E“‘sr<
`
`_~%°“""“PEPEPENC;
`
`
`
`

`
`
`
`
`
`EDITION
`
`
`
`
`
` E?
`53
`
` 1999
`PHYSICIANS’
`DESK
`I:E
`
`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
`Director of Product Management: David P. Reiss
`Senior Drug Information Specialist: Thomas Fleming, RPh
`Drug Information specialist: Maria Deutsch, MS, RPh, CDE
`Senior Product Manager: Mark A. Friedman
`Editor, Special Projects: David W. Sifton
`Associate Product Manager: Bill Shaughnessy
`Director of Sales: Dikran N. Barsamian
`Vice President of Production: David A. Pitler
`National Sales Manager: Anthony Sorce
`Director of Print Purchasing: Marjorie A. Duffy
`National Account Manager: Don Bruccoleri
`Director of Operations: Carrie Williams
`Account Managers:
`Manager of Production: Kimberly H. Vivas
`Marion Gray, RPh
`Senior Production coordinators: Amy B. Brooks, Dawn McCall
`Lawrence C. Keary
`Production Coordinator: Mary‘ Ellen R. Breun
`Jeffrey F. Pfohl
`PDR Data Manager: Jeffrey D. Schaefer
`Christopher N. Schmidt
`Senior Format Editor: Gregory J. Westley
`Stephen M. Silverberg
`.
`Suzanne E. Yarrow, RN
`Index Editors: Johanna M. Mazur, Robert N. ‘Woerner
`Art Associate: Joan K. Akerlind
`National Sales Manager, Trade Group: Bill Gaffney
`Director of Direct Marketing: Michael Bennett
`Senior Digital Imaging coordinator: Shawn W. Cahill‘
`Direct Marketing Manager: Lorraine M. Loening
`Digital Imaging coordinator: Frank J. McElroy, lll
`Electronic Publishing Designer: Robert K. Grossman
`Promotion Manager: Donna R. Lynn
`Director, Professional Support Services: Mukesh Mehta, RPh
`Fulfillment Managers: Stephanie DeNardi, Kenneth Siebert
`
`
`.
`
`¥ 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 othenivise) without the prior written permission of 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” for Herbal Medicines”, PDR” Medical Dictiona_ry""', PDR” Nurse's Handbook”, PDR” 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 BeDe||; Vice President, Corporate
`Human Resources: Pamela M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Senior Vice President, I-Tnance, and Chief financial Officer: Thomas
`W. Ehardt; Vice President, Directory Services: Stephen B. Greenberg; I/ice President, New Business Planning: Linda G. Hope; Executive Vice President, Healthcare Publishing
`and Communications: Thomas J. Kelly; Executive Wce 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
`5
`'
`
`® Printed on recycled paper
`
`ISBN: 1-563632888
`
`Astrazeneca Ex. 2045 p. 2
`
`Medicalconsultant
`
`®
`
`
`
`

`
`
`
`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 (Blue Pages)
`Section 3
`
`201
`
`’
`
`Lists all fully described products by prescribing category. An overview of the headings
`appears on pages 201 and 202.
`
`Product Identification Guide (Gray Pages)
`V
`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)
`I
`401
`
`Section
`Includes entries for over 2,200 pharmaceuticals. Listings are
`The main section of the book.
`arranged alphabetically by manufacturer.
`'
`
`Diagnostic Product Information
`
`Section 6
`
`.
`
`3467
`
`Gives usage guidelines for a variety of common diagnostic agents. Arranged alphabetically by manufacturer.
`
`........................ ..220
`Drug Information Centers .............................................................................................
`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 .................................................................................................... ..347
`Provides the exact interpretation of each risk/benefit rating.
`
`U.S. Food and Drug Administration Telephone Directory .............................................
`Gives numbers of key reporting programs and information services.
`
`........................... ..348‘
`
`Poison Control centers ........................................................................................................................ ..3478
`A national directory arranged alphabetically by state and city.
`
`Astrazeneca Ex. 2045 p. 3
`
`

`
`ZE NECA PHARMACEUTICALS/3425
`
`MERREM I.V. is also supplied as ADD~Vantage Vials con-
`taining sufficient meropenem to deliver 500 mg or 1 g for
`intravenous administration.
`500 mg/20 mL Injection Vial (NDC 0310-0325-20)
`500 mg/100 mL Infusion Vial (NDC 0310-0325-11)
`1 g/30 mL Injection Vial (NDC 0310-0321-30)
`1 g/100 ml. Infusion Vial (NDC 0310-0321-11)
`500 mg/15 ml. ADD-Vantage (NDC 0310-0325-15)
`l g/15 mL ADD-Vantage (NDC 03100321-15)
`REFERENCES
`1. Nations Committee for Clinical Laboratory Standards.
`Methods for Dilution Antimicrobial Susceptibility Tests
`for Bacteria that Grow Aerobically - Third Edition. Ap-
`proved Standard NCCLS Document M7-A3, Vol. 13, No.
`25, NCCLS, Villanova, PA, December, 1993.
`2. Nations Committee for Clinical Laboratory Standards.
`Performance Standards for Antimicrobial Disk Suscepti-
`bility Tests ~ Fifth Edition. Approved Standard NCCLS
`Document M2-A5, Vol. 13, No. 24. NCCLS, Villanova, PA.
`December 1993.
`3. Nations Committee for Clinical Laboratory Standards.
`Methods for Antimicrobial Susceptibility Testing of Ana-
`erobic Bacteria — Third Edition. Approved Standard NC-
`CLS Document M11-A3, Vol. 13, No. 26, NC-C-LS, Vill-
`anova, PA. December 1993.
`4. Cockcro DW, Gault MH. Prediction of creatinine clear-
`ance from serum creatinine. Nephron. 1976; 1631-41.
`iADD-Van age is a registered trademark of Abbott Labora-
`tories Inc.
`MERREM® (meropenern for injection} is manufactured by:
`Sumitorno Pharmaceuticals Co. Ltd
`Dita Works
`Tsurusaki 2200
`Oita-shi
`Oita
`Japan
`Manufactured for:
`Zeneca Pharmaceuticals
`A business unit of Zeneca Inc.
`Wilmington, DE 19850-5437
`SIC 64041-00
`Rev F 07/96
`Shown in Product Identification Guide, page 346
`
`NOLVADEX®
`[nol ’vd-dex]
`tamoxifen citrate
`
`DESCRIPTION
`NOLVADEX® (tamoxifen citrate) Tablets, a nonsteroidal
`antiestrogen, are for oral administration. NOLVADEX Tab-
`lets are available as:
`10 mg Tablets. Each tablet contains 15.2 mg of tamoxifen
`citrate which is equivalent to 10 mg of tamoxifen.
`20 mg Tablets. Each tablet contains 30.4 mg of tamoxifen
`citrate which is equivalent to 20 mg of tamoxifen.
`Inactive Ingredients: carboxymethylcellulose calcium, mag-
`nesium stearate, mannitol and starch.
`Chemically, NOLVADEX is the trans-isomer of a triphenyl-
`ethylene derivative. The chemical name is (Z)2-I4-(1.2-db
`phenyl-1-butenyl) phenoxyl-N, N-dimethylethanamine
`2~hydroxy-1,2,3-propanetricarboxylate (1:1). The structural
`and empirical formulas are:
`.
`
`(CH3)2N(CH2)2O©\ /0
`g
`C:c
`
`-CHO
`ea 7
`
`\
`
`C2H5
`
`(C3gH37NO3)
`Tamoxifen citrate has a molecular weight of 563.62, the
`pKa’ is 8.85, the equilibrium solubility in water at 37°C is
`0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.
`CLINICAL PHARMACOLOGY
`NOLVADEX is a nonsteroidal agent which has demon-
`strated potent antiestrogenic properties in animal test sys-
`tems. The antiestrogenic effects may be related to its ability
`to compete with estrogen for binding sites in target tissues
`such as breast. Tamoxifen inhibits the induction of rat
`mammary carcinoma induced by dimethylbenzanthracene
`(DMBA) and causes the regression of already established
`DMBA—induced tumors. In this rat model, tamoxifen ap-
`pears to exert its antitumor eifects by binding the estrogen
`receptors.
`In cytosols derived from human breast adenocarcinomas,
`tamoxifen competes with estradiol for estrogen receptor pro-
`tein.
`
`Consult 1 999 PDR® supplements and future editions for revisions
`
`Continued on next page
`
`Astrazeneca Ex. 2045 p. 4
`
`MERREM I.V.) may be stored for up to 2 hours at controlled
`room temperature l5~25°C (5El—77"l7) or for up to 12 hours
`at 4”C (39°Fl.
`Intravenous infusion Administration
`Stability in Infusion Vials: MERREM I.V. infusion vials con-
`stituted with Sodium Chloride Injection 0.9% (MERREM
`I.V. concentrations ranging from 2.5 to 50 mg/ml.) are stable
`for up to 2 hours at controlled room temperature 15—25”C
`(55-77°F‘) or for up to 18 hours at 4°C (39"F). Infusion vials
`of MERREM I.V. constituted with Dextrose Injection 5%
`(MERREM I.V. concentrations ranging from 2.5 to 50 mg/
`mL) are stable for up to 1 hour at controlled room temper-
`ature 15»25°C (59~77"F) or for up to 8 hours at 4°C (39"Fl.
`Stability in Plastic l.V. Bags: Solutions prepared for infusion
`(MERREM I.V. concentrations ranging from I to 20 mg/ml.)
`may be stored in plastic intravenous bags with diluents as
`shown below:
`
`Number of
`Hours Stable
`at Controlled Number
`Room
`of Hours
`Temperature
`Stable
`15~25°C
`at 4"C
`(£3.9fl7°F,l
`(_;;2:1«:2
`
`4
`1
`1
`
`I
`
`1
`
`1
`
`I
`1
`
`1
`
`3
`2
`4
`4
`2
`
`1
`
`24
`4
`2
`
`2
`
`4
`
`6
`
`6
`8
`
`4
`
`12
`16
`24
`12
`24
`
`4
`
`Sodium Chloride
`Injection 0.9%
`Dextrose Injection 5.0%
`Dextrose Injection 10.0%
`Dextrose and Sodium Chloride
`Injection 5.0%/0.9%
`Dextrose and Sodium Chloride
`Injection 5.0%/0.2%
`Potassium Chloride in
`Dextrose
`Injection 0.15%/5.0%
`Sodium Bicarbonate in
`Dextrose
`Injection 0.02%/5.0%
`Dextrose Injection 5.0%
`in Normosol®-M
`Dextrose Injection 5.0%
`in Ringers Lactate Injection
`Dextrose and Sodium Chloride
`Injection 2.5%/0.45%
`Mannitol Injection 2.5%
`Ringers Injection
`Ringers Lactate Injection
`Sodium Lactate Injection I/6 N
`Sodium Bicarbonate
`Injection 5.0%
`
`Solutions of MERREM
`Stability in Baxter Minibag Plus:
`I.V. (MERREM I.V. concentrations ranging from 2.5 to 20
`mg/mL) in Baxter Minibag Plus bags with Sodium Chloride
`Injection 0.9% may be stored for up to 4 hours at controlled
`room temperatures 15-25°C (59~77°l?‘) or for up to 24 hours
`at 4°C (39°F). Solutions of MERREM I.V. (MERREM I.V.
`concentrations ranging from 2.5 to 20 mg/mL) in Baxter
`Minibag Plus bags with Dextrose Injection 5.0% may be
`stored up to 1 hour at controlled room temperatures 15-
`25°C (59—77°F) or for up to 6 hours at 4°C (39°F).
`Stability in Plastic Syringes, Tubing and Intravenous Infu-
`sion Sets:
`Solutions of MERREM I.V. (MERREM I.V. con-
`centrations ranging from 1 to 20 mg/ml.) in Water for Injec-
`tion or Sodium Chloride Injection 0.9% (for up to 4 hours) or
`in Dextrose Injection 5.0% (for up to 2 hours) at controlled
`room temperatures 15«25°C (59~7'7"F) are stable in plastic
`syringes, plastic tubing. drip chambers, and volume control
`devices of common intravenous infusion sets.
`ADD-Vantage Vials: ADD-Vantage vials diluted in Sodium
`Chloride Injection 0.45% (MERREM I.V. concentrations
`ranging from 5 to 20 mg/mL) may be stored for up to 6 hours
`at controlled room temperature 15—25°C (59~77°F) or for 24
`hours at 4°C (39°F). ADD-Vantage vials diluted in Sodium
`Chloride Injection 0.9% (MERREM I.V. concentrations
`ranging from 1-20 mg/mL) may be stored for up to 4 hours
`at controlled room temperature 15—25°C (59~77“F) or for 24
`hours at 4"C (39°F). ADD-Vantage vials diluted with Dex-
`trose Injection 5.0% (MERREM I.V. concentrations ranging
`from 1-20 mg/ml.) may be stored for up to 1 hour at con-
`trolled room temperature 15~25°C (59—-77°F) or for 8 hours
`at 4°C (39°F).
`NOTE: Parenteral drug products should be inspected visu-
`ally for particulate matter and discoloration prior to admin-
`istration, whenever solution and container permit.
`HOW SUPPLIED
`MERREM I.V. is supplied in 20 mL and 30 mL injection vi-
`als containing sufiicient meropenem to deliver 500 mg or 1 g
`for intravenous administration, respectively. MERREM I.V.
`is supplied in 100 mL infusion vials containing sufficient
`meropenem to deliver 500 mg or 1 g for intravenous admin-
`istration. The dry powder should be stored at controlled
`room temperature 20—25°C (68-577“Fl [see USP].
`
`PRODUCT lNFDRMATlON
`
`To Prepare Admixture:
`1. Squeeze the bottom of the diluent container gently to in-
`flate the portion of the container surrounding the end of
`the drug vial.
`
`
`
`lI lI
`
`2. With the other hand, push the drug vial down into the
`container telescoping the walls of the container. Grasp
`the inner cap of the vial through the walls of the con-
`tainer. (See Figure 5.)
`
`
`
`. 3. Pull the inner cap from the drug vial. (See Figure 6.) Ver-
`ify that the rubber stopper has been pulled out and invert
`the system several times, allowing the drug and diluent
`to mix.
`
`
`
`Y-"t".°°
`
`4. Mix contents thoroughly and use within the specified
`time.
`Preparation For Administration: lUse Aseptic Technique)
`1. Confirm the activation and admixture of vial con-
`tents.
`Check for leaks by squeezing container firmly. If leaks
`are found, discard unit as sterility may be impaired.
`Close flow control clamp of administration set.
`Remove cover from outlet port at bottom of container.
`Insert piercing pin of administration set into port
`with a twisting motion until the pin is firmly seated.
`NOTE: See full directions on administration set car-
`ton.
`.
`6. Lift the free end of the hanger loop on the bottom of
`the vial, breaking the two tie strings. Bend the loop
`outward to lock it in the upright position, then sus-
`pend container from hanger.
`7. Squeeze and release drip chamber to establish proper
`fluid level in chamber.
`8. Open flow control clamp and clear air from set. Close
`clamp.
`9. Attach set to venipuncture device. If device is not in-
`dwelling, prime and make venipuncture.
`10.
`Regulate rate of administration with flow control
`clamp.
`WARMNG: Do not use flexible container in series connec-
`tions.
`'
`COMPATIBILITY AND STABILITY
`Compatibility of MERREM I.V. with other drugs has not
`been established. B.-IERREIVI I.V. should not be mixed with
`or physically added to solutions containing other drugs.
`Freshly prepared solutions of MERREM I.V. should be used
`whenever possible. However, constituted solutions of MER-
`REM I.V. maintain satisfactory potency at controlled room
`temperature l5—25°C (59-77°F) or under refrigeration at
`4°C (39°F) as described below. Solutions of intravenous
`MERREIVI I.V. should not be frozen.
`Intravenous Bolus Administration
`MERREM I.V. injection vials constituted with sterile Water
`for Injection for bolus administration (up to 50 mg/ml. of
`
`

`
`3426/ZENECA PHARM/\CEUTlCALS
`
`No|vadex—-Cont.
`
`._......,...._.__
`NSABP B-09 study in women age 50-59 years, only women
`with both estrogen and progesterone receptorlevels 10 fmol
`or greater clearly benefited, while .there.was a nonstatisti-
`Tamoxifen is extensively metabolized after oral administra-
`Cally significant trend toward adverse effect in women with
`tion. Studies in women receiving 20 mg of “C tamoxifen
`both estrogen and progesterone receptor levels less than 10
`fmol. In women age 60—70 years, there was a trend toward
`have shown that approximately 65% of the administered
`a beneficial effect of NOLVADEX without any clear relation-
`dose was excreted from the body over a period of 2 weeks
`with fecal excretion as the primary route of elimination. The
`ship to estrogen or progesterone receptor status.
`Three prospective studies (ECOG-1178, Toronto, NATO) us-
`drug was excreted mainly as polar conjugates, with un-
`ing NOLVADEX sdjuvantly as a single agent demonstrated
`changed drug and unconjugated metabolites accounting for
`an improved disease-free survival following total mastec-
`less than 30% of the total fecal radioactivity
`tomy and axillary dissection for postmenopausal women ‘
`N-desmethyl tamoxifen was the major metabolite found in
`with positive axillary nodes compared to placebo/no treat-
`patients’ plasma. The biological activity of N-desmethyl
`ment controls. The NATO study also demonstrated an over-
`tamoxifen appears to be similar to tamoxifen. 4-Hydroxytzr
`all survival benefit.
`moxifen and a side chain primary alcohol derivative of
`NSABP B-14, a prospective, double-blind, randomized
`tamoxifen have been identified as minor metabolities in
`study, evaluated NOLVADEX versus placebo in the treat-
`plasma.
`ment of women with axillary node-negative, estrogen-recap
`Following a single oral dose of 20 mg tamoxifen, an average
`tor positive (2 10 fmol/mg cytosol protein) breast cancer (as
`peak plasma concentration of 40 ng/mL (range 35 to 45 ng/
`adjuvant therapy, following total mastectomy and axillary
`mL) occurred approximately 5 hours after dosing. The de-
`dissection, or segmental resection, axillary dissection, and
`cline in plasma concentrations of tamoxifen is biphasic with
`breast radiation). After five years of treatment, a significant
`a terminal elimination half-life of about Sto 7 days. The
`improvement in discase—free survival was demonstrated in
`average peak plasma concentration for N-desmethyl tamox-
`women receiving NOLVADEX. This benefit was apparent
`ifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic adminis-
`both in women under age 50 and in women at or beyond age
`50. In this trial women who received tamoxifen for five
`tration of 10 mg tamoxifen given twice daily for three
`months to patients results in average steady-state plasma
`years and were disease-free at the end of this 5-year period
`concentrations of 120 ng/mL (range 67-183 ng/mL) for
`were offered an additional five years of NOLVADEX, or pla-
`tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-
`cebo in a double-blind randomized scheme. With four years
`desmethyl tamoydfen. The average steady-state plasma con-
`of follow-up after this rerandomization, 92% of the women
`centrations of tamoxifen and N-desmethyl tamoxifen after
`that received five years of NOLVADEX followed by placebo
`administration of 20 mg tamoxifen once daily for three
`are alive and disease-free, compared to 86% of the women
`scheduled to receive 10 years of NOLVADEX. This difi”er-
`months are 122 ng/mL (range 71-183 ng/ml») and 353
`ng/mL (range 152-706 rig/mL), respectively. After initiation
`ence was not statistically significant. One additional ran-
`of therapy, steady state concentrations for tamoxifen are
`domized study (NATO) demonstrated improved disease-free
`achieved in about 4 weeks and steady state concentrations
`survival for NOLVADEX compared to no adjuvant therapy
`for N-desmethyl tamoxifen are achieved in about 8 weeks,
`following total mastectomy and axillary dissection in post-
`suggesting a half-life of approximately 14 days for this me-
`menopausal women with axillary node-negative breast can-
`tabolite.
`cer. In this study, the benefits of NOLVADEX appeared to be
`In a 3-month crossover steady-state bioavailability study
`independent of estrogen receptor status.
`with NOLVADEX 10 mg twice a day versus NOLVADEX 20
`Three prospective, randomized studies (Ingle, Pritchard,
`mg given once daily,
`the results deomonstrated that
`Buchanan) compared NOLVADEX to ovarian ablation
`(oophorectomy or ovarian irradiation) in premenopausal
`NOLVADEX 20 mg taken once daily has comparable bio-
`availability to NOLVADEX 10 mg taken twice a day.
`women with advanced breast cancer. Although the objective
`response rate, time to treatment failure, and survival were
`Clinical Studies: The Early Breast Cancer Trialists’ Col-
`laborative Group (EBCTCG) conducted worldwide over-
`similar with both treatments, the limited patient accrual
`prevented a demonstration of equivalence. In an overview
`views of systemic adjuvant therapy for early breast cancer
`analysis of survival data from the three studies, the hazard
`in 1985 and again in 1990. In 1992, 10-year outcome data
`ratio for death (NOLVADEX/ovarian ablation) was 1.00 with
`were reported for 29,892 women in 40 randomized trials of
`two-sided 95% confidence intervals of 0.73 to 1.37. Elevated
`adjuvant tamoxifen using doses of 20-40 mg/day for 1-5+
`years (median 2 years). Fifty-one percent were entered into
`serum and plasma estrogens have been obseived in premen-
`opausal women receiving NOLVADEX. However, the data
`trials comparing tamoxifen to no adjuvant therapy and 49%
`were entered into trials of tamoxifen in combination with
`from the randomized studies do not suggest an adverse ef-
`fect. A limited number of premenopausal patients with dis-
`chemotherapy vs. the same chemotherapy alone. Twenty-
`ease progression during NOLVADEX therapy responded to
`nine percent were <50 years of age and 71% were 250
`subsequent ovarian ablation.
`years. Fifty-seven percent were node-positive and 43% were
`in Sweden of adjuvant
`In a large randomized trial
`nodenegative. Fifty percent of the tumors were estrogen re-
`NOLVADEX 40 mg/day for 2-5 years, the incidence of sec-
`ceptor (ER) positive (210 fmol/mg), 18% were ER poor (<10
`ond primary breast tumors was reduced in the tamoxifen
`fmol/mg), and 32% were ER unknown.
`arm (p<0.05). In the NSABP B-14 trial in which patients
`The overall recurrence-free survival at 10 years of follow-up
`were randomized to NOLVADEX 20 mg/day for 5 years ver-
`was 51.2% for tamoxifen versus 44.7% for control (logrank
`sus placebo, the incidence of second primary breast cancers
`2p <0.00001). Overall survival at 10 years was 58.8% for
`is also reduced.
`tamoxifen versus 52.6% for control (logrank 2p <0.00001).
`Published results from 122 patients (119 evaluable) and
`Both the absolute risk of relapse and the absolute benefit of
`case reports in 16 patients (13 evaluable) treated with
`treatment with tamoxifen were greater in women with pos-
`NOLVADEX have shown that NOLVADEX is effective for
`itive nodes than in women with negative nodes. In women
`the palliative treatment of male breast cancer. Sixty-six of
`with positive nodes, 10-year recurrence-free survival was
`these 132 evaluable patients responded to NOLVADEX
`41.9% for tamoxifen versus 33.1% for control (logrank 1p
`<0.00001). Ten-year survival was 50.4% for tamoxifen ver-
`which constitutes a 50% objective response rate.
`sus 42.2% for control (logrank 1p <0.00001). In women with
`INDICATIONS AND USAGE
`negative nodes, recurrence-free survival was 68.1% for
`Adjuvant Therapy: NOLVADEX is indicated for the treat-
`tamoxifen versus 63.1% for control (logrank lp <0.00001).
`ment of axillary node-negative breast cancer in women fol-
`Survival at 10 years was 74.5% for tamoxifen versus 71.0%
`lowing total mastectomy or segmental mastectomy, axillary
`for control (logrank 1p 2 0.0002).
`dissection, and breast irradiation. Data are insulficient to
`The reduction in the annual odds of recurrence with tamox-
`predict which women are most likely to benefit and to de-
`ifen was 12% in women <50 years of age versus 29% in
`termine if NOLVADEX provides any benefit in women with
`women 250 years. Similarly, the reduction in the annual
`tumors less than 1 cm.
`odds of death was 6% versus 20%. The reduction in the an-
`NOLVADEX is indicated for the treatment of node-positive
`nual odds of recurrence with tamoxifen was significantly
`breast cancer in postmenopausal women following total
`greater in ER positive (32%) than in ER poor (13%) tumors
`mastectomy, or segmental mastectomy, axillary dissection,
`(lp <0.00001). The reduction in recurrence and mortality
`and breast irradiation. In some NOLVADEX adjuvant stud-
`was greater in those studies that used tamoxifen for longer
`ies, most of the benefit to date has been in the subgroup
`(22 years) rather than shorter (<2 years) periods. There
`with 4 or more positive axillary nodes.
`was no indication that doses greater than 20 mg per day
`The estrogen and progesterone receptor values may help to
`were more effective.
`predict whether adjuvant NOLVADEX therapy is likely to
`Two studies (Hubay and NSABP B-09) demonstrated an im-
`be beneficial.
`proved disease-free survival following radical or modified
`Therapy for Advanced Disease: NOLVADEX is effective in
`radical mastectomy in postmenopausal women or women 50
`the treatment of metastatic breast cancer in women and
`years of age or older with surgically curable breast cancer
`men. In premenopausal women with metastatic breast can-
`with positive axillary nodes when NOLVADEX was added to
`cer, NOLVADEX is an alternative to oophorectomy or ovar-
`adjuvant cytotoxic chemotherapy. In the Hubay study,
`ian irradiation. Available evidence indicates that patients
`NOLVADEX was added to “low-dose" CMF (cyclophospha-
`whose tumors are estrogen receptor positive are more likely
`mide, methotrexate and fluorouracil). In the NSABP B-09
`to benefit from NOLVADEX therapy.
`study, NOLVADEX was added to melphalan [L-phenylala
`CONTRAINDICATIONS
`nine mustard (P)! and fluorouracil (F).
`NOLVADEX is contraindicated in patients with known by-
`In the Hubay study, patients with a positive (more than 3
`fmol) estrogen receptor were more likely to benefit. In the . persensitivity to the drug.
`Information will be superseded by supplements and subsequent editions
`
`PHYSICIANS’ DESK REFERENCE®
`
`WARNINGS
`Visual disturbance including corneal changes, cataracts and
`retinopathy have been reported‘ in patients receiving
`NOLVADEX.
`As with other additive hormonal therapy (estrogens and an-
`drogens), hypercalcemia has been reported in some breast
`cancer patients with bone metastases within a few weeks of
`starting treatment with NOLVADEX. If hypercalcemia does
`occur, appropriate measures should be taken and, if severe,
`NOLVADEX should be discontinued.
`An increased incidence of endometrial cancer has been re-
`ported in association with NOLVADEX treatment. The un-
`derlying mechanism is unknown, but may be related to the
`estrogen-like effect of NOLVADEX. Any patients receiving
`or having previously received NOLVADEX, who report ab-
`normal vaginal bleeding should be promptly evaluated. Pa-
`tients receiving or having previously received NOLVADEX
`should have routine gynecological care and they should
`promptly inform their physician if they experience any ab-
`normal gynecological symptoms, eg, menstrual irregulari-
`ties, abnormal vaginal bleeding, changes in vaginal dis-
`charge, or pelvic pain or pressure.
`An increased incidence of endometrial changes including
`hyperplasia and polyps have been reported in association
`with NOLVADEX treatment. The incidence and pattern of
`4 this increase suggest that the underlying mechanism is re-
`lated to the estrogenic properties of NOLVADEX.
`In a large randomized trial
`in Sweden of adjuvant
`NOLVADEX 40 mg/day for 2—5 years, an increased inci-
`dence of uterine cancer was noted. Twenty-three of 1,372
`patients randomized to receive NOLVADEX versus 4 of
`1,357 patients randomized to the observation group devel-
`oped cancer of the uterus lRR = 5.6 (1.9-16.2), p<.001l. One
`of the patients with cancer of the uterus who was random- .
`ized to receive NOLVADEX never took the drug. After ap-
`proximately 68 years of follow-up in the NSABP B-14 trial,
`15 of 1,419 women randomized to receive NOLVADEX 20
`mg/day for 5 years developed uterine cancer and 2 of the
`1,424 women randomized to receive placebo, who subse-
`quently were treatcd with NOLVADEX, also developed uter-
`ine cancer. Most of the uterine cancers were diagnosed at an
`early stage, but deaths from uterine cancer have been re-
`ported.
`NOLVADEX has been associated with changes in liver en-
`zyme levels, and on rare occasions, a spectrum of more se-
`vere liver abnormalities including fatty liver, cholestasis,
`hepatitis and hepatic necrosis. A few of these serious cases
`included fatalities. In most reported cases the relationship
`to NOLVADEX is uncertain. However, some positive rechal-
`lenges and dechallenges have been reported.
`In the Swedish trial using adjuvant NOLVADEX 40 mg/day
`for 2-5 years, 3 cases of liver cancer have been reported in
`the NOLVADEX-treated group versus 1 case in the ob-
`servation group.
`In other clinical
`trials evaluating
`NOLVADEX, no other cases of liver cancer have been re-
`ported to date.
`Data from the NSABP B-14 study show no increase in other
`(non-uterine)
`cancers
`among
`patients
`receiving
`NOLVADEX. However, a number of second primary tumors,
`occurring at sites other than the endometrium, have been
`reported following the treatment of breast cancer with
`NOLVADEX in clinical trials. Whether an increased risk for
`other (non-uterine) cancers is associated with NOLVADEX
`is still uncertain and continues to be evaluated.
`Pregnancy Category D: NOLVADEX may cause fetal harm
`when administered to a pregnant woman. Women should be
`advised not to become pregnant while taking NOLVADEX
`and should use barrier or nonhormonal contraceptive meas-
`ures if sexually active. Effects on reproductive functions are
`expected from the antiestrogenic properties of the drug. In
`reproductive studies in rats at dose levels equal to or below
`the human dose, nonteratogenic developmental skeletal
`changes were seen and were found reversible. In addition,
`in fertility studies in rats and in tcratology studies in rab-
`bits using doses at or below those used in humans, a lower
`incidence of embryo implantation and a higher incidence of
`fetal death or retarded in utero growth were observed, with
`slower learning behavior in some rat pups when compared
`to historical controls. Several pregnant marmosets were
`closed during organogenesis or in the last half of pregnancy
`No deformations were seen and, although the dose was high
`enough to terminate pregnancy in some animals, those that
`did maintain pregnancy showed no evidence of teratogenic
`malformations.
`In rodent models of fetal reproductive tract development,
`tamoxifen (at doses 0.3 to 2.4-fold the human maximum rec-
`ommended dose on a mg/m2 basis) caused changes in both
`sexes that are similar to those caused by estradiol, ethy-
`nylestradiol and diethylstilbestrol. Although the clinical rel-
`evance of these changes is unknown, some of these changes,
`especially vaginal adenosis, are similar to those seen in
`young women who were exposed to diethylstilbestrol in
`utcro and who have a 1 in 1000 risk of developing clear-cell
`adenocarcinoma of the vagina or cervix. To date, in utera
`exposure to tamoxifen has not been shown to cause vaginal
`adenosis, or clear-cell adenocarcinoma of the vagina or cer-
`
`-
`I
`
`Astrazeneca Ex. 2045 p. 5
`
`

`
`Adverse Eifect
`
`Hot Flashes
`Weight Gain (:>5%)
`Fluid Retention
`Vaginal Discharge
`' Nausea
`Irregndar Menses
`- Weight Loss (>5%)
`Skin Changes
`Increased BUN
`Diarrhea
`Increased SGOT
`Increased Alkaline
`Phosphatase
`Vomiting
`Increased Bilirubin
`Increased Creatinine
`Thrombocytopenia*
`Leukopenia”
`Thrombotic Events
`Deep Vein Thrombosis
`Pulmonary Embolism
`Superficial Phlebitie
`
`92: of Women
`NOLVADEX
`(n=1-424)
`
`Placebo
`{n:1440l
`
`68.9
`38.1
`32.4
`29.6
`25.7
`24.6
`22.6
`18.?
`18.1
`11.2
`4.8
`3.0
`
`2.1
`1.8
`1.7
`1.5
`0.4
`
`0.8
`0.4
`0.3
`
`47.6
`40.1
`29.’?
`15.2
`23.9
`18.8
`18.0
`15.3
`20.2
`14.0
`2.8
`4.6
`
`1.’?
`1.2
`1.0
`1.2
`1.1
`
`0.3
`0.1
`0.0
`
`I
`V
`
`PRODUCT INFORMATION
`
`vix, in young women. However, only a small number of
`young women have been exposed to tamoxifen in adore, and
`a smaller number have been followed long enough (to age
`15-20) to determine whether vaginal or cervical neoplasia
`could occur as a result of this exposure.
`There are no adequate and well controlled trials of tamox-
`ifen in pregnant women. There have been a small number of
`reports ofvaginal bleeding, spontaneous abortions, birth de-
`fects, and fetal deaths in pregnant women. If this drug is
`used during pregnancy, or the patient becomes pregnant
`while taking this drug, or within approximately two months
`afier discontinuing therapy, the patient should be apprised
`of the potential risks to the fetus including the potential
`long term risk of a DES-like syndrome.
`PRECAUTIONS