Side Effects of Cenestin (conjugated estrogens)

Cenestin (conjugated estrogens) contains synthetic conjugated estrogens produced from plant material used as an external source and replacement for the natural female hormone. 

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). 

Menopausal women produce less estrogen which leads to symptoms of hot flashes, vaginal dryness, shrinking in vaginal tissue and painful intercourse. Using conjugated estrogens can help treat such symptoms in menopausal women. Conjugated estrogens can also help in prevention of bone loss in menopausal women.

Common side effects of Cenestin include

• nausea,
• headache,
• pain,
• swelling of breasts,
• weight change,
• abdominal pain,
• anxiety,
• fluid retention (edema),
• vaginal bleeding, and
• mood disturbances.

Serious side effects of Cenestin include

• an increased risk of heart attacks, stroke, breast cancer, and blood clots in postmenopausal women (50-79 years old),
• increased risk of endometrial cancer, and
• an increased risk of impaired cognition and/or dementia among women over age 65.

Drug interactions of Cenestin include St. John's wort, phenobarbital, carbamazepine, and rifampin, which can accelerate the breakdown of conjugated estrogens, leading to low levels of absorbed drug and reduced effectiveness.

• Grapefruit juice and medications like erythromycin, clarithromycin, ketoconazole, and ritonavir can slow down the breakdown of conjugated estrogens in the liver, leading to increased levels of estrogens and increased estrogen side effects. 

Cenestin is not recommended during pregnancy because it may cause birth defects in a fetus. 

Use of Cenestin is not recommended in nursing mothers because conjugated estrogens enter breast milk and may have harmful effects on the newborn. Conjugated estrogens can also affect the quality and quantity of breast milk. 

There are many side effects of conjugated estrogens. Common side effects of conjugated estrogens are

• nausea,
• headache,
• pain,
• swelling of breasts,
• weight change, abdominal pain, anxiety, edema, vaginal bleeding, and mood disturbances.

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 (deep vein thrombosis or DVT) or lungs (pulmonary embolism) 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 to 79 years old) taking conjugated estrogens, 0.625 mg daily, in combination with medroxyprogesterone (Provera, Depo-Provera, Depo-Sub Q Provera 104), 2.5 mg daily, for five years, had an increased risk of

• heart attacks,
• stroke,
• breast cancer, and
• blood clots.

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.

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

• Cardiovascular Disorders
• Malignant Neoplasms

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.

In a 12-week clinical trial that included 72 women treated with 0.625 mg and 2 x 0.625 mg Cenestin and 48 women treated with placebo, adverse reactions that occurred at a rate of ≥ 5 percent are summarized in Table 1.

Table 1: Number (%) of Patients with Adverse Reactions with ≥ 5 Percent Occurrence Rate By Body System and Treatment Group

In a second 12-week clinical trial that included 52 women treated with 0.45 mg Cenestin and 51 women treated with placebo, adverse reactions that occurred at a rate of >5 percent are summarized in Table 2.

Table 2: Number (%) of Patients with a ≥ 5 Percent Occurrence Rate by Body System and Treatment Group

In a 16-week clinical trial that included 36 women treated with 0.3 mg Cenestin and 34 women treated with placebo, adverse reactions that occurred at a rate of ≥5 percent are summarized in Table 3.

Table 3: Number (%) of Patients with Adverse Reactions with ≥ 5 Percent Occurrence Rate By Body System and Treatment Group

Post Marketing Experience

The following adverse reactions have been identified during post-approval use of Cenestin. 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 distension, nausea
• Investigations: weight increased
• Metabolism & Nutrition Disorders: fluid retention
• Neoplasms: breast cancer
• Nervous System Disorders: headache, insomnia, somnolence
• Psychiatric Disorder: depression
• Reproductive System and Breast Disorders: breast enlargement, breast pain, breast swelling, breast tenderness
• Skin & Subcutaneous Tissue Disorders: alopecia, pruritus, pruritus generalized, rash pruritic, rash

• No drug-drug interaction studies have been conducted with Cenestin.

Metabolic Interactions

• In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4).
• Therefore, inducers and 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.