Does Premarin (conjugated estrogens) cause side effects?

Premarin (conjugated estrogens) are female hormones used primarily to treat the symptoms of menopause and states in which there is a deficiency of estrogen, for example, in women who have had their ovaries removed. 

Conjugated estrogens are a mixture of several different estrogens (estrogen salts) derived from natural sources and blended to approximate the composition of estrogens in the urine of pregnant horses. The main components are sodium estrone sulphate and sodium equilin sulfate. 

Estrogens have widespread effects on many tissues in the body. Estrogens cause growth and development of the female sexual organs and maintain female sexual characteristics such as the growth of underarm and pubic hair, body contours, and skeleton. Estrogens also increase secretions from the cervix and growth of the inner lining of the uterus (endometrium).

Common side effects of Premarin include

Serious side effects of Premarin include

Drug interactions of Premarin include warfarin, because estrogens increase the liver's ability to manufacture factors that promote the clotting of blood.

  • Rifampin, barbiturates, carbamazepine, griseofulvin, phenytoin, St. John's wort, and primidone all increase the elimination of estrogen by enhancing the liver's ability to eliminate estrogens.
  • Use of any of these medications with Premarin may result in a reduction of the beneficial effects of estrogens.
  • Conversely, drugs such as erythromycin, ketoconazole, itraconazole, and ritonavir may reduce the elimination of estrogens by the liver and lead to increased levels of estrogens in the blood.
  • Grapefruit juice also may increase levels of estrogen by increasing the absorption of estrogens from the intestine. Increased levels of estrogens in the blood may result in more estrogen-related side effects.

Estrogens should not be given to pregnant women due to the risk of harm to a fetus. Estrogens are secreted in breast milk and may cause unpredictable effects in the infant. 

Estrogens may also reduce the quality of breast milk. Premarin should not be taken by women who are breastfeeding.

What are the important side effects of Premarin (conjugated estrogens)?

WARNING

ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA

Estrogen-Alone Therapy

Endometrial Cancer

  • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.
  • Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
  • 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 genital bleeding.

Cardiovascular Disorders and Probable Dementia

  • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia.
  • The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo.
  • The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
  • In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.
  • Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen Plus Progestin Therapy

Cardiovascular Disorders and Probable Dementia

  • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia.
  • The WHI estrogen plus progestin substudy reported increased risks of 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 daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo.
  • The WHIMS estrogen plus progestin ancillary study of the WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Breast Cancer

  • The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer.
  • In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins.
  • Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Common side effects of conjugated estrogens are:

Other side important effects include:

  • vaginal spotting,
  • loss of periods or
  • excessively prolonged periods,
  • breast pain,
  • breast enlargement and
  • an increase or decrease in sexual drive.

Effects of estrogen on the skin include rash, and melasma (tan or brown patches) that may develop on the forehead, cheeks, or temples and may persist even after estrogens are stopped.

In the eyes, conjugated estrogens may cause an increase in the curvature of the cornea, and, as a result, patients with contact lenses may develop intolerance to their lenses.

Estrogens may increase calcium levels in the blood (hypercalcemia) in patients with breast and bone cancer.

Some patients may experience increased blood pressure and triglyceride levels.

There is an increased risk of cholesterol gallstones among men and women taking estrogens.

Estrogens also may inhibit the flow of bile from the liver (cholestasis) and uncommonly cause jaundice.

Estrogens can cause salt (sodium) and water retention (edema). Therefore, patients with heart failure or reduced function of their kidneys who are taking estrogens should be carefully observed for retention of water and its complications.

Blood clots in the legs or lungs occasionally occur in women taking conjugated estrogens. This potentially serious complication of estrogen therapy is dose-related, that is, it occurs more commonly with higher doses. Therefore, the lowest effective doses that relieve symptoms should be used.

Cigarette smokers are at a higher risk for blood clots. Therefore, patients requiring estrogen therapy should quit smoking.

Estrogens can promote a build up of the lining of the uterus (endometrial hyperplasia) and increase the risk of endometrial cancer. (Women who have undergone surgical removal of the uterus--hysterectomy--are not susceptible to endometrial hyperplasia.) The addition of a progestin to estrogen therapy prevents the development of endometrial cancer.

The Women's Health Initiative found that postmenopausal women (50-79 years old) taking conjugated estrogens, 0.625 mg daily, in combination with medroxyprogesterone, 2.5 mg daily, for five years, had an increased risk of heart attacks, stroke, breast cancer, and blood clots, while postmenopausal women taking conjugated estrogens without progesterone experienced only increased strokes but not increased blood clots, heart disease, or breast cancer.

There was an increased risk of impaired cognition and/or dementia among women over age 65 treated with either estrogens or estrogens and medroxyprogesterone.

Premarin (conjugated estrogens) side effects list for healthcare professionals

The following serious adverse reactions are discussed elsewhere in labeling:

  • Cardiovascular Disorders
  • Malignant Neoplasms

Clinical Study 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 clinical practice.

During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus between 40 and 65 years of age (88 percent Caucasian), 1,012 women were treated with conjugated estrogens, and 332 were treated with placebo.

Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥ 1 percent in any treatment group.

Table 1: TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY ≥ 1 PERCENT

  PREMARIN0.625 mg (n=348) PREMARIN0.45 mg (n=338) PREMARIN0.3 mg (n=326) Placebo (n=332)
Body as a whole
  Abdominal pain 38 (11) 28 (8) 30 (9) 21 (6)
  Asthenia 16 (5) 8 (2) 14 (4) 3 (1)
  Back pain 18 (5) 11 (3) 13 (4) 4 (1)
  Chest pain 2 (1) 3 (1) 4 (1) 2 (1)
  Generalized edema 7 (2) 6 (2) 4 (1) 8 (2)
  Headache 45 (13) 47 (14) 44 (13) 46 (14)
  Moniliasis 5 (1) 4 (1) 4 (1) 1 (0)
  Pain 17 (5) 10 (3) 12 (4) 14 (4)
  Pelvic pain 10 (3) 9 (3) 8 (2) 4 (1)
Cardiovascular system
  Hypertension 4 (1) 4 (1) 7 (2) 5 (2)
  Migraine 7 (2) 1 (0) 0 3 (1)
  Palpitation 3 (1) 3 (1) 3 (1) 4 (1)
 Vasodilatation 2 (1) 2 (1) 3 (1) 5 (2)
Digestive system
  Constipation 7 (2) 6 (2) 4 (1) 3 (1)
  Diarrhea 4 (1) 5 (1) 5 (2) 8 (2)
  Dyspepsia 7 (2) 5 (1) 6 (2) 14 (4)
  Eructation 1 (0) 1 (0) 4 (1) 1 (0)
  Flatulence 22 (6) 18 (5) 13 (4) 8 (2)
  Increased appetite 4 (1) 1 (0) 1 (0) 2 (1)
  Nausea 16 (5) 10 (3) 15 (5) 16 (5)
Metabolic and nutritional
  Hyperlipidemia 2 (1) 4 (1) 3 (1) 2 (1)
  Peripheral edema 5 (1) 2 (1) 4 (1) 3 (1)
  Weight gain 11 (3) 10 (3) 8 (2) 14 (4)
Musculoskeletal system
  Arthralgia 6 (2) 3 (1) 2 (1) 5 (2)
  Leg cramps 10 (3) 5 (1) 9 (3) 4 (1)
  Myalgia 2 (1) 1 (0) 4 (1) 1 (0)
Nervous system
  Anxiety 6 (2) 4 (1) 2 (1) 4 (1)
  Depression 17 (5) 15 (4) 10 (3) 17 (5)
  Dizziness 9 (3) 7 (2) 4 (1) 5 (2)
  Emotional lability 3 (1) 4 (1) 5 (2) 8 (2)
  Hypertonia 1 (0) 1 (0) 5 (2) 3 (1)
  Insomnia 16 (5) 10 (3) 13 (4) 14 (4)
  Nervousness 9 (3) 12 (4) 2 (1) 6 (2)
Skin and appendages
  Acne 3 (1) 1 (0) 8 (2) 3 (1)
  Alopecia 6 (2) 6 (2) 5 (2) 2 (1)
  Hirsutism 4 (1) 2 (1) 1 (0) 0
  Pruritus 11 (3) 11 (3) 10 (3) 3 (1)
  Rash 6 (2) 3 (1) 1 (0) 2 (1)
  Skin discoloration 4 (1) 2 (1) 0 1 (0)
  Sweating 4 (1) 1 (0) 3 (1) 4 (1)
Urogenital system
  Breast disorder 6 (2) 3 (1) 3 (1) 6 (2)
  Breast enlargement 3 (1) 4 (1) 7 (2) 3 (1)
  Breast neoplasm 4 (1) 4 (1) 7 (2) 7 (2)
  Breast pain 37 (11) 39 (12) 24 (7) 26 (8)
  Cervix disorder  8 (2) 4 (1) 5 (2) 0
  Dysmenorrhea 12 (3) 10 (3) 4 (1) 2 (1)
  Endometrial disorder 4 (1) 2 (1) 2 (1) 0
  Endometrial hyperplasia 16 (5) 8 (2) 1 (0) 0
  Leukorrhea 17 (5) 17 (5) 12 (4) 6 (2)
  Metrorrhagia 11 (3) 4 (1) 3 (1) 1 (0)
  Urinary tract infection 1 (0) 2 (1) 1 (0) 4 (1)
  Uterine fibroids enlarged 6 (2) 1 (0) 2 (1) 2 (1)
  Uterine spasm 11 (3) 5 (1) 3 (1) 2 (1)
  Vaginal dryness 1 (0) 2 (1) 1 (0) 6 (2)
  Vaginal hemorrhage 46 (13) 13 (4) 6 (2) 0
  Vaginal moniliasis 14 (4) 10 (3) 12 (4) 5 (2)
  Vaginitis 18 (5) 7 (2) 9 (3) 1 (0)

Postmarketing Experience

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

Genitourinary system
Breasts
Cardiovascular
Gastrointestinal
Skin
Eyes
  • Retinal vascular thrombosis, intolerance to contact lenses.
Central nervous system
Miscellaneous

What drugs interact with Premarin (conjugated estrogens)?

 
  • Estrogens increase the liver's ability to manufacture factors that promote the clotting of blood. Because of this, patients receiving warfarin (Coumadin), a drug that thins the blood and prevents clotting by reducing clotting factors, need to be monitored for loss of the blood thinning effect if treatment with an estrogen is begun.
  • Rifampin (Rifadin), barbiturates, carbamazepine (Tegretol), griseofulvin (Grifulvin), phenytoin (Dilantin), St. John's wort, and primidone all increase the elimination of estrogen by enhancing the liver's ability to eliminate estrogens. Use of any of these medications with estrogens may result in a reduction of the beneficial effects of estrogens.
  • Conversely, drugs such as erythromycin, ketoconazole (Nizoral), itraconazole (Sporanox), and ritonavir (Norvir) may reduce the elimination of estrogens by the liver and lead to increased levels of estrogens in the blood.
  • Grapefruit juice also may increase levels of estrogen by increasing the absorption of estrogens from the intestine. Increased levels of estrogens in the blood may result in more estrogen-related side effects.

Treatment & Diagnosis

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Medically Reviewed on 1/27/2021
References
FDA Prescribing Information

Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.