...¢%..—g«-xDESK
`
`
` _~M..’wE”PEM39
`
`
`
`

`
` ED_R®
`
`
`
`1999
`
`EDITION
`
`
`53
`
`PH\/S|ClAl\lS'
`DESK
`l3EFEl3El\lCE®
`
`
`
`
`
`Medical Consultant
`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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`S, RPh, CDE
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`Editor, Special Projects: David W. Sifton
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`senior Format Editor: Gregory J. Westley
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`.
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`w 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
`rophthalmologt/°. Pocket PDFt", and The PDFl° Family Guide to Prescription Drugs® are registered trademarks used herein under license. FDR Companion GuldeTM,
`FDR” for Herbal Medicines”, PDB° Medical Dictionary”. FDR‘ Nurse's Handbook”, PDFt° Nurse's Dictionarym. The PDR° Family Guide Encyclopedia of Medical
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`Operations: John R. Ware
`® Printed on recycled paper
`
`ISBN: 1-56363288-8
`
`Astrazeneca Ex
`
`.2126 p_2
`
`

`
`CONTENTS
`
`
`
`
`
`Manufacturers’ Index. (White Pages) 1 I
`
`
`
`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 V
`
`Section 4
`
`
`
`Presents fullcolor, 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 .......................................................................... ..348'
`Gives numbers of key reporting programs and information services.
`
`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 zafirlukast 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 of ACCOLATE is 20 mg twice daily
`in adults and children 12 years and older. Since food re-
`duces the bioavailability of zaflrlukast, 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 CW,‘ 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% 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 effectiveness 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) (685
`77°F) [see USP]. Protect from light and moisture. Dispense
`in the original sir-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
`
`ARIMIDEX®
`anastrozole
`TABLETS
`
`Ha
`
`DESCRIPTION
`ARIMIDEX® (ansstrozole) tablets for oral administration
`contain 1 mg of ansstrozole, a non-steroidal aromatase in-
`hibitor. It is chemically described as 1,3-Benzenediacetonb
`trile, u, a, a’, oi’-tetramethyl—5—(ll-l-1,2,4-triazol-1-ylmethyl).
`Its molecular formula is CUHWN5 and its structural for-
`mula is:
`
`FL)
`\N
`
`H35
`HC
`3
`
`on
`
`CH3
`
`on CH5
`
`-
`
`Anastrozole is an off—white powder with a molecular weight
`of 293.4. Ansstrozole 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, poviclone, 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 estrono by ax-ornztase in peripheral tis-
`Informatlon will be superseded by supplements and subsequent editions
`
`sues, such as adipose tissue, with further conversion of es-
`trono to eetradiol. Many breast cancers also contain aro-
`‘ mataso; the importance of tumor~generated estrogens is un-
`certain.
`Treatment of breast cancer has included oflbrts to decrease
`estrogen levels by ovariectomy premenopausally and by use
`of aotiestrogens and progeetational agents both pre- and
`' post-tnenopau-sally, 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 aldostérone.
`Pharmacokinetics
`Inhibition of aromatase activity is primarily due to onastro-
`zole, the parent dmg. Studies with radiolabeled drug have
`demonstrated that orally administered anastrozole is well
`absorbed into the systemic circulation with S3 to 85% of the
`radiolabel recovered in urine and feces. Food does not afibct
`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 pharmacoklnetic parameters are
`similar in patients and in healthy postmenopausal volun-
`teers. The pharmacokinetics of anastrozole are linear over
`the dose range of 1 to 20 mg and do not change with re-
`peated dosing. 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»sl::.>.te levels are approximately three to four-fold
`higher
`than levels observed after a single dose of
`ARIMIDIDC. 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-dealkylation,
`hydroxylation and glucoronidation. Three metabolites of
`anastrozole have been identified in human plasma and
`urine. The known metabolites are triazole, a glucumnide
`conjugate of hydroxy-anastrozole, and a glucuronide of
`anastrozole itself. Several minor (less than 5% of the radi0~
`active dose) metabolites have not been identified.
`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
`mL/rnin/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 ADIVIINISTRATION sections).
`Special Populations
`Geriatric: Anastrozole pharrnacoliinetics 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 insufiiciency. 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/min/1.73m2) 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
`pbarmacokinetics 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 AI\ID
`ADMINISTRATION), so that no dosage adjustment
`is
`needed.
`Drug-Drug Interactions: Anastrozole inhibited reactions
`catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in uizfro
`with Ki values which were approximately 30 times higher
`than the mean steady-state Cmx values observed Following
`a lung daily dose. Anastrozole had no inhibitory effect 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 oitrn and in viva results, it is un.
`likely that co-administration of ARIMIDEX 1 mg with other
`drugs will result in clinically significant inhibition of cytg.
`chrome P450 mediated metabolism.
`Pharmacodynamios
`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 ifARll\/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,ARlMIDEX 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 estrsdiol 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.
`sesced by examining the effects on corticosteroid synthesis.
`For all doses, anastrozole did not effect cortisol or aldoste»
`rone secretion at baseline or in response to ACTH. No glu.
`cocortiooid 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 of ARIMIDEX. ARIMIDEX does not possess direct
`pmgestogenic, androgenic, or estrogenic activity in animals,
`but does perturb the circulating levels of progesterone, an-
`drogens, and estrogens.
`Clinical Studies
`Anastrozo e was studied in two well-controlled clinical trials
`(0004, a North American study; 0005, a predominately En-
`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 t e 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-
`measurab e disease were randomized to receive either a sin-
`gle daily ose of 1 mg or 10 mg OIARIMIDEX or megestrol
`acetate 40 mg four times a day. The studies were double-
`blinded with respect to ARIMIDEX. Time to progression
`and objective response (only patients with measurable dis-
`ease coul
`be considered partial responders) rates were the _
`primary ethcacy variables. Objective response rates were
`calculate 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 trial. 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 4-2% in Trial 0005 were
`reported by the primary investigator to have responded. In
`Trial 0004, 81% of patients were ER-positive, 13% were ER-
`unlmown, and 6% were ER-negative. In Trial 0005, 58% of
`patients were ER-positive, 37% were Elivunlinown, 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 cllfferences were statistically significant.
`Msgestvol
`ARIMIDEX ARIMIDEX Acetate
`1 mg
`10 mg
`160 mg
`
`Trial 0004
`(N. Amgigi)
`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 (70)
`
`(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
`
`(113135)
`
`(ri:118)
`
`(n=125)
`
`Trial 0005
`(Europe, Australia,
`S.Africa)
`Median Followup
`(months)*
`Median Time to Death
`(months)
`2 Year Survival
`Probability ("70)
`Median Time to
`Progression (months)
`Objective Response
`(all patients) (5%)
`Stable Disease
`for >24 weeks (96)
`Progression (%)
`*‘ Surviving Patients
`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 indicae
`tion that ARIMIDEX 10 mg is superior to ARIMIDEX 1 mg.
`Megestrol
`ARIMNJEX ARlMIDEX Acetate
`1 mg
`10 mg
`160 mg
`
`V
`
`'
`
`Vomiting
`Cough
`Increased
`Diarrhea
`Constipation
`Abdominal
`Pain
`Anorexia
`Bone Pain
`Fharyngitis
`Dizziness
`Rash
`Dry Mouth
`Peripheral
`Edema
`Pelvic Pain
`Depression
`Chest Pain
`Parestliesia
`Vaginal
`Hemorrhage
`Weight Gain
`Sweating
`Increased
`Appetite
`
`224
`22
`22
`18
`18
`18
`17
`16
`16
`15
`15
`14
`14
`14
`13
`12
`
`6
`4
`4
`
`0
`
`(9.2)
`(8.4)
`(8.4)
`(6.9)
`(6.9)
`((5.9)
`(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)
`
`(0)
`
`23
`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)
`
`16
`19
`7
`21
`18
`11
`19
`15
`15
`19
`13
`28
`13
`5
`13
`9
`
`13
`30
`16
`
`13
`
`(6.3)
`(7.5)
`(2.8)
`(8.3)
`(7.1)
`(4.3)
`(7.5)
`(5.9)
`(5.9)
`(T5)
`(5.1)
`(11.1)
`(5.1)
`(2.0)
`(5.1)
`(3.6)
`
`(5.1)
`(11.9)
`(6.3)
`
`(5.1)
`
`‘C 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 cam
`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:
`ture
`Nervous: Somnolencc; 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.
`
`Myalgia; arthralgia; pathological frac-
`
`Number ln) and Percentage of Patients
`Megestrol
`ARIMIDEX ARIMIDEX
`Acetate
`1mg
`10 mg
`160 mg
`(n=262)
`(n=246)
`(n:253)
`
`Adverse Event
`Group
`Gastrointestinal
`Disturbance
`Hot Flushes
`Edema
`Thomboembolic
`Disease
`Vaginal Dtyness
`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 1998 PDR® supplements and future editions for revisions
`
`ing pregnancy or if the patient becomes pregnant while re»
`ceiving this drug, the patient should be apprised of the po-
`tential hazard 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 lnteractions:
`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 mil
`crosomes. Anaslrozole 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 Liitro studies, it is unlikely that cmadininistration of
`a 1-mg dose of ARlM1DEX with other drugs will result in
`clinically significant drug inhibition of cytochrome P450-
`mediated metabolism of the other drugs.
`Drugflaboratory 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,
`CHOVKI gene mutation assay) or clastogenic either in vitro
`(chromosome aberrations in human lymphocytes) or in viva
`(micronucleus test in rats).
`lmpairment 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 doses equal
`to or greater than 1 mg/kg/day (which produced plasma
`anastrozole C35,,“ and AUCOIQA b, 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 ariastrozole C,5,,,,,, and
`AUCP3, b, 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 efilects
`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 eflicacy 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 well-coir
`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 scet.ate~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 (:1) and Percentage of Patients
`with Adverse Event 1‘
`
`ARIMIDEX ARIMIDEX
`1 mg
`10 mg
`(n=262)
`(n=246)
`in
`%
`n
`%
`
`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)
`
`Megestrol
`Acetate
`160 mg
`(n=253)
`n
`%
`
`47
`28
`24
`21
`29
`19
`53
`
`(18.5)
`(11.1)
`(9.5)
`(8.3)
`(11.5)
`(7.5)
`(20.9)
`
`Adverse Event
`
`-
`
`Asthenia
`Nausea
`Headache
`Hot Flushes
`Pain
`Back Pain
`Dyspuea
`
`1 1 l l 1 Ell l
`
`l
`
`Astrazeneca Ex. 2126 p. 5
`
`31.0
`
`24.3
`
`50.5
`
`4.4
`
`12.6
`24.4
`91.9
`
`30.9
`
`24.8
`
`50.9
`
`5.3
`
`15.3
`25.4
`89.8
`
`31.5
`
`19.8
`
`39.1
`
`3.9
`
`14.4
`23.2
`912.0
`
`Trials 0004 & 0005
`(Pooled Data)
`Median Time to Death
`(months)
`2 Year Survival
`Probability (96)
`Median Time to
`Progression (months)
`Objective Rcspose
`(all patients) (%)
`
`(n:263)
`
`(u:248)
`
`(n:Z53)
`
`26.7
`
`56.1
`
`4.8
`
`12.5
`
`25.5
`
`54.6
`
`5.3
`
`12.5
`
`22.5
`
`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 ‘/3, respectively,
`the recommended human dose on 9. mg/m2 basis), adminis~
`tration during the period of orgauogenesis showed that
`amastrozole increased pregnancy loss (increased pre- and/or
`post-implantation loss, increased resorption, and decreased
`numbers of live fetuses); eflects were doserelated in rats.
`Placental weights were significantly increased in rats at
`doses of 0.1 mg/kyday 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
`AUCO44 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, anastrozole caused pregnancy failure at
`doses equal to or greater than 1.0 mg/kg/day (about 16,l:imes
`the recommended human dose on 2. mg/m2 basis); there was
`no evidence of teratogeriicity in rabbits administered 0.2
`mg/kg/day (about 3 times the recommended human dose on
`21 mg/m2 basis).
`There are no adequate and vvellwontrolled studies in preg—
`nant women using ARIMIDEX. KARIMIDEX is used dur-
`
`

`
`l l§i l
`
`PHYSICIANS’ DESK_REFEFlENCE®
`
`(57.5%) pa.
`CASODl*3X-LHRII analogue therapy and
`tients treated with flutarnicle-l;llRlI analogue therapy had
`died. There was no significant Lliilcrcnce in survival be.
`tween treatment groups (soc Figure 1). The hazard ratio for
`time to death (survival) woe 0.37 (95% confidence izitcrivsil
`0.72 to 1.05).
`
`F.lcuLe.1
`The Kaplan-Meier Probability of Death
`For Both Antiamirogon Treatment Groups
`
`
`
`Proportionsurviving
`
`1.0 N‘
`0.9
`0.!
`0.7
`0.5
`
`0.5 9.4
`
`0.3 7
`0.2
`M
`on
`
`——~ Casodex plus LHRH-A
`- - - Flulamide plus LHRH~A
`t"vArTfifi*rrT1‘7TVr’r"rT’T'WTT'r'I“r*1‘T‘r—rT’r
`365
`no
`1095
`Men ms
`
`0
`
`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).
`
`Frigate:
`The Kaplan-Meier Curve For Time to Progression
`For Both Antlandrogen Treatment Groups
`1.0
`0.9
`0.3
`0.7
`0.5 l
`0.5
`0.41
`0.3
`0.2
`0.1
`0.0
`
`
`
`Proportionnotprogressing
`
`—— Cascndcx plus u-mun
`
`— - ~ Fluiamide plus LHRH»A
`
`r~r—1-—m—.—n—.—\—r—:—:~x—1—w—r-r-r-y—y-1-r
`
`0
`365
`730
`1095
`1460
`1825
`
`Days to progression
`
`Quality of life was assessed with self-administered patient
`questionnaires on pain, social functioning, emotional well-
`being, vitality, activity limitation, bed disability, overall
`health, physical c