Estring^®
estradiol vaginal ring
2 mg

ESTRING (estradiol vaginal ring) is a slightly opaque ring with a whitish core containing a drug reservoir of 2 mg estradiol. Estradiol, silicone polymers and barium sulfate are combined to form the ring. When placed in the vagina, ESTRING releases estradiol, approximately 7.5 µg/24 hours, in a consistent stable manner over 90 days. ESTRING has the following dimensions: outer diameter 55 mm; cross-sectional diameter 9 mm; core diameter 2 mm. One ESTRING should be inserted into the upper third of the vaginal vault, to be worn continuously for three months.

Estradiol is chemically described as estra-1,3,5(10)-triene-3,17β-diol. The molecular formula of estradiol is C₁₈H₂₄O₂ and the structural formula is:

The molecular weight of estradiol is 272.39.

ESTRING (estradiol vaginal ring) is indicated for the treatment of urogenital symptoms associated with post-menopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).

Two pivotal controlled studies have demonstrated the efficacy of ESTRING (estradiol vaginal ring) in the treatment of post-menopausal urogenital symptoms due to estrogen deficiency.

In a U.S. study where ESTRING was compared with conjugated estrogens vaginal cream, no difference in efficacy between the treatment groups was found with respect to improvement in the physician's global assessment of vaginal symptoms (83% and 82% of patients receiving ESTRING and cream, respectively) and in the patient's global assessment of vaginal symptoms (83% and 82% of patients receiving ESTRING and cream, respectively) after 12 weeks of treatment. In an Australian study, ESTRING was also compared with conjugated estrogens vaginal cream and no difference in the physician's assessment of improvement of vaginal mucosal atrophy (79% and 75% for ESTRING and cream, respectively) or in the patient's assessment of improvement in vaginal dryness (82% and 76% for ESTRING and cream, respectively) after 12 weeks of treatment.

In the U.S. study, symptoms of dysuria and urinary urgency improved in 74% and 65%, respectively, of patients receiving ESTRING as assessed by the patient. In the Australian study, symptoms of dysuria and urinary urgency improved in 90% and 71%, respectively, of patients receiving ESTRING as assessed by the patient.

In both studies, ESTRING and conjugated estrogens vaginal cream had a similar ability to reduce vaginal pH levels and to mature the vaginal mucosa (as measured cytologically using the maturation index and/or the maturation value) after 12 weeks of treatment. In supportive studies, ESTRING was also shown to have a similar significant treatment effect on the maturation of the urethral mucosa.

Endometrial overstimulation, as evaluated in non-hysterectomized patients participating in the U.S. study by the progestogen challenge test and pelvic sonogram, was reported for none of the 58 (0%) patients receiving ESTRING and 4 of the 35 patients (11%) receiving conjugated estrogens vaginal cream.

Of the U.S. women who completed 12 weeks of treatment, 95% rated product comfort for ESTRING as excellent or very good compared with 65% of patients receiving conjugated estrogens vaginal cream, 95% of ESTRING patients judged the product to be very easy or easy to use compared with 88% of cream patients, and 82% gave ESTRING an overall rating of excellent or very good compared with 58% for the cream.

• Estrogens should not be used in women with any of the following conditions:
  • Known or suspected pregnancy (see BOXED WARNING).
  • Undiagnosed abnormal genital bleeding.
  • Known or suspected cancer of the breast.
  • Known or suspected estrogen-dependent neoplasia.
• ESTRING (estradiol vaginal ring) should not be used in patients hypersensitive to any of its ingredients.

While the majority of studies have not shown an increased risk of breast cancer in women who have ever used estrogen replacement therapy, some have reported a moderately increased risk (relative risks of 1.3 to 2.0) in those taking higher doses or those taking lower doses for prolonged periods of time, especially in excess of ten years. Other studies have not shown this relationship.

Congenital lesions with malignant potential, gallbladder disease, cardiovascular disease, elevated blood pressure and hypercalcemia have been associated with systemic estrogen treatment.

See div of Information for Patients which appears at the end of this insert.

It is recommended that ESTRING be removed during treatment with other vaginally administered preparations.

Drug-drug and drug-laboratory interactions have been reported with estrogen administration overall, but were not observed in clinical trials with ESTRING. However, the possibility of the following interactions should be considered when treating patients with ESTRING.

• 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.
• Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.

Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, and liver (see CONTRAINDICATIONS and BOXED WARNING).

Estrogens should not be used during pregnancy (see CONTRAINDICATIONS and BOXED WARNING).

This product is not intended for nursing mothers. As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. In addition, estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.

Of the total number of subjects in clinical studies of ESTRING (including subjects treated with ESTRING, placebo, and comparator drug; n=951), 25% were 65 and over, while 4% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

The biological safety of the silicone elastomer has been studied in various in vitro and in vivo test models. The results show that the silicone elastomer is non-toxic, non-pyrogenic, non-irritating, and non-sensitizing. Long-term implantation induced encapsulation equal to or less than the negative control (polyethylene) used in the USP test. No toxic reaction or tumor formation was observed with the silicone elastomer.

In general, ESTRING (estradiol vaginal ring) was well tolerated. In the two pivotal controlled studies, discontinuation of treatment due to an adverse event was required by 5.4% of patients receiving ESTRING and 3.9% 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% or greater in the two pivotal controlled studies by patients receiving ESTRING or conjugated estrogens vaginal cream are uled in Table 2.

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

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

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

Given the nature and design of ESTRING (estradiol vaginal ring), it is unlikely that overdosage will occur. However, should overdosage occur, it may manifest itself as nausea, vomiting, and/or vaginal bleeding. Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children.

One ESTRING (estradiol vaginal ring) 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. The need to continue treatment should be assessed at 3 or 6 month intervals.

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.

Each ESTRING (estradiol vaginal ring) is individually packaged in a heat-sealed rectangular pouch consisting of three layers, from outside to inside: polyester, aluminum foil, and low density polyethylene, respectively. The pouch is provided with a tear-off notch on one side.

NDC 0013-2150-36 ESTRING (estradiol vaginal ring) 2 mg - available in single packs.

Store at controlled room temperature 15° to 30° C (59° to 86° F).

INTRODUCTION

This leaflet describes when and how to use ESTRING (estradiol vaginal ring), and the risks and benefits of estrogen treatment. Please read this information carefully before starting treatment.

Estrogens have important benefits but also some risks. You must decide, with your doctor, whether the risks to you of estrogen use are acceptable because of their benefits. If you use estrogens, check with your doctor to be sure you are using the dose that is appropriate for you, and that you don't use them longer than necessary. How long you need to use estrogens should be decided by you and your doctor.

Insertion and Removal

ESTRING INSERTION

After 90 days there will no longer be enough estradiol in the ring to maintain its full effect in relieving your vaginal or urinary symptoms. ESTRING should be removed at that time and replaced with a new ESTRING, if your doctor determines that you need to continue your therapy.

ESTRING can be inserted and removed by you or your doctor. To insert ESTRING yourself, choose the position that is most comfortable for you: standing with one leg up, squatting, or lying down.

• After washing and drying your hands, remove ESTRING from its pouch using the tear-off notch on the side. (Since the ring becomes slippery when wet, be sure your hands are dry before handling it.)
• Hold ESTRING between your thumb and index finger and press the opposite sides of the ring together as shown.
  
• Gently push the compressed ring into your vagina as far as you can.
  

ESTRING PLACEMENT

The exact position of ESTRING is not critical, as long as it is placed in the upper third of the vagina.

When ESTRING is in place, you should not feel anything. If you feel uncomfortable, ESTRING is probably not far enough inside. Use your finger to gently push ESTRING further into your vagina.

There is no danger of ESTRING being pushed too far up in the vagina or getting lost. ESTRING can only be inserted as far as the end of the vagina, where the cervix (the narrow, lower end of the uterus) will block ESTRING from going any further (see diagram of Female Anatomy).

ESTRING USE

Once inserted, ESTRING should remain in place in the vagina for 90 days.

Most women and their partners experience no discomfort with ESTRING in place during intercourse, so it is NOT necessary that the ring be removed. If ESTRING should cause you or your partner any discomfort, you may remove it prior to intercourse (see ESTRING Removal, below). Be sure to reinsert ESTRING as soon as possible afterwards.

ESTRING may slide down into the lower part of the vagina as a result of the abdominal pressure or straining that sometimes accompanies constipation. If this should happen, gently guide ESTRING back into place with your finger.

There have been rare reports of ESTRING falling out in some women following intense straining or coughing. If this should occur, simply wash ESTRING with lukewarm (NOT hot) water and reinsert it.

ESTRING DRUG DELIVERY

Once in the vagina, ESTRING begins to release estradiol immediately. ESTRING will continue to release a low, continuous dose of estradiol for the full 90 days it remains in place.

It will take about 2 to 3 weeks to restore the tissue of the vagina and urinary tract to a healthier condition and to feel the full effect of ESTRING in relieving vaginal and urinary symptoms. If your symptoms persist for more than a few weeks after beginning ESTRING therapy, contact your doctor.

One of the most frequently reported effects associated with the use of ESTRING is an increase in vaginal secretions. These secretions are like those that occur normally prior to menopause and indicate that ESTRING is working. However, if the secretions are associated with a bad odor or vaginal itching or discomfort, be sure to contact your doctor.

ESTRING REMOVAL

To remove ESTRING:

• Wash and dry your hands thoroughly.
• Assume a comfortable position, either standing with one leg up, squatting, or lying down.
• Loop your finger through the ring and gently pull it out.
  
• Discard the used ring in a waste receptacle.
  (Do not flush ESTRING).

If you have any additional questions about removing ESTRING, contact your doctor or healthcare giver.