VAGIFEM® (ESTRADIOL VAGINAL TABLETS)

VAGIFEM - estradiol tablet, film coated 
Novo Nordisk

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VAGIFEM® (ESTRADIOL VAGINAL TABLETS)

25 µg

ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA.

Three independent, case controlled studies have reported an increased risk of endometrial cancer in post-menopausal women exposed to exogenous estrogens for more than one year. This risk was independent of the other known risk factors for endometrial cancer. These studies are further supported by the finding that incident rates of endometrial cancer have increased sharply since 1969 in eight different areas of the United States with population-based cancer-reporting systems, an increase which may be related to the rapidly expanding use of estrogens during the last decade.

The three case-controlled studies reported that the risk of endometrial cancer in estrogen users was about 4.5 to 13.9 times greater than in nonusers. The risk appears to depend on both duration of treatment and on estrogen dose.

In view of these findings, when estrogens are used for the treatment of menopausal symptoms, the lowest dose that will control symptoms should be utilized and medication should be discontinued as soon as possible. When prolonged treatment is medically indicated, the patient should be reassessed, on at least a semi-annual basis, to determine the need for continued therapy.

Close clinical surveillance of all women taking estrogens is important. In all cases of undiagnosed persistent or reoccurring abnormal vaginal bleeding, adequate diagnostic measures should be undertaken to rule out malignancy.

There is no evidence at present that “natural” estrogens are more or less hazardous than “synthetic” estrogens at equi-estrogenic doses.

DESCRIPTION

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.

17ß-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:

Molecular Structure

CLINICAL PHARMACOLOGY

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 ß-estradiol is chemically and biologically identical to the endogenous human 17 ß-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 1Day 14Day 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 unconjugated 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 that occurs with oral estrogens.

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 1Day 14Day 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 intravaginally 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)

Graph of Average Severity Score to Week 12

Figure 2 (Comparator)

Graph of Average Severity Score to Week 24

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)
VAGIFEMPlacebo

Total Number of

Patients enrolled

9147

Patients with uterus

(non- hysterectomized)

4824
Total Biopsies3221
Atrophic Endometrium27 (84%)18 (86%)
Weakly Proliferative0 (0%)0 (0%)
Proliferative1 (3%)0 (0%)
Simple Hyperplasia1 (3%)0 (0%)
Complex Hyperplasia0 (0%)0 (0%)
Insufficient Tissue3 (9%)3 (14%)
Table 4: ENDOMETRIAL BIOPSY RESULTS COMPARING VAGIFEM TO COMPARATOR GIVEN OVER 24 WEEKS
VAGIFEMComparator

Total Number of

Patients enrolled

8079

Patients with uterus

(non- hysterectomized)

8079
Total Biopsies4949
Atrophic Endometrium34 (68%)15 (30%)
Weakly Proliferative0 (0%)4 (8%)
Proliferative1 (2%)7 (14%)
Simple Hyperplasia0 (0%)1 (2%)
Complex Hyperplasia0 (0%)1 (2%)
Insufficient Tissue14 (28%)21 (42%)

INDICATIONS AND USE

VAGIFEM® is indicated for the treatment of atrophic vaginitis.

CONTRAINDICATIONS

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. endometrial 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 thromboembolic disorders.

8. A past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast malignancy).

WARNINGS

1. 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.

2. 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.

3. 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.

a. Thromboembolic disease. It is now well established that users of oral contraceptives have an increased risk of various thromboembolic and thrombotic vascular diseases, such as thrombophlebitis, pulmonary embolism, stroke, and myocardial 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 thromboembolism, or during periods of prolonged immobilization.

While an increased rate of thromboembolism and thrombotic 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 thrombophlebitis. When estrogen doses of this size are used, any of the thromboembolic and thrombotic adverse effects associated with oral contraceptive use should be considered a clear risk.

b. 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.

c. 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.

d. 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.

4. Hypercalcemia. Administration of estrogens may lead to severe hypercalcemia 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.

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

PRECAUTIONS

A. 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 estrogens 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 hypercalcemia 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.

B. Information for the Patient

See text of Patient Package Insert which appears below.

C. 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:

a. Increased prothrombin and factors VII, VIII, IX, and X, decreased antithrombin III; increased norepinephrine induced platelet aggregability.

b. 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.

c. Impaired glucose tolerance.

d. Reduced response to metyrapone test.

e. Reduced serum folate concentration.

f. Increased serum triglyceride and phospholipid concentration.

D. 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).

E. 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 diethylstilbesterol (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.

F. 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.

G. Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

H. 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.

ADVERSE EVENTS

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.
VAGIFEMPlacebo
(n=91)(n=47)
ADVERSE EVENT%%
HEADACHE96
ABDOMINAL PAIN74
UPPER RESPIRATORY
     TRACT INFECTION54
MONILIASIS GENITAL52
BACK PAIN76
Table 6: ADVERSE EVENTS REPORTED IN 5% OR GREATER NUMBER OF PATIENTS RECEIVING VAGIFEM® IN THE OPEN LABEL STUDY.
VAGIFEM
(n=80)
ADVERSE EVENT%
PRURITUS GENITAL6
HEADACHE10
UPPER RESPIRATORY
     TRACT INFECTION11

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.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

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.

HOW SUPPLIED

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

Novo Nordisk Pharmaceuticals, Inc.

Princeton, NJ 08540

1-888-824-4336

www.novonordisk-us.com

Manufactured by

Novo Nordisk A/S

2880 Bagsvaerd, Denmark

PATIENT PACKAGE INSERT

Introduction

This leaflet describes when and how to use VAGIFEM® (estradiol vaginal tablets) and the risks and benefits of estrogen treatment. Please read this information carefully before starting treatment.

Estrogens have important benefits but also some risks. You must decide, with your doctor or health care provider, whether the risks to you of estrogen use are acceptable because of their benefits. If you use estrogens, check with your health care provider to be sure you are using the dose that is appropriate for you, and that you don’t use them longer than necessary. How long you need to use estrogens should be decided by you and your health care provider. Estrogens are hormones made by the ovaries of normal women. Between ages 45 and 55, the ovaries normally stop making estrogens. This leads to a drop in body estrogen levels which causes the “change of life” or menopause (the end of monthly menstrual periods). If both ovaries are removed during an operation before natural menopause takes place, the sudden drop in estrogen levels causes “surgical menopause.”When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating (“hot flashes” or “hot flushes”). Using estrogen drugs can help the body adjust to lower estrogen levels and reduce these symptoms. Most women have only mild menopausal symptoms or none at all and may not need to use estrogen drugs. VAGIFEM DOES NOT PROVIDE ENOUGH ESTROGEN TO REDUCE THESE SYMPTOMS.

The declining estrogen levels associated with advancing age after menopause may also result in thinning and drying of the tissue in the vagina and urinary tract (urogenital atrophy). Vaginal symptoms of this condition include dryness in the vagina (atrophic vaginitis), genital itching and burning, and pain with intercourse. Urinary symptoms may include urinary urgency and pain on urination. Small amounts of estrogen delivered directly to the local tissue can be used to help reduce these symptoms.

Use Of VAGIFEM®

(Estradiol Vaginal Tablets)

VAGIFEM is a local estrogen therapy designed to relieve vaginal symptoms, a major component of the urogenital symptoms found in postmenopausal estrogen deficiency. VAGIFEM® (estradiol vaginal tablets) exerts its effect locally in the lower urogenital tract, particularly the vagina, and has not been associated with significant effects in other estrogen-sensitive organs or tissues of the body. Consequently, VAGIFEM provides relief of local symptoms of menopause only.

Description

VAGIFEM® (estradiol vaginal tablets) contains 25µg (micrograms) of estrogen (estradiol). VAGIFEM releases estradiol into the vagina. A gel layer forms when the tablet comes in contact with the vagina. The estradiol is released from this gel layer. See Figure 1.

Tablet Dissolving

Fig. 1

Dosage

One (1) VAGIFEM tablet inserted vaginally once daily for the first two (2) weeks. Then one (1) tablet twice weekly. (See table below).

Administration Regimen
Days:1234567

Week 1

1 Vagifem tablet every day

///////

Week 2

1 Vagifem tablet every day

///////

Week 3 and Thereafter

1 Vagifem tablet twice weekly

//

Directions for use of VAGIFEM®:

Step 1: Tear off a single applicator.

Opening of applicator wrapper

Fig. 2

Step 2: Separate the plastic wrap and remove the applicator from the plastic wrap. See Figure 2.

Sitting position: insertion of applicator

Fig. 3

Step 3: First select the best position for vaginal insertion of VAGIFEM® (estradiol vaginal tablets) that is most comfortable for you. See suggested reclining Figure 3 or standing Figure 4 position illustrated below:

Standing position: insertion of applicator

Fig. 4

Step 4: The applicator should be held so that the finger of one hand can press the applicator plunger. See Figure 5.

Finger placement on applicator

Fig. 5

Step 5: The other hand should be used to guide the applicator gently and comfortably through the vaginal opening (see Figures 3 and 4 above). If the tablet has come out of the applicator prior to insertion, do not attempt to replace it. Use a fresh tablet-filled applicator.

Step 6: The applicator should be inserted (without forcing) as far as comfortably possible, or until half of the applicator is inside your vagina, whichever is less.

Step 7: Once the tablet-filled applicator has been inserted, gently press the plunger until a click is heard and the plunger is fully depressed. This will eject the tablet inside your vagina where it will dissolve slowly over several hours.

Step 8: After depressing the plunger, gently remove the applicator and dispose of it the same way you would a plastic tampon applicator. The applicator is of no further use and should be discarded properly.

Insertion may be done at any time of the day. It is advisable to use the same time daily for all applications of VAGIFEM® (estradiol vaginal tablets).

If you have any questions, please consult your health care provider or pharmacist.

Who Should Not Use VAGIFEM®

(Estradiol Vaginal Tablets)

VAGIFEM should not be used:

During pregnancy - Women who are definitely postmenopausal cannot become pregnant. Women who believe they are postmenopausal because their menstrual cycles have recently stopped should confirm that they are not pregnant before using any form of estrogen-containing drug. Using estrogens while pregnant may cause the unborn child to have birth defects. Estrogens do not prevent miscarriage.

In the presence of unusual vaginal bleeding which has not been evaluated by a health care provider. Unusual vaginal bleeding after menopause can be a warning sign of cancer of the uterus. Estrogens may increase the risk of cancer of the uterus in women who have had their menopause (“change of life”). If you use any estrogen-containing drug, it is important to visit your health care provider regularly and report any unusual vaginal bleeding right away. Your health care provider should evaluate any unusual vaginal bleeding to find out the cause.

If there is a history of certain types of cancer - Estrogens may increase the risk of certain types of cancer, usually uterine or breast. VAGIFEM has not been associated with an increased risk of uterine cancer. Although there are reports of increased risk of breast cancer in women on hormone replacement therapy, VAGIFEM is administered locally and is not expected to pose an increased risk.

After childbirth or when breastfeeding a baby - VAGIFEM should not be used to try to stop the breasts from filling with milk after a baby is born. Women who are breast-feeding should avoid using any drugs because many drugs pass through to the baby in the milk. While nursing a baby, drugs should only be taken on the advice of your healthcare giver.

Possible Risks From Treatment With Estrogens

The following risk factors apply to estrogens in general:

Cancer of the uterus - Estrogens increase the risk of developing a condition (endometrial hyperplasia) that may lead to cancer of the lining of the uterus (endometrial cancer).

The risk of endometrial cancer is greater in estrogen users than nonusers. Studies have shown that this increased risk depends on estrogen dose, duration of treatment, and treatment regimen.

Using progestin therapy together with estrogen therapy may reduce the higher risk of uterine cancer related to estrogen use.

If the uterus has been removed (total hysterectomy), there is no danger of developing cancer of the uterus.

Cancer of the breast - Most studies have not shown a higher risk of breast cancer in women who have ever used estrogens. However, some studies have reported that breast cancer developed more often (up to twice the usual rate) in women who used estrogens for long periods of time (especially more than 10 years) or who used higher doses for shorter time periods. VAGIFEM® (estradiol vaginal tablets) is not expected to increase this risk since it is a low dose, applied topically in the vagina, is minimally absorbed into the systemic circulation and is used for relatively short periods of time. Regular breast examinations by a health professional and monthly self-examination are recommended for all women.

Gallbladder disease and abnormal blood clotting - Gallbladder disease and abnormal blood clotting are risk factors associated with medium to high doses of estrogen. Most studies of low-dose estrogen usage by women do not show an increased risk of these complications, and to date there have not been complications with VAGIFEM (estradiol vaginal tablets) treatment.

Side Effects

Few side effects have been reported: vaginal spotting, vaginal discharge, allergic reaction and skin rash.

Estrogens In General

In addition to the risks listed above, the following side effects have been reported with estrogen use: Nausea and vomiting, breast tenderness or enlargement, enlargement of benign tumors (“fibroids”) of the uterus, retention of excess fluid. Estrogen may worsen some conditions, such as asthma, epilepsy, migraine, heart disease, or kidney disease. Spotty darkening of the skin, particularly on the face.

If you use estrogens, you may reduce your risks by doing these things:

See your health care provider regularly. While you are using estrogens, it is important to visit your health care provider at least annually for a check-up. If you develop vaginal bleeding while taking estrogens, call your health care provider; you may need further evaluation. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast X-ray), you may need to have more frequent breast examinations.

Reassess your need for estrogens. You and your health care provider should reevaluate whether or not you still need estrogens at least every six months.

Be alert for warning signs. If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your health care provider immediately: Abnormal bleeding from the vagina (possible uterine cancer); pains in the calves or chest, sudden shortness of breath, or coughing blood (possible clot in the legs, heart, or lungs); severe headache or vomiting, dizziness, faintness, changes in vision or speech, weakness or numbness of an arm or leg (possible clot in the brain or eye); breast lumps (possible breast cancer; ask your health care provider to show you how to examine your breasts monthly); yellowing of skin or eyes (possible liver problem); pain, swelling, or tenderness in the abdomen (possible gallbladder problem).

1. Estrogens increase the risk of developing a condition called endometrial hyperplasia that may lead to cancer of the lining of the uterus. Progestin, another hormone drug, is usually prescribed with higher-dose estrogen preparations in order to lower the risk of developing endometrial hyperplasia. Progestins are not usually needed for women using VAGIFEM® (estradiol vaginal tablets) alone.

2. Vaginal infection is generally more common in postmenopausal women. Vaginal infections should be treated by your health care provider with the appropriate antimicrobial therapy before initiation of VAGIFEM. If a vaginal infection develops during use of VAGIFEM, it may be continued while the infection is being treated. See your health care provider if you have vaginal discomfort or suspect you have a vaginal infection.

3. Your health care provider has prescribed this drug for you and you alone. Do not give the drug to anyone else.

4. Keep this and all drugs out of the reach of children.

5. This leaflet provides a summary of important information about VAGIFEM. If you want more information, ask your health care provider or pharmacist to show you the professional labeling. The professional labeling is also published in a book called the “Physicians’ Desk Reference” which is available in book stores and public libraries. Generic drugs carry virtually the same labeling information as their brand name versions.

HOW SUPPLIED

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

Novo Nordisk Pharmaceuticals, Inc.

Princeton, NJ 08540

1-888-824-4336

www.novonordisk-us.com

Manufactured by

Novo Nordisk A/S

2880 Bagsvaerd, Denmark

Package Label Principal Display Panel

NDC 0169-5173-04

Vagifem®

estradiol vaginal tablets

25µg

18 vaginal tablets

Novo Nordisk®

Carton Panel for 18 tablets

VAGIFEM 
estradiol   tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0169-5173
Route of AdministrationVAGINALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ESTRADIOL (estradiol) ESTRADIOL25 ug
Inactive Ingredients
Ingredient NameStrength
No Inactive Ingredients Found
Product Characteristics
ColorWHITE (WHITE) Score no score
ShapeROUND (ROUND) Size6mm
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10169-5173-0418 APPLICATOR In 1 CARTONcontains a APPLICATOR
11 TABLET In 1 APPLICATORThis package is contained within the CARTON (0169-5173-04)
20169-5173-038 APPLICATOR In 1 CARTONcontains a APPLICATOR
21 TABLET In 1 APPLICATORThis package is contained within the CARTON (0169-5173-03)
30169-5173-995 APPLICATOR In 1 CARTONcontains a APPLICATOR
31 TABLET In 1 APPLICATORThis package is contained within the CARTON (0169-5173-99)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02090809/11/2001

Labeler - Novo Nordisk (622920320)
Establishment
NameAddressID/FEIOperations
Novo Nordisk A/S586793291MANUFACTURE
Revised: 05/2006Novo Nordisk