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See BOXED WARNINGS, WARNINGS and PRECAUTIONS

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 practice.

In the two pivotal controlled studies, discontinuation of treatment due to an adverse event was required by 5.4 percent of patients receiving ESTRING (estradiol vaginal ring) and 3.9 percent of patients receiving conjugated estrogens vaginal cream. The most common reasons for withdrawal from ESTRING (estradiol vaginal ring) treatment due to an adverse event were vaginal discomfort and gastrointestinal symptoms.

The adverse events reported with a frequency of 3 percent or greater in the two pivotal controlled studies by patients receiving ESTRING (estradiol vaginal ring) or conjugated estrogens vaginal cream are listed in Table 4.

Table 4: Adverse Events Reported by 3 Percent or More of Patients Receiving Either ESTRING (estradiol vaginal ring) or Conjugated Estrogens Vaginal Cream in Two Pivotal Controlled Studies

Other adverse events (listed alphabetically) occurring at a frequency of 1 to 3 percent in the two pivotal controlled studies by patients receiving ESTRING (estradiol vaginal ring) include: anxiety, bronchitis, chest pain, cystitis, dermatitis, diarrhea, dyspepsia, dysuria, flatulence, gastritis, genital eruption, urogenital pruritus, hemorrhoids, leg edema, migraine, otitis media, skin hypertrophy, syncope, toothache, tooth disorder, urinary incontinence.

Post-Marketing Experience

1. A few cases of toxic shock syndrome (TSS) have been reported in women using vaginal rings. TSS is a rare, but serious disease that may cause death. Warning signs of TSS include fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness, or a sunburn-rash on face and body.
2. A few cases of ring adherence to the vaginal wall, making ring removal difficult, have been reported. Vaginal wall ulceration or erosion should be carefully evaluated. If an ulceration or erosion has occurred, consideration should be given to leaving the ring out and not replacing it until healing is complete in order to prevent the ring from adhering to the healing tissue.
3. A few cases of bowel obstruction and vaginal ring use have been reported. Persistent abdominal complaints consistent with obstruction should be carefully evaluated.

The following additional adverse events were reported at least once by patients receiving ESTRING (estradiol vaginal ring) in the worldwide clinical program, which includes controlled and uncontrolled studies. A causal relationship with ESTRING (estradiol vaginal ring) has not been established.

Body as a Whole:allergic reaction CNS/Peripheral Nervous System: dizziness Gastrointestinal: enlarged abdomen, vomiting

Metabolic/Nutritional Disorders: weight decrease or increase Musculoskeletal: arthropathy (including arthrosis) Psychiatric: depression, decreased libido, nervousness

Reproductive: breast engorgement, breast enlargement, intermenstrual bleeding, genital edema, vulval disorder

Skin/Appendages: pruritus, pruritus ani

Urinary: micturition frequency, urethral disorder

Vascular: thrombophlebitis

Vision: abnormal vision

The following additional adverse reactions have been reported with estrogens:

Genitourinary system: abnormal uterine bleeding/spotting; dysmenorrheal/pelvic pain; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer

Breasts: tenderness, enlargement, pain, nipple disc harge, galactorrhea; fibrocystic breast changes; breast cancer

Cardiovascular: deep and superficial venous th rombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure

Gastrointestinal: nausea, vomiting;abdominal cramps, bloating; c holestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas

Skin: chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism, rash

Eyes:retinal vascular thrombosis; intolerance to contact lenses

Central Nervous System: headache; migraine; dizziness; mental depression; exacerbation of chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia

Miscellaneous: increase or decrease in weight; glucose intolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; angioedema; anaphylactoid/anaphylactic reactions; hypocalcemia (preexisting condition); exacerbation of asthma; increased triglycerides

Drug and Laboratory Test Interactions

1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels, as measured by protein-bound iodine (PBI), T₄ levels (by column or by radioimmunoassay) or T₃ levels by radioimmunoassay. T₃ resin uptake is decreased, reflecting the elevated TBG. Free T₄ and free T₃ concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, (i.e., corticosteroid binding globulin [CBG], sex hormone-binding globulin [SHBG]), leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL₂cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
5. Impaired glucose tolerance.

Last reviewed on RxList: 10/16/2008
This monograph has been modified to include the generic and brand name in many instances.