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
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`Jeffrey F. Pfohl
`PDR Data Manager: Jeffrey D. Schaefer
`Christopher N. Schmidt
`Senior Format Editor: Gregory J. Westley
`Stephen M. Silverberg
`.
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`Index Editors: Johanna M. Mazur, Robert N. ‘Woerner
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`Director of Direct Marketing: Michael Bennett
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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
`_ 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.2126 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. 2126 p. 3
`
`

`
`3404/ZENECA PHARMACEUTICALS
`
`Accolate--~Cont.
`
`There is no experience to date with zsfirlukast overdose in
`humans. It is reasonable to employ the usual supportive
`measures in the event of an overdose; e.g., 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 MACCOLATE 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 cross-study comparisons,
`zafirlukast is reduced in elderly patients (65 years of age
`and older), such that Cmx and AUC are approximately
`twice those of younger adults. In clinical trials, a 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 50-60‘?/8 greater than those of normal adults.
`ACCOLATE 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 eilectiveness of ACCOLATE in pediatric pa-
`tients below the age of 12 years have not been established.
`HOW SUPPLIED
`20 mg Tablets, (NDC 0310-0402) 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, (20“-25“ 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 Inc.
`Wilmington, Delaware 19850-5437
`By: IPR Pharmaceuticals Inc.
`Carolina, Puerto Rico
`G 06/98
`670005
`Shown in Product Identification Guide, page 345
`
`
`ARIMlDEX®
`anastrozole
`TABLETS
`
`Ba
`
`_
`DESCRIPTION
`ARIMIDEX® (anastrozole) tablets for oral administration
`contain 1 mg of anastrozole, a non-steroidal arcmatase in-
`hibitor. It is chemically described as 1,3-Benzenediacetonb
`trile, or, oi, oi’, oz’-tetramethyl-5-(1H-1,2,4-triazob1-ylmethyl).
`Its molecular formula is C1»,H19N5 and its structural for-
`mula is:
`
`/2)N\N/
`
`H30
`H c
`"
`
`cm
`
`CH3
`
`on 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-met»
`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
`
`sues, such as adipose tissue, with further conversion of es-
`trone to estradiol. Many breast cancers also contain aro-
`‘ matase; the importance of tumor-generated estrogens is un-
`certain.
`Treatment of breast cancer has included efforts to decrease
`estrogen levels by ovariectomy premenopausally and by use
`of antiestrogens and progestational agents both pre- and
`post-menopausally, and these interventions lead to de-
`creased tumor mass or delayed progression of tumor growth
`in some women.
`Anastrozole is a potent and selective non-steroidal aro-
`matase inhibitor. It significantly lowers serum estradiol
`concentrations and has no detectable effect on formation of
`adrenal corticosteroids or aldosterone.
`Pharmacokinetics
`Inhibition of aromatase activity is primarily due to enactm-
`zole, the parent drug. Studies with radiolabeled drug have
`demonstrated that orally administered anastrozole is well
`absorbed into the systemic circulation with 83 to 85% of the
`radiolabel recovered in urine and feces. Food does not affect
`the extent of absorption. Elimination of anastrozole is pri-
`marily via hepatic metabolism (approximately 85%) and to
`a lesser extent, renal excretion (approximately 11%), and
`anastrozole has a mean terminal elimination half-life of ap-
`proximately 50 hours in postmenopausal women. The major
`circulating metabolite of anastrozole, triazole, lacks phar-
`macologic activity. The pharmacokinetic parameters are
`similar in patients and in healthy postmenopausal volun-
`teers. The pharmacokinetice of anasttozole are linear over
`the dose range of 1 to 20 mg and do not change with re-
`peated closing. Consistent with the approximately 2-day ter-
`minal elimination half-life, plasma concentrations approach
`steady-state levels at about 7 days of once daily dosing and
`- steady-state levels are approximately three to four-fold
`higher
`than levels observed after a single dose of
`ARIMIDEX. Anastrozole is 40% bound to plasma proteins in
`the therapeutic range.
`Metabolism and Excretion: Studies of postmenopausal
`women demonstrated that anastrozole is extensively metab-
`olized with about 10% of the dose excreted in the urine as
`unchanged drug within 72 hours of dosing, and the remain-
`der (about 60% of the dose) excreted in the urine as metab-
`olites. Metabolism of anastrozole occurs by N-deelkylation,
`hydroxylation and glucoronidation. Three metabolites of
`anastrozole have been identified in human plasma and
`urine. The known metabolites are triazole, a glucuronide
`conjugate of hydroxy-anastrozole, and a glucuronide of
`anastrozole itself. Several minor (less than 5% of the radio-
`active close) metabolites have not been identified.
`1 Because renal elimination is not a significant pathway of
`elimination, total body clearance of anastrozole is un-
`changed even in severe (creatinine clearance less than 30
`rnL/min/l.73m2) renal impairment; dosing adjustment in
`patients with renal dysfunction is not necessary (see Special
`Populations and DOSAGE AND ADMINISTRATION sec-
`tions). Dosage adjustment is also unnecessary in patients
`with stable hepatic cirrhosis (see Special Populations and
`DOSAGE AND ADMINISTRATION sections).
`Special Populations
`Geriatric: Anastrozole pharmacokinetics have been inves-
`tigated in postmenopausal female volunteers and patients
`with breast cancer. No age related effects were seen over the
`range <50 to >80 years.
`'
`‘ Race: Anastrozole pharmacokine-tic differences due to race
`have not been studied.
`Renal Insufficiency: Anastrozole pharmacokinetics have
`been investigated in subjects with renal insuificiency. Anas-
`trozole renal clearance decreased proportionally with creat-
`inine clearance and was approximately 50% lower in volun-
`teers with severe renal impairment (creatinine clearance
`less than 30 mL/minf1.73m2) compared to controls. Since
`only about 10% of anastrozole is excreted unchanged in the
`urine, the reduction in renal clearance did not influence the
`total body clearance (see DOSAGE AND ADMINISTRA-
`TION).
`Hepatic Insufficiency: Hepatic metabolism accounts for ap-
`proximately 85% of anastrozole elimination. Anastrozole
`pharmacokinetics have been investigated in subjects with
`hepatic cirrhosis related to alcohol abuse. The apparent oral
`clearance (CL/F) of anastrozole was approximately 30%
`lower in subjects with stable hepatic cirrhosis than in con-
`trol subjects with normal liver function. However, plasma
`anastrozole concentrations in the subjects with hepatic cir-
`rhosis were within the range of concentrations seen in nor-
`mal subjects across all clinical trials (see DOSAGE AND
`ADMINISTRATION), so that no dosage adjustment
`is
`needed.
`Drug~Drug Interactions: Anastrozole inhibited reactions
`catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in uL'tro
`with Ki values which were approximately 30 times higher
`than the mean steady-state Cm,‘ values observed following
`a 1-mg daily dose. Anastrozole had no inhibitory efiect on
`reactions catalyzed by cytochrome P450 2A6 or 2D6 in uitro.
`Administration of a single 30 mg/kg or multiple 10 mg/kg
`doses of anastrozole to subjects had no effect on the clear-
`ance of antipyrine or urinary recovery of antipyrine metab-
`
`=
`
`'
`
`PHYSICIANS’ DESK REFERENCE®
`
`olites. Based on these in citro and in uivo results, it is un-
`likely that co-administration of ARIMIDEX 1 mg with other
`drugs will result in clinically significant inhibition of cyto.
`chrome P450 mediated metabolism.
`Pharmacodynamics
`Effect on Estradiol: Mean serum concentrations of estra.
`diol were evaluated in multiple daily dosing trials with 0.5,
`1, 3, 5, and 10 mg ii'ARll\/IIDEX in postmenopausal women
`with advanced breast cancer. Clinically significant suppres.
`sion of serum estradiol was seen with all doses. Doses of 1
`mg and higher resulted in suppression of mean serum con.
`centrations of estradiol to the lower limit of detection (3,?
`pmol/L). The recommended daily dose, ARIMIDEX 1 mg, re.
`duced estradiol by approximately 70% within 24 hours and
`by approximately 80% after 14 days of daily dosing. Sup.
`pression of serum estradiol was maintained for up to 6 days
`after cessation of daily dosing with ARIMIDEX 1 mg.
`Effect on Corticosteroids:
`In multiple daily dosing trials
`with 3, 5, and 10 mg, the selectivity of anastrozole was as-
`sessed by examining the effects on corticosteroid synthesis.
`For all doses, anastrozole did not effect cortisol or aldoste-
`rune secretion at baseline or in response to ACTH. No glu-
`cocorticoid or mineralocorticoicl replacement therapy is nec-
`essary with anastrozole-
`In multiple daily dosing trials
`Other Endocrine Effects:
`with 5 and 10 mg, thyroid stimulation hormone (TSH) was
`measured; there was no increase in TSH during the admin-
`istration ofARIMIDEX. ARIMIDEX does not possess direct
`progestogenic, androgenic, or estrogenic activity in animals,
`but does perturb the circulating levels of progesterone, an-
`drogens, and estrogens.
`Clinical Studies
`Anastrozole was studied in two well-controlled clinical trials
`(0004, a North American study; 0005, a predominately Eu-
`ropean study) in postmenopausal women with advanced
`breast cancer who had disease progression following tamox-
`ifen therapy for either advanced or early breast cancer.
`Some of the patients had also received previous cytotoxic
`treatment. Most patients were ER-positive; a smaller frac-
`tion were ER-unknown or ER-negative (the ER-negative pa-
`tients were eligible only if they had had a positive response
`to tamoxifen). Eligible patients with measurable and non-
`measurable disease were randomized to receive either a sin-
`gle daily dose of 1 mg or 10 mg ofARlMIDEX or megestrol
`acetate 40 mg four times a day. The studies were double-
`blinded with respect to ARIIVIIDEX. Time to progression
`and objective response (only patients with measurable dis-
`ease could be considered partial responders) rates were the
`primary efificacy variables. Objective response rates were
`calculated based on the Union Internationale Contre le
`Cancer (UICC) criteria. The rate of prolonged (more than 24
`weeks) stable disease, the rate of progression, and survival
`were also calculated.
`Both trials included over 375 patients; demographics and
`other baseline characteristics were similar for the three
`treatment groups in each tidal. Patients in the 0005 trial
`had responded better to prior tamoxifen treatment. Of the
`patients entered who had prior tamoxifen therapy for ad-
`vanced disease (58% in Trial 0004; 57% in Trial 0005), 18%
`of these patients in Trial 0004 and 42% in ’l\‘ial 0005 were
`reported by the primary investigator to have responded. In
`Trial 0004, 81% of patients were ER-positive, 13% were ER-
`unknown, and 6% were ER-negative. In Trial 0005, 58% of
`patients were ER-positive, 37% were ER-unknown, and 5%
`were ER-negative. In Trial 0004, 62% of patients had mea-
`surable disease compared to 79% in Trial 0005. The sites of
`metastatic disease were similar among treatment groups
`for each trial. On average, 40% of the patients had soft tis-
`sue metastases, 60% had bone metastases, and 40% had vis-
`ceral (15% liver) metastases.
`As shown in the table below, similar results were observed
`among treatment groups and between the two trials. None
`of the within-trial differences were statistically significant.
`Megestrol
`ARIMIDEX ARIMIDEX Acetate
`1 mg
`10 mg
`160 mg
`
`Trial 0004
`(N. America)
`Median Follow-up
`(months)*
`Median Time to Death
`(months)
`2 Year Survival
`Probability (%)
`Median Time to
`Progression (months)
`Objective Response
`(all patients) (%)
`Stable Disease
`for >24 Weeks (70)
`Progression (%)
`
`(n:128)
`31.3
`
`(n-—-130)
`30.9
`
`(n=128)
`32.9
`
`29.6
`
`62.0
`
`5.7
`
`12.5
`35.2
`86.7
`
`25.7
`
`58.0
`
`5.3
`
`10,0
`29.2
`85.4
`
`26.7
`
`53.1
`
`5.1
`
`10.2
`.
`32.8
`90.6
`
`Astrazeneca Ex. 2126 p. 4
`
`

`
`PRODUCT INFORMATION
`
`ZENECA PHARMACEUTICALS/3405
`
`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
`Appetite
`
`224
`22
`22
`18
`
`18
`18
`17
`16
`16
`15
`15
`14
`14
`14
`13
`12
`
`(3
`4
`4
`
`O
`
`(9.2)
`(8.4)
`(8.4)
`(6.9)
`
`(6.9)
`(6.9)
`(6.5)
`(8.1)
`(6.1)
`(5.7)
`(5.7)
`(5.3)
`(5.3)
`(5.3)
`(5.0)
`(4.6)
`
`(2.3)
`(1.5)
`(1.5)
`
`(0)
`
`26
`18
`18
`18
`
`14
`19
`26
`23
`12
`15
`11
`21
`17
`6
`18
`15
`
`4
`9
`3
`
`1
`
`(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)
`
`(0.4)
`
`15
`19
`7
`21
`
`18
`11
`19
`15
`15
`19
`13
`28
`13
`5
`13
`9
`
`13
`30
`16
`
`13
`
`(3.3)
`(7.5)
`(2.8)
`(8.3)
`
`(7.1)
`(4.3)
`(7.5)
`(5.9)
`(5.9)
`(7.5)
`(5.1)
`(11.1)
`(5.1)
`(20)
`(5.1)
`(3.6)
`
`(5.1)
`(11.9)
`(6.3)
`
`(5.1)
`
`T A patient may have more than one adverse event.
`
`1 l l 1! ll al3 EEiI
`
`lEl iii i III3i
`
`Trial 0005
`(Europe, Australia,
`§._;gg.§>
`Median Follow-up
`(months)*
`Median Time to Death
`(months)
`2 Year Survival
`Probability C%)
`Median Time to
`Progression (months)
`Objective Response
`(all patients) (96)
`Stable Disease
`for >24 weeks ('70)
`Progression (%)
`
`*‘ Surviving Patients
`
`(n:z135)
`31.0
`
`(n=118)
`30.9
`
`(l’1=125)
`31.5
`
`24.3
`
`50.5
`
`4.4
`
`12.6
`2-1.4
`91.9
`
`24.8
`
`50.9
`
`5.3
`
`15.3
`25.4
`89.8
`
`19.8
`
`39.1
`
`3.9
`
`14.4
`23.2
`92.0
`
`More than 1/3 of the patients in each treatment group in
`both studies had either an objective response or stabiliza-
`tion 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 randomiza-
`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.
`Megestrol
`ARIMIDEX ARlMIDEX Acetate
`1 mg
`10 mg
`160 mg
`
`(n=263)
`
`(n:248)
`
`(n:253)
`
`26.7
`
`25.5
`
`22.5
`
`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 (In) and Percentage of Patients
`Megestrol
`ARIMIDEX ARIMIDEX
`Acetate
`1mg
`10 mg
`160 mg
`(n=262)
`(n=246)
`(112253)
`
`Adverse Event
`Group
`Gastrointestinal
`Disturbance
`Hot Flushes
`Edema
`Thomboembolic
`Disease
`Vaginal Dryness
`Weight Gain
`
`n
`
`77
`33
`19
`
`9
`5
`4
`
`%
`
`(29.4)
`(12.6)
`(7.3)
`
`(3.4)
`(1.9)
`(1.5)
`
`n
`
`81
`29
`28
`
`4
`3
`10
`
`%
`
`(32.9)
`(11.8)
`(11.4)
`
`(1.6)
`(1.2)
`(4.1)
`
`n
`
`54
`35
`35
`
`12
`2
`30
`
`%
`
`(21.3)
`(13.8)
`(13.8)
`
`(4.7)
`(0.8)
`(11.9)
`
`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 Ex. 2126 p. 5
`
`ing pregnancy or if the patient becomes pregnant while re-
`ceiving this drug, the patient should, be apprised of the po-
`tential hazord to the fetus or potential risk for loss of the
`pregnancy.
`PRECAUTIONS
`General: Before starting treatment with ARIMIDEX, preg-
`nancy must be excluded (see WARNINGS).
`ARIMIDEX should be administered under the supervision
`of a qualified physician experienced in the use of anticancer
`agents.
`Laboratory Tests: Three-fold elevations. of mean serum
`gamma glutamyl transferase (GT) levels have been ob-
`served among patients with liver metastases receiving
`ARIMIDEX. or megestrol acetate. These changes were likely
`related to the progression of liver metastases in these pa-
`tients. although other contributing factors could not be
`ruled out.
`(See CLINICAL PHARMACOLOGY)
`Drug Interactions:
`Anastrozole inhibited in oitro metabolic reactions catalyzed
`by cytochromes P450 1A2. 2C8/9, 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 viva
`and in vim; studies, it is unlikely that co-administration of
`a 1-mg dose of ARlMlDEX with other drugs will result in
`clinically significant drug inhibition of cytochrome P450-
`mediated metabolism of the other drugs.
`DruglLaboratory Test Interactions: No clinically signifi-
`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.
`Mutagenesls: ARIMIDEX has not been shown to be muta-
`genic in in uitro tests (Amos and E. coli bacterial tests,
`CHO-K1 gene mutation assay) or clastogenic either in vitro
`(chromosome aberrations in human lymphocytes) or in viva
`(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
`anastrozolc C3_.,,,,,,,( and AUCMM h, 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 C35,“, and
`AUC0_.24 hr that were 22 times and 16 times higher than the
`respective values found in post-menopausal 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 progres-
`sion were similar for the over 65 and younger patients.
`ADVERSE REACTIONS
`ARIMIDEX was generally well tolerated in two we1l-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 megestrol 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 (n) and Percentage of Patients
`with Adverse Event 1‘
`
`ARIMIDEX ARIMIDEX
`1 mg
`10 mg
`(n=262)
`(n=246)
`
`in
`
`42
`41
`34
`32
`28
`28
`24
`
`%
`
`(16.0)
`(15.6)
`(13.0)
`(12.2)
`(10.7)
`(10.7)
`(9.2)
`
`n
`
`33
`48
`44
`29
`38
`26
`27
`
`%
`
`(13.4)
`(19.5)
`(17.9)
`(10.6)
`(15.4)
`(10.6)
`(11.0)
`
`Megestrol
`Acetate
`160 mg
`(n=253)
`
`n
`
`47
`28
`24
`21
`29
`19
`53
`
`%
`
`(18.6)
`(11.1)
`(9.5)
`(8.3)
`(11.5)
`(7.5)
`(20.9)
`
`Adverse Event
`
`Asthenia
`Nausea
`Headache
`Hot Flushes
`Pain
`Back Pain
`Dyspnea
`
`EE
`
`i Iil :lil E liI 1
`
`Trials 0004 & 0005
`(Pooled Data)
`Median Time to Death
`(months)
`2 Year Survival
`Probability (70)
`Median Time to
`Progression (months)
`Objective Respose
`(all patients) (%)
`
`56.1
`
`4.8
`
`12.5
`
`54.6
`
`5.3
`
`12.5
`
`46.3
`
`4.6
`
`12.3
`
`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 mg/kg in rats
`and rabbits (about 3/4 and 1.5 times the recommended hu-
`man dose, respectively, on 21 mg/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 1/3, respectively,
`the recommended human dose on a mg/m2 basis), adminis-
`tration during the period of organogenesis showed that
`anastrozole 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 Cssmx and
`AUC044 h, that were 19 times and 9 times higher than the
`respective values found in healthy postmenopausal 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/kg/day (about 16.times
`the recommended human dose on 21 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/m2 basis).
`There are no adequate and well-controlled studies in preg-
`nant women using ARIMIDEX. If ARIMIDEX is used dur-
`
`

`
`PHYSKZIANS’ DESK_REFERENCE®
`
`CASODEX-LHRII analogue therapy and 235 (57.5%) pa.
`tients treated with flutainhle-l;liRll analogue therapy bod
`died. There was no significant tliflbrcnce in survival be.
`tween treatment groups (see Figure 1). The l'\a7.ard ratio for
`time to death (survival) was 0.87 (95% coniiderme intc.r~.v;al
`0.72 to 1.05).
`
`F.lQQL$..‘l.
`The Kaplan-Meier Probability of Death
`For Both Antiandrogen Treatment Groups
`
`1.0 N
`
`\.
`“‘°
`
`\,
`
`»
`.‘
`~
`
`
`
`o.a
`o.7
`as
`0.5
`9.4
`0.3 7
`0.2 V W» Cssodex plus LHRH«A
`GA
`A v - Flulamide plus LHRH-A
`0.0
`’\"’\"T‘!’7fi"F1"\“lWfi‘Tfi"V"\’T’T"T‘T1”f'rfi"1‘P‘7‘r'1”Y
`365
`730
`1095
`1460
`1825
`
`
`
`Proportionsurviving
`
`0
`
`
`
`....._..wMm.mtmm.nlmmwm
`
`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).
`
`figure;
`The Kaplan-Meier Curve For Time to Progression
`For Both Antiandrogen Treatment Groups
`1.0
`0.9
`0.8
`0.7
`0.6 l
`0.5
`0.4
`D.3
`0.2
`0.1
`0.0
`
`
`
`Proportionnotprogressing
`
`—— Casodex plus LHRH-A
`" ' ~ Flulamide plus LHRH»A
`
`r~r-r—z—v-:-rw—1—x—r-r—m—1—x—r-r-r-r-x~r-r
`0
`365
`730
`1035
`1460
`1825
`
`
`
`Days to progression
`
`Quality of life was assessed with self-administered patient
`questionnaires on pain, social fu