‘
`
`www.pdr.net
`
`-‘
`
`AstraZeneca Exhibit 2126 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01910
`
`

`

`W”
`
`EDITION
`
`
`
` fl
`53
`
`
`‘ i999
`PHYSICIANS #
`DESK
`PEFEPENCE
`
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`Ronald Arky, MD, Charles S. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard Medical School
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`v Copyright © 1999 and published by Medical Economics Company, Inc. at Montvale, NJ 07645—1742. All rights reserved. None ofthe 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-
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`® Printed on recycled paper
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`ISBN: 1563632888
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`AstraZeneca Exhibit 2126 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 2
`
`Section 5
`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.
`
`Drug Information Centers ...............................................................................................' .......................... 2 20
`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 ................................................ ............................. 348'
`Gives numbers of key repOIting programs and information services.
`
`Poison Control Centers .......................................................................................................................... 3478
`A national directOIy arranged alphabetically by state and city.
`
`AstraZeneca Exhibit 2126 p. 3
`
`

`

`There is no experience to date with zafirluksst overdose in
`humans. It is reasonable to employ the usual supportive
`measures in the event of an overdose; eg, remove unab~
`sorbed material from the gastrointestinal tract, employ clin«
`ical monitoring, and institute supportive therapy, if re
`quired.
`DOSAGE AND ADMINISTRATION
`The recommended dose ofACCOLATE is 20 mg twice daily
`in adults and children 12 years and older. Since food re
`duces the bioavailability of zafirlukast, ACCOLATE should
`be taken at least 1 hour before or 2 hours after meals.
`Elderly Patients:
`the clearance of
`Based on crosssstudy comparisons,
`zafirlukast is reduced in elderly patients (65 years of age
`and older), such that Cmax and AUC are approximately
`twice those of younger adults. In clinical trials, 3 dose of 20
`mg twice daily was not associated with an increase in the
`overall incidence of adverse events or withdrawals because
`of adverse events in elderly patients.
`Patients with Hepatic Impairment:
`The clearance of zafirlukast is reduced in patients with sta-
`ble alcoholic cirrhosis such that the Cm, and AUC are ap-
`proximately 50A60‘l‘a greater than those of normal adults.
`ACCOLA'I‘E has not been evaluated in patients with hepa-
`titis or in long»term studies of patients with cirrhosis.
`Patients with Renal Impairment:
`Dosage adjustment is not required for patients with renal
`impairment.
`Pediatric Patients:
`The safety and ellectiveness of ACCOLATE in pediatric ps~
`tients below the age of 12 years have not been established)
`HOW SUPPLIED
`20 mg Tablets, (NDC 03100402) white, round, biconvex,
`coated tablets identified with “ZENECA” debossed on one
`side and “ACCOLATE 20” debossed on the other side are
`supplied in opaque HDPE bottles of 60 tablets and hospital
`Unit Dose blister packages of 100 tablets)
`Store at controlled room temperature, (20325“ C) (68%
`77°F) [see USP]. Protect from light and moisture. Dispense
`in the original air-tight container.
`Manufactured for:
`Zeneca Pharmaceuticals
`A Business Unit of Zeneca lnc.
`Wilmington, Delaware 19850—5437
`By: [PR Pharmaceuticals Inc.
`Carolina, Puerto Rico
`G 06/98
`670005
`Shown in Product Identification Guide, page 345
`
`
`PHYSICIANS’ DESK REFERENCE®
`3404/ZENECA PHARMACEUTICALS
`
`olites. Based on these in vitm and in uico results, it is on
`sues, such as adipose tissue, with further conversion of es.
`Accolate-wCont.
`trons to estradiol. Many breast cancers also contain are
`likely that co-administration of ARIMIDEX 1 mg with other
`drugs will result in clinically significant inhibition of cyto-
`l matase; the importance of tumor~generated estrogens is un-
`certain.
`chrome P450 mediated metabolism.
`Treatment of breast cancer has included efforts to decrease
`Pharmacodynamics
`Effect on Estradiol: Mean serum concentrations of estra.
`estrogen levels by ovaricctomy premenopausally and by use
`of antiestrogene and progestational agents both pre- and
`diol were evaluated in multiple daily dosing trials with 05,
`postmenopausally, and these interventions lead to def
`1, 3, 5, and 10 mg ii'ARlMlDEX in postmenopausal women
`creased tumor mass or delayed progression of tumor growth
`with advanced breast cancer Clinically significant Suppres.
`in some women.
`sion of serum estradiol was seen with all doses. Doses of 1
`Anastrozole is a potent and selective nonssteroidal aroA
`mg and higher resulted in suppression of mean serum con.
`matasc inhibitor. It significantly lowers serum estradiol
`centrations of estradiol to the lower limit of detection (3,7
`concentrations and has no detectable effect on formation of
`pmol/L). The recommended daily dose, ARIMIDEX 1 mg, re-
`adrenal corticosteroids or aldosterone.
`Pharmacokinetics
`duced estradiol by approximately 70% within 24 hours and
`by approximately 80% after 14 days of daily dosing. Sup.
`Inhibition of aromatase activity is primarily due to anastro'
`pression of serum estradiol was maintained for up to 6 days
`zole, the parent drug. Studies with radiolabeled drug have
`after cessation of daily dosing with ARIMIDEX 1 mg.
`demonstrated that orally administered anastrozole is well
`Effect on Corticosteroids:
`In multiple daily dosing trials
`absorbed into the systemic circulation with 83 to 85% of the
`radiolabel recovered in urine and feces. Food does not affect
`with 3, 5, and 10 mg, the selectivity of anastrozole was as
`the extent of absorption. Elimination of anastrozole is pri-
`sessed by examining the effects on corticosteroid synthesis,
`For all doses, anastrozole did not effect cortisol or aldoste»
`marily via hepatic metabolism (approximately 85%) and to
`a lesser extent, renal excretion (approximately 11%), and
`rone secretion at baseline or in response to ACTH) No glu.
`snastrozole has a mean terminal elimination halfdife of ap-
`cocorticoid or mineralocorticoid replacement therapy is nec-
`proximately 50 hours in postmenopausal women. The major
`essary with anastrozolei
`circulating metabolite of anastrozole, triazole, lacks phar‘
`In multiple daily dosing trials
`Other Endocrine Effects:
`macologic activity. The pharmacokinetic parameters are
`with 5 and 10 mg, thyroid stimulation hormone (TSH) was
`similar in patients and in healthy postmenopausal volun-
`measured; there was no increase in TSH during the admin.
`teers. The pharmacokinetics of anastrozole are linear over
`istration ofARlMlDEX. ARIMIDEX does not possess direct
`the dose range of 1 to 20 mg and do not change with re-
`progestogenic, androgenic, or estrogenic activity in animals,
`peated dosing. Consistent with the approximately 2—day ter.
`but does perturb the circulating levels of progesterone, an-
`minal elimination half—life, plasma concentrations approach
`drogens, and estrogens.
`steady‘state levels at about 7 days of once daily dosing and
`Clinical Studies
`steadyvstate levels are approximately three to four-fold
`Anastrozole was studied in two well~controllcd clinical trials
`higher
`than levels observed after a single dose of
`ARIMIDEX. Anastrozole is 40% bound to plasma proteins in
`(0004, a North American study; 0005, a predominately Eu-
`the therapeutic range.
`ropean study) in postmenopausal women with advanced
`Metabolism and Excretion: Studies of postmenopausal
`breast cancer who had disease progression following tamoxs
`women demonstrated that anastrozole is extensively metab»
`ifen therapy for either advanced or early breast cancer.
`olized with about 10% of the dose excreted in the urine as
`Some of the patients had also received previous cytotoxic
`unchanged drug within 72 hours of dosing, and the remain-
`treatment. Most patients were Ell-positive; a smaller frac»
`der (about 60% of the dose) excreted in the urine as metab-
`tion were Ell-unknown or BER—negative (the Eli-negative pa-
`olites. Metabolism of anastrozole occurs by N-deelkylation,
`tients were eligible only if they had had a positive response
`hydroxylation and glucoronidation. Three metabolites of
`to tamoxifen). Eligible patients with measurable and non‘
`anastrozole have been identified in human plasma and
`measurable disease were randomized to receive either a sin»
`urine. The known metabolites are triazole, a glucuronide
`gle daily dose of 1 mg or 10 mg ofARlMIDEX or megestrol
`conjugate of hydroxy-anastrozole, and a glucuronide of
`acetate 40 mg four times a day The studies were double-
`anastrozole itself. Several minor (less than 5% of the radio-
`blinded with respect to ARIMIDEXi Time to progression
`active dose) metabolites have not been identified.
`and objective response (only patients with measurable dis‘
`, Because renal elimination is not a significant pathway of
`case could be considered partial responders) rates were the
`elimination, total body clearance of anastrozole is un-
`primary efficacy variables. Objective response rates were
`changed even in severe (creatinine clearance less than 30
`calculated based on the Union Internationale Contre 1e
`mL/min/l.73m2) renal impairment; dosing adjustment in
`Cancer (UICC) criteria. The rate of prolonged (more than 24
`patients with renal dysfunction is not necessary (see Special
`weeks) stable disease, the rate of progression, and survival
`Populations and DOSAGE AND ADMINISTRATION sec-
`were also calculated.
`tions) Dosage adjustment is also unnecessary in patients
`Both trials included over 375 patients; demographics and
`with stable hepatic cirrhosis (see Special Populations and
`other baseline characteristics were similar for the three
`DOSAGE AND ADMINISTRATION sections).
`treatment groups in each trial. Patients in the 0005 trial
`Special Populations
`had responded better to prior tamoxifen treatment. Of the
`Geriatric: Anastrozole pharmacokinetics have been inves
`patients entered who had prior tamoxifen therapy for ad-
`tigated in postmenopausal female volunteers and patients
`vanced disease (58% in Trial 0004; 57% in Trial 0005), 18%
`with breast cancer. No age related effects were seen over the
`of these patients in Trial 0004 and 42% in ’ll‘ial 0005 were
`range <50 to >80 years.
`’
`reported by the primary investigator to have responded In
`‘ Race: Anastrozole pharmacokinetic differences due to race
`Trial 0004, 81% of patients were Eltpositive, 13% were ER~
`have not been studied.
`unknown, and 6% were ER-negative. In Trial 0005, 58% of
`Renal Insufficiency: Anastrozole pharmacokinetics have
`patients were FIR-positive, 37% were ERvunlmown, and 5%
`been investigated in subjects with renal insufficiency. Anas-
`were ERmegative. In Trial 0004, 62% of patients had mea-
`trozole renal clearance decreased proportionally with creat—
`surable disease compared to 79% in Trial 0005. The sites of
`ininc clearance and was approximately 50% lower in volun-
`metastatic disease were similar among treatment groups
`teers with severe renal impairment (creatinine clearance
`for each trial, On average, 40% of the patients had soft tis«
`less than 30 mL/min/L73m2) compared to controls. Since
`sue metastases, 60% had bone metastases, and 40% had Vis-
`only about 10% of anastrozole is excreted unchanged in the
`ceral (15% liver) metastases.
`urine, the reduction in renal clearance did not influence the
`As shown in the table below, similar results were observed
`total body clearance (see DOSAGE AND ADMINISTRA—
`among treatment groups and between the two trials. None
`TION).
`of the withinvtrial differences were statistically significant.
`Hepatic Insufficiency: Hepatic metabolism accounts for ap-
`Megestrol
`proximately 85% of anastrozole elimination. Anastrozole
`ARlMlDEX ARIMIDEX Acetate
`pharmacokinetics have been investigated in subjects with
`1 mg
`10 mg
`160 mg
`
`hepatic cirrhosis related to alcohol abuse. The apparent oral
`clearance (CL/F) of anastrozole was approximately 30%
`Trial 0004
`lower in subjects with stable hepatic cirrhosis than in con
`trol subjects with normal liver function. However, plasma
`(N. America)
`anastrozole concentrations in the subjects with hepatic cir'
`Median Follow-up
`rhosis were within the range of concentrations seen in nor—
`(months)*
`Median Time to Death
`mal subjects across all clinical trials (see DOSAGE AND
`ADMINISTRATION), so that no dosage adjustment
`is
`(months)
`needed.
`2 Year Survival
`Probability (%)
`Drug~Drug lnteractions: Anastrozole inhibited reactions
`Median Time to
`catalyzed by cytochrome P450 1A2, 208/9, and 3A4 in vitro
`with Ki values which were approximately 30 times higher
`Progression (months)
`Objective Response
`than the mean steady’state Cmax values observed following
`a 11mg daily dose. Anastrozole had no inhibitory effect on
`102
`10.0
`12.5
`(all patients) (‘70)
`_
`Stable Disease
`reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro.
`32,8
`29.2
`35.2
`for >24 weeks (‘70)
`Administration of a single 30 mg/kg or multiple 10 rug/kg
`
`Progression (‘70) 90,6 86.7 85.4
`doses of anastrozole to subjects had no effect on the clear-
`
`
`ance of antipyrine or urinary recovery of antipyrine metab—
`
`-
`
`ARIMIDEX®
`anastrozole
`TABLETS
`
`Ba
`
`_
`DESCRIPTION
`ARIMIDEX® (anastrozole) tablets for oral administration
`contain 1 mg of anastrozole, a non-steroidal aromatase in»
`hibitor. It is chemically described as l,3-Benzenediacetoni«
`trile, o, u, of, o’-tetramethyl-5~(1H-1,2,4'triazol-l»ylmethyl).
`Its molecular formula is CmHmNs and its structural for
`mula is:
`
`0'3N /
`\N
`
`H30
`H c
`3
`
`CM
`
`OH;
`
`CM CH3
`
`Anastrozole is an off-white powder with a molecular weight
`of 293.4. Anastrozole has moderate aqueous solubility (0.5
`mg/mL at 25°C); solubility is independent of pH in the phys-
`iological range. Anastrozole is freely soluble in methanol,
`acetone, ethanol, and tetrahydrofuran, and very soluble in
`acetonitrile.
`Each tablet contains as inactive ingredients: lactose, mag-
`nesium stearate, hydroxypropylmethylcellulose, polyethy-
`lene glycol, povidone, sodium starch glycolate, and titanium
`dioxide.
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Many breast cancers have estrogen receptors and growth of
`these tumors can be stimulated by estrogens. In post-men»
`opausal women, the principal source of circulating estrogen
`(primarily estradiol) is conversion of adrenally-generated
`androstenedione to estrone by aromatase in peripheral tis-
`lnformation will be superseded by supplements and subsequent editions
`
`
`
`.
`
`'
`
`-
`
`
`
`(n2128)
`31.3
`
`(n=130)
`30.9
`
`29.6
`
`62.0
`
`5.7
`
`25.7
`
`58.0
`
`5.3
`
`(112128)
`32.9
`
`26,7
`
`53.1
`
`51
`
`AstraZeneca Exhibit 2126 p. 4
`
`

`

`ZENECA PHARMACEUTICALS/3405
`PRODUCT INFORMATION
`ing pregnancy or if the patient becomes pregnant while res
`Trial 0005
`
`ceiving this drug, the patient should, be apprised of the pc.
`(Europe, Australia,
`tential hazard to the fetus or potential risk for loss of the
`S.Africa)
`pregnancy.
`Median Followup
`PRECAUTIONS
`(months)*
`Median Time to Death
`General: Before starting treatment with ARIMIDEX, preg
`(months)
`nancy must be excluded (see WARNINGS).
`2 Year Survival
`ARIMIDEX should be administered under the supervision
`Probability (70)
`of a qualified physician experienced in the use of anticancer
`Median Time to
`agents.
`Laboratory Tests: Three-fold elevations. of mean serum
`Progression (months)
`Objective Response
`gamma glutamyl transferase (GT) levels have been ob»
`14.4
`15,3
`12.6
`(all patients) (70)
`served among patients with liver metastases receiving
`Stable Disease
`ARIMIDEX. or megestrol acetate. These changes were likely
`23.2
`25.4
`24.4
`for >24 weeks (’70)
`related to the progression of liver metastases in these pa-
`
`
`
`01.9 89.8Progression (%) 92.0
`tients, although other contributing factors could not be
`ruled out.
`* Surviving Patients
`(See CLINICAL PHARMACOLOGY)
`Drug interactions:
`Anastrozole inhibited in vitro metabolic reactions catalyzed
`by cytochromes P450 1A2. 208/9. and 3A4 but only at rela-
`tively high concentrations. Anastrozole did not inhibit P450
`2A6 or the polymorphic P450 2136 in human liver mi.
`crosomes. Anastrozole did not alter the pharmacokinetics of
`antipyrine. Although there have been no formal interaction
`studies other than with antipyrine, based on these in oivo
`li
`: and in vim; studies, it is unlikely that conduiinistration of
`a Ling dose of ARIMlDEX with other drugs will result in
`clinically significant drug inhibition of cytochrome P450-
`mediated metabolism of the other drugs.
`No clinically signifi-
`Drug/Laboratory Test Interactions:
`* cant changes in the results of clinical laboratory tests have
`: been observed.
`Carcinogenesis: No long~term animal studies have been
`conducted to assess
`the
`carcinogenic potential
`of
`. ARIMIDEX.
`ARIMIDEX has not been shown to be muta-
`2’ Mutagenesls:
`genic in in vitro tests (Ames and E. coli bacterial tests,
`2 CHO-K1 gene mutation assay) or clastogenic either in vitro
`;
`(chromosome aberrations in human lymphocytes) or in vivo
`(micronucleus test in rats).
`Impairment of Fertility: Studies to investigate the effect of
`‘ ARIMIDEX on fertility have not been conducted; however,
`chronic studies indicated hypertrophy of the ovaries and the
`- presence of follicular cysts in rats administered closes equal
`.
`to or greater than 1 mg/kg/day (which produced plasma
`; anastrozole C35mm and AUCO,24 m that were 19 and 9 times
`higher than the respective values found in healthy post-
`' menopausal humans at the recommended dose). In addi-
`tion, hyperplastic uteri were observed in chronic studies of
`female dogs administered doses equal to or greater than 1
`mg/kg/day (which produced plasma anastrozole Csmax and
`l AUCO_24 m that were 22 times and 16 times higher than the
`.
`respective values found in postmenopausal humans at the
`'
`recommended dose). It is not known whether these efiects
`on the reproductive organs of animals are associated with
`impaired fertility in humans.
`(See WARNINGS).
`Pregnancy: Pregnancy Category D:
`Nursing Mothers:
`It is not known if anastrozole is ex-
`creted in human milk. Because many drugs are excreted in
`human milk, caution should be exercised when ARIMIDEX
`is administered to a nursing woman (see WARNINGS and
`PRECAUTIONS)
`Pediatric Use: The safety and efficacy ofARIMIDEX in pe-
`diatric patients have not been established.
`Geriatric Use: Fifty percent of patients in studies 0004 and
`0005 were 65 or older. Response rates and time to progTESv
`sion were similar for the over 65 and younger patients.
`ADVERSE REACTIONS
`ARIMIDEX was generally well tolerated in two well-con-
`trolled clinical trials (i.e., Trials 0004 and 0005), with less
`than 3.3% of the ARIMIDEX-treated patients and 4.0% of
`the megestml acetate~treated patients withdrawing due to
`an adverse event.
`The principal adverse event more common with ARIMIDEX
`than megestrol acetate was diarrhea. Adverse events re-
`ported in greater than 5% of the patients in any of the treat-
`ment groups in these two well-controlled clinical trials, re»
`gardless of causality, are presented below:
`Number in) and Percentage of Patients
`with Adverse Event 1‘
`
`l l l lg l ill ll
`
`(13:12:?)
`
`19.8
`
`39.1
`
`3.9
`
`(n3135)
`
`(11:118)
`
`31.0
`
`24.3
`
`50.5
`
`4.4
`
`30.9
`
`24.8
`
`50.9
`
`5.3
`
`More than 1/3 of the patients in each treatment group in
`both studies had either an objective response or stabilize
`tiou of their disease for greater than 24 weeks. Among the
`263 patients who received ARIMIDEX 1 mg there were 11
`complete responders and 22 partial responders In patients
`who had an objective response more than 80% were still
`responding at 6 months from randomization and more than
`45% were still responding at 12 months from randomisa—
`tion.
`When data from the two controlled trials are pooled, the ob«
`jective response rates and median times to progression and
`death were similar for patients randomized to ARIMIDEX 1
`mg and megestrol acetate. There is, in this data, no indica‘
`tion that ARIMIDEX 10 mg is superior to ARIMIDEX 1 mg.
`Meges‘lrol
`ARIMIDEX ARlMIDEX Acetate
`
`1 mg
`10 m9
`160 mg
`
`(n2263)
`
`(nz248)
`
`(n:253)
`
`Trials 0004 & 0005
`(Pooled Data)
`Median Time to Death
`(months)
`2 Year Survival
`Probability (70)
`Median Time to
`Progression (months)
`Objective Respose
`
`12.5 12.5(all patients) (%) 12.3
`
`26.7
`
`56.1
`
`4.8
`
`
`
`25.5
`
`54.6
`
`5.3
`
`
`
`22.5
`
`46.3
`
`46
`
`Objective response rates and median times to progression
`and death for ARIMIDEX 1 mg were similar to megestrol
`acetate for women over or under 65. There were too few non-
`white patients studied to draw conclusions about racial dif—
`ferences in response.
`INDICATIONS AND USAGE
`ARIMIDEX is indicated for the treatment of advanced
`breast cancer in postmenopausal women with disease pro-
`gression following tamoidfen therapy.
`Patients with ER-negative disease and patients who did not
`respond to previous tamoxifen therapy rarely responded to
`ARIMIDEX.
`CONTRAINDICATIONS
`None known.
`WARNINGS
`ARIMIDEX can cause fetal harm when administered to a
`pregnant woman. Anastrozole has been found to cross the
`placenta following oral administration of 0.1 tug/kg in rats
`and rabbits (about 3/4 and 1.5 times the recommended hu»
`man dose, respectively, on a rug/m2 basis. Studies in both
`rats and rabbits at doses equal to or greater than 0.1 and
`0.02 mg/kg/day, respectively (about 3/4 and 1I3, respectively,
`the recommended human dose on a rug/m2 basis), adminis
`tration during the period of organogenesis showed that
`anasttozole increased pregnancy loss (increased pre- and/or
`post-implantation loss, increased resorption, and decreased
`numbers of live fetuses); effects were dose—related in rats.
`Placental weights were significantly increased in rats at
`doses of 0.1 mg/kg/day or more.
`Evidence of fetotoxicity, including delayed fetal develop—
`ment (i.e., incomplete ossification and depressed fetal body
`weights), was observed in rats administered doses of 1 mg/
`kg/day (which produced plasma anastrozole 055mK and
`AUCO_24 h, that were 19 times and 9 times higher than the
`respective values found in healthy post-menopausal hu-
`mans at the recommended dose). There was no evidence of
`teratogenicity in rats administered doses up to 1.0 mg/kg/
`day. In rabbits, ansstrozole caused pregnancy failure at
`doses equal to or greater than 1.0 mg/lig/day (about 16times
`the recommended human dose on 3 mg/m2 basis); there was
`no evidence of teratogenicity in rabbits administered 0.2
`mg/kg/day (about 3 times the recommended human dose on
`a mg/rn2 basis).
`There are no adequate and well‘controlled studies in preg—
`nant women using ARIMIDEX. If ARIMIDEX is used dur-
`
`Megestrol
`Acetate
`ARIMIDEX ARIMIDEX
`1 mg
`10 mg
`160 mg
`(n=262)
`(151-1246)
`(11:25.3)
`
`
`Adverse Event
`n
`%
`n
`%
`n
`70
`
`
`-
`
`Asthenia
`Nausea
`Headache
`Hot Flushes
`Pain
`Back Pain
`Dyspnea
`
`42
`41
`34
`32
`28
`28
`24
`
`(16.0)
`(15.6)
`(13.0)
`(12.2)
`(10.7)
`(10.7)
`(9.2)
`
`33
`48
`44
`29
`38
`26
`27
`
`(13.4)
`(19.5)
`(17.9)
`(10.6)
`(15.4)
`(10.6)
`(11.0)
`
`47
`28
`24
`21
`29
`19
`53
`
`(18.6)
`(11.1)
`(9.5)
`(8.3)
`(11.5)
`(7.5)
`(20.9)
`
`l lllI lIlll
`
`ill i lll illli lixi .
`
`;
`
`
`
`Vomiting
`Cough
`Increased
`Diarrhea
`Constipation
`Abdominal
`Pain
`Anorexia
`Bone Pain
`Pharyngitis
`Dizziness
`Rash
`Dry Mouth
`Peripheral
`Edema
`Pelvic Pain
`Depression
`Chest Pain
`Paresthesia
`Vaginal
`Hemorrhage
`Weight Gain
`Sweating
`Increased
`
`0 (0) 1 (0,4) 13Appetite (5.1)
`
`24
`22
`22
`18
`
`18
`18
`17
`16
`16
`15
`15
`14
`14
`14
`13
`12
`
`(3
`4
`4
`
`
`
`(9.2)
`(8.4)
`(8.4)
`(6.9)
`
`(6.9)
`(6.9)
`(6.5)
`(6.1,)
`(6.1)
`(5.7)
`(5.7)
`(5.3)
`(5.3)
`(5.3)
`(5.0)
`(4.6)
`
`(2.3)
`(1.5)
`(1.5)
`
`
`
`26
`18
`18
`18
`
`14
`19
`26
`23
`12
`15
`11
`21
`17
`6
`18
`15
`
`4
`9
`3
`
`
`
`(10.6)
`(7.3)
`(7.3)
`(7.3)
`
`(5.7)
`(7.7)
`(11.8)
`(9.3)
`(4.9)
`(6.1)
`(4.5)
`(8.5)
`(6.9)
`(2.4)
`(7.3)
`(6.1)
`
`(1.6)
`(3.7)
`(1.2)
`
`
`
`16
`19
`7
`21
`
`18
`11
`19
`15
`15
`19
`13
`28
`13
`5
`13
`9
`
`13
`30
`16
`
`
`
`(8.3)
`(7.5)
`(2.8)
`(8.3)
`
`(7.1)
`(4.3)
`(7.5)
`(5.9)
`(5.9)
`(7.5)
`(5.1)
`(11.1)
`(5.1)
`(2.0)
`(5.1)
`(3.6)
`
`(5.1)
`(11.9)
`(6.3)
`
`T A patient may have more than one adverse event.
`
`Other less frequent (2% to 5%) adverse experiences reported
`in patients receiving ARIMIDEX 1 mg in either Trial 0004
`or Trial 0005 are listed below. These adverse experiences
`are listed by body system and are in order of decreasing fre«
`quency within each body system regardless of assessed cau‘
`sality.
`Body as a Whole: Flu syndrome; fever; neck pain; malaise;
`accidental injury; infection
`Cardiovascular: Hypertension; thromhophlebitis
`Hepatic: Gamma GT increased; SGOT increased; SGPT in-
`creased
`Hematologic:
`Anemia; leukopenia
`Metabolic and Nutritional:
`Alkaline phosphatase in‘
`creased; weight loss
`‘
`levels increased by 0.5
`Mean serum total cholesterol
`mmol/L among patients receiving ARIMIDEX. Increases in
`LDL cholesterol have been shown to contribute to these
`changes.
`Musculoskeletal: Myalgia; arthralgia; pathological frac~
`ture
`Nervous: Somnolence; confusion; insomnia; anxiety; ner~
`vousness
`Respiratory: Sinusitis; bronchitis; rhinitis
`Skin and Appendages: Hair thinning; pruritus
`Urogenital: Urinary tract infection; breast pain
`Vaginal bleeding has been reported infrequently, mainly in
`patients during the first few weeks after changing from ex-
`isting hormonal therapy to treatment with ARIMIDEX. If
`bleeding persists, further evaluation should be considered.
`The incidences of the following adverse event groups, poten-
`tially causally related to one or both of the therapies be—
`cause of their pharmacology, were statistically analyzed:
`weight gain, edema, thromboembolic disease, gastrointesti-
`nal disturbance, hot flushes, and vaginal dryness. These six
`groups, and the adverse events captured in the groups, were
`prospectively defined. The results are shown in the table be
`low.
`
`Number (n) and Percentage of Patients
`Megestrol
`ARIMIDEX ARIMIDEX
`Acetate
`1mg
`10 mg
`160mg
`(n=262)
`(n=246)
`(112253)
`
`Adverse Event
`
`Group
`n
`%
`n
`%
`n
`Gastrointestinal
`Disturbance
`,HotFlushes
`Edema
`Thomboembolic
`(4.7)
`12
`(1.6)
`4
`(3.4)
`9
`Disease
`(0.8)
`2
`(1.2)
`3
`(1.9)
`5
`Vaginal Dryness
`
`
`
`
`
`
`4 (1.5) 10 (4.1) 30WeightGain (11.9)
`
`77
`33
`19
`
`(29.4)
`(12.6)
`(7.3)
`
`81
`29
`28
`
`(32.9)
`(11.8)
`(11.4)
`
`%
`
`54
`35
`35
`
`(21.3)
`(13.8)
`(13.8)
`
`More patients treated with megestrol acetate reported
`weight gain as an adverse event compared to patients
`treated with ARIMIDEX 1 mg (p<0.0001). Other differences
`were not statistically significant.
`An examination of the magnitude of change in weight in all
`patients was also conducted. Thirty-four percent (87/253) of
`the patients treated with megestrol acetate experienced
`weight gain of 5% or more and 11% (27/253) of the patients
`treated with megestrol acetate experienced weight gain of
`10% or more. Among patients treated with ARIMIDEX 1
`
`Continued on next page
`Consult 1999 PDR® supplements and future editions for revisions
`
`AstraZeneca Exhibit 2126 p. 5
`
`

`

`
`
`...,.Mummmmmmmmmmwmm
`
`figure},
`The Kaplan-Meler Probability of Death
`For Both Antiandrogen Treatment Groups
`
`1.0 N
`
`0.3
`9.7
`0.6
`0.5
`
`x.
`b
`
`x,
`
`,
`
`0.4 0.3 7
`
`0,2 , W» Casodex plus LHRH<A
`03
`A . - Fluiamide plus LHRHA
`0.0
`rem—m—fiTfls—wrvmrww-rm‘wfl
`365
`730
`1095
`1460
`l825
`
`0
`
`
`
`Proportionsurviving
`
`Days to death
`
`There was no significant difference in time to objective tu-
`mor progression between treatment groups (see Figure 2).
`Objective tumor progression was defined as the appearance
`of any bone metastases or the worsening of any existing
`bone metastases on bone scan attributable to metastatic
`disease, or an increase by 25% or more of any existing mea~
`surable extraskeletal metastases. The hazard ratio for time
`to progression of CASODEX plus LHRH analogue to that of
`flutamide plus LHRH analogue was 0.93 (95% confidence
`interval, 0.79 to 1.10).
`
`PHYSlClANS’ DESKREFERENCE®
`
`3406/ZENECA PHARMACEUTICALS
`CASODEXALHRH analogue therapy. and 235 (57.5%) pa»
`The inactive ingredients of CASODEX Tablets are lactose,
`Arimidewaontr
`tients treated with Homicide-LURE analogue therapy had
`magnesium stearate, methylhydroxypropylcellulose, poly
`died. There was no significant difference in survival be»
`ethylene glycol, polyvidone, sodium starch glycollate, and ti»
`tamum dioxide.
`tween treatment groups (see Figure 1). The hazard ratio for
`time to death (survival) was 0.87 (95% confidence interval
`CLINICAL PHARMACOLOGY~- .
`0.72 to 1.05).
`' Mechanism of Ac