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PREMPRO® AND PREMPHASE®Adverse Reactions (conjugated estrogens and medroxyprogesterone acetate)

6 ADVERSE REACTIONS

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

6.1 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
Body SystemPREMPRO
0.625 mg/2.5 mg
continuous
PREMPRO
0.625 mg/5 mg
continuous
PREMPHASE
0.625 mg/5 mg
sequential
  Adverse event (n = 340)(n = 338)(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 edema12 (4%) 12 (4%)8 (2%)
  Headache64 (19%)52 (15%) 66 (19%)
  Infection2 (<1%) 4 (1)%0
  Moniliasis4 (1%) 3 (<1%)4 (1%)
  Pain12 (4%) 14 (4%)15 (4%)
  Pelvic pain11 (3%) 13 (4%)16 (5%)
Cardiovascular System
  Hypertension7 (2%) 7 (2%)6 (2%)
  Migraine 6 (2%) 8 (2%) 7 (2%)
  Palpitation2 (<1%)3 (<1%)4 (1%)
  Vasodilatation2 (<1%)7 (2%)2 (<1%)
Digestive System
  Diarrhea4 (1%) 3 (<1%) 7 (2%)
  Dyspepsia5 (1%)5 (1%)7 (2%)
  Eructation02 (<1%)4 (1%)
  Flatulence25 (7%)27 (8%)24 (7%)
  Increased appetite1 (<1%)5 (1%)5 (1%)
  Nausea26 (8%)19 (6%)26 (7%)
Metabolic and Nutritional
  Edema5 (1%) 6 (2%)3 (<1%)
  Glucose tolerance
  decreased
2 (<1%)5 (1%)4 (1%)
  Peripheral edema 11 (3%)10 (3%) 11 (3%)
    Weight gain9 (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%)
  Hypertonia4 (1%)4 (1%)7 (2%)
  Insomnia7 (2%)6 (2%)4 (1%)
  Nervousness4 (1%) 9 (3%) 6 (2%)
Skin and Appendages
  Acne1 (<1%) 5 (1%)4 (1%)
  Alopecia3 (<1%)4 (1%)0
  Dry skin2 (<1%)3 (<1%)4 (1%)
  Pruritus20 (6%)18 (5%)13 (4%)
  Rash8 (2%)6 (2%)7 (2%)
  Sweating 2 (<1%)4 (1%)2 (<1%)
Urogenital System
  Breast engorgement5 (1%)5 (1%)0
  Breast enlargement14 (4%) 14 (4%) 14 (4%)
  Breast neoplasm2 (<1%)2 (<1%)4 (1%)
  Breast pain110 (32%)123 (36%)109 (31%)
  Cervix disorder10 (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%)
  Menorrhagia01 (<1%)5 (1%)
  Metrorrhagia 13 (4%)5 (1%)7 (1%)
  Papanicolaou smear
  suspicious
5 (1%) 08 (2%)
  Urinary incontinence4 (1%)2 (<1%)1 (<1%)
  Uterine spasm7 (2%)4 (1%)7 (2%)
  Vaginal hemorrhage5 (1%)3 (<1%)8 (2%)
  Vaginal moniliasis5 (1%)6 (2%)7 (2%)
  Vaginitis13 (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 event214 (65)208 (63)188 (57)164 (49)
Body as a Whole
  Abdominal pain38 (11)33 (10)24 (7)21 (6)
  Asthenia11 (3)11 (3)12 (4)3 (1)
  Back pain12 (4)12 (4)8 (2)4 (1)
  Chest pain4 (1)2 (1)1 (0)2 (1)
  Generalized edema7 (2)5 (2)6 (2)8 (2)
  Headache45 (14)45 (14)57 (17)46 (14)
  Moniliasis3 (1)6 (2)4 (1)1 (0)
  Pain9 (3)10 (3)17 (5)14 (4)
  Pelvic pain9 (3)7 (2)5 (2)4 (1)
Cardiovascular System
  Hypertension2 (1)3 (1)1 (0)5 (2)
  Migraine11 (3)8 (2)5 (2)3 (1)
  Palpitation1 (0)1 (0)2 (1)4 (1)
  Vasodilatation03 (1)1 (0)5 (2)
Digestive System
  Constipation5 (2)7 (2)6 (2)3 (1)
  Diarrhea5 (2)2 (1)6 (2)8 (2)
  Dyspepsia10 (3)9 (3)6 (2)14 (4)
  Flatulence16 (5)18 (5)13 (4)8 (2)
  Increased appetite6 (2)2 (1)02 (1)
  Nausea13 (4)13 (4)16 (5)16 (5)
Metabolic and nutritional
  Peripheral edema7 (2)8 (2)4 (1)3 (1)
  Weight gain9 (3)8 (2)6 (2)14 (4)
Musculoskeletal System
  Arthralgia2 (1)3 (1)3 (1)5 (2)
  Leg cramps13 (4)7 (2)10 (3)4 (1)
Nervous System
  Anxiety5 (2)4 (1)1 (0)4 (1)
  Depression23 (7)11 (3)11 (3)17 (5)
  Dizziness3 (1)8 (2)6 (2)5 (2)
  Emotional lability10 (3)10 (3)9 (3)8 (2)
  Insomnia8 (2)7 (2)9 (3)14 (4)
  Nervousness6 (2)3 (1)4 (1)6 (2)
Skin and Appendages
  Acne7 (2)3 (1)03 (1)
  Alopecia1 (0)6 (2)4 (1)2 (1)
  Pruritus8 (2)10 (3)9 (3)3 (1)
  Rash06 (2)4 (1)2 (1)
  Skin discoloration5 (2)1 (0)3 (1)1 (0)
  Sweating3 (1)1 (0)04 (1)
Urogenital System
  Breast disorder7 (2)6 (2)5 (2)6 (2)
  Breast enlargement18 (5)9 (3)5 (2)3 (1)
  Breast neoplasm8 (2)7 (2)5 (2)7 (2)
  Breast pain87 (26)66 (20)41 (13)26 (8)
  Cervix disorder7 (2)2 (1)2 (1)0
  Dysmenorrhea14 (4)18 (5)9 (3)2 (1)
  Hematuria4 (1)3 (1)1 (0)2 (1)
  Leukorrhea7 (2)14 (4)9 (3)6 (2)
  Metrorrhagia7 (2)14 (4)4 (1)1 (0)
  Urinary tract infection01 (0)1 (0)4 (1)
  Uterine spasm13 (4)11 (3)7 (2)2 (1)
  Vaginal dryness2 (1)1 (0)06 (2)
  Vaginal hemorrhage18 (5)14 (4)7 (2)0
  Vaginal moniliasis13 (4)11 (3)8 (2)5 (2)
  Vaginitis6 (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.

6.2 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.

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