Adverse Drug Reaction Overview
See Warnings/Precautions regarding potential induction of malignant neoplasia and other adverse effects similar to those observed with oral contraceptives.
The following additional adverse reactions have been reported with conjugated estrogens vaginal cream or are undesirable effects associated with ET/HT:
Blood and lymphatic system disorders
Altered coagulation tests (see WARNINGS AND PRECAUTIONS, Drug-Laboratory Tests Interactions).
Cardiac disorders
Palpitations; increase in blood pressure (see WARNINGS AND PRECAUTIONS); coronary thrombosis, pulmonary embolism, venous thrombosis, myocardial infarction.
Endocrine disorders
Increased blood sugar levels; decreased glucose tolerance, precocious puberty.
Eye disorders
Neuro-ocular lesions (e.g. retinal vascular thrombosis, optic neuritis); visual disturbances; steepening of the corneal curvature; intolerance to contact lenses.
Gastrointestinal disorders
Nausea; vomiting; abdominal discomfort (cramps, pressure, pain, bloating), pancreatitis; ischemic colitis.
General disorders and administration site conditions
Fatigue; changes in appetite; changes in body weight; changes in libido, aggravation of porphyria, hypocalcemia (in patients with pre-existing conditions of hypocalcemia), angioedema, hypersensitivity, anaphylactic/anaphylactoid reactions, increased triglycerides.
Hepatobiliary disorders
Gallbladder disorder; cholestatic jaundice, asymptomatic impaired liver function.
Musculoskeletal and connective tissue disorders
Musculoskeletal pain including leg pain not related to thromboembolic disease (usually transient, lasting 3-6 weeks) may occur, arthralgia, leg cramps.
Neoplasms, benign
Fibrocystic breast changes; enlargement of hepatic hemangiomas; growth potentiation of benign meningioma.
Nervous system disorders
Aggravation of migraine episodes; headaches; migraines, dizziness; cerebrovascular accident/stroke; exacerbation of chorea, neuritis.
Psychiatric disorders
Mental depression; nervousness; irritability, mood disturbances, dementia.
Renal and urinary disorders
Cystitis-like syndrome; dysuria; sodium retention; edema.
Reproductive system and breast disorders
Abnormal uterine bleeding; change in menstrual flow; dysmenorrhea/pelvic pain; vaginal itching/discharge; dyspareunia; endometrial hyperplasia; pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion; breast swelling and tenderness, galactorrhea, breast discharge, amenorrhea, increase in size of uterine leiomyomata, vaginitis, application site reactions of vulvovaginal discomfort including burning, irritation and genital pruritus, vaginal candidiasis; leukorrhea.
Skin and subcutaneous tissue disorders
Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; haemorrhagic eruption; loss of scalp hair; hirsutism and acne, allergic reactions and rashes, generalized rash, uticaria, pigmentation of the skin, pruritis.
Vascular disorders
Isolated cases of: thrombophlebitis; thromboembolic disorders.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Low Dose Regimen
In a 12-week, randomized, double-blind, placebo-controlled trial of conjugated estrogens vaginal cream [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-2x/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, there were no statistically significant differences in adverse reactions between PVC and placebo. The most common adverse drug reactions ≥ 1% are shown below (Table 1).
Table 1: Number (%) of Patients Reporting Treatment Emergent Adverse Drug Reactions ≥ 1% | ||||
Treatment | ||||
Body Systema Adverse Event | PVC 21/7 N= 143 | Placebo 21/7 N = 72 | PVC 2x/wk N = 140 | Placebo N= 68 |
BODY AS A WHOLE | ||||
Abdominal Pain | 11 (7.7) | 2 (2.8) | 9 (6.4) | 6 (8.8) |
CARDIOVASCULAR SYSTEM | ||||
Hypertension | 2 (1.4) | 2 (2.8) | 5 (3.6) | 0 |
Migraine | 2 (1.4) | 0 | 0 | 2 (2.9) |
DIGESTIVE SYSTEM | ||||
Abdominal Distension | 2 (1.4) | 1 (1.4) | 2 (1.4) | 1 (1.5) |
Nausea | 5 (3.5) | 4 (5.6) | 3 (2.1) | 4 (5.9) |
Vomiting | 3 (2.1) | 2 (2.8) | 3 (2.1) | 3 (4.4) |
METABOLIC AND NUTRITIONAL | ||||
Peripheral Edema | 2 (1.4) | 0 | 0 | 0 |
Weight Gain | 3 (2.1) | 1 (1.4) | 1 (0.7) | 0 |
MUSCULOSKELETAL SYSTEM | ||||
Arthralgia | 4 (2.8) | 5 (6.9) | 5 (3.6) | 4 (5.9) |
SKIN AND APPENDAGES | ||||
Pruritus | 3 (2.1) | 1 (1.4) | 5 (3.6) | 0 |
Rash | 3 (2.1) | 1 (1.4) | 5 (3.6) | 0 |
UROGENITAL SYSTEM | ||||
Breast Pain | 8 (5.6) | 2 (2.8) | 4 (2.9) | 0 |
Cystitis | 1 (0.7) | 1 (1.4) | 2 (1.4) | 1 (1.5) |
Leukorrhea | 3 (2.1) | 2 (2.8) | 4 (2.9) | 6 (8.8) |
Metrorrhagia | 3 (2.1) | 2 (2.8) | 0 | 1 (1.5) |
Vaginal Hemorrhage | 1 (0.7) | 1 (1.4) | 2 (1.4) | 2 (2.9) |
Vaginitis | 8 (5.6) | 3 (4.2) | 7 (5.0) | 3 (4.4) |
Vuluovaginitis | 0 | 1 (1.4) | 2 (1.4) | 0 |
a. Body system totals for the No. of Patients are not necessarily the sum of the individual adverse events since a patient may report two or more different adverse events in the same body system. | ||||
Other Clinical Trial Adverse Drug Reactions (<1%)
The following adverse events were reported at an incidence of <1% for Premarin Vaginal Cream regardless of drug relationship.
Body As A Whole: Carcinoma; Chills; Cyst; Fever; Injection Site Pain
Cardiovascular System: Cardiovascular Physical; Hemorrhage; Palpitation; Tachycardia
Digestive System: Cheilitis; Cholecystitis; Cholelithiasis; Colitis; Eructation; Esophagitis; Gastritis; Gingivitis; Increased Appetite; Oral Moniliasis; Periodontal Abscess; Tenesmus
Metabolic And Nutritional: Hyperglycemia; Hyperlipemia
Musculoskeletal System: Bone Disorder; Muscle Spasms; Musculoskeletal Stiffness
Nervous System: Agitation; Attention Deficit/Hyperactivity; Confusion; Hostility; Memory Impairment
Respiratory System: Pleural Disorder; Sputum Increased
Skin And Appendages: Alopecia; Hair Disorder; Herpes Simplex; Herpes Zoster; Lichenoid Dermatitis; Night Sweats; Sunburn; Urticaria
Special Senses: Dry Eyes; Ear Disorder; Eye Pain; Lacrimation Disorder
Urogenital System: Breast Disorder; Endometrial Disorder; Genital Edema; Hematuria; Urethral Pain; Urinary Incontinence; Urine Abnormality; Uterine Fibroids Enlargement
If adverse symptoms persist, the prescription of HRT should be re-considered.
Post-Marketing Adverse Drug Reactions
The following adverse reactions have been reported with 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/spotting, dysmenorrhea/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, anaphylactic reactions, exacerbation of asthma, increased triglycerides, hypersensitivity.
Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.