Estring Drug Information

ESTRING is indicated for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.

One ESTRING (estradiol vaginal system) is to be inserted as deeply as possible into the upper one-third of the vaginal vault. The ring is to remain in place continuously for three months, after which it is to be removed and, if appropriate, replaced by a new ring. Should the ring be removed or fall out at any time during the 90-day treatment period, the ring should be rinsed in lukewarm water and re-inserted by the patient, or, if necessary, by a physician or nurse.

Retention of the ring for greater than 90 days does not represent overdosage but will result in progressively greater underdosage with the attendant risk of loss of efficacy and increasing risk of vaginal infections and/or erosions. Instructions for Use ESTRING (estradiol vaginal system) insertion The ring should be pressed into an oval and inserted into the upper third of the vaginal vault. The exact position is not critical.

When ESTRING is in place, the patient should not feel anything. If the patient feels discomfort, ESTRING is probably not far enough inside. Gently push ESTRING further into the vagina.

ESTRING use ESTRING should be left in place continuously for 90 days and then, if continuation of therapy is deemed appropriate, replaced by a new ESTRING. Straining at defecation may make ESTRING move down in the lower part of the vagina. If so, it may be pushed up again with a finger.

If ESTRING is expelled totally from the vagina, it should be rinsed in lukewarm water and reinserted by the patient (or doctor/nurse if necessary). ESTRING removal ESTRING may be removed by hooking a finger through the ring and pulling it out. For patient instructions, see Patient Information.

• See 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 ESTRING controlled studies, discontinuation of treatment due to an adverse event was required by 5.4 percent of patients receiving ESTRING and 3.9 percent of patients receiving conjugated estrogens vaginal cream. The most common reasons for withdrawal from ESTRING 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 or conjugated estrogens vaginal cream are listed in Table 3. TABLE 3: Adverse Events Reported by 3 Percent or More of Patients Receiving Either ESTRING or Conjugated Estrogens Vaginal Cream in Two Pivotal Controlled Studies 2 3 Postmarketing Experience 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. Vaginal erosion, vaginal ulceration, adherence of the vaginal ring to the vaginal wall:
• Cases of ring adherence to the vaginal wall, making ring removal difficult, have occurred. Some cases have required surgical removal of vaginal rings.
• Cases of vaginal erosion and vaginal ulceration that may manifest as vaginal irritation, erythema. abrasion or spotting have occurred. 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. Cases of bowel obstruction and vaginal ring use have been reported. Persistent abdominal complaints consistent with obstruction should be carefully evaluated. Cases of hypersensitivity have been reported. The following additional adverse events were reported at least once by patients receiving ESTRING in the worldwide clinical program, which includes controlled and uncontrolled studies. A causal relationship with ESTRING 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

F. Pregnancy ESTRING should not be used during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens as an oral contraceptive inadvertently during early pregnancy.

H. Pediatric Use ESTRING is not indicated in children. Clinical studies have not been conducted in the pediatric population.

ESTRING is contraindicated in women with any of the following conditions: 1. Abnormal genital bleeding with unknown etiology. 2. Known or suspected estrogen-dependent neoplasia. 3.

Active DVT, PE, or a history of these conditions. 4. Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions. 5. Known anaphylactic reaction or angioedema or hypersensitivity to ESTRING. 6.

Known liver impairment or disease. 7. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.

Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of ESTRING together with institution of appropriate symptomatic care.