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Estrogens (Vaginal)

This monograph includes information on the following:

1) Conjugated Estrogens
2) Dienestrol
3) Estradiol
4) Estrone *
5) Estropipate 

BAN:
Dienestrol—Dienoestrol
Estradiol—Oestradiol
Estrone—Oestrone

VA CLASSIFICATION
Primary: GU500
Secondary: HS102

Commonly used brand name(s): Estrace3; Estring3; Oestrilin4; Ogen5; Ortho Dienestrol2; Premarin1.

Other commonly used names are
Dienoestrol —Dienestrol
, Oestradiol —Estradiol
, Oestrone —Estrone
, and Piperazine Estrone Sulfate — Estropipate
.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Urogenital symptoms suppressant—

Indications

General considerations
Vaginal estrogen doses that maintain the serum estradiol concentration in the postmenopausal range do not produce systemic effects of the hormone, such as suppression of vasomotor symptoms of menopause or protection against cardiovascular disease or osteoporosis, and they are not indicated for these uses. While sufficiently high serum estradiol concentrations can be produced from use of vaginal estrogens, use of oral or transdermal estrogen therapy may be preferred instead if systemic benefits are desired {10} {26} {27}.

After menopause, serum estradiol concentrations are approximately 10 to 20 picograms per mL (pg/mL) (40 to 70 picomoles per L [pmol/L]) and serum estrone concentrations are approximately 30 to 70 pg/mL (110 to 260 pmol/L) {39}. If vaginal administration provides serum estrogen concentrations greater than these concentrations, systemic effects of estrogen should be considered and their potential side effects appropriately managed, such as adding a progestin to the treatment regimen to decrease estrogen-induced endometrial hyperplasia.

Women without a uterus are best treated with unopposed estrogen therapy; combined estrogen-progestin therapy is not needed {05}.

Accepted

Urethritis, atrophic, postmenopausal (treatment)—Estradiol vaginal insert is indicated to treat atrophic urethritis in postmenopausal women who have symptoms of dysuria or urinary frequency, urgency, or incontinence {08} {20}.

Vaginitis, atrophic (treatment)—Conjugated estrogens {05} {06}, dienestrol {02} {03}, estradiol vaginal cream {01}, [estradiol vaginal insert] {09} {23} {26}, and estropipate {07} are indicated to treat symptoms of atrophic vaginitis due to estrogen deficiency that may include dyspareunia. Estradiol vaginal insert1 {08} and estrone {04} are indicated to treat atrophic vaginitis in postmenopausal women only (also called senile vaginitis).

Vulvar atrophy—Conjugated estrogens {05} {06}, dienestrol {02} {03}, estradiol vaginal cream {01}, [estradiol vaginal insert] , estrone {04}, and estropipate {07} are indicated for treatment of symptomatic atrophic vulva due to estrogen deficiency, including kraurosis vulvae and pruritus vulvae {04} {09}.

Unaccepted
Although a few studies show that estrogens have some effect on neurotransmitters and may improve memory and cognitive function, estrogen is not indicated or effective in the treatment of clinical depression {01} {38}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Naturally occurring estrogens: Estradiol (E 2), estrone (E 1), and estriol (E 3) in humans {10}.
    Conjugated estrogens are a mixture of estrogenic metabolites found in equine urine {29}; the complete profile is not known. The primary estrogens, sodium estrone sulfate and sodium equilin sulfate, make up 79.5 to 88% of the total mixture {29}. Other estrogens defined by USP as concomitant components are the sodium sulfated conjugates of 17-alpha-dihydroequilin, 17-alpha-estradiol, and 17-beta-dihydroequilin.
    Semi-synthetic estrogen: Estropipate (estrone sulfate piperazine compound) {07}.
    Synthetic nonsteroidal estrogen: Dienestrol {03}.
Molecular weight—
    Dienestrol: 266.34 {28}
    Estradiol: 272.39 {28}
    Estrone: 270.37 {28}
    Estropipate: 436.58 {28}

Mechanism of action/Effect:


Estrogens:

Estrogens passively diffuse into target cells of responsive tissues, complex with the estrogen receptors, and enter the cell's nucleus to initiate or enhance gene transcription of protein synthesis after binding to DNA {20} {30}.

The magnitude of estrogen's effect and its influence upon different hormones depends on the endogenous estrogen concentration in the plasma, and the product formulation and type and dose of exogenous estrogen administered {01} {21}. A 2:1 ratio of serum estradiol to estrone normally found in premenopausal women can be achieved with intravaginal or transdermal use; this ratio is not achievable with oral use. Total estrogen serum concentrations is dose-dependent.



Urogenital symptoms suppressant:

After the menopause when ovarian follicles are absent, symptoms of estrogen deficiency begin when the serum estradiol concentration falls {01} {30}. Restoring the more potent estrogens, such as estradiol, or increasing the estrone concentration helps to lessen or stop symptoms of genital itching, vaginal dryness, dyspareunia, dysuria, urinary frequency, urgency, and urinary or stress incontinence {08} {10} {20}. Clinical data show estrogens cause the vaginal and urethral environment to return to normal. As the vaginal pH falls below 5, normal flora recolonize, and the vaginal and urethral mucosa mature. The maturation of the mucosa is clinically apparent with the disappearance of parabasal cells and an increase in the number of intermediate and superficial epithelial cells {08} {13} {19} {24} {25}.

Estrogens may act to increase the collagen content in the urethra and bladder base and cause growth of urethral epithelium {20}. How intravaginal administration distributes estrogen to the urethral mucosa is not known, but it is likely due to an increased systemic concentration or is provided by local access to urogenital tissue through a venous plexus {20}.

In most menopausal patients, vaginal estrogen doses that maintain the serum estradiol concentrations at postmenopausal levels produce mainly local vaginal effects without sufficiently stimulating the endometrium to resume menstrual-like cycles {24}. For some patients, the dose may be sufficient to stimulate the endometrium; rarely, endometrial hyperplasia occurs {22}. Also, at these low doses, vaginal estrogens do not significantly suppress the gonadotropins FSH or LH, lessen systemic menopausal symptoms, or diminish the rate of bone loss {10} {26}. Systemic effects must be considered and expected if serum estrogen concentrations increase beyond the postmenopausal range {10}.



Other actions/effects:

Estrogens help develop and maintain the female reproductive system, urogenital tissue tone and elasticity, and secondary sex characteristics {30}. Estrogens, acting with other hormones and cytokines, stimulate the growth and development of breast tissue and skeleton formation, and are integral to the physiology of puberty, menstruation, ovulatory cycles, and pregnancy {30}.

Absorption:

Estrogens are well absorbed from the vagina, mucous membranes, subcutaneous fat, and gastrointestinal tract {10}. Vaginal absorption is dependent on estrogen particle size, dose and type of estrogen, vehicle used, and status of the vaginal mucosa {11}. Smaller-sized particles of estrogens (micronized) show rapid absorption while coarser particles absorb slowly over a longer period of time {21}. Low doses of estrogen used several times a week or ultralow doses given continuously, such as with the estradiol vaginal insert, achieve mainly local effects, while daily vaginal dosing can produce high systemic concentrations and effects. Conjugated or sulfated estrogens and creams and suppositories provide longer effects. Atrophied mucosa exhibits more systemic absorption for 3 to 4 months {16} until mucosa is revitalized by estrogens, after which less of the estrogen is absorbed systemically {11}.

For conjugated estrogens—Conjugates of estrogens, largely estrone sulfate, are absorbed intravaginally but to a lesser extent than estradiol {10}.

For estradiol vaginal insert: 8% (range 3 to 13%) of the daily release from the estradiol vaginal insert is absorbed systemically {08}. After an initial 24-hour peak release of 50 mcg, 7.5 mcg is released every 24 hours for 90 days of continuous use {08} {12}. Maximum peak concentration is approximately 38% lower after 3 months, when the second vaginal insert is used and the vaginal mucosa is no longer atrophied {08}.

Protein binding:

Moderate to high (50 to 80%) {07}; to sex hormone–binding globulin and albumin.

Vaginal conjugated estrogens, by delivering supraphysiologic doses to the liver, are capable of inducing the synthesis of proteins, such as sex hormone–binding globulin, and sulfating estrogens to create a drug reservoir of estrogen. Except for conjugated estrogens, vaginally administered estrogens in appropriate doses can deliver physiologic doses of estrogen to the liver that do not induce production of hepatic proteins {10} {26}.

Biotransformation:

Estrogens are metabolized primarily by hepatic {01} {05} {07} and local target tissues such as skeletal muscles, the kidneys, and the gonads. Tissues dynamically metabolize and interconvert between estrogens—estrone and estradiol—as well as between their metabolites, such as unconjugated and conjugated estrogen sulfates, and unesterified and esterified estrogens {01}. On a dose-to-dose basis, a higher ratio of estradiol to estrone serum concentrations can be achieved through use of vaginal or transdermal products as compared with oral products {11}.

During hepatic metabolism estrogens are desulfated, resulfated, and oxidized to less active estrogens, to nonestrogenic substances that interact with catecholamine receptors in the CNS, and to conjugates of glucuronic acid that may be quickly eliminated {01}.

Vaginal metabolism of estradiol is minimal; conjugated estrogens, however, are metabolized in the vaginal epithelia {10}.

Half-life:

For estradiol—20 minutes {14}.

Time to peak concentration:

For estradiol vaginal insert—Time to peak is 0.5 to 1 hour {08}, declining to a constant release after 24 hours, reaching the steady-state serum concentration within 7 to 10 days {08} {13}.

Duration of action:

For estradiol vaginal insert—3 months {08}.

Elimination:
    Renal—Major route for excretion of acidic ionized conjugates, such as glucuronides and sulfates {08} {13}.
    Fecal—Minimal; reabsorbed from intestines and recirculated through portal venous system {10}.


Precautions to Consider

Note: Vaginally administered estrogen attains serum estradiol concentrations that are about 25 to 40% of that reached by the same dose given orally. Risk of endometrial proliferation should be considered with use of vaginal estrogen, even if systemic effects are not produced {22}. If the serum estrone and estradiol concentrations increase beyond the postmenopausal range, systemic effects of the hormones should be considered with vaginal use {10} {21}.


Carcinogenicity

Risk of developing endometrial cancer for users of vaginal estrogens has not been determined, but is probably related to estrogen dose and duration of treatment. Developing endometrial cancer is less likely if the vaginal dose affects only the urogenital tissue, not the uterine lining, and is not greatly absorbed systemically. Low doses used intravaginally for prolonged periods of time may increase risk of endometrial hyperplasia and, although no cases have been reported, endometrial carcinoma {22}.

The following data are based on use of oral estrogens. Estrogens may increase the incidence of breast cancer in some postmenopausal women. Long-term studies are still needed to fully characterize potential risk. The majority of data available do not seem to support a significant increase in risk for patients using physiologic doses {16} {33}. Patients using estrogen in either high doses or low doses for a prolonged period of time, especially longer than 10 years, potentially may have greater risk {33}. Short-term use of estrogens for treatment of menopausal symptoms does not appear to increase risk, and no additional risk has been attributed to adding a progestin to the therapy {35} {36}. Regular breast examinations or mammography will help detect any developing problems {01}.

When nonusers were compared with users of an oral estrogen-only cycle, no risk of endometrial hyperplasia was shown for the first year of use. When oral estrogens were taken for a prolonged period of time or at higher-than-physiologic doses, the risk increased 2 to 12 times. {31} Furthermore, the risk can be increased as much as 24 times when oral estrogens are used for 5 years or longer. Although the magnitude of the risk decreases substantially within 6 months after unopposed oral estrogen therapy is discontinued, some risk can continue for 8 to 15 years {35}. Studies show a lower incidence of endometrial hyperplasia and, potentially, endometrial cancer when patients take a progestin for a minimum period of 10 to 14 days a month along with an estrogen cycle {32} {34}.

In certain animal species, long-term, continuous administration of systemic estrogens increases the frequency of cancers of the breast, cervix, liver, pancreas, testes, uterus, and vagina. Results of animal studies may not apply to humans because of the general hormonal differences in sex steroids among species {01} {02}.

Pregnancy/Reproduction

Pregnancy—
Estrogens are not recommended for use during pregnancy. This recommendation is based on studies showing an association of congenital malformations with use of oral diethylstilbestrol (DES). Patients who become pregnant while taking estrogens should be informed of the potential risks to the fetus. Pregnancy occurs rarely in menopausal women because of the natural change in their hormonal milieu; on the rare chance of its occurrence, a fetus surviving to term is unlikely.

FDA Pregnancy Category X {01} {02} {05} {07}.

Breast-feeding

Estrogens are distributed into breast milk. Use of estrogens by breast-feeding women is not recommended {01} {02} {03} {05} {07}.

Geriatrics


Studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of vaginal estrogens in the elderly {01} {02} {03} {05} {07}.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Plasma binding globulins, such as:
Sex hormone–binding globulin (SHBG), serum
Thyroxine-binding globulin (TBG), serum
Renin substrate    (conjugated estrogens elevate SHBG, TBG, and renin substrate, but not corticosteroid-binding globulin, when doses of 0.2 to 2 mg are given vaginally; other estrogens given vaginally in doses to maintain physiologic concentrations of estradiol in postmenopausal women do not show these effects {10} {26})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Note: If vaginal doses increase the serum estradiol concentrations beyond the postmenopausal range, consider the precautions for systemic estrogens.


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Allergy to cream components, including parabens{37}
» Neoplasia, estrogen-dependent, known or suspected{16}    (may promote tumor growth or interfere with the action of antiestrogen treatment regimens for any systemically absorbed {01} {02} {03}dose. Carefully chosen patients with these conditions have used low vaginal doses for treating urogenital conditions; however, estrogen use in these patients is still considered to introduce an unknown risk {25})


» Genital or uterine bleeding, abnormal or undiagnosed    (use of estrogens may delay diagnosis; on occurrence, estrogen should be discontinued until clinical evaluation is completed. Condition may worsen if cause of abnormal uterine bleeding is endometrial hyperplasia or endometrial cancer {01} {02} {03} {05} {06} {07})


Risk-benefit should be considered when the following medical problems exist
Cervicitis or
Vaginal infection or
Vaginitis     (use of vaginal estrogen may worsen these conditions or, for the estradiol vaginal insert, cause ulceration {26}; on occurrence, discontinuing use of estrogen may not be necessary but the underlying irritation or infection should be treated as appropriate {08})


Endometriosis or
Leiomyomata, uterine    (may be aggravated by use of estrogens {09})


Hepatic function impairment, severe    (systemic doses may worsen this condition)

    (severe hepatic function impairment can decrease estrogen metabolism, especially when using conjugated estrogens. Carefully chosen patients with severe hepatic function impairment have used low vaginal doses of estrogens for treating urogenital conditions. Locally or vaginally administered estradiol and estrone have less effect on the liver than conjugated estrogens {16} {25})


Thrombophlebitis or thromboembolic disorders, active{01}{02}{03}{05}{07}    (concurrent use of any estrogen is not recommended by many physicians until condition is resolved; although low doses of vaginal estrogens to treat urogenital conditions make the association for exacerbation of an active condition unlikely)


Vaginal narrowing or
Vaginal prolapse or
Vaginal stenosis    (use of the estradiol vaginal insert may cause abdominal or back pain, vaginal irritation or ulceration, urinary incontinence {23} {26}, or frequent device expulsion {08} in some of these patients {19} )



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Breast examination and
Mammography and
Papanicolaou (Pap) test and
Physical examinations    (recommended annually or more often as determined by physician, with emphasis on examining blood pressure, breasts, abdomen, and pelvic organs, including a Papanicolaou [Pap] test {01} {02} {05} {06} {07}; regular self-examination to detect breast problems should be done by patient)


Endometrial biopsy    (patients with a uterus should be monitored for signs of endometrial cancer, and malignancy should be ruled out in cases of persistent or recurring abnormal vaginal bleeding {30})




Side/Adverse Effects

Note: The risk of any serious adverse effect is minimal for women using low doses of estrogen. Even women who have special risk factors successfully use estrogens.
Consider the side effects of systemic estrogens if serum estradiol concentrations increase beyond the postmenopausal range as shown by laboratory tests or evidence of patient complaints, especially complaints of uterine bleeding or breast tenderness. Risk of endometrial proliferation should be considered with use of vaginal estrogens, with or without systemic effects {22} {23} {27}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Breast pain or enlargement {23}{24}{25}{27}
    
headache {23}{24}{25}{27}
    
nausea {23}{24}{25}{27}
    
vulvovaginal candidiasis (itching of the vagina or genitals; thick, white vaginal discharge without odor or with a mild odor)—estrogens usually prevent{23}{25}{27}
    
vulvovaginitis (itching, stinging, or redness of the genital area){23}{24}{25}{26}{27}—estrogens usually prevent

Note: Vulvovaginal candidiasis or vulvovaginitis occur more frequently in untreated postmenopausal patients, but since they are reported in up to 13% of vaginal estrogen users, infection or irritation should be evaluated and treated {09}. Although estrogen is used in treating vulvovaginal irritation, vulvovaginitis may be caused by other ingredients in the vaginal formulation.
Breast pain, headache, or nausea can indicate systemic absorption, and may require reduction of dose or frequency if systemic absorption is not desired {04}.


Incidence rare
    
Uterine bleeding or spotting, unusual or unexpected {25}{26}
    
vaginal discomfort, pain, or ulceration due to a foreign object (feeling of vaginal pressure; vaginal burning or pain)—with use of estradiol vaginal insert{08}{19}{23}{24}{25}{26}

Note: Any unusual or unexpected uterine bleeding or spotting, especially if persistent or recurrent, should be evaluated for endometrial hyperplasia or endometrial cancer. If workup is uneventful, then lowering patient's estrogen dose or frequency or adding a progestin for at least 10 to 14 days a month may be needed.




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Abdominal or back pain{08}{25}{26}{27}
    
leukorrhea (clear vaginal discharge)—usually indicates therapeutic effect{25}{26}{27}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Estrogens (Vaginal).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to cream components, such as parabens



Carcinogenicity—
For patients taking estrogens or progestins, risk of endometrial cancer for vaginal estrogen users is not fully understood or easily quantified, but thought to be less likely if doses are kept low enough to treat urogenital conditions locally; also, endometrial hyperplasia is less likely to occur

Pregnancy—Use of estrogens during pregnancy is not recommended because of reported congenital abnormalities caused by diethylstilbestrol (DES); although pregnancy is not usually a concern for perimenopausal patients, patient should inform physician immediately if pregnancy is suspected





Breast-feeding—Use is not recommended because estrogens are distributed into breast milk
Other medical problems, especially estrogen-dependent neoplasia (known or suspected) or genital or uterine bleeding (abnormal or undiagnosed)

Proper use of this medication
» Reading patient package insert (PPI) carefully

Washing hands immediately before and after vaginal administration; avoiding contact with eyes; washing it out of eyes with water if medication accidentally gets into eyes

» Understanding directions of use and that full therapeutic effect may take 3 or 4 months to appear; checking with physician for changes in dose and not using medication longer than prescribed

Proper administration technique
For cream dosage form—Understanding the markings on applicator and how to withdraw the proper dose

For cream and suppository dosage form—Following directions regarding the filling of the applicator with medication; understanding the insertion technique; and, depending on the applicator type supplied by the product's packaging, either discarding the disposable applicators after each use or, if reusable, cleaning and drying applicators thoroughly after each use

For estradiol vaginal insert—Knowing how to place, reposition, or remove the vaginal insert in the upper part of vagina, and how to dispose of the old vaginal insert safely, especially avoiding flushing it down the toilet
» Compliance with therapy

» Proper dosing
Missed dose:

For weekly dosing of suppository or cream—Using as soon as possible within 1 or 2 days; however, not using if almost time for next dose; not doubling doses

For daily dosing of suppository or cream—Using missed dose within 12 hours. Not using missed dose if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular annual visits to physician, or more often, as determined by physician

» Checking breasts by self-examination regularly and having clinical examination and mammography as required by physician; reporting unusual breast lumps or discharge

» Stopping medication immediately and checking with physician if pregnancy is suspected

If scheduled for laboratory tests, telling physician about estrogen use; certain blood tests and tissue biopsies are affected

For all vaginal creams
» Not using latex condoms for up to 72 hours after vaginal estrogen treatment because oils in the vaginal cream dosage form may weaken latex products

Using medication at bedtime to increase effectiveness; wearing sanitary napkin to protect clothing

Avoiding exposing male partner to estrogen vaginal cream through sexual intercourse; having sexual intercourse, when desired, prior to administering vaginal dose

For estradiol vaginal insert
Not needing to remove for sexual intercourse unless desired

Washing the vaginal insert before reinsertion when expelled or if taken out for sexual intercourse

Replacing with new vaginal insert after 3 months


Side/adverse effects
Signs of potential side effects, especially breast pain or enlargement; headache; nausea; vulvovaginal candidiasis; vulvovaginitis; unusual or unexpected uterine bleeding or spotting; vaginal discomfort, pain, or ulceration due to a foreign object (for estradiol vaginal insert)

Reporting to physician if vaginal use produces systemic estrogen side/adverse effects, such as uterine bleeding or breast tenderness; understanding that vaginal administration can produce systemic estrogen effects and, on their occurrence, may warrant a dosage reduction


General Dosing Information
It is required that the patient package insert (PPI) be given to patients {01}.

Generally, the lowest dose to control urogenital symptoms is used. The patient is often titrated over a 6-week period and re-evaluated at 3- to 6-month intervals to assess whether to continue her estrogen treatment or to make dosage or frequency adjustments {01}.

Doses that maintain serum estradiol concentrations within the postmenopausal range will not cause endometrial stimulation or monthly uterine bleeding {08}. While serum estradiol concentrations of 140 to 200 picomoles per liter (pmol/L) suppress vasomotor symptoms, these concentrations do not frequently occur when low maintenance doses of estrogen are applied or used vaginally 2 to 3 times a week. Concentrations below 70 pmol/L {26} associated with atrophy of the endometrium are produced instead {26}.

Postmenopausal patients should be counseled that they will not show an improved lipoprotein cholesterol profile or be protected against bone loss while their serum estradiol concentration remains in the postmenopausal range {10}. Although sufficiently high serum estradiol concentrations can be produced from use of vaginal estrogens, use of oral, transdermal, or parenteral estrogen therapy may be preferred instead for these uses.

For vaginal creams
The cream vehicles for some vaginal estrogen products contain mineral oil or other lipid-based components that may adversely affect the performance of latex barrier devices, such as condoms, cervical caps, or diaphragms, to prevent pregnancy or sexually transmitted diseases.

Low doses given vaginally cause few systemic effects and, rarely, cause endometrial stimulation; concomitant progestin treatment for 10 to 14 days is recommended by some medical organizations for patients with a uterus and is especially important when uterine bleeding or systemic effects {08} occur. Usually when 2 or 3 low maintenance doses a week are used intravaginally, cyclic treatment of 3 weeks on and 1 week off is sufficient to prevent endometrial proliferation without adding a progestin {01}.

If oral estrogens are given for 10 to 14 days as a priming dose, then the initial dosage regimen for vaginal treatment is discontinued and the maintenance treatment regimen is initiated instead {06}.

Patient counseling on withdrawing the proper dose into applicator is important, especially when transferring a patient to a different product. Applicator markings indicate the amount of cream in grams. Patients may confuse the dose (in mg) with the amount of cream to be applied (in grams).

For vaginal cream or suppository
To properly place vaginal cream or suppository, patient lies on back with knees drawn up and apart, gently inserting applicator into vagina, carefully releasing dose by pressing plunger downward to original position. Cleaning the applicator, if reusable, is accomplished by separating the plunger from the barrel and washing each separately with soap and water; never using boiling or hot water. Applicator unit is reassembled after each part dries thoroughly. A new disposable applicator can be used with each dose if one is contained in the packaging {01} {05}.

For estradiol vaginal insert
Systemic effects from a daily dose of 7.5 mcg of estradiol released over 24 hours are minimal, making concomitant progestin treatment unnecessary as use of the vaginal insert at this dose rarely causes endometrial stimulation {08}. Use of the vaginal insert beyond ninety days does not result in an overdose, but rather an underdose, and increases the likelihood of vaginal infections or epithelial ulcers {08} occurring due to lack of efficacy.

Insertion technique—Pinching or pressing the sides of the vaginal insert together, between forefinger and middle finger, into a smaller oval-shape allows placement into the upper third of the vagina, and can be managed by patient or physician {23}. Patient can place vaginal insert while lying on her back with knees up or while standing with one foot raised on a chair. Although an exact placement in the vagina is not critical, any discomfort felt by the patient requires that the vaginal insert be moved higher by gently pushing the insert further into the vagina {08}.

Removal technique—Removed by hooking a finger through the ring-shaped vaginal insert and gently pulling it out through the vagina {08}.

Removal of the vaginal insert is not needed for sexual intercourse unless preferred by the patient {23} {26}; in one study, only 6 of approximately 182 postmenopausal patients (17%) removed the vaginal insert for sexual intercourse {19}. Straining on defecation may cause the vaginal insert to move lower in the vagina or to be expelled accidentally from the vagina {08} {19}.

If the vaginal insert is removed by the patient or expelled accidentally, rinsing in lukewarm water is sufficient before replacing the vaginal insert back into the vagina {08}.

CONJUGATED ESTROGENS

Summary of Differences
Indications: Atrophic vaginitis and vulvar atrophy.

Pharmacology/pharmacokinetics: Mixture of estrogenic metabolites, extracted from the urine of pregnant mares; highly sulfated. Vaginal conjugated estrogens provide longer duration of action and induce liver to increase proteins, such as SHBG, TBG, and renin substrate; metabolized by vaginal mucosa; absorbed slower than other estrogens.

Medical considerations/Contraindications—May exacerbate existing hepatic function impairment.


Vaginal Dosage Forms

CONJUGATED ESTROGENS VAGINAL CREAM

Usual adult dose
Atrophic vaginitis or
Vulvar atrophy
Intravaginal or topical, 0.3 to 1.25 mg of conjugated estrogens (one-half to two grams of cream) daily or as directed by physician based on the lowest dose needed for three weeks, with no medication used in the fourth week; the schedule being repeated each month {05} {06} {22}.


Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


625 mcg (0.625 mg) per gram (Rx) [Premarin{05} (benzyl alcohol) (cetyl esters wax) (cetyl alcohol) (glycerin) (glyceryl monostearate) (methyl stearate) (mineral oil) (propylene glycol monostearate) (sodium lauryl sulfate) (white wax)]

Canada—


625 mcg (0.625 mg) per gram (Rx) [Premarin{06} (cetyl alcohol) (phenylethyl alcohol)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer {05}.

Auxiliary labeling:
   • For vaginal use only.

Note: Include mandatory patient package insert (PPI) when dispensing.


Additional information:


• Canadian brand of Premarin is gluten-, paraben-, sugar-, sulfite-, and tartazine-free {06}.


• Calibrated applicator measures in 0.5 gram increments up to 2 grams of cream {05}.



DIENESTROL

Summary of Differences
Indications: Atrophic vaginitis and vulvar atrophy.

Pharmacology/pharmacokinetics: Source—Synthetic, nonsteroidal estrogen.


Vaginal Dosage Forms

DIENESTROL CREAM USP

Usual adult dose
Atrophic vaginitis or
Vulvar atrophy
Initial: Intravaginal, 0.5 mg (one applicatorful) one or two times a day for one or two weeks {02} {03}, the dose then being reduced to either 0.25 or 0.5 mg (one-half or one applicatorful) a day for an additional one or two weeks. {02} {03}

Maintenance: Intravaginal, 0.5 mg (one applicatorful) one to three times a week for three weeks with no medication used in the fourth week after vaginal mucosa is no longer atrophied {02} {03}; this schedule being repeated each month.


Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


0.01% (Rx) [Ortho Dienestrol{02} (benzoic acid) (butylated hydroxyanisole) (citric acid) (glutamic acid) (glycerin) (glyceryl monostearate) (peanut oil) (sodium hydroxide) (water)]

Canada—


0.01% (Rx) [Ortho Dienestrol{03} (benzoic acid) (butylated hydroxyanisole) (citric acid) (glutamic acid) (glycerin) (glyceryl monostearate) (peanut oil) (sodium hydroxide) (water)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in collapsible tubes or tight containers. {29}

Auxiliary labeling:
   • For vaginal use only.

Note: Include mandatory patient package insert (PPI) when dispensing.


Additional information:
Applicator is not calibrated {05}.


ESTRADIOL

Summary of Differences
Indications: Atrophic vaginitis, vulvar atrophy, and atrophic postmenopausal urethritis.

Pharmacology/pharmacokinetics: Natural estrogen easily absorbed vaginally without metabolism by vaginal mucosa; does not induce hepatic protein synthesis.

Medical considerations/Contraindications—Does not exacerbate existing hepatic function impairment; vaginal insert is more likely to be expelled or cause problems for women with narrow vaginas, vaginal prolapse or vaginal stenosis; cream may exacerbate allergy to parabens.

Side/Adverse effects: Vaginal insert, as a foreign device, may cause vaginal discomfort, pain, or ulceration.


Vaginal Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use or indications that are not included in U.S. product labeling.

ESTRADIOL VAGINAL CREAM USP

Usual adult dose
Atrophic vaginitis or
Vulvar atrophy
Initial: Intravaginal, 200 to 400 mcg of estradiol (two to four grams of cream) daily for one or two weeks, the dosage then being gradually reduced to one-half the initial dosage for one or two weeks {01}.

Maintenance: Intravaginal, 100 mcg of estradiol (one gram of cream) one to three times a week for three weeks with no medication used in the fourth week after vaginal mucosa is no longer atrophied {01}; this schedule being repeated each month {01}.


Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


0.01% (Rx) [Estrace{01} (2208 4000 CPS) (edetate disodium) (glyceryl monostearate) (hydroxypropyl methylcellulose) (methylparaben) (propylene glycol) (sodium lauryl sulfate) (stearyl alcohol) (tertiary-butylhydroquinone) (water) (white ceresin wax)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in collapsible tubes or tight containers. {29}

Auxiliary labeling:
   • For vaginal use only.

Note: Include mandatory patient package insert (PPI) when dispensing.


Additional information:
Calibrated applicator measures 1 to 4 grams of cream in increments of 1 gram {01}.


ESTRADIOL VAGINAL INSERT

Note: Also called estradiol vaginal ring {08} {09}.


Usual adult dose
[Atrophic vaginitis] or
Urethritis, atrophic, postmenopausal or
[Vulvar atrophy, postmenopausal]
Intravaginal, 2 mg (one vaginal insert) releases 7.5 mcg from its ring-shape over twenty-four hours when worn continuously high in the upper third of the vagina and is replaced every ninety days {08}.


Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


2 mg delivering 7.5 mcg per 24 hours (Rx) [Estring (barium sulfate in device) (silicone polymers in device){08}]

Canada—


2 mg delivering 7.5 mcg per 24 hours (Rx) [Estring (barium sulfate in device) (silicone polymers in device){09}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. {08}

Auxiliary labeling:
   • For vaginal use only.

Note: Include mandatory patient package insert (PPI) when dispensing.



ESTRONE

Summary of Differences
Indications: Atrophic vaginitis, postmenopausal, and vulvar atrophy.

Pharmacology/pharmacokinetics: Natural estrogen easily absorbed vaginally without metabolism by vaginal mucosa; does not induce hepatic proteins synthesis.

Medical considerations/Contraindications—Does not exacerbate existing hepatic function impairment; cream may exacerbate allergy to parabens.


Vaginal Dosage Forms

ESTRONE VAGINAL CREAM

Usual adult dose
Atrophic vaginitis, postmenopausal or
Vulvar atrophy
Intravaginal, 2 to 4 mg of estrone (two to four grams of cream) daily or as directed by physician based on the lowest dose needed {04}.


Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg per gram (Rx) [Oestrilin{04} (methylparaben) (mineral oil) (propylparaben)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer {04}.

Auxiliary labeling:
   • For vaginal use only.

Note: Include mandatory patient package insert (PPI) when dispensing.


Additional information:
Calibrated applicator measures 1 to 4 grams of cream in increments of 1 gram {04}.


ESTRONE VAGINAL SUPPOSITORIES

Note: Also called cones {04}.


Usual adult dose
Atrophic vaginitis, postmenopausal or
Vulvar atrophy
Intravaginal, 250 to 500 mcg daily or as directed by physician based on the lowest dose needed {04}.


Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


250 mcg (Rx) [Oestrilin{04} (gelatin) (glycerin)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer {04}.

Auxiliary labeling:
   • For vaginal use only.

Note: Include mandatory patient package insert (PPI) when dispensing.



ESTROPIPATE

Summary of Differences
Indications: Atrophic vaginitis and vulvar atrophy.

Pharmacology/pharmacokinetics: Semi-synthetic estrogen.

Medical considerations/Contraindications—Cream may exacerbate allergy to parabens.


Vaginal Dosage Forms

ESTROPIPATE VAGINAL CREAM USP

Note: Formerly called piperazine estrone sulfate.


Usual adult dose
Atrophic vaginitis or
Vulvar atrophy
Intravaginal, 3 to 6 mg of estropipate (two to four grams of cream) daily for three weeks with no medication used the fourth week, the schedule being repeated each month {07}.


Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


1.5 mg per gram (Rx) [Ogen (anhydrous lanolin) (cetyl alcohol) ( cis- N-(3-chloroallyl) hexaminium chloride) (citric acid) (glycerin) (glyceryl monostearate) (higher fatty alcohols) (methylparaben) (mineral oil) (piperazine hexahydrate) (propylparaben) (sodium biphosphate) ( water){07}]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer {07}.

Auxiliary labeling:
   • For vaginal use only.

Note: Include mandatory patient package insert (PPI) when dispensing.


Additional information:
Calibrated applicator measures 1 to 4 grams of cream in increments of 1 gram {07}.



Revised: 08/20/1997



References
  1. Estradiol vaginal cream package insert (Estrace, Bristol-Myers Squibb—US), Rev 3/96, Rec 4/97.
  1. Dienestrol package insert (Ortho Dienestrol, Ortho—US), Rev 8/87, Rec 11/95.
  1. Dienestrol (Ortho Dienestrol, Janssen-Ortho). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 32nd ed. Ottawa: Canadian Pharmaceutical Association; 1997. p. 1163.
  1. Estrone (Oestrilin, Desbergers). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 32nd ed. Ottawa: Canadian Pharmaceutical Association; 1997. p. 1163.
  1. Conjugated estrogens package insert (Premarin, Wyeth-Ayerst—US), Rev 1/95, Rec11/95.
  1. Conjugated estrogens (Premarin, Wyeth-Ayerst). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 32nd ed. Ottawa: Canadian Pharmaceutical Association; 1997. p. 1264-5.
  1. Estropipate package insert (Ogen, Abbott—US), Rev 3/94, Rec 11/95.
  1. Estradiol vaginal insert package insert (Estring, Pharmacia & Upjohn—US), Rev 4/96, Rec 10/96.
  1. Estradiol vaginal insert product monograph (Estring, Pharmacia & Upjohn—Canada), Rev 6/95, Rec 6/96.
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  1. Schaier C, Bryne C, Keyl P, et al. Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States). Cancer Causes and Control 1994; 5: 491-500.
  1. Goette DK, Odom RB. Vaginal medications as a cause for varied widespread dermatitides. Cutis 1980 Oct; 26(4): 406-9.
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