PHARMACY LIBRA.RY
`
`213'J CH..'L~lBERUN H.\ll
`•125 IJ. Cll.~RTER ST .• ;,WJ,SON, WI
`
`53705
`
`Roxane Labs., Inc.
`Exhibit 1013
`Page 001
`
`

`
`Internatio nal Edito ria l Board
`D.R. Abernethy. BaWmorc, MD, USA
`S. Bank, Nrw York. NY. USA
`P.J. Barnes. Loudon, [uglnnd
`PN. Bennet!. Bat/1, Engl<md
`W.M. Bennett, Portlm1d, OR. USA
`G . Bianchi Porro. Milan, Italy
`W R Bowie. Vancouver. BC, Cmrada
`A.M Blecken~dge, Liverpool, England
`D.B Caine, Vancouocr, BC, Canada
`L de Angells. Trieste, Italy
`Fl Frountelder. Portland, OR. USA
`ED Frels, Washil1gto11, DC, USA
`W.H. Frishman, Val/mila, NY. USA
`B. G. Gozzord. London, En,~tland
`DC Horrtson. Cmci11nati, OH, USA
`F.D. Hart, London, Eugland
`E C Husklsson. Lomlou, Engla111f
`T. Itch, Osaka, /npall
`D. Jewltt. Loudon, En,~land
`G. D. Johnston. fM{nsl, N. Ireland
`M.H. Loder. L.ondon, Eng/ami
`M.J.S. Longman, Binui11g!lm111 Englatul
`H. Lode. H~rlin, Germany
`H. I. Malboch. San Francisco, CA, USA
`F.H. McDowell. Wlrite Pin ius, NY, USA
`F.M. Muggla, Nrw York, NY. USA
`K.G. Naber. Strnulling, Gcrrrmny
`S. Notte!, Mo1•tr,•al, PQ, CmJada
`C.E Nord. Huddinge, Stveden
`H. Pardell, 811rcdumz, Spni11
`P Patsalos. London, England
`R Pauwels, Glle11l, Belgmm
`J.C . Petrie, Aberdet>11, Scotland
`B.N.C Prichard, umdon, Euglm•d
`S H. Roth. Phoemx, AZ, USA
`S Shuster. Frnmlilr.~ham, £.11,11lmrd
`B.N Singh, Los Angel~'», CA, USA
`T.M. Speight. Aucklmrd, Nt•w Z..almrd
`J .S. Turner. Gaiues!lillc, GA, USA
`J . Turnldge, Adelaide. SA, Australia
`J.A. Vole. Brrmi11gltnm, Euglm1d
`D.J . Zegarelll. New York, NY. USA
`
`Aim and Scope: Drugs promotes optimum phnrmacotherapy by providing a
`programme of review articles covering the most impo rtant aspects of clinical
`pharmacology and therapeutics.
`Tite ]oumal includes:
`• Leading/ Cltrrent opinion a rticles providing an overv iew of contentio us or
`emerging issues
`• Definitive reviews of drugs and drug classes and their place in disease
`management
`• Therapy in Practice articles including recommendations for specific clini(cid:173)
`cal s ituations
`• Adis Drug Evaluations reviewing the properties and place in the rapy of
`both newer and established drugs
`• Adis New Drug Profiles with exp ert commentary.
`All manuscripts are s ubject to peer review by international experts. Letters
`to the editor are welcomed and will be considered for publication.
`
`Editor: Dene C. Peters
`
`Publication Manager: Kim S lattery
`
`Editorial Office and Inquiries: Ad is Inte rnational Ltd, 41 Cento rian Drive,
`Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand. lnformation
`on the preparation of ma n uscripts wi ll be provided to authors.
`
`F.-m~ il : rlnrgs@:u li•.tcn .n7
`
`h ttp://www.adis.com
`
`Drugs (ISSN 0012-6667) is published by Adls International Limited, 41 Centorian
`Drive, Private Bag 65901, Maira ng i Bay, Auckland 10, New Zealand. Annual 2001
`subscription price: SUS1995; japan ¥332 478. Annual subscription consists of
`15 issues. (Further subscription information is given at the back of each issue.)
`Policy Statement: Although great care has been taken in compiling the content of
`this publication, the publisher and its servants are not responsible or in any way
`liable for the currency or the information, for any errors, omissiollS or inaccuracies,
`or for any consequences arising therefrom. Inclusion or exclusion of any p roduct
`does not imply its use is e ither advocated or rejected. Use of trade names is for
`product identification only and does not imply endorsement. Opinions expressed
`do not necessarily reflect the views of the Publisher, Editor or Editorial
`Board.
`Copyright: © 2001 Adis International Ltd. All rights reserved throughout the
`world and in all languages. No part of this publication may be reproduced,
`transmitted or stored in any form or by any means either mechanical o r electronic,
`including photocopying, recording, or through an information storage and re(cid:173)
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`The appearance of the code at the top of lh~ fi rst page of nn article in this journal
`indicates the copyrigilt owneo·'s consent !hill copies of the article may be made for
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`~"' fee of $US27.50 per copy is paid d irectly lu the Copyrig ht Clearance Center Lnc.,
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`extend to other kinds of copying such as copying for genera.l d istribution, for adver(cid:173)
`tising or p romotional purposes, for crea ting n<'W collcctovc works, ot lor resale.
`
`Roxane Labs., Inc.
`Exhibit 1013
`Page 002
`
`

`
`\Tol. 61,~o. 1, 2001 =====D=rugs
`
`Contents
`
`Current Opinion
`
`Leading Artic les
`
`Review Articles
`
`Emergence of Methicillin-Resistant Stnphylococws nuretts
`with Intermediate Glycopeptide Resistance: Clinical
`Significance and Treatment Options
`MJ Rybnk, RL Akins
`
`The Role of Fluoroquinolones in Tuberculosis Today
`5£ Beming
`The Emerging Roles of Non-Nucleoside Reverse
`Transcriptase Inhibitors in Antiretroviral Th erapy
`C Moyle
`
`Response to Inhaled Nitric Oxide in Prematme and
`Term Neonates
`T Hoehn, MF Krause
`Cholines terase Inhibitors for Alzheimer's Disease
`f Cmtzendler, JC Morris
`
`Therapy in Practice Treatments for Androgenetic Alopecia and Alopecia Areata:
`Current Options and Future Prospects
`VM Meidnn, £ Touilou
`
`Adis New Drug
`Profile
`
`Inhaled Budesonide/Formoterol Combination
`JK McGnuin, KL Con, B jnruis
`Inhaled Budesorude/Formoterol Combination: Viewpoints
`L-P Boulet, B) Lipworlh
`
`Adis Drug
`Evaluations
`
`Errata
`
`Fluoxetine: A Review of its Therapeutic Potential in the
`Treatment of Depression Associated with Physical Illness
`SM Cheer, KL Con
`Olanzapine: An Updated Review of its Use in the
`Management of Schizophrenia
`N Bhnnn, RH Foster, R Olney, CL Plosker
`
`1-7
`
`9-18
`
`19-26
`
`27-39
`
`41-52
`
`53-69
`
`71-78
`
`79-80
`
`81-110
`
`111-161
`
`52
`
`PHARMACY LIBRARY
`
`2130 CHAltBE'lLIN H.\ll
`425 H. CHARTERS ~. MACr50N, WI 53706
`
`Drugs i~ indexed in hrrlt•.r M<'llicus, Medliue, EM BASE./F.xcerpla Medica, Current Coutcuts/Ciirricnl ML'IIicirr~. Currerrt Corrlcnts/Uft Scierrces,
`8105/S"' Dntnoose, lrrlmrntiounl Phnrmnwrticnl Abstracts (IPAJ and CABS. Individual articles are av<ilable through the ADONIS
`document delivery service md on-line via the World Wide Web through lngenta. Further details are avtilable from tfie publisher.
`
`Roxane Labs., Inc.
`Exhibit 1013
`Page 003
`
`

`
`ADIS DRUG EVALUATION
`
`Orugs'2001 61 (I). Bl·liO
`00 I 2-0661/0 I /mJ I <lOS I!S21.50to
`
`Fluoxetine
`A Review of its Therapeutic Potential in the Treatment
`of Depression Associated with Physical illness
`
`Susan M. Cheer and Karen L Goa
`Ad is International Limited, Auckland, New Zealand
`
`Various sections of the manuscript reviewed by:
`M. A11ssen11, Psychiah·ic Unit, Liege, Belgium; M. lsnnc, Psychopharmacology Evaluation Unit, University
`Hospital, London, EnglaJ1d; M. Larler, Institute of Psychiatry, Londor\, Englnnd; S.H. Preskom , Psychiah·y
`Department, University of Kansas School of Medicine, Wichita, Kansas, USA; f. G. Rnbki11, Department of
`Psychiatry, College of Physicians a nd Surgeons, Columbia University, New York, New York, USA.
`
`Data Selection
`Sources: Medicalllteralure published in any language since 1966 on Fluoxetlne, idenllfied using Medllne and EMBASE, supplemented by
`AdlsBase (a proprietary database of Adis International. Auckland, New Zealand). Additional references were Identified from the reference
`lists of published articles. Bibliographical Information, including contributory unpublished data, was also requested from the company
`developing the drug.
`Search strategy: Medline search terms were 'Fiuoxetine' or 'LY 11 0140' and ('cardiovascular-diseases' or 'neoplasms' or 'HIV' or
`'acquired-immunodeficiency-syndrome' or 'dlabetes-mellilus' or 'hypJtension-orthostatic'). EMBASE search terms were 'Fiuoxetine' or 'LY
`110140' and ('stroke' or 'cardiovascular-disease' or 'cancer' or 'human-immunodeficiency-virus' or 'acquired-Immune-deficiency-syndrome'
`or 'diabetes-mellitus' or 'heart-infarction' or 'orthostatic-hypotension'). AdisBase search terms were 'Fiuoxetine' or 'LY 11 0140' and ('stroke'
`or 'cardiovascular-disease' or 'cardiovascular-disorders' or 'cancer' or 'HIV' or 'acquired-immunodeficiency-syndrome' or 'diabetes-mellitus'
`or 'orthoslatic-hypotenslon'. Searches were last updaled 24 Oct 2000.
`Selection: Studies in patients with depression and HIV/AIDS, diabetes mellitus, stroke or cancer who received fluoxetine.lnclusion of studies
`was based mainly on the methods section of the trials. When available, large, well controlled trials with approprtate statistical methodology
`were preferred, Relevant pharmacodynamic and pharmacoklnetic data are also Included.
`Index terms: tluoxetine, comorbid physical illness, depression, pharmacodynamics, pharmacokinetics, therapeutic use.
`
`Contents
`
`Summary
`I . Introduction .
`2. Pharmacodynamic Properties
`2. 1 General Pharmacodynamic Profile
`2.2 In Patients w ith Depression a nd Comorbid Physical illness
`2.2.1 Glucose Control in Patients with Diabetes Mellitus
`2.2.2 CD4+ Status In Patients wrth HIV/AIDS
`2.3 Pharmacodynamic Drug Interactions
`3. Phormacokinetlc Properties
`. . .
`3. 1 Absorption a nd Distribution
`3.2 Metabolism and Elimination .
`3.3 Special Patient Groups .
`3.4 Pharmacoklnetic Drug Interactions
`4. Therapeutic Efficacy .
`4.1 Comparison with Placebo .
`4.1.1 Patients with Depression and HIV I AIDS .
`
`82
`86
`87
`87
`88
`88
`89
`90
`90
`90
`90
`90
`91
`92
`93
`93
`
`. '
`
`Roxane Labs., Inc.
`Exhibit 1013
`Page 004
`
`

`
`4. 1.2 Patients with Depression and Diabetes Mellitus
`4.1 .3 Patients with Post-Stroke Depression
`. . . . , .
`4. 1.4 Patients with Depression and Cancer
`. . . , .
`4.2 Comparison with Other Antidepressants
`. . . . . . .
`4.2.1 Comparison with Tricyclic and Heterocyclic Antidepressants .
`4.2.2 Comparison with Other Serotonin Reuptake Inhibitors In Patients with
`Depression and HIV I AIDS
`4.3 Noncomparatlve Trials . . .
`5. Tolerability . . . . . . . . . . . . .
`5.1 General Tolerability Profile .
`5.2 Other Effects
`. . . . . . . .
`5.2. 1 Sexual Dysfunction .
`5.2.2 Bodywelght Change
`5.2.3 Suicidal Ideation
`. .
`5.2.4 Serotonin Syndrome
`6. Dosage and Administration . . .
`7. Place of Fluoxetine In the Management of Depression In Patients with
`Physical illness . . . . , . . . . . . . . . . . . . .
`7. 1 Patients with Depression and HIV I AIDS
`. . . . .
`7.2 Patients with Depression and Diabetes Mellitus.
`7.3 Patients with Post-Stroke Depression .
`7.4 Patients with Depression and Cancer
`7.5 Overdose
`. . . , . . . .
`7.6 Pha•macological Considerations.
`7.7 Conclusion .. .. . . , . .. , .
`
`. . '
`
`93
`94
`95
`95
`95
`
`97
`97
`97
`97
`99
`99
`99
`100
`100
`100
`
`101
`101
`102
`103
`103
`104
`104
`105
`
`Summary
`Abstract
`
`Fluoxetine is a potent and selective inhibitor of neuronal serotonin (5-hydroxy(cid:173)
`tryptamine) reuptake. Fluoxetine reduces food. energy and carbohydrate intake
`and increases resting energy expenditure. which may account for the moderate
`and transient bodyweight loss observed with its use. Glucose tolerance and/or
`hypoglycaemia in patients with type 2 diabetes mellilus improve with nuoxetine
`therapy.
`The ability of Ouoxetine to inhibit cytochrome P450 (CYP) isoenzymes
`(CYP206. CYP2C and CYP3A4), is potentially important for patients with phys(cid:173)
`ical illness who may be taking multiple concomitant medications.
`Fluoxetine was more effective than placebo in 2 double-blind, randomised
`I rials, a nd according to limited data appears Lobe equally effective compared with
`other SS RJs ~md tTicyclic antidepressants (TCAs), in the treatmenl of depression
`in patienls wilh HIV/AIDS. The efficacy of nuoxetine is :ilso superior to !hat of
`plm:ebo in the treatme nt of de pression in patients with diabetes mellitus a nd stroke
`as shown in double-blind ra ndomised trials. altho ug h its efficacy relative to thai
`of nortriptyline in stroke i ~ uncertain. l"'luoxctine had ~imi l a1 efTil:tu.:y tu that of
`desipramine in patients with cancer, with improved Hamilton Depression Rating
`Scale a nd quality-of-life scores from baseline; however, the drug was not more
`effective than placebo in a double-blind randomised trial.
`Medically healthy individuals tolerate fluoxetine well. L1ke other SSRis,
`fluoxerine lacks the anticholinergic. cardiovascular, sedative and weight-increas(cid:173)
`ing properties of TCAs. and is safer in overdose than TCAs ;md monoamine
`
`0rugs 2001:61 (1)
`
`Roxane Labs., Inc.
`Exhibit 1013
`Page 005
`
`

`
`Fluoxetine: A Review
`
`83
`
`Pharmacodynamic
`Properties
`
`Pharmacokinetic
`Properties
`
`oxidase inhibitors. Rutes of sexual dysfunction and suicidal ideation with fluox(cid:173)
`etine appear s imilar lO those seen with othe r SSR is.
`Conclusion: Fluoxetine has sl10wn superior efficacy compared with pluoebo
`in the treatment of depression in patients with HlV/AIDS. diabetes mellitus or
`stroke; however. it has not s ignil'icantly improved depresstve symptoms versus
`placebo in patients with cancer. The efficacy of fluoxetine appears s imilar to that
`of desipramine in patients with stroke, cancer or HJV. and is similur to that of
`sertraline or paroxetine in patients w ith HlV/AIDS; compmisons with noruip(cid:173)
`tyline give equivocal results. The potential for d rug interactions with fluoxeti ne
`use should be carefully considere.d because most patients with comorbid physical
`illness will be receiving multiple comedic<ttions. Although fluoxetine has proved
`effective as an antidepressant in this populatio n in several clinical trials, its drug
`interaction profile and long half-life are a potential limitation, and these properties
`sho uld be carefully considered in relation to the starus of each patient.
`
`Fluoxetine and its major metabolite, norl1uoxetine, are potent and selective in(cid:173)
`hibitors of neuronal serotonin (5-hydl'oxytryptamine; SHT) reuptake. ln comparati vc
`in vitro stud ies, fluoxetine s hows less selectivity in its effects on serotonin
`reuptake than most other serotonin reuptake inhibitors (SSRis), including sertra(cid:173)
`line and paroxetine. Fluoxetine has little or no affinity for 01-, a2- and P-adreno(cid:173)
`ccptors, muscurinic, sero to nin5- HT 1, S-HT2, histamine H 1, opioid. dopamine and
`y-aminobutyric acid B receptors.
`Total daily food intake in healthy volunteers with normal bodyweight, and
`e nergy and carbohydrate intake in patients with type l diabetes mellitus are re(cid:173)
`duced with t1uoxetine treatment, whereas resting energy expenditure in patients
`with mutlcralc uucsiLy is illcten5eu; these effeets may result in bodyweight loss.
`Treatment with fluoxetine improves glucose tolerance ::mellor hypoglycaemia in
`patients with type 2 diabetes mellitus irrespective of the bodyweight- lowering
`effects of the drug. Discontinuation of !l uoxetine treatment may result in hyper(cid:173)
`glycaemia. Unlike rricyclic a ntidepressants (TCAs).tluoxetine has no significant
`clinical effects on cognitive or psychomotor abilities. Fluoxetine treatment docs
`not significantly alter CD4+ counts in patients with HIV/AfDS.
`Case reports indicate that fluoxeti ne can decrease the ant[emetic efficacy of
`ondansetron, a 5-HT3 antagonist; this effect probably results from the accumuJa(cid:173)
`tion of serotonin. which competes with ondansetron at the receptor.
`
`Fluoxetine is well absorbed fo llowing oral administration, with mean peak
`plasma concentrations (Crnax) of 15 to 55 ~tg/L after n single dose of 30 or 40mg.
`The time to Cnoax (lmax.l is 6 to 8 hours. Coadministration of fluoxetine with food
`increases the tmax by 3 to 5 hours but docs not aJter the area under the plasma
`concentra tion-time curve orCmax· Steady-state p lasma concentratio ns are reached
`afte r 2 to 4 weeks oftluoxetine rreatment. The volume of distribution offluoxetine
`ra nges from 12 to 43 L/kg after s ingle o r multiple doses and the drug is ttighly
`protein bound.
`Tra nsformation of fluoxetine into norfluoxetine (the primary acti ve metabo(cid:173)
`lite) occurs 11fter extensive firs t-pass hepatic metabolism involving cytochrome
`P450 (CYP) 2C and 206 isoenzymes. As a potent inhibitorofCYP206, fluoxet(cid:173)
`ine is capable of inhibiting its own metabolism, which results in nonli near phar(cid:173)
`macokinetics and hig h
`interindividual phar macokinetic var iability. The
`elimination half-life (t';!p) of tluoxetine is 2 to 7 (mean 4) days after multiple
`doses; nortluoxetine has a t y!p of 7 to 15 days.
`
`e Adls lnfetnoltonot Umlted. All righls reserved.
`
`Drugs 2001: 61 (1)
`
`Roxane Labs., Inc.
`Exhibit 1013
`Page 006
`
`

`
`Therapeutic Efficacy
`
`The clearance of fluoxetinc is reduced and L'!,p increased in patients with
`hepatic impairment. fn contra~!. the pharmacokinetics of fluoxetine and nor(cid:173)
`fluoxetine are not significantly altered in patients with renal failure. The to~p
`values of fluoxetine (40 mg/day for 43 days) and norfluoxetine were im;reused
`by 28 and 35%, respectively, in hea.hhy elderly volunt eer~ in a multiple-dose
`sn1dy.
`Flunxetine inhibits CYP2D6. CYP2C and CYP3A4, which ure involved in the
`metabolism of a wide r(lnge or drug~ (including TCAs. some antiarrhythmics,
`antipsychotics and P-blockers). Caution is advised when coadministering flu(cid:173)
`oxetine with drugs metabolised by these pathways. In patients with dh1betes
`mellllus. lluoxetme may enhance or prolong the hypoglycaemic response to sul(cid:173)
`phonylureas.
`Fluoxetine has been compared with placebo and other antidepressants in patients
`with depression and various ~:omorbid physical illnesses. Trials were double(cid:173)
`blind and randomised except where stared.
`Patients with Depression and HIV/AIDS: Fluoxetine (20 to 60 mg/day t'or
`7 or 8 weeks) with or without group therapy significantly improved symptoms
`of depression (in multiple assessment sca le~) compared with placebo in patients
`who were l-IlY-seropositive in 2 trials, although re$tllts were significant only in
`an evaltluble-putients analysis in I of the~e studie~: there were no statistically
`significant tlifferences from placebo in a third smaller tlial. The response to
`tluoxetine was mai ntained over an extended 26-week period (including 18 weeks
`that were noncomparative) in I trial.
`Fluoxetine 20 to 40 mg/day appeared to have similar efficacy to desipramine
`(target dose 75 to 100 mg/day), sertraline (50 to 150 mg/day) or paroxetine (20
`to 40 mg/day) in ~mall (n = 12 to 24 ), 6-week n·ials.
`Patients with Depression and Diabetes Mellitus: Significantly more tlu(cid:173)
`oxetine (20 to 40 mg/day) than placebo recipients were classified as responders
`[a decrease in Beck Depression Inventory (BDl) scores of~50%J in an intent-to(cid:173)
`treat analysis (n = 60) of an 8-week trial; however. signilicant differences did not
`occur between treatment groups in response rates asses~ed using the Hamilton
`Depression Rating Scale (1-i.DRS) or in the percentage of patients achieving re(cid:173)
`mission of depression. ln an analysis of evaluable pmiems, fluoxetine signifi(cid:173)
`cantly improved symptoms of depression from baseline (HDRS and BDJ) to a
`greater extent than placebo. Patients had either type I or type 2 diabetes mellitus.
`Patients with Post-Stroke Depression: Auoxetine ( 20 mg/day for up to 45
`days) improved symptoms of depression from baseline [Montgomery and Asberg
`Depression Raring Scale (MADRS) I to a significantly greater extent than placebo
`in an intem-to-treat analysis of 31 patients with post-stroke depression. In addi(cid:173)
`tion, fluoxetine (20 mg/day) and nortriptyline (25 to 75 rng/day) were equally
`more effecti ve than plucebo (change in HDRS scores from baseline; p < 0.001
`combined drug treatments) in patients with post-stroke depression (n = 48) in a
`6-week st.udy. albeit nf nnnrundomi~NI design.
`In contrast. the efficacy of fluoxetine ( 10 to 40 mg/tluy for 12 week~) was no
`different from that of plncebo and significantly lower than that of nonriptyline
`(25 to 100 mglday) [p = 0.0021 in the treatment of mild to moderate ckprcssion
`in an intent-to-treat analysis (n = 40) in elderly patient~ recovering from stroke
`(measured as a >50% redu..:tion in HDRS scores). The lack of efficacy or nuoxet(cid:173)
`ine may have resulted from lower thnn steady-stme concentrations in some
`
`i,'1 Adls tnternotionot Umlled AI right• rmef\'ed.
`
`Drugs 2001. 111 (1)
`
`Roxane Labs., Inc.
`Exhibit 1013
`Page 007
`
`

`
`Fluoxetine: A Review
`
`Tolerability
`
`pmients and/or the heterogeneous population sample with respect to type of de(cid:173)
`pression .
`There were no statistically significant differences in percentage change in HDRS
`score~ from baseline among fluoxetine (I 0 to 20 mg/dayl, desipramine (50 to I 00
`mg/dny} or trazodone (50 to I 00 mglday) rc~:ipients in the treltment of post-stroke
`depression in 24 patients in a double-blind rantlomised tri;tl.
`Patients with Depression and Cancer: There was no ~ignilicant tlifterem:e
`in the eflicacy of fluoxetine (20 mg/day) versus placebo in the treatment or de(cid:173)
`pression and anxiety in 91 patients with cam:er [measured as Ho~pital Anxiety
`and Depression Scale (HADS) scores of<S, and improvement of;:::50% in HADS
`or MADRS]. However, fluox etine (20 to 60 mg/day) and desipramine (25 to 100
`mg/day) had similar efficacy in the lrcatmt:nt of 38 women with C<~ncer. with
`~DRS improved by 43% from baseline in both groups (p <0.001 for both treat(cid:173)
`ments).
`Because of the limited nature of the tolerability data in patients with physical
`illness, this summary focuses on the generaltolerabiUty protile of fluoxetine in
`otherwise healthy individuals with depression. These data may underestimate the
`adverse eftccts of nuoxetine in patients with other medical illnesses.
`In a survey of 12 692 fluo.~etine recipients. adverse events which m;curred at
`a freque ncy of~S% during the first month of treatment included nausen ( 16.2%),
`malaise ( 10.5%). hcudacht: (9.4%), insomnia (7.9%), an)(iety (7.4%). drowsi(cid:173)
`ness/sedation (6.7%). diarrhoea (5.8%), dizziness (5.4%). vomiting (5.4%) and
`agitation (5.0%). Tn a smaller survey of 19 ranuomised. placebo-conrrolled trials.
`adverse events which were reported by 2:5% of respondents and occurred at a
`higher frequency (p s U.tJ5ltn pauems receiving nuoxetine (20 tu RO utg/thJy: 11
`= 1322) than placebo (n = 569) included nausea, insomnia, nervousness. somno(cid:173)
`lence. anxiety. anorexia, diarrhoea. tremor. dizziness. sweating. asthenia and
`dyspepsia. Many adverse events experienced with fluoxetine occur early in treat(cid:173)
`ment, with some abating with continued use.
`Fluoxetine. like other SSR!s, lacks TCA-Iike anticholinergic. cnrdiOV<IScular.
`sedative and bodyweight-increasing properties, as well as lethality in overdose.
`In contrast. fluox etine was associated with higher frequencies of nausea. insom(cid:173)
`nia, anxiety, diarrhoea. :.uwrexia and rhin itis than TCAs in n survey of 19
`randomised clinical trials in patients with major depression. Adverse effects as(cid:173)
`sociated with fluoxetine caused fewer premature treatment tem1inations than ad(cid:173)
`verse effects associated with TCAs (p < 0.001 ).
`The incidence of sexual dysfunction with fluoxetine use varies considerably:
`sexual dy~function was reported by 5.2% and 58% of fluoxetine recipients in 2
`separate nnalyses. Jn each swdy. the level of sexual dysfunction reported with
`fluoxetine use was similar to thm reported with the use of other SSRis (analyses
`included 1256 and 693 patients: data for both studies were published in abstracts
`with no statistical analysis).
`Treuuncnt with Jluoxetine has been associated with u moderate and tr<~nsic nt
`boclyweight loss in otherwise healthy individuals with depression. Significant
`bodyweight loss was reported for patients (including some with type 2 diabetes
`mcllitlls) treated with fluoxetine (60 mg/day for 36 or 60 weeks) compared with
`placebo in a retrospective analysis of950 patients from 3 double-blind. placebo(cid:173)
`controlled trials (analysis published as an abstract). Elderly patients (> 75 years
`or age) who were medically ill were also reponed to have lost signilicantly more
`
`~ ,Adls tnterno11onot Umlted. At rights reSB<Ved
`
`Drugs2001:6t tl)
`
`Roxane Labs., Inc.
`Exhibit 1013
`Page 008
`
`

`
`Dosage and
`Administration
`
`bodyweighl (average 4.6kg. p = 0.0062) than other groups in a retrospective
`amtlysis. In addition. significantly more tluoxeline recipients with post-stroke
`depression lost ~8% of initial bodyweight compared with nortriptyline-treated
`patients (p = 0.0004; analysis of 25 patients).
`The overall picture from large cohort and prospective studies lnd retrospecli ve
`analyses indicates that the incidence of suicide or suicidal acts in patients using
`fluoxetine is similar to that !"or patients using other SSRis or TCAs.
`Fluoxctinc alone does not appear 10 induce serotonin syndrome: however, this
`event hus been reported with the coadministration of tluoxetine and monoamine
`oxidase inhibitors (MAGis).
`
`In patients with depression, the initial recommended fluoxeti ne dosage is 20
`mglday, with additional increases loa maximum of 80 mg/day if patients do not
`exhibit clinical improvement after several weeks of treatment. Dosage should be
`reduced for patients with hepatic impairment; reductions in dosage should also
`be considered for elderly patients and patients using multiple concomitant med(cid:173)
`ications or those with concunent diseuse. Pluoxetine may alter glyc;lcmic control
`in patients with diabetes mellitus; this may require an adjustment in insulin and/or
`om I hypoglycaemic dosage when fluoxetinc therapy is instituted or discontinued.
`To reduce the risk. of serotonin syndrome, lluoxetine should not be used in
`combination with an MAO I. and there should be~ 14 days between discontinuing
`trentmem with nn MAOl and starting lluoxetine therapy and ~5 weeks between
`slopping tluoxetine and starting an MAO!. Caution is advised when coadminister(cid:173)
`ing fluoxetine and drugs that arc active in the CNS. and/or drugs metabolised by
`CYP206 or CYP3A.
`
`1. Introduction
`
`The prevalence of depressive illness has been
`estimated at approximately 5% of the general pop(cid:173)
`ulation of the United Stales. Ill However. approxi(cid:173)
`mnrcly 25 to 50% of patients with chronic medical
`conditions are clinically depressed.l11 The rates, ae(cid:173)
`tiology and course of depression in these patients
`vary from illness to illness.
`Depression occurs in 4 to 22% of patients with
`HIV/AI DS.'2•31 with rates of depression remaining
`constant with advancing HIV illness.l~l Depression
`associated with H!V /A IDS probably results from a
`complex interaction of psychological ancl neuro(cid:173)
`logical factors;l5t it may be reactive secondary to
`leurning of HIV infection, organic in origin or related
`to higher rates of preinfection depression_l.l.6.?J
`Lifetime rates of depression are elevated in patients
`with HIV and approximately 80% of patients with
`HI V and depression have had depressive episodes
`
`prior to infection.181 There is no consistent evidence
`that antiretroviral medications are risk factors for
`depression,l~l and the literature does not support the
`hypothesis that HIV causes mood changes or that
`AIDS-related dementia manifests as depression.l51
`The prevalence of major depressive disorder is
`approximately 9 to 27% in patients with diabetes
`mellitus (data from structured diagnostic inter(cid:173)
`views from 4 controlled studies; reviewed by
`Goodn ick et nJ.191), wirh relapse rates being 8 times
`greater in these patients than in medically healthy
`individuals.ll01 Depression severity directly inter(cid:173)
`acts with the incidence of complaints ancl level of
`hyperglycaemia in patients with type I diubctcs
`mellitus.l91 In addition, depression has been asso(cid:173)
`ciated with an increased rate of diabetic complica(cid:173)
`tions in patients with type 2 diabetes mellitus.1111
`Furthermore. in elderly patients with diabetes mel(cid:173)
`litus, major depression adversely affects cognitive
`
`"l Adls lr}femotlonol Umlted. Allighls re>efWd
`
`Drugs 2001: 61 (I)
`
`Roxane Labs., Inc.
`Exhibit 1013
`Page 009
`
`

`
`Fluoxctine: A Review
`
`87
`
`functioning,L12J and the relative severity of depres(cid:173)
`sion correlates with worsened glucose controi.PJJ
`Up to 50% of patients with stJoke may develop
`depression (major or minor) during the acute post(cid:173)
`stroke period (reviewed by Starkstein and Robin(cid:173)
`son114l). Patients with major depression experience
`spontaneous remission I to 2 years post-stroke,
`whereas the majority of those with minor depres(cid:173)
`sion remain depressed 2 years after stroke.ll 41 De(cid:173)
`pression associated witJ1 stroke may, in part, be
`related ro the areas of the brain affected by tJ1e
`stroke.l15· 171 The severity of major depression was
`greater in patients with left hemisphere brain injury
`than in those with right hemisphere or brain stem
`infarctions in a study of I 03 patients attending a
`stroke clinic,l151 and was related to the proximity
`of the lesion to the left frontal pole in a study of 36
`patients (evaluated with computerised tomog(cid:173)
`raphy)) 161 Research indicates that post-stroke de(cid:173)
`press ion is involved in a complex interactive
`relationship with physical impairment and is as(cid:173)
`sociated with cognitive defici ts. This reduced
`physical and cognitive functioning impairs social
`functioning (reviewed by Starkstein and Robin(cid:173)
`sonll4t).
`Prevalence rates for depression in patients witJ1
`cancer range widely. from as low as 4.5% to as high
`as 58% (reviewed by Massie and Holland11BI): vari(cid:173)
`ations are due to differences in the indices used to
`measure depression, patient populations, hospital(cid:173)
`isation status, and cancer stage and type.lt91 The
`prevalence of depression in hospitalised patients
`with cancer is 20 to 25%.1 18t The incidence of de(cid:173)
`pression in patienrs with cancer appears to be re(cid:173)
`lated to the stage of cancer, the level of patient
`disability.l 191 the degree of pain experienced, and a
`history of affective illness or alcoholism.l18.20l l n
`addition, depression may result from cancer med(cid:173)
`ications.l 181
`The diagnosis of depression in patients with
`physical illness is often difficult and may be com(cid:173)
`plicated by somatic symptoms (such as anorexia,
`bodyweight loss, fatigue and insomnia) that are
`common to both depression and the comorbid ill(cid:173)
`ness.t4·20l Furthermore, depressive symptoms may
`
`be accepted as a natural or inevitable part of the
`original disease and thus go untreated.l11 As a con(cid:173)
`sequence, depression is diagnosed in fewer than
`half of those with depressive disorders and physi(cid:173)
`cal illness. and appropriately treated in only 30%
`of patients who are correctly diagnosed.l 1l
`Antidepressant treatment in patients with phys(cid:173)
`ical illness has included serotonin (5-hydroxy(cid:173)
`tryptamine: 5-HT) reuptake inhibitors (SS Rls).
`tricycl ic antidepressants (TCAs), monoamine oxi(cid:173)
`dase inhibitors (MAOls), amfebut<tmone (buprop(cid:173)
`ion)120·211 and ven1afaxine,f221 although there has been
`little systematic study on Lhe efficacy of antide(cid:173)
`pressants in the treatment of this patient group.1231
`This review specifically examines the use of the
`SSRL tluoxetine in the treatment of depression in
`patients with HlV/AJDS. diabetes mellitus. stroke
`or cancer. There are no comparative or placebo(cid:173)
`controlled trials of tluoxetine treatment for d~p res­
`in patients with c;lrdiovascu lar disease
`sion
`(CVD); thus this patient group has not been in(cid:173)
`cluded in the review.
`
`2. Pharmacodynamic Properties
`
`It is not within the scope of this article to pro(cid:173)
`vide a detailed review of the pharmacodynamic
`properties of tluoxetine in medically healthy pop(cid:173)
`ulations; comprehensive reviews have been pre(cid:173)
`sented in detail in other publications.J2-1·27t This
`section includes a brief overview of the general
`phnnnacodynnmic profile of flu oxetine but high(cid:173)
`lights the phaJmacodynamic effects of the drug
`that may affect the progression of physical disease
`in patients with comorbid depression.
`
`2.1 General Pharmaco::lynamlc Profile
`
`Fluoxetine and its active metabolite nortluoxet(cid:173)
`inc (section 3.2) a