Estrogens, conjugated (monograph)

Estrogens, conjugated (monograph)

Estrogens, conjugated (monograph)

warning

• Estrogens increase the risk of uterine cancer in postmenopausal women. (See “Endometrial Cancer” under “Precautions.”)

• Do not use estrogens with or without progestins to prevent cardiovascular disease (see Reducing Cardiovascular Risk under Uses and Cardiovascular Disease under Precautions) or dementia (see Alzheimer's Disease under Uses).

• The Women's Health Initiative (WHI) study of estrogen alone reported an increased risk of stroke and DVT in postmenopausal women who received 0.625 mg of conjugated estrogens daily for approximately 7 years.

• The WHI estrogen plus progestin study reported an increased risk of MI, stroke, invasive breast cancer, pulmonary embolism, and DVT in postmenopausal women who received conjugated estrogen therapy 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily for ≥ 5 years.

• The WHI Memory Study (WHIMS) reported an increased risk of developing probable dementia in postmenopausal women ≥65 years of age who received long-term therapy (4-5 years) with conjugated estrogens in combination with medroxyprogesterone acetate or conjugated estrogens alone. It is not known whether this finding also applies to younger postmenopausal women.

• Other dosages of conjugated estrogens with medroxyprogesterone and other combinations or dosage forms of estrogens with progestins not evaluated in WHI studies; Since there is no comparable data, we assume that the risks are similar.

• Prescribe estrogens (with or without progestins) at the lowest effective dose and for the shortest duration according to the treatment goals and risks for the individual woman.

introduction

Mixture of estrogens available either as preparations that meet current official USP standards (e.g. conjugated estrogens USP) or as unofficial preparations (e.g. synthetic conjugated estrogens A and synthetic conjugated estrogens B produced synthetically from plant sources).

Uses for estrogens, conjugated

ERT

Treatment of moderate to severe vasomotor symptoms associated with menopause.

Treatment of severe vaginal dryness, pain during intercourse, and vulvar and vaginal atrophy associated with menopause. If used exclusively for this indication, consider using topical vaginal preparations.

osteoporosis

Prevention of osteoporosis. Used in combination with other interventions (e.g., diet, calcium, vitamin D, exercise, physical therapy) to delay further bone loss and progression of osteoporosis in postmenopausal women.

Estrogens are effective in preventing osteoporosis, but are associated with a number of side effects. If prevention of postmenopausal osteoporosis is the only indication for therapy, consider alternative therapy (e.g., alendronate, raloxifene, risedronate).

Has been shown to be effective in treating osteoporosis in postmenopausal women. Previously recommended as first-line therapy; However, recommendations on the appropriate use of HRT have been revised based on the results of the WHI study. (See Warning.) Evaluate the risks and benefits of long-term HRT use in the treatment of osteoporosis, taking into account the increased risk of breast cancer and cardiovascular disease and the availability of other pharmacologic modalities (e.g., alendronate, calcitonin, calcium, raloxifene). , risedronate, vitamin D) and lifestyle factors that can be changed.

Has been used in a limited number of anorexic women with chronic amenorrhea to reduce calcium loss† [off-label] and thereby reduce the risk of osteoporosis.

Corticosteroid-induced osteoporosis

Used to prevent bone loss in postmenopausal women receiving low- to moderate-dose corticosteroid therapy† [off-label].

Hypoestrogenism

Treatment of hypoestrogenism secondary to hypogonadism, castration or primary ovarian failure. Used to induce puberty in adolescents with delayed puberty due to hypogonadism.

Metastatic breast carcinoma

Palliative treatment of metastatic breast cancer in selected women and men. One of several second-line agents.

Prostate cancer

Palliative treatment of advanced androgen-dependent prostate cancer.

Abnormal uterine bleeding

Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.

Reducing cardiovascular risk† [off-label]

ERT or HRT do not reduce the incidence of cardiovascular disease. AHA, American College of Obstetricians and Gynecologists, FDA and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with pre-existing heart disease (secondary prevention).

Alzheimer's disease

Previous use of HRT, but not current HRT unless such use has lasted more than 10 years, which is associated with a reduced risk of Alzheimer's disease† [off-label]. Estrogens have not been proven to prevent the progression of Alzheimer's disease; The American Academy of Neurology recommends that estrogens not be used to treat Alzheimer's disease.

Initiation of ERT or HRT in women ≥65 years was not associated with improvement in cognitive function. Some women receiving ERT or HRT experience adverse effects. The incidence of probable dementia was higher in women who received ERT or HRT than in women who received placebo. (See Warning.) The use of ERT or HRT to prevent dementia or cognitive decline in women ≥ 65 years is not recommended.

Postpartum breast swelling

Used in the past to prevent postpartum mammary gland swelling† [off-label]; The FDA has withdrawn approval of estrogen-containing drugs for this indication because estrogens have not been proven safe for this use. (See Breastfeeding under “Precautions.”)

pregnancy

Not effective for any purpose during pregnancy; Use contraindicated in pregnant women. (See “Pregnancy” under “Precautions.”)

Estrogens, conjugate dosage and administration

Generally

• In women with an intact uterus, a progestin is generally added to estrogen therapy (HRT). The addition of a progestin for ≥ 10 days per estrogen cycle or daily estrogen reduces the incidence of endometrial hyperplasia and the associated risk of endometrial cancer in women with an intact uterus.

• As an alternative to progestins, the use of bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces the risk of endometrial hyperplasia.

• ERT is appropriate in women who have had a hysterectomy (to avoid unnecessary exposure to progestins).

Administration

Conjugated estrogens USP are usually administered orally; may also be administered intravaginally or by deep IM or slow IV injection.

Administer synthetic conjugated estrogens A and synthetic conjugated estrogens B orally.

Estrogen therapy is generally administered in a continuous daily dosage or alternatively in a cyclic dosage. When administered cyclically, estrogen is usually administered once daily for 3 weeks, followed by a week without the drug, or once daily for 25 days, followed by 5 days off; The treatment is repeated as needed.

When parenteral administration of conjugated estrogens (USP) is required, intravenous injection is preferred due to the faster response compared to intramuscular injection.

Oral administration

Oral preparations containing medroxyprogesterone acetate in combination with conjugated estrogens USP as monophasic or biphasic therapy are commercially available in mnemonic dispenser packaging to facilitate the user's adherence to the prescribed dosing schedule.

An oral preparation containing bazedoxifene acetate in a fixed combination with conjugated estrogens is commercially available in a 30-day pack including 2 blister packs of 15 tablets each.

IV administration

For solution and drug compatibility, see Compatibility under Stability.

Administer by direct IV injection.

Restoration

Reconstitute the 25 mg conjugated estrogen USP vial with 5 mL of sterile water for injections. Do not shake vigorously. Administer immediately after reconstitution.

Board of Directors

Administer slowly (to avoid flushing reactions).

IM management

Administer by deep IM injection.

Restoration

Reconstitute the 25 mg conjugated estrogen USP vial with 5 mL of sterile water for injections. Do not shake vigorously. Administer immediately after reconstitution.

Vaginal administration

Administer intravaginally as a vaginal cream.

dosage

Adjust the dosage individually to the disease being treated as well as the patient's tolerance and therapeutic response.

To minimize the risk of adverse effects, use the lowest possible effective dosage. Because of the possible increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, estrogen, estrogen/progestogen, or conjugated estrogens in fixed combination with bazedoxifene should be limited to the lowest effective doses and shortest duration of therapy consistent with the treatment goals and risks of the individual woman.

Regularly evaluate the use of estrogen, estrogen/progestogen, or conjugated estrogens in fixed combination with bazedoxifene (ie, at 3 to 6 month intervals).

Pediatric patients

Hypoestrogenism

Orally

Conjugated estrogens USP: 0.15 mg daily may induce breast development. Increase dosage every 6 to 12 months to achieve adequate bone aging and epiphyseal closure.

Conjugated estrogens USP: 0.625 mg daily (with progestins), sufficient to induce artificial cyclical menstruation and maintain bone mineral density (BMD) after skeletal maturity.

Adult

Estrogen replacement therapy

Vasomotor symptoms

Orally

Conjugated Estrogens USP: Initially, 0.3 mg daily continuously or in cyclic dosage (25 days on, 5 days off). Adjust dosage depending on patient response.

Synthetic conjugated estrogens A: Initially 0.45 mg daily. May increase dosage up to 1.25 mg daily.

Synthetic conjugated estrogens B: Initially 0.3 mg daily. May increase dosage up to 1.25 mg daily. Adjust dosage depending on patient response.

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: First, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily. Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; Medroxyprogesterone acetate 5 mg daily on days 15-28 of the cycle.

Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.

Vulvar and vaginal atrophy

Orally

Conjugated Estrogens USP: Initially, 0.3 mg daily continuously or in cyclic dosage (25 days on, 5 days off). Adjust dosage depending on patient response.

Synthetic conjugated estrogens A: 0.3 mg daily.

Synthetic conjugated estrogens B: 0.3 mg daily.

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: First, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily. Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; Medroxyprogesterone acetate 5 mg daily on days 15-28 of the cycle.

Vaginal

Conjugated estrogens USP: 0.5-2 g daily in a cyclic regimen (3 weeks on, 1 week off).

osteoporosis

Prevention in postmenopausal women

Orally

Conjugated Estrogens USP: Initially, 0.3 mg daily continuously or in cyclic dosage (25 days on, 5 days off). Adjust dosage based on clinical and BMD response.

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: First, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily. Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily. Adjust dosage based on clinical and BMD response.

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; Medroxyprogesterone acetate 5 mg daily on days 15-28 of the cycle.

Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.

Hypoestrogenism

Female hypogonadism

Orally

Conjugated estrogens USP: 0.3-0.625 mg daily in a cyclic regimen (3 weeks on, 1 week off). Adjust dosage depending on the severity of symptoms and the responsiveness of the endometrium.

Female castration or primary ovarian failure

Orally

Conjugated Estrogens USP: 1.25 mg daily in a cyclic regimen. Adjust dosage based on symptom severity and clinical response.

Metastatic breast carcinoma

Orally

Conjugated estrogens USP: 10 mg 3 times daily for ≥3 months.

Prostate cancer

Orally

Conjugated estrogens USP: 1.25-2.5 mg 3 times daily.

Abnormal uterine bleeding

IV or IM

Conjugated Estrogens USP: 25 mg; may repeat the dose in 6-12 hours.

Precautions for estrogens, conjugated

Contraindications

• Undiagnosed abnormal genital bleeding.

• Known or suspected breast cancer or history of breast cancer (except when used for palliative treatment of metastatic disease in appropriately selected individuals).

• Known or suspected estrogen-dependent neoplasm.

• Active DVT or pulmonary embolism; History of DVT or pulmonary embolism.

• Active or recent (within the past year) arterial thromboembolic disease (e.g., stroke, MI).

• Liver disease or impairment.

• Known protein C, protein S or antithrombin deficiency or other known thrombophilic disorders.

• Known or suspected pregnancy.

• Known hypersensitivity to estrogen or any of the ingredients in the formulation.

Warnings/Precautions

Warnings

Cardiovascular diseases

Estrogen/progestogen therapy is associated with an increased risk of heart attack, stroke, DVT, and pulmonary embolism. Estrogen therapy is associated with an increased risk of stroke and DVT. (See Warning.) Stop taking estrogen immediately if any of these events occur or are suspected. The use of ERT or HRT is not recommended in women with a history of stroke or transient ischemic attacks. (See “Contraindications” under “Warnings.”)

Appropriately treat risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity) and/or venous thromboembolism (personal or family history of venous thromboembolism, obesity, systemic lupus erythematosus). (See “Contraindications” under “Warnings.”)

Whenever possible, discontinue estrogen use at least 4-6 weeks before surgery associated with an increased risk of thromboembolism or during prolonged immobilization.

Endometrial cancer

The use of unopposed estrogen therapy in women with a uterus is associated with an increased risk of uterine cancer. Clinical monitoring and evaluation are essential. Perform diagnostic testing to rule out malignancy in women with undiagnosed, persistent, or recurrent abnormal vaginal bleeding.

The frequency of endometrial hyperplasia is significantly reduced with the simultaneous use of progestogens. Concomitant use of the estrogen agonist/antagonist bazedoxifene also reduces the risk of endometrial hyperplasia associated with conjugated estrogens.

Breast cancer

HRT is associated with an increased risk of breast cancer or an increase in abnormal mammograms that require further investigation.

All postmenopausal women should have an annual breast exam by a doctor and monthly self-exams. Schedule regular mammograms based on the patient's age and risk factors.

dementia

ERT or HRT in women ≥65 years of age have been associated with an increased risk of developing probable dementia. Whether these results apply to younger women is unknown. (See Alzheimer's disease under Uses.)

Gallbladder disease

ERT is associated with an increased risk of gallbladder disease requiring surgery.

Hypercalcemia

Estrogens can cause severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, discontinue the drug and initiate appropriate therapy to reduce serum calcium concentrations.

Eye effects

Retinal thrombosis has been reported. Discontinue examination pending examination if sudden partial or complete loss of vision or sudden onset of proptosis, diplopia, or migraine occurs. Discontinue taking estrogens if examination reveals papilledema or retinal vascular lesions.

General precautions

Increased blood pressure

In rare cases, a significant increase in blood pressure is due to idiosyncratic responses to estrogen. ERT is generally not associated with increased blood pressure. Monitor blood pressure periodically.

Hypertriglyceridemia

Estrogen therapy may be associated with an increase in plasma triglyceride concentrations, which may lead to pancreatitis in women with elevated serum lipids. If pancreatitis occurs, discontinuation of therapy should be considered.

Fluid retention

Estrogens can cause some fluid retention; Use with caution and careful monitoring in patients with conditions that could be aggravated by fluid retention (e.g. cardiac or renal impairment).

Hypocalcemia

Use with caution in patients with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

Hereditary angioedema

Estrogens may worsen symptoms of angioedema in women with hereditary angioedema.

Ovarian cancer

In some epidemiological studies, long-term estrogen therapy was associated with an increased incidence of ovarian cancer. Other studies showed no clinically meaningful association.

Endometriosis

Estrogens can worsen endometriosis.

Malignant transformation of remaining endometrial implants has been rarely reported in women receiving unopposed estrogen following hysterectomy. Consider adding progestin in women with residual endometriosis after hysterectomy.

Other conditions

Estrogens can aggravate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; Use with caution in patients with these conditions.

Special precautions for vaginal administration

Exposure to conjugated estrogen USP vaginal cream can weaken latex condoms. Be aware that the cream may weaken and contribute to the protective failure of latex or rubber condoms, diaphragms, or wallets.

Using fixed combinations

When a progestin is used in conjunction with estrogen therapy, precautions, cautions, and contraindications associated with progestin therapy should be observed.

When bazedoxifene is used in combination with conjugated estrogens, the usual cautions, cautions, contraindications, and interactions associated with bazedoxifene should be observed. For each drug in the fixed-dose combination, warnings for specific population groups (e.g. pregnant or lactating women, people with liver or kidney impairment, geriatric patients) should be taken into account.

Specific populations

pregnancy

Category X. (See “Contraindications” under “Warnings.”)

In utero exposure of women to diethylstilbestrol (DES [no longer commercially available in US]) is associated with an increased risk of vaginal adenosis, cervical squamous dysplasia, and vaginal clear cell cancer later in life.

Men's exposure to DES in utero is associated with an increased risk of genital abnormalities and possibly testicular cancer later in life.

Women who receive DES during pregnancy may have an increased risk of breast cancer; Causal relationship unproven.

lactation

Administration of estrogens to breastfeeding women has been associated with reduced milk supply and poorer milk quality. Detectable amounts of estrogens have been found in the milk of women receiving these medications. Caution is advised. Fixed combination conjugated estrogens/bazedoxifene are not recommended for use in nursing women.

Pediatric use

Estrogen therapy has been used to induce puberty in adolescents with some forms of pubertal delay. Safety and effectiveness of estrogens in children unless otherwise established.

If bone growth is not yet complete, estrogen therapy should be used with caution and careful monitoring, as estrogens can cause premature epiphyseal closure.

Estrogen therapy leads to premature breast development and vaginal keratinization in prepubertal girls and can cause vaginal bleeding. Estrogen therapy in boys can alter the normal pubertal process.

Geriatric use

No significant differences in safety in women ≥ 65 years compared to younger women; An increased incidence of stroke and invasive breast cancer has been reported in women aged 75 years and older compared to younger women.

Conjugated estrogens/bazedoxifene in fixed combination are not recommended for use in women ≥ 75 years.

Possible increased risk of developing probable dementia in women ≥ 65 years. (See “Dementia” under “Precautions.”)

Clinical trials of estrogens alone or in combination with a progestin did not include enough patients ≥ 65 years of age to determine whether geriatric patients respond differently than younger patients.

Liver dysfunction

Estrogens may be poorly metabolized in patients with impaired liver function. (See “Contraindications” under “Warnings.”)

Caution is advised in patients with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice recurs.

Renal dysfunction

Use with caution. (See Fluid Retention under “Precautions.”)

Common side effects

Abdominal pain, asthenia, flatulence, leg cramps, pruritus, vaginal bleeding, vaginitis, vaginal moniliasis.

Interactions with other medications

Appears to be partially metabolized by CYP3A4.

Drugs affecting hepatic microsomal enzymes

CYP3A4 inhibitors: Possible pharmacokinetic interaction (increased plasma estrogen concentration).

CYP3A4 inducers: Possible pharmacokinetic interaction (decreased plasma estrogen concentration).

Specific medications and foods

Estrogenic conjugate pharmacokinetics

absorption

Bioavailability

Conjugated estrogens are well absorbed through the mucous membranes and from the gastrointestinal tract.

Eat

Conjugated Estrogens USP: A high-fat meal does not affect the extent of oral absorption.

Synthetic conjugated estrogens A: influence of food unknown.

Synthetic conjugated estrogens B: effects of food unknown.

distribution

extent

Widespread; highest concentrations in the target organs of sex hormones.

Plasma protein binding

50-80%.

Elimination

metabolism

Metabolized in the liver; Kidney, gonads and muscle tissue are partially involved. Estrogens are partially metabolized by CYP3A4.

Extensive metabolic conversion occurs in the liver (e.g., estradiol is converted to estrone, both are converted to estriol).

Estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, secretion of the conjugates via bile into the intestine, and hydrolysis in the intestine, followed by reabsorption.

Elimination route

Estrogens and their metabolites are primarily excreted in the urine.

Half-life

Conjugated estrogens: 10-28 hours.

stability

storage

Orally

Tablets

20-25°C (can be exposed to 15-30°C).

Parenteral

Powder for injection

2-8°C.

Vaginal

cream

20-25°C (can be exposed to 15-30°C).

compatibility

Parenteral

It is stated to be incompatible with protein hydrolyzate, ascorbic acid or other solutions with acidic pH.

Solution Compatibility104

Drug Compatibility

Y Site CompatibilityHID

Actions

• Conjugated Estrogens USP is a blend of conjugated equine estrogens derived from natural sources and present as sodium salts of the water-soluble estrogen sulfates, blended to represent the average material composition from the urine of pregnant mares. It is a mixture of sodium estrone sulfate and sodium equilin sulfate, which also contains 17α-dihydroequiline, 17α-estradiol, 17β-dihydroequiline, equilenin, 17α-dihydroequilenin, 17β-dihydroequilenine, δ8,9-dehydroestrone and 17β-estradiol.

• Synthetic Conjugated Estrogens A is a blend of conjugated estrogens produced synthetically from plant sources (e.g. soy and yams). It contains the sodium salts of water-soluble estrogen sulfates, mixed in a 9-component mixture of estrone sulfate and sodium equilin sulfate, as well as the accompanying components 17α-dihydroequiline, 17α-estradiol, 17β-dihydroequiline, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin and 17β-estradiol as Sodium sulfate conjugates.

• Synthetic conjugated estrogens B are a blend of conjugated estrogens that are synthetically produced from plant sources. It contains the sodium salts of water-soluble estrogen sulfates, mixed in a 10-component mixture of estrone sulfate and sodium equilin sulfate, as well as the accompanying components 17α-dihydroequiline, 17α-estradiol, 17β-dihydroequiline, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin, 17β-estradiol and δ8,9-dehydroestrone as sodium sulfate conjugates. This mixture contains the 10 estrogenic substances contained in currently available commercial preparations of conjugated estrogens USP.

• Exogenous estrogens trigger, to varying degrees, all of the pharmacological responses normally caused by endogenous estrogens.

Advice for patients

• It is important to provide the patient with a copy of the manufacturer's patient information.

• Risk of uterine cancer in postmenopausal women. It is important to report any unusual vaginal bleeding to doctors.

• Risk of heart attack, stroke, breast cancer and venous thromboembolism. It is important not to use estrogens to prevent heart disease, myocardial infarction, or stroke.

• It is important for women to tell doctors if they are pregnant, plan to become pregnant, or want to breastfeed.

• It is important to inform physicians about existing or planned concomitant therapies, including prescription and over-the-counter medications and herbal supplements, as well as comorbidities.

• It is important to inform patients of other important precautionary information. (See Precautions.)

Preparations

Excipients in commercial drug preparations may have clinically significant effects in some individuals; Details can be found on the respective product labeling.

For information about shortages of one or more of these drugs, visit the ASHP Drug Shortages Resource Center.

Conjugated Estrogens USP

Conjugated estrogen combinations

Conjugated estrogens A, synthetic

Conjugated estrogens B, synthetic

AHFS DI Essentials™. © Copyright 2024, Selected changes September 18, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-Label: Use is not currently included in U.S. Food and Drug Administration-approved labeling.

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