Estring Prescribing Information
Estrogen-Alone Therapy
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding. (See WARNINGS, Malignant Neoplasms, Endometrial Cancer.)
Cardiovascular Disorders and Probable Dementia
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders, and Probable Dementia.)
The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders.)
The WHI Memory Study (WHIMS)estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.)
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.
Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Estrogen Plus Progestin Therapy
Cardiovascular Disorders and Probable Dementia
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia.)
The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders.)
The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.)
Breast Cancer
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS, Malignant Neoplasms, Breast Cancer.)
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE plus MPA, and other combinations and dosage forms of estrogens and progestins.
Estrogens with or without progestins should be prescribed at the lowest doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
ESTRING is indicated for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.
One ESTRING (estradiol vaginal system) 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.
Instructions for Use
ESTRING (estradiol vaginal system) 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 Patient Information.
ESTRING is contraindicated in women with any of the following conditions:
- 1.
- Undiagnosed abnormal genital bleeding.
- 2.
- Known, suspected, or history of breast cancer.
- 3.
- Known or suspected estrogen-dependent neoplasia.
- 4.
- Active DVT, PE, or a history of these conditions.
- 5.
- Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions.
- 6.
- Known anaphylactic reaction or angioedema or hypersensitivity to ESTRING.
- 7.
- Known liver impairment or disease.
- 8.
- Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.
- 9.
- Known or suspected pregnancy.
See BOXED WARNINGS, 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 4.
| 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
ESTRING® (estradiol vaginal system) is a slightly opaque ring with a whitish core containing a drug reservoir of 2 mg estradiol. Estradiol, silicone polymers, barium sulfate and silicone fluid (as dispersing agent) are combined to form the ring. When placed in the vagina, ESTRING releases estradiol, approximately 7.5 mcg per day, 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.