PREMARIN (conjugated estrogens) Adverse Reactions

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 estrogen replacement therapy or are undesirable effects associated with hormone replacement therapy:

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, myocardial infarction.

Endocrine disorders

Increased blood sugar levels; decreased glucose tolerance, carbohydrate tolerance

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, gallbladder disorder; ischemic colitis.

General disorders and administration site conditions

Fatigue; changes in appetite; changes in body weight; changes in libido, exacerbation of porphyria, hypocalcemia (in patients with disease that can predispose to severe hypocalcemia), exacerbation of asthma, angioedema, hypersensitivity; anaphylactic/anaphlactoid reactions, increased triglycerides.

Hepatobiliary disorders

Gallbladder disorder; cholestatic jaundice.

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.

Nervous system disorders

Aggravation of migraine episodes; headaches; dizziness; cerebrovascular accident/stroke, exacerbation of epilepsy, stroke, exacerbation of chorea, somnolence, insomnia.

Psychiatric disorders

Mental depression; nervousness; irritability, anxiety, mood disturbances, dementia, fatigue.

Renal and urinary disorders

Cystitis; dysuria; sodium retention; edema.

Reproductive system and breast disorders

Breakthrough bleeding; spotting; change in menstrual flow and abnormal withdrawal bleeding or flow, dysmenorrheal/pelvic pain; vaginal itching/discharge; dyspareunia; endometrial hyperplasia; pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion; vaginal candidiasis, amenorrhea, vaginitis, increase in size of uterine leiomyomata, breast swelling and tenderness, breast pain, enlargement, galactorrhea, breast discharge; growth potentiation of benign meningioma; 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, urticaria, pruritus, generalized rash, rash (allergic) with without pruritus, alopecia.

Vascular disorders

Isolated cases of: thrombophlebitis; thromboembolic disorders, venous thrombosis.

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.

A phase III double-blind, randomized study was conducted to compare the efficacy and safety of various regimens of PREMARIN (conjugated estrogens) and medroxyprogesterone acetate (MPA). Efficacy was determined by the incidence of endometrial hyperplasia at the twelve month evaluation. A total of 1,724 generally healthy postmenopausal women (mean age, 54.0 years ± SD 4.6) participated in the study. The patients were considered as having completed the study if they participated in all 13 cycles (28 days/cycle). The five arms in the study were: 2 for Premplus®, 2 for Premplus Cycle®, and 1 for PREMARIN alone.

Prior to treatment, the following were performed: physical examinations, vital signs, papanicolaou smear, laboratory safety screen, mammography, follicle stimulating hormone (FSH), and endometrial biopsy. During the patient visit for Cycle 6, all but the mammography and FSH were performed. At the end of the study, Cycle 13, all but the FSH were performed.

No dose-dependent incidence of adverse experiences was seen in the multicenter efficacy and safety study. Significantly (p< 0.05) fewer (12%) PREMARIN treated patients reported breast pain than in the PREMARIN /MPA groups. Headache was the most common drug-related study event in the PREMARIN alone group, reported by 69 (20%) patients. Table 1 summarizes the treatment-emergent drug-related study events reported by 2% or more of the patients.

+ Patients were counted only once for a particular study event.
* Breast pain also includes breast discomfort, breast soreness, breast tenderness, mastodynia, nipple soreness and nipple tenderness.
** Cervix disorder includes cervical dysplasia, cervical erosion, cervical hypersecretion.
† Pap smear abnormal refers to positive Pap smear class III through V.
*** Vaginal bleeding includes menorrhagia, metrorrhagia, uterine hemorrhage, and vaginal hemorrhage.
a, b, d, = Significant difference ( p < 0.05) from treatment group Premplus® (0.625/2.5 mg), Premplus® (0.625/5.0 mg), Premplus Cycle® (0.625/10.0 mg) and PREMARIN (0.625 mg) respectively.

The above Table 1 summarizes the treatment-emergent drug-related study events reported by greater than 2% of the patients. The number of patients with any study event is not necessarily the sum of the individual events since a patient might have reported two or more different study events. The addition of progestin to estrogen replacement therapy may contribute to breast pain. This is reflected by the greater percentage of patients with breast pain on combination therapy than on PREMARIN alone.

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 tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Genitourinary System
Abnormal uterine bleeding, dysmenorrhea/pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leucorrhea.

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.

Eyes
Retinal vascular thrombosis, intolerance to contact lenses.

Central Nervous System
Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability, exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma.

Miscellaneous
Increase or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgia, leg cramps , changes in libido, urticaria, angioedema, anaphylactoid/anaphylactic reactions, exacerbation of asthma, increased triglycerides, hypersensitivity.

Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.