Estring (Estradiol)


Pharmacia & Upjohn



Action And Clinical Pharmacology: Estring 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 g/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 3 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.

Pharmacokinetics: After a brief initial peak (sl50 g), estradiol vaginal ring releases a low and consistent amount of estradiol, approximately 7.5 g/24 hours, during 90 days. Average in vitro release rates (in g/24 hours) over 7 batches were: day 1: 47.6±6.4; day 9: 7.3±0.4; day 16: 7.7±0.4; day 45: 7.3±0.2; day 90: 7.3±0.5. The average in vivo release rate over an 88.4 day period was 9.0±0.06 g/24 hours (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.

Estrogens used in therapeutics are well absorbed through the skin, mucous membranes, and the gastrointestinal 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 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 postinitial 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 I). The initial estradiol peak postapplication 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 postmenopausal women who inserted up to 4 rings consecutively at 3-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 postmenopausal women, 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.

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.

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 sulfates. Of the several estrogen metabolites, urinary estrone and estrone sulfate (E1S), post-Estring use, are in the normal postmenopausal range.

Mean percent dose excreted in the 24-hour urine as estradiol, 4 and 12 weeks postapplication 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.

The estradiol from the vaginal ring replaces the missing or decreasing endogenous estrogen production in the postmenopausal woman and eliminates or reduces urogenital estrogen deficiency signs and symptoms. Substitution therapy with estradiol vaginal ring restores vaginal pH to premenopausal values and restores the histology and physiology of the vaginal and urethral epithelium to the premenopausal 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 g/24 hours for a period of up to 90 days. Its use in postmenopausal 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.

Indications And Clinical Uses: 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).

Clinical Use: Two pivotal controlled studies have demonstrated the efficacy of Estring in the treatment of postmenopausal 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 nonhysterectomized 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.

Contra-Indications: Patients with the following conditions: known or suspected estrogen-dependent malignancy; undiagnosed vaginal bleeding; known or suspected pregnancy; patients hypersensitive to any of its ingredients.

Other higher dose estrogen replacement therapies are contraindicated in patients with the following additional conditions: active hepatic dysfunction or disease, particularly of the obstructive type; history of cerebrovascular accident, coronary thrombosis, or presence of classical migraine; history of thrombophlebitis or thromboembolic disease; partial or complete loss of vision or diplopia due to ophthalmic vascular disease.

Manufacturers’ Warnings In Clinical States: Before estrogens are administered the patient should have a complete physical examination, including examination of breasts and pelvic organs. Unless done recently, a Papanicolaou smear should be taken.

In addition, any woman with symptoms/signs of abnormal vaginal discharge, vaginal discomfort, or any undiagnosed persistent or recurring abnormal vaginal bleeding should be examined fully, to exclude malignancy, ulceration, infection, or unresponsive atrophic vaginitis. Minor signs of irritation are often transient.

For patients with signs of ulceration or severe inflammation due to unresponsive atrophic vaginitis, withdrawal from treatment should be considered.

One of the well documented adverse effects of estrogen replacement therapy is its stimulation of cell growth, with resultant endometrial proliferation. Endometrial biopsy results in postmenopausal women treated for 3 months with Estring showed the incidence of proliferation to be no higher than in untreated peri- and postmenopausal women. The potential risk of endometrial carcinoma still has to be considered if vaginal bleeding occurs. Data currently available on long-term unopposed treatment with Estring, although limited, do not indicate a proliferative effect on the endometrium. Long-term studies on the effect of Estring on the endometrium are ongoing.

Although the estrogen content of oral contraceptive therapy has been associated with an increased risk of various thromboembolic, thrombotic and vascular diseases, to date no such increased risk in postmenopausal users of estrogens has been detected. Nevertheless, the physician should be alert to the earliest manifestations of thrombotic disorders. If these occur or are suspected, estrogen therapy should be discontinued immediately.

Although there is no clear association between the post-menopausal use of estrogens and breast cancer, there is a need for caution in prescribing estrogens of any kind to women with a strong family history of breast cancer or patients who have breast nodules, fibrocystic disease or abnormal mammograms.

Precautions: General: 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 (see Information for the Patient).

If any medical procedures are performed, the pathologist should be advised of the patient’s therapy when specimens are sent for examination.

Patients should be advised to inform their physician if irritation, pain, discharge or bleeding occur.

X-Ray Procedures: If any x-ray procedures of the lower abdominal tract take place, the vaginal ring should be removed since the barium sulfate containing core is visible on x-ray and could disturb the procedure or evaluation of x-rays.

Liver Disease: Liver function tests should be made periodically in subjects who have, or are suspected of having, hepatic disease. It is advisable that patients with acute intermittent porphyria be treated with caution and that periodic medical examinations be performed.

Other Endocrine or Metabolic Effects: Although no effect of low dose vaginal estradiol supplementation has been seen on glucose tolerance, fluid retention, elevation of blood pressure or other liver or endocrine functions, patients with predisposition to or signs indicating an effect on those variables could indicate caution.

Pregnancy: Estring is indicated for postmenopausal treatment. Women of childbearing potential should, therefore, not be prescribed this product.

Drug Interactions: Enzyme inducers, for example barbiturates, hydantoins, carbamazepine and rifampin can enhance estrogen metabolism, resulting in breakthrough bleeding or vaginal spotting. However, due to the low dose released, and since the estrogen is administered vaginally, thereby circumventing the first pass metabolism of the liver, it is unlikely that this interaction is relevant for Estring.

Uterine Bleeding and Mastodynia: Although uncommon with Estring, certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.

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.

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.

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.

Other: Hypercoagulability and hyperlipidemia have been reported in women on other types of estrogen replacement therapy, but these have not been seen with Estring patients.

Fluid retention is another known risk factor with estrogen therapy and may be harmful to patients with asthma, epilepsy, migraine and cardiac or renal dysfunction. Estring treatment has not been associated with any indication of increase in body weight up to 48 weeks of treatment.

Adverse Reactions: 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 nontoxic, nonpyrogenic, nonirritating, and nonsensitizing. 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 was well tolerated. In the 2 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 reason 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 2 pivotal controlled studies by patients receiving Estring or conjugated estrogens vaginal cream are listed in Table II.

Other adverse events (listed alphabetically) occurring at a frequency of 1 to 3% in the 2 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.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The following symptoms and treatment of overdose are for estrogens in general: excessive doses of estrogens may result in nausea, vomiting, abdominal cramps, headache, dizziness and general malaise. Treatment should be discontinued and symptomatic treatment administered.

It is highly unlikely that overdosage would occur with Estring, as the principle of its release mechanism prevents overdose.

Dosage And Administration: One Estring 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 3 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.

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 Insertion: Estring 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 Information for the Patient.

Availability And Storage: Each slightly opaque vaginal ring, made of a silicone elastomer sheath surrounding a whitish silicone elastomer core, contains: estradiol 2 mg, barium sulfate as a marker and silicone fluid as a dispersing agent. The estradiol is released slowly, 7.5 g/24 hours. 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. Store at room temperature (15 to 30°C).

ESTRING® Pharmacia & Upjohn Estradiol Estrogen

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