Estring

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

DOSAGE AND ADMINISTRATION 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. The patient should not feel ESTRING when it is in place and it should not interfere with sexual intercourse. 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 .

CONTRAINDICATIONS 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.

WARNINGS 1. Endometrial Cancer with Unopposed Estrogen in Women with a Uterus In ESTRING-treated menopausal women with a uterus with persistent or recurring abnormal genital bleeding of unknown etiology, perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to assess for endometrial cancer. There is an increased risk of endometrial cancer with the use of systemic estrogens alone in women with a uterus. The reported endometrial cancer risk among unopposed systemic estrogen users is about 2 to 12 times greater than in non-users and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of systemically administered estrogens for less than one year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after systemic estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestogen to estrogen-alone therapy has been shown to reduce the risk of endometrial hyperplasia (possible precursor to endometrial cancer). There is, however, a different risk profile associated with the use of progestogens plus estrogens compared to estrogen-alone regimens. 2. Risks Associated with Concomitant Use of Estrogen Plus Progestogen If ESTRING is administered with a progestogen, there are possible risks associated with the concomitant use of estrogen with progestogen that differ from those of estrogen-alone regimens. Refer to the prescribing information for progestogens indicated for the prevention of endometrial hyperplasia in nonhysterectomized women receiving estrogens for a discussion of the risks of estrogen and progestogen concomitant therapy. 3. Risks with Systemic Estrogen-Alone Therapy Systemic absorption occurs with the use of ESTRING, although the exposure is generally lower than that of systemic estrogens indicated for vasomotor symptoms. As such, the relevance or extent of the following risks of systemic estrogens to ESTRING is not known. The following adverse reactions have been reported with systemic estrogen therapy: Cardiovascular diseases: The Women’s Health Initiative (WHI) estrogen-alone trial reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), and stroke, in postmenopausal women (50 to 79 years of age, average age 63.4 years) during 7.2 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] relative to placebo. (See CLINICAL STUDIES .) Breast cancer: In the WHI estrogen-alone trial, after an average follow-up of 7.1 years, daily oral CE-alone was not associated with an increased risk of invasive breast cancer. (See CLINICAL STUDIES .) However, a large meta-analysis including 24 prospective studies of postmenopausal women comparing current use of estrogen only products with use duration of 5 to 14 years (average of 9 years) versus never use reported a relative risk for breast cancer of 1.33 (95% CI, 1.28 to 1.38). Ovarian cancer: A large meta-analysis including 17 prospective studies of postmenopausal women compared current use of estrogen-only products versus never user and reported a relative risk for ovarian cancer of 1.37 (95% CI 1.26, 1.50). The duration of hormone therapy use that was associated with an increased risk of ovarian cancer is unknown. 4 Others: gallbladder disease requiring surgery, severe hypercalcemia in women with breast cancer and metastases, retinal vascular thrombosis, substantial increases in blood pressure from idiosyncratic reactions, exacerbation of hypertriglyceridemia leading to pancreatitis, cholestatic jaundice, exacerbation of hypothyroidism, fluid retention, hypocalcemia, exacerbation of conditions including hereditary angioedema, asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas.

ADVERSE REACTIONS 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 ADVERSE EVENT ESTRING (n = 257) % Conjugated Estrogens Vaginal Cream (n = 129) % Musculoskeletal Back Pain 6 8 Arthritis 4 2 Arthralgia 3 5 Skeletal Pain 2 4 CNS/Peripheral Nervous System Headache 13 16 Psychiatric Insomnia 4 0 Gastrointestinal Abdominal Pain 4 2 Nausea 3 2 Respiratory Upper Respiratory Tract Infection 5 6 Sinusitis 4 3 Pharyngitis 1 3 Urinary Urinary Tract Infection 2 7 Female Reproductive Leukorrhea 7 3 Vaginitis 5 2 Vaginal Discomfort/Pain 5 5 Vaginal Hemorrhage 4 5 Asymptomatic Genital Bacterial Growth 4 6 Breast Pain 1 7 Resistance Mechanisms Genital Moniliasis 6 7 Body as a Whole Flu-Like Symptoms 3 2 Hot Flushes 2 3 Allergy 1 4 Miscellaneous Family Stress 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.