Divigel (Teva Canada) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Divigel^® (estradiol gel) 0.1% is indicated in the treatment of moderate to severe vasomotor symptoms associated with menopause.

Divigel should be prescribed with an appropriate dosage of progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma.

Geriatrics: No clinical studies were conducted to evaluate the effect of Divigel on women more than 65 years old.

Pediatrics: Divigel should not be used in children

CONTRAINDICATIONS

• 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
• Liver dysfunction or disease as long as liver function tests have failed to return to normal
• 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 arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary heart disease [CHD])
• Active or past history of confirmed venous thromboembolism (such as deep vein thrombosis or pulmonary embolism) or active thrombophlebitis
• Partial or complete loss of vision due to ophthalmic vascular disease
• Breast feeding
• Classic migraine

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

The Women’s Health Initiative (WHI) trial examined the health benefits and risks of oral combined estrogen plus progestin therapy (n=16,608) and oral estrogen-alone therapy (n=10,739) in postmenopausal women aged 50 to 70 years.^{5, 38, 39}

The estrogen plus progestin arm of the WHI trial (mean age 63.3 years) indicated an increased risk of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary emboli and deep vein thrombosis in postmenopausal women receiving treatment with combined conjugated equine estrogens (CEE, 0.625 mg/day) and medroxyprogesterone acetate (MPA, 2.5 mg/day) for 5.2 years compared to those receiving placebo.³⁹

The estrogen-alone arm of the WHI trial (mean age 63.6 years) indicated an increased risk of stroke and deep vein thrombosis in hysterectomized women treated with CEE-alone (0.625 mg/day) for 6.8 years compared to those receiving placebo.³⁸

Therefore, the following should be given serious consideration at the time of prescribing:

• Estrogens with or without progestins should not be prescribed for primary or secondary prevention of cardiovascular diseases
• Estrogens with or without progestins should be prescribed at the lowest effective dose for the approved indication
• Estrogens with or without progestins should be prescribed for the shortest period possible for the recognized indication

Carcinogenesis and Mutagenesis

Breast cancer

Available epidemiological data indicate that the use of combined estrogen plus progestin by postmenopausal women is associated with an increased risk of invasive breast cancer.

In the estrogen plus progestin arm of the WHI trial, among 10,000 women over a one-year period, there were:

• 8 more cases of invasive breast cancer (38 on combined Hormone Replacement Therapy

  (HRT) versus 30 on placebo).¹

The WHI study also reported that the invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology but were larger (mean [SD] 1.7 cm [1.1] vs. 1.5 cm [0.9], respectively; P=0.04) and were at a more advanced stage compared with those diagnosed in the placebo group. The percentage of women with abnormal mammograms (recommendations for short-interval follow-up, a suspicious abnormality, or highly suggestive of malignancy) was significantly higher in the estrogen plus progestin group versus the placebo group. This difference appeared at year one and persisted in each year thereafter.⁵

In the 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.³⁸

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).

There is a need for caution in prescribing estrogens for women with known risk factors associated with the development of breast cancer, such as strong family history of breast cancer (first degree relative) or who present a breast condition with an increased risk (abnormal mammograms and/or atypical hyperplasia at breast biopsy).

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 HRT 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 replacement therapy should be fully considered and discussed with patients. It is important that the modest increased risk of being diagnosed with breast cancer after 4 years of treatment with combined estrogen plus progestin HRT (as reported in the results of the WHI trial) be discussed with the patient and weighed against its known benefits.

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

Ovarian cancer:

Some recent epidemiological studies have found that the use of hormone replacement 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.

Endometrial hyperplasia & endometrial carcinoma

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. Estrogen should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risk of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

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 estrogen plus progestin is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women.^{39, 16, 14} The results of the WHI trial indicate that the use of estrogen-alone and estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women.^{39, 38}

WHI Trial Findings

In the combined estrogen plus progestin arm of the WHI trial, among 10,000 women over a one-year period, there were:

• 8 more cases of stroke (29 on combined HRT versus 21 on placebo)
• 7 more cases of CHD (37 on combined HRT versus 30 on placebo)³⁹

In the estrogen-alone arm of the WHI trial of women with prior hysterectomy, among 10,000 women over a one-year period, there were/was:

• 12 more cases of stroke (44 on estrogen-alone therapy versus 32 on placebo)
• No statistically significant difference in the rate of CHD³⁸

HERS and HERS II Findings

In the Heart and Estrogen/progestin Replacement Study (HERS) of postmenopausal women with documented heart disease (n=2763, average age 66.7 years), a randomized placebo-controlled clinical trial of secondary prevention of coronary heart disease (CHD), treatment with 0.625 mg/day oral conjugated equine estrogen (CEE) plus 2.5 mg oral medroxyprogesterone acetate (MPA) demonstrated no cardiovascular benefit. Specifically, during an average follow-up of 4.1 years, treatment with CEE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the hormone-treated group than in the placebo group in year 1, but not during the subsequent years.¹⁶

From the original HERS trial, 2321 women consented to participate in an open label extension of HERS known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. After 6.8 years, hormone therapy did not reduce the risk of cardiovascular events in women with CHD.¹⁴

Blood Pressure

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

Endocrine and Metabolism

Glucose and lipid metabolism

A worsening of glucose tolerance and lipid metabolism have been observed in a significant percentage of peri- and post-menopausal patients. Therefore, diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate or lipid metabolism, especially in triglyceride blood levels.

Women with familial hyperlipidemias or porphyria need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started.

Calcium and phosphorus metabolism

Because the prolonged use of estrogens influences the metabolism of calcium and phosphorus, estrogens should be used with caution in patients with metabolic and malignant bone diseases associated with hypercalcemia and in patients with renal insufficiency.

Hypothyroidism

Patients who require thyroid hormone replacement therapy and who are also taking estrogen should have their thyroid function monitored regularly to assure that thyroid hormone levels remain in an acceptable range (see Drug-Laboratory Test Interactions).

Geritourinary

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.

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.

Hematologic

Venous thromboembolism

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

In the estrogen plus progestin arm of the WHI trial, among 10,000 women on combined HRT over a one-year period, there were 18 more cases of venous thromboembolism, including 8 more cases of pulmonary embolism.³⁹

In the estrogen-alone arm of the WHI trial, among 10,000 women on estrogen therapy over a one-year period, there were 7 more cases of venous thromboembolism, although there was no statistically significant difference in the rate of pulmonary embolism.³⁸

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 HRT, 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.

Jaundice

Caution is advised in patients with a history of liver and/or biliary disorders. If cholestatic jaundice develops during treatment, the treatment should be discontinued and appropriate investigations carried out.

Liver function tests

Liver function tests should be done periodically in subjects who are suspected of having hepatic disease. For information on endocrine and liver function tests, see the section under Monitoring and Laboratory Tests.

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 estrogen plus progestin in women age 65 and over may increase the risk of developing probable dementia.

The Women's Health Initiative Memory Study (WHIMS), a clinical substudy of the WHI, was designed to assess whether postmenopausal hormone replacement therapy (oral estrogen plus progestin or oral estrogen-alone) reduces the risk of dementia in women aged 65 and over (age range 65-79 years) and free of dementia at baseline.^{30, 31}

In the estrogen plus progestin arm of the WHIMS (n=4532), women with intact uteri were treated with daily 0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA) or placebo for an average of 4.05 years. The results, when extrapolated to 10,000 women treated over a one-year period showed:

• 23 more cases of probable dementia (45 on combined HRT versus 22 on placebo).³⁰ In the estrogen-alone arm of the WHIMS (n=2947), women with prior hysterectomy were treated with daily 0.625 mg CEE or placebo for an average of 5.21 years. The results, when extrapolated to 10,000 women treated over a one-year period showed:
• 12 more cases of probable dementia (37 on estrogen-alone versus 25 on placebo), although this difference did not reach statistical significance.³¹

When data from the estrogen plus progestin arm of the WHIMS and the estrogen-alone arm of the WHIMS were combined, as per the original WHIMS protocol, in 10,000 women over a one-year period, there were:

• 18 more cases of probable dementia (41 on estrogen plus progestin or estrogen-alone versus 23 on placebo).³¹

Renal

Fluid retention

Pregnant Women: Estrogen products, including Divigel, should not be used in pregnancy. (see CONTRAINDICATIONS.)

Nursing Mothers: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving estrogen therapy. Caution should be exercised when estrogen products, including Divigel, are administered to a nursing woman.

Pediatric Use: Safety and efficacy of Divigel in pediatric patients have not been established.

Geriatric Use: There have not been sufficient numbers of geriatric patients involved in studies utilizing Divigel^® to determine whether those over 65 years of age differ from younger subjects in their response to Divigel.

Monitoring and Laboratory Tests

Before Divigel 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.

Miscellaneous

Alcohol based gels are flammable. Avoid fire, flame, or smoking until the gel has dried.

Occlusion of the area where the topical drug product is applied, with clothing or other barriers, is not recommended until the gel is completely dried.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

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

The following adverse reactions have been reported with estrogen/progestin combination in general:

Blood and lymphatic system

disorders

Altered coagulation tests (see Warnings and Precautions, Drug-Laboratory Tests Interactions).

Cardiac disorders Palpitations; increase in blood pressure (see

Warnings and Precautions); coronary thrombosis.

Endocrine disorders Increased blood sugar levels; decreased glucose

tolerance.

Eye disorders

Neuro-ocular lesions (e.g. retinal thrombosis, optic neuritis); visual disturbances; steepening of the corneal curvature; intolerance to contact lenses.

Gastrointestinal disorders

Nausea; vomiting; abdominal discomfort (cramps, pressure, pain, bloating).

General disorders and

administration site conditions

Fatigue; changes in appetite; changes in body weight; change in libido.

Hepatobiliary disorders Gallbladder disorder; asymptomatic impaired liver function; cholestatic jaundice.

Musculoskeletal and connective

tissue disorders

Musculoskeletal pain including leg pain not related to thromboembolic disease (usually transient, lasting 3-6 weeks) may occur.

Nervous system disorders Aggravation of migraine episodes; headaches;

dizziness; neuritis.

Psychiatric disorders

Mental depression; nervousness; irritability.

Renal and urinary disorders Cystitis; dysuria; sodium retention; edema.

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.

Skin and subcutaneous tissue

disorders

Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; haemorrhagic eruption; loss of scalp hair; hirsutism and acne.

Vascular disorders Isolated cases of: thrombophlebitis;

thromboembolic disorders.

Clinical Trial Adverse Drug Reaction:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Divigel was studied at doses of 0.25, 0.5 and 1.0 g/day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5% Caucasian). The adverse events that occurred at a rate equal or greater than 5% in any of the treatment groups are summarized in Table 1.

Table 1: Number (%) of Subjects with Common Adverse Events^* in a 12-Week Placebo-Controlled Study of

Divigel^®

^* Adverse events reported by ≥5% of patients in any treatment group.

In a 12-week placebo-controlled study of Divigel, application site reactions at least possibly related were seen in <1% of subjects.

Table 2 Number (%) of Subjects with AEs Occurring in ≥1% of Subjects in A 12-

Week Placebo Controlled Study of Divigel

a. Subjects may be counted in more than one AE category. b. Value in [ ] is percentage of subjects based on N for subjects with intact uterus in the Phase 3

Placebo-Controlled Study: 53 for placebo; 64 for Estradiol Gel, 0.1%, 0.25 g/day; 60 for Estradiol Gel, 0.1%, 0.5 g/day; 56 for Estradiol Gel, 0.1%, 1.0 g/day; and 180 for all Estradiol Gel, 0.1% combined.

Less Common [< 1%] Clinical Trial Adverse Reactions:

Cardiac Disorders

Palpitations, Angina Pectoris, Arrhythmia

Gastrointestinal Disorders

Dyspepsia, Vomiting, Abdominal Pain Lower

General Disorders & Administration Site Conditions

Fatigue, Non-cardiac Chest Pain, Oedema Peripheral Pain

Hepatobiliary Disorders

Cholelithiasis

Immune System Disorders

Hypersensitivity

Infections and Infestations

Pharyngitis, Viral Infection

Injury, Poisoning and Procedural Complications

Joint Sprain, Back Injury

Musculoskeletal and Connective Tissue Disorders

Myalgia, Musculoskeletal Pain, Pain in Extremity

Nervous System Disorders

Migraine

Psychiatric Disorders

Insomnia, Anxiety, Nervousness, Irritability

Reproductive System and Breast Disorders

Genital Pruritus Female, Menstruation Irregular, Ovarian Cyst, Dysmenorrhoea, Menorrhagia

Respiratory, Thoracic and Mediastinal Disorders

Cough, Pharyngolaryngeal Pain, Sinus Congestion

Skin and Subcutaneous Tissue Disorders

Rash

The following additional adverse reactions have been reported with estrogen and/or progestin therapy.

1. 1. Genitourinary system: Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer; vaginal discharge.
2. 2. Breasts: Tenderness; enlargement; pain; nipple discharge; galactorrhea, fibrocystic breast changes; breast cancer; nipple pain.
3. 3.

   Cardiovascular: Deep and superficial venous thrombosis; pulmonary embolism;

   thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.

4. 4.

   Gastrointestinal: Nausea; vomiting; abdominal cramps; bloating; cholestatic jaundice;

   increased incidence of gallbladder disease; pancreatitis; enlargement of hepatic hemangiomas; abdominal pain.

5. 5. Skin: Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus; rash.
6. 6. Eyes: Retinal vascular thrombosis; intolerance to contact lenses.
7. 7.

   Central Nervous System: Headache; migraine; dizziness; mental depression; chorea;

   nervousness; mood disturbances; irritability; exacerbation of epilepsy; dementia.

8. 8. Miscellaneous: Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; urticaria; angioedema; anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides; muscle cramps.

If adverse symptoms persist, the prescription of HRT should be reconsidered.

DRUG INTERACTIONS

Overview

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

Preparations inducing liver enzymes (e.g., barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone or rifampin) may interfere with the activity of orally administered estrogens.

Drug-Drug Interactions

The metabolism of estrogens (and progestagens) may be increased by concomitant use of substances known to induced drug-metabolizing enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones (see Table 3 and 4 for further information as reported in the literature).

Herbal preparations containing St. John’s Wort (Hypericum perforatum) may induce the metabolism of estrogens (see section on Drug-Herb Interactions). At transdermal administration, the first pass effect in the liver is avoided and thus, transdermally applied estrogens (and progestagens) might be less affected than oral hormones by enzyme inducers.)

Clinically, an increased metabolism of estrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

Table 3 – Drugs which may affect the Concentrations of Ethinyl Estradiol

Table 4 – Modification of Other Drug Action by Co-administration with Certain Drugs Containing Ethinyl Estradiol (e.g. oral contraceptives containing ethinyl estradiol)

Drug products containing ethinyl estradiol may inhibit the metabolism of other compounds or induce the conjugation of other compounds.

Drug-Food Interactions

Interaction of DIVIGEL^® with food has not been established.

Drug-Herb Interactions

It was found that some herbal products (e.g. St. John’s wort) which are available as over-the-counter (OTC) products might interfere with steroid metabolism and therefore alter the efficacy and safety of estrogen/progestin.

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

Drug-Laboratory Test Interactions

The results of certain endocrine and liver function tests may be affected by estrogen-containing products:

• increased prothrombin time and partial thromboplastin time; increased levels of fibrinogen and fibrinogen activity; increased coagulation factors VII, VIII, IX, X; increased norepinephrine-induced platelet aggregability; decreased antithrombin III;
• increased thyroxine-binding globulin (TBG), leading to increased circulating total thyroid hormone (T₄) as measured by column or radioimmunoassay; T₃ resin uptake is decreased, reflecting the elevated TBG; free T₄ concentration is unaltered;
• other binding proteins may be elevated in serum i.e., corticosteroid binding globulin (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids respectively; free or biologically active hormone concentrations are unchanged;
• increased plasma HDL and HDL₂ cholesterol sub-fraction concentrations, reduced LDL cholesterol concentration;
• impaired glucose tolerance;
• increased serum triglycerides and phospholipids concentration;
• reduced response to metyrapone test.

In clinical trials with Divigel, there have been no known effects on fibrinogen, antithrombin III, TBG, CBG, SHBG, protein C system (protein C/S) or activated protein C resistance (APC resistance) due to factor V Leiden mutation.

• The results of the above laboratory tests should not be considered reliable unless therapy has been discontinued for two to four weeks.
• The pathologist should be informed that the patient is receiving hormone replacement therapy (HRT) when relevant specimens are submitted.

Drug-Lifestyle Interactions

Divigel is an alcohol based gel. Alcohol based gels are flammable. Avoid fire, flame or smoking until the gel has dried.

Occlusion of the area where the topical gel product is applied with clothing or other barriers, is not recommended until the gel is completely dry.

DOSAGE AND ADMINISTRATION

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Divigel (estradiol gel) 0.1%, at doses of 0.25, 0.5, and 1.0 g/day, is indicated for transdermal use in the treatment of moderate to severe vasomotor symptoms associated with menopause. Each gram of Divigel contains 1 mg of estradiol.

Patients should be treated with the lowest effective dose of Divigel. Generally, women should be started at 0.25 grams Divigel daily. Subsequent dosage adjustments may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider.

Divigel should be applied once daily on the skin of either the right or left upper thigh. The application surface area should be about 5 by 7 inches (approximately the size of two palm prints). The entire contents of a unit dose packet should be applied each day. To avoid potential skin irritation, Divigel should be applied to the right or left upper thigh on alternating days. Divigel should not be applied on the face, breasts, or irritated skin or in or around the vagina. After application, the gel should be allowed to dry before dressing. The application site should not be washed within 1 hour after applying Divigel. Contact of the gel with eyes should be avoided. Hands should be washed after application.

OVERDOSAGE

For management of a suspected drug overdose, contact your Regional Poison Control Centre.

Symptoms of Overdosage:

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. Overdosage with estrogen may cause nausea, breast discomfort, fluid retention, bloating or vaginal bleeding in women.

Divigel does not contain progestins. However, in the case where a progestin is co-administered, progestin overdosage has been characterized by depressed mood, tiredness, acne and hirtsuitism.

Treatment of Overdosage:

Symptomatic treatment should be given.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Divigel is a transdermal preparation comprised of a gel (0.1%) available in three doses of 0.25 mg, 0.5 mg and 1.0 mg estradiol respectively.

Upon application to intact skin, Divigel provides continuous systemic delivery of estrogen by releasing estradiol, the major estrogenic hormone secreted by the human ovary.

In comparison, orally administered estrogens are rapidly metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrogen and estradiol. Therefore, transdermal administration of estradiol produces therapeutic plasma levels with lower circulating levels of estrone conjugates and requires smaller total doses than does oral therapy.

Pharmacodynamics

Divigel provides estrogen therapy by delivering estradiol, the major estrogenic hormone secreted by the human ovary, to the systemic circulation following topical application. Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics

A. Absorption

Estradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor.

In a 14-day, Phase 1, multiple-dose study, Divigel^® demonstrated linear and approximately dose-proportional estradiol pharmacokinetics at steady state for both AUC_0-24 and C_max following once daily dosing to the skin of either the right or left upper thigh (Table 5). ).

Table 5: Mean (%CV) Pharmacokinetic Parameters for Estradiol (uncorrected for baseline) on Day 14 Following

Multiple Daily Doses of Divigel^® 0.1%

^*Median (Min, Max).

Steady-state serum concentrations of estradiol are achieved by day 12 following daily application of Divigel^® to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1.

Figure 1: Mean (SD) Serum Estradiol Concentrations (Values Uncorrected for

Baseline) on Day 14 Following Multiple Daily Doses of Divigel 0.1%

0

20

40

60

80

100

0 4 8 12 16 20 24

Time (hours)

0.25 mg 0.5 mg 1.0 mg

The effect of sunscreens and other topical lotions on the systemic exposure of Divigel^® has not been evaluated. Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels.

B. Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

C. Metabolism

Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Estradiol from Divigel^® avoids first pass metabolism and provides estradiol/estrone ratios at steady state in the range of 0.42 to 0.65.

D. Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal half-life for estradiol was about 10 hours following administration of Divigel.

E. Special Populations

Divigel has been studied only in postmenopausal women. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

F. Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice, may increase plasma concentrations of estrogens and result in side effects.

G. Potential for Estradiol Transfer and Effects of Washing

As with most topical products, there is a potential for estradiol transfer following physical contact with Divigel application sites. The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 g of Divigel (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh to arm contact with a partner for 15 minutes. While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive.

The effect of application site washing on skin surface levels and serum concentrations of estradiol was determined in 16 healthy postmenopausal women after application of 1.0 g of Divigel to a 200 cm² area on the thigh. Washing the application site with soap and water 1 hour after application removed all detectable amounts of estradiol from the surface of the skin, and resulted in a 30-38% decrease in the mean total 24-hour exposure to estradiol.

STORAGE AND STABILITY

Store at controlled room temperature of 15 to 30°C.

Keep out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Divigel (estradiol gel) 0.1% is a clear, colorless, smooth, opalescent gel supplied in single-dose foil packets of 0.25, 0.5, and 1.0 g, corresponding to 0.25, 0.5, and 1.0 mg estradiol, respectively.

Non-medicinal ingredients: Carbomer, ethanol, propylene glycol, purified water and triethanolamine

Supplied in cartons, packets of 30 foil pouches.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Estradiol

Chemical name: Estra-1,3,5(10)-triene-3, 17β-diol

Molecular mass: 281.39 (hemihydrate)

272.38 (anhydrous)

Molecular formula: C₁₈H₂₄O_2. ½ H₂0

Structural formula:

Physicochemical properties:

Physical Form: White or creamy white hygroscopic crystals or crystalline powder

Solubility: Practically insoluble in water; 1 in 28 in alcohol (40 mg/mL); 1 in 17 in acetone

(60 mg/mL); 1 in 435 in chloroform (2 mg/mL); soluble in dioxane and solutions of alkali hydroxides; sparingly soluble in fixed oils; soluble in propylene glycol, 74 mg/g (80 mg/mL)

Melting Point: 173-179^o C

CLINICAL TRIALS

Effects on Vasomotor Symptoms

A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of Divigel for vasomotor symptoms in 495 postmenopausal women (86.5% White; 10.1% Black) between 34 and 89 years of age (mean age 54.6) who had at least 50 moderate to severe hot flushes per week at baseline (2 week period prior to treatment). Subjects applied placebo, Divigel 0.25 g (0.25 mg estradiol), Divigel 0.5 g (0.5 mg estradiol) or Divigel 1.0 g (1.0 mg estradiol) once daily to the thigh. Reductions in both the mean daily frequency and the mean daily severity of moderate to severe hot flushes were statistically significant for the 0.5 g/day and the 1.0 g/day Divigel doses when compared to placebo at week 4. Statistically significant reductions in both the mean daily frequency and the mean daily severity of moderate to severe hot flushes for the Divigel 0.25 g/day dose when compared to placebo were delayed to week 7. There were statistically significant reductions in mean daily frequency and severity of hot flushes for all three Divigel doses (0.25 g/day, 0.5 g/day and 1.0 g/day) compared to placebo at week 12. See Table 6 for results.

Table 6: Summary of Changes From Baseline in the Mean Daily Frequency and Severity of

Hot Flushes during Divigel^® Treatment (ITT Population)

†P-value for comparison versus placebo from a van Elteren’s test stratified by pooled centre.

Figure 2 Change from Baseline in Mean Daily Frequency of MSVS by Week Using LOCF (ITT Population) – USL Study P04-001

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‡, †, * Statistically significant compared to placebo at the 0.001, 0.01, and 0.05 levels, respectively.

Figure 3 Change from Baseline in Mean Daily Severity of MSVS by Week Using LOCF (ITT Population)

• USL Study P04-001

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  Time (Weeks)

  Placebo USL-221 0.25 g USL-221 0.5 g USL-221 1.0 g

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  ‡, †, * Statistically significant compared to placebo at the 0.001, 0.01, and 0.05 levels, respectively.

Women's Health Initiative Studies

The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of oral conjugated estrogens (CE 0.625 mg) alone per day or in combination with medroxyprogesterone acetate (CE 0.625 mg/MPA 2.5 mg) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction (MI), silent MI and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the estrogen-plus-progestin substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The estrogen-alone substudy was stopped early because an increased risk of stroke was observed and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after an average follow-up of 6.8 years are presented in Table 7.

Table 7: Relative and Absolute Risk Seen In the Estrogen-Alone Substudy Of WHI^a

^a Nominal confidence intervals unadjusted for multiple looks and multiple comparisons

^b Results are based on centrally adjudicated data for an average follow-up of 7.1 years

^c Results are based on an average follow-up of 6.8 years

^d Not included in Global Index

^e All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease ^f A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes

For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the “global index” was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (see BOXED WARNINGS, WARNINGS, and PRECAUTIONS).

Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE alone compared with placebo (see Table 7).

The estrogen-plus-progestin substudy was also stopped early, because according to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years (RR 1.15, 95% nCI 1.03-1.28).

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women years in the group treated with CE/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (see BOXED WARNINGS, WARNINGS, and PRECAUTIONS).

Results of the estrogen-plus-progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other), are presented in Table 8 below. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.²

Table 8: Relative and Absolute Risk Seen in the Estrogen-Plus Progestin Substudy of WHI at an Average of 5.6

Years^a

^a Results are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95% nCI 0.82-1.18) ^b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

^c Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer

Women’s Health Initiative Memory Study

The estrogen-alone Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45% were aged 65 to 69 years, 36% were 70 to 74 years, and 19% were 75 years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen-alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen-alone group was 1.49 (95% confidence interval (CI), 0.83-2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (see BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use).

The estrogen-plus-progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were aged 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) daily on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen-plus-progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21-3.48) compared to placebo.

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). It is unknown whether these findings apply to younger postmenopausal women. (see BOXED WARNING, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)²

DETAILED PHARMACOLOGY

See Action and Clinical Pharmacology (Part 1).

TOXICOLOGY

Estradiol was shown to have low acute oral toxicity in mice when tested alone or in combination with medroxyprogesterone acetate (MPA). In repeat-dose dermal irritation studies of rabbits dosed for 28 days, no evidence of primary or cumulative skin irritancy was observed. Divigel was not a skin sensitizer when tested using the Buehler method in guinea pigs. A slight degree of ocular irritancy was observed in the rabbit following administration of Divigel and this irritancy was reduced with eye washing. Divigel showed no phototoxicity or photosensitivity in guinea pigs.

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