Cenestin

In the U.S.

• Alora
• Cenestin
• Climara
• Divigel
• Elestrin
• Emcyt
• Enjuvia
• Esclim
• Estinyl
• EstroGel
• Evamist
• Femtrace
• Gynodiol
• Menest
• Menostar
• Minivelle
• Ogen .625
• Ogen 1.25
• Ogen 2.5
• Premarin
• Vivelle
• Vivelle-Dot

In Canada

• Estraderm
• Estradot Transdermal
• Estradot Transdermal Therapeutic System
• Estradot Transdermal Therapeutic System
• Estrogel
• Oesclim
• Rhoxal-Estradiol Derm 50
• Rhoxal-Estradiol Derm 75
• Roxal-Estradiol Derm 100
• Vivelle 100 Mcg
• Vivelle 25 Mcg

Available Dosage Forms:

• Tablet
• Cream
• Patch, Extended Release
• Gel/Jelly
• Spray
• Emulsion
• Tablet, Enteric Coated
• Capsule

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Use of this medicine before puberty is not recommended. Growth of bones can be stopped early. Girls and boys may develop growth of breasts. Girls may have vaginal changes, including vaginal bleeding.

This medicine may be used to start puberty in teenagers with some types of delayed puberty.

Geriatric

Elderly people are especially sensitive to the effects of estrogens. This may increase the chance of side effects during treatment, especially stroke, invasive breast cancer, and memory problems.

Pregnancy

Estrogens are not recommended for use during pregnancy or right after giving birth. Becoming pregnant or maintaining a pregnancy is not likely to occur around the time of menopause.

Certain estrogens have been shown to cause serious birth defects in humans and animals. Some daughters of women who took diethylstilbestrol (DES) during pregnancy have developed reproductive (genital) tract problems and, rarely, cancer of the vagina or cervix (opening to the uterus) when they reached childbearing age. Some sons of women who took DES during pregnancy have developed urinary-genital tract problems.

Breast Feeding

Use of this medicine is not recommended in nursing mothers. Estrogens pass into the breast milk and their possible effect on the baby is not known.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Dasabuvir
• Ombitasvir
• Paritaprevir
• Ritonavir
• Tranexamic Acid

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Anagrelide
• Aprepitant
• Boceprevir
• Bosentan
• Bupropion
• Carbamazepine
• Ceritinib
• Conivaptan
• Dabrafenib
• Darunavir
• Dasabuvir
• Dexamethasone
• Donepezil
• Eliglustat
• Enzalutamide
• Fosphenytoin
• Griseofulvin
• Idelalisib
• Isotretinoin
• Lesinurad
• Lixisenatide
• Lumacaftor
• Mitotane
• Modafinil
• Netupitant
• Oxcarbazepine
• Paclitaxel
• Paclitaxel Protein-Bound
• Phenytoin
• Piperaquine
• Pitolisant
• Pixantrone
• Prednisone
• Rifabutin
• Rifampin
• St John's Wort
• Sugammadex
• Theophylline
• Tizanidine
• Topiramate
• Valproic Acid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

For all patients

• Asthma or
• Calcium, too much or too little in blood or
• Diabetes or
• Epilepsy or seizures or
• Heart problems or
• Kidney problems or
• Liver tumors, benign or
• Lupus erythematosus, systemic or
• Migraine headaches—Estrogens may worsen these conditions.

• Blood clotting problems, or history of during previous estrogen therapy—Estrogens usually are not used until blood clotting problems stop; using estrogens is not a problem for most patients without a history of blood clotting problems due to estrogen use.

• Breast cancer or
• Bone cancer or
• Cancer of the uterus or
• Fibroid tumors of the uterus—Estrogens may interfere with the treatment of breast or bone cancer or worsen cancer of the uterus when these conditions are present.

• Bulging eyes or
• Double vision or
• Migraine headache or
• Vision changes, sudden onset including or
• Vision loss, partial or complete—Estrogens may cause these problems. Tell your doctor if you have had any of these problems, especially while taking estrogen or oral contraceptives (“birth control pills”).

• Changes in genital or vaginal bleeding of unknown causes—Use of estrogens may delay diagnosis or worsen condition. The reason for the bleeding should be determined before estrogens are used.

• Endometriosis or
• Gallbladder disease or gallstones, or history of or
• High cholesterol or triglycerides, or history of or
• Liver disease, or history of or
• Pancreatitis (inflammation of pancreas) or
• Porphyria—Estrogens may worsen these conditions. Although estrogens can improve blood cholesterol, they can worsen blood triglycerides for some people.

• Hypothyroid (too little thyroid hormone)—Dose of thyroid medicine may need to be increased.

For males treated for breast or prostate cancer:

• Blood clots or
• Heart or circulation disease or
• Stroke—Males with these medical problems may be more likely to have clotting problems while taking estrogens; the high doses of estrogens used to treat male breast or prostate cancer have been shown to increase the chances of heart attack, phlebitis (inflamed veins) caused by a blood clot, or blood clots in the lungs.

This section provides information on the proper use of a number of products that contain estrogen. It may not be specific to Cenestin. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it and do not take or use it for a longer time than your doctor ordered. For patients taking any of the estrogens by mouth, try to take the medicine at the same time each day to reduce the possibility of side effects and to allow it to work better.

This medicine usually comes with patient information or directions. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.

For patients taking any of the estrogens by mouth or by injection:

• 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.

For patients using the transdermal (skin patch):

• Wash and dry your hands thoroughly before and after handling the patch.
• Apply the patch to a clean, dry, non-oily skin area of your lower abdomen, hips below the waist, or buttocks that has little or no hair and is free of cuts or irritation. The manufacturer of the 0.025-mg patch recommends that its patch be applied to the buttocks only. Furthermore, each new patch should be applied to a new site of application. For instance, if the old patch is taken off the left buttock, then apply the new patch to the right buttock.
• Do not apply to the breasts. Also, do not apply to the waistline or anywhere else where tight clothes may rub the patch loose.
• Press the patch firmly in place with the palm of your hand for about 10 seconds. Make sure there is good contact, especially around the edges.
• If a patch becomes loose or falls off, you may reapply it or discard it and apply a new patch.
• Each dose is best applied to a different area of skin on your lower abdomen, hips below the waist, or buttocks so that at least 1 week goes by before the same area is used again. This will help prevent skin irritation.

For patients using the topical emulsion (skin lotion):

• Washing and drying hands thoroughly before each application.
• Apply while you are sitting comfortably. Apply one pouch to each leg every morning.
• Apply the entire contents of one pouch to clean, dry skin on the left thigh. Rub the emulsion into the entire thigh and calf for 3 minutes until thoroughly absorbed.
• Apply entire contents of the second pouch to clean, dry skin on the right thigh. Rub the emulsion into the entire thigh and calf for 3 minutes until thoroughly absorbed.
• Rub any remaining emulsion on both hands on the buttocks.
• Washing and drying hands thoroughly after application.
• To avoid transfer to other individuals, allow the application areas to dry completely before covering with clothing.

If you are using the Evamist® transdermal spray:

• Spray the medicine on your skin on the inside of your forearm, between the elbow and the wrist.
• Do not allow your child to touch the area of the arm where the medicine was sprayed. If you cannot avoid to come nearer with your child, wear clothes with long sleeves to cover the application site.
• If your child comes in direct contact with the arm where the medicine was sprayed, wash your child's skin right away with soap and water.
• Do not allow your pets to lick or touch the arm where the medicine was sprayed.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For conjugated estrogens
• For oral dosage form (tablets):
  • For treating breast cancer in women after menopause and in men:
    • Adults—10 milligrams (mg) three times a day for at least 3 months.
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    • Adults—0.3 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may change the dose based on how your body responds to the medication.
  • To prevent loss of bone (osteoporosis):
    • Adults—0.3 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may change the dose based on how your body responds to the medication.
  • For treating ovary problems (female hypogonadism or for starting puberty):
    • Adults and teenagers—0.3 to 0.625 milligram (mg) a day. Your doctor may want you to take the medicine only on certain days of the month.
  • For treating ovary problems (failure or removal of both ovaries):
    • Adults—1.25 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating prostate cancer:
    • Adults—1.25 to 2.5 milligram (mg) three times a day.
• For injection dosage form:
  • For controlling abnormal bleeding of the uterus:
    • Adults—25 milligrams (mg) injected into a muscle or vein. This may be repeated in six to twelve hours if needed.

For esterified estrogens
• For oral dosage form (tablets):
  • For treating breast cancer in women after menopause and in men:
    • Adults—10 milligrams (mg) three times a day for at least three months.
  • For treating a genital skin condition (vulvar atrophy) or inflammation of the vagina (atrophic vaginitis), or to prevent loss of bone (osteoporosis):
    • Adults—0.3 to 1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating ovary problems (failure or removal of both ovaries):
    • Adults—1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating ovary problems (female hypogonadism):
    • Adults—2.5 to 7.5 mg a day. This dose may be divided up and taken in smaller doses. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating symptoms of menopause:
    • Adults—0.625 to 1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating prostate cancer:
    • Adults—1.25 to 2.5 mg three times a day.

For estradiol
• For oral dosage form:
  • For treating breast cancer in women after menopause and in men:
    • Adults—10 milligrams (mg) three times a day for at least 3 months.
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), ovary problems (female hypogonadism or failure or removal of both ovaries), or symptoms of menopause:
    • Adults—At first, 1 to 2 milligrams (mg) one time per day for at least 3 months. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may also need to change the dose based on how your body responds to the medication.
  • For treating prostate cancer:
    • Adults—1 to 2 milligrams (mg) three times a day.
  • To prevent loss of bone (osteoporosis):
    • Adults—0.5 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
• For topical emulsion dosage form (skin lotion):
  • For treating symptoms of menopause:
    • Adults—1.74 grams (one pouch) applied to the skin of each leg (thigh and calf) once a day in the morning.
• For transdermal dosage form (skin patches):
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), symptoms of menopause, ovary problems (female hypogonadism or failure or removal of both ovaries), or to prevent loss of bone (osteoporosis):
    For the Climara patches
    • Adults—0.025 to 0.1 milligram (mg) (one patch) applied to the skin and worn for one week. Then, remove that patch and apply a new one. A new patch should be applied once a week for three weeks. During the fourth week, you may or may not wear a patch. Your health care professional will tell you what you should do for this fourth week. After the fourth week, you will repeat the cycle.
    For the Alora, Estraderm, Estradot, Vivelle, or Vivelle-Dot patches
    • Adults—0.025 to 0.1 mg (one patch) applied to the skin and worn for one half of a week. Then, remove that patch and apply and wear a new patch for the rest of the week. A new patch should be applied two times a week for three weeks. During the fourth week, you may or may not apply new patches. Your health care professional will tell you what you should do for this fourth week. After the fourth week, you will repeat the cycle.

For estradiol cypionate
• For injection dosage form:
  • For treating ovary problems (female hypogonadism):
    • Adults—1.5 to 2 milligrams (mg) injected into a muscle once a month.
  • For treating symptoms of menopause:
    • Adults—1 to 5 milligrams (mg) injected into a muscle every 3 to 4 weeks.

For estradiol valerate
• For injection dosage form:
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), symptoms of menopause, or ovary problems (female hypogonadism or failure or removal of both ovaries):
    • Adults—10 to 20 milligrams (mg) injected into a muscle every 4 weeks as needed.
  • For treating prostate cancer:
    • Adults—30 milligrams (mg) injected into a muscle every 1 or 2 weeks.

For estrone
• For injection dosage form:
  • For controlling abnormal bleeding of the uterus:
    • Adults—2 to 5 milligrams (mg) a day, injected into a muscle for several days.
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    • Adults—0.1 to 0.5 milligram (mg) injected into a muscle 2 or 3 times a week. Your doctor may want you to receive the medicine each week or only during certain weeks of the month.
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    • Adults—0.1 to 1 milligram (mg) a week. This is injected into a muscle as a single dose or divided into more than one dose. Your doctor may want you to receive the medicine each week or only during certain weeks of the month.
  • For treating prostate cancer:
    • Adults—2 to 4 milligrams (mg) injected into a muscle 2 or 3 times a week.

For estropipate
• For oral dosage form (tablets):
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    • Adults—0.75 to 6 milligrams (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    • Adults—1.5 to 9 milligrams (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • To prevent loss of bone (osteoporosis):
    • Adults—0.75 milligram (mg) a day. Your doctor may want you to take the medicine each day for twenty-five days of a thirty-one–day cycle.

For ethinyl estradiol
• For oral dosage form (tablets):
  • For treating breast cancer in women after menopause and in men:
    • Adults—1 milligram (mg) three times a day.
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    • Adults—0.05 milligram (mg) one to three times a day for 3 to 6 months. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating prostate cancer:
    • Adults—0.15 to 3 milligrams (mg) a day.
  • For treating symptoms of menopause:
    • Adults—0.02 to 0.05 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.

For ethinyl estradiol and norethindrone
• For oral dosage form (tablets):
  • For treating symptoms of menopause:
    • Adults—1 tablet (5 mcg ethinyl estradiol and 1 mg of norethindrone) each day.
  • To prevent loss of bone (osteoporosis):
    • Adults—1 tablet (5 mcg ethinyl estradiol and 1 mg of norethindrone) each day.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

If you forget to wear or change a patch, put one on as soon as you can. If it is almost time to put on your next patch, wait until then to apply a new patch and skip the one you missed. Do not apply extra patches to make up for a missed dose.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Cenestin (synthetic conjugated estrogens, A) Tablets are available as:

0.3 mg round, green, film-coated tablets debossed with the letters, dp, on one side and the number 41 on the other side.

0.45 mg round, orange, film-coated tablets debossed with the letters, dp, on one side and the number 46 on the other side.

0.625 mg round, red, film-coated tablets debossed with the letters, dp, on one side and the number 42 on the other side.

0.9 mg round, white, film-coated tablets debossed with the letters, dp, on one side and the number 43 on the other side.

1.25 mg round, blue, film-coated tablets debossed with the letters, dp, on one side and the number 44 on the other side.

Cardiovascular Disorders

An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

Stroke

In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.3)]. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1

In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10, 000 women-years) [see Clinical Studies (14.3)]. The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

Coronary Heart Disease

In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death ) was reported in women receiving estrogen-alone compared to placebo2[see Clinical Studies (14.3)].

Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).

In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.3)].

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE 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 CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall.

Venous Thromboembolism

In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years3[see Clinical Studies (14.3)]. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.

In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4[see Clinical Studies (14.3)]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Malignant Neoplasms

Endometrial cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. 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 risks of 15- to 24-fold for 5 to 10 years or more and 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-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital 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 postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Breast cancer

The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80)5[see Clinical Studies (14. 3)].

The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo6[see Clinical Studies (14.3)]. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups [see Clinical Studies (14.3)].

Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Ovarian Cancer

The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77 - 3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association.

Probable Dementia

In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8[see Use in Specific Populations (8.5), and Clinical Studies (14.4)].

In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8[see Use in Specific Populations (8.5), and Clinical Studies (14.4)].

When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8[see Use in Specific Populations (8.5), and Clinical Studies (14.4)].

Gallbladder Disease

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

Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

Visual Abnormalities

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or renal vascular lesions, estrogens should be permanently discontinued.

Addition of a Progestin when a Woman has not had a Hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.

Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.

Hypertriglyceridemia

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.

Hepatic Impairment and/or Past History of Cholestatic Jaundice

Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.

Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Fluid Retention

Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal impairment, warrant careful observation when estrogen-alone is prescribed.

Hypocalcemia

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

Exacerbation of Endometriosis

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

Hereditary Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

Exacerbation of Other Conditions

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

Laboratory Tests

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.

Drug/Laboratory Test Interactions

Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

Increased TBG levels leading to increased circulating total thyroid hormone levels, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.

Other binding proteins may be elevated in serum for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels.

Impaired glucose tolerance.

No drug-drug interaction studies have been conducted with Cenestin

Metabolic Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s wort (Hypericum perforatum) preparations, 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 may result in side effects.

How Supplied

Cenestin (synthetic conjugated estrogens, A) Tablets are available as:

0.3 mg	Round, green, film-coated, and are debossed with the letters, dp, on one side and the number, 41 on the other side. Available in bottles of: 100 NDC 51285-441-02
0.45 mg	Round, orange, film-coated, and are debossed with the letters, dp, on one side and the number, 46 on the other side. Available in bottles of: 100 NDC 51285-446-02
0.625 mg	Round, red, film-coated, and are debossed with the letters, dp, on one side and the number, 42 on the other side. Available in bottles of: 100 NDC 51285-442-02
0.9 mg	Round, white, film-coated, and are debossed with the letters, dp, on one side and the number, 43 on the other side. Available in bottles of: 100 NDC 51285-443-02
1.25 mg	Round, blue, film-coated, and are debossed with the letters, dp, on one side and the number, 44 on the other side. Available in bottles of: 100 NDC 51285-444-02

Storage and Handling

Store at 20 to 25°C (68-77°F); excursions are permitted to 15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature].

Dispense in tight container.

Dispense in child-resistant packaging.

Keep out of the reach of children.

Pharmacist: Include one “Information for the patient” leaflet with each package dispensed.

See FDA-approved patient labeling (Patient Information).

Vaginal Bleeding

Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)].

Possible Serious Adverse Reactions with Estrogen-Alone Therapy

Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1, 5.2, 5.3)].

Possible Less Serious but More Common Adverse Reactions with Estrogen-Alone Therapy

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headaches, breast pain and tenderness, nausea and vomiting.

Manufactured By:

Teva Women’s Health, Inc.

Subsidiary of Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Cenestin® (sin nes tin)

(synthetic conjugated estrogens, A)

Tablets

Read this Patient Information before you start taking Cenestin and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

What is the most important information I should know about Cenestin (an estrogen mixture)? • Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are taking Cenestin. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. • Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline in brain function). • Using estrogen-alone may increase your chances of getting strokes or blood clots. • Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older. • Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia. • Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. • Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older. • You and your healthcare provider should talk regularly about whether you still need treatment with Cenestin.

What is Cenestin?

Cenestin is a prescription medicine that contains a mixture of estrogen hormones.

What is Cenestin used for?

Cenestin is used after menopause to:

• reduce moderate or severe hot flushes   Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause”.   When estrogen levels begin dropping, some women get 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”). In some women, the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe. • treat moderate to severe menopausal changes in and around the vagina   You and your healthcare provider should talk regularly about whether you still need treatment with Cenestin to control these problems. If you use Cenestin only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

Who should not take Cenestin?

Do not take Cenestin if you:

· have unusual vaginal bleeding   Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. · currently have or have had certain cancers   Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should take Cenestin. · had a stroke or heart attack · currently have or have had blood clots · currently have or have had liver problems · have been diagnosed with a bleeding disorder · are allergic to Cenestin or any of its ingredients
See the list of ingredients in Cenestin at the end of this leaflet. · think you may be pregnant   Cenestin is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not take Cenestin if the test is positive and talk to your healthcare provider.

What should I tell my healthcare provider before I take Cenestin?

Before you take Cenestin, tell your healthcare provider if you:

· have any unusual vaginal bleeding   Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any vaginal bleeding to find out the cause. · have any other medical conditions   Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. · are going to have surgery or will be on bed rest   Your healthcare provider will let you know if you need to stop taking Cenestin. · are breastfeeding   The hormones in Cenestin can pass into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how Cenestin works. Cenestin may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take Cenestin?

• Take Cenestin exactly as your healthcare provider tells you to take it. • Take 1 Cenestin tablet at the same time each day. • You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether you still need treatment with Cenestin.

What are the possible side effects of Cenestin?

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

· heart attack · stroke · blood clots · dementia · breast cancer · cancer of the lining of the uterus (womb) · cancer of the ovary · high blood pressure · high blood sugar · gallbladder disease · liver problems · changes in your thyroid hormone levels · enlargement of benign tumors of the uterus (“fibroids”)

Call your healthcare provider right away if you get any of the following warning signs, or any other unusual symptoms that concern you:

· new breast lumps · unusual vaginal bleeding · changes in vision or speech · sudden new severe headaches · severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

Less serious, but common side effects include:

· headache · breast tenderness or pain · irregular vaginal bleeding or spotting · stomach or abdominal cramps, bloating · nausea and vomiting · hair loss · fluid retention · vaginal yeast infection

These are not all the possible side effects of Cenestin. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or does not go away.

You may report side effects to Teva Branded Pharmaceutical Products at 1-888-483-8279 or to FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with Cenestin?

· Talk with your healthcare provider regularly about whether you should continue taking Cenestin. · If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. • The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb).   See you healthcare provider right away if you get vaginal bleeding while taking Cenestin. · Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else.   If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. · If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances of getting heart disease.   Ask your healthcare provider for ways to lower your chances of getting heart disease.

How should I store Cenestin?

• Store Cenestin at room temperature between 68°F to 77°F (20°C to 25°C).

Keep Cenestin and all other medicines out of the reach of children.

General information about safe and effective use of Cenestin.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Cenestin for conditions for which it was not prescribed. Do not give Cenestin to other people, even if they have the same symptoms you have. It may harm them.

This leaflet provides a summary of the most important information about Cenestin. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about Cenestin that is written for health professionals.

What are the ingredients in Cenestin?

Active Ingredient: synthetic conjugated estrogens, A

Inactive Ingredients: ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80 (except 0.45 mg tablets), pregelatinized starch, titanium dioxide, and triethyl citrate.

· 0.3 mg tablets also contain FD&C Blue No. 2 aluminum lake and D&C Yellow No. 10 aluminum lake. · 0.45 mg tablets also contain FD&C Yellow No. 6/Sunset Yellow FCF lake. · 0.625 mg tablets also contain FD&C Red No. 40 aluminum lake. · 0.9 mg tablets do not contain any additional color additives. · 1.25 mg tablets also contain FD&C Blue No. 2 aluminum lake.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured By:

Teva Women’s Health, Inc.

Subsidiary of Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Revised: 03/2015