6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)]
- Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]
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.
| Body System | PREMPRO 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 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.
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.
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.