Drug Interactions
No drug-herb interactions with ESTRING have been established.
Physicians and other health care providers should be aware of other non-prescription products concomitantly used by the patient, including herbal and natural products from health stores.
Interactions with food have not been established.
No formal Drug-Drug Interaction studies with ESTRING have been conducted.
Use of ESTRING should be discontinued during treatment with vaginal antimicrobial therapy (see Warnings and Precautions, Genitourinary, Vaginal Infection).
Interactions with laboratory tests have not been established.
The pathologist should be informed that the patient is receiving hormone replacement therapy (HRT) when relevant specimens are submitted.
ESTRING is a local vaginal estrogen therapy product. The following drug interactions are based on the experience of systemic estrogen treatment.
Estrogens may diminish the effectiveness of anticoagulant, antidiabetic and antihypertensive agents.
Preparations inducing liver enzymes (e.g., barbiturates, hydantoins, carbamazepine, meprobamates, or rifampicin) can enhance estrogen metabolism, resulting in breakthrough bleeding or vaginal spotting.
Information for the Patient
Estring
Special Handling Instructions
Not applicable.
Dosage and Administration
ESTRING may be removed by hooking a finger through the ring and pulling it out. For patient instructions, see Information for the Patient.
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 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).
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.
Some women may be unsuitable for treatment with ESTRING, in particular those with short narrow vaginas due to previous surgery or the effect of atrophy, or those with a degree of uterovaginal prolapse severe enough to prevent retention of the ring.
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 continuation of therapy is deemed appropriate, replaced by a new ring. The need to continue treatment should be assessed at 3 or 6 month intervals.
As ESTRING is a symptomatic treatment indicated for the postmenopausal urogenital complaints due to estrogen deficiency, ESTRING may be reintroduce at any time following a period without treatment (missed dose), as long as the patient is still an appropriate candidate for this product. The need to continue treatment should be assessed at 3- to 6-month intervals.
Adverse Reactions
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.
enlarged abdomen, vomiting.
micturition frequency, urethral disorder.
abnormal vision.
If adverse symptoms persist, the prescription of HRT should be re-considered.
See Warnings and Precautions regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives.
The following adverse reactions have been reported with estrogen/progestin combination in general:
Reproductive System and Breast Disorders: Breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea; vaginal itching/discharge; dyspareunia; endometrial hyperplasia; pre-menstrual-like syndrome: reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion, breast swelling and tenderness.
weight decrease or increase.
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.
breast engorgement, breast enlargement, intermenstrual bleeding, genital edema, vulval disorder.
depression, decreased libido, nervousness.
Indications and Clinical Use
ESTRING (17 β-estradiol) is indicated for postmenopausal urogenital complaints due to estrogen deficiency such as feeling of dryness in the vagina (atrophic vaginitis) with or without pruritus vulvae, dyspareunia, dysuria and urinary urgency (atrophic mucosa in the urethra and trigonum).
Overdosage
Numerous reports of ingestion of large doses of estrogen products and estrogen- containing oral contraceptives by young children have not revealed acute serious ill effects. Over dosage with estrogen may cause nausea, breast discomfort, fluid retention, bloating or vaginal bleeding in women.
Treatment should be discontinued and symptomatic treatment administered.
It is highly unlikely that overdosage would occur with ESTRING (estradiol), as the principle of its release mechanism prevents overdose.
Dosage Forms, Composition and Packaging
Each slightly opaque ring, made of a silicone elastomer sheath surrounding a whitish silicone elastomer core, containing a drug reservoir of 2 mg estradiol, barium sulphate as a marker and silicone fluid as a dispersing agent. Each ring contains 2 mg estradiol which is released slowly, 7.5 µg/24 hours. One ring is individually packed in a heat-sealed rectangular pouch consisting of, from outside to inside: polyester/aluminum foil/low density polyethylene. The pouch is provided with a tear-off notch on one side. Each pouch is packed into a cardboard carton containing a Patient Information Leaflet.
Warnings and Precautions
Available epidemiological data indicate that use of oral estrogen with or without progestin by postmenopausal women is associated with an increased risk of developing venous thromboembolism (VTE).
Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index >30 kg/m2) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking.
The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. In women on HRT, attention should be given to prophylactic measures to prevent VTE following surgery. Also, patients with varicose veins should be closely supervised. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, hormone therapy should be discontinued immediately, given the risks of long-term disability or fatality.
If feasible, estrogens should be discontinued at least 4 weeks before major surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness should discontinue medication.
Patients with a previous history of classical migraine and who develop a recurrence or worsening of migraine symptoms should be reevaluated.
Women using hormonal replacement therapy (HRT) sometimes experience increased blood pressure. Blood pressure should be monitored with HRT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HRT therapy may have to be discontinued.
Estrogen therapy during pregnancy is associated with an increased risk of fetal congenital reproductive tract disorders, and possibly other birth defects. Studies of women who received diethylstilbestrol (DES) during pregnancy have shown that female offspring have an increased risk of vaginal adenosis, squamous cell dysplasia of the uterine cervix and clear cell vaginal cancer later in life; male offspring have an increased risk of urogenital abnormalities and possibly testicular cancer later in life. Although some of these changes are benign, other are precursors of malignancy.
HRT may cause an exacerbation of epilepsy.
Estrogens should not be used during pregnancy. Any possibility of pregnancy must be ruled out before prescribing ESTRING. If pregnancy occurs during ESTRING treatment, ESTRING should be discontinued immediately.
Clinical studies of ESTRING did not include sufficient number of subjects aged 65 and over to determine if they responded differently from younger subjects.
Some women may be unsuitable for treatment with ESTRING, in particular those with short narrow vaginas due to previous surgery or the effect of atrophy, or those with a degree of uterovaginal prolapse severe enough to prevent retention of the ring.
A potential problem related to the vaginal ring is a tendency in a limited number of patients for the ring to slide down, move or fall out. This was noticed primarily during the first 3 weeks of treatment and was the reason for withdrawal from treatment for 3% of the patients on their first ring.
Risks and benefits of treatment with ESTRING should be re-assessed at least annually. ESTRING should only be continued as long as the benefits outweigh the risks.
ESTRING is a vaginal administered estrogen product with low systemic absorption following continuous use for 3 months (see Action and Clinical Pharmacology, Pharmacokinetics, Absorption). It is expected that low systemic exposure to estradiol and estrone resulting from ESTRING use should elicit lower estrogen-dependent side effects. However, the following warnings and precautions associated with oral estrogen therapy should be considered in the absence of comparable data with other dosage forms of estrogens.
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.
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens has been reported.
A worsening of glucose tolerance and lipid metabolism has been observed in a significant percentage of peri- and post-menopausal patients. Therefore, diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate or lipid metabolism, especially in triglyceride blood levels.
Women with familial hyperlipidemias need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started.
Women with porphyria need special surveillance.
Pre-existing uterine leiomyomata may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyomata requires discontinuation of medication and appropriate investigation.
ESTRING is not indicated for use in the pediatric population.
Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt appropriate diagnostic measures to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.
Women should be advised to inform their physician if irritation, pain, discharge, unusual or unexpected bleeding occur during treatment.
Although uncommon with ESTRING, certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding.
There is a need for caution in prescribing estrogens of any kind to women with a strong family history (first degree relative) of breast cancer or women who have nodules, fibro cystic disease or abnormal mammograms and/or atypical hyperplasia at breast biopsy.
In the oral estrogen-alone arm of the Women’s Health Initiative (WHI) trial, there was no statistically significant difference in the rate of invasive breast cancer in hysterectomized women treated with conjugated equine estrogens versus women treated with placebo.
It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease (see Contraindications).
Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated.
It is recommended that women undergo mammography prior to the start of HRT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.
The overall benefits and possible risks of hormone replacement therapy should be fully considered and discussed with patients.
Instructions for regular self-examination of the breasts should be included in this counselling.
Available epidemiological evidence indicates that the use of combined oral estrogen plus progestin in women age 65 and over may increase the risk of developing probable dementia.
A few 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.
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12-times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears 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 estrogen therapy is discontinued. There is no evidence that the use of natural estrogens result in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. The endometrial safety of long-term or repeated intra-vaginal estrogen administration is uncertain. Adding a progestin to systemic estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Therefore, estrogen should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma.
Clinical surveillance of all women taking estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.
If any x-ray procedures of the lower abdominal tract take place, ESTRING should be removed since the barium sulphate containing core is visible on x-ray and could disturb the procedure or evaluation of x-rays.
Observational studies have found the use of hormone replacement therapy (estrogen-alone and estrogen plus progestin therapies), in particular for five or more years, has been associated with a small increase in the risk of ovarian cancer.
Although uncommon with ESTRING, certain patients may develop undesirable manifestations of estrogenic stimulation, such as mastodynia.
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.
In any woman experiencing persistent or severe discomfort due to the presence of the ring or excessive movement of the ring, treatment should be discontinued. Treatment should be discontinued in patients with signs of ulceration or severe inflammation due to unresponsive atrophic vaginitis.
Before ESTRING (estradiol) is administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial biopsy should be done when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests.
The first follow-up examination should be done within 3-6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.
The importance of regular self-examination of the breasts should be discussed with the patient.
Women treated with ESTRING should be advised to keep their regular medical checkups to assess the need for continuing therapy.
Estrogens may cause fluid retention. Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy or asthma. If, in any of the above-mentioned conditions, a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits and risks of treatment should be reassessed based on the individual case.
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.
Estrogens should not be used during lactation. ESTRING should not be prescribed to nursing mothers. Estrogens have been detected in the breast-milk of mothers receiving these drugs, and the effect on breast-fed infants has not been determined. Suppression of lactation may occur.
The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and the Women's Health Initiative (WHI) trial indicate that the use of continuous combined oral conjugated estrogens (CEE) and medroxyprogesterone acetate (MPA) is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women. The results of the WHI trial indicate that the use of oral estrogen-alone and oral estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women.
Storage and Stability
Store at room temperature (15-30°C). Keep in a safe place out of the reach of children and pets.
Action and Clinical Pharmacology
Circulating, unbound estrogens are known to modulate pharmacological 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.
| Estrogen | Cmax (pg/mL) | Css-48 h (pg/mL) | Css-4 w (pg/mL) | Css-12 w (pg/mL) |
| Estradiol (E2) | 63.2a | 11.2 | 9.5 | 8.0 |
| Baseline-adjusted E2 b | 55.6 | 3.6 | 2.0 | 0.4 |
| Estrone (E1) | 66.3 | 52.5 | 43.8 | 47.0 |
| Baseline-adjusted E1 | 20.0 | 6.2 | −2.4 | 0.8 |
a. n=14.
b. Based on means.
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 (E2) levels attesting to the rapid absorption of estradiol via the vaginal mucosa. The time to attain peak serum estradiol levels (Tmax) 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 (E1) over the following 12 weeks during which the ring was maintained in the vaginal vault remained relatively unchanged (see Table 2). The initial estradiol peak post-application of the second ring in the same women resulted in 38% lower Cmax, 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, the mean dose of estradiol systemically 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. After a brief initial peak (~50 µg), estradiol vaginal ring releases a low and consistent amount of estradiol, approximately 7.5 µg/24 hours, during 90 days. Average in vitro release rates over 7 batches were: | Day 1 | Day 9 | Day 16 | Day 45 | Day 90 | | 47.6±6.4 (in µg/24 h) | 7.3±0.4 | 7.7±0.4 | 7.3±0.2 | 7.3±0.5 | The average in vivo release rate over an 88.4 day period was 9.0±0.06 µg/24 h (n=215), calculated by subtracting the amount of estradiol in the ring at the end of the treatment period from the amount of estradiol measured in the ring before treatment, and averaging the amount over the treatment period. This gives a slightly higher value than is actually released, since it does not take the initial burst of estradiol into account. 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. At menopause the ovaries cease to secrete estradiol (E2), leading to symptoms of estrogen deficiency such as sweating, hot flushes and sleep disturbance. A couple of years after the actual menopause, increasing numbers of women also report symptoms of urogenital estrogen deficiency such as vaginal dryness, genital pruritus, dyspareunia, dysuria and urinary urgency. These latter symptoms respond well to vaginal estrogen replacement therapy. 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 (E1S), post-ESTRING use, are in the normal post-menopausal range. The estradiol from ESTRING (estradiol vaginal ring) replaces the missing or decreasing endogenous estrogen production in the post menopausal woman, and eliminates or reduces urogenital estrogen deficiency signs and symptoms. Substitution therapy with estradiol vaginal ring restores vaginal pH to pre-menopausal values and restores the histology and physiology of the vaginal and urethral epithelium to the pre-menopausal state. 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 up to 90 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 estrogens.
ContraindicationsKnown or suspected estrogen-dependent malignant neoplasia (e.g. endometrial cancer).
Known, suspected, or past history of breast cancer.
Undiagnosed abnormal genital bleeding.
Known or suspected pregnancy.
Known or suspected hypersensitivity to any component of the product. For a complete listing, see Dosage Forms, Composition and Packaging.
Endometrial hyperplasia.
Lactation.
Liver dysfunction or disease as long as liver function tests have failed to return to normal.
Active or past history of arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary heart disease).
Active or past history of confirmed venous thromboembolism (such as deep vein thrombosis or pulmonary embolism) or active thrombophlebitis.
Partial or complete loss of vision due to ophthalmic vascular disease.
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