A. General
1. Addition of a progestin when a woman has not had a hysterectomy
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration,
or daily with estrogen in a continuous regimen, have reported a lowered incidence
of endometrial hyperplasia than would be induced by estrogen treatment alone.
Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens
compared to estrogen alone regimens. These include a possible increased risk of breast cancer,
adverse effects on lipoprotein metabolism (lowering HDL, raising LDL), and impairment of glucose tolerance.
2. Elevated blood pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial,
a generalized effect of estrogen therapy on blood pressure was not seen.
Blood pressure should be monitored at regular intervals with estrogen use.
3. Hypertriglyceridemia
In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated
with elevations of plasma triglycerides leading to pancreatitis and other complications.
Consider discontinuation of treatment if pancreatitis or other complications develop.
4. Impaired liver function and past history of cholestatic jaundice
ESTRING vaginal ring should be used with caution in patients with impaired liver function.
Estrogens may be poorly metabolized in patients with impaired liver function.
For patients with a history of cholestatic jaundice associated with past
estrogen use or with pregnancy, caution should be exercised and in the case
of recurrence, medication should be discontinued.
5. Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels.
Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone,
thus maintaining free T4 and T3 serum concentrations in the normal range.
Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may
require increased doses of their thyroid replacement therapy. These patients should have
their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Hypocalcemia
Estrogens should be used with caution in individuals with severe hypocalcemia.
7. Fluid retention
Estrogens may cause some degree of fluid retention. Patients who have conditions that
might be influenced by this factor, such as a cardiac or renal dysfunction,
warrant careful observation when estrogens are prescribed.
8. Exacerbation of endometriosis
Endometriosis may be exacerbated with administration of estrogens.
A few cases of malignant transformation of residual endometrial implants have been
reported in women treated post-hysterectomy with estrogen alone therapy.
For patients known to have residual endometriosis post-hysterectomy,
the addition of progestin should be considered.
9. Exacerbation of other conditions
Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy,
migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas
and should be used with caution in women with these conditions.
10. 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.
11. 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.
12. 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.
B. Information for the Patient
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe ESTRING.
C. Laboratory Tests
Serum follicle stimulating hormone and estradiol levels have not been shown to be useful in the management of moderate to severe symptoms of vulvar and vaginal atrophy.
D. Drug and Laboratory Test Interactions
- 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 thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
- Other binding proteins may be elevated in serum, (i.e., corticosteroid binding globulin [CBG], sex hormone-binding globulin [SHBG]), leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
- Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
- Impaired glucose tolerance.
E. Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testes and liver.
F. Pregnancy
ESTRING should not be used during pregnancy. (See CONTRAINDICATIONS.)
There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
G. Nursing Mothers
ESTRING should not be used during lactation. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug.
H. Pediatric Use
ESTRING is not indicated for pediatric use and no clinical data have been collected in children.
I. Geriatric Use
There have not been sufficient numbers of geriatric patients involved in studies utilizing ESTRING to determine whether those over 65 years of age differ from younger subjects in their response to ESTRING.
In the estrogen alone substudy of the Women’s Health Initiative (WHI) study, 46 percent (n = 4,943) of subjects were 65 years of age and older, while 7.1 percent (n = 767) of subjects were 75 years of age and older. There was a higher relative risk (daily CE 0.625 mg versus placebo) of stroke in women less than 75 years of age compared to women 75 years and older.
In the estrogen alone substudy of the Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years of age, was randomized to receive daily conjugated estrogens (CE 0.625 mg daily) or placebo. After an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 versus 25 cases per 10,000 women-years compared with placebo.
Of the total number of subjects in the estrogen plus progestin substudy of WHI, 44 percent (n = 7,320) were 65 years of age and older, while 6.6 percent (n = 1,095) were 75 years of age and older. In women 75 years of age and older compared to women less than 75 years of age, there was a higher relative risk of nonfatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75, the increased risk of nonfatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women-years, respectively.
In the estrogen plus progestin WHIMS substudy, a population of 4,532 postmenopausal women, aged 65 to 79 years, was randomized to receive CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo.
Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE alone group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer’s disease.
When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)