Side Effects of Prempro (conjugated estrogens/medroxyprogesterone)

Prempro (conjugated estrogens and medroxyprogesterone) is a combination of female hormones prescribed for women who are experiencing symptoms associated with menopause such as hot flashes, vaginal dryness, vaginal atrophy, and uterine bleeding. Prempro is also used to treat osteoporosis. 

Conjugated estrogens are 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. 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). 

Medroxyprogesterone is a derivative of progesterone, a naturally occurring female progestin. Progestins are responsible for changes in the mucus and inner lining of the uterus (endometrium) during the second half (secretory phase) of the menstrual cycle. 

Progestins prepare the endometrium for implantation of the embryo. Once an embryo implants in the endometrium, for example, and pregnancy occurs, progestins help maintain the pregnancy. At high doses, progestins can prevent ovulation (release of the egg from the ovary) and thereby prevent pregnancy. 

Common side effects of Prempro include

• nausea,
• vomiting,
• stomach pain,
• tenderness,
• bloating,
• fluid accumulation (edema),
• headaches,
• breakthrough bleeding, and
• spotting.

Serious side effects of Prempro include

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

Drug interactions of Prempro include St. John's wort, phenobarbital, carbamazepine, and rifampin, because they may increase break-down of estrogens in the liver, reducing blood levels of estrogens and possibly reducing the effect of estrogens.

Erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice may reduce the break-down of estrogens in the liver, increasing blood concentrations of estrogens and possibly increasing side effects of estrogens. 

Prempro should not be given to pregnant women due to the risk of harm to the fetus. Estrogens are secreted in breast milk and cause unpredictable effects in the infant. Estrogens should not be taken by women who are breastfeeding.

The most common side effects of Prempro and Premphase are:

• nausea,
• vomiting,
• stomach pain,
• tenderness,
• bloating, and
• fluid accumulation
• (edema).

Other important side effects include:

• Headaches,
• breakthrough bleeding, and
• spotting.

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.

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 trial 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 1-year clinical trial that included 678 postmenopausal women treated with Prempro and 351 postmenopausal women treated with PREMPHASE, the following adverse reactions occurred at a rate ≥ 1 percent, see Table 1.

TABLE 1: ALL TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY ≥ 1 PERCENT

In addition, phargyngitis and sinusitis were reported as two of the more frequent adverse events ( > 5 percent) in the Prempro clinical study. For pharyngitis, of the 121 events, six events were considered by the investigator causally related to study drug. For sinusitis, of the 73 events, one event was considered as casually related to study drug.

During the first year of a 2-year clinical trial with postmenopausal women between 40 and 65 years of age (88 percent Caucasian), 989 postmenopausal women received continuous regimens of Prempro, and 332 received placebo tablets. Table 2 summarizes adverse reactions that occurred at a rate ≥ 1 percent in at least 1 treatment group.

TABLE 2: ALL TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY OF ≥ 1 PERCENT

In addition, the following events were considered as related to the study drug with an incidence less than 1 percent, including

• accidental injury,
• infection,
• myalgia,
• cough increased,
• rhinitis,
• sinusitis, and
• upper respiratory infection.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Prempro or PREMPHASE. 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.

Genitourinary System

• Abnormal uterine bleeding,
• dysmenorrhea or pelvic pain,
• increase in size of uterine leiomyomata,
• vaginitis,
• vaginal candidiasis,
• amenorrhea,
• changes in cervical secretion,
• ovarian cancer,
• endometrial hyperplasia,
• endometrial cancer.

Breasts

• Tenderness,
• enlargement,
• pain,
• nipple discharge,
• galactorrhea,
• fibrocystic breast changes,
• breast cancer.

Cardiovascular

• Deep and superficial venous thrombosis,
• pulmonary embolism,
• superficial thrombophlebitis,
• myocardial infarction,
• stroke,
• increase in blood pressure.

Gastrointestinal

• Nausea,
• vomiting,
• abdominal pain,
• bloating,
• cholestatic jaundice,
• increased incidence of gallbladder disease,
• pancreatitis,
• changes in appetite,
• ischemic colitis.

Skin

• Chloasma or melasma that may persist when drug is discontinued,
• erythema multiforme,
• erythema nodosum,
• loss of scalp hair,
• hirsutism,
• pruritus,
• urticaria,
• rash,
• acne.

Eyes

• Retinal vascular thrombosis,
• intolerance of contact lenses.

Central Nervous System

• Headache,
• migraine,
• dizziness,
• mental depression,
• exacerbation of chorea,
• mood disturbances,
• anxiety,
• irritability,
• exacerbation of epilepsy,
• dementia,
•  growth potentiation of benign meningioma.

Miscellaneous

• Increase or decrease in weight,
• arthralgia,
• glucose intolerance,
• edema,
• changes in libido,
• exacerbation of asthma,
• increased triglycerides,
• hypersensitivity.

Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

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 CE plus MPA.

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.
• Aminoglutethimide administered concomitantly with MPA may significantly depress the bioavailability of MPA.