Estracomb: Uses, Side Effects and Dosage

ABOUT THIS MEDICATION

What the medication is used for:

ESTRACOMB* should only be used if you have a uterus (it has not been surgically removed)

• To reduce moderate or severe

  menopausal symptoms.

• To prevent osteoporosis

Some women are more likely to develop osteoporosis after menopause than others. If you have been prescribed ESTRACOMB* only for the prevention of osteoporosis you should discuss other alternative therapies with your doctor. . In addition, you should discuss adequate diet, calcium and vitamin D intake, cessation of smoking and regular physical weight-bearing exercise with your doctor or pharmacist.

ESTRACOMB* 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:

Uses of Estrogens

The main estrogen produced by your ovaries prior to menopause is estradiol, and this is the same estrogen that is in ESTRADERM* and ESTRAGEST*. When applied to the skin, the ESTRADERM* and ESTRAGEST* patches continually release small, controlled quantities of estradiol, which pass through your skin and into your bloodstream. The amount of estrogen prescribed depends on your body's needs.

Treatment with ESTRACOMB* offers relief from menopausal symptoms for women with uteri. With ESTRACOMB*, you receive estradiol throughout the entire 28-day cycle, and norethindrone acetate (NETA), a progestin, during the last 2 weeks of the 28-day cycle. The progestin provides important protection for your uterus (See Uses Of Progestins).

Your body normally makes estrogens and progestins (female hormones) mainly in the ovaries. Between ages 45 and 55, the ovaries gradually stop making estrogens. This leads to a decrease in body estrogen levels and a natural menopause (the end of monthly menstrual periods). If both ovaries are removed during an operation before natural menopause takes place, the sudden decrease in estrogen levels causes "surgical menopause".

Menopause is not a disease - it is a natural life event and different women experience menopause and its symptoms differently. Not all women suffer obvious symptoms of estrogen deficiency. When the estrogen levels begin decreasing, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating ("hot flashes" or " hot flushes"). Using estrogen drugs can help the body adjust to lower estrogen levels and reduce these symptoms.

Osteoporosis is a thinning of the bones that makes them weaker and allows them to break more easily. In osteoporosis, the bones of the spine, wrists and hips break most often. The bones of both men and women start to thin after about age 40, but women lose bone faster after menopause.

Using estrogens after menopause slows down bone thinning and may prevent bones from breaking.

Uses Of Progestins

Progestins used in hormone replacement therapy have similar effects to the female sex hormone progesterone. During the child bearing years, progesterone is responsible for regulation of the menstrual cycle. The estradiol delivered by ESTRACOMB* not only relieves your menopausal symptoms, but, like estrogens produced by your body, may also stimulate growth of the inner lining of the uterus, the endometrium. In menopausal and postmenopausal women with intact uteri, stimulation of growth of the endometrium may result in irregular bleeding. In some cases this may progress into a disorder of the uterus known as endometrial hyperplasia (overgrowth of the lining of the uterus), which increases the risk of endometrial cancer (cancer of the lining of the uterus). The development of estrogen-mediated disorders of the uterus can be reduced if a progestin, such as norethindrone acetate, is given regularly for a certain number of days with your estrogen replacement therapy. Each cycle of progestin administration should induce a periodic bleeding, during which time the inner lining of the uterus is shed., This protects against endometrial hyperplasia.

When it should not be used

Certain medical conditions may be aggravated by estrogens and progestins, therefore these hormones should not be used at all under these conditions.

ESTRACOMB* should not be used under these conditions:

• if you are pregnant or think you may be

  pregnant. Since pregnancy may be possible early in menopause while you are still having spontaneous periods, the use of

  non-hormonal birth control should be discussed with your physician at this time. If you take estrogen during pregnancy, there is a small risk of your unborn child having birth defects.

• if you are breast-feeding. Ask your doctor or

  pharmacist for advice.

• if you currently have or have ever had cancer

  of the breast, or uterus or endometrium (lining of the womb) or any other cancer which is sensitive to estrogens

  • if you have been diagnosed with endometrial hyperplasia (overgrowth of the lining of the uterus)
  • if you have unexplained changes in unexpected or unusual genital bleeding that has not been investigated.

  • if you have active thrombophlebitis

    (inflamed varicose veins)

  • if you currently have a problem with abnormal blood clots forming in your blood vessels or have ever had such a problem in the past. This may cause painful inflammation of the veins (thrombophlebitis) or blockage of a blood vessel in the legs (deep vein thrombosis), lungs (pulmonary embolism) or other organs
  • if you have ever had a heart attack, coronary heart disease or stroke
  • if you currently have a serious liver disease
  • if you have migraine
  • if you have had partial or complete loss of vision due to blood vessel disease in the eye.
  • if you have a disease of blood pigment called porphyria
  • if you have ever had any unusual allergic reaction to estrogens or any other component of ESTRACOMB* (see What the medicinal ingredient are and What the nonmedicinal ingredients are).

ESTRACOMB* is not a contraceptive, nor will it restore fertility.

Talk to your doctor if you have any further questions or if you think that any of the above may apply to you.

What the medicinal ingredient are:

ESTRACOMB* contains two types of transdermal therapeutic systems (patches) that are used in sequence. The round patch is called

ESTRADERM* 50 (ESTRADERM*) and the twin patch is called ESTRAGEST* 250/50 (ESTRAGEST*).

ESTRADERM* contains a natural estrogen hormone, estradiol, while ESTRAGEST* contains estradiol as well as a progestin, norethindrone acetate (NETA).

What the nonmedicinal ingredients are:

cellulose compounds, ethanol, ethylene-vinyl acetate copolymer, light mineral oil, polyester and polyisobutylene.

What dosage forms it comes in:

One ESTRACOMB* package contains four ESTRADERM* 50 patches (two patches per week) and four ESTRAGEST* 250/50 patches (two patches per week) for a 28-day treatment cycle.

• 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 lump, 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-examination 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 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 ingredients) 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. 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.

• 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.

therefore not generally required in women who have had a hysterectomy.

• Ovarian cancer

In some studies, the use of estrogen-alone 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 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 estrogens by postmenopausal 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 post-menopausal 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.

Before you use ESTRACOMB* talk to your doctor or pharmacist if you:

• have a history of allergy or intolerance to any medications or other substances
• have been told that you have a condition called hereditary angioedema of if you have had episodes of rapid swelling of the hands, feet, face, lips, eyes, tongue, throat (airway blockage) or digestive tract

• have a personal history of breast disease

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

• have experienced any unusual or undiagnosed vaginal bleeding
• have a history of uterine fibroids or endometriosis
• have a history of liver disease or liver tumours, jaundice (yellowing of the eyes and/or skin) or itching related to estrogen use or during pregnancy
• have a history of migraine headache
• have a history of high blood pressure
• have a personal or family history of blood clots, or a personal history of heart disease or stroke
• phlebitis (inflamed varicose veins)
• have a history of kidney disease, asthma or epilepsy (seizures)
• 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 been diagnosed with lupus
• gall bladder disease
• depression
• have been diagnosed with hearing loss due to otosclerosis
• have a history of high cholesterol or high

triglycerides

• are pregnant or may be pregnant
• are breastfeeding

• have had a hysterectomy (surgical

  removal of the uterus)

• smoke

• are undergoing surgery or need long bed

  rest.

Ask your doctor and pharmacist to answer any questions you may have.

INTERACTION WITH THIS MEDICATION

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines. Remember also those not prescribed by a doctor.

This particularly includes the following: anti-anxiety medicines (e.g.barbiturates,

meprobamate), anti-epileptic medicines (e.g. pheno barbital, phenytoin or carbamazepine), an anti-inflammatory medicine called

phenylbutazone, antibiotics and other anti-infective medicines (e.g. rifampicin, rifabutin, nevirapine, efavirenz), and herbal medicines (e.g. St John’s wort).

These medicines may be affected by

ESTRACOMB* or, conversely, they may affect how well ESTRACOMB* works. Your doctor may need to adjust the dose of your treatment.

PROPER USE OF THIS MEDICATION

Usual dose:

Each ESTRACOMB* pack contains four ESTRADERM* and four ESTRAGEST* patches. The round ESTRADERM* patch provides the estrogen, estradiol. The twin ESTRAGEST* patch provides estradiol and the progestin, norethindrone acetate (NETA). These patches contain and release different amounts of active ingredient, as follows:

• ESTRADERM*: 10 cm² round patch,

  containing 4 mg estradiol and releasing about 50 µg estradiol a day

• ESTRAGEST*: 20 cm² goggle-shaped

  patch, containing 10 mg estradiol and 30 mg norethindrone acetate, and releasing about 50 µg estradiol and 250 µg NETA a day

When ESTRACOMB* is applied to the skin, the patches release small amounts of estradiol and

NETA, which pass directly through the skin into your bloodstream.

All eight patches are to be used in a 28-day treatment cycle.

Therapy is started with the ESTRADERM* patches which are used for the first 2 weeks followed by the ESTRAGEST* patches for the next 2 weeks (See Figure 1). The ESTRADERM* and ESTRAGEST* patches are applied twice weekly on the same days of each week. Each patch should be worn continuously for 3-4 days.

Regular cyclical bleeding usually starts towards the end of the ESTRAGEST* application phase (i.e., while you are wearing the 4th ESTRAGEST* patch of that cycle). The duration of bleeding is around 6 days. Bleeding is of light intensity or spotting for 60-70% of this time. Tell your doctor if you have heavy or irregular bleeding after a few months of treatment.

As therapy with ESTRACOMB* is continuous, the next treatment cycle is started with ESTRADERM* immediately after removal of the last ESTRAGEST* patch, and regardless of whether there is still bleeding (i.e., you will have a patch on at all times).

It is important that you take your medication as your physician has prescribed. Do not discontinue or change your therapy without consulting your physician first.

How And Where To Apply ESTRACOMB*

It is recommended that you change the site of application each time the patch is applied.

However, each time you apply a patch you should always apply it to the same area of your body (i.e., if the patch is applied to the buttocks, move the patch from right side to left side, twice a week or more if there is any redness under the patch).

1. 1. Preparing The Skin

In order for the patch to stick, the skin should be clean, dry and free of creams, lotions or oils. If you wish, you may use body lotion after the patch has been properly applied to the skin. The skin should not be irritated or broken, since this may alter the amount of hormone you get. Contact with water (bath, pool, or shower) won't affect the patch, although very hot water or steam may loosen it and therefore should be avoided (see Helpful Hints).

1. 2. Where To Apply The ESTRADERM* Or ESTRAGEST* Patches

The buttock is the preferred place to apply the patches. Other suitable application sites are the side, lower back or lower abdomen (see Figure 1). Change the site of application each time you put a patch on. You can use the same spot more than once but not twice in a row.

Figure 1

Avoid areas of the skin where clothing may rub the patch off or areas where the skin is very hairy or folded. Also avoid areas where the patch is likely to be exposed to the sun since this may affect how the patch works.

DO NOT APPLY THE PATCHES TO YOUR BREAST, since this may cause unwanted effects and discomfort.

1. 3.

   Opening The Pouch

   Each ESTRADERM* or ESTRAGEST* patch is individually sealed in a protective pouch. Tear open this pouch at the indented notch and remove the patch (see Figures 2a and 2b). Do not use scissors, as you may accidentally cut and destroy the patch. There may or may not be bubbles in the patch, but this is normal. Do not cut the twin ESTRAGEST* patch in half.

   Figure 2a

   Figure 2b

   1. 4. Removing The Liner

One side of the patch has the adhesive that sticks to your skin. The adhesive is covered by a protective liner that must be removed.

To separate the patch from the liner, hold the patch with your thumb on the smooth liner, your other fingers on the patch. See positioning in Figure 3. Press your thumb against your other fingers by using the motion of snapping your fingers slowly.

Figure 3

This will allow you to easily separate the patch and liner. Holding the edge of the patch you can now peel away the liner (Figure 4). Avoid touching the adhesive.

Figure 4

Don't worry if the patch buckles slightly because you can flatten it out after the liner has been removed. Apply the patch soon after opening the pouch and removing the liner.

1. 5.

   Applying The ESTRADERM* And ESTRAGEST* Patches

   Apply the adhesive side to the spot you have chosen. Press it firmly in place with the palm of your hand for about 10 seconds, then run your finger around the edge, making sure there is good contact with the skin.

2. 6. When And How To Remove The Patch

The ESTRADERM* and ESTRAGEST* patches should be changed twice weekly. Always change it on the same 2 days of the week. If you forget to change it at the scheduled time, there is no cause for alarm. Just change it as soon as possible and continue to follow your usual schedule.

After you remove the patch fold it in half with the adhesive sides inwards. Throw it away, safely out of the reach of children or pets.

Any adhesive left on your skin should rub off easily. You can also use mineral oil, baby oil or rubbing alcohol to remove adhesive from the skin. Apply a new ESTRADERM* or ESTRAGEST* patch on a different spot of clean, dry skin.

Helpful Hints

What to do if the patch falls off

Should a patch fall off in a very hot bath or shower, shake the water off the patch. Dry your skin completely and reapply the patch as soon as possible (to a new area of skin) and continue your regular schedule. Make sure you choose a clean, lotion-free area of the skin. If it still does not stick completely to your skin, then use a new patch. No matter what day this happens, go back to changing the patch on the same days as the initial schedule.

If hot baths, saunas or whirlpools are something you enjoy and you find that the patch is falling off, you may consider removing the patch temporarily while you are in the water. If you do remove the patch temporarily, the adhesive side of the patch should be placed on the protective liner that was removed when originally applying the patch. Wax paper may be used as an alternate to the liner.

This prevents the contents of the patch from emptying by evaporation while you are not wearing it.

In addition to exposure to very hot water, there are some other causes for the patch failing to stick. If you are having patches fall off regularly, this could be happening as a result of:

• using any type of bath oil
• using soaps with a high cream content
• using skin moisturizers before applying the patch

Patch adhesion may be improved if you avoid using these products, and by cleansing the site of application with rubbing alcohol before you apply the patch.

What to do if your skin becomes red or irritated under or around the patch

As with any product that covers the skin for a period of time (such as bandages), the ESTRADERM* and ESTRAGEST* patches can produce some skin irritation in some women. This varies according to the sensitivity of each woman.

Usually this redness does not pose any health concern to you, but to reduce this problem, there are some things that you may do:

• choose the buttock as the site of application

• change the site of application of the

  ESTRADERM* or ESTRAGEST* patch every time a new patch is applied, usually twice weekly

Experience with ESTRADERM* has shown that if you allow the patch to be exposed to the air for approximately 10 seconds after the protective liner has been removed, skin redness may not occur.

If redness and/or itching continues, you should consult your physician.

Overdose:

Symptoms

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

Progestin (norethindrone acetate) overdosage may cause depressed mood, tiredness, acne and hirsutism.

If more medication has been taken than what has been prescribed, remove the patch and contact either your doctor, hospital, or emergency department immediately.

For management of a suspected drug overdose, contact your regional Poison Control Center.

Treatment

Owing to the mode of administration (transdermal), plasma levels of estradiol-17ß and norethindrone acetate can be rapidly reduced by removal of the patch.

Missed Dose:

If you miss applying a patch, apply a new patch as soon as you remember. No matter what day that happens, go back to changing this patch on the same day as your initial schedule.

Always Remember

Your doctor has prescribed ESTRACOMB* for you after a careful review of your medical needs. Use it only as directed and do not give it to anyone else. Your doctor should re-examine you at least once a year.

If you have any questions, contact your doctor or pharmacist.

SSIDE EFFECTS AND WHAT TO DO ABOUT THEM

All medicines can have side effects. Sometimes they are serious, most of the time they are not.

Check with your doctor as soon as possible if any of the following occur:, swelling of the lower legs, ankles, fingers or abdomen due to fluid retention (oedema) persisting for more than 6 weeks, change in weight, change in your sex drive, easy bruising, excessive nose bleeds, painful and/or heavy periods (may be signs of growth of fibroids in uterus), back pain or menstrual period-like pain, breast tenderness and excessive vaginal secretions (may be a sign that too much estrogen is taken), change in vaginal discharge (may be a sign that too much estrogen is taken), vaginal thrush (vaginal fungal infection with severe itching, vaginal discharge), intolerable breast tenderness, persistent or severe skin irritation, itching under the patch, reddening of the skin after the patch has been removed; hair loss, excessive hairiness, rash, itching, dryness or discoloration of the skin, spotty darkening of the skin, particularly on the face or abdomen (chloasma), acne, purple skin patches, decline of memory or mental ability, headache, nervousness, rapid change in mood, contact lens discomfort, gall bladder disease (tendency to form gall stones).

This is not a complete list of side effects. For any unexpected effects while taking ESTRACOMB*, contact your doctor or pharmacist.

ESTRADERM* and ESTRAGEST* should be stored in a cool dry place ( not above 25^◦C). Do not freeze. Store in the original package.

ESTRADERM* and ESTRAGEST* patches should be kept out of the reach and sight of children and pets before and after use.

Use ESTRACOMB* within 6 months of purchase or before the expiry date shown on the pack, whichever comes first.

Do not use any ESTRACOMB* pack that is damaged or shows signs of tampering.

HOW TO STORE IT

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance: Online: www.healthcanada.gc.ca/medeffect

Toll-free telephone: 1-866-234-2345 toll-free fax 1-866-678-6789 Postage Paid mail:

Canada Vigilance Program

Health Canada

AL 0701C

Ottawa ON K1A 0K9

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

Please consult your doctor or pharmacist with any questions or concerns you may have regarding your individual condition.

This document plus the full product monograph, prepared for health professionals can be found at: http://www.novatis.ca

or by contacting the sponsor, Novartis Pharmaceuticals Canada Inc., at:

1-800-363-8883

Last revised: February 05, 2009

Novartis Pharmaceuticals Canada Inc.

385 Bouchard Blvd

Dorval, Quebec H9S 1A9

* Registered trademark