Managing the symptoms of menopause in hysterectomized women

 
Managing the symptoms of menopause
in hysterectomized women
A conversation starter

PREMARIN is used after menopause to reduce moderate to severe hot flashes; to treat
moderate to severe menopausal changes in and around the vagina; and to help reduce the
chances of getting osteoporosis (thin, weak bones).
If you are using or are considering using PREMARIN only to treat vaginal symptoms, consider
topical therapies first. If you are using or are considering using PREMARIN only to prevent
osteoporosis due to menopause, talk with your healthcare provider about whether a different
treatment or medicine without estrogens might be better for you. PREMARIN should
be used at the lowest effective dose and for the shortest duration consistent with your
treatment goals and risks.
A beginner’s guide to symptoms of menopause

Menopause can make a bigger impact on your body than you may think
After menopause, there is a change in the level of estrogens your ovaries produce.1
This can have an impact on many of your body’s systems, and it can lead to some of
the following effects:

   Hot flashes
   Central nervous system2-4

  Bone loss                                                         Vaginal
  Skeletal system
                2,5                                                 discomfort/changes
                                                                    (dryness, itching, burning,
                                                                    painful intercourse)
                                                                    Reproductive system2,6

                                                                                                  2
Up to 80% of surveyed women going through menopause
       experience hot flashes, but that’s not all7…

   1 out of 2 of those women experience hot flashes that are
   moderate to severe.8
   If you are experiencing vaginal discomfort, you are not alone

   51     %      of postmenopausal women in a survey said they’ve learned to live
                 with the vulvar and vaginal symptoms of menopause as “a normal
                 part of getting older”8

   25%           of postmenopausal women in the same survey said they have felt pain
                 during sex8

   Even though you can’t feel it, bone loss can be a serious effect of
   menopause—and it can ultimately lead to osteoporosis5,9
   The rate of bone loss is highest in the early years postmenopause9

   The more bone mass you lose, the more thin and weak your bone becomes.5
                       Approximately 50%
             of women aged 50 years or older have low bone mass.10

        There are prescription treatments available to help you
              manage certain symptoms of menopause11

                                                                                       3
Is prescription PREMARIN® (conjugated estrogens tablets, USP)
             an appropriate treatment for your symptoms?

             What is PREMARIN?
             PREMARIN is a prescription medicine that contains a blend of estrogen hormones.

             What does PREMARIN do?
             PREMARIN treats the following symptoms of menopause:

                                                                                                                   Relieves
                                                                                                                   moderate to
                                                                                                                   severe vulvar
                                                                                                                   and vaginal
 Reduces                                                                                                           atrophy due
 moderate                                                                                                          to menopause
 to severe hot                                        Prevents                                                     (dryness, itching,
 flashes due to                                       postmenopausal                                               burning, painful
 menopause                                            bone loss                                                    intercourse)
                                                                          In women with a uterus, PREMARIN
                                                                          should be taken with a progestin

   If you are using or are considering using PREMARIN only to treat vaginal symptoms, consider topical therapies first. If you
   are using or are considering using PREMARIN only to prevent osteoporosis due to menopause, talk with your healthcare
   provider about whether a different treatment or medicine without estrogens might be better for you. PREMARIN should
   be used at the lowest effective dose and for the shortest duration consistent with your treatment goals and risks.

   Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal
   bleeding right away while you are using PREMARIN. 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.

                         Estrogen therapy is an effective treatment for certain
                            moderate to severe symptoms of menopause11

Please see accompanying Full Prescribing Information, including Boxed Warning.                                                     4
PREMARIN® (conjugated estrogens tablets, USP)
           can help reduce your moderate to severe hot flashes12,13

         Results from a 12-week clinical trial measuring the effect of PREMARIN on
         moderate to severe hot flashes due to menopause, compared to placebo12,13

                                                                              Reduction in number of hot flashes* per day
                                                                         16
                                                                                      PREMARIN
                                                                                       (0.3 mg)
                         Mean number of moderate to severe hot flashes

                                                                                        (n=30)
                                                                         14
                                                                                                           Placebo
                                                                                                           (n=28)
                                                                         12

                                                                                                          -6.0
                                                                         10           -11.3
                                                                         8

                                                                         6

                                                                         4

                                                                         2
                                                                                                                            P
What is the most important information I should know
            about PREMARIN® (conjugated estrogens tablets, USP)?

What are the risks with taking estrogen?                         Estrogens increase the risk of gallbladder disease.
Using estrogen-alone may increase your chances of getting:       Discontinue estrogen if loss of vision, pancreatitis or liver
                                                                 problems occur.
• Strokes or blood clots (VTE)
• Cancer of the uterus (womb)                                    How long should I take PREMARIN?
  – Report any unusual vaginal bleeding right away while you    • PREMARIN should be used at the lowest effective dose
    are using PREMARIN. Vaginal bleeding after menopause           and for the shortest duration consistent with your treatment
    may be a warning sign of cancer of the uterus (womb).          goals and risks.
    Your healthcare provider should check any unusual vaginal    • You and your healthcare provider should talk regularly about
    bleeding to find out the cause.                                whether you still need treatment with PREMARIN.
Using estrogens with progestins may increase your chances        What are the most common side effects with PREMARIN?
of getting:                                                      The most common (≥5%) side effects are:
• Heart attacks                                                  • Abdominal pain      • Depression
• Strokes
• Breast cancer                                                  • Asthenia            • Insomnia
• Blood clots                                                    • Pain                • Breast pain
These are not all the possible risks and side effects of         • Back pain           • Endometrial hyperplasia
PREMARIN. For more information, ask your healthcare              • Headache            • Leucorrhea
provider or pharmacist.                                          • Flatulence          • Vaginal hemorrhage
When should estrogens not be used?                               • Nausea              • Vaginitis
Estrogens, with or without progestins, should not be used        What is PREMARIN indicated for?
to prevent:
                                                                 PREMARIN is used after menopause to:
• Heart disease
• Heart attacks                                                  • Reduce moderate to severe hot flashes due to menopause
• Strokes                                                        • Treat menopausal changes in and around the vagina
• Dementia (decline in brain function)                           • Help reduce the chances of getting osteoporosis (thin,
  – Using estrogens, with or without progestins, may increase     weak bones)
    your chances of getting dementia, based on a study of        What if I only have symptoms of vaginal changes due
    women 65 years of age or older.                              to menopause?
PREMARIN should not be used if you:                              Consider topical therapies first.
• Have unusual vaginal bleeding                                  What if I want to use PREMARIN only to prevent
• Have or had cancer                                             osteoporosis due to menopause?
• Had a stroke or heart attack                                   Talk with your healthcare professional about whether a
• Have or had blood clots                                        different treatment or medicine without estrogens might be
• Have or had liver problems                                     better for you.
• Have a bleeding disorder
• Are allergic to any of its ingredients
• Think you may be pregnant
In general, the addition of a progestin is recommended for
women with a uterus to reduce the chances of getting cancer
of the uterus.

Please see accompanying Full Prescribing Information, including Boxed Warning.                                                   6
What was the Women’s Health Initiative
                                (WHI) estrogen alone study?12,15

 Who:      The US National Institutes of Health (NIH)
 What:	Conducted a large study, including nearly 11,000 healthy, postmenopausal women without a
        uterus between the ages of 50 and 79
 Why: 	To determine the effect of estrogen therapy [0.625 mg of PREMARIN® (conjugated estrogens tablets,
         USP)] in the prevention of coronary heart disease and on the rate of invasive breast cancer
 How: 	Participants took either PREMARIN or a placebo and their results were measured every year
        for nearly 7 years, until March 2004, when the NIH stopped the trial because an increased risk
        of stroke was observed

      NOTE: The WHI study had two arms, the estrogen alone arm (for women without a uterus) and the estrogen plus progestin arm (for women
      with a uterus). The study results were different for each arm, but this information pertains to the estrogen alone arm only.

            The WHI study assessed the effects of estrogen on chronic disease incidence rates12,15

             Primary outcome               Primary adverse outcome                     The WHI also reported outcomes on

                                                                                             All Stroke                Hip Fracture
                   Coronary                            Invasive
                   Heart Disease                       Breast Cancer
                                                                                             Blood Clots
                                                                                             (DVT or PE)               Colorectal Cancer

      Coronary Heart Disease (CHD): includes nonfatal myocardial infarctions (MIs), silent MIs, and CHD deaths.
      Blood Clots: includes deep vein thrombosis (DVT) or pulmonary embolism (PE).
      All Stroke: 3 categories include hemorrhagic, ischemic, and other stroke.16

           • It is important to understand that the WHI was not a study to measure how well PREMARIN
             relieved menopausal symptoms15
           • Lower doses of PREMARIN (0.3 mg and 0.45 mg) were not studied in the WHI15

Do not use estrogens with or without progestins to prevent heart disease, heart attacks, strokes or dementia
(decline in brain function). Using estrogens, with or without progestins, may increase your chance of getting dementia,
based on a study of women 65 years of age or older.
Using estrogen-alone may increase your chances of getting strokes or blood clots. Using estrogens with progestins
may increase your chances of getting heart attacks, strokes, breast cancer,
or blood clots.
Estrogen should be used at the lowest dose possible, only for as long as
needed. You and your healthcare provider should talk regularly about whether
you still need treatment.

Please see accompanying Full Prescribing Information, including Boxed Warning.                                                               7
Putting the WHI estrogen alone results into perspective

            The WHI showed there was no benefit in using estrogens for the prevention of
            coronary heart disease.12,17
            The following outcomes were observed in the WHI15-20

                                        Approximate difference in number of annual events with
                                       PREMARIN per 1000 patient years, compared with placebo
                                                    Primary Outcome
                                                    Coronary                             No difference17
                                                    Heart Disease

                                                    Primary Adverse Outcome
                                                    Invasive                            No difference18
                                                    Breast Cancer

                                                    Blood Clots
                                                    (DVT or PE)                            1 more19*

                                                    All Stroke                             2 more16†

                                                    Hip Fracture                            1 fewer 20

                                                    Colorectal Cancer                    No difference15

                                     WHI = Women’s Health Initiative

            Coronary Heart Disease (CHD): includes nonfatal myocardial infarctions (MIs), silent MIs, and CHD deaths.
            Blood Clots: includes deep vein thrombosis (DVT) or pulmonary embolism (PE).
            *DVT = Absolute risk per 1000 patient years was 2.3 events with PREMARIN vs 1.5 events with placebo (HR=1.47 [1.06-2.06]).
             PE = no difference.19
            All Stroke: 3 categories include hemorrhagic, ischemic, and other stroke.16
             †All Stroke = Absolute risk per 1000 patient years was 4.5 events with PREMARIN vs 3.3 events with placebo (HR=1.37 [1.09-1.73]).16

             Ischemic Stroke: Absolute risk per 1000 patient years was 3.8 events with PREMARIN vs 2.5 events with placebo (HR=1.55 [1.19-2.01]).16

            •	Lower PREMARIN doses (0.3 mg and 0.45 mg) were not studied15
            •	WHI was not a study to measure how well PREMARIN relieved menopausal symptoms15

Do not use estrogens with or without progestins to prevent heart disease, heart attacks, strokes or dementia (decline in
brain function). Using estrogens, with or without progestins, may increase your chance of getting dementia, based on a
study of women 65 years of age or older.
Estrogen should be used at the lowest dose possible, only for as long as needed. You and your healthcare provider should
talk regularly about whether you still need treatment.
PREMARIN should not be used if you have unusual vaginal bleeding, have or had
cancer, had a stroke or heart attack, have or had blood clots or liver problems,
have a bleeding disorder, are allergic to any of its ingredients, or think you may
be pregnant. In general, the addition of a progestin is recommended for women
with a uterus to reduce the chance of getting cancer of the uterus.

Please see accompanying Full Prescribing Information, including Boxed Warning.                                                                        8
Putting the WHI estrogen alone results into perspective (cont’d)

    In WHI, risks differed based on patient age15,17,19
                                 Based on secondary analysis prespecified in the WHI study protocol…
                                  Approximate difference in number of annual events with PREMARIN
                                    per 1000 patient years, compared with placebo (by age groups)

                                              50- to 59-year-olds                   60- to 69-year-olds                    70- to 79-year-olds

               Primary Outcome
               Coronary                        No difference                         No difference                            1 more*
               Heart Disease17

               Primary Adverse Outcome
               Invasive                        No difference                         No difference                         No difference
               Breast Cancer15

               Blood Clots
               (DVT or PE)19                   No difference                           2 more†                               2 more‡

               All Stroke17                    No difference                           2 more§                                2 more||

    CHD: includes nonfatal MIs, silent MIs, and CHD deaths.
    *CHD (70-79) = Absolute risk per 1000 patient years was 9.8 events with PREMARIN vs 8.8 events with placebo (HR=1.13 [0.82-1.54]).17
    Blood Clots: includes deep vein thrombosis (DVT) or pulmonary embolism (PE).
    †DVT (60-69) = Absolute risk per 1000 patient years was 2.3 events with PREMARIN vs 1.7 events with placebo (HR=3.02 [1.51-6.06]).

      PE (60-69) = Absolute risk per 1000 patient years was 1.7 events with PREMARIN vs 1.0 events with placebo (HR = 2.80 [1.28-6.16]).19
    ‡ DVT (70-79) = Absolute risk per 1000 patient years was 3.4 events with PREMARIN vs 2.2 events with placebo (HR = 4.54 [2.22-9.31]).

      PE (70-79) = No difference.19
    All Stroke: 3 categories include hemorrhagic, ischemic, and other stroke.16
     § All Stroke (60-69) = Absolute risk per 1000 patient years was 5.1 events with PREMARIN vs 3.1 events with placebo (HR=1.62 [1.15-2.27]).17
     II All Stroke (70-79) = Absolute risk per 1000 patient years was 7.6 events with PREMARIN vs 5.9 events with placebo (HR=1.21 [0.84-1.75]).17

               In the US, the average age that women begin menopause is 51 years,
                     and the average age of enrollment in WHI was 63 years18,21

Estrogens increase the risk of gallbladder disease. Discontinue estrogen if loss of vision,
pancreatitis, or liver problems occur. If you take thyroid medication, consult your healthcare
provider, as use of estrogens may change the amount needed.
The most common (≥5%) side effects are abdominal pain, asthenia,
pain, back pain, headache, flatulence, nausea, depression, insomnia,
breast pain, endometrial hyperplasia, leucorrhea, vaginal hemorrhage,
and vaginitis.

Please see accompanying Full Prescribing Information, including Boxed Warning.                                                                       9
PREMARIN® (conjugated estrogens tablets, USP)
                     can help treat these menopausal symptoms

              What is PREMARIN?
              PREMARIN is a prescription medicine that contains a blend of estrogen hormones.
              What does PREMARIN do?
              PREMARIN treats the following symptoms of menopause:

                                                                                                         Relieves
                                                                                                         moderate to
                                                                                                         severe vulvar
                                                                                                         and vaginal
  Reduces                                                                                                atrophy due
  moderate                                                                                               to menopause
  to severe hot                                    Prevents                                              (dryness, itching,
  flashes due to                                   postmenopausal                                        burning, painful
  menopause                                        bone loss                                             intercourse)
                                                                      In women with a uterus, PREMARIN
                                                                      should be taken with a progestin

  If you are using or are considering using PREMARIN only to treat vaginal symptoms due to menopause,
  consider topical therapies first. If you are using or are considering using PREMARIN only to prevent
  osteoporosis due to menopause, talk with your healthcare professional about whether a different
  treatment or medicine without estrogens might be better for you. PREMARIN should be used at the
  lowest effective dose and for the shortest duration consistent with your treatment goals and risks.
  Balancing the benefits of treatment with the risks seen in WHI estrogen
  alone substudy
  Compared with placebo during a 1-year period, for every 1000 hysterectomized women taking PREMARIN,
  there were:
  •N
    o increases in invasive breast cancer,                         • 1 more blood clot (DVT or PE)19
   colorectal cancer, or coronary heart disease15,17,18             • 1 fewer hip fracture20
  • 2 more strokes16

    PREMARIN has proven efficacy in treating moderate to severe hot flashes and
 vaginal changes due to menopause, while also preventing postmenopausal bone loss

Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal
bleeding right away while you are using PREMARIN. 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.
Using estrogen-alone may increase your chances of getting strokes or blood clots.
Using estrogens with progestins may increase your chances of getting heart attacks,
strokes, breast cancer, or blood clots.

Please see accompanying Full Prescribing Information, including Boxed Warning.                                          10
References: 1. Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L. A longitudinal study of the perimenopausal transition: altered profiles of steroid and
pituitary hormones, SHBG, and bone mineral density. Maturitas. 2008;61(1-2):67-77. 2. Gustafsson JA. Estrogen receptor—a new dimension in estrogen mechanism of action.
J Endocrinol. 1999;163(3):379-383. 3. Mhyre AJ, Dorsa DM. Estrogen activates rapid signaling in the brain: role of estrogen receptor and estrogen receptor beta in neurons
and glia. Neuroscience. 2006;138(3):851-858. 4. Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL. Pathophysiology and treatment of hot flashes. Mayo Clin Proc. 2002;77(11):
1207-1218. 5. Nilsson S, Mäkelä S, Treuter E, et al. Mechanisms of estrogen action. Physiol Rev. 2001;81(4):1535-1565. 6. Simon JA. Identifying and treating sexual dysfunction
in postmenopausal women: the role of estrogen. J Womens Health. 2011;20(10):1453-1465. 7. National Institutes of Health. National Institutes of Health state-of-the-science
conference statement: management of menopause-related symptoms. Ann Intern Med. 2005;142(12 part 1):1003-1013. 8. Data on file. Pfizer Inc, New York, NY. 9. Hedlund LR,
Gallagher JC. The effect of age and menopause on bone mineral density of the proximal femur. J Bone Miner Res. 1989;4(4):639-642. 10. Looker AC, Melton LJ, Harris TB,
Borrud LG, Shepherd JA. Prevalence and trends in low femur bone density among older US adults: NHANES 2005-2006 compared with NHANES III. J Bone Min Res. 2010;
25(I):64-71. 11. The North American Menopause Society (NAMS). The 2012 hormone therapy position statement of The North American Menopause Society. Menopause.
2012;19(3):257-271. 12. PREMARIN [prescribing information]. Pfizer Inc, February 2012. 13. Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH. Relief of vasomotor
symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;75(6):1065-1079. 14. Stefanick ML.
Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration. Am J Med. 2005;118(12B):
64S-73S. 15. Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with
hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712. 16. Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. Effects of
conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation. 2006;113:2425-2434. 17. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal
hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297(13):1465-1477. 18. Stefanick ML, Anderson GL, Margolis KL, et al;
Women’s Health Initiative Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy.
JAMA. 2006;295(14):1647-1657. 19. Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med.
2006;166(7):722-780. 20. Jackson RD, Wactawski-Wende J, LaCroix AZ, et al; Women’s Health Initiative Investigators. Effects of conjugated equine estrogen on risk of fractures
and BMD in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized trial. J Bone Miner Res. 2006;21(6):817-828. 21. The North
American Menopause Society (NAMS). Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society.
Menopause. 2010;17(2):242-255.

PRM649912-01                          © 2014 Pfizer Inc.                      All rights reserved.                    July 2014
HIGHLIGHTS OF PRESCRIBING INFORMATION                                                                          ------------------------------------- DOSAGE FORMS AND STRENGTHS -------------------------------------
These highlights do not include all the information needed to use                                              Tablets: 0.3, 0.45, 0.625, 0.9, and 1.25 mg (3)
PREMARIN safely and effectively. See full prescribing information for PREMARIN.                                --------------------------------------------- CONTRAINDICATIONS ---------------------------------------------
PREMARIN® (conjugated estrogens) Tablets, USP for oral use                                                     • Undiagnosed abnormal genital bleeding (4)
Initial U.S. Approval: 1942                                                                                    • Known, suspected, or history of breast cancer except in appropriately selected patients being
                                                                                                                  treated for metastatic diseases (4, 5.2)
     WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER                                      • Known or suspected estrogen-dependent neoplasia (4, 5.2)
                                   AND PROBABLE DEMENTIA                                                       • Active DVT, PE, or a history of these conditions (4, 5.1)
                 See full prescribing information for complete boxed warning.                                  • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these
 Estrogen-Alone Therapy                                                                                           conditions (4, 5.1)
 • There is an increased risk of endometrial cancer in a woman with a uterus who uses                          • Known anaphylactic reaction or angioedema with PREMARIN (5.7)
   unopposed estrogens (5.2)                                                                                   • Known liver impairment or disease (4, 5.12)
 • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or                   • Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
   dementia (5.1, 5.3)                                                                                            (4)
                                                                                                               • Known or suspected pregnancy (4, 8.1)
 • Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke
   and deep vein thrombosis (DVT) (5.1)                                                                        --------------------------------------- WARNINGS AND PRECAUTIONS ---------------------------------------
 • The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased                    • Estrogens increase the risk of gallbladder disease (5.4)
   risk of probable dementia in postmenopausal women 65 years of age and older (5.3)                           • Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or
                                                                                                                  cholestatic jaundice occurs (5.5, 5.6, 5.11, 5.12)
 Estrogen Plus Progestin Therapy
                                                                                                               • Monitor thyroid function in women on thyroid replacement therapy (5.13, 5.18)
 • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular
   disease or dementia (5.1, 5.3)                                                                              --------------------------------------------- ADVERSE REACTIONS --------------------------------------------
                                                                                                               Most common adverse reactions (≥ 5 percent) are: abdominal pain, asthenia, pain, back pain, head-
 • The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary
                                                                                                               ache, flatulence, nausea, depression, insomnia, breast pain, endometrial hyperplasia, leucorrhea,
   embolism (PE), and myocardial infarction (MI) (5.1)
                                                                                                               vaginal hemorrhage, and vaginitis. (6.1)
 • The WHI estrogen plus progestin substudy reported increased risks of invasive breast
   cancer (5.2)                                                                                                To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at
 • The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of                      1-800-FDA-1088 or www.fda.gov/medwatch
   probable dementia in postmenopausal women 65 years of age and older (5.3)                                   --------------------------------------------- DRUG INTERACTIONS ---------------------------------------------
                                                                                                               • Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism (7.1)
------------------------------------------- INDICATIONS AND USAGE ------------------------------------------
PREMARIN is a mixture of estrogens indicated for:                                                              --------------------------------------- USE IN SPECIFIC POPULATIONS --------------------------------------
• Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause (1.1)                                    • Nursing Mothers: Estrogen administration has been shown to decrease the quantity and quality of
• Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause (1.2)                               breast milk (8.3)
• Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure (1.3)                • Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported
• Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with                   in the Women’s Health Initiative Memory ancillary studies of the Women’s Health Initiative (5.3,
   Metastatic Disease (1.4)                                                                                       8.5)
• Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only) (1.5)               See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
• Prevention of Postmenopausal Osteoporosis (1.6)
                                                                                                                                                                                                        Revised: 12/2014
-------------------------------------- DOSAGE AND ADMINISTRATION ---------------------------------------
• Daily administration of 0.3, 0.45, 0.625, 0.9, and 1.25 mg (2.1, 2.2, 2.3, 2.5, 2.6)
• Cyclic administration of 0.3, 0.625, and 1.25 mg (2.1, 2.2, 2.3)

FULL PRESCRIBING INFORMATION: CONTENTS *                                                                          5.17 Exacerbation of Other Conditions
                                                                                                                  5.18 Laboratory Tests
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER                                              5.19 Drug-Laboratory Test Interactions
AND PROBABLE DEMENTIA                                                                                          6 ADVERSE REACTIONS
1 INDICATIONS AND USAGE                                                                                           6.1 Clinical Study Experience
  1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause                                         6.2 Postmarketing Experience
  1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause                  7 DRUG INTERACTIONS
  1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure                     7.1 Metabolic Interactions
  1.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men                 8 USE IN SPECIFIC POPULATIONS
			    with Metastatic Disease                                                                                    8.1 Pregnancy
  1.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only)                    8.3 Nursing Mothers
  1.6 Prevention of Postmenopausal Osteoporosis                                                                   8.4 Pediatric Use
2 DOSAGE AND ADMINISTRATION                                                                                       8.5 Geriatric Use
  2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause                                         8.6 Renal Impairment
  2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause                     8.7 Hepatic Impairment
  2.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure                 10 OVERDOSAGE
  2.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men                 11 DESCRIPTION
			    with Metastatic Disease                                                                                 12 CLINICAL PHARMACOLOGY
  2.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only)                    12.1 Mechanism of Action
  2.6 Prevention of Postmenopausal Osteoporosis                                                                   12.2 Pharmacodynamics
3 DOSAGE FORMS AND STRENGTHS                                                                                      12.3 Pharmacokinetics
4 CONTRAINDICATIONS                                                                                            13 NONCLINICAL TOXICOLOGY
5 WARNINGS AND PRECAUTIONS                                                                                        13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  5.1 Cardiovascular Disorders                                                                                 14 CLINICAL STUDIES
  5.2 Malignant Neoplasms                                                                                         14.1 Effects on Vasomotor Symptoms
  5.3 Probable Dementia                                                                                           14.2 Effects on Vulvar and Vaginal Atrophy
  5.4 Gallbladder Disease                                                                                         14.3 Effects on Bone Mineral Density
  5.5 Hypercalcemia                                                                                               14.4 Effects on Female Hypogonadism
  5.6 Visual Abnormalities                                                                                        14.5 Women’s Health Initiative Studies
  5.7 Anaphylactic Reaction and Angioedema                                                                        14.6 Women’s Health Initiative Memory Study
  5.8 Addition of a Progestin When a Woman Has Not Had a Hysterectomy                                          15 REFERENCES
  5.9 Elevated Blood Pressure                                                                                  16 HOW SUPPLIED/STORAGE AND HANDLING
  5.10 Hypertriglyceridemia                                                                                       16.1 How Supplied
  5.11 Hepatic Impairment and/or Past History of Cholestatic Jaundice                                             16.2 Storage and Handling
  5.12 Hypothyroidism                                                                                          17 PATIENT COUNSELING INFORMATION
  5.13 Fluid Retention                                                                                            17.1 Vaginal Bleeding
  5.14 Hypocalcemia                                                                                               17.2 Possible Serious Adverse Reactions With Estrogens
  5.15 Hereditary Angioedema                                                                                      17.3 Possible Less Serious But Common Adverse Reactions With Estrogens
  5.16 Exacerbation of Endometriosis                                                                           * Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION                                                                               woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate
                                                                                                           to determine if treatment is still necessary.
      WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER                                 PREMARIN may be taken without regard to meals.
                                    AND PROBABLE DEMENTIA                                                  2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause
 Estrogen-Alone Therapy                                                                                    Patients should be treated with the lowest effective dose. Generally, women should be started at
                                        Endometrial Cancer                                                 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual
 There is an increased risk of endometrial cancer in a woman with a uterus who uses                        patient response. This dose should be periodically reassessed by the healthcare provider.
 unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the                  PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical
 risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate                 regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically
 diagnostic measures, including directed or random endometrial sampling when indicated,                    appropriate on an individual basis.
 should be undertaken to rule out malignancy in postmenopausal women with undiagnosed
 persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].                   2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to
                                                                                                           Menopause
                         Cardiovascular Disorders and Probable Dementia
                                                                                                           Patients should be treated with the lowest effective dose. Generally, women should be started at
 Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or                 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual
 dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)].                    patient response. This dose should be periodically reassessed by the healthcare provider.
 The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of                   PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical
 stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age)                     regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically
 during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone,                 appropriate on an individual basis.
 relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)].
                                                                                                           2.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian
 The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased                  Failure
 risk of developing probable dementia in postmenopausal women 65 years of age or older
                                                                                                           PREMARIN therapy should be initiated and maintained with the lowest effective dose to achieve
 during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown
                                                                                                           clinical goals. Female hypogonadism: 0.3 mg or 0.625 mg daily, administered cyclically (e.g.,
 whether this finding applies to younger postmenopausal women [see Warnings and Precautions
                                                                                                           three weeks on and one week off). Doses are adjusted depending on the severity of symptoms
 (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].
                                                                                                           and responsiveness of the endometrium [see Clinical Studies (14.4)].
 In the absence of comparable data, these risks should be assumed to be similar for other                  Female castration or primary ovarian failure: 1.25 mg daily, cyclically. Adjust dosage, upward or
 doses of CE and other dosage forms of estrogens.                                                          downward, according to severity of symptoms and response of the patient. For maintenance,
 Estrogens with or without progestins should be prescribed at the lowest effective doses and               adjust dosage to lowest level that will provide effective control.
 for the shortest duration consistent with treatment goals and risks for the individual woman.             2.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women
 Estrogen Plus Progestin Therapy                                                                           and Men with Metastatic Disease
                         Cardiovascular Disorders and Probable Dementia                                    Suggested dosage is 10 mg three times daily, for a period of at least three months.
 Estrogen plus progestin therapy should not be used for the prevention of cardiovascular                   2.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation
 disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5,                 Only)
 14.6)].                                                                                                   1.25 mg to 2 x 1.25 mg three times daily. The effectiveness of therapy can be judged by
 The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism              phosphatase determinations as well as by symptomatic improvement of the patient.
 (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age)               2.6 Prevention of Postmenopausal Osteoporosis
 during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone
                                                                                                           PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical
 acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical
                                                                                                           regimens (regimens such as 25 days on drug followed by 5 days off drug), as is medically
 Studies (14.5)].
                                                                                                           appropriate on an individual basis.
 The WHIMS estrogen plus progestin ancillary study of the WHI, reported an increased risk                  Patients should be treated with the lowest effective dose. Generally, women should be started
 of developing probable dementia in postmenopausal women 65 years of age or older during                   at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the
 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo.            individual clinical and bone mineral density responses. This dose should be periodically
 It is unknown whether this finding applies to younger postmenopausal women [see Warnings                  reassessed by the healthcare provider.
 and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].
                                                                                                      3 DOSAGE FORMS AND STRENGTHS
                                           Breast Cancer
                                                                                                      PREMARIN (conjugated estrogens tablets, USP)
 The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive
 breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.5)].                          Tablet Strength                  Tablet Shape/Color                     Imprint
                                                                                                           0.3 mg                           oval/green                             PREMARIN
 In the absence of comparable data, these risks should be assumed to be similar for other
                                                                                                      			                                                                          0.3
 doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins.
                                                                                                           0.45 mg                          oval/blue                              PREMARIN
 Estrogens with or without progestins should be prescribed at the lowest effective doses and          			                                                                          0.45
 for the shortest duration consistent with treatment goals and risks for the individual woman.             0.625 mg                         oval/maroon                            PREMARIN
                                                                                                      			                                                                          0.625
1 INDICATIONS AND USAGE                                                                                    0.9 mg                           oval/white                             PREMARIN
     1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause                          			                                                                          0.9
     1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to                     1.25 mg                          oval/yellow                            PREMARIN
                                                                                                      			                                                                          1.25
		Menopause.
     Limitation of Use                                                                                4 CONTRAINDICATIONS
     When prescribing solely for the treatment of moderate to severe symptoms of vulvar and               PREMARIN therapy is contraindicated in individuals with any of the following conditions:
     vaginal atrophy due to menopause, topical vaginal products should be considered.                     • Undiagnosed abnormal genital bleeding
     1.3 Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian                  • Known, suspected, or history of breast cancer except in appropriately selected patients
		Failure                                                                                                   being treated for metastatic disease
                                                                                                          • Known or suspected estrogen-dependent neoplasia
     1.4 Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and
                                                                                                          • Active DVT, PE, or a history of these conditions
		 Men with Metastatic Disease
                                                                                                          • Active arterial thromboembolic disease (for example stroke and MI), or a history of these
     1.5 Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation                 conditions
		Only)                                                                                                   • Known anaphylactic reaction or angioedema with Premarin
     1.6 Prevention of Postmenopausal Osteoporosis.                                                       • Known liver impairment or disease
     Limitation of Use                                                                                    • Known protein C, protein S or antithrombin deficiency, or other known thrombophilic
                                                                                                            disorders.
     When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should
                                                                                                          • Known or suspected pregnancy
     only be considered for women at significant risk of osteoporosis and non-estrogen medication
     should be carefully considered                                                                   5 WARNINGS AND PRECAUTIONS
                                                                                                      5.1 Cardiovascular Disorders
2 DOSAGE AND ADMINISTRATION
                                                                                                           An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An
    Generally, when estrogen therapy is prescribed for a postmenopausal woman with a uterus, a
                                                                                                           increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy.
    progestin should be considered to reduce the risk of endometrial cancer [see Boxed Warning].
                                                                                                           Should any of these events occur or be suspected, estrogen with or without progestin therapy
    A woman without a uterus does not need progestin. In some cases, however, hysterectomized              should be discontinued immediately.
    women with a history of endometriosis may need a progestin [see Warnings and Precautions
                                                                                                           Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco
    (5.2, 5.16)].
                                                                                                           use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example,
    Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective         personal or family history of VTE, obesity, and systemic lupus erythematosus) should be managed
    dose and for the shortest duration consistent with treatment goals and risks for the individual        appropriately.
Stroke                                                                                                 The most important randomized clinical trial providing information about breast cancer in
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was           estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg).
reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to                After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased
women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The               risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use
increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.5)]. Should        of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women.
a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.             The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for               cases per 10,000 women-years, for CE plus MPA compared with placebo.6 Among women
those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per             who reported prior use of hormone therapy, the relative risk of invasive breast cancer was
10,000 women-years).1                                                                                  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
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke
                                                                                                       relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per
was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg)
                                                                                                       10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive
compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-
                                                                                                       breast cancers were larger, were more likely to be node positive, and were diagnosed at a more
years) [see Clinical Studies (14.5)]. The increase in risk was demonstrated after the first year
                                                                                                       advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo
and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should
                                                                                                       group. Metastatic disease was rare, with no apparent difference between the two groups. Other
be discontinued immediately.
                                                                                                       prognostic factors, such as histologic subtype, grade and hormone receptor status did not
Coronary Heart Disease                                                                                 differ between the groups [see Clinical Studies (14.5)].
In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events           Consistent with the WHI clinical trial, observational studies have also reported an increased
(defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-            risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for
alone compared to placebo2 [see Clinical Studies (14.5)].                                              estrogen-alone therapy, after several years of use. The risk increased with duration of use, and
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant               appeared to return to baseline over about 5 years after stopping treatment (only the observa-
reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than              tional studies have substantial data on risk after stopping). Observational studies also suggest
10 years since menopause (8 versus 16 per 10,000 women-years).1                                        that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased       progestin therapy as compared to estrogen-alone therapy. However, these studies have not
risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared          found significant variation in the risk of breast cancer among different estrogen plus progestin
to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative             combinations, doses, or routes of administration.
risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in           The use of estrogen-alone and estrogen plus progestin has been reported to result in an
years 2 through 5 [see Clinical Studies (14.5)].                                                       increase in abnormal mammograms, requiring further evaluation.
In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of                All women should receive yearly breast examinations by a healthcare provider and perform
age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and      monthly breast self-examinations. In addition, mammography examinations should be scheduled
Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA               based on patient age, risk factors, and prior mammogram results.
(2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years,             Ovarian Cancer
treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal
                                                                                                       The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk
women with established CHD. There were more CHD events in the CE plus MPA-treated group
                                                                                                       of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for
than in the placebo group in year 1, but not during the subsequent years. Two thousand, three
                                                                                                       CE plus MPA versus placebo was 1.58 (95 percent CI 0.77-3.24). The absolute risk for CE plus
hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in
                                                                                                       MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic
an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional
                                                                                                       studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or
2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women
                                                                                                       more years, has been associated with an increased risk of ovarian cancer. However, the duration
in the CE (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and
                                                                                                       of exposure associated with increased risk is not consistent across all epidemiologic studies,
overall.
                                                                                                       and some report no association.
Venous Thromboembolism (VTE)
                                                                                                       5.3 Probable Dementia
In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women
                                                                                                       In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized
receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-
                                                                                                       women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.
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           After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women
[see Clinical Studies (14.5)]. Should a VTE occur or be suspected, estrogen-alone therapy              in the placebo group were diagnosed with probable dementia. The relative risk of probable
should be discontinued immediately.                                                                    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
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE
                                                                                                       women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].
was reported in women receiving daily 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 the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 post-
in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000              menopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA
women-years) were also demonstrated. The increase in VTE risk was demonstrated during the              (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group
first year and persisted4 [see Clinical Studies (14.5)]. Should a VTE occur or be suspected,           and 21 women in the placebo group were diagnosed with probable dementia. The relative risk
estrogen plus progestin therapy should be discontinued immediately.                                    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
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the
                                                                                                       per 10,000 women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].
type associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.                                                                                        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
5.2 Malignant Neoplasms                                                                                risk for probable dementia was 1.76 (95 percent CI 1.19-2.60). Since both ancillary studies
Endometrial Cancer                                                                                     were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen           younger postmenopausal women8 [see Use in Specific Populations (8.5), and Clinical Studies
therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed                 (14.6)].
estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on              5.4 Gallbladder Disease
duration of treatment and on estrogen dose. Most studies show no significant increased risk            A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal
associated with use of estrogens for less than 1 year. The greatest risk appears associated with       women receiving estrogens has been reported.
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.               5.5 Hypercalcemia
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is          Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and
important. Adequate diagnostic measures, including directed or random endometrial sampling             bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate
when indicated, should be undertaken to rule out malignancy in postmenopausal women with               measures taken to reduce the serum calcium level.
undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the           5.6 Visual Abnormalities
use of natural estrogens results in a different endometrial risk profile than synthetic estrogens      Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue
of equivalent estrogen dose. Adding a progestin to postmenopausal estrogen therapy has been            medication pending examination if there is sudden partial or complete loss of vision, or a
shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial           sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal
cancer.                                                                                                vascular lesions, estrogens should be permanently discontinued.
Breast Cancer                                                                                          5.7 Anaphylactic Reaction and Angioedema
The most important randomized clinical trial providing information about breast cancer in              Cases of anaphylaxis, which developed within minutes to hours after taking PREMARIN and
estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-            require emergency medical management, have been reported in the postmarketing setting. Skin
alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not             (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise)
associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]5 [see Clinical   or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.
Studies (14.5)].                                                                                       Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention
                                                                                                       has occurred postmarketing in patients taking PREMARIN. If angioedema involves the tongue,
glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction            of another drug and may not reflect the rates observed in clinical practice.
     with or without angioedema after treatment with PREMARIN should not receive PREMARIN again.                During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus
     5.8 Addition of a Progestin When a Woman Has Not Had a Hysterectomy                                        between 40 and 65 years of age (88 percent Caucasian), 1,012 women were treated with
     Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration           conjugated estrogens, and 332 were treated with placebo.
     or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial           Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥ 1 percent
     hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may                 in any treatment group.
     be a precursor to endometrial cancer.                                                                       Table 1: TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY ≥ 1 PERCENT
     There are, however, possible risks that may be associated with the use of progestins with
                                                                                                            			                               PREMARIN     PREMARIN    PREMARIN      Placebo
     estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.       						                                                                   (n=332)
     5.9 Elevated Blood Pressure                                                                            			                                0.625 mg     0.45 mg      0.3 mg
     In a small number of case reports, substantial increases in blood pressure have been attributed        			                                 (n=348)     (n=338)      (n=326)
     to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial,     Body as a whole
     a generalized effect of estrogen therapy on blood pressure was not seen.                               		 Abdominal pain                    38 (11)    28 (8)       30 (9)       21 (6)
     5.10 Hypertriglyceridemia                                                                              		 Asthenia                          16 (5)     8 (2)        14 (4)       3 (1)
     In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with               		 Back pain                         18 (5)     11 (3)       13 (4)       4 (1)
     elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment      		 Chest pain                        2 (1)      3 (1)         4 (1)       2 (1)
     if pancreatitis occurs.                                                                                		 Generalized edema                 7 (2)      6 (2)        4 (1)        8 (2)
                                                                                                            		 Headache                          45 (13)    47 (14)      44 (13)      46 (14)
     5.11 Hepatic Impairment and/or Past History of Cholestatic Jaundice
                                                                                                            		 Moniliasis                        5 (1)      4 (1)        4 (1)        1 (0)
     Estrogens may be poorly metabolized in patients with impaired liver function. For women with           		 Pain                              17 (5)     10 (3)       12 (4)       14 (4)
     a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution         		 Pelvic pain                       10 (3)     9 (3)        8 (2)        4 (1)
     should be exercised, and in the case of recurrence, medication should be discontinued.                  Cardiovascular system
     5.12 Hypothyroidism                                                                                    		 Hypertension                      4 (1)      4 (1)        7 (2)        5 (2)
     Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women                		 Migraine                          7 (2)      1 (0)        0            3 (1)
     with normal thyroid function can compensate for the increased TBG by making more thyroid               		 Palpitation                       3 (1)      3 (1)        3 (1)        4 (1)
     hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women               		 Vasodilatation                    2 (1)      2 (1)        3 (1)        5 (2)
     dependent on thyroid hormone replacement therapy who are also receiving estrogens may                   Digestive system
     require increased doses of their thyroid replacement therapy. These women should have their            		 Constipation                      7 (2)      6 (2)        4 (1)        3 (1)
     thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable     		 Diarrhea                          4 (1)      5 (1)        5 (2)        8 (2)
     range.                                                                                                 		 Dyspepsia                         7 (2)      5 (1)        6 (2)        14 (4)
     5.13 Fluid Retention                                                                                   		 Eructation                        1 (0)      1 (0)        4 (1)        1 (0)
     Estrogens may cause some degree of fluid retention. Women with conditions that might be                		 Flatulence                        22 (6)     18 (5)       13 (4)       8 (2)
     influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when      		 Increased appetite                4 (1)      1 (0)        1 (0)        2 (1)
     estrogen alone is prescribed.                                                                          		 Nausea                            16 (5)     10 (3)       15 (5)       16 (5)
     5.14 Hypocalcemia                                                                                       Metabolic and nutritional
                                                                                                            		 Hyperlipidemia                    2 (1)      4 (1)        3 (1)        2 (1)
     Estrogen therapy should be used with caution in individuals with hypoparathyroidism as
                                                                                                            		 Peripheral edema                  5 (1)      2 (1)        4 (1)        3 (1)
     estrogen-induced hypocalcemia may occur.
                                                                                                            		 Weight gain                       11 (3)     10 (3)       8 (2)        14 (4)
     5.15 Hereditary Angioedema                                                                              Musculoskeletal system
     Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary                     		 Arthralgia                        6 (2)      3 (1)        2 (1)        5 (2)
     angioedema.                                                                                            		 Leg cramps                        10 (3)     5 (1)        9 (3)        4 (1)
     5.16 Exacerbation of Endometriosis                                                                     		 Myalgia                           2 (1)      1 (0)        4 (1)        1 (0)
     A few cases of malignant transformation of residual endometrial implants have been reported             Nervous system
     in women treated post-hysterectomy with estrogen-alone therapy. For women known to have                		 Anxiety                           6 (2)      4 (1)        2 (1)        4 (1)
     residual endometriosis post-hysterectomy, the addition of progestin should be considered.              		 Depression                        17 (5)     15 (4)       10 (3)       17 (5)
     5.17 Exacerbation of Other Conditions                                                                  		 Dizziness                         9 (3)      7 (2)        4 (1)        5 (2)
                                                                                                            		 Emotional lability                3 (1)      4 (1)        5 (2)        8 (2)
     Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
                                                                                                            		 Hypertonia                        1 (0)      1 (0)        5 (2)        3 (1)
     porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
                                                                                                            		 Insomnia                          16 (5)     10 (3)       13 (4)       14 (4)
     caution in women with these conditions.
                                                                                                            		 Nervousness                       9 (3)      12 (4)       2 (1)        6 (2)
     5.18 Laboratory Tests                                                                                   Skin and appendages
     Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful         		 Acne                              3 (1)      1 (0)        8 (2)        3 (1)
     in the management of moderate to severe vasomotor symptoms and moderate to severe                      		 Alopecia                          6 (2)      6 (2)        5 (2)        2 (1)
     symptoms of vulvar and vaginal atrophy.                                                                		 Hirsutism                         4 (1)      2 (1)        1 (0)        0
     Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism             		 Pruritus                          11 (3)     11 (3)       10 (3)       3 (1)
     due to hypogonadism, castration and primary ovarian failure.                                           		 Rash                              6 (2)      3 (1)        1 (0)        2 (1)
     5.19 Drug-Laboratory Test Interactions                                                                 		 Skin discoloration                4 (1)      2 (1)        0            1 (0)
     Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;              		 Sweating                          4 (1)      1 (0)        3 (1)        4 (1)
     increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity,     Urogenital system
     IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of             		 Breast disorder                   6 (2)      3 (1)        3 (1)        6 (2)
     antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of           		 Breast enlargement                3 (1)      4 (1)        7 (2)        3 (1)
     fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.                        		 Breast neoplasm                   4 (1)      4 (1)        7 (2)        7 (2)
     Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid         		 Breast pain                       37 (11)    39 (12)      24 (7)       26 (8)
     hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-            		 Cervix disorder                   8 (2)      4 (1)        5 (2)        0
     immunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the            		 Dysmenorrhea                      12 (3)     10 (3)       4 (1)        2 (1)
     elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement           		 Endometrial disorder              4 (1)      2 (1)        2 (1)        0
     therapy may require higher doses of thyroid hormone.                                                   		 Endometrial hyperplasia           16 (5)     8 (2)        1 (0)        0
     Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin          		 Leukorrhea                        17 (5)     17 (5)       12 (4)       6 (2)
     (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating cortico-            		 Metrorrhagia                      11 (3)     4 (1)        3 (1)        1 (0)
     steroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and         		 Urinary tract infection           1 (0)      2 (1)        1 (0)        4 (1)
     estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin             		 Uterine fibroids enlarged         6 (2)      1 (0)        2 (1)        2 (1)
     substrate, alpha-1-antitrypsin, ceruloplasmin).                                                        		 Uterine spasm                     11 (3)     5 (1)        3 (1)        2 (1)
     Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations,       		 Vaginal dryness                   1 (0)      2 (1)        1 (0)        6 (2)
     reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.       		 Vaginal hemorrhage                46 (13)    13 (4)       6 (2)        0
                                                                                                            		 Vaginal moniliasis                14 (4)     10 (3)       12 (4)       5 (2)
     Impaired glucose tolerance.
                                                                                                            		 Vaginitis                         18 (5)     7 (2)        9 (3)        1 (0)
6 ADVERSE REACTIONS
    The following serious adverse reactions are discussed elsewhere in labeling:                                6.2 Postmarketing Experience
    • Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)]                              The following additional adverse reactions have been identified during post-approval use of
    • Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]                                   PREMARIN. Because these reactions are reported voluntarily from a population of uncertain
    6.1 Clinical Study Experience                                                                               size, it is not possible always to reliably estimate their frequency or establish a causal relationship
    Because clinical trials are conducted under widely varying conditions, adverse reaction rates               to drug exposure.
    observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
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