6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in labeling:
- Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)]
- Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]
6.1 Clinical Study Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus between 40 and 65 years of age (88 percent Caucasian), 1,012 women were treated with conjugated estrogens, and 332 were treated with placebo.
Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥ 1 percent in any treatment group.
| PREMARIN 0.625 mg (n=348) | PREMARIN 0.45 mg (n=338) | PREMARIN 0.3 mg (n=326) | Placebo (n=332) | |
|---|---|---|---|---|
| Body as a whole | ||||
| Abdominal pain | 38 (11) | 28 (8) | 30 (9) | 21 (6) |
| Asthenia | 16 (5) | 8 (2) | 14 (4) | 3 (1) |
| Back pain | 18 (5) | 11 (3) | 13 (4) | 4 (1) |
| Chest pain | 2 (1) | 3 (1) | 4 (1) | 2 (1) |
| Generalized edema | 7 (2) | 6 (2) | 4 (1) | 8 (2) |
| Headache | 45 (13) | 47 (14) | 44 (13) | 46 (14) |
| Moniliasis | 5 (1) | 4 (1) | 4 (1) | 1 (0) |
| Pain | 17 (5) | 10 (3) | 12 (4) | 14 (4) |
| Pelvic pain | 10 (3) | 9 (3) | 8 (2) | 4 (1) |
| Cardiovascular system | ||||
| Hypertension | 4 (1) | 4 (1) | 7 (2) | 5 (2) |
| Migraine | 7 (2) | 1 (0) | 0 | 3 (1) |
| Palpitation | 3 (1) | 3 (1) | 3 (1) | 4 (1) |
| Vasodilatation | 2 (1) | 2 (1) | 3 (1) | 5 (2) |
| Digestive system | ||||
| Constipation | 7 (2) | 6 (2) | 4 (1) | 3 (1) |
| Diarrhea | 4 (1) | 5 (1) | 5 (2) | 8 (2) |
| Dyspepsia | 7 (2) | 5 (1) | 6 (2) | 14 (4) |
| Eructation | 1 (0) | 1 (0) | 4 (1) | 1 (0) |
| Flatulence | 22 (6) | 18 (5) | 13 (4) | 8 (2) |
| Increased appetite | 4 (1) | 1 (0) | 1 (0) | 2 (1) |
| Nausea | 16 (5) | 10 (3) | 15 (5) | 16 (5) |
| Metabolic and nutritional | ||||
| Hyperlipidemia | 2 (1) | 4 (1) | 3 (1) | 2 (1) |
| Peripheral edema | 5 (1) | 2 (1) | 4 (1) | 3 (1) |
| Weight gain | 11 (3) | 10 (3) | 8 (2) | 14 (4) |
| Musculoskeletal system | ||||
| Arthralgia | 6 (2) | 3 (1) | 2 (1) | 5 (2) |
| Leg cramps | 10 (3) | 5 (1) | 9 (3) | 4 (1) |
| Myalgia | 2 (1) | 1 (0) | 4 (1) | 1 (0) |
| Nervous system | ||||
| Anxiety | 6 (2) | 4 (1) | 2 (1) | 4 (1) |
| Depression | 17 (5) | 15 (4) | 10 (3) | 17 (5) |
| Dizziness | 9 (3) | 7 (2) | 4 (1) | 5 (2) |
| Emotional lability | 3 (1) | 4 (1) | 5 (2) | 8 (2) |
| Hypertonia | 1 (0) | 1 (0) | 5 (2) | 3 (1) |
| Insomnia | 16 (5) | 10 (3) | 13 (4) | 14 (4) |
| Nervousness | 9 (3) | 12 (4) | 2 (1) | 6 (2) |
| Skin and appendages | ||||
| Acne | 3 (1) | 1 (0) | 8 (2) | 3 (1) |
| Alopecia | 6 (2) | 6 (2) | 5 (2) | 2 (1) |
| Hirsutism | 4 (1) | 2 (1) | 1 (0) | 0 |
| Pruritus | 11 (3) | 11 (3) | 10 (3) | 3 (1) |
| Rash | 6 (2) | 3 (1) | 1 (0) | 2 (1) |
| Skin discoloration | 4 (1) | 2 (1) | 0 | 1 (0) |
| Sweating | 4 (1) | 1 (0) | 3 (1) | 4 (1) |
| Urogenital system | ||||
| Breast disorder | 6 (2) | 3 (1) | 3 (1) | 6 (2) |
| Breast enlargement | 3 (1) | 4 (1) | 7 (2) | 3 (1) |
| Breast neoplasm | 4 (1) | 4 (1) | 7 (2) | 7 (2) |
| Breast pain | 37 (11) | 39 (12) | 24 (7) | 26 (8) |
| Cervix disorder | 8 (2) | 4 (1) | 5 (2) | 0 |
| Dysmenorrhea | 12 (3) | 10 (3) | 4 (1) | 2 (1) |
| Endometrial disorder | 4 (1) | 2 (1) | 2 (1) | 0 |
| Endometrial hyperplasia | 16 (5) | 8 (2) | 1 (0) | 0 |
| Leukorrhea | 17 (5) | 17 (5) | 12 (4) | 6 (2) |
| Metrorrhagia | 11 (3) | 4 (1) | 3 (1) | 1 (0) |
| Urinary tract infection | 1 (0) | 2 (1) | 1 (0) | 4 (1) |
| Uterine fibroids enlarged | 6 (2) | 1 (0) | 2 (1) | 2 (1) |
| Uterine spasm | 11 (3) | 5 (1) | 3 (1) | 2 (1) |
| Vaginal dryness | 1 (0) | 2 (1) | 1 (0) | 6 (2) |
| Vaginal hemorrhage | 46 (13) | 13 (4) | 6 (2) | 0 |
| Vaginal moniliasis | 14 (4) | 10 (3) | 12 (4) | 5 (2) |
| Vaginitis | 18 (5) | 7 (2) | 9 (3) | 1 (0) |
6.2 Postmarketing Experience
The following additional adverse reactions have been identified during post-approval use of PREMARIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible always to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary system
Abnormal uterine bleeding; dysmenorrheal or pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leukorrhea.
Breasts
Tenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer, gynecomastia in males.
Cardiovascular
Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure.
Gastrointestinal
Nausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis.
Skin
Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, rash.