast cancer cancer of the lining of the uterus (womb) cancer of the ovary dementia gallbladder disease high or low blood calcium levels changes in vision high blood pressure high levels of fat in your blood (triglycerides) liver problems changes in thyroid hormone levels swelling or fluid retention cancer changes of endometriosis enlargement of benign tumors of the uterus (“fibroids”) worsening swelling of face or tongue (angioedema) in women who have a history of angioedema changes in laboratory test results such as bleeding time and high blood sugar levels Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: new breast lumps unusual vaginal bleeding changes in vision or speech sudden new severe headaches severe pains in your chest or legs with or without shortness of breath, weakness and fatigue vomiting Common side effects of estradiol and progesterone capsules include:
breast tenderness headache	nausea vaginal bleeding		vaginal discharge pelvic pain
Tell your healthcare provider if you have any side effects that bother you or do not go away. These are not all of the possible side effects of estradiol and progesterone capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Amneal Pharmaceuticals at 1-877-835-5472.
What can I do to lower my chances of a serious side effect with estradiol and progesterone capsules? Talk with your healthcare provider regularly about whether you should continue using estradiol and progesterone capsules. If you have a uterus, talk with your healthcare provider about whether estradiol and progesterone capsules is right for you. In general, the addition of a progestogen is recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb). See your healthcare provider right away if you get vaginal bleeding while using estradiol and progesterone capsules. 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 (breast X-ray), you may need to have breast exams more often. 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.
How should I store estradiol and progesterone capsules? Store at room temperature between 68°F to 77°F (20°C to 25ºC). Keep estradiol and progesterone capsules and all medicines out of the reach of children.
General information about the safe and effective use of estradiol and progesterone capsules. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use estradiol and progesterone capsules for a condition for which it was not prescribed. Do not give estradiol and progesterone capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about estradiol and progesterone capsules that is written for health professionals.
What are the ingredients in estradiol and progesterone capsules? Active ingredients: estradiol, USP and progesterone, USP Inactive ingredients: FD&C Red #40, gelatin, glycerin, glyceryl monocaprylocaprate, lauroyl polyoxylglycerides, purified water, and titanium dioxide. Estradiol and progesterone capsules are supplied in blister cartons of 30 capsules. For more information, go to www.amneal.com or call Amneal Pharmaceuticals at 1-877-835-5472. Distributed by: Amneal Pharmaceuticals LLC; Bridgewater, NJ 08807
This Patient Information has been approved by the U.S. Food and Drug Administration.; Rev. 02-2026-01

PRINCIPAL DISPLAY PANEL

ESTRADIOL AND PROGESTERONE 
estradiol and progesterone capsule

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 69238-1690
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
ESTRADIOL (UNII: 4TI98Z838E) (ESTRADIOL - UNII:4TI98Z838E)	ESTRADIOL	1 mg
PROGESTERONE (UNII: 4G7DS2Q64Y) (PROGESTERONE - UNII:4G7DS2Q64Y)	PROGESTERONE	100 mg

Inactive Ingredients
Ingredient Name	Strength
FD&C RED NO. 40 (UNII: WZB9127XOA)
GELATIN (UNII: 2G86QN327L)
GLYCERIN (UNII: PDC6A3C0OX)
GLYCERYL MONOCAPRYLOCAPRATE (UNII: G7515SW10N)
LAUROYL PEG-32 GLYCERIDES (UNII: H5ZC52369M)
WATER (UNII: 059QF0KO0R)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics
Color	pink	Score	no score
Shape	OVAL	Size	12mm
Flavor		Imprint Code	1A1
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 69238-1690-3	1 in 1 CARTON	05/20/2022
1		30 in 1 BLISTER PACK; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA214293	05/20/2022	01/14/2026

Labeler - Amneal Pharmaceuticals NY LLC (123797875)

Establishment
Name	Address	ID/FEI	Business Operations
Amneal Pharmaceuticals of New York, LLC		123797875	analysis(69238-1690) , label(69238-1690) , manufacture(69238-1690) , pack(69238-1690)

Revised: 2/2026

Document Id: 59936d20-723e-4511-81aa-6fa766ccff86

34391-3

Set id: 08ac4bbb-49c3-4b76-989c-3cbb913c66ce

Version: 12

Effective Time: 20260225