Does Premarin Vaginal Cream (conjugated estrogens) cause side effects?

Premarin Vaginal Cream (conjugated estrogens) is a mixture of several different estrogens (estrogen salts) that are derived from natural sources and blended to approximate the composition of estrogens in the urine of pregnant horses used to relieve vaginal symptoms in postmenopausal women who have vaginal dryness, inflammation, or painful intercourse due to atrophy of the vagina and vulva. 

The main components are sodium estrone sulphate and sodium equilin sulfate. Estrogens have widespread effects on 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 Vaginal Cream include

  • breakthrough bleeding or spotting,
  • loss of periods,
  • excessively prolonged periods,
  • breast pain,
  • breast enlargement, and
  • changes in sex drive.

Serious side effects of Premarin Vaginal Cream include

Premarin Vaginal Cream may cause an increase in the curvature of the cornea, and patients with contact lenses may develop intolerance to their lenses. 

Premarin Vaginal Cream drug interaction studies have not been conducted. Estrogens are broken down in the liver by certain enzymes. Drugs that increase or decrease the activity of these enzymes may interfere with the action of Premarin Vaginal Cream drug.

  • Rifampin, barbiturates, carbamazepine, griseofulvin, phenytoin, St. John's wort, and primidone may increase the elimination of estrogen by enhancing the liver's ability to eliminate estrogens. Use of any of these medications with Premarin Vaginal Cream drug 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 and increased effects.
  • 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. 

Premarin Vaginal Cream drug should be avoided during pregnancy since they increase the risk of fetal abnormalities. Estrogens are secreted in milk and cause unpredictable effects in the infant. In general, Premarin Vaginal Cream should not be used by women who are breastfeeding.

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

Among the most common endocrine side effects are:

  • breakthrough vaginal bleeding
  • spotting,
  • loss of periods,
  • excessively prolonged periods,
  • breast pain or
  • breast enlargement, and
  • changes in sexuality (increases or decreases in libido).

Other important side effects include:

Melasma--tan or brown patches--may develop on the forehead, cheeks, or temples. These may persist even after the estrogen is stopped.

Conjugated estrogens may increase the curvature of the cornea, and patients with contact lenses may develop intolerance to their lenses.

Blood clots are an occasional, serious side effect of estrogen therapy and are dose-related. (The higher the dose of estrogen, the greater the risk of blood clots.) Cigarette smokers are at a higher risk than non-smokers for blood clots, and patients requiring estrogens should be encouraged to quit smoking.

Estrogens can promote thickening of the lining of the uterus (endometrial hyperplasia) and increase the risk of uterine cancer. At diagnosis, endometrial cancers in recipients of estrogens are generally at an earlier stage and are less aggressive when they are discovered. Survival from endometrial cancer also is better in women taking estrogens than in those not taking estrogens.

The addition of a progestin to estrogen therapy offsets the risk of endometrial cancer. Conflicting data exists on the association between estrogens and breast cancer. There may be a small increase in risk. The effect of concomitant progestin therapy on the risk of estrogen-induced breast cancer is unclear. Conjugated estrogens are well-absorbed from the vagina and into the blood. The amount absorbed depends on the frequency of use and the amount used.

Thus, more frequent use or larger amounts of vaginal estrogens can have effects throughout the body (see conjugated estrogens, Premarin). The Women's Health Initiative found that postmenopausal women (50-79 years old) taking conjugated estrogens had an increased risk of breast cancer, blood clots, and stroke. There was also an increased risk of impaired cognition and/or dementia among women over age 65.

Premarin Vaginal Cream (conjugated estrogens) side effects list for healthcare professionals

The following serious adverse reactions are discussed elsewhere in labeling:

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.


PREMARIN0.625 mg (n=348)PREMARIN0.45 mg (n=338)PREMARIN0.3 mg (n=326)Placebo (n=332)
Body as a whole
  Abdominal pain38 (11)28 (8)30 (9)21 (6)
  Asthenia16 (5)8 (2)14 (4)3 (1)
  Back pain18 (5)11 (3)13 (4)4 (1)
  Chest pain2 (1)3 (1)4 (1)2 (1)
  Generalized edema7 (2)6 (2)4 (1)8 (2)
  Headache45 (13)47 (14)44 (13)46 (14)
  Moniliasis5 (1)4 (1)4 (1)1 (0)
  Pain17 (5)10 (3)12 (4)14 (4)
  Pelvic pain10 (3)9 (3)8 (2)4 (1)
Cardiovascular system
  Hypertension4 (1)4 (1)7 (2)5 (2)
  Migraine7 (2)1 (0)03 (1)
  Palpitation3 (1)3 (1)3 (1)4 (1)
 Vasodilatation2 (1)2 (1)3 (1)5 (2)
Digestive system
  Constipation7 (2)6 (2)4 (1)3 (1)
  Diarrhea4 (1)5 (1)5 (2)8 (2)
  Dyspepsia7 (2)5 (1)6 (2)14 (4)
  Eructation1 (0)1 (0)4 (1)1 (0)
  Flatulence22 (6)18 (5)13 (4)8 (2)
  Increased appetite4 (1)1 (0)1 (0)2 (1)
  Nausea16 (5)10 (3)15 (5)16 (5)
Metabolic and nutritional
  Hyperlipidemia2 (1)4 (1)3 (1)2 (1)
  Peripheral edema5 (1)2 (1)4 (1)3 (1)
  Weight gain11 (3)10 (3)8 (2)14 (4)
Musculoskeletal system
  Arthralgia6 (2)3 (1)2 (1)5 (2)
  Leg cramps10 (3)5 (1)9 (3)4 (1)
  Myalgia2 (1)1 (0)4 (1)1 (0)
Nervous system
  Anxiety6 (2)4 (1)2 (1)4 (1)
  Depression17 (5)15 (4)10 (3)17 (5)
  Dizziness9 (3)7 (2)4 (1)5 (2)
  Emotional lability3 (1)4 (1)5 (2)8 (2)
  Hypertonia1 (0)1 (0)5 (2)3 (1)
  Insomnia16 (5)10 (3)13 (4)14 (4)
  Nervousness9 (3)12 (4)2 (1)6 (2)
Skin and appendages
  Acne3 (1)1 (0)8 (2)3 (1)
  Alopecia6 (2)6 (2)5 (2)2 (1)
  Hirsutism4 (1)2 (1)1 (0)0
  Pruritus11 (3)11 (3)10 (3)3 (1)
  Rash6 (2)3 (1)1 (0)2 (1)
  Skin discoloration4 (1)2 (1)01 (0)
  Sweating4 (1)1 (0)3 (1)4 (1)
Urogenital system
  Breast disorder6 (2)3 (1)3 (1)6 (2)
  Breast enlargement3 (1)4 (1)7 (2)3 (1)
  Breast neoplasm4 (1)4 (1)7 (2)7 (2)
  Breast pain37 (11)39 (12)24 (7)26 (8)
  Cervix disorder 8 (2)4 (1)5 (2)0
  Dysmenorrhea12 (3)10 (3)4 (1)2 (1)
  Endometrial disorder4 (1)2 (1)2 (1)0
  Endometrial hyperplasia16 (5)8 (2)1 (0)0
  Leukorrhea17 (5)17 (5)12 (4)6 (2)
  Metrorrhagia11 (3)4 (1)3 (1)1 (0)
  Urinary tract infection1 (0)2 (1)1 (0)4 (1)
  Uterine fibroids enlarged6 (2)1 (0)2 (1)2 (1)
  Uterine spasm11 (3)5 (1)3 (1)2 (1)
  Vaginal dryness1 (0)2 (1)1 (0)6 (2)
  Vaginal hemorrhage46 (13)13 (4)6 (2)0
  Vaginal moniliasis14 (4)10 (3)12 (4)5 (2)
  Vaginitis18 (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
  • Retinal vascular thrombosis,
  • intolerance to contact lenses.
Central nervous system

What drugs interact with Premarin Vaginal Cream (conjugated estrogens)?

  • Data from a single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both drugs is not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens.

Metabolic Interactions

  • In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4).
  • Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's Wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, 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 estrogens and may result in side effects.

Treatment & Diagnosis

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Medically Reviewed on 11/30/2020
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Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.