Premphase Side Effects
Generic Name: conjugated estrogens / medroxyprogesterone
Note: This document contains side effect information about conjugated estrogens / medroxyprogesterone. Some of the dosage forms listed on this page may not apply to the brand name Premphase.
For the Consumer
Applies to conjugated estrogens / medroxyprogesterone: oral tablet
Along with its needed effects, conjugated estrogens/medroxyprogesterone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking conjugated estrogens/medroxyprogesterone:
- Bloating or swelling of the face, arms, hands, lower legs, or feet
- blood in the urine
- blurred vision
- chest pain
- clear or bloody discharge from the nipple
- cough or hoarseness
- dimpling of the breast skin
- fast, irregular, pounding, or racing heartbeat or pulse
- feeling faint, dizzy, or lightheaded
- feeling of warmth or heat
- fever or chills
- flushing or redness of the skin, especially on the face and neck
- inverted nipple
- lower back or side pain
- lump in the breast or under the arm
- pain during sexual intercourse
- painful or difficult urination
- persistent crusting or scaling of the nipple
- pounding in the ears
- redness or swelling of the breast
- severe cramping of the uterus
- sore on the skin of the breast that does not heal
- thick, white vaginal discharge with no odor or with a mild odor
- tingling of the hands or feet
- unusual weight gain or loss
- vaginal bleeding that is unusual and heavy
- vaginal or genital itching
- vaginal yeast infection
Incidence not known
- Absent, missed, or irregular menstrual periods
- acid or sour stomach
- breast pain or tenderness
- darkened urine
- decreased vision or other changes in vision
- difficulty with speaking
- double vision
- inability to move the arms, legs, or facial muscles
- inability to speak
- loss of appetite
- pain or discomfort in the arms, jaw, back, or neck
- pain or feeling of pressure in the pelvis
- pain, redness, or swelling in the arm or leg
- painful or tender cysts in the breasts
- pains in the stomach, side, or abdomen, possibly radiating to the back
- slow speech
- sudden shortness of breath or troubled breathing
- unexpected or excess milk flow from the breasts
- yellow eyes or skin
Some side effects of conjugated estrogens/medroxyprogesterone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
- Blemishes on the skin
- body aches or pain
- difficulty with moving
- dry skin
- dryness of the vagina
- excessive muscle tone
- feeling paranoid
- flu-like symptoms
- fullness or swelling of the breasts
- hair loss or thinning of the hair
- headache, severe and throbbing
- leg cramps
- loss of bladder control
- menstrual periods that are longer or heavier
- muscle pain or stiffness
- pain in the joints
- pain or tenderness around the eyes and cheekbones
- pimples or acne
- quick to react or overreact emotionally
- rapidly changing moods
- sore mouth or tongue
- stuffy or runny nose
- tender, swollen glands in the neck
- tightness of the chest or wheezing
- trouble with sleeping
- trouble with swallowing
- vaginal discharge that is clear or white
- voice changes
- white patches in the mouth or on the tongue
Incidence not known
- Changes in appetite
- hives or welts
- inability to have or keep an erection
- increased hair growth, especially on the face
- increased interest in sexual intercourse
- loss in sexual ability, desire, drive, or performance
- loss of scalp hair
- pain in the ankles or knees
- painful, red lumps under the skin, mostly on the legs
- patchy brown or dark brown discoloration of the skin
- redness of the skin
- weight changes
For Healthcare Professionals
Applies to conjugated estrogens / medroxyprogesterone: oral tablet
General side effects have included headache (28% to 36%), abdominal pain (16% to 23%), asthenia (6% to 10%), back pain (13% to 16%), and flu-like symptoms (10% to 13%), pelvic pain (4% to 5%), infection (14% to 18%), and generalized pain (11% to 13%).[Ref]
The manufacturer recommends close observation if conjugated estrogens must be used in patients who may be particularly sensitive to fluid retention because of underlying asthma, epilepsy, migraine, heart disease, and renal dysfunction.[Ref]
Metabolic side effects of estrogen have included increased serum triglyceride levels resulting in pancreatitis in patients with familial lipoprotein metabolic defects. However, metabolic effects in patients treated with conjugated estrogens include generally favorable alterations in plasma lipid profiles. Specifically, increased HDL and decreased cholesterol and LDL levels occur.
Metabolic side effects of medroxyprogesterone have included weight changes (increases and decreases), glucose intolerance, and changes in serum cholesterol concentrations.[Ref]
Weight gain is more frequently encountered than weight loss during medroxyprogesterone therapy. In women using intramuscular medroxyprogesterone for contraception, the mean weight gain after one year of therapy is 2.5 kg. After two, four, and six years, patients gain a mean of 3.7, 6.3, and 7.5 kg, respectively.
Data regarding the effect of medroxyprogesterone on lipid profiles have been conflicting. Some studies report possible negative effects on lipid profiles while others have documented a reduction in total and low density lipoprotein cholesterol and an increase in high density lipoprotein cholesterol levels.[Ref]
Cardiovascular side effects of estrogens have included increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism.
Cardiovascular side effects of medroxyprogesterone have included thromboembolic disorders such as thrombophlebitis, deep vein thrombosis, pulmonary embolism, cerebrovascular accidents, and retinal thrombosis. In addition, edema, hypertension, tachycardia, and syncope have been reported. Because medroxyprogesterone can cause edema, it should be used cautiously in patients with underlying disease (like migraine headaches, asthma, heart disease, renal dysfunction, or seizure disorders) which may be exacerbated by edema or fluid retention.[Ref]
A number of studies have suggested that the risk of endometrial carcinoma is removed (or delayed) by the administration of progestins in combination with estrogen therapy.
The risk of breast cancer due to use of conjugated estrogens is controversial. Meta analysis of epidemiological data supports a modest risk increase associated with long-term hormone replacement therapy (HRT).
A study of Swedish women has reported that a 10% increase in the relative risk of breast cancer may occur and that the risk is related to increasing duration of estrogen use had a 70% greater relative risk of breast cancer than controls. That study, however, examined use of a variety of estrogen preparations of which estradiol was the most frequently prescribed. In addition, women who took progestins did not demonstrate a decreased risk of breast cancer and may even have been at higher risk.
The Toronto Breast Cancer Study has reported that women who receive unopposed conjugated estrogens for less than 15 years are not at increased risk of breast cancer. In that study, an increase in the risk of breast cancer for women who used conjugated estrogens form more than 15 years was not ruled out.
The Case Control Surveillance Study reported "no evidence that the use of unopposed conjugated estrogens increases the risk of breast cancer, even after long duration of use or long latent intervals, but the possibility of a modest increase (less than doubling) could not be excluded."
Follow-up data to the Nurses' Health Study of 1992 concluded, however, that there is an increased risk of breast cancer in women taking estrogen replacement therapy and that the risk is not reduced by concurrent use of progestins. (In that study, greater risk was associated with advanced age and prolonged duration of hormonal therapy.)
A study of middle-aged women in the Puget Sound area concluded that "on the whole, the use of estrogen with progestin HRT [hormone replacement therapy] does not appear to be associated with an increased risk of breast cancer in middle-aged women."
A significant increase in the incidence of breast cancer in beagle dogs in addition to an apparent increase in the incidence of endometrial cancer in rhesus monkeys was noted in early animal carcinogenicity studies.
International long-term studies designed to assess the risk of medroxyprogesterone in humans, sponsored by the World Health organization, failed to find an increased risk of cancer in users of medroxyprogesterone. Overall, there was no significant increase in the risk of breast cancer, cervical cancer, or epithelial ovarian cancer. Data from these studies did, however, support a significant (8 fold) reduction in the incidence of endometrial cancer among medroxyprogesterone users.
A New Zealand study suggested that women taking depot medroxyprogesterone acetate may be at higher risk for breast cancer during the first 5 years, but therapy for more than 5 years confers no increased risk of breast cancer.
A prospective cohort study (11 years) of 37,105 women by Gapstur et al evaluated the histology of the breast cancer in women with ever HRT use. Little evidence of association was found between duration of ever HRT use and the incidence of ductal carcinoma in situ or invasive ductal/lobular carcinoma. The duration of ever HRT use was associated with risk of invasive carcinoma with a favorable prognosis [relative risk (RR) = 1.81, 95% confidence interval (CI), 1.07 to 3.07 for HRT use less than or equal to 5 years and RR = 2.65, CI, 1.32 to 5.23 for HRT use > 5 years, p = 0.005]. The relative risk of invasive carcinoma with a favorable prognosis for current users (adjusted for age and other risk factors) was 4.42, CI, 2.00 to 9.76 for less than or equal to 5 years and 2.63, CI 1.18 to 5.89 for > 5 years). Risk of invasive ductal or lobular carcinoma for current users less than or equal to 5 years was RR = 1.38, CI, 1.03 to 1.85.[Ref]
Oncologic side effects of unopposed estrogen therapy have included an increased risk of endometrial carcinoma and breast cancer.[Ref]
Gastrointestinal side effects of conjugated estrogen therapy have included nausea and vomiting. Some studies have demonstrated a 2 to 4 fold increase in gallbladder disease in postmenopausal women taking estrogen therapy.
Gastrointestinal side effects of medroxyprogesterone have included nausea, abdominal pain, bloating, and anorexia in up to 5% of patients treated.
Postmarketing reports have included ischemic colitis.[Ref]
Cases of oral pigmentation and ischemic colitis have been reported rarely.[Ref]
Withdrawal bleeding is a common complaint among postmenopausal women receiving sequential (10 to 14 days per cycle) medroxyprogesterone therapy. In postmenopausal women receiving continuous medroxyprogesterone and estrogen therapy, 75% or more are amenorrheic by one year of therapy.
In women receiving medroxyprogesterone for contraception, more than 50% are amenorrheic by one year of therapy.
In women on estrogen replacement therapy, the addition of medroxyprogesterone or other progestin for at least 10 to 14 days of each cycle significantly reduces the risk of endometrial hyperplasia and, thus, the risk of endometrial carcinoma. Low-dose continuous medroxyprogesterone therapy also reduces the risk of endometrial hyperplasia associated with the use of unopposed estrogen.
In patients in whom abnormal bleeding persists or is severe, the possibility of an organic pathology should be considered and ruled out.[Ref]
Genitourinary side effects of conjugated estrogens-medroxyprogesterone have included mastodynia (12% to 38%). Dysmenorrhea and pelvic pain have also been reported.
Conjugated estrogens may also cause abnormal uterine bleeding (which must be carefully distinguished from bleeding related to endometrial carcinoma). In addition, conjugated estrogens may increase the size of preexisting uterine leiomyomata. Several cases of pseudoincontinence (excessive vaginal discharge perceived by patients as urinary incontinence) have been reported in premenopausal women who have undergone hysterectomy oophorectomy and received postoperative conjugated estrogens.
Genitourinary side effects of medroxyprogesterone have included primarily menstrual changes such as amenorrhea, irregular bleeding, spotting, and heavy bleeding. Changes in libido and anorgasmia may also occur.[Ref]
Cushing's syndrome is uncommon and appears to be associated with a long duration of therapy and moderate to high doses of medroxyprogesterone. Doses used for hormonal replacement therapy and for long-term contraception are not associated with Cushing's syndrome.
Medroxyprogesterone has mild glucocorticoid activity. In cases of medroxyprogesterone induced Cushing's syndrome, low cortisol and adrenocorticotrophic hormone (ACTH) levels with a reduced pituitary-adrenal reserve have been documented. Acute adrenal insufficiency may ensure following withdrawal of medroxyprogesterone.[Ref]
Endocrine side effects of estrogen have included increased levels of thyroxin-binding globulin, leading to an increase in total thyroid serum levels and a decrease in resin uptake of T3. Free thyroid hormone levels remain unchanged. Other endocrine effects include decreased fasting plasma glucose.
Endocrine side effects of medroxyprogesterone have included breast tenderness, galactorrhea with or without hyperprolactinemia, prevention of lactation, hirsutism, and Cushing's syndrome.[Ref]
Dermatologic side effects of conjugated estrogens have included pruritus and rash (5% to 10%).
Dermatologic side effects of medroxyprogesterone have included acne, reduced hair growth, alopecia, melasma, chloasma, rash, excessive sweating, dry skin, scleroderma, erythema multiforme, and erythema nodosum. Melasma may persist following discontinuation of therapy.[Ref]
Conflicting data concerning the effects of medroxyprogesterone on bone mineral density have been reported.
In one study, women 25 to 51 years of age receiving medroxyprogesterone 150 mg intramuscularly every three months for five or more years for long-term contraception had a reduction in bone mineral density compared with premenopausal controls. However, bone mineral density in the treatment group was still significantly greater than that observed in postmenopausal controls.
A study of 200 women who received medroxyprogesterone 150 mg intramuscularly every three months for a median duration of 12 years (range 2 to 26 years) reported that bone density was significantly reduced in medroxyprogesterone users. However, bone mineral density in women starting depot medroxyprogesterone after the age of 20 years and using it for 15 or fewer years was greater than the remainder of the cohort.
A study to determine the potential for postmenopausal fracture due to residual effects of depot medroxyprogesterone in former users reported the risk to be small and unlikely to have substantial impact in postmenopausal women. No significant differences in bone density were found, however, women who had used depot medroxyprogesterone for greater than 2 years had a trend toward lower bone densities.
Bone density in 185 women receiving long-term depot medroxyprogesterone for a mean of 5 years (range of 1-16 years) was only minimally below the normal population despite decreased estrogen levels.[Ref]
Musculoskeletal side effects of medroxyprogesterone have included changes in bone mineral density. Such effect are thought to be due to medroxyprogesterone induced estrogen deficiency. Arthralgias and leg cramps have also been reported.[Ref]
Nervous system side effects have included headache, migraine, dizziness, mental depression, exacerbation of chorea, mood disturbances, anxiety, irritability, exacerbation of epilepsy, dementia, and growth potentiation of benign meningioma. A case of chorea has been reported in association with conjugated estrogen therapy.[Ref]
Hepatic side effects of estrogen therapy have included cases of focal nodular hyperplasia, liver cell adenomas, hepatic hemangiomas and well differentiated hepatocellular carcinomas.
Hepatic side effects associated with medroxyprogesterone therapy have included elevations in liver function tests, jaundice, cholestatic jaundice, and cholelithiasis.[Ref]
Hypersensitivity side effects of conjugated estrogen have included anaphylaxis. Some of these reactions may have been associated with the dyes contained in some conjugated estrogen formulations.
Hypersensitivity side effects of medroxyprogesterone have included urticaria, angioneurotic edema, and anaphylaxis or anaphylactoid reactions[Ref]
Rare cases of exacerbations of pulmonary lymphangioleiomyomatosis have occurred. In addition, combinations of high-dose conjugated estrogens and progestin have been reported to increase the hypoxic ventilatory response.[Ref]
Psychiatric side effects of conjugated estrogens have included cases of rapid mood cycling in patients with severe depression.[Ref]
Hematologic side effects of conjugated estrogens have included hypercoagulability.
Hematologic side effects of medroxyprogesterone have included rare reports of hematologic dyscrasias. Hypercoagulability with or without thromboembolic activity has been reported.[Ref]
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