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Prempro

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Prempro, Premphase

Side Effects
Interactions

SIDE EFFECTS

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

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 PREMPRO PREMPRO PREMPHASE

Body System
Adverse event
0.625 mg/2.5 mg
continuous
(n = 340)
0.625 mg/5 mg
continuous
(n = 338)
0.625 mg/5 mg
sequential
(n = 351)
Body As A Whole
  Abdominal pain 35 (10%) 51 (15%) 58 (17%)
  Asthenia 13 (4%) 18(5%) 21 (6%)
  Back pain 19 (6%) 16(5%) 23 (7%)
  Chest pain 5 (1%) 4 (1%) 4 (1%)
  Flu syndrome 1 ( < 1%) 1 ( < 1%) 4 (1%)
  Generalized edema 12 (4%) 12 (4%) 8 (2%)
  Headache 64 (19%) 52 (15%) 66 (19%)
  Infection 2 ( < 1%) 4 (1)% 0
  Moniliasis 4 (1%) 3 ( < 1%) 4 (1%)
  Pain 12 (4%) 14 (4%) 15 (4%)
  Pelvic pain 11(3%) 13 (4%) 16(5%)
Cardiovascular System
  Hypertension 7 (2%) 7 (2%) 6 (2%)
  Migraine 6 (2%) 8 (2%) 7 (2%)
  Palpitation 2 ( < 1%) 3 ( < 1%) 4 (1%)
  Vasodilatation 2 ( < 1%) 7 (2%) 2 ( < 1%)
Digestive System
  Diarrhea 4 (1%) 3 ( < 1%) 7 (2%)
  Dyspepsia 5 (1%) 5 (1%) 7 (2%)
  Eructation 0 2 ( < 1%) 4 (1%)
  Flatulence 25 (7%) 27 (8%) 24 (7%)
  Increased appetite 1 ( < 1%) 5 (1%) 5 (1%)
  Nausea 26 (8%) 19 (6%) 26 (7%)
Metabolic and Nutritional
  Edema 5 (1%) 6 (2%) 3 ( < 1%)
  Glucose tolerance decreased 2 ( < 1%) 5 (1%) 4 (1%)
  Peripheral edema 11(3%) 10 (3%) 11(3%)
  Weight gain 9 (3%) 10 (3%) 11(3%)
Musculoskeletal System
  Arthralgia 6 (2%) 2 ( < 1%) 7 (2%)
  Leg cramps 8 (2%) 11(3%) 12 (3%)
Nervous System
  Depression 14 (4%) 26 (8%) 29 (8%)
  Dizziness 9 (3%) 8 (2%) 7 (2%)
  Emotional lability 5 (1%) 5 (1%) 6 (2%)
  Hypertonia 4 (1%) 4 (1%) 7 (2%)
  Insomnia 7 (2%) 6 (2%) 4 (1%)
  Nervousness 4 (1%) 9 (3%) 6 (2%)
Skin and Appendages
  Acne 1 ( < 1%) 5 (1%) 4 (1%)
  Alopecia 3 ( < 1%) 4 (1%) 0
  Dry skin 2 ( < 1%) 3 ( < 1%) 4 (1%)
  Pruritus 20 (6%) 18(5%) 13 (4%)
  Rash 8 (2%) 6 (2%) 7 (2%)
  Sweating 2 ( < 1%) 4 (1%) 2 ( < 1%)
Urogenital System
  Breast engorgement 5 (1%) 5 (1%) 0
  Breast enlargement 14 (4%) 14 (4%) 14 (4%)
  Breast neoplasm 2 ( < 1%) 2 ( < 1%) 4 (1%)
  Breast pain 110(32%) 123 (36%) 109(31%)
  Cervix disorder 10 (3%) 6 (2%) 10 (3%)
  Dysmenorrhea 26 (8%) 18(5%) 44(13%)
  Leukorrhea 19 (6%) 13 (4%) 29 (8%)
  Menstrual disorder 7 (2%) 1 ( < 1%) 5 (1%)
  Menorrhagia 0 1 ( < 1%) 5 (1%)
  Metrorrhagia 13 (4%) 5 (1%) 7 (1%)
  Papanicolaou smear suspicious 5 (1%) 0 8 (2%)
  Urinary incontinence 4 (1%) 2 ( < 1%) 1 ( < 1%)
  Uterine spasm 7 (2%) 4 (1%) 7 (2%)
  Vaginal hemorrhage 5 (1%) 3 ( < 1%) 8 (2%)
  Vaginal moniliasis 5 (1%) 6 (2%) 7 (2%)
  Vaginitis 13 (4%) 13 (4%) 10 (3%)

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

Body System
Adverse event
PREMPRO
0.625/2.5
continuous
(N=331)
PREMPRO
0.45/1.5
continuous
(N=331)
PREMPRO
0.3/1.5
continuous
(N=327)
PLACEBO
daily
(N=332)
Any adverse event 214(65) 208 (63) 188(57) 164(49)
Body as a Whole
  Abdominal pain 38(11) 33 (10) 24(7) 21(6)
  Asthenia 11(3) 11(3) 12(4) 3(1)
  Back pain 12(4) 12(4) 8(2) 4(1)
  Chest pain 4(1) 2(1) 1(0) 2(1)
  Generalized edema 7(2) 5(2) 6(2) 8(2)
  Headache 45 (14) 45 (14) 57 (17) 46 (14)
  Moniliasis 3(1) 6(2) 4(1) 1(0)
  Pain 9(3) 10(3) 17(5) 14(4)
  Pelvic pain 9(3) 7(2) 5(2) 4(1)
Cardiovascular System
  Hypertension 2(1) 3(1) 1(0) 5(2)
  Migraine 11(3) 8(2) 5(2) 3(1)
  Palpitation 1(0) 1(0) 2(1) 4(1)
  Vasodilatation 0 3(1) 1(0) 5(2)
Digestive System
  Constipation 5(2) 7(2) 6(2) 3(1)
  Diarrhea 5(2) 2(1) 6(2) 8(2)
  Dyspepsia 10(3) 9(3) 6(2) 14(4)
  Flatulence 16(5) 18(5) 13(4) 8(2)
  Increased appetite 6(2) 2(1) 0 2(1)
  Nausea 13(4) 13(4) 16(5) 16(5)
Metabolic and nutritional
  Peripheral edema 7(2) 8(2) 4(1) 3(1)
  Weight gain 9(3) 8(2) 6(2) 14(4)
Musculoskeletal System
  Arthralgia 2(1) 3(1) 3(1) 5(2)
  Leg cramps 13(4) 7(2) 10(3) 4(1)
Nervous System
  Anxiety 5(2) 4(1) 1(0) 4(1)
  Depression 23(7) 11(3) 11(3) 17(5)
  Dizziness 3(1) 8(2) 6(2) 5(2)
  Emotional lability 10(3) 10(3) 9(3) 8(2)
  Insomnia 8(2) 7(2) 9(3) 14(4)
  Nervousness 6(2) 3(1) 4(1) 6(2)
Skin and Appendages
  Acne 7(2) 3(1) 0 3(1)
  Alopecia 1(0) 6(2) 4(1) 2(1)
  Pruritus 8(2) 10(3) 9(3) 3(1)
  Rash 0 6(2) 4(1) 2(1)
  Skin discoloration 5(2) 1(0) 3(1) 1(0)
  Sweating 3(1) 1(0) 0 4(1)
Urogenital System
  Breast disorder 7(2) 6(2) 5(2) 6(2)
  Breast enlargement 18(5) 9(3) 5(2) 3(1)
  Breast neoplasm 8(2) 7(2) 5(2) 7(2)
  Breast pain 87 (26) 66 (20) 41 (13) 26(8)
  Cervix disorder 7(2) 2(1) 2(1) 0
  Dysmenorrhea 14(4) 18(5) 9(3) 2(1)
  Hematuria 4(1) 3(1) 1(0) 2(1)
  Leukorrhea 7(2) 14(4) 9(3) 6(2)
  Metrorrhagia 7(2) 14(4) 4(1) 1(0)
  Urinary tract infection 0 1(0) 1(0) 4(1)
  Uterine spasm 13(4) 11(3) 7(2) 2(1)
  Vaginal dryness 2(1) 1(0) 0 6(2)
  Vaginal hemorrhage 18(5) 14(4) 7(2) 0
  Vaginal moniliasis 13(4) 11(3) 8(2) 5(2)
  Vaginitis 6(2) 8(2) 7(2) 1 (0)

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.

Read the Prempro, Premphase (conjugated estrogens, medroxyprogesterone acetate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

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.

Read the Prempro, Premphase Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 2/21/2012
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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Prempro, Premphase - User Reviews

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