6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.2)]
- Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.3)]
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 12-week, randomized, double-blind, placebo-controlled trial of PREMARIN Vaginal Cream (PVC), a total of 423 postmenopausal women received at least 1 dose of study medication and were included in all safety analyses: 143 women in the PVC-21/7 treatment group (0.5 g PVC daily for 21 days, then 7 days off), 72 women in the matching placebo treatment group; 140 women in the PVC-2×/wk treatment group (0.5 g PVC twice weekly), 68 women in the matching placebo treatment group. A 40-week, open-label extension followed, in which a total of 394 women received treatment with PVC, including those subjects randomized at baseline to placebo. In this study, the most common adverse reactions ≥ 1 percent in the double blind phase are shown below (Table 1) [see Clinical Studies (14.1)].
| Treatment | ||||
|---|---|---|---|---|
| Body System*/Adverse Reaction | PVC 21/7 N=143 | Placebo 21/7 N=72 | PVC 2×/week N=140 | Placebo 2×/week N=68 |
| Number (%) of Patients with Adverse Reaction | ||||
| ||||
| Body As A Whole | ||||
| Abdominal Pain | 1 (0.7) | 1 (1.4) | 0 | 1 (1.5) |
| Headache | 5 (3.5) | 1 (1.4) | 3 (2.1) | 1 (1.5) |
| Moniliasis | 2 (1.4) | 1 (1.4) | 1 (0.7) | 0 |
| Pain | 2 (1.4) | 0 | 1 (0.7) | 0 |
| Pelvic Pain | 4 (2.8) | 2 (2.8) | 4 (2.9) | 0 |
| Cardiovascular System | ||||
| Migraine | 0 | 0 | 0 | 1 (1.5) |
| Vasodilation | 3 (2.1) | 2 (2.8) | 2 (1.4) | 0 |
| Musculoskeletal System | ||||
| Muscle Cramp | 2 (1.4) | 0 | 0 | 0 |
| Nervous System | ||||
| Dizziness | 1 (0.7) | 0 | 0 | 1 (1.5) |
| Skin and Appendages | ||||
| Acne | 0 | 0 | 2 (1.4) | 0 |
| Erythema | 0 | 1 (1.4) | 0 | 0 |
| Pruritus | 2 (1.4) | 1 (1.4) | 1 (0.7) | 0 |
| Urogenital System | ||||
| Breast Enlargement | 1 (0.7) | 1 (1.4) | 0 | 0 |
| Breast Pain | 7 (4.9) | 0 | 3 (2.1) | 0 |
| Dysuria | 2 (1.4) | 0 | 0 | 0 |
| Leukorrhea | 3 (2.1) | 1 (1.4) | 4 (2.9) | 5 (7.4) |
| Metrorrhagia | 0 | 0 | 0 | 2 (2.9) |
| Urinary Frequency | 0 | 1 (1.4) | 0 | 0 |
| Urinary Tract Infection | 0 | 1 (1.4) | 0 | 0 |
| Urinary Urgency | 1 (0.7) | 1 (1.4) | 0 | 0 |
| Vaginal Hemorrhage | 2 (1.4) | 0 | 1 (0.7) | 1 (1.5) |
| Vaginal Moniliasis | 2 (1.4) | 0 | 0 | 0 |
| Vaginitis | 2 (1.4) | 1 (1.4) | 3 (2.1) | 3 (4.4) |
| Vulvovaginal Disorder | 4 (2.8) | 0 | 3 (2.1) | 2 (2.9) |
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of PREMARIN Vaginal Cream. 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 or spotting, dysmenorrhea or pelvic pain, increase in size of uterine leiomyomata, vaginitis (including vaginal candidiasis), change in cervical secretion, cystitis-like syndrome, application site reactions of vulvovaginal discomfort, (including burning, irritation, and genital pruritus), endometrial hyperplasia, endometrial cancer, precocious puberty, leukorrhea.
Breasts
Tenderness, enlargement, pain, discharge, fibrocystic breast changes, breast cancer, gynecomastia in males.
Cardiovascular
Deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, increase in blood pressure.
Gastrointestinal
Nausea, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease.
Skin
Chloasma that may persist when drug is discontinued, loss of scalp hair, hirsutism, rash.
Eyes
Retinal vascular thrombosis, intolerance to contact lenses.
Central Nervous System
Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability, dementia.
Miscellaneous
Increase or decrease in weight, glucose intolerance, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.
Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.