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-3,17(beta)-diol. The molecular formula of estradiol is C 18 H 24 O 2 and the structural formula is:
The molecular weight of estradiol is 272.39.
Estrogens used in therapeutics are well absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism possibly reducing the induction of several other hepatic proteins.
In a Phase I study of 14 postmenopausal women, the insertion of ESTRING (estradiol vaginal ring) rapidly increased serum estradiol (E 2 ) levels attesting to the rapid absorption of estradiol via the vaginal mucosa. The time to attain peak serum estradiol levels (T max ) was 0.5 to 1 hour. Peak serum estradiol concentrations post-initial burst declined rapidly over the next 24 hours and were virtually indistinguishable from the baseline mean (range: 5 to 22 pg/mL). Serum levels of estradiol and estrone (E 1 ) over the following 12 weeks during which the ring was maintained in the vaginal vault remained relatively unchanged (see Table 1).
The initial estradiol peak post-application of the second ring in the same women resulted in ~ 38% lower C max , apparently due to reduced systemic absorption via the revitalized vaginal epithelium. The relative systemic exposure from the initial peak of ESTRING accounted for approximately 4% of the total estradiol exposure over the 12 week period.
The constant and stable release of estradiol from ESTRING was demonstrated in a Phase II study of 166-222 post-menopausal women who inserted up to four rings consecutively at three month intervals. Low dose systemic delivery of estradiol from ESTRING resulted in mean steady state serum estradiol estimates of 7.8, 7.0, 7.0, 8.1 pg/mL at weeks 12, 24, 36, and 48, respectively. Similar reproducibility is also seen in levels of estrone. Lower systemic exposure to estradiol and estrone is further supported by serum levels measured during a pivotal Phase III study.
In post-menopausal women, mean dose of estradiol systemicaly absorbed unchanged from ESTRING is ~ 8% [95% CI: 2.8-12.8%] of the daily amount released locally. Low systemic exposure to estradiol and estrone resulting from ESTRING should elicit lower estrogen-dependent effects.
Circulating, unbound estrogens are known to modulate pharmacologic response. Estrogens circulate in blood bound to sex-hormone binding globulin (SHBG) and albumin. A dynamic equilibrium exists between the conjugated and the unconjugated forms of estradiol and estrone, which undergo rapid interconversion.
Exogenously delivered or endogenously derived estrogens are primarily metabolized in the liver to estrone and estriol, which are also found in the systemic circulation. Estrogen metabolites are primarily excreted in the urine as glucuronides and sulphates. Of the several estrogen metabolites, urinary estrone and estrone sulphate (E 1 S), post-ESTRING use, are in the normal post-menopausal range.
Mean percent dose excreted in the 24-hour urine as estradiol, 4 and 12 weeks post-application of ESTRING in a Phase I study was 5% and 8%, respectively, of the daily released amount.
No formal drug-drug interactions studies have been done with ESTRING. It is anticipated that lower exposure to systemic estrogens may reduce the potential for drug interactions thus maintaining the benefit to risk ratio of concomitant drugs.
In vivo , estrogens diffuse through cell membranes, distribute throughout the cell, bind to and activate the estrogen receptors, thereby eliciting their biological effects. Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver and bone of women. ESTRING delivers estradiol constantly at a mean rate of ~ 7.5 µg/24 hours for a period of 24 days. Its use in post-menopausal patients in Phase I and II studies showed no apparent effects on systemic levels of hepatic protein SHBG, or FSH. Lowering of the pretreatment vaginal pH from a mean of 6.0 to a mean of 4.6 (as found in fertile women) over the 12 to 48 week treatment period, and improvements evident in the vaginal mucosal epithelium seen in all studies attest to the local dynamic effects of estrogen.
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' global assessment of vaginal symptoms (83% and 82% of patients receiving ESTRING and cream, respectively) and in the patient' 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' assessment of improvement of vaginal mucosal atrophy (79% and 75% for ESTRING and cream, respectively) or in the patient' 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.
See text 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.
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 listed in Table 2.
Other adverse events (listed 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
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.
ESTRING (estradiol vaginal ring) 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 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 may be removed by hooking a finger through the ring and pulling it out.
For patient instructions, see Information for Patients .
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.
STORAGE --Store at controlled room temperature15° to 30°C (59° to 86°F).
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.
Estrogens are hormones made by the ovaries of women during their reproductive years. Between ages 45 and 55, the ovaries normally stop making estrogens. This leads to a drop in body estrogen levels which causes the "change of life" or menopause (the end of monthly menstrual periods). If both ovaries are removed during an operation before natural menopause takes place, the sudden drop in estrogen levels results in what is known as "surgically induced menopause".
When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating ("hot flashes" or "hot flushes"). Using estrogen drugs can help the body adjust to lower estrogen levels and reduce these symptoms. ESTRING (estradiol vaginal ring) DOES NOT PROVIDE ENOUGH ESTROGEN TO REDUCE THESE SYMPTOMS.
The declining estrogen levels associated with advancing age after menopause may also result in thinning and drying of the tissue in the urinary tract and vagina (urogenital atrophy). Vaginal symptoms of this condition include dryness in the vagina (atrophic vaginitis), genital itching and burning, and pain with intercourse. Urinary symptoms may include urinary urgency and pain on urination. Small amounts of estrogen delivered directly to the local tissue can be used to help reduce these symptoms.
ESTRING is a local estrogen therapy designed to relieve vaginal and urinary symptoms of postmenopausal estrogen deficiency for a full 90 days. ESTRING exerts its effect locally in the lower urogenital tract and has not been shown to have significant effects in other estrogen-sensitive organs or tissues of the body. Consequently, ESTRING PROVIDES RELIEF OF LOCAL SYMPTOMS OF MENOPAUSE ONLY.
ESTRING (estradiol vaginal ring) contains a drug reservoir of 2 mg of the estrogen, estradiol, in its core. ESTRING releases estradiol into the vagina in a consistent, stable manner for 90 days. The soft, flexible ring is placed in the upper third of the vagina (by the physician or the patient) and worn continuously for 90 days, then removed and replaced if continuation of therapy is indicated.
ESTRING should not be used:
During pregnancy (see BOXED WARNING ).
Women who are definitely postmenopausal cannot become pregnant. Women who believe they are postmenopausal because their menstrual cycles have recently stopped should confirm that they are not pregnant before using any form of estrogen-containing drug. Using estrogens while pregnant may cause the unborn child to have birth defects. Estrogens do not prevent miscarriage.
In the presence of unusual vaginal bleeding which has not been evaluated by a doctor (see BOXED WARNING ).
Unusual vaginal bleeding after menopause can be a warning sign of cancer of the uterus. Estrogens may increase the risk of cancer of the uterus in women who have had their menopause ("change of life"). If you use any estrogen-containing drug, it is important to visit your doctor regularly and report any unusual vaginal bleeding right away. Your doctor should evaluate any unusual vaginal bleeding to find out the cause.
If there is a history of certain types of cancer.
Estrogens may increase the risk of certain types of cancer. In general, ESTRING should not be used in women who have ever had cancer of the breast or uterus.
During treatment for vaginal infection with vaginal antimicrobial therapy.
It is recommended that ESTRING be discontinued while other vaginal medications are being used to treat a vaginal infection. Use of ESTRING can be resumed after termination of the other vaginal medication, and after first consulting with a physician.
After childbirth or when breast-feeding a baby.
ESTRING should not be used to try to stop the breasts from filling with milk after a baby is born. Women who are breast-feeding should avoid using any drugs because many drugs pass through to the baby in the milk. While nursing a baby, drugs should only be taken on the advice of your healthcare giver.POSSIBLE RISKS FROM TREATMENT WITH ESTROGENS
The following risk factors apply to estrogens in general:
Cancer of the uterus.
Estrogens increase the risk of developing a condition (endometrial hyperplasia) that may lead to cancer of the lining of the uterus (endometrial cancer). The risk of endometrial cancer is greater in estrogen users than nonusers. Studies have shown that this increased risk depends on estrogen dose, duration of treatment, and treatment regimen.
If the uterus has been removed (total hysterectomy), there is no danger of developing cancer of the uterus.
Cancer of the breast.
Most studies have not shown a higher risk of breast cancer in women who have ever used estrogens. However, some studies have reported that breast cancer developed more often (up to twice the usual rate) in women who used estrogens for long periods of time (especially more than 10 years), or who used higher doses for shorter time periods.
Regular breast examinations by a health professional and monthly self-examination are recommended for all women.
Gallbladder disease and abnormal blood clotting.
Gallbladder disease and abnormal blood clotting are risk factors associated with medium to high doses of estrogen. Most studies of low dose estrogen usage by women do not show an increased risk of these complications, and to date have not been seen with ESTRING (estradiol vaginal ring) treatment.
Like all medications, ESTRING (estradiol vaginal ring) may cause side effects. The most frequently reported side effect is increased vaginal secretions. Many of these vaginal secretions are like those that occur normally prior to menopause and indicate that ESTRING is working. Vaginal secretions that are associated with a bad odor, vaginal itching, or other signs of vaginal infection are NOT normal and may indicate a risk or a cause for concern. Other side effects may include vaginal discomfort, abdominal pain, or genital itching.
Estrogens in General
In addition to the risks listed above, the following side effects have been reported with estrogen use:
REDUCING RISK OF ESTROGEN USE
If you use estrogens, you may reduce your risks by doing these things:
See your doctor regularly.
While you are using estrogens, it is important to visit your doctor at least once a year for a check-up. If you develop vaginal bleeding while taking estrogens, call your doctor - you may need further evaluation. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast X-ray), you may need to have more frequent breast examinations.
Reassess your need for estrogens.
You and your doctor should reevaluate whether or not you still need estrogens at least every 6 months.
Be alert for warning signs.
If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your doctor immediately:
Each ESTRING (estradiol vaginal ring) is individually packaged in a heat-sealed rectangular pouch. 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 units.
Storage: Store at controlled room temperature 15° to 30° C (59° to 86°F).
(estradiol vaginal ring) 2 mg
Insertion and Removal
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.