C.E.S. Tablets: Uses, Side Effects and Dosage

ABOUT THIS MEDICATION

What the medication is used for:

C.E.S.^® is used to:

• Relieve menopausal and post-menopausal symptoms.

• Help reduce your chances of developing osteoporosis (brittle

  bones).

• Treat itching, burning, dryness in or around the vagina

  (atrophic vaginitis).

• Treat vulvar atrophy (changes of the external genitalia

  associated with low estrogen levels).

• Treat conditions known as "hypogonadism" and "primary

  ovarian failure" that result in low estrogen secretion early in reproductive life, or to treat the condition of low estrogen levels that follows "castration" (surgical removal of the ovaries).

• Treat inoperable progressing prostatic cancer in male patients.

C.E.S.^® should be confined to women who have been diagnosed with osteoporosis or who are at increased risk of developing this condition. If you use C.E.S.^® only to prevent osteoporosis associated with menopause, you should talk to your physician about whether a different treatment or medicine without estrogens might be better for you. Adequate diet, calcium and vitamin D intake, cessation of smoking, as well as regular weight-bearing exercise should be discussed with your doctor or pharmacist in addition to taking C.E.S.^®.

If you use C.E.S. ^® only to treat symptoms of vulvar atrophy or atrophic vaginitis (itching, burning vagina) associated with menopause, talk with your healthcare provider about whether a vaginal (topical) treatment might be better for you.

C.E.S.^® should not be used by women with intact uteri unless prescribed in association with a progestin.

C.E.S.^® should only 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 hormones replacement therapy (HRT) with your doctor. You should regularly talk with your doctor about whether you still need treatment with HRT.

What it does:

C.E.S.^® (conjugated estrogens) is a medicine that contains a mixture of estrogen hormones. It replaces estrogens in your body, which naturally decreases at menopause. Estrogens are female hormones that are produced by a woman’s ovaries and are necessary for normal sexual development and the regulation of menstrual periods during the childbearing years.

When a woman is between the ages of 45 and 55, the ovaries normally stop making estrogens. This leads to a drop in body estrogen levels and marks the beginning of menopause (the end of monthly menstrual periods). A sudden drop in estrogen levels also occurs if both ovaries are removed during an operation before natural menopause takes place. This is referred to as surgical menopause.

When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating (“hot flushes”). In some women the symptoms are mild; in others they can be severe. These symptoms may last only a few months or longer. Taking C.E.S.^® can alleviate these symptoms but, C.E.S.^® should be used for the shortest time possible.

After menopause, same women develop osteoporosis. This is a thinning of the bones that makes them weaker and allows them to break more easily, often leading to fractures of the vertebrae, hip and wrist bones.

Using C.E.S.^® tablets, in addition to adequate diet, calcium and vitamin D intake, regular weight-bearing exercise, and cessation of smoking, slows down bone thinning and may prevent bones from breaking.

When it should not be used:

Before using C.E.S.^® be sure to tell your doctor if you have any of the following medical problems, as C.E.S.^® should not be used under these conditions:

• Known, suspected, or past history of breast cancer.
• Known or suspected hormone-dependent cancer. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take C.E.S.^®.
• Unexpected or unusual genital bleeding.
• Have (or have had) blood clot disorders, including blood clots in the legs or lungs.
• Have thrombophlebitis (inflammation of the veins).
• Serious liver disease.
• Active or past history of heart disease, heart attacks or

stroke.

• If you are allergic to C.E.S.^® or any of its ingredients, or have had any unusual reactions to its ingredients (see What the medicinal ingredients are and What the non-medicinal ingredients are).

• If you are pregnant or suspect you may be pregnant. Since

  pregnancy may be possible early in the pre-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 accidentally take estrogens during pregnancy, there is a small risk of your unborn child having birth defects.

• If you have partially or completely lost vision due to blood

  vessel disease of the eye.

• If you have overgrowth of the lining of the uterus

  (endometriosis).

• Are breast feeding.
• If you have migraine headaches.

What the medicinal ingredient is:

Conjugated estrogens

What the nonmedicinal ingredients are:

Each C.E.S.^® Tablet contains the following nonmedicinal ingredients:

Calcium carbonate, calcium sulphate, carnauba wax, methylparaben, microcrystalline cellulose, sucrose, talc, titanium dioxide and white wax.

In addition, the following ingredients are contained in specific strengths as indicated:

Acacia (1.25 mg), calcium phosphate, colloidal silicon dioxide, lactose, magnesium carbonate, starch, stearic acid (0.625 mg & 1.25 mg), D&C yellow N°10 (0.3 mg, 1.25 mg), erythrosine aluminium lake (0.9 mg), FD&C blue N°1 (0.3 mg), FD&C blue N°2 (0.3 mg, 0.625 mg), FD&C yellow N°6 (0.3 mg, 1.25 mg), FD&C Red N°40 (0.625 mg), hydroxypropyl cellulose (0.3 mg), hydroxypropylmethyl cellulose, magnesium stearate (0.3 mg & 0.9 mg), povidone, pharmaceutical glaze (1.25 mg), sodium benzoate (0.3 mg, 0.625 mg & 0.9 mg).

What dosage forms it comes in:

C.E.S.^® tablets for oral administration are available as:

• C.E.S.^® 0.3 mg: each oval, green sugar coated tablet contains

  0.3 mg conjugated estrogens CSD, in bottles of 100;

• C.E.S.^® 0.625 mg: each oval, maroon sugar coated tablet

  contains 0.625 mg conjugated estrogens CSD, in bottles of 100 and 1000;

• C.E.S.^® 0.9 mg: each oval, pink sugar coated tablet contains

  0.625 mg conjugated estrogens CSD, in bottles of 100; and

• C.E.S.^® 1.25 mg: each oval, yellow sugar coated tablet

  contains 1.25 mg conjugated estrogens CSD, in bottles of 100.

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 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 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 HRT.

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).

If you still have your uterus, you should take a progestin medication (another hormone drug) regularly for a certain number of days of each month 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 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 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 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.

BEFORE you use C.E.S.^® talk to your doctor or pharmacist if you:

• have a history of allergy or intolerance to any medications or other substances
• 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, liver tumours, or jaundice (yellowing of the eyes and/or skin) or itching related to estrogen use or during pregnancy
• 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
• 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
• 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 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

Other existing conditions you should discuss with your health professional include thyroid problems, fluid retention, gallbladder disease, and depression. If you have upcoming surgery or prolonged bed rest, you should also discuss these.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor or pharmacist if you are taking any other medications, including prescription medications, over-the-counter medications, vitamins or herbal products (such as St. John’s wort). Some medications (such as medications for high blood pressure, diabetes, blood clots, sleeping, anxiety, seizures, pain-relief, and tuberculosis) may affect how C.E.S.^® works. C.E.S.^® may also affect how other medicines work.

PROPER USE OF THIS MEDICATION

Usual dose:

Take this medicine by mouth (orally) only as directed by your doctor. Do not take more of it and do not take it for a longer period of time than your doctor ordered. The length of time you take the medicine will depend on the medical problem for which you are taking conjugated estrogens. Discuss with your doctor how long you will need to take these medicines.

Nausea may occur during the first few weeks after you start taking estrogens. This effect usually disappears with continued use. If the nausea is bothersome, it can usually be prevented or reduced by taking each dose with food or immediately after food.

Overdose:

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

No serious ill effects have been reported following acute ingestion of large doses of estrogens. The following effects have been selected on the basis of their potential clinical significance:

• Nausea or vomiting
• Withdrawal bleeding

Treatment of overdose is symptomatic and patients should consult their physician.

Missed Dose:

If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.

SIDE 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: abdominal discomfort, indigestion, sleep disturbance, irritability, anxiety, unusual fatigue, cold sweat, swelling of the ankles, fingers or abdomen due to fluid retention (oedema) persisting for more than 6 weeks, change in weight, change in your sex drive, change in vaginal discharge, (may be a sign that too

much estrogen is taken), hair loss, excessive hairiness, spotty darkening of the skin particularly on the face or abdomen (chloasma), rash, itching, acne, dryness or discoloration of the skin, purple skin patches, contact lens discomfort.

This is not a complete list of side effects. For any unexpected effects while taking C.E.S.^®, contact your doctor or pharmacist.

HOW TO STORE IT

• Keep out of reach of children;
• Store at room temperature between (15°-30°C);
• Store away from heat and direct light;
• Do not store in the bathroom, near the kitchen sink, or in other damp places. Heat or moisture may cause the medicine to break down;

• Do not keep outdated medicine or medicine no longer needed.

  Be sure that any discarded medicine is out of the reach of children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the 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-freehone: 1-866-234-2345

Toll-free fax 1-866-678-6789

Postage Paid Mail:

Canada Vigilance Program

Health Canada

AL 0701C

Ottawa, Ontario 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

This document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor, Valeant Canada limitée/Limited, at:

1-800-361-1448

Last revised: June 03 2009