Estrogel Propak: Uses, Side Effects and Dosage

ABOUT THIS MEDICATION

What the medication is used for:

There are two products in this package: ESTROGEL^® (17ß-estradiol, as estradiol hemihydrate, transdermal gel) and PROMETRIUM^® (progesterone capsules) and they have different uses.

ESTROGEL PROPAK^TM (17ß-estradiol and micronized progesterone) is indicated in patients for whom treatment with both ESTROGEL^® and PROMETRIUM^® is appropriate.

ESTROGEL^®

ESTROGEL^® is approved for use in the following situation:

• replacement of estrogen in menopausal women with

  symptoms of menopause, which may include hot flushes, disturbed sleep and vaginal dryness.

ESTROGEL^® should not be used by women who have not had a hysterectomy (surgical removal of the uterus) unless prescribed in association with a progestin medication.

PROMETRIUM^®

PROMETRIUM^® (micronized progesterone) is approved for use in the following situation:

• In women with an intact uterus (have not had surgery to remove the uterus) who are using estrogen replacement therapy for menopause

Progesterone, as in PROMETRIUM^® capsules, has a strong influence on the inner lining of the uterus and is used with estrogen therapy during and after menopause. The purpose of using progesterone is to protect the inner lining of the uterus from overgrowth caused by estrogen therapy.

ESTROGEL PROPAK^® should be used only under the supervision of a doctor, with regular follow-up at least once a year to identify side effects associated with its use. Your first follow-up visit should be within 3 to 6 months of starting treatment. Your visit may include a blood pressure check, a breast exam, a Pap smear and pelvic exam. You should have a mammogram before starting treatment and at regular intervals as recommended by your doctor. Your doctor may recommend some blood tests.

You should carefully discuss the risks and benefits of hormone replacement therapy (HRT) with your doctor. You should regularly talk with your doctor about whether you still need treatment with HRT.

What it does:

ABOUT MENOPAUSE

Menopause is not a disease. Menopause is a natural, pre-determined point in a women's life when the ovaries decrease their production of the female hormones, estrogen and progesterone. In most women, this occurs between the ages of 45 and 55 or sooner if the ovaries have been removed by surgery.

The symptoms associated with menopause vary for every woman. The most common symptom is hot flushes/flashes. Other symptoms some women may develop after menopause include insomnia (reduced quality of sleep) and vaginal atrophy (dryness). Your doctor can provide you with further information on menopause.

ESTROGEL PROPAK^TM contains 2 medicines used together.

The active ingredient in ESTROGEL^® is estradiol, a natural female hormone. In healthy women of childbearing age, estradiol is the main estrogen produced by the ovaries. When using ESTROGEL^®, two pump pressures will deliver 2.5 gram of gel, which provides 1.5 milligram of the estrogen substance estradiol. The gel should be applied to the skin over a large area (>2000 cm2), such as both arms. It will be quickly absorbed into the underlying layers of the skin. Over time, the estradiol will be slowly released into the bloodstream.

ESTROGEL^® does not contain progestins.

The active ingredient in PROMETRIUM^® capsules is progesterone, a natural female hormone. In healthy women of childbearing age, progesterone is produced by the ovaries each month during the second part of the menstrual cycle. Progesterone plays a role in the monthly shedding of the inner lining of the uterus (endometrium) and the menstrual bleeding that follows.

For information on the dose and how frequently these products should be taken, please see PROPER USE OF THIS MEDICATION below.

When it should not be used:

Do not use ESTROGEL PROPAK^TM if you:

• have an allergic or an unusual reaction to progesterone, soya,

  peanut or to any of the ingredients in PROMETRIUM^®;

• have had an allergic or unusual reaction to ESTROGEL^® or to

  any of its ingredients;

• have liver disease;

• have or have had cancer or abnormalities of the breast or

  uterus (endometrial cancer);

• have overgrowth of the lining of the uterus (endometrial

  hyperplasia);

• have experienced undiagnosed or unexpected vaginal

  bleeding;

• are pregnant or suspect you may be pregnant;

• are breast-feeding;

• have a history of coronary heart disease (including heart

  attack) or stroke;

• have migraine headaches;

• have a history of blood clots or have had abnormal increase in

  blood clotting;

• have active thrombophlebitis (inflammation of the veins);

• have partially or completely lost vision due to blood vessel

  disease of the eye

• known or suspected hormone dependant cancer.

What the medicinal ingredient is:

ESTROGEL PROPAK^TM contains two medicines. One is ESTROGEL^® which contains 17β-estradiol. The other is PROMETRIUM^® which contains micronized progesterone

What the nonmedicinal ingredients are:

ESTROGEL^® also contains carbopol 980, ethanol, purified water and triethanolamine.

PROMETRIUM^® also contains sunflower oil, gelatin, glycerin, soya lecithin (may contain traces of medium chain triglycerides), titanium dioxide.

What dosage forms it comes in:

ESTROGEL^® is packaged in 80 g metered-dose pumps. Each metered-actuation delivers 1.25 g of gel (0.75 mg of 17ß-estradiol).

Each PROMETRIUM^® capsule contains 100 mg (milligrams) of micronized progesterone.

ESTROGEL PROPAK^TM (17ß-estradiol and micronized progesterone) is available in a carton containing one ESTROGEL^® 80 g metered-dose pump and one blister pack of 30 PROMETRIUM^® 100 mg capsules.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

The Women’s Health Initiative (WHI) trial is a large clinical study that assessed the benefits and risks of oral combined estrogen plus progestin therapy and oral estrogen-alone therapy compared with placebo (a pill with no active ingredient) in postmenopausal women.

The WHI trial indicated an increased risk of myocardial infarction (heart attack), stroke, breast cancer, pulmonary emboli (blood clots in the lungs) and deep vein thrombosis (blood clots in the large veins) in postmenopausal women taking oral combined estrogen plus progestin .

The WHI trial indicated an increased risk of stroke and deep vein thrombosis in postmenopausal women with prior hysterectomy (surgical removal of the uterus) taking oral estrogen-alone .

The Women’s Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of probable dementia (madness) in postmenopausal women 65 years of age or older.

Therefore, you should highly consider the following:

• There is an increased risk of developing invasive breast cancer, heart attack, stroke and blood clots in both lungs and large veins with the use of estrogen plus progestin therapy.
• There is an increased risk of stroke and blood clots in the large veins with the use of estrogen-alone therapy.
• Estrogens with or without progestins should not be used for the prevention of heart disease or stroke or dementia.
• Estrogens with or without progestins should be used at the lowest effective dose and for the shortest period of time possible. Regular medical follow-up is advised.

Breast Cancer

The results of the WHI trial indicated an increased risk of breast cancer in post-menopausal women taking combined estrogen plus progestin compared to women taking placebo.

The results of the WHI trial indicated no difference in the risk of breast cancer in postmenopausal women with prior hysterectomy taking estrogen-alone compared to women taking placebo.

Estrogens with or without progestins should not be taken by women who have a personal history of breast cancer. In addition, women with a family history of breast cancer or women with a history of breast lumps, breast biopsies or abnormal mammograms (breast x-rays) should consult with their doctor before starting hormone replacement therapy.

Women should have a mammogram before starting HRT and at regular intervals during treatment as recommended by their doctor.

Regular breast examinations by a doctor and regular breast self-examinations are recommended for all women. You should review technique for breast self-examination with your doctor.

Overgrowth of the lining of the uterus and cancer of the uterus

The use of estrogen-alone therapy by post menopausal women who still have a uterus increases the risk of developing endometrial hyperplasia (overgrowth of the lining of the uterus), which increases the risk of endometrial cancer (cancer of the lining of the uterus).

The purpose of adding a progestin medication to estrogen therapy is to reduce the risk of endometrial hyperplasia.

You should discuss progestin therapy and risk factors for endometrial hyperplasia and endometrial carcinoma with your doctor. You should also report any unexpected or unusual vaginal bleeding to your doctor.

If you have had your uterus removed, you are not at risk of developing endometrial hyperplasia or endometrial carcinoma. Progestin therapy is therefore not generally required in women who have had a hysterectomy.

Ovarian Cancer

In some studies the use of estrogen-alone therapy and estrogen plus progestin therapies for 5 or more years has been associated with an increased risk of ovarian cancer.

Heart Disease and Stroke

The results of the WHI trial indicated an increased risk of stroke and coronary heart disease in post-menopausal women taking combined estrogen plus progestin compared to women taking placebo.

The results of the WHI trial indicated an increased risk of stroke, but no difference in the risk of coronary heart disease in post-menopausal women with prior hysterectomy taking estrogen alone compared to women taking placebo.

Abnormal Blood Clotting

The results of the WHI trial indicated an increased risk of blood clots in the lungs and large veins in post-menopausal women taking combined estrogen plus progestin compared to women taking placebo.

The results of the WHI trial indicated an increased risk of blood clots in the large veins, but no difference in the risk of blood clots in the lungs in post-menopausal women with prior hysterectomy taking estrogen-alone compared to women taking placebo.

The risk of blood clots also increases with age, if you or a family member has had blood clots, if you smoke or if you are severely overweight. The risk of blood clots is also temporarily increased if you are immobilized for long periods of time and following major surgery. You should discuss risk factors for blood clots with your doctor since blood clots can be life-threatening or cause serious disability.

Gallbladder Disease

The use of estrogen therapy by post menopausal women has been associated with an increased risk of gallbladder disease requiring surgery.

Dementia

The Women’s Health Initiative Memory Study (WHIMS) was a substudy of the WHI trial and indicated an increased risk of dementia (loss of memory and intellectual function) in postmenopausal women age 65 and over taking oral combined estrogen plus progestin compared to women taking placebo. The WHIMS indicated no difference in the risk of dementia in post-menopausal women age 65 and over with prior hysterectomy taking oral estrogen-alone compared to women taking placebo.

Contact Sensitization

Products applied onto the skin may result in sensitization. Although it is extremely rare, skin sensitization may evolve into severe hypersensitivity reaction with continued use of the gel.

BEFORE you use ESTROGEL PROPAK^TM talk to your doctor or pharmacist if you:

• have a history of allergy or intolerance to

  PROMETRIUM^® or any of its ingredients (see What the medicinal ingredient is/ What the nonmedicinal ingredients are), or are allergic to soya or peanut or to any other substances or medications;

• have a history of allergy or intolerance to ESTROGEL^®

  or any of its ingredients, or to any medications or other substances;

• have a history of liver disease, liver tumours, or jaundice

  (yellowing of the eyes and/or skin) or itching related to estrogen use or during pregnancy;

• have a personal history of breast disease (including breast

  lumps) and/or breast biopsies, or a family history of breast cancer);

• have a history of endometrial hyperplasia (overgrowth of

  the lining of the uterus);

• have experienced undiagnosed or unusual vaginal

  bleeding;

• have experienced pressure or pain in your abdomen or

  pelvis;

• have a history of uterine fibroids (abnormally thick tissue

  in the uterus) or endometriosis (disorder of the uterine lining);

• have a personal or family history of blood clots, or a

  personal history of heart disease, heart attack or stroke;

• have a history of migraine headache;

• have a personal history of active thrombophlebitis

  (inflammation of the veins);

• have or have had a partial or complete loss of vision due

  to blood vessel disease of the eye;

• are pregnant or may be pregnant;
• smoke;
• have a history of high blood pressure;

• have a history of kidney disease, epilepsy (seizures) or

  asthma;

• have a history of bone disease (this includes certain

  metabolic conditions or cancers that can affect blood levels of calcium and phosphorus) ;

• have been diagnosed with diabetes;

• have been diagnosed with porphyria (a disease of blood

  pigment);

• have a history of high cholesterol or high triglycerides (a

  type of fat in the blood);

• have a history of depression.
• have had a hysterectomy (surgical removal of the uterus)

• have been told that you have a condition called hereditary

  angioedema or if you have had episodes of rapid swelling of the hands, feet, face, lips, eyes, tongue, throat (airway blockage), or digestive tract;

• have been diagnosed with lupus;
• have been diagnosed with hearing loss due to otosclerosis.

• breastfeeding

  PROMETRIUM^® may cause some people to feel dizzy or sleepy, 1-4 hours after ingestion of the capsules. Therefore, before you drive or do anything else that requires alertness, make sure you are not experiencing these side effects.

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with ESTROGEL^® include: Barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone or rifampin, atorvastatin, antibiotics, aminoglutethimide, some herbal products (e.g. St. John’s wort), phenobarbital, phenytoin troglitazone, ascorbic acid, acetaminophen, oral contraceptives containing ethinyl estradiol, progestin.

Estrogens may diminish the effectiveness of anticoagulant (substance that prevents coagulation), antidiabetic (drugs treating diabetes mellitus) and antihypertensive agents (drugs treating high blood pressure).

Some medications (such as certain anti-seizure medications or antibiotics) may affect how PROMETRIUM^® Capsules work. PROMETRIUM^® Capsules may also affect how your other medicines work.

Tell your doctor or pharmacist if you are taking any other medications, including prescription medications, over-the-counter medications, vitamins or herbal products.

PROPER USE OF THIS MEDICATION

Usual dose:

ESTROGEL^®

Do not apply ESTROGEL^® on the breasts since this may cause unwanted effects and discomfort. Do not apply ESTROGEL^® to the face or to irritated or damaged skin.

The recommended dosage of ESTROGEL^® is two pump pressures (2.5 g) per day on a cyclic schedule from day 1 to day 25 of each calendar month or from day 1 to day 21 of a 28-day cycle. ESTROGEL^® may be applied either in the morning or evening after washing, but preferably about the same time each day. If your periods have stopped, or are irregular, you can start using ESTROGEL^® at any time.

Under the supervision of your doctor, the dose of ESTROGEL^® can be adjusted to meet your individual needs. Attempts to adjust the necessary dosage should be made after two months of treatment. Breast tenderness and/or unexpected bleeding are generally signs that the dose is too high and needs to be lowered. However, if the selected dose fails to control your menopausal symptoms, a higher dose may be prescribed.

You and your doctor should talk regularly about whether you still need treatment with estrogen.

HOW AND WHEN TO APPLY ESTROGEL^®

ESTROGEL^® Pump:

• Remove the large pump cover.

  When you open a new pump, press on the pump once or twice in order to prime the pump and discard these doses.

• Press firmly on the pump once, collect the gel in your hand and apply the gel on one arm, as illustrated. Repeat and apply the gel on the opposite arm.

• ESTROGEL^® should be applied using clean hands onto clean, dry skin. The gel should be spread over a large area of skin (at least 2,000 cm²), which corresponds to approximately 4 times the size of your hand. It is recommended to apply

  ESTROGEL^® to both arms, as illustrated. Other recommended areas of application are the abdomen or the inner thighs, as illustrated. It is not necessary to rotate the site of administration. Do not apply ESTROGEL^® on the breasts since this may cause unwanted effects and discomfort. Do not apply ESTROGEL^® to the face or to irritated or damaged skin.

• Allow the gel to dry for 2

  minutes before covering with clothes. ESTROGEL^® does not stain and does not smell.

• The pump contains enough gel for approximately 1 month's use (i.e. 64 metered-doses) at the recommended dose of two pumps/per day (2.5 g). After that, the amount of gel delivered may be lower and thus, it is recommended to change the pump.

• Always replace the small

  protective cap back in the tip of the pump as well as the large pump cover after each use, as illustrated.

PROMETRIUM^®

Take PROMETRIUM^® (micronized progesterone) only as directed by your doctor or pharmacist.

Hormone Replacement Therapy for Menopause

The recommended dose is 2 capsules (200 mg) of PROMETRIUM^® per day for the last 14 days of estrogen treatment each cycle or 3 capsules per day (300 mg) for the last 12-14 days of estrogen treatment each cycle. If you are being treated with 2 capsules (200 mg) a day you should take them both at bedtime. If you are being treated with 3 capsules (300 mg) a day, you should split the daily dose in two parts by taking one capsule in the morning and two at bedtime. PROMETRIUM^® should be started on the first estrogen cycle. The length of time that you will take PROMETRIUM^® will depend of the length of time that you are treated with estrogen. PROMETRIUM^® should be taken as long as you take estrogen and you have an intact uterus (have not had surgery to remove the uterus).

A few days after completing a PROMETRIUM^® course of 3 capsules daily, the inner lining of the uterus will usually shed. This is accompanied by vaginal bleeding (resembling a normal monthly period). With a dosage of 2 capsules daily, many women will not have such vaginal bleedings, although the lining of the uterus will also be protected against overgrowth.

Overdose:

In case of drug overdose, contact your doctor, or a poison control centre, or go to the emergency room of the hospital near you immediately, even if there are no symptoms.

When someone accidentally takes too much ESTROGEL^®, the following symptoms may arise: nausea (urge to vomit), breast discomfort, fluid retention, abdominal cramps, headache, dizziness, bloating or vaginal bleeding in women.

When someone accidentally takes too much PROMETRIUM^® (micronized progesterone), the following symptoms may arise: nausea, vomiting, sleepiness, dizziness, depressive mood, tiredness, acne and hairiness.

Missed Dose:

ESTROGEL^®

If a dose of this medication has been missed, it should be taken as soon as possible. However if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double dose. If you are in doubt, contact your healthcare provider.

PROMETRIUM^®

If you are being treated with 2 capsules a day (total dose at bedtime) and you forget to take this dose, you should take one capsule the following morning and continue taking the rest of the capsules as prescribed. If you are being treated with 3 capsules a day and you forget to take a morning or evening dose, you should not take the missed dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Very rarely, skin irritation can occur with ESTROGEL^®.

Depending on the dosage of estrogen and the sensitivity of the patient, the following side effects are possible:

• genital bleeding or spotting (minor vaginal bleeding) in between the normal periods,
• headaches or depressive mood;
• breast tenderness/swelling;
• nausea (urge to vomit), abdominal discomfort (cramps, pressure, pain);
• worsening of varicose veins (visible and bulging veins);
• fatigue (tiredness).

Other side effects that have been observed with estrogen and progestin combinations in general are:

• water retention (bloating, swelling);
• (endometrial hyperplasia) overgrowth of the lining of the uterus;

• gallbladder disorder, impaired liver function, jaundice

  (yellowing of the eyes or skin);

• menstrual cramps;
• vaginal itching/discharge;
• pain during sexual intercourse;
• pain on urination or difficulty urinating;
• premenstrual syndrome (PMS);
• inflammation of the bladder;
• brown, blotchy spots on exposed skin (pregnancy mask);
• skin rash, tender red lumps or nodules or other skin reactions;
• loss of hair, hairiness;
• acne;
• palpitations (unpleasant sensation of irregular and/or forceful beating of the heart);
• pain, swelling or redness of the calf or leg which may indicate a blood clot;
• chest pain or shortness of breath which may indicate a blood clot;
• increase in blood pressure;
• depression;
• nervousness;
• irritability;
• visual disturbances, intolerance to contact lenses;
• changes in appetite and body weight;
• change in sexual drive;

• pain in the joints and muscles, usually lasting only 3-

  6 weeks.

Depending on the dosage of PROMETRIUM^® (micronized progesterone) and the sensitivity of the patient, the following side effects are possible: genital bleeding or spotting (minor vaginal bleeding) in between the normal periods (mainly during the first two months); irregular menstrual periods; dizziness or vertigo; sleepiness; abdominal discomfort (cramps, pressure, pain); nausea (urge to vomit); fatigue (tiredness); aggravation of migraine headaches, headaches or depressive mood; lightheadedness (feeling faint); breast tenderness/swelling; liver disease.

Side effects observed in women taking progestins in general: a severe allergic reaction which may include hives, itchiness, skin redness, swelling, wheezing, increase heart rate and difficulty breathing; rash with or without itching; rare cases of loss of consciousness; hot flashes; impaired concentration; confusion; swelling; and difficulty with speech.

During your first 2-4 months of HRT, you may experience minor unscheduled vaginal bleeding (at times other than when you would expect a normal period). This is a normal response of your body as it adjusts to the return of estrogen and progesterone to the levels that were seen before menopause. Should unscheduled vaginal bleeding persist, you should consult your doctor.

This is not a complete list of side effects. For any unexpected effects while taking ESTROGEL PROPAK^TM, contact your doctor or pharmacist.

HOW TO STORE IT

ESTROGEL PROPAK^TM should be stored at room temperature between 15°C and 30°C.

ESTROGEL^® should be stored with the cap on securely.

The date the capsules should be used by is printed on the strip after the term "Exp." (expiry date).

Keep out of reach of children.

GENERAL THINGS TO REMEMBER

1. 1.

   This medication has been prescribed only for your current

   medical problem. Do not use it for other medical problems.

2. 2.

   Do not allow other people to use your medications and do

   not use medications meant for other people.

3. 3.

   Tell any doctor treating you what medications you are

   taking. Always carry a medical information card stating which medications you are using. This can be very important in case you are involved in an accident.

4. 4.

   Return unused medications to the pharmacy for safe

   disposal.

5. 5.

   Make sure that other people you live with or who look

   after you read this information.

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways:

----------------------------------------------------------------

• Report online at www.healthcanada.gc.ca/medeffect
• Call toll-free at 1-866-234-2345

• Complete a Canada Vigilance Reporting Form and:

  • Fax toll-free to 1-866-678-6789, or

  • Mail to: Canada Vigilance Program Health Canada

    Postal Locator 0701E

    Ottawa ON K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect^TM Canada Web site at

www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the management of the side effect, please contact your health care provider. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

Also, you can report any suspected adverse reactions associated with the use of health products to Merck Canada Inc. by one of the following 2 ways:

• Call toll-free at 1-800-567-2594

• Fax toll-free to 1-800-369-3090, or

  Mail to: Merck Canada Inc.

  Pharmacovigilance

  P.O. Box 1005

  Pointe-Claire–Dorval, QC H9R 4P8

This document plus the full product monograph, prepared for health professionals, can be found at:

http://www.merck.ca

or by contacting the sponsor, Merck Canada Inc., at: 1-800-567-2594.

Last revised: June 25, 2013

ESTROGEL PROPAK^TM is a trademark of Schering-Plough Canada Inc. Used under license.

ESTROGEL^® is a registered trademark of Schering-Plough

Canada Inc. Used under license.

PROMETRIUM^® is a registered trademark of Merck Sharp & Dohme Corp. Used under license.

©2013, Merck Canada Inc., a subsidiary of Merck & Co., Inc. All rights reserved.