Note: This document contains side effect information about conjugated estrogens / medroxyprogesterone. Some dosage forms listed on this page may not apply to the brand name Premphase.

Applies to conjugated estrogens / medroxyprogesterone: oral tablet.

Serious side effects of Premphase

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:

Less common

• 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
• dizziness
• 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
• headache
• inverted nipple
• lower back or side pain
• lump in the breast or under the arm
• nervousness
• 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
• sweating
• 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
• anxiety
• backache
• breast pain or tenderness
• confusion
• constipation
• darkened urine
• decreased vision or other changes in vision
• difficulty with speaking
• double vision
• fainting
• heartburn
• inability to move the arms, legs, or facial muscles
• inability to speak
• indigestion
• loss of appetite
• nausea
• 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
• vomiting
• yellow eyes or skin

Other side effects of Premphase

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:

More common

• Back pain
• depression
• excess gas in the stomach or intestines
• lack or loss of strength

Less common

• Blemishes on the skin
• body aches or pain
• congestion
• depersonalization
• diarrhea
• difficulty with moving
• dry skin
• dryness of the vagina
• dysphoria
• euphoria
• 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
• rash
• sleeplessness
• 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
• irritability
• 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

The most commonly reported adverse events have included abdominal pain, asthenia, back pain, headache, flatulence, nausea, depression, pruritus, breast pain, dysmenorrhea, and leukorrhea.^[Ref]

Cardiovascular

Common (1% to 10%): Chest pain, generalized edema, hypertension, vasodilation, edema

Uncommon (0.1% to 1%): Palpitation

Postmarketing reports: Deep and superficial venous thrombosis, pulmonary embolism, superficial thrombophlebitis, myocardial infarction, stroke, increase in blood pressure^[Ref]

The Women's Health Initiative (WHI) sub-study reports an increased risk of deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction in postmenopausal women 50 to 79 years old with a duration of 5.6 years of daily conjugated estrogen 0.625 mg-medroxyprogesterone 2.5 mg use compared with placebo. The WHI estrogen-alone study reported increased risks of stroke and DVT during 7.1 years of daily conjugated estrogen treatment.

-Stroke Risk (WHI substudy; conjugated estrogen 0.625 mg-medroxyprogesterone 2.5 mg daily): A statistically significant increased stroke risk: 33 versus 25 per 10,000 women-years

-Coronary Heart Disease (WHI substudy; conjugated estrogen 0.625 mg-medroxyprogesterone 2.5 mg): A statistically non-significant increased risk: 41 versus 34 per 10,000 women-years

-Venous Thromboembolism (VTE): (WHI substudy; conjugated estrogen 0.625 mg-medroxyprogesterone 2.5 mg): A statistically significant (VTE) risk: 35 versus 17 per 10,000 women-years. Specifically, DVT: 26 versus 13 per 10,000 women-years and PE:18 versus 8 per 10,000 women-years

The Heart and Estrogen/Progestin Replacement Study (HERS) demonstrated no cardiovascular benefit in postmenopausal women with established coronary heart disease (CHD) taking daily conjugated estrogen 0.625 mg-medroxyprogesterone 2.5 mg (average follow-up of 4.1 years). In the HERS II study, an open label extension of HERS, an additional 2.7 years of follow-up showed rates of CHD remained comparable to placebo.^[Ref]

Oncologic

Common (1% to 10%): Breast neoplasm

Uncommon (0.1% to 1%): Endometrial hyperplasia

Postmarketing reports: Ovarian cancer, endometrial hyperplasia, endometrial cancer, breast cancer^[Ref]

Breast Cancer: An increased risk of breast cancer was reported in the WHI substudy of daily conjugated estrogen 0.626 mg-medroxyprogesterone 2.5 mg use. After a mean follow-up of 5.6 years, the risk was 41 versus 33 cases per 10,000 women. In the women taking conjugated estrogen-medroxyprogesterone, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage. Metastatic disease was rate and not different compared to placebo.

Ovarian Cancer: A statistically non-significant risk of ovarian cancer was reported in the WHI substudy of daily conjugated estrogen 0.626 mg-medroxyprogesterone 2.5 mg use. After a mean follow-up of 5.6 years, the risk was 4 versus 3 cases per 10,000 women. A large meta-analysis showed a significant increased risk of ovarian cancer in women using both estrogen-alone and estrogen plus progestin. The duration of hormone therapy use associated with an increased risk of ovarian cancer is unknown.^[Ref]

Endocrine

Very common (10% or more): Breast pain (up to 36%)

Common (1% to 10%): Breast enlargement

Uncommon (0.1% to 1%): Breast engorgement

Postmarketing reports: Breast tenderness, breast enlargement, breast pain, nipple discharge, galactorrhea, fibrocystic breast changes, changes in libido^[Ref]

Genitourinary

Very common (10% or more): Dysmenorrhea (up to 13%)

Common (1% to 10%): Pelvic pain, cervix disorder, leukorrhea, menstrual disorder, metrorrhagia, suspicious PAP smear, vaginal moniliasis, vaginitis, uterine spasm, vaginal hemorrhage

Uncommon (0.1% to 1%): Menorrhagia, urinary incontinence, hematuria, urinary tract infection, vaginal dryness

Postmarketing reports: Abnormal uterine bleeding, dysmenorrhea or pelvic pain, increase in size of uterine leiomyomata, vaginitis, vaginal candidiasis, amenorrhea, changes in cervical secretion^[Ref]

Hypersensitivity

Postmarketing reports: Anaphylaxis, angioedema, hypersensitivity^[Ref]

Metabolic

Common (1% to 10%): Decreased glucose tolerance (hyperglycemia), weight gain

Uncommon (0.1% to 1%): Increased appetite

Postmarketing reports: Appetite changes, weight increases and decreases, glucose intolerance, increased triglycerides^[Ref]

Gastrointestinal

Very common (10% or more): Abdominal pain (up to 17%)

Common (1% to 10%): Diarrhea, dyspepsia, eructation, flatulence, nausea

Frequency not reported: Gallbladder disease

Postmarketing reports: Nausea, vomiting, abdominal pain, bloating, increased incidence of gallbladder disease, pancreatitis ischemic colitis^[Ref]

Dermatologic

Common (1% to 10%): Pruritus, Rash

Uncommon (0.1% to 1%): Acne, alopecia, dry skin, sweating, skin discoloration

Postmarketing reports: Chloasma or melasma that may persist when drug is discontinue, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, urticaria, rash, acne^[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, arthralgia, leg cramps

Postmarketing reports: Arthralgia^[Ref]

Nervous system

Very common (10% or more): Headache (up to 19%)

Common (1% to 10%): Migraine, dizziness, hypertonia

Postmarketing reports: Headache, migraine, dizziness, exacerbation of chorea, exacerbation of epilepsy, growth potentiation of benign meningioma^[Ref]

In the WHIMS (Women's Health Initiative Memory Study) an ancillary study of WHI, the absolute risk of probable dementia for conjugated estrogen 0.625 mg-medroxyprogesterone 2.5 mg was 45 versus 22 cases per 10,000 women-years. These studies were conducted in women 65 to 79 years old and therefore it is unknown if this risk applies to younger postmenopausal women.^[Ref]

Psychiatric

Common (1% to 10%): Emotional lability, depression, Insomnia, nervousness, anxiety

Postmarketing reports: Mental depression, mood disturbances, anxiety, irritability, dementia^[Ref]

Hepatic

Postmarketing reports: Cholestatic jaundice^[Ref]

Respiratory

Common (1% to 10%): Pharyngitis, sinusitis

Postmarketing reports: Asthma exacerbation^[Ref]

Other

Common (1% to 10%): Asthenia, pain^[Ref]

Immunologic

Common (1% to 10%): Flu syndrome

Uncommon (0.1% to 1%): Infection, moniliasis