EDE
`53
`
`EDITION
`
`
`
`i999
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`PHVSICI/ANS’
`DESl<
`I:E
`
`E®9
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`MedicalConsultant
`
`
`
`Ronald Arky, MD, Charles 8. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard Medical School
`. Vice President of Directory services: Stephen B. Greenherg
`Director of Product Management: David P. Reiss
`Senior Drug Information Specialist: Thomas Fleming, RPh
`Drug Information Specialist: Maria Deutsch, MS, RPh, CDE
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`Editor, Special Projects: David W. Sifton
`'
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`Account Managers:
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`senior Production Coordinators: Amy B. Brooks, Dawn McCall
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`Production coordinator: Mary Ellen R. Breun
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`PDR Data Manager: Jeffrey D. Schaefer
`Christopher N. Schmidt
`Senior Format Editor: Gregory J. Westley
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`Index Editors: Johanna M. Mazur, Robert N. Woemer
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`
`
`Copyright© 1999 and published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights reserved. None of the content of this publication
`r
`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 otherwise) without the prior written permission oi the publisher. PHYSICIANS‘ DESK REFERENCE‘, PDR‘, PDR For Nonprescription Drugs‘, PDR For
`- Ophthalmology’. Pocket PDR”, and The PDR“ Family Guide to Prescription Drugs® are registered trademarks used herein under license. PDR Companion Guide“,
`PDR“ tor Herbal Medicines”, PDR“ Medical Dictionary“, PDR“ Nurse's Handbook”, PDFt° Nurse's Dictionary”, The PDR’ Family Guide Encyclopedia of Medical
`Care”, PDR’ Electronic Library”, and PDR“ Drug interactions, Side Effects, indications, Contraindications System” 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 BeDeli; Vice President, Corporate
`Human Resources: Pamela M. Bilash; i/ice President and Chief information Officer: Steven M. Bressier; Senior Vice President, l-‘rnance, 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 Ex
`
`.2127 p_2
`
`

`
`
`
`CONTENTS
`
`
`
`
`
`
`
`IManufacturers’ 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 (Blue 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 ....................................................................................................................... ..22O
`A national directory of institutions that answer queries regarding drugs. Arranged alphabetically by state and city.
`'
`
`...........................
`Key to controlled Substances categories .......................
`Gives the definition of each category and the prescribing limitations that apply.
`
`......................................... ..347
`
`Key to. FDA Use-In-Pregnancy Ratings ............................................................................................ ... ..... ..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.
`A
`
`Poison Control Centers ........................................................................................................................ ..347 8
`A national directory arranged alphabetically by state and city.
`
`Astrazeneca Ex. 2127 p. 3
`
`

`
`830/BFHSTOL-MYERS SQUIBB
`
`
`Duricef—Cont.
`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
`Esiradiol (17[3-estradiol) is a white, crystalline solid, chem-
`ically described as estra-1,3,5(10)-triene-3,17B-diol. It has
`an empirical formula of C13Hz,,O2 and molecular weight of
`272.37. The structural formula is:
`CH;
`
`OH
`
`HO
`
`HOW SUPPLIED
`DURICEF® (cefadroxil monohydrate, USP) 500 mg Cap-
`sules: opaque, maroon and whiixa hard gelatin capsules, im-
`printed with “PPP” and "784" on one end and with
`“DU'RlCEF” and, "500 mg” on the other end. Capsules are
`supplied as follows:
`NDC 0087-0784-O7
`Bottle of 20
`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 ‘I‘ablets: white to 03“ 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 0OB7—0782r41
`NDC 0087-0783-42
`NDC 0087-0783-05
`NDC 0087-0783-41
`
`PHYSICIANS’ DESK REFERlENcE®
`rium of circulating conjugated and unconjugated estmgem-c
`forms which are continually interconverted, especially be_
`tween estrone and estradiol and between esterified and mm
`esterified forms. Although naturally-occurring estrogens ch-.
`culate in the blood largely bound to sex hormone-binding
`globulin and albumin, only unbound estrogens enter target
`tissue cells. A significant proportion of the circulating estm
`gen exists as sulfate conjugates, especially estrone sulfate
`which serves as a circulating reservoir for the formation of
`more active estrogenic species. A certain proportion of the
`estrogen is excreted into the bile and then reabsorbed {mm
`the intestine. During this enterohepatic recirculation, est“,
`gens are desulfated and resulfated and undergo deg-;ada_
`tion through conversion to less active estrogens (estriol and
`other estrogens), oxidation to nonestrogenic substances
`(catecholestrogens, which interact with catecholamine me.
`tabolism. especially in the central nervous system), and w,,_
`jugation with glucuronic acids (which are then rapidly ex;
`creted in the urine).
`When given orally, naturally-occurring estrogens and thei,
`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 estm
`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® (Estradio| Tablets, USP) is indicated in the:
`1. Treatment ofmoderate to severe vasomotor symptoms as-
`sociated with the menopause. There is no adequate evidence
`that estrogens are eflective for nervous symptoms or depres-
`sion which might occur during menopause and they should
`not be used to treat these conditions.
`2. Treatment of vulval and vaginal atrophy.
`3. Treatment ofhypoestrogenism 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. ‘Ireatrnent 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 elficacy for this indication have been carried out
`in white menopausal women, without stratification by other
`risk factors, and tend to show a universally salutary effect
`on bone. Thus, patient selection must be individualized
`based on the balance ofrisks 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 frac-
`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 8
`rate comparable to the immediate postmenopausal period.
`There is no evidence that estrogen replacement therapy T9‘
`stores bone mass to premenopausal levels.
`_
`At skeletal maturity there are sex and race diflerences 111
`both the total amount of bone present and its density, in-
`favor of men and blacks. Thus, women are at higher risk
`than men because they start with less bone mass and. fill‘
`several years following natural or induced menopause, the
`rate of bone mass decline is accelerated. White and Asian
`women are at higher risk than black women. Early men°'
`pause is one of the strongest predictors for the development
`of osteoporosis. In addition, other factors afiecting the Skel'
`eton which are associated with osteoporosis include gene“
`factors (small build, family history), and endocrine factors
`(nulliparity, thyrotoxicosia, hyperparathyroidism, Cushi!IB’5
`syndrome, hyper-prolactinemia, Type I diabetes), lifestyle
`(cigarette smoking, alcohol abuse, sedentary exercise l13b'
`its) and nutrition (below average body weight, dietary C31‘
`cium intake).
`.
`The mainstays ofprevention and management of oste0p0l'°'
`sis are estrogen, adequate lifetime calcium intake, and 9*‘
`
`Astrazeneca Ex. 2127 p. 4
`
`Bristol-Myers Squibb Company
`Princeton, NJ D8543
`USA
`
`Shown in Product Identification Guide, page 307
`
`E
`
`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
`(3): M7-A2, Villanova, PA, April, 1990.
`0782Dl.M-05
`Revised March 1998
`E3-B001-3-98
`
`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 moncstearate, hydroxypropyl methylcellulose,
`2208 4000 cps, sodium lauryl sulfate, methylparaben, ede-
`tate disodium and tertiary-butylhydroquinone.
`ESTRACE® (BtracIioI Tablets, USP) for oral administration
`contains 0.5, l or 2 mg of micronized estradiol per tablet.
`ESTRACE Tablets, 05 mg, contain the following inactive
`ingredients: acacia, dihasic calcium phosphate, lactose,
`magnesium stearate, colloidal silicon dioxide, starch (corn),
`and talc.
`ESTRACE Tablets, 1 mg, contain the following inactive in-
`gredients: acacia, lJ&C Red No. 27 (aluminum lake), dibasic
`calcium phosphate, FD&C Blue No. 1 (aluminum lake), lac-
`tose, magnesium stearate, colloidal silicon dioxide, starch
`(com), 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 diifuse 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.
`E5TRACE®
`With other hormones, such as pituitary hormones and pro-
`(ESTRADIOL VAGINAUCREAIVI, USP. 0.01%)
`gesterone, they cause enlargement of the breasts through
`[es’tr&ce]
`promotion of ductal growth, stromal development, and the
`accretion of fat. Estrogens are intricately involved with
`ESTRACE®
`IESTRADIOL TABLETS. USP)
`other hormones, especially progesterone, in the processes of
`the ovulatory menstrual cycle and pregnancy, and affect 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 ofall 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 ofthe menstrual cycle.
`taken to rule out malignancy in all cases ofundiagnosed
`This is converted primarily to estrone, which circulates in
`persistent or recurring abnormal vaginal bleeding.
`roughly equal proportion to estradiol, and to small amoimts
`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—especlal1y 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 ineflective 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
`engorgemt.
`skin, mucous membranes, and gastrointestinal tract. When
`Estrogen therapy during pregnancy is associated with
`applied for a local action, absorption is usually suificient to
`an increased risk of congenital defects in the reproduc-
`cause systemic eflects. When conjugated with aryl and alkyl
`tive organs of the 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
`action, such that a single intramuscular injection of estra-
`during pregnancy have shown that female offspring"
`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.
`risk 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 l)ES during pregnancy is associated with a
`liver (first pass eflect), but also at local target tissue sites.
`subsequent increased risk of breast cancer in the moth-
`Complex metabolic processes result 'in a dynamic equilib-
`Information will be superseded by supplements and subsequent editions
`
`

`
`
`
`
`
`
` ODUCT INFORMATION
`.
`pogcmenopausal women absorb dietary calcium less
`.fi1'°‘§e” fly than premenopausal women and require an aver-
`°flimetP15oo mg/day of elemental calcium to remain in neu-
`Qge 0 alcium balance. By comparison, premenopausal
`"R1 0 require about 1000 mg/day and the average calcium
`'w‘:fn5n the USA is 400-600 mg/day. Therefore, when not
`B
`ated, calcium supplementation may be helpful.
`I :55;-aindic
`- bpbearing exercise and nutrition may be important
`‘-wlllg (-,5 to the prevention and management of osteoporosis.
`1m_m,,bi1ization and prolonged bed rest produce rapid bone
`while weight-bearing exercise has been shown both to
`2:139 boneloss and to increase bone mass. The optimal
`and amount of physical activity that would prevent os-
`orosis have not been established, however in two stud-
`.es an hour ofwalking and running exercise twice or three
`’,,,,;e. weekly significantly increased lumbar spine bone
`mass.
`ICATIONS
`co
`‘Estrogens should not be used in individuals with any of the
`(drawing conditions:
`1 Known or suspected pregnancy (see BOXED WARN-
`Ifigs). Estrogens may cause fetal harm when administered
`m 5 pregnant woman.
`‘
`_
`2, Undiagnosed abnormal genital bleeding.
`.
`3, Known or suspected cancer of the breast except in appro-
`prjately selected patients being treated for metastatic dis-
`zisfinown 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
`ater 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 olfset 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 oifspring have an increased risk of uro-
`genital abnormalities and possibly testicular cancer later in
`life. Although some of these dianges 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 eslzogen (5 mg
`conjugated estrogens per day), comparable to those used to
`treat cancer of the prostate and breast, have been shown in
`alarge prospective clinical trial in men to increase the risks
`ofnonfatal myocardial infarction, pulmonary embolism, and
`thrombopblebitis. These risks cannot necessarily be extrap-
`°13€ed 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 eflective dose.
`4. Elevated blood pressure. Occasional blood pressure iri-
`Cfeases during estrogen replacement therapy have been at-
`tributed to idiosyncratic reactions to estrogens. More often,
`blood pressure has remained the some or has dropped One
`Siudy showed that postmenopausal estrogen users have
`higher blood pressure than nonusers. Two other studies
`Showed slightly lower blood pressure among estrogen users
`Wmpared to nonusers. Postmenopausal estrogen use does
`not increase the risk of stroke. Nonetheless, blood pressure
`Should be monitored at regular intervals with estrogen use.
`5- Hvpercalcemia. Administration of estrogens may lead to
`Severe hypercalcemia in patients with breast cancer and
`
`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 n 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 eflects 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 efiects, but these is-
`sues will require further study before they are clarified.
`2. Cardiovascular risk. A causal relationship between estro-
`gen replacement theropy and reduction, of cardiovascular
`disease in postmenopausal women has not been proverc Fur-
`thermore, the effect 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-efi'ect 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 ofthese 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, rnore 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 effects of
`added progestins on the risk of ischemic heart disease are
`not known, all available progestins reverse at least some of
`the favorable eifects 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. Hypercoagulabilitv. Some studies have shown that
`women taking estrogen replacement therapy have hyperco-
`agulability, primarily related to decreased antitbrombin ac-
`tivity. This efl‘ect 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 insuflicient information on hypercoagulability in
`women who have had previous thromboembclic disease.
`5. Familial hyperlipoprotelnemia. 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 lipopratein 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 SQUIBB/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 ESTRACEG) (Estradiol Tab-
`lets, USP) item 5.
`D. Drug]Laboratory Test Interactions.
`1. Accelerated prothrombin time, partial thromboplastln
`time, and platelet aggregation time; increased platelet
`count; increased factors II, Vll 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 hcrmone concentrations are unchanged. Other plasma
`proteins may be increased (angiotensinogen/renin sub-
`strate, alpha-1-antitrypsin, ceruloplasmin).
`4.
`Increased plasma HDL and I-IDL-2 subfraction concen-
`trations, reduced LDL cholesterol concentration, increased
`triglycerides levels.
`5.
`Impaired glucose tolerance.
`I
`6. Reduced response to metyrapone test.
`~
`7. Reduced serum folate concentration.
`E. Carcinogenesis, Mutagenesis, and Impairment of Fertili-
`ty. Long term continuous administration of natural and
`synthetic estrogens in certain animal species increases the
`frequ