Estring estradiol 2 mg System, 1 pouch — NDC 0013-1042-01 (Billing 00013-1042-01)

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, diabe… [Excerpted — this section continues on DailyMed.]

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

D. 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), T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG.

Free T 4 and free T 3 concentrations are unaltered. Women 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, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

4. Increased plasma high-density (HDL) and HDL 2 cholesterol subfraction concentrations, reduced low-density (LDL) cholesterol concentration, increased triglycerides levels. 5.

Impaired glucose tolerance.

PRECAUTIONS A. General 1. Location of ESTRING Some women have experienced moving or gliding of ESTRING within the vagina.

Instances of ESTRING being expelled from the vagina in connection with moving the bowels, strain, or constipation have been reported. If this occurs, ESTRING can be rinsed in lukewarm water and reinserted into the vagina by the patient. 2.

Vaginal Irritation ESTRING may not be suitable for women with narrow, short, or stenosed vaginas. Narrow vagina, vaginal stenosis, prolapse, and vaginal infections are conditions that make the vagina more susceptible to ESTRING-caused irritation or ulceration. Women with signs or symptoms of vaginal irritation should alert their physician.

3. Vaginal Infection Vaginal infection is generally more common in postmenopausal women due to the lack of the normal flora of fertile women, especially lactobacillus, and the subsequent higher pH. Vaginal infections should be treated with appropriate antimicrobial therapy before initiation of ESTRING.

If a vaginal infection develops during use of ESTRING, then ESTRING should be removed and reinserted only after the infection has been appropriately treated. B. Patient Information Physicians are advised to discuss the PATIENT INFORMATION leaflet with women for whom they prescribe ESTRING.

C. Laboratory Tests Serum FSH and estradiol levels have not been shown to be useful in the management of moderate to severe symptoms of vulvar and vaginal atrophy. D.

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), T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations are unaltered.

Women 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, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4.

Increased plasma high-density (HDL) and HDL 2 cholesterol subfraction concentrations, reduced low-density (LDL) cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance.

E. Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testes and liver. 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. G.

Nursing Mothers ESTRING should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of mothers receiving estrogens.

Caution should be exercised when ESTRING is administered to a nursing woman. H. Pediatric Use ESTRING is not indicated in children.

Clinical studies have not been conducted in the pediatric population. I. Geriatric Use The… [Excerpted — this section continues on DailyMed.]