Vagifem Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Vagifem^® (estradiol vaginal tablet) is indicated for:

• The treatment of the symptoms of atrophic vaginitis due to estrogen deficiency. Addition of a progestin is not recommended.

Geriatrics (>65 years of age): Clinical studies of Vagifem^® did not include sufficient number of subjects aged 65 and over to determine if they responded differently from younger subjects.

Pediatrics (<18 years of age): Vagifem^® is not indicated for use in the pediatric population.

CONTRAINDICATIONS

Vagifem^® (estradiol vaginal tablet) is contraindicated in women with:

• Hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• Known or suspected estrogen-dependent malignant neoplasia (e.g. endometrial cancer).
• Endometrial hyperplasia
• Known, suspected, or past history of breast cancer
• Undiagnosed abnormal genital bleeding.
• Known or suspected pregnancy.
• Active or past history of confirmed venous thromboembolism (such as deep vein thrombosis or pulmonary embolism) or active thrombophlebitis.
• Lactation

WARNINGS AND PRECAUTIONS

General

Risks and benefits of treatment with Vagifem^® should be re-assessed at least annually. Vagifem^® should only be continued as long as the benefits outweigh the risks.

Vagifem^® is a topical, low-dose vaginal estrogen therapy product (see Action and Clinical Pharmacology – Pharmacokinetics – Absorption). The following warnings and precautions associated with oral estrogen therapy should be considered in the absence of comparable data with other dosage forms of estrogens.

Carcinogenesis and Mutagenesis

Breast cancer

There is a need for caution in prescribing estrogens of any kind to women with a strong family history (first degree relative) of breast cancer or women who have nodules, fibro cystic disease or abnormal mammograms and/ or atypical hyperplasia at breast biopsy.

In the oral estrogen-alone arm of the WHI trial, there was no statistically significant difference in the rate of invasive breast cancer in hysterectomized women treated with conjugated equine estrogens versus women treated with placebo.²

It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease (see Contraindications).

Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated.

It is recommended that women undergo mammography prior to the start of HT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.

The overall benefits and possible risks of hormone therapy should be fully considered and discussed with patients.

Instructions for regular self-examination of the breasts should be included in this counseling.

Endometrial hyperplasia & endometrial carcinoma

There is no systemic effect under local estrogen treatment with Vagifem^®, the addition of a progestin is not recommended.

Endometrial histology was evaluated in 5 clinical trials conducted in the USA and Canada. Endometrial biopsies were evaluated at the end of the study in nonhysterectomized subjects. Table 1 provides a summary of endometrial biopsies taken at the end of 3 short-term studies and Table 2 provides a summary of endometrial biopsies taken at the end of 2 long-term studies. Only one woman treated with Vagifem^® developed simple endometrial hyperplasia. There were two cases of endometrial hyperplasia in women treated with conjugated estrogen vaginal cream (2g containing 625 µg/g of conjugated equine estrogen), and no cases of endometrial hyperplasia in women treated with placebo.

Ovarian Cancer

Recent epidemiologic studies have found the use of hormone therapy (estrogen-alone and estrogen plus progestin therapies), in particular for five or more years, has been associated with an increased risk of ovarian cancer.

Cardiovascular

The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and the Women's Health Initiative (WHI) trial indicate that the use of continuous combined oral conjugated estrogens (CEE) and medroxyprogesterone acetate (MPA) is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women.^{1, 4, 5} The results of the WHI trial indicate that the use of oral estrogen-alone and oral estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women.^{1, 2}

Blood Pressure

Women using hormone therapy sometimes experience increased blood pressure. Blood pressure should be monitored with HT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HT may have to be discontinued.

Endocrine and Metabolism

Glucose and lipid metabolism

Although no effect of low dose vaginal estradiol supplementation has been seen on glucose tolerance, fluid retention, elevation of blood pressure or other liver or endocrine functions, women with predisposition to or signs indicating an effect on those variables could indicate caution.

Hyperlipidemia has been reported in women on other types of estrogen replacement therapy, but it has not been observed in women using Vagifem^®.

Genitourinary

Vaginal Bleeding

Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt appropriate diagnostic measures to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.

Women should be advised to inform their physician if irritation, pain, discharge, unusual or unexpected bleeding occur during treatment.

Women with signs of ulceration or severe inflammation due to unresponsive atrophic vaginitis, withdrawal from treatment should be considered and appropriate investigations should be conducted.

Applicator Trauma

Trauma induced by the Vagifem^® applicator may occur, especially in patients with severely atrophic vaginal mucosa. After gynecological surgery, any vaginal applicator should be used with caution and only if clearly indicated.

Uterine leiomyomata

Pre-existing uterine leiomyomata may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyomata requires discontinuation of medication and appropriate investigation.

Endometriosis

Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.

Vaginal Infection

Vaginal infection is generally more common in postmenopausal women due to the lack of the normal flora seen in fertile women, especially lactobacillus, and the subsequent higher pH. Vaginal infections should be treated with appropriate antimicrobial therapy before initiation of Vagifem^®. If a vaginal infection develops during the maintenance phase of the treatment, appropriate therapy should be instituted. The next dose of Vagifem^® should be inserted once the therapy is completed.

Hematologic

Venous thromboembolism

Available epidemiological data indicate that use of oral estrogen with or without progestin by postmenopausal women is associated with an increased risk of developing venous thromboembolism (VTE).

The benefits and risks of hormone therapy should be carefully weighed when prescribing Vagifem^® to women with a risk factor for thrombotic disorders. The physician should be alert to the earliest manifestations of thrombotic disorders. If these occur or are suspected, estrogen therapy should be discontinued immediately. Women with a positive family history and women with a history of thromboembolic disorders during pregnancy or in association with estrogen use should be kept under special observation.

Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index > 30 kg/m²) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking.

The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. In women on HT, attention should be given to prophylactic measures to prevent VTE following surgery. Also, patients with varicose veins should be closely supervised. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, hormone therapy should be discontinued immediately, given the risks of long-term disability or fatality.

If feasible, estrogens should be discontinued at least 4 weeks before major surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Hepatic/Biliary/Pancreatic

Gallbladder diseases

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens has been reported.

Neurologic

Cerebrovascular insufficiency

Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis or loss of consciousness should discontinue medication.

Patients with a previous history of classical migraine and who develop a recurrence or worsening of migraine symptoms should be reevaluated.

Dementia

Available epidemiological data indicate that the use of combined oral estrogen plus progestin in women age 65 and over may increase the risk of developing probable dementia.

Epilepsy

HT may cause an exacerbation of epilepsy.

Renal

Fluid retention

Estrogens may cause fluid retention.

Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy or asthma. If, in any of the above-mentioned conditions, a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits and risks of treatment should be reassessed based on the individual case.

Special Populations

Pregnant Women: Estrogen should not be used in pregnancy. Any possibility of pregnancy must be ruled out before prescribing Vagifem^®. If pregnancy occurs during Vagifem^® treatment, the medication should be discontinued immediately.

Nursing Women: Estrogens should not be used during lactation. Vagifem^® should not be prescribed for nursing mothers.

Pediatrics (<18 years of age): Vagifem^® is not indicated for use in the pediatric population.

Geriatrics (>65 years of age): Clinical studies of Vagifem^® did not include sufficient number of subjects aged 65 and over to determine if they responded differently from younger subjects.

Conditions which need Supervision:

Due to the local administration of low dose estradiol in Vagifem^®, the recurrence or aggravation of some conditions is less likely than with systemic estrogen treatment, such as:

• Leiomyomata (uterine fibroids) or endometriosis
• A history of, or risk factors for, thromboembolic disorders (see below)
• Hypertension
• Liver disorders (e.g. liver adenoma)
• Diabetes mellitus with or without vascular involvement
• Cholelithiasis
• Migraine or (severe) headache
• Systemic lupus erythematosus
• A history of endometrial hyperplasia (see below)
• Epilepsy
• Asthma
• Otosclerosis.

Therapy should be discontinued if any of the following situations is discovered:

• Jaundice or deterioration in liver function
• Significant increase in blood pressure
• New onset of migraine- type headache
• Pregnancy

Monitoring and Laboratory Tests

Before Vagifem^® is administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial biopsy should be done only when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests.

The first follow-up examination should be done within 3-6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.

The importance of regular self-examination of the breasts should be discussed with the patient.

Women treated with Vagifem^® should be advised to keep their regular medical checkups to assess the need for continuing therapy.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Reproductive system and breast disorders

Breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea ; vaginal itching/discharge; dyspareunia ; endometrial hyperplasia; pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion; breast swelling and tenderness.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Comparative Studies

In an open-labelled, multi-centre, comparative clinical trial conducted in Canada, women were treated with either Vagifem^® (N=80) or conjugated estrogen vaginal cream (N=79) for up to 6 months. Vagifem (25 µg estradiol) was administered daily for 2 weeks, then twice weekly with at least 3 days between each application, for the remaining 22 weeks; 2 g of the comparator drug, containing approximately 1.25 mg conjugated estrogen, was given daily for 3 weeks, withheld for 1 week, then repeated cyclically (3 weeks on, 1 week off) for up to 24 weeks. Table 3 lists the percentage and reasons for discontinuation form the study.

Placebo Controlled Studies

A placebo-controlled comparison study was done in the U.S., in which 230 patient were randomized to receive either placebo, 17 β-estradiol 10 µg vaginal tablets, or Vagifem^® (25 µg estradiol). Patients inserted one tablet intra-vaginally each day for 14 days, then one tablet twice weekly for the remaining 10 weeks. All patients were assessed for vaginal symptoms.

Overall, Vagifem^® is well tolerated, is comparable to placebo in overall incidence of treatment-emergent adverse events, has not demonstrated a potential for causing adverse events associated with endogenous levels of estrogen that differs from other topical hormone therapies and has not demonstrated a potential for causing adverse events associated with cumulative dosing in long-term therapy extending to 64 weeks.

In 8 clinical trials, conducted in North America and Europe, involving 438 women treated with Vagifem^® for atrophic vaginitis, including 115 women treated for 52 weeks, approximately 21% of women experienced a treatment emergent adverse event that could possibly or probably be related to Vagifem^®.

Table 4 lists the treatment-emergent adverse events reported by 5% or greater of the women in short term (up to 24 weeks) studies conducted in Canada and the United States.

Other Clinical Trial Adverse Drug Reactions (<5%)

The following adverse events were reported at an incidence of <5% for Vagifem^® regardless of drug relationship.

Skin/Appendages: Acne; Dermatitis contact; Nail disorder; Pruritus; Pruritus genital; Rash; Skin disorder; Skin ulceration; Urticaria

Musculoskeletal: Arthralgia; Arthritis; Arthritis aggravated; Arthrosis; Bone Disorder; Myalgia

Central Nervous System: Dizziness; Hypertonia; Hypoaesthesia; Migraine; Involuntary muscle contractions; Paraesthesia

Vision Disorders: Blepharitis; Conjunctivitis

Psychiatric Disorders: Agitation; Anxiety; Increased appetite; Depression; Insomnia; Libido decrease; Nervousness; Somnolence

Gastrointestinal: Abdominal pain; Constipation; Diarrhea; Diverticulitis; Dyspepsia; Flatulence; Gastroesophageal reflux; Nausea; Tooth disorder; Vomiting

Endocrine Disorders: Goiter

Cardiovascular: Hearth murmur; Hypertension; Palpitation

Vascular Disorders (non-CVD): Cerebrovascular disorder; Thrombophlebitis leg superficial

Respiratory System: Bronchitis; Bronchospasm; Coughing; Pharyngitis; Rhinitis; Sinusitis

Urinary System: Dysuria, Haematuria; Micturition frequency; Urethral disorder; Urinary incontinence; Urinary tract infection

Reproductive Disorders: Abdominal pain; Breast disorder (not otherwise specified); Breast pain; Endometrial hyperplasia; Leukorrhea; Perineal pain; Postmenopausal bleeding; Vaginitis; Vaginitis ulcerative; Vulva discomfort

Foetal Disorders: Spinal malformation

Neoplasm: Basal cell carcinoma; Breast fibroadenomosis: Renal carcinoma; Uterine fibroid; Vaginal neoplasm benign

Hearing and Vestibular: Ear disorder NOS; Earache

Liver and Biliary: Gama-GT increased, Hepatitis, SGOT and SGPT increased

Metabolic and Nutritional: LHD increased; Oedema legs; Phosphatase alkaline increased

Platelet, bleeding & clotting: Haematoma; Purpura

Immune system: Herpes simplex; Infection.; Fungal infection; Candidiasis genital; Lymphadenopathy

Body as a whole: Allergic reaction; Allergy; Aesthenia; Back pain; Carpal tunnel syndrome; Fatigue; Fever; Headache; Hot flushes; Influenza-like symptoms; Leg pain; Neck rigidity; Oedema peripheral; Pain

Post-Market Adverse Drug Reactions

The following events have been spontaneously reported during Vagifem^® use in clinical practice. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Neoplasm benign and malignant:

Breast cancer; endometrial cancer

Immune system disorders:

Hypersensitivity

Metabolism and nutrition disorders:

Fluid retention

Psychiatric disorders:

Insomnia; depression

Nervous system disorders:

Migraine aggravated

Vascular disorders:

Deep venous thrombosis

Gastrointestinal disorders:

Diarrhea

Skin and subcutaneous disorders:

Urticaria; rash erythematous; rash pruritic

Reproductive system and breast disorders:

Endometrial hyperplasia; vaginal irritation; vaginal pain; vaginismus; vaginal ulceration

General disorders and administration site conditions:

Drug ineffective

Investigations:

Weight increase; blood estrogen increase

DRUG INTERACTIONS

Overview

Vagifem^® is a topical vaginal estrogen therapy product. The following drug-interactions are based on the experience of systematic estrogen treatment.

Enzyme inducers, (e.g. barbiturates, hydantoins, carbamazepine, meprobamates, or rifampicin) can enhance estrogen metabolism, resulting in breakthrough bleeding or vaginal spotting.

Estrogens may diminish the effectiveness of anticoagulant, antidiabetic and antihypertensive agents.

Drug-Drug Interactions

No Drug-Drug Interactions with Vagifem^® have been reported.

See Warnings and Precautions regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives.

Drug-Food Interactions

No Drug-Food Interactions with Vagifem^® have been reported.

Drug-Herb Interactions

No Drug-Herb Interactions with Vagifem^® have been reported.

Physicians and other health care providers should be made aware of other non-prescription products concomitantly used by the patient, including herbal and natural products.

Drug-Laboratory Interactions

There are no studies investigating Drug-Laboratory interactions with Vagifem^®.

The pathologist should be informed that the patient is receiving hormone therapy (HT) when relevant specimens are submitted.

DOSAGE AND ADMINISTRATION

Dosing Considerations

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used.

Vagifem^® may be used in women with or without an intact uterus.

During treatment, especially during the first 2 weeks, minimal absorption may be seen however, as plasma estradiol levels after the first 2 weeks usually do not exceed postmenopausal levels; the addition of a progestin is not recommended.

Recommended Dose and Dosage Adjustment

Treatment may be started on any convenient day.

Initial dose: 1 vaginal tablet daily for 2 weeks

Maintenance dose: 1 vaginal tablet twice a week with a 3 or 4 day interval between doses

Missed Dose

If a patient misses a dose, it should be administered as soon as possible. If it is close to the patient’s next scheduled dose, the missed dose should be skipped, and the patient should continue with her normal schedule. The patient should not take two doses at the same time.

Administration

Accidental injury during administration of Vagifem^® may occur if the applicator is introduced too high into the vagina. Women should be shown how to administer Vagifem^® correctly. No incidences of applicator injury were reported in the clinical trials of Vagifem^®.

Vagifem^® (estradiol vaginal tablet) is gently inserted into the vagina as far as it can comfortably go without force, using the supplied applicator. Detailed instructions for use are provided in Part III: Consumer Information.

OVERDOSAGE

No cases of overdose have been reported

Numerous reports of ingestion of large doses of estrogen products and estrogen-containing oral contraceptives by young children have not revealed acute serious ill effects. In general, excessive doses of estrogen may result in nausea, vomiting, abdominal cramps, headache, dizziness and general malaise.

The dose of estradiol in Vagifem^® is very low compared with oral estrogen products. Treatment of overdose should be symptomatic.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Vagifem^® (estradiol vaginal tablet) is a hydrophilic, cellulose-derived matrix tablet which hydrates upon contact with moisture, releasing 17ß-estradiol (Figure 1). The estradiol in Vagifem^® is chemically and biologically identical to the endogenous human estradiol and is therefore classified as a human estrogen. 17ß-estradiol is the primary estrogen and the most active of the ovarian hormones.

Figure 1. Diffusion of estradiol from a dry vaginal tablet

Dry Tablet

Upon contact with vaginal mucosa, a gel layer forms on the surface.

As moisture permeates the tablet, it is eroded and soluble estradiol diffuses out of the gel layer.

Pharmacodynamics

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 the tissue of the reproductive tract, breast, pituitary, hypothalamus, liver and bone of women. Estrogens regulate growth, differentiation and function 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.

Endogenous 17β-estradiol induces and maintains the primary and secondary female sexual characteristics. Most of the activities of 17β-estradiol appear to be exerted via binding to specific estrogen receptors in target cells of tissue. The steroid-receptor complex is bound to the cell’s DNA and induces synthesis of specific proteins.

The hormone deficient state associated with menopause leads to atrophic changes in the urogenital epithelial and subepithelial tissues. Vaginal blood flow is reduced, causing decreased lubrification during sexual arousal rendering the tissue more susceptible to trauma. Thinning of the vaginal mucosa occurs, cellular and glycogen production declines, decreasing the colonization of lactobacilli and thus lactic acid production. The usual acidity of the vagina, which serves as a potent defence mechanism, is lost. Symptoms associated with the atrophic changes are vaginal dryness, genital itching and burning and dyspareunia. The goal of local estrogen therapy is to provide sufficient estrogen to reverse atrophic changes in the local tissues and relieve associated symptoms.

Maturation of the vaginal epithelium is dependent on estrogen. Estrogen increases the number of superficial and intermediate cells as compared to basal cells.

Estrogen keeps pH in the vagina down to around 4.5 which enhances normal bacterial flora, Lactobacillus Doderlein predominating.

Pharmacokinetics

Absorption:

Estrogens are well absorbed through skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal route of estrogen delivery avoids firs-pass metabolism. After administration of Vagifem^®, 17 β-estradiol is absorbed form the vaginal mucosa.

A single-centre, randomized, double-blind, comparison study was conducted in U.S. to investigate the effects of Vagifem^® treatment on serum hormone concentrations. Subjects were treated with Vagifem^® daily for 2 weeks followed by twice weekly administration for 10 weeks. Serum estradiol (E₂) and estrone (E₁) levels were measured after the first dose at 1, 2, 4, 5, 6, 7, 8, 10, 12 and 24 hours after administration at each study visit. E₁S (estrone sulfate) and FSH levels were determined after the first dose at 6, 12 and 24 hours after administration at each study visit. Study visits were scheduled on the first day of dosing after 1, 2, 4, 8, and 12 weeks of

treatment. A total of 28 healthy women with atrophic vaginitis received Vagifem^® of which 22 completed the study.

Figure 2 illustrates the serum E₂ levels following the first dose after 2 and 12 weeks of treatment. This study showed that the vaginal application of Vagifem^® over a 12-week period did not result in accumulation of estradiol as measured by the AUC_0-24 (Table 6). C_max of serum estradiol was constant from the first day of treatment (week 0) to the end of treatment (week 12). There was a small statistically significant increase in mean E₁S (estrone sulfate) concentrations during the 12 weeks of therapy. The mean concentrations over the 24-hour period after dosing at weeks 0, 2 and 12 ranged from 360-469 pg/mL, 572-673 pg/mL, and 470-556 pg/mL, respectively, for women treated with Vagifem^®. Mean FSH (averaged over the 24-hour sampling period) decreased significantly, with a median change of -9.0 IU/L at week 2 and -4.4 IU/L at week 12.

Figure 2: Serum E₂ Levels (Mean ± 2x Standard Error) After Application of Vagifem^® at Weeks 0, 2, and 12

Distribution:

Circulating, unbound estrogens are known to modulate pharmacological response. Estrogens circulate in the blood bound to sex-hormone binding globulin (SHBG) and albumin.

Metabolism:

Exogenously-derived or enogenously-derived estrogens are primarily metabolized in the liver to estrone and estradiol, which are also found in the systemic circulation. Vagifem^® intravaginal administration avoids first-pass metabolism that occurs with oral estrogens.

Excretion:

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

STORAGE AND STABILITY

Store in a dry place, protected from light. Store between 15°C - 30°C. Do not refrigerate. Store in original package.

Keep in a safe place out of the reach of children and pets.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Vagifem^® (estradiol vaginal tablet) is a small, white, film-coated tablet containing 25.8µg of estradiol hemihydrate equivalent to 25µg of estradiol.

Each tablet contains the following inactive ingredients: lactose monohydrate, maize starch, methylhydroxypropylcellulose, magnesium stearate and polyethylene glycol 6000.

Each white tablet is 6mm in diameter and is contained in a single-use high density polyethylene/polypropylene applicator. Each tablet-filled applicator is packaged separately in a laminated blister package.

Vagifem^® is available in cartons of 15 pre-loaded applicators.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: estradiol hemihydrate

Chemical name: oestra-1,3,5(10)-triene 3, 17ß-diol hemihydrate

Molecular formula: C₁₈H₂₄O₂ • ½ H₂O

Molecular mass: 281.4

Figure 3: Structural formula

OH

OH

OH₂ •½

Description: White or almost white crystalline powder or colourless crystals

Solubility: Practically insoluble in water

Melting point: 173 - 179°C

CLINICAL TRIALS

Efficacy and Safety Studies

Comparative Studies

In an open-labelled, multi-centre, comparative clinical trial conducted in Canada, women were treated with either Vagifem^® (N=80) or conjugated estrogen vaginal cream (N=79) for up to 24 weeks. Vagifem (25 µg estradiol) was administered daily for 2 weeks, then twice weekly with at least 3 days between each application, for the remaining 22 weeks; 2 g of the comparator drug, containing approximately 1.25 mg conjugated estrogen, was given daily for 3 weeks, withheld for 1 week, then repeated cyclically (3 weeks on, 1 week off) for up to 24 weeks. Relief of atrophic vaginitis was evaluated by grading dryness, soreness and irritation on a 4-point scale as 0=none, 1=mild, 2=moderate and 3=severe. A composite score, calculated as the average score of the three symptoms, was used to compare the efficacy of the two products. Of the patients entering into the treatment phase of the study, 10% in the Vagifem^® group discontinued their treatment and 32% discontinued in the comparator group.

Vagifem^® was no different from the conjugated estrogen vaginal cream in relieving symptoms of postmenopausal estrogen defficient-related atrophic vaginitis (Table 6). The average severity score of the three symptoms over time for the comparator study is shown in Figure 4. Women assessed the ease of use of the products and overall, Vagifem^® was rated easier to use and more acceptable than conjugated estrogen vaginal cream.

Figure 4: The composite score over time for both treatments.

In four (4) North American clinical trials involving 53 women treated for 12 weeks, 43 for 24 weeks, 19 for 28 weeks and 101 treated for 52 weeks, all with Vagifem^®, and 79 women treated with conjugated estrogen vaginal cream for 24 weeks, the use of Vagifem^® significantly increased the percentage of superficial and intermediate cells which was reflected in an increase in Maturation Value Index starting at week 2 of therapy. Consistent FSH decrease was seen with conjugated estrogen vaginal cream but not with Vagifem^®. No clinically relevant systemic absorption was observed with Vagifem^®.

Placebo-Controlled Studies

A double-blind, multi-centered, placebo-controlled comparison study was conducted in the U.S. in which 230 patients were randomized to receive either placebo, 17β-estradiol 10 µg or Vagifem^® (25 µg estradiol). 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 using composite score. Vagifem^® was more effective than placebo in the relief of symptoms of dryness, soreness and irritation associated with atrophic vaginitis (See Figure 5).

Figure 5: The composite score over time for Vagifem^® versus Placebo

DETAILED PHARMACOLOGY

See Action and Clinical Pharmacology section under Part I.

Pharmacokinetics

See Pharmacokinetics section under Part I.

TOXICOLOGY

Exposure levels to estradiol and estrone following Vagifem^® treatment are not outside the range seen in untreated postmenopausal women. The dosage of 25µg estradiol in Vagifem^® (estradiol vaginal tablet) is low compared to natural production in fertile women and exposure is low compared to other methods of administering estrogen.

During long term maintenance therapy of up to 52 weeks no significant increase in the plasma concentrations of either E₂ or E₁ or E₁S over baseline was demonstrated.

Carcinogenicity / Teratology

Estradiol, given subcutaneously in mice, resulted in increased incidences of mammary, pituitary, uterine, cervical, vaginal, lymphoid and testicular tumours. Oral estradiol resulted in an increased incidence of mammary tumours. An increased incidence of mammary and/or pituitary tumours was noted in rats. Malignant kidney tumours occurred in intact and castrated males and in ovariectomized females but not in intact females. Diffuse fibromyomatous uterine and abdominal lesions were observed in guinea-pigs.

Estradiol is carcinogenic and teratogenic to the genital tract when given in high doses to animals. These effects are of minor significance to the postmenopausal use of the low exposure level of estradiol found in Vagifem^®.

Local Tolerance

A local vaginal tolerance study was conducted in rabbits. Minor bleeding was observed from the vagina after manipulation with the applicator. Post mortem hyperaemia and minor edema in the vagina was also observed. Microscopy showed that the tablet with or without estradiol did not cause irritation of the vaginal mucosa or the underlying tissue. The reaction observed in animals manipulated with the applicator only was induced mechanically. No reaction was ascribed to the tablets.

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