1999
`
`www.pdr.net
`
`Bill?
`53
`
`EDITION '
`
`PEFEPENCE
`
`P VSICIANS
`_
` _ DESK
`
`AstraZeneca Exhibit 2127 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01910
`
`

`

`EDI?
`53
`
`EDITION
`
`
`
`i999
`
`
`
`
`
`PHVSICIANS’ #
`DESK
`PEFEPENCE
`
`
`
`
`
`Ronald Arky, MD, Charles S. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard Medical School
`. Vice President of Directory Services: Stephen B. Greenberg
`
`Senior Drug Information Specialist: Thomas Fleming, RPh
`Drug Information Specialist: Maria Deutsch, MS, RPh, CDE
`Editor, Special Projects: David W. Sifton
`'
`Vice President of Production: David A. Pitler
`Director of Print Purchasing: Marjorie A. Duffy
`Director of Operations: Carrie Williams
`Manager of Production: Kimberly H. Vivas
`Senior Production Coordinators: Amy B. Brooks, Dawn McCall
`Production Coordinator: Mary Ellen R. Breun
`
`Director of Product Management: David P. Reiss
`Senior Product Manager: Mark A. Friedman
`Associate Product Manager: Bill Shaughnessy
`Director of Sales: Dikran N. Barsamian
`National Sales Manager: Anthony Sorce
`National Account Manager: Don Bruccoleri
`Account Managers:
`Marion Gray, RPh
`Lawrence C. Keary
`Jeffrey F. Pfohl
`PDR Data Manager: Jeffrey D. Schaefer
`Christopher N. Schmidt
`Senior Format Editor: Gregory J. Westley
`Stephen M. Silverberg
`Index Editors: Johanna M. Mazur, Robert N. Woemer
`_
`Suzanne E. Yarrow, RN
`Art Associate: Joan K. Akerlind
`National Sales Manager, Trade Group: Bill Gaffney
`Senior Digital Imaging Coordinator: Shawn W. Cahill
`Director of Direct Marketing: Michael Bennett
`Digital Imaging Coordinator: Frank J. McElroy,
`Ill
`Direct Marketing Manager: Lorraine M. Loening
`Electronic Publishing Designer: Robert K. Grossman
`Promotion Manager: Donna R. Lynn
`Fulfillment Managers: Stephanie DeNardi. Kenneth Siebert
`Director, Professional Support Services: Mukesh Mehta, RPh
`
`
`.
`
`* Copyright © 1999 and published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights reserved. None of the content of this publication
`- . may be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, record-
`ing, or othenNise) without the prior written permission of the publisher. PHYSICIANS‘ DESK REFERENCE°, PDR", PDR For Nonprescription Drugs“, PDR For
`' Ophthalmology”, Pocket PDR", and The FDR” Family Guide to Prescription Drugs® are registered trademarks used herein under license. PDR Companion Guidem,
`PDR‘m for Herbal Medicines“, PDR" Medical DictionaryW, PDR" Nurse's HandbookTM, PDR" Nurse's DictionaryTM, The PDR‘a Family Guide Encyclopedia of Medical
`CareTM, PDR‘ Electronic Library”, and FOR” Drug Interactions, Side Effects, Indications, Contraindications SystemTM are trademarks used herein under license.
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDell; Vice President, Corporate
`Human Resources: Pamela M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Senior Vice President, Finance, and Chief Financial Officer: Thomas
`W. Ehardt; Vice President, Directory Services: Stephen B. Greenberg; Vice President, New Business Planning: Linda G. Hope; Executive Vice President, Healthcare Publishing
`and Communications: Thomas J. Kelly; Executive Vice President, Magazine Publishing: Lee A. Maniscalco; Vice President, Group Publisher: Terrence W. Meacock; Vice
`President, Production: David A. Pitler; Vice President, Group Publisher: Thomas C. Pizor; Vice President, Magazine Business Management: Eric Schlett; Senior Vice President,
`Operations: John R. Ware
`® Printed on recycled paper
`
`ISBN: 1-56363288—8
`
`AstraZeneca Exhibit 2127 p. 2
`
`

`

`
`
`CONTENTS
`
`
`
`
`
`
`
`'Manufacturers’ Index (White Pages) 1
`
`Section 1
`
`Lists all pharmaceutical manufacturers participating in PHYSICIANS' DESK REFERENCE.
`Includes addresses, phone numbers, and emergency contacts. Shows each manufacturer’s
`products and the page number of those described in PDR.
`
`
`
`Brand and Generic Name Index (Pink Pages) 101
`
`Section 2
`
`Gives the page number of each product by brand and generic name.
`
`
`
`Product Category Index (Biue Pages) 201
`
`Section 3
`
`Lists all fully described products by prescribing category. An overview of the headings
`appears on pages 201 and 202.
`
`
`
`Product Identification Guide (Gray Pages) 301
`
`Section 4
`
`Presents full-color, actual-size photos of tablets and capsules, plus pictures of a variety of other
`dosage forms and packages. Arranged alphabetically by manufacturer.
`
`
`
`Product Information (White Pages) 401
`
`Section 5
`
`Includes entries for over 2,200 pharmaceuticals. Listings are
`The main section of the book.
`arranged alphabetically by manufacturer.
`
`
`
`Diagnostic Product Information 3467
`
`Section 6
`
`Gives usage guidelines for a variety of common diagnostic agents. Arranged alphabetically by manufacturer.
`
`Drug Information Centers ......................................................................................................................... 220
`A national directory of institutions that answer queries regarding drugs. Arranged alphabetically by state and city.
`'
`
`Key to Controlled Substances Categories ....................................................... _........................................... 347
`Gives the definition of each category and the prescribing limitations that apply.
`Key to. FDA Use-in-Pregnancy Ratings .............................................................................................. L ....... 347
`Provides the exact interpretation of each risk/benefit rating.
`
`U.S. Food and Drug Administration Telephone Directory ............................................................................ 348
`Gives numbers of key reporting programs and information services.
`‘
`
`Poison Control Centers .......................................................................................................................... 3478
`A national directory arranged alphabetically by state and city.
`
`AstraZeneca Exhibit 2127 p. 3
`
`

`

`DURICEF® (cefadroxil monohydrate, USP) 500 mg Cap-
`sules: opaque, maroon and white hard gelatin capsules, im-
`printed with “PPP” and "784” on one end and with
`“DURICEF” and. “500 mg” on the other end. Capsules are
`supplied as follows:
`Bottle of 20
`NDC 0087-0784-07
`NDC 0087-0784-46
`Bottle of 50
`NDC 0087-0784-42
`Bottle of 100
`NDC 0087-0784-44
`10 strips of 10 individually labeled
`blisters with 1 capsule per blister
`Store at controlled room temperature (15°-30° C).
`DURICEF® 1 gram Tablets: white to off white, top bisected,
`oval shaped, imprinted with “PPP” on one side of the bisect
`and "785” on the other side of the bisect. Tablets are sup-
`plied as follows:
`NDC 0087-0785-43
`Bottle of 50
`NDC 0087—0785-42
`Bottle of 100
`NDC 0087-0785-45
`4 packs of 10 individually labeled
`blisters with 1 tablet per blister
`Store at controlled room temperature (15°—30° C).
`DURICEF® for Oral Suspension is orange-pineapple fla-
`vored, and is supplied as follows:
`125 mg/5 mL
`NDC 0087-0786-42
`NDC 0087-0786-41
`NDC 0087—0782-42
`NDC 0087-0782-41
`NDC 0087-0783-42
`NDC 0087-0783-05
`NDC 0087-0783-41
`
`250 mg/5 mL
`
`500 mg/5 mL
`
`50 mL Bottle
`100 mL Bottle
`50 mL Bottle
`100 mL Bottle
`50 mL Bottle
`75 mL Bottle
`100 mL Bottle
`
`Prior to reconstitution: Store at controlled room tempera-
`ture (15°-30° C).
`'
`REFERENCES
`1. National Committee for Clinical Laboratory Standards,
`Approved Standard, Performance Standards for Antimi-
`crobial Disk Susceptibility Test, 4th Edition, Vol. 10 (7):
`M2—A4, Villanova, PA, April, 1990. 2. National Committee
`for Clinical Laboratory Standards, Approved Standard:
`Methods for Dilution Antimicrobial Susceptibility Tests
`for Bacteria that Grow Aerobically, 2nd Edition, Vol. 10
`(B): M7-AZ, Villanova, PA, April, 1990.
`0782DIM-05
`Revised March 1998
`E3-BOOl-3-98
`
`Bristol-Myers Squibb Company
`Princeton, NJ 08543
`USA
`
`Shown. in. Product Identification Guide, page 307
`
`ESTRACE®
`IESTRADIOL VAGINAL’CREAM, USP, 0.01%)
`[es’trdce]
`ESTRACE®
`(ESTRADIOL TABLETS, USP)
`
`R
`
`ESTRACE® (Estradiol Vaginal Cream, USP) contains 0.1 mg
`estradiol per gram in a nonliquefying base containing puri-
`fied water, propylene glycol, stearyl alcohol, white ceresin
`wax, glyceryl monostearate, hydroxypropyl methylcellulose,
`2208 4000 cps, sodium lauryl sulfate, methylparaben, ede-
`tate disodium and tertiary-butylhydroquinone.
`ESTRACE® (Estradiol Tablets, USP) for oral administration
`contains 0.5, 1 or 2 mg of micronized estradiol per tablet.
`ESTRACE Tablets, 0.5 mg, contain the following inactive
`ingredients: acacia, dibasic calcium phosphate, lactose,
`magnesium stearate, colloidal silicon dioxide, starch (corn),
`and talc.
`ESTRACE Tablets, 1 mg, contain the following inactive in-
`gredients: acacia, D&C Red No. 27 (aluminum lake), dibasic
`calcium phosphate, FD&C Blue No. 1 (aluminum lake), lac-
`tose, magnesium stearate, colloidal silicon dioxide, starch
`(corn), and talc.
`ESTRACE Tablets, 2 mg, contain the following inactive in-
`gredients: acacia, dibasic calcium phosphate, FD&C Blue
`No. 1 (aluminum lake), FD&C Yellow No. 5 (tartrazine)
`(aluminum lake), lactose, magnesium stearate, colloidal sil-
`icon dioxide, starch (corn), and talc.
`CLINICAL PHARMACOLOGY
`Estrogen drug products act by regulating the transcription
`of a limited number of genes. Estrogens diffuse through cell
`membranes, distribute themselves throughout the cell, and
`bind to and activate the nuclear estrogen receptor, a DNA-
`binding protein which is found in estrogen-responsive tis-
`sues. The activated estrogen receptor binds to specific DNA
`sequences, or hormone-response elements, which enhance
`the transcription of adjacent genes and in turn lead to the
`observed effects. Estrogen receptors have been identified in
`tissues of the-reproductive tract, breast, pituitary, hypothal-
`amus, liver, and bone of women.
`Estrogens are important in the development and mainte-
`nance of the female reproductive system and secondary sex
`characteristics. By a direct action, they cause growth and
`development of the uterus, fallopian tubes, and vagina.
`With other hormones, such as pituitary hormones and pro-
`gesterone, they cause enlargement of the breasts through
`promotion of ductal growth, stromal development, and the
`accretion of fat. Estrogens are intricately involved with
`other hormones, especially progesterone, in the processes of
`the ovulatory menstrual cycle and pregnancy, and aflect the
`Rx only
`release of pituitary gonadotropins. They also contribute to
`the shaping of the skeleton, maintenance of tone and elas-
`
`ticity of urogenital structures, changes in the epiphyses of
`WARNINGS
`the long bones that allow for the pubertal growth spurt and
`1. ESTROGENS HAVE BEEN REPORTED TO INCREASE
`its termination, and pigmentation of the nipples and geni-
`tals.
`THE RISK OF ENDOMETRIAL CARCINOMA IN POST-
`MENOPAUSAL WOMEN.
`Estrogens occur naturally in several forms. The primary
`Close clinical surveillance of all women taking estrogens
`source of estrogen in normally cycling adult women is the
`is important. Adequate diagnostic measures, including
`ovarian follicle, which secretes 70 to 500 micrograms of es-
`endometrial sampling when indicated, should be under-
`tradiol daily, depending on the phase of the menstrual cycle.
`taken to rule out malignancy in all cases of undiagnosed
`This is converted primarily to estrone, which circulates in
`persistent or recurring abnormal vaginal bleeding.
`roughly equal proportion to estradiol, and to small amounts
`There is no evidence that “natural” estrogens are more
`of estriol. After menopause, most endogenous estrogen is
`or
`less hazardous than “synthetic” estrogens at
`produced by conversion of androstenedione, secreted by the
`equiestrogenic doses.
`adrenal cortex, to estrone by peripheral tissues. Thus, es-
`2. ESTROGENS SHOULD NOT BE USED DURING
`trone—especially in its sulfate ester form—is the most
`PREGNANCY.
`abundant circulating estrogen in postmenopausal women.
`There is no indication for estrogen therapy during preg-
`Although circulating estrogens exist in a dynamic equilib-
`nancy or during the immediate postpartum period. Es-
`rium of metabolic interconversions, estradiol is the princi-
`trogens are inefiective for the prevention or treatment of
`pal intracellular human estrogen and is substantially more
`threatened or habitual abortion. Estrogens are not indi-
`potent than estrone or estriol at the receptor.
`cated for
`the prevention of postpartum breast
`Estrogens used in therapy are well absorbed through the
`engorgement.
`skin, mucous membranes, and gastrointestinal tract. When
`Estrogen therapy during pregnancy is associated with
`applied for a local action, absorption is usually suficient to
`an increased risk of congenital defects in the reproduc-
`cause systemic efiects. When conjugated with aryl and alkyl
`tive organs ofthe fetus, and possibly other birth defects.
`groups for parenteral administration, the rate of absorption
`Studies of women who received diethylstilbestrol (DES)
`of oily preparations is slowed with a prolonged duration of
`during pregnancy have shown that female ofi'spring'
`action, such that a single intramuscular injection of estra-
`diol valerate or estradiol cypionate is absorbed over several
`have an increased risk of vaginal adenosis, squamous
`weeks.
`cell dysplasia ofthe uterine cervix, and clear cell vaginal
`Administered estrogens and their esters are handled within
`cancer later in life; male offspring have an increased
`the body essentially the same as the endogenous hormones.
`nsk of urogenital abnormalities and possibly testicular
`cancer later in life. The 1985 DES Task Force concluded
`Metabolic conversion of estrogens occurs primarily in the
`that use of DES during pregnancy is associated with a
`liver (first pass efl‘ect), but also at local target tissue sites.
`subsequent increased risk of breast cancer in the moth-
`Complex metabolic processes result 'in a dynamic equilib-
`lnformation will be superseded by supplements and subsequent editions
`
`830/BRISTOL—MYERS SQUIBB
`
` Duricef—Cont.
`HOW SUPPLIED
`
`ers, although a causal relationship remains unproven
`and the observed level of excess risk is similar to that for
`a number of other breast cancer risk factors;-
`
`DESCRIPTION
`Estradiol (NB-estradiol) is a white, crystalline solid, chem-
`ically described as estra-l,3,5(10)-triene-3,17B-diol. It has
`an empirical formula of CmH2402 and molecular weight of
`272.37. The structural formula is:
`CH3
`
`OH
`
`HO
`
`
`
`
`
`PHYSICIANS’ DESK REFERENCE®
`
`rium of circulating conjugated and unconjugated estrogem-c
`forms which are continually interconverted, especially be_
`tween estrone and estradiol and between esterified and non.
`esterified forms. Although naturally-occurring estrogens Cir.
`culate in the blood largely bound to sex hormone-bind;n
`globulin and albumin, only unbound estrogens enter target
`tissue cells. A significant proportion of the circulating estro.
`gen exists as sulfate conjugates, especially estrone SUIfate
`which serves as a circulating reservoir for the formation 0i
`more active estrogenic species. A certain proportion of the
`estrogen is excreted into the bile and then reabsorbed fmm
`the intestine. During this enterohepatic recirculation, estro.
`gens are desulfated and resulfated and undergo degrada.
`tion through conversion to less active estrogens (estriol and
`other estrogens), oxidation to nonestrcgenic substances
`(catecholestrogens, which interact with catecholamine me.
`tabolism, especially in the central nervous system), and con-
`jugation with glucuronic acids (which are then rapidly ex!
`creted in the urine).
`When given orally, naturally-occurring estrogens and their
`esters are extensively metabolized (first pass effect) and cir~
`culate primarily as estrone sulfate, with smaller amounts of
`other conjugated and unconjugated estrogenic species. This
`results in limited oral potency. By contrast, synthetic estro.
`gens, such as ethinyl estradiol and the nonsteroidal estro
`gens, are degraded very slowly in the liver and other fig.
`sues, which results in their high intrinsic potency. Estrogen
`drug products administered by non-oral routes are not sub-
`ject to first-pass metabolism, but also undergo significant
`hepatic uptake, metabolism, and enterohepatic recycling.
`INDICATIONS AND USAGE
`ESTRACE® (Estradiol Vaginal Cream, USP, 0.01%) is indi-
`cated in the treatment of vulva] and vaginal atrophy.
`ESTRACE® (Estradiol Tablets, USP) is indicated in the:
`1. Treatment of moderate to severe vasomotor symptoms as-
`sociated with the menopause. There is no adequate evidence
`that estrogens are efl‘ective for nervous symptoms or depres-
`sion which might occur during menopause and they should
`not be used to treat these conditions.
`2. Treatment of vulva] and vaginal atrophy.
`3. Treatment of hypoestrogenism due to hypogonadism, cas-
`tration or primary ovarian failure.
`4. Treatment of breast cancer (for palliation only) in appro-
`priately selected women and men with metastatic disease.
`5. Treatment of advanced androgen-dependent carcinoma of
`the prostate (for palliation only).
`6. Prevention of osteoporosis.
`Since estrogen administration is associated with risk, selec-
`tion of patients should ideally be based on prospective iden-
`tification of risk factors for developing osteoporosis. Unfor-
`tunately, there is no certain way to identify those women
`who will develop osteoporotic fractures. Most prospective
`studies of efficacy for this indication have been carried out
`in white menopausal women, without stratification by other
`risk factors, and tend to show a universally salutary efi‘ect
`on bone. Thus, patient selection must be individualized
`based on the balance of risks and benefits.A more favorable
`risk/benefit ratio exists in a hysterectomized woman be-
`cause she has no risk of endometrial cancer (see BOXED
`WARNINGS).
`Estrogen replacement therapy reduces bone resorption and
`retards or halts postmenopausal bone loss. Case—control
`studies have shown an approximately 60 percent reduction
`in hip and wrist fractures in women whose estrogen replace-
`ment was begun within a few years of menopause. Studies
`also suggest that estrogen reduces the rate of vertebral frat-
`tures. Even when started as late as 6 years after meno-
`pause, estrogen prevents further loss of bone mass for as
`long as the treatment is continued. The results of a two-
`year, randomized, placebo-controlled, double-blind, dose-
`ranging study have shown that treatment with 0.5 mg 85'
`tradiol daily for 23 days (of a 28 day cycle) prevents verte-
`bral bone mass loss in postmenopausal women. When
`estrogen therapy is discontinued, bone mass declines at a
`rate comparable to the immediate postmenopausal period.
`There is no evidence that estrogen replacement therapy “3'
`stores bone mass to premenopausal levels.
`.
`At skeletal maturity there are sex and race differences {11
`both the total amount of bone present and its density, 111-
`favor of men and blacks. Thus, women are at higher risk
`than men because they start with less bone mass and, for
`several years following natural or induced menopause, the
`rate of bone mass decline is accelerated. White and Asran
`women are at higher risk than black women. Early meno‘
`pause is one of the strongest predictors for the development
`of osteoporosis. In addition, other factors affecting the skel'
`etou which are associated with osteoporosis include genetic
`factors (small build, family history), and endocrine factors
`(nulliparity, thyrotoxicosis, hyperparathyroidism, Cushing’s
`syndrome, hyperprolactinemia, Type I diabetes), lifestyle
`(cigarette smoking, alcohol abuse, sedentary exercise hab'
`its) and nutrition (below average body weight, dietary 031'
`cium intake).
`.
`The mainstays of prevention and management of osteopom'
`sis are estrogen, adequate lifetime calcium intake, and ex‘
`
`
`
`
`
`
`
`AstraZeneca Exhibit 2127 p. 4
`
`

`

`
`
`RODUCT INFORMATION
`
`Postmenopausal women absorb dietary calcium less
`”01.9" tly than premenopausal women and require an aver-
`9fi°lefP15oo mg/day of elemental calcium to remain in neu-
`ocalcium balance. By comparison, premenopausal
`equire about 1000 mg/day and the average calcium
`,
`the USA is 400—600 mg/day. Therefore, when not
`handicated, calcium supplementation may be helpful.
`00 - hpbearing exercise and nutrition may be important
`:w‘igncts to the preven 'on and management of osteoporosis.
`mobilization and prolonged bed rest produce rapid bone
`1
`5 while weight—bearing exercise has been shown both to
`fine boneless and to increase bone mass. The optimal
`and amount of physical activity that would prevent os—
`porosis have not been established, however in two stud-
`an hour ofwalking and running exercise twice or three
`ekly significantly increased lumbar spine bone
`times We
`mess.
`CONTRAINDICATIONS
`.Estrogens should not be used in individuals with any of the
`following conditions:
`1, Known or suspected pregnancy (see BOXED, WARN-
`INGS). Estrogens may cause fetal harm when adrmmstered
`to a pregnant woman.
`‘
`_
`2. Undiagnosed abnormal genital bleeding.
`.
`3. Known or suspected cancer of the breast except in appro-
`priately selected patients being treated for metastatic dis-
`9.
`it’sKnown or suspected estrogen-dependent neoplasia.
`5. Active thrombophlebitis or thromboembolic disorders.
`WARNINGS
`1. Induction of malignant neoplasms.
`Endometrial cancer. The reported endometrial cancer risk
`among unopposed estrogen users is about 2- to 12-fold
`greater than in non—users, and appears dependent on dura-
`tion of treatment and on estrogen dose. Most studies show
`no significant increased risk associated with use of estro-
`gens for less than one year. The greatest risk appears asso-
`ciated with prolonged use—with increased risks of 15- to 24-
`fold for five to ten years or more. In three studies, persis—
`tence of risk was demonstrated for 8 to over 15 years after
`cessation of estrogen treatment. In one study a significant
`decrease in the incidence of endometrial cancer occurred six
`months after estrogen withdrawal. Concurrent progestin
`therapy may oliset this risk but the overall health impact in
`postmenopausal women is not known (see PRECAU-
`TIONS).
`Breast Cancer. While the majority of studies have not
`shown an increased risk of breast cancer in women who
`have ever used estrogen replacement therapy, some have re-
`ported a moderately increased risk (relative risks of 1.3—2.0)
`in those taking higher doses or those taking lower doses for
`prolonged periods of time, especially in excess of 10 years.
`Other studies have not shown this relationship.
`While the effects of added progestins on the risk of breast
`cancer are also unknown, available epidemiological evi-
`dence Suggests that progestins do not reduce, and may en—
`hance, the moderately increased breast cancer incidence
`that has been reported with prolonged estrogen replace-
`ment therapy (see PRECAUTIONS).
`Congenital lesions with malignant potential. Estrogen
`therapy during pregnancy is associated with an increased
`risk of fetal congenital reproductive tract disorders, and
`possibly other birth defects. Studies of women who received
`DES during pregnancy have shown that female ofispring
`have an increased risk of vaginal adenosis, squamous cell
`dysplasia of the uterine cervix, and clear cell vaginal cancer
`later in life; male ofi'spring have an increased risk of uro-
`genital abnormalities and possibly testicular cancer later in
`life. Although some of these changes are benign, others are
`precursors of malignancy.
`2. Gallbladder disease. Two studies have reported a 2- to
`4-fold increase in the risk of gallbladder disease requiring
`surgery in women receiving postmenopausal estrogens.
`3. Cardiovascular disease. Large doses of estrogen (5 mg
`coniUgated estrogens per day), comparable to those used to
`treat cancer of the prostate and breast, have been shown in
`a large prospective clinical trial in men to increase the risks
`ofnonfatal myocardial infarction, pulmonary embolism, and
`thrombopblebitis. These risks cannot necessarily be extrap-
`olated from men to women. However, to avoid the theoreti—
`cal cardiovascular risk to women caused by high estrogen
`doses, the dose for estrogen replacement therapy should not
`exceed the lowest efl‘ective dose.
`4. Elevated blood pressure. Occasional blood pressure in-
`Creases during estrogen replacement therapy have been at-
`tributed to idiosyncratic reactions to estrogens. More often,
`blood pressure has remained the same or has dropped. One
`Study showed that postmenopausal estrogen users have
`higher blood pressure than nonusers. Two other studies
`shOWed slightly lower blood pressure among estrogen users
`cOllftpared to nonusers. Postmenopausal estrogen use does
`Mt increase the risk of stroke. Nonetheless, blood pressure
`should be monitored at regular intervals with estrogen use.
`5- vaercalcemia. Administration of estrogens may lead to
`severe hypercalcernia in patients with breast cancer and
`
` ieS.
`
`
`
`
`bone metastases. If this occurs, the drug should be stopped
`and appropriate measures taken to reduce the serum cal-
`cium level.
`PRECAUTIONS
`A. General
`1. Addition of a progestin. Studies of the addition of a pro-
`gestin for 10 or more days of a cycle of estrogen administra-
`tion have reported a lowered incidence of endometrial hy-
`perplasia than would be induced by estrogen treatment
`alone. Morphological and biochemical studies of endometria
`suggest that 10 to 14 days of progestin are needed to provide
`maximal maturation of the endometrium and to reduce the
`likelihood of hyperplastic changes.
`There are, however, possible risks which may be associated
`with the use of progestins in estrogen replacement regi-
`mens. These include: (1) adverse effects on lipoprotein me-
`tabolism (lowering HDL and raising LDL) which could di—
`minish the purported cardioprotective effect of estrogen
`therapy (see PRECAUTIONS below); (2) impairment of glu-
`cose tolerance; and (3) possible enhancement of mitotic ac-
`tivity in breast epithelial tissue, although few epidemiolog-
`ical data are available to address this point (see WARN-
`INGS).
`The choice of progestin, its dose, and its regimen may be
`important in minimizing these adverse efi'ects, but these is-
`sues will require further study before they are clarified.
`2. Cardiovascular risk. A causal relationship between estro-
`gen replacement therapy and reduction of cardiovascular
`disease in postmenopausal women has not been proven. Fur-
`thermore, the efi‘ect of added progestins on this putative ben-
`efit is not yet known.
`In recent years many published studies have suggested that.
`there may be a cause-eEect relationship between postmen-
`opausal oral estrogen replacement therapy without added
`progestins and a decrease in cardiovascular disease in
`women. Although most of the observational studies which
`assessed this statistical association have reported a 20% to
`50% reduction in coronary artery disease risk and associ-
`ated mortality in estrogen takers, the following should be
`considered when interpreting these reports:
`(1) Because only one of these studies was randomized and it
`was too small to yield statistically significant results, all rel-
`evant studies were subject to selection bias. Thus, the ap-
`parently reduced risk of coronary artery disease cannot be
`attributed with certainty to estrogen replacement therapy.
`It may instead have been caused by life-style and medical
`characteristics of the women studied with the result that
`healthier women were selected for estrogen therapy. In gen-
`eral, treated women were of higher socioeconomic and edu-
`cational status, more slender, more physically active, more
`likely to have undergone surgical menopause, and less
`likely to have diabetes than the untreated women. Although
`some studies attempted to control for these selection fac-
`tors, it is common for properly designed randomized trials
`to fail to confirm benefits suggested by less rigorous study
`designs. Thus, ongoing and future large-scale randomized
`trials may fail to confirm this apparent benefit.
`(2) Current medical practice often includes the use of con-
`comitant progestin therapy in women with intact uteri (see
`PRECAUTIONS and WARNINGS). While the efi'ects of
`added progestins on the risk of ischemic heart disease are
`not known, all available progestins reverse at least some of
`the favorable efl‘ects of estrogens on HDL and LDL levels.
`3. Physical examination. A complete medical and family
`history should be taken prior to the initiation of any estro-
`gen therapy. The pretreatment and periodic physical exami-
`nations should include special reference to blood pressure,
`breasts, abdomen, and pelvic organs, and should include a
`Papanicolaou smear. As a general rule, estrogen should not
`be prescribed for longer than one year without reexamining
`the patient.
`4. Hypercoagulability. Some studies have shown that
`women taking estrogen replacement therapy have hyperco-
`agulability, primarily related to decreased antithrombin ac-
`tivity. This eflect appears dose- and duration-dependent and
`is less pronounced than that associated with oral contracep-
`tive use. Also, postmenopausal women tend to have in-
`creased coagulation parameters at baseline compared to
`pre-menopausal women. There is some suggestion that low
`dose postmenopausal mestranol may increase the risk of
`thromboembolism, although the majority of studies (of pri-
`marily conjugated estrogens users) report no such increase.
`There is insufficient information on hypercoagulability in
`women who have had previous thromboembolic disease.
`5. Familial hyperlipoproteinemia. Estrogen therapy may
`be associated with massive elevations of plasma triglycer-
`ides leading to pancreatitis and other complications in pa-
`tients with familial defects of lipoprotein metabolism.
`6. Fluid retention. Because estrogens may cause some de—
`gree of fluid retention, conditions which might be exacer-
`bated by this factor, such as asthma, epilepsy, migraine, and
`cardiac or renal dysfunction, require careful observation.
`7. Uterine bleeding and mastodynia. Certain patients
`may develop undesirable manifestations of estrogenic stim-
`ulation, such as abnormal uterine bleeding and mastodynia.
`
`BRISTOL-MYERS SOUIBB/831
`
`
`
`
`8. Impaired liver function. Estrogens may be poorly metab-
`olized in patients with impaired liver function and should
`be administered with caution.
`ESTRACE® (Estradiol Tablets, USP), 2 mg, contain FD&C
`Yellow No. 5 (tartrazine) which may cause allergic-type re-
`actions (including bronchial asthma) in certain susceptible
`individuals. Although the overall incidence of FD&C Yellow
`No. 5 (tartrazine) sensitivity in the general population is
`low, it is frequently seen in patients who also have aspirin
`hypersensitivity.
`See text of Patient Package
`B. Information for the Patient.
`Insert below.
`Advise patients that the number of doses per tube of ES-
`TRACE® (Estradiol Vaginal Cream, USP, 0.01%) will vary
`with dosage requirements and patient handling.
`C. Laboratory Tests. Estrogen administration should gen-
`erally be guided by clinical response at the smallest dose,
`rather than laboratory monitoring, for relief of symptoms
`for those indications in which symptoms are observable. For
`prevention of osteoporosis, however, see DOSAGE AND AD-
`MINISTRATION section under ESTRACE® (Estradiol Tab-
`lets, USP) item 5.
`D. Drug/Laboratory Test Interactions.
`1. 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 com-
`plex, and beta-thromboglobulin; decreased levels of anti-
`factor Xa and antithrombin III, decreased antithrombin III
`activity; increased levels of fibrinogen and fibrinogen activ-
`ity; increased plasminogen antigen and activity.
`2.
`Increased thyroid-binding globulin (TBG) leading to in—
`creased circulating total thyroid hormone, as measured by
`protein-bound iodine (FBI), T4 levels (by column or by ra-
`dioimmunoassay) or T3 levels by radioimmunoassay. T3
`resin uptake is decreased, reflecting the elevated TBG. Free
`T4 and free T3 concentrations are unaltered.
`3. Other binding proteins may be elevated in serum, i.e.,
`corticosteroid binding globulin (CBG), sex hormone—binding
`globulin (SHBG), leading to increased circulating corticos-
`teroids and sex steroids, respectively. Free or biologically ac-
`tive hormone concentrations are unchanged. Other plasma
`proteins may be increased .(angiotensinogen/renin sub-
`strate, alpha-1~antitrypsin, ceruloplasmin).
`4.
`Increased plasma HDL and HDL-Z subfraction concen-
`trations, reduced LDL cholesterol concentration, increased
`triglycerides levels.
`5.
`Impaired glucos