VAGIFEM® (estradiol vaginal tablets) are small, white, film-coated tablets containing 25.8µg of estradiol hemihydrate equivalent to 25µg of estradiol.

Each tablet contains the following inactive ingredients: hypromellose, lactose monohydrate, maize starch and magnesium stearate. The film coating contains hypromellose and polyethylene glycol. Each white tablet is 6 mm in diameter and is placed in a disposable applicator. Each tablet-filled applicator is packaged separately in a blister pack. 17β-estradiol hemihydrate is a white, almost white or colorless crystalline solid, chemically described as estra-1,3,5 (10)-triene-3,17 diol.

The chemical formula is C₁₈H₂₄O₂•½ H₂O with a molecular weight of 281.4.

The structural formula is:

Last updated on RxList: 7/25/2008

VAGIFEM® is indicated for the treatment of atrophic vaginitis.

VAGIFEM is gently inserted into the vagina as far as it can comfortably go without force, using the supplied applicator.

• Initial dose: One (1) VAGIFEM tablet, inserted vaginally, once daily for two (2) weeks. It is advisable to have the patient administer treatment at the same time each day.
• Maintenance dose: One (1) VAGIFEM tablet, inserted vaginally, twice weekly.

The need to continue therapy should be assessed by the physician with the patient. Attempts to discontinue or taper medication should be made at three to six month intervals.

Each VAGIFEM® (estradiol vaginal tablets), 25µg is contained in a disposable, single-use applicator, packaged in a blister pack. Cartons contain 8 or 18 applicators with inset tablets.

8  applicators:  NDC 0169-5173-03
18 applicators: NDC 0169-5173-04

Storage: Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF). [See USP Controlled Room Temperature.]

Vagifem® is a trademark owned by Novo Nordisk A/S. Revised July 2003. Nordisk Pharmaceuticals, Inc. Princeton, NJ 08540. 1-888-824-4336. www.novonordisk-us.com. Manufactured by Novo Nordisk A/S 2880 Bagsvaerd, Denmark. FDA Rev date: 11/6/2002

Last updated on RxList: 7/25/2008

Adverse events generally have been mild: vaginal spotting, vaginal discharge, allergic reaction and skin rash. Adverse events with an incidence of 5% or greater are reported for two comparative trials. Data for patients receiving either VAGIFEM or placebo in the double blind study are listed in Table 5, and data for patients receiving VAGIFEM in the open label comparator study are listed in Table 6.

Table 5: ADVERSE EVENTS REPORTED IN 5% OR GREATER NUMBER OF PATIENTS RECEIVING VAGIFEM® IN THE PLACEBO CONTROLLED TRIAL.

ADVERSE EVENT	VAGIFEM (n=91) %	Placebo (n=47) %
HEADACHE	9	6
ABDOMINAL PAIN	7	4
UPPER RESPIRATORY TRACT INFECTION	5	4
MONILIASIS GENITAL	5	2
BACK PAIN	7	6

Table 6: ADVERSE EVENTS REPORTED IN 5% OR GREATER NUMBER OF PATIENTS RECEIVING VAGIFEM® IN THE OPEN LABEL STUDY.

ADVERSE EVENT	VAGIFEM (n=80) %
PRURITUS GENITAL	6
HEADACHE	10
UPPER RESPIRATORY TRACT INFECTION	11

Other adverse events that occurred in 3-5% of VAGIFEM subjects included: allergy, bronchitis, dyspepsia, haematuria, hot flashes, insomnia, pain, sinusitis, vaginal discomfort, vaginitis. A causal relationship to VAGIFEM has not been established.

Drug/Laboratory Test Interactions

Certain endocrine and liver function tests may be affected by estrogen-containing oral contraceptives. The following similar changes may be expected with larger doses of estrogens:

1. Increased prothrombin and factors VII, VIII, IX, and X, decreased antithrombin III; increased nore-pinephrine induced platelet aggrega-bility.
2. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by PBI, T4 by column, or T4 by radioimmunoassay. Free T4 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.
3. Impaired glucose tolerance. d. Reduced response to metyrapone test. e. Reduced serum folate concentration. f. Increased serum triglyceride and phospholipid concentration.

Last updated on RxList: 7/25/2008

Induction of malignant neoplasms

Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, and liver. There are now reports that estrogens increase risk of carcinoma of the endometrium in humans (See Boxed Warning).

At the present time there is no satisfactory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast, although a recent long-term follow-up of a single physician's practice has raised this possibility. Because of the animal data, there is a need for caution in prescribing estrogens for women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammograms.

Gallbladder disease

A recent study has reported a 2- to 3-fold increase in the risk of surgically confirmed gallbladder disease in women receiving postmenopausal estrogens, similar to the 2-fold increase previously noted in users of oral contraceptives.

Effects similar to those caused by estrogen-progestogen oral contraceptives

There are several serious adverse effects of oral contraceptives, most of which have not, up to now, been documented as consequences of postmenopausal estrogen therapy. This may reflect the comparatively low doses of estrogens used in postmenopausal women. It would be expected that the larger doses of estrogen used to treat prostatic or breast cancer are more likely to result in these adverse effects, and, in fact, it has been shown that there is an increased risk of thrombosis in men receiving estrogens for prostatic cancer.

Thromboembolic disease

It is now well established that users of oral contraceptives have an increased risk of various throm-boembolic and thrombotic vascular diseases, such as thrombophlebitis, pulmonary embolism, stroke, and myocar-dial infarction. Cases of retinal thrombosis, mesenteric thrombosis, and optic neuritis have been reported in oral-contraceptive users.There is evidence that the risk of several of these adverse reactions is related to the dose of the drug. An increased risk of postsurgery thromboembolic complications has also been reported in users of oral contraceptives. If feasible, estrogen should be discontinued at least 4 weeks before surgery of the type associated with an increased risk of throm-boembolism, or during periods of prolonged immobilization. While an increased rate of thromboembolism and throm-botic disease in postmenopausal users of estrogens has not been found, this does not rule out the possibility that such an increase may be present, or that subgroups of women who have underlying risk factors, or who are receiving large doses of estrogens, may have increased risk. Therefore, estrogens should not be used (except in treatment of malignancy) in a person with a history of such disorders in association with estrogen use. They should be used with caution in patients with cerebral vascular or coronary artery disease and only for those in whom estrogens are clearly needed. Large doses of estrogens (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men, to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and throm-bophlebitis. When estrogen doses of this size are used, any of the throm-boembolic and thrombotic adverse effects associated with oral contraceptive use should be considered a clear risk.

Hepatic adenoma

Benign hepatic adenomas appear to be associated with the oral contraceptives. Although benign, and rare, these may rupture and may cause death through intra-abdominal hemorrhage. Such lesions have not yet been reported in association with other estrogen or progestogen preparations but should be considered in estrogen users having abdominal pain and tenderness, abdominal mass, or hypovolemic shock. Hepatocellular carcinoma has also been reported in women taking estrogen-containing oral contraceptives. The relationship of this malignancy to these drugs is not known at this time.

Elevated blood pressure

Women using oral contraceptives sometimes experience increased blood pressure which, in most cases, returns to normal on discontinuing the drug. There is now a report that this may occur with the use of estrogens in the menopause and blood pressure should be monitored with estrogen use, especially if high doses are used.

Glucose tolerance

A worsening of glucose tolerance has been observed in a significant percentage of patients on estrogen-containing oral contraceptives. For this reason, diabetic patients should be carefully observed while using estrogens.

Hypercalcemia

Administration of estrogens may lead to severe hyper-calcemia in patients with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

Rare Event

Trauma induced by the VAGIFEM® applicator may occur, especially in patients with severely atrophic vaginal mucosa.

General Precautions.

1. A complete medical and family history should be taken prior to the initiation of any estrogen therapy. The pretreatment and periodic physical examinations should include special references to blood pressure, breast, abdomen, and pelvic organs, and should include a Papanicolaou smear. As a general rule, estrogens should not be prescribed for longer than one year without another physical exam being performed.
2. Fluid retention - Because estro- gens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac and renal dysfunction, require careful observation.
3. Familial Hyperlipoproteinemia -Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.
4. Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc.
5. Prolonged administration of unopposed estrogen therapy has been reported to increase the risk of endometrial hyperplasia in some patients.
6. Preexisting uterine leiomyomata may increase in size during estrogen use.
7. The pathologist should be advised of estrogen therapy when relevant specimens are submitted.
8. Patients with a history of jaundice during pregnancy have an increased risk of recurrence of jaundice while receiving estrogen-containing oral-contraceptive therapy. If jaundice develops in any patient receiving estrogen, the medication should be discontinued while the cause is investigated.
9. Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients.
10. Because estrogens influence the metabolism of calcium and phosphorus, they should be used with caution in patients with metabolic bone diseases that are associated with hy-percalcemia or in patients with renal insufficiency.
11. Because of the effects of estrogens on epiphyseal closure, they should be used judiciously in young patients in whom bone growth is not yet complete.
12. Insertion of the VAGIFEM® applicator - Patients with severely atrophic vaginal mucosa should be instructed to exercise care during insertion of the applicator. After gynecological surgery, any vaginal applicator should be used with caution and only if clearly indicated.
13. Vaginal infection - Vaginal infection is generally more common in postmenopausal women due to the lack of normal flora seen in fertile women, especially lactobacilla; hence the subsequent higher pH. Vaginal infections should be treated with appropriate antimicrobial therapy before initiation of VAGIFEM therapy.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, vagina and liver. (See CONTRAINDICATIONS AND WARNINGS)

Pregnancy Category X

Estrogens are not indicated for use during pregnancy or the immediate postpartum period. Estrogens are ineffective for the prevention or treatment of threatened or habitual abortion. Treatment with diethyl-stilbesterol (DES) during pregnancy has been associated with an increased risk of congenital defects and cancer in the reproductive organs of the fetus, and possibly other birth defects. The use of DES during pregnancy has also been associated with a subsequent increased risk of breast cancer in the mothers.

Nursing Mothers

As a general principle, administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. In addition, estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Estrogens are not indicated for the prevention of postpartum breast engorgement.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of VAGIFEM® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Last updated on RxList: 7/25/2008

Numerous reports of ingestion of large doses of estrogen containing oral contraceptives by young children indicate that acute serious ill effects do not occur. Overdosage with estrogens may cause nausea, and withdrawal bleeding may occur in females.

The use of VAGIFEM is contraindicated in women who exhibit one or more of the following:

1. Known or suspected breast carcinoma.
2. Known or suspected estrogen-dependent neoplasia; e.g. endome-trial carcinoma.
3. Abnormal genital bleeding of unknown etiology.
4. Known or suspected pregnancy. (See PRECAUTIONS)
5. Porphyria.
6. Hypersensitivity to any VAGIFEM constituents.
7. Active thrombophlebitis or throm-boembolic disorders.
8. A past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast malignancy).

Last updated on RxList: 7/25/2008

In vivo estrogens diffuse through cell membranes, distribute throughout the cell, bind to and activate the estrogen receptors, thereby eliciting their biological effects. Estrogen receptors have been identified in tissue of the reproductive tract, breast, pituitary, hypothalamus, liver and bone of women. The estrogen contained in VAGIFEM, 17 β-estradi-ol is chemically and biologically identical to the endogenous human 17 β-estradiol and is, therefore, classified as a human estrogen.

Estrogens regulate growth, differentiation and functioning of many different tissues within and outside of the reproductive system. Estrogens are intricately involved with other hormones, especially progesterone, and during the ovulatory phase of the menstrual cycle cause proliferation of the endometrium. Most of the activity of estrogens appear to be exerted via estrogen receptors in target cells of tissues of the woman's reproductive tract: breast, pituitary, hypothalamus, brain, liver, and bone. The steroid-receptor complex is bound to the cell's DNA and induces synthesis of specific proteins. Maturation of the vaginal epithelium is dependent on estrogen as it increases the number of superficial and intermediate cells as compared with basal cells. Estrogen keeps the pH of the vagina at approximately 4.5 which enhances normal bacterial flora, predominately, Lactobacillus döderlein.

Pharmacokinetics

Absorption

Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

A single-center, randomized, double-blind comparison study conducted in the U.S. showed that vaginal application of VAGIFEM® over a 12-week course demonstrated a mean Cmax of estradiol of 50 pg/mL and that there was no significant accumulation of estradiol as measured by the AUC_0-24 (See Table 1 below).

Table 1: MEAN (±STANDARD DEVIATION) PHARMACOKINETIC PARAMETERS FOR ESTRADIOL (Uncorrected for base line) Timepoint

	Day 1	Day 14	Day 84
PK Parameter:
AUC (pg·hr/mL)	538(±265)	567(±246)	563(±341)
Cmax (pg/mL)	51(±34)	47(±21)	49(±27)

Distribution

Circulating, unbound estrogens are known to modulate pharmacological response. Estrogens circulate in the blood bound to sex-hormone binding globulin (SHBG) and albumin. A dynamic equilibrium exists between the conjugated and the unconjugat-ed forms of estradiol and estrone, which undergo rapid interconversion.

Metabolism

Exogenously-delivered or endogenously-derived estrogens are primarily metabolized in the liver to estrone and estriol, which are also found in the systemic circulation. VAGIFEM intravaginal administration avoids first-pass metabolism thatoccurs withoralestrogens.

The levels of E₁ seen during 12 weeks of VAGIFEM administration do not show any accumulation of E1, and the observed values are within the postmenopausal range. See Table 2 below.

Table 2: MEAN (±STANDARD DEVIATION) PHARMACOKINETIC PARAMETERS FOR ESTRONE (Uncorrected for base line) Timepoint

	Day 1	Day 14	Day 84
E1:
AUC (pg·hr/mL)	649(±230)	744(±267)	681(±271)
Cmax (pg/mL)	35(±12)	39(±13)	35(±12)

Excretion

Estrogen metabolites are primarily excreted in the urine as glucuronides and sulfates.

Drug-Drug Interactions

No formal drug-drug interaction studies have been done with VAGIFEM.

Clinical Studies

A placebo-controlled comparison study was done in the U.S., in which 230 patients were randomized to receive either placebo, VAGIFEM, or 10µg estradiol vaginal tablets. Patients inserted one tablet intravagi-nally each day for 14 days, then one tablet twice weekly for the remaining 10 weeks. All patients were assessed for vaginal symptoms. VAGIFEM® was superior to placebo in the relief of symptoms of the dryness, soreness, and irritation associated with atrophic vaginitis. This change of symptoms was seen at Week 7 and was maintained throughout to Week 12. (See Figure 1)

An open, controlled comparison study was done in Canada in which 159 patients were randomized to receive either VAGIFEM or the conjugated estrogen vaginal cream, comparator drug. Two (2) grams (~ 1.25 mg conjugated estrogens) of the comparator drug, which is the highest approved dose, was given daily for 3 weeks, withheld for 1 week, then repeated cyclically (3 weeks on, 1 week off) for up to 24 weeks; VAGIFEM was administered daily for 2 weeks, then twice weekly for the remaining 22 weeks. Of all patients entering into treatment phase of the study 10% of patients discontinued their treatment in the VAGIFEM group and 32% discontinued their treatment in the comparator group. In this study, patients were assessed for relief of symptoms. VAGIFEM 25µg was not less effective than the approved comparator product at the 2.0 gm dose in the relief of symptoms.

Symptoms of dryness, soreness, and irritation were rated as 0 = none, 1 = mild, 2 = moderate and 3 = severe. The average severity score of the three symptoms over time for the placebo controlled and comparator studies are shown in the following figures:

Figure 1: (Placebo controlled)

Figure 2: (Comparator)

The endometrium was evaluated at the end of each study by endometrial biopsy. See Tables 3 & 4 below.

Table 3: ENDOMETRIAL BIOPSY RESULTS COMPARING VAGIFEM WITH PLACEBO OVER 12 WEEKS OF TREATMENT (US Trial)

	VAGIFEM	Placebo
Total Number of Patients enrolled	91	47
Patients with uterus (non-hysterectomized)	48	24
Total Biopsies	32	21
Atrophic Endometrium	27 (84%)	18 (86%)
Weakly Proliferative	0 (0%)	0 (0%)
Proliferative	1 (3%)	0 (0%)
Simple Hyperplasia	1 (3%)	0 (0%)
Complex Hyperplasia	0 (0%)	0 (0%)
Insufficient Tissue	3 (9%)	3 (14%)

Table 4: ENDOMETRIAL BIOPSY RESULTS COMPARING VAGIFEM TO COMPARATOR GIVEN OVER 24 WEEKS

	VAGIFEM	Comparator
Total Number of Patients enrolled	80	79
Patients with uterus (non-hysterectomized)	80	79
Total Biopsies	49	49
Atrophic Endometrium	34 (68%)	15 (30%)
Weakly Proliferative	0 (0%)	4 (8%)
Proliferative	1 (2%)	7 (14%)
Simple Hyperplasia	0 (0%)	1 (2%)
Complex Hyperplasia	0 (0%)	1 (2%)
Insufficient Tissue	14 (28%)	21 (42%)

Last updated on RxList: 7/25/2008

See text of Patient Package Insert which appears in the PRECAUTIONS section.

Last updated on RxList: 7/25/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ESTRADIOL TABLET - VAGINAL

(ES-tra-DYE-ol)

COMMON BRAND NAME(S): Vagifem

WARNING: Estrogens given alone and with another hormone (progestin) for replacement therapy after menopause have sometimes caused rare but very serious side effects. Discuss the risks and benefits of hormone treatment and your personal health history with your doctor.

Estrogens have been reported to increase the chance of cancer of the uterus (endometrial cancer). Taking a progestin with estrogen decreases this risk. Tell your doctor immediately if you have any unusual vaginal bleeding.

Estrogens may also increase your risk of cancer of the ovaries, stroke, dementia, and serious blood clots in the legs. Estrogen given in combination with progestin can infrequently cause heart disease (e.g., heart attacks), stroke, serious blood clots (pulmonary embolism and deep venous thrombosis), dementia, and cancer of the breast. Some of these risks appear to depend on the length of time this drug is used and the amount of estrogen per dose. Therefore, this medication should be used for the shortest possible length of time at the lowest effective dose, so you can obtain the benefits and reduce the chance of serious side effects from long-term treatment. Also, the risks are greater with estrogen products taken by mouth, absorbed through the skin, or injected because more estrogen gets into the blood. Therefore, if you need treatment only for vaginal menopause symptoms, products applied directly inside the vagina are preferred and should be considered first. Discuss the details with your doctor and check with him/her regularly (e.g., every 3 to 6 months) to see if you still need to use this medication.

Estrogen treatment alone does not appear to increase your risk of breast cancer when used for up to 7 years after menopause. However, talk to your doctor about the risks if you need to take estrogen for a longer period.

Products that contain estrogen should not be used to prevent heart disease or dementia.

If you use this drug for an extended period, you should have a complete physical exam at regular intervals (e.g., once a year) or as directed by your doctor. See Notes section.

USES: This medication is a female estrogen hormone (estradiol) and is usually given to women who no longer produce the amount of estrogen they produced before menopause. It is a very effective treatment for reducing vaginal menopause symptoms (e.g., dryness, burning, itching).

HOW TO USE: Follow the instructions and dosing schedule carefully.

Insert the applicator into the vagina as directed and push the plunger to release the medication. Insert one tablet vaginally once daily for the first two weeks and then one tablet twice a week, or as directed by your doctor. It is best to schedule each dose about the same time of the day.

Inform your doctor if your symptoms persist or worsen.

SIDE EFFECTS: Dizziness, lightheadedness, headache, stomach upset, bloating, nausea, weight changes, increased/decreased interest in sex, and breast tenderness may occur. If any of these effects persist or worsen, notify your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (e.g., severe depression, memory loss), vision changes (e.g., change in contact lens fit, loss of vision), swelling of hands or feet, breast lumps, unusual vaginal bleeding (e.g., spotting, breakthrough bleeding, prolonged/recurrent bleeding), unusual vaginal discharge/itching/odor, stomach/abdominal/pelvic pain, yellowing eyes or skin.

Seek immediate medical attention if any of these unlikely but very serious side effects occur: calf pain/swelling, sudden severe headache, chest pain, trouble breathing, weakness on one side of the body, slurred speech.

A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using estradiol, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: undiagnosed abnormal vaginal bleeding, certain cancers (e.g., breast cancer, especially non-metastatic type), blood clots, active/recent stroke or heart attack.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: family medical history (especially breast lumps and cancer), asthma, diabetes, seizures, migraine headaches, liver disease, heart disease (e.g., high blood pressure, heart attacks, congestive heart failure), kidney disease, low thyroid hormone (hypothyroidism), abnormal calcium level in the blood, depression, high blood pressure during pregnancy (toxemia), yellowing of eyes and skin (cholestatic jaundice) during pregnancy or with past estrogen use, womb problems (e.g., uterine fibroids, endometriosis), cholesterol or lipid problems, gallbladder disease, excessive weight gain, certain blood disorder (porphyria).

If you will be having surgery or will be confined to a chair or bed for a long period of time (e.g., a long plane flight), notify your doctor beforehand. Special precautions may need to be taken in these circumstances while you are taking this drug.

This drug may make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

This drug may cause a patchy darkening of the skin on the face (melasma). Sunlight may intensify this darkening and you may need to avoid prolonged sun exposure and sunlamps. Consult your doctor regarding use of sunscreens and protective clothing.

Cigarette smoking can increase the chance of blood clots while taking this medicine (especially in women over the age of 35).

This medication must not be used during pregnancy. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is unknown if this medication passes into breast milk. Estrogens may have undesirable effects on a nursing infant. Therefore, breast-feeding while using this medication is not recommended.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medicine, tell your doctor or pharmacist of all prescription and nonprescription drugs you may use, especially of: other vaginal products.

This product can affect the results of certain lab tests. Make sure laboratory personnel and your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. This medicine may be harmful if swallowed. Symptoms of overdose may include severe nausea/vomiting or excessive vaginal bleeding.

NOTES: Do not share this medication with others. Keep all medical and laboratory appointments. You should have a complete physical examination that includes blood pressure measurements and breast/pelvic examinations at regular intervals (e.g., once a year) or as directed by your doctor. Follow your doctor's instructions on how to examine your own breasts and report any lumps immediately. You should also be regularly screened for cervical cancer (e.g., Pap test) and have periodic mammograms as determined by your doctor. Consult your doctor for more details.

To help manage hot flashes, keep a cool body temperature (e.g., use a fan, drink cool beverages, dress lightly/in layers, avoid hot/spicy foods). Limiting caffeine and alcohol, exercising regularly, and learning relaxation techniques may also help reduce hot flashes. Vaginal lubricants can help lessen discomfort during intercourse.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature about 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.