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Femring
Overview
What is Femring?
Femring (estradiol acetate vaginal ring)
is an off-white, soft, flexible ring with a central core containing estradiol
acetate.
Femring is made of cured silicone elastomer composed of dimethyl polysiloxane
silanol, silica (diatomaceous earth), normal propyl orthosilicate, stannous
octoate; barium sulfate and estradiol acetate. The rings have the following
dimensions: outer diameter 56 mm, cross-sectional diameter 7.6 mm, core diameter
2 mm.
Femring is available in two strengths: Femring 0.05 mg/day has a central core
that contains 12.4 mg of estradiol acetate, which releases at a rate equivalent
to 0.05 mg of estradiol per day for 3 months. Femring 0.10 mg/day has a central
core that contains 24.8 mg of estradiol acetate, which releases at a rate
equivalent to 0.10 mg of estradiol per day for 3 months.
Estradiol acetate is chemically described as
estra-1,3,5(10)-triene-3,17β-diol-3-acetate. The molecular formula of estradiol
acetate is CHO and the structural formula is:
The molecular weight of estradiol acetate is 314.42.
What does Femring look like?
What are the available doses of Femring?
Sorry No records found.
What should I talk to my health care provider before I take Femring?
Sorry No records found
How should I use Femring?
Femring therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms due to menopause.
2. Treatment of moderate to severe vulvar and vaginal atrophy due to
menopause.
Generally, when estrogen is prescribed for a postmenopausal woman
with a uterus, a progestin should also be considered to reduce the risk of
endometrial cancer. A woman without a uterus does not need a progestin. In some
cases, however, hysterectomized women with a history of endometriosis may need a
progestin.
Use of estrogen-alone, or in combination with a progestin, should be with the
lowest effective dose and for the shortest duration consistent with treatment
goals and risks for the individual woman. Postmenopausal women should be
re-evaluated periodically as clinically appropriate to determine if treatment is
still necessary. (See and
.)
Two doses of Femring are available, 0.05 mg/day and 0.10 mg/day, for the
treatment of moderate to severe vasomotor symptoms and/or vulvar and vaginal
atrophy due to menopause.
Patients should be started at the lowest dose. The lowest effective dose of
Femring has not been determined.
Hands should be thoroughly washed before and after ring
insertion.
Femring Insertion
Insert upon removal from the protective pouch.
The opposite sides of the vaginal ring should be pressed together and
inserted into the vagina. The exact position is not critical to its function.
When Femring is in place, the patient should not feel anything. If the patient
feels discomfort, the vaginal ring is probably not far enough inside the vagina.
Gently push Femring further into the vagina.
Femring Use
Femring should remain in place for 3 months and then be replaced by a new
Femring.
The patient should not feel Femring when it is in place and it should not
interfere with sexual intercourse. Straining upon bowel movement may make
Femring move down in the lower part of the vagina. If so, it may be repositioned
with a finger.
If Femring is expelled totally from the vagina, it should be rinsed in
lukewarm water and reinserted by the patient (or healthcare provider if
necessary).
Femring Removal
Femring may be removed by looping a finger through the ring and pulling it
out.
For patient instructions, see .
What interacts with Femring?
- Femring should not be used in women with any of the following conditions:
- Undiagnosed abnormal genital bleeding.
- Known, suspected, or history of breast cancer.
- Known or suspected estrogen-dependent neoplasia.
- Active deep vein thrombosis, pulmonary embolism or history of these conditions.
- Active arterial thromboembolic disease (for example, stroke and myocardial infarction) or a history of these conditions.
- Known liver dysfunction or disease.
- Known or suspected pregnancy.
What are the warnings of Femring?
Cyclobenzaprine HCl may enhance the effects of alcohol, barbiturates, and
other CNS depressants.
See
Femring is used only in the vagina, however, the risks associated with oral
estrogens should be taken into account.
An increased risk of stroke and deep vein thrombosis (DVT) has
been reported with estrogen-alone therapy. An increased risk of pulmonary
embolism, DVT, stroke, and myocardial infarction has been reported with estrogen
plus progestin therapy. Should any of these events occur or be suspected,
estrogens with or without progestins should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension,
diabetes mellitus, tobacco use, hypercholesterolemia and obesity) and/or venous
thromboembolism (for example, personal history or family history of VTE, obesity
and systemic lupus erythematosus) should be managed appropriately.
In the Women's Health Initiative (WHI) estrogen-alone substudy, a
statistically significant increased risk of stroke was reported in women 50 to
79 years of age receiving daily conjugated estrogens CE (0.625 mg) compared to
women of the same age receiving placebo (45 versus 33 per 10,000 women-years).
The increase in risk was demonstrated in year one and persisted. (See .) Should a stroke occur or be suspected, estrogens should be
discontinued immediately.
Sub-group analyses of women 50 to 59 years of age suggest no increased risk
of stroke for those women receiving CE (0.625 mg) versus those receiving placebo
(18 versus 21 per 10,000 women-years).
In the WHI estrogen plus progestin substudy, a statistically significant
increased risk of stroke was reported in all women receiving daily CE (0.625 mg)
plus MPA (2.5 mg) compared to placebo (33 versus 25 per 10,000 women-years). The
increase in risk was demonstrated after the first year and persisted. (See .)
In the WHI estrogen-alone substudy, no overall effect on coronary
heart disease (CHD) events (defined as nonfatal myocardial infarction [MI],
silent MI, or CHD death) was reported in women receiving estrogen-alone compared
to placebo. (See .)
Subgroup analyses of women 50 to 59 years of age suggest a statistically
non-significant reduction in CHD events (CE 0.625 mg compared to placebo) in
women with less than 10 years since menopause (8 versus 16 per 10,000
women-years).
In the WHI estrogen plus progestin substudy, there was a statistically
non-significant increased risk of CHD events in women receiving daily CE (0.625
mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per
10,000 women-years). An increase in relative risk was demonstrated in year 1,
and a trend toward decreasing relative risk was reported in years 2 through
5.
In postmenopausal women with documented heart disease (n = 2,763, average age
66.7 years), in a controlled clinical trial of secondary prevention of
cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS),
treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no
cardiovascular benefit. During an average follow-up of 4.1 years, treatment with
CE plus MPA did not reduce the overall rate of CHD events in postmenopausal
women with established coronary heart disease. There were more CHD events in the
CE plus MPA-treated group than in the placebo group in year 1, but not during
the subsequent years. Two thousand three hundred and twenty one (2,321) women
from the original HERS trial agreed to participate in an open-label extension of
HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a
total of 6.8 years overall. Rates of CHD events were comparable among women in
the CE/MPA group and the placebo group in the HERS, the HERS II, and
overall.
In the WHI estrogen-alone substudy, the risk of VTE (DVT and
pulmonary embolism [PE]), was increased for women receiving daily CE (0.625 mg)
compared to placebo (30 versus 22 per 10,000 women-years), although only the
increased risk of DVT reached statistical significance (23 versus 15 per 10,000
women-years). The increase in VTE risk was demonstrated during the first 2
years. (See .) Should a VTE occur or be suspected, estrogens should
be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant
2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg)
plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000
women-years). Statistically significant increases in risk for both DVT (26
versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years)
were also demonstrated. The increase in VTE risk was observed during the first
year and persisted. (See .) Should a VTE occur or be suspected, estrogens should be
discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before
surgery of the type associated with an increased risk of thromboembolism or
during periods of prolonged immobilization.
An increased risk of endometrial cancer has been reported with
the use of unopposed estrogen therapy in a woman with a uterus. The reported
endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold
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 one year. The greatest risk appears associated
with prolonged use, with increased risks of 15- to 24-fold for five to ten years
or more, and this risk has been shown to persist for at least 8 to 15 years
after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus
progestin therapy is important. Adequate diagnostic measures, including directed
or random endometrial sampling when indicated, should be undertaken to rule out
malignancy in all cases of undiagnosed persistent or recurring abnormal genital
bleeding.
There is no evidence that the use of natural estrogens results in a different
endometrial risk profile than synthetic estrogens of equivalent estrogen dose.
Adding a progestin to estrogen therapy has been shown to reduce the risk of
endometrial hyperplasia, which may be a precursor to endometrial cancer.
The most important randomized clinical trial providing
information about breast cancer in estrogen-alone users is the Women’s Health
Initiative (WHI) substudy of daily CE (0.625 mg). In the WHI estrogen-alone
substudy, after an average of 7.1 years of follow-up, daily CE (0.625 mg) was
not associated with an increased risk of invasive breast cancer (relative risk
[RR] 0.80). (See .)
The most important clinical trial providing information about breast cancer
in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus
MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin
substudy reported an increased risk of breast cancer in women who took daily CE
plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus
progestin therapy was reported by 26 percent of the women. The relative risk of
invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases
per 10,000 women-years for estrogen plus progestin compared with placebo. Among
women who reported prior use of hormone therapy, the relative risk of invasive
breast cancer was 1.86 and the absolute risk was 46 versus 25 cases per 10,000
women-years for estrogen plus progestin compared with placebo. Among women who
reported no prior use of hormone therapy, the relative risk of invasive breast
cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000
women-years for estrogen plus progestin compared with placebo. In the same
substudy, invasive breast cancers were larger and diagnosed at a more advanced
stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo
group. Metastatic disease was rare with no apparent difference between the two
groups. Other prognostic factors, such as histologic subtype, grade and hormone
receptor status did not differ between the groups. (See .)
Consistent with the WHI clinical trial, observational studies have also
reported an increased risk of breast cancer for estrogen plus progestin therapy,
and a smaller increased risk for estrogen-alone therapy, after several years of
use. The risk increased with duration of use, and appeared to return to baseline
over about 5 years after stopping treatment (only the observational studies have
substantial data on risk after stopping). Observational studies also suggest
that the risk of breast cancer was greater, and became apparent earlier, with
estrogen plus progestin therapy as compared to estrogen-alone therapy. However,
these studies have not generally found significant variation in the risk of
breast cancer among different estrogens or among different estrogen plus
progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin has been reported to
result in an increase in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider
and perform monthly breast self-examinations. In addition, mammography
examinations should be scheduled based on patient age, risk factors and prior
mammogram results.
The WHI estrogen plus progestin substudy reported a statistically
non-significant increased risk of ovarian cancer. After an average follow-up of
5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo
was 1.58 (95 percent nCI 0.77-3.24). The absolute risk for CE plus MPA versus
placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic
studies, the use of estrogen-only products, in particular for 5 or more years,
has been associated with an increased risk of ovarian cancer. However, the
duration of exposure associated with increased risk is not consistent across all
epidemiologic studies and some report no association.
In the estrogen-alone Women's Health Initiative Memory Study
(WHIMS), an ancillary study of WHI, a population of 2,947 hysterectomized women
65 to 79 years of age was randomized to daily CE (0.625 mg) or placebo. In the
WHIMS estrogen plus progestin ancillary study, a population of 4,532
postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg)
plus MPA (2.5 mg) or placebo.
In the WHIMS estrogen-alone ancillary study, after an average follow-up of
5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo
group were diagnosed with probable dementia. The relative risk of probable
dementia for CE-alone versus placebo was 1.49 (95 percent nCI 0.83-2.66). The
absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25
cases per 10,000 women-years. (See and .)
In the WHIMS estrogen plus progestin ancillary study, after an average
follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the
placebo group were diagnosed with probable dementia. The relative risk of
probable dementia for CE plus MPA versus placebo was 2.05 (95
percent nCI 1.21-3.48). The absolute risk of probable dementia for CE plus MPA
versus placebo was 45 versus 22 cases per 10,000 women-years. (See and .)
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 nCI 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 and
.)
A 2- to 4-fold increase in the risk of gallbladder disease
requiring surgery in postmenopausal women receiving estrogens has been
reported.
Estrogen administration may lead to severe hypercalcemia in women
with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug
should be stopped and appropriate measures taken to reduce the serum calcium
level.
Retinal vascular thrombosis has been reported in women receiving
estrogens. Discontinue medication pending examination if there is sudden partial
or complete loss of vision, or a sudden onset of proptosis, diplopia or
migraine. If examination reveals papilledema or retinal vascular lesions,
estrogens should be permanently discontinued.
What are the precautions of Femring?
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 an
increased risk of breast cancer.
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 estrogens
on blood pressure was not seen.
3. Hypertriglyceridemia
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be
associated with elevations of plasma triglycerides leading to pancreatitis.
Consider discontinuation of treatment if pancreatitis develops.
4. Hepatic impairment and/or a past history of cholestatic
jaundice
Estrogens may be poorly metabolized in women with impaired liver function.
For women 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. Women with normal thyroid function can compensate for the increased TBG
by making more thyroid hormone, thus maintaining free T
and T serum concentrations in the normal range. Women
dependent on thyroid hormone replacement therapy who are also receiving
estrogens may require increased doses of their thyroid replacement therapy.
These women should have their thyroid function monitored in order to maintain
their free thyroid hormone levels in an acceptable range.
6. Fluid retention
Estrogens may cause some degree of fluid retention. Women with conditions
that might be influenced by this factor, such as cardiac or renal dysfunction,
warrant careful observation when estrogens are prescribed.
7. Hypocalcemia
Estrogens should be used with caution in women with hypoparathyroidism as
estrogen-induced hypocalcemia may occur.
8. Exacerbation of endometriosis
A few cases of malignant transformation of residual endometrial implants have
been reported in women treated post-hysterectomy with estrogen-alone therapy.
For women known to have residual endometriosis post-hysterectomy, the addition
of progestin should be considered.
9. Exacerbation of other conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus,
epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic
hemangiomas, and should be used with caution in women with these conditions.
10. Vaginal use and expulsion
Femring may not be suitable for women with conditions that make the vagina
more susceptible to vaginal irritation or ulceration, or make expulsions more
likely, such as narrow vagina, vaginal stenosis, vaginal infection, cervical
prolapse, rectoceles and cystoceles. If local treatment of a vaginal infection
is required, Femring can remain in place during treatment.
Physicians are advised to discuss the PATIENT INFORMATION leaflet
with patients for whom they prescribe Femring.
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.
Long-term continuous administration of natural and synthetic
estrogens in certain animal species increases the frequency of carcinomas of the
breast, uterus, cervix, vagina, testis, and liver.
Estradiol acetate was assayed for mutation in four histidine-requiring
strains of and in two
tryptophan-requiring strains of .
Estradiol acetate did not induce mutation in any of the bacterial strains tested
under the conditions employed.
Femring should not be used during pregnancy. (See .)
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.
Femring 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 estrogens.
Femring is not indicated in children. Clinical studies have not
been conducted in the pediatric population.
There have not been sufficient numbers of geriatric women
involved in clinical studies utilizing Femring to determine whether those over
65 years of age differ from younger subjects in their response to Femring.
The Women’s Health Initiative Study
In the Women's Health Initiative (WHI) estrogen-alone substudy (daily
conjugated estrogens 0.625 mg versus placebo), there was a higher relative risk
of stroke in women greater than 65 years of age.
In the WHI estrogen plus progestin substudy, there was a higher relative risk
of nonfatal stroke and invasive breast cancer in women greater than 65 years of
age.
The Women’s Health Initiative Memory Study
In the Women’s Health Initiative Memory Study (WHIMS) of postmenopausal women
65 to 79 years of age, there was an increased risk of developing probable
dementia in the estrogen-alone and the estrogen plus progestin groups when
compared to placebo.
Since both substudies were conducted in women 65 to 79 years of age, it is
unknown whether these findings apply to younger postmenopausal women.
- 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 antifactor 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), T levels (by column or by radioimmunoassay) or T levels by radioimmunoassay. T resin uptake is decreased, reflecting the elevated TBG. Free T and free T concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
- Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
- Increased plasma HDL and HDL cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
- Impaired glucose tolerance.
What are the side effects of Femring?
See and
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 a 13-week clinical trial that included 225 postmenopausal women treated
with Femring and 108 women treated with placebo vaginal rings, adverse events
that occurred at a rate of ≥ 2 percent are summarized in .
The following additional adverse reactions have been identified
during post-approval use of Femring. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug
exposure.
1. Genitourinary system
Uterine cancer, vaginal hemorrhage, ovarian cyst, irregular menstruation,
metrorrhagia, menorrhagia, dysmenorrhea, uterine enlargement.
2. Breasts
Breast cancer, fibrocystic breast disease, breast disorder, breast mass,
breast enlargement, breast pain, nipple pain, breast discharge.
3. Cardiovascular
Chest pain, increased blood pressure, irregular heart rate, pulmonary
embolism, cerebrovascular accident (stroke), hemiparesis, transient ischemic
attack, thrombosis.
4. Gastrointestinal
Abdominal pain, pancreatitis, cholecystitis, cholelithiasis, vomiting.
5. Skin
Generalized erythema, erythema multiforme, erythema nodosum, rash, hirsutism,
pruritis.
6. Eyes
Blindness, contact lens intolerance.
7. Central Nervous System
Dizziness, headache, depression, nervousness, mood disturbances,
irritability.
8. Miscellaneous
Medical device complication, back pain, angioedema, weight
increased/decreased, edema, libido increased/decreased, urticaria,
hypersensitivity, anaphylaxis.
| Adverse Event | Placebo(n = 108) | Estradiol0.05 mg/day(n = 113) | Estradiol0.10 mg/day(n = 112) | ||||
| n (%) | n (%) | n (%) | |||||
| Headache (NOS) | 10 (9.3) | 8 (7.1) | 11 (9.8) | ||||
| Intermenstrual Bleeding | 2 (1.9) | 9 (8.0) | 11 (9.8) | ||||
| Vaginal Candidiasis | 3 (2.8) | 7 (6.2) | 12 (10.7) | ||||
| Breast Tenderness | 2 (1.9) | 7 (6.2) | 12 (10.7) | ||||
| Back Pain | 4 (3.7) | 7 (6.2) | 4 (3.6) | ||||
| Genital Disorder Femal (NOS) | 9 (8.3) | 3 (2.7) | 3 (2.7) | ||||
| Upper Respiratory Tract Infection(NOS) | 6 (5.6) | 5 (4.4) | 4 (3.6) | ||||
| Abdominal Distension | 3 (2.8) | 8 (7.1) | 3 (2.7) | ||||
| Vaginal discharge | 9 (8.3) | 2 (1.8) | 3 (2.7) | ||||
| Vulvovaginitis (NOS) | 7 (6.5) | 6 (5.3) | 1 (0.9) | ||||
| Nausea | 5 (4.6) | 3 (2.7) | 2 (1.8) | ||||
| Arthralgia | 4 (3.7) | 2 (1.8) | 2 (1.8) | ||||
| Sinusitis (NOS) | 2 (1.9) | 2 (1.8) | 4 (3.6) | ||||
| Uterine Pain | 1 (0.9) | 2 (1.8) | 5 (4.5) | ||||
| Nasopharyngitis | 3 (2.8) | 2 (1.8) | 2 (1.8) | ||||
| Pain in Limb | 3 (2.8) | 1 (0.9) | 3 (2.7) | ||||
| Urinary Tract Infection (NOS) | 2 (1.9) | 1 (0.9) | 4 (3.6) | ||||
| Vaginal Irritation | 4 (3.7) | 1 (0.9) | 2 (1.8) |
- 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.
- A few cases of ring adherence to the vaginal or bladder wall, making ring removal difficult, have been reported in women using vaginal rings. Patients should be carefully evaluated for vaginal or bladder wall ulceration or erosion. If an ulceration or erosion has occurred, consideration should be given to leaving the ring out and not replacing it until healing is complete to prevent the ring from adhering to the vaginal tissue.
- A few cases of bowel obstruction associated with vaginal ring use have been reported. Persistent abdominal complaints consistent with obstruction should be carefully evaluated.
- A few cases of inadvertent ring insertion into the urinary bladder, which may require surgical removal, have been reported for women using vaginal rings. Persistent unexplained urinary symptoms should be carefully evaluated.
What should I look out for while using Femring?
Femring should not be used in women with any of the following
conditions:
See
Femring is used only in the vagina, however, the risks associated with oral
estrogens should be taken into account.
An increased risk of stroke and deep vein thrombosis (DVT) has
been reported with estrogen-alone therapy. An increased risk of pulmonary
embolism, DVT, stroke, and myocardial infarction has been reported with estrogen
plus progestin therapy. Should any of these events occur or be suspected,
estrogens with or without progestins should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension,
diabetes mellitus, tobacco use, hypercholesterolemia and obesity) and/or venous
thromboembolism (for example, personal history or family history of VTE, obesity
and systemic lupus erythematosus) should be managed appropriately.
In the Women's Health Initiative (WHI) estrogen-alone substudy, a
statistically significant increased risk of stroke was reported in women 50 to
79 years of age receiving daily conjugated estrogens CE (0.625 mg) compared to
women of the same age receiving placebo (45 versus 33 per 10,000 women-years).
The increase in risk was demonstrated in year one and persisted. (See .) Should a stroke occur or be suspected, estrogens should be
discontinued immediately.
Sub-group analyses of women 50 to 59 years of age suggest no increased risk
of stroke for those women receiving CE (0.625 mg) versus those receiving placebo
(18 versus 21 per 10,000 women-years).
In the WHI estrogen plus progestin substudy, a statistically significant
increased risk of stroke was reported in all women receiving daily CE (0.625 mg)
plus MPA (2.5 mg) compared to placebo (33 versus 25 per 10,000 women-years). The
increase in risk was demonstrated after the first year and persisted. (See .)
In the WHI estrogen-alone substudy, no overall effect on coronary
heart disease (CHD) events (defined as nonfatal myocardial infarction [MI],
silent MI, or CHD death) was reported in women receiving estrogen-alone compared
to placebo. (See .)
Subgroup analyses of women 50 to 59 years of age suggest a statistically
non-significant reduction in CHD events (CE 0.625 mg compared to placebo) in
women with less than 10 years since menopause (8 versus 16 per 10,000
women-years).
In the WHI estrogen plus progestin substudy, there was a statistically
non-significant increased risk of CHD events in women receiving daily CE (0.625
mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per
10,000 women-years). An increase in relative risk was demonstrated in year 1,
and a trend toward decreasing relative risk was reported in years 2 through
5.
In postmenopausal women with documented heart disease (n = 2,763, average age
66.7 years), in a controlled clinical trial of secondary prevention of
cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS),
treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no
cardiovascular benefit. During an average follow-up of 4.1 years, treatment with
CE plus MPA did not reduce the overall rate of CHD events in postmenopausal
women with established coronary heart disease. There were more CHD events in the
CE plus MPA-treated group than in the placebo group in year 1, but not during
the subsequent years. Two thousand three hundred and twenty one (2,321) women
from the original HERS trial agreed to participate in an open-label extension of
HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a
total of 6.8 years overall. Rates of CHD events were comparable among women in
the CE/MPA group and the placebo group in the HERS, the HERS II, and
overall.
In the WHI estrogen-alone substudy, the risk of VTE (DVT and
pulmonary embolism [PE]), was increased for women receiving daily CE (0.625 mg)
compared to placebo (30 versus 22 per 10,000 women-years), although only the
increased risk of DVT reached statistical significance (23 versus 15 per 10,000
women-years). The increase in VTE risk was demonstrated during the first 2
years. (See .) Should a VTE occur or be suspected, estrogens should
be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant
2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg)
plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000
women-years). Statistically significant increases in risk for both DVT (26
versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years)
were also demonstrated. The increase in VTE risk was observed during the first
year and persisted. (See .) Should a VTE occur or be suspected, estrogens should be
discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before
surgery of the type associated with an increased risk of thromboembolism or
during periods of prolonged immobilization.
An increased risk of endometrial cancer has been reported with
the use of unopposed estrogen therapy in a woman with a uterus. The reported
endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold
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 one year. The greatest risk appears associated
with prolonged use, with increased risks of 15- to 24-fold for five to ten years
or more, and this risk has been shown to persist for at least 8 to 15 years
after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus
progestin therapy is important. Adequate diagnostic measures, including directed
or random endometrial sampling when indicated, should be undertaken to rule out
malignancy in all cases of undiagnosed persistent or recurring abnormal genital
bleeding.
There is no evidence that the use of natural estrogens results in a different
endometrial risk profile than synthetic estrogens of equivalent estrogen dose.
Adding a progestin to estrogen therapy has been shown to reduce the risk of
endometrial hyperplasia, which may be a precursor to endometrial cancer.
The most important randomized clinical trial providing
information about breast cancer in estrogen-alone users is the Women’s Health
Initiative (WHI) substudy of daily CE (0.625 mg). In the WHI estrogen-alone
substudy, after an average of 7.1 years of follow-up, daily CE (0.625 mg) was
not associated with an increased risk of invasive breast cancer (relative risk
[RR] 0.80). (See .)
The most important clinical trial providing information about breast cancer
in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus
MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin
substudy reported an increased risk of breast cancer in women who took daily CE
plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus
progestin therapy was reported by 26 percent of the women. The relative risk of
invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases
per 10,000 women-years for estrogen plus progestin compared with placebo. Among
women who reported prior use of hormone therapy, the relative risk of invasive
breast cancer was 1.86 and the absolute risk was 46 versus 25 cases per 10,000
women-years for estrogen plus progestin compared with placebo. Among women who
reported no prior use of hormone therapy, the relative risk of invasive breast
cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000
women-years for estrogen plus progestin compared with placebo. In the same
substudy, invasive breast cancers were larger and diagnosed at a more advanced
stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo
group. Metastatic disease was rare with no apparent difference between the two
groups. Other prognostic factors, such as histologic subtype, grade and hormone
receptor status did not differ between the groups. (See .)
Consistent with the WHI clinical trial, observational studies have also
reported an increased risk of breast cancer for estrogen plus progestin therapy,
and a smaller increased risk for estrogen-alone therapy, after several years of
use. The risk increased with duration of use, and appeared to return to baseline
over about 5 years after stopping treatment (only the observational studies have
substantial data on risk after stopping). Observational studies also suggest
that the risk of breast cancer was greater, and became apparent earlier, with
estrogen plus progestin therapy as compared to estrogen-alone therapy. However,
these studies have not generally found significant variation in the risk of
breast cancer among different estrogens or among different estrogen plus
progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin has been reported to
result in an increase in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider
and perform monthly breast self-examinations. In addition, mammography
examinations should be scheduled based on patient age, risk factors and prior
mammogram results.
The WHI estrogen plus progestin substudy reported a statistically
non-significant increased risk of ovarian cancer. After an average follow-up of
5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo
was 1.58 (95 percent nCI 0.77-3.24). The absolute risk for CE plus MPA versus
placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic
studies, the use of estrogen-only products, in particular for 5 or more years,
has been associated with an increased risk of ovarian cancer. However, the
duration of exposure associated with increased risk is not consistent across all
epidemiologic studies and some report no association.
In the estrogen-alone Women's Health Initiative Memory Study
(WHIMS), an ancillary study of WHI, a population of 2,947 hysterectomized women
65 to 79 years of age was randomized to daily CE (0.625 mg) or placebo. In the
WHIMS estrogen plus progestin ancillary study, a population of 4,532
postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg)
plus MPA (2.5 mg) or placebo.
In the WHIMS estrogen-alone ancillary study, after an average follow-up of
5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo
group were diagnosed with probable dementia. The relative risk of probable
dementia for CE-alone versus placebo was 1.49 (95 percent nCI 0.83-2.66). The
absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25
cases per 10,000 women-years. (See and .)
In the WHIMS estrogen plus progestin ancillary study, after an average
follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the
placebo group were diagnosed with probable dementia. The relative risk of
probable dementia for CE plus MPA versus placebo was 2.05 (95
percent nCI 1.21-3.48). The absolute risk of probable dementia for CE plus MPA
versus placebo was 45 versus 22 cases per 10,000 women-years. (See and .)
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 nCI 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 and
.)
A 2- to 4-fold increase in the risk of gallbladder disease
requiring surgery in postmenopausal women receiving estrogens has been
reported.
Estrogen administration may lead to severe hypercalcemia in women
with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug
should be stopped and appropriate measures taken to reduce the serum calcium
level.
Retinal vascular thrombosis has been reported in women receiving
estrogens. Discontinue medication pending examination if there is sudden partial
or complete loss of vision, or a sudden onset of proptosis, diplopia or
migraine. If examination reveals papilledema or retinal vascular lesions,
estrogens should be permanently discontinued.
What might happen if I take too much Femring?
Overdosage of estrogen may cause nausea and vomiting, breast tenderness,
dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur
in women. Treatment of overdose consists of discontinuation of Femring with
institution of appropriate symptomatic care.
How should I store and handle Femring?
Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Each Femring (estradiol acetate vaginal ring) is individually packaged in a pouch consisting of one side medical grade paper and the other side polyester/polyethylene laminate. NDC 54868-6030-0 Femring 0.10 mg/day (estradiol acetate vaginal ring) is available in single units.Relabeling of "Additional Barcode" byPhysicians Total Care, Inc.Tulsa, OK 74146 Each Femring (estradiol acetate vaginal ring) is individually packaged in a pouch consisting of one side medical grade paper and the other side polyester/polyethylene laminate. NDC 54868-6030-0 Femring 0.10 mg/day (estradiol acetate vaginal ring) is available in single units.Relabeling of "Additional Barcode" byPhysicians Total Care, Inc.Tulsa, OK 74146 Each Femring (estradiol acetate vaginal ring) is individually packaged in a pouch consisting of one side medical grade paper and the other side polyester/polyethylene laminate. NDC 54868-6030-0 Femring 0.10 mg/day (estradiol acetate vaginal ring) is available in single units.Relabeling of "Additional Barcode" byPhysicians Total Care, Inc.Tulsa, OK 74146
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Endogenous estrogens are largely responsible for the development
and maintenance of the female reproductive system and secondary sexual
characteristics. Although circulating estrogens exist in a dynamic equilibrium
of metabolic interconversions, estradiol is the principal intracellular human
estrogen and is substantially more potent than its metabolites, estrone and
estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian
follicle which secretes 70 to 500 mcg of estradiol daily depending on the phase
of the menstrual cycle. After menopause, most endogenous estrogen is produced by
conversion of androstenedione, secreted by the adrenal cortex, to estrone by
peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone
sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive
tissues. To date, two estrogen receptors have been identified. These vary in
proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins,
luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a
negative feedback mechanism. Estrogens act to reduce the elevated levels of
these hormones seen in postmenopausal women.
Drug delivery from Femring is rapid for the first hour and then
declines to a relatively constant rate for the remainder of the 3-month dosing
interval. In vitro studies have shown that this initial release is higher as the
rings age upon storage. Estradiol acetate is rapidly hydrolyzed to estradiol
which is absorbed through the vaginal mucosa as evidenced by the mean time to
maximum concentration (t) for estradiol of about 1
hour (range 0.25 to 1.5 hrs). Following the maximum concentration (C), serum estradiol decreases rapidly such that by 24 to 48
hours postdose, serum estradiol concentrations are relatively constant through
the end of the 3-month dosing interval, see for results
from rings stored for 16 months
Figure 1. Mean serum estradiol concentrations
following multiple dose administration of Femring (0.05 mg/day estradiol)
(second dose administered at 13 weeks) (inset: mean (±SD) of serum
concentration-time profile for dose 1 from 0-24 hours)
Following administration of Femring (0.05 mg/day estradiol), average serum
estradiol concentration was 40.6 pg/mL; the corresponding apparent in vivo
estradiol delivery rate was 0.052 mg/day. Following administration of Femring
(0.10 mg/day estradiol), average serum estradiol concentration was 76 pg/mL;
apparent in vivo delivery rate was 0.097 mg/day. Results are summarized in below.
Consistent with the avoidance of first pass metabolism achieved by vaginal
estradiol administration, serum estradiol concentrations were slightly higher
than estrone concentrations.
The distribution of exogenous estrogens is similar to that of
endogenous estrogens. Estrogens are widely distributed in the body and are
generally found in higher concentrations in the sex hormone target organs.
Estrogens circulate in the blood largely bound to sex hormone binding globulin
(SHBG) and to albumin.
Exogenous estrogens are metabolized in the same manner as
endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of
metabolic interconversions. These transformations take place mainly in the
liver. Estradiol is converted reversibly to estrone, and both can be converted
to estriol, which is the major urinary metabolite. Estrogens also undergo
enterohepatic recirculation via sulfate and glucuronide conjugation in the
liver, biliary secretion of conjugates into the intestine, and hydrolysis in the
gut followed by reabsorption. In postmenopausal women, a significant proportion
of the circulating estrogens exist as sulfate conjugates, especially estrone
sulfate, which serves as a circulating reservoir for the formation of more
active estrogens.
Estradiol, estrone, and estriol are excreted in the urine along
with glucuronide and sulfate conjugates.
No pharmacokinetic studies were conducted in special populations,
including patients with renal or hepatic impairment.
In vitro and in vivo studies have shown that estrogens are
metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or
inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4
such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital,
carbamazepine and rifampin may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in therapeutic effects and/or changes in the
uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin,
clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may
increase plasma concentrations of estrogens and may result in side effects.
Non-Clinical Toxicology
Femring should not be used in women with any of the following conditions:See
Femring is used only in the vagina, however, the risks associated with oral estrogens should be taken into account.
An increased risk of stroke and deep vein thrombosis (DVT) has been reported with estrogen-alone therapy. An increased risk of pulmonary embolism, DVT, stroke, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogens with or without progestins should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia and obesity) and/or venous thromboembolism (for example, personal history or family history of VTE, obesity and systemic lupus erythematosus) should be managed appropriately.
In the Women's Health Initiative (WHI) estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily conjugated estrogens CE (0.625 mg) compared to women of the same age receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted. (See .) Should a stroke occur or be suspected, estrogens should be discontinued immediately.
Sub-group analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in all women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to placebo (33 versus 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. (See .)
In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. (See .)
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE 0.625 mg compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in the HERS, the HERS II, and overall.
In the WHI estrogen-alone substudy, the risk of VTE (DVT and pulmonary embolism [PE]), was increased for women receiving daily CE (0.625 mg) compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years. (See .) Should a VTE occur or be suspected, estrogens should be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted. (See .) Should a VTE occur or be suspected, estrogens should be discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold 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 one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Women’s Health Initiative (WHI) substudy of daily CE (0.625 mg). In the WHI estrogen-alone substudy, after an average of 7.1 years of follow-up, daily CE (0.625 mg) was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80). (See .)
The most important clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86 and the absolute risk was 46 versus 25 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. (See .)
Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not generally found significant variation in the risk of breast cancer among different estrogens or among different estrogen plus progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results.
The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent nCI 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.
In the estrogen-alone Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg) or placebo. In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
In the WHIMS estrogen-alone ancillary study, after an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent nCI 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. (See and .)
In the WHIMS estrogen plus progestin ancillary study, after an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent nCI 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. (See and .)
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 nCI 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 and .)
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.
Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of ursodiol by reducing its absorption. Aluminum-based antacids have been shown to adsorb bile acids and may be expected to interfere with ursodiol in the same manner as the bile acid sequestering agents. Estrogens, oral contraceptives, and clofibrate (and perhaps other lipid-lowering drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodiol.
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 an increased risk of breast cancer.
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 estrogens on blood pressure was not seen.
3. Hypertriglyceridemia
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis develops.
4. Hepatic impairment and/or a past history of cholestatic jaundice
Estrogens may be poorly metabolized in women with impaired liver function. For women 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. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T and T serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention
Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
7. Hypocalcemia
Estrogens should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
8. Exacerbation of endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
9. Exacerbation of other conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic hemangiomas, and should be used with caution in women with these conditions.
10. Vaginal use and expulsion
Femring may not be suitable for women with conditions that make the vagina more susceptible to vaginal irritation or ulceration, or make expulsions more likely, such as narrow vagina, vaginal stenosis, vaginal infection, cervical prolapse, rectoceles and cystoceles. If local treatment of a vaginal infection is required, Femring can remain in place during treatment.
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Femring.
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.
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Estradiol acetate was assayed for mutation in four histidine-requiring strains of and in two tryptophan-requiring strains of . Estradiol acetate did not induce mutation in any of the bacterial strains tested under the conditions employed.
Femring should not be used during pregnancy. (See .)
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.
Femring 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 estrogens.
Femring is not indicated in children. Clinical studies have not been conducted in the pediatric population.
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Femring to determine whether those over 65 years of age differ from younger subjects in their response to Femring.
The Women’s Health Initiative Study
In the Women's Health Initiative (WHI) estrogen-alone substudy (daily conjugated estrogens 0.625 mg versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age.
In the WHI estrogen plus progestin substudy, there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age.
The Women’s Health Initiative Memory Study
In the Women’s Health Initiative Memory Study (WHIMS) of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in the estrogen-alone and the estrogen plus progestin groups when compared to placebo.
Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.
See and
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 a 13-week clinical trial that included 225 postmenopausal women treated with Femring and 108 women treated with placebo vaginal rings, adverse events that occurred at a rate of ≥ 2 percent are summarized in .
The following additional adverse reactions have been identified during post-approval use of Femring. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
1. Genitourinary system
Uterine cancer, vaginal hemorrhage, ovarian cyst, irregular menstruation, metrorrhagia, menorrhagia, dysmenorrhea, uterine enlargement.
2. Breasts
Breast cancer, fibrocystic breast disease, breast disorder, breast mass, breast enlargement, breast pain, nipple pain, breast discharge.
3. Cardiovascular
Chest pain, increased blood pressure, irregular heart rate, pulmonary embolism, cerebrovascular accident (stroke), hemiparesis, transient ischemic attack, thrombosis.
4. Gastrointestinal
Abdominal pain, pancreatitis, cholecystitis, cholelithiasis, vomiting.
5. Skin
Generalized erythema, erythema multiforme, erythema nodosum, rash, hirsutism, pruritis.
6. Eyes
Blindness, contact lens intolerance.
7. Central Nervous System
Dizziness, headache, depression, nervousness, mood disturbances, irritability.
8. Miscellaneous
Medical device complication, back pain, angioedema, weight increased/decreased, edema, libido increased/decreased, urticaria, hypersensitivity, anaphylaxis.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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Interactions
Interactions
A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).