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					                   1I31:

      RECCI/ED

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DOES NOT CIRCULATE
         ONCE-DA11Y

                      20
                      MG
                           TM




1’AROXETINE [IC’




                           I
                           S
                                       A CLEAR                                                                   REFINEMENT
              IN THE                        T1u&mwNT                                                                             OF DEPiussIoN
                              PaxilTM vs Prozac                                                                             Effective
                              Depression Relief
                               Pax,fln=57

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  Comparative               Pharmacokinetics                    And Selectivity                                            ...with an improved
                                             #{149}                 Prozac                     Zoloft’
                                                                                                                              pharmacokinetic                           profile
Active metabolites                                                        Yes                          Yes
                                              4
                                                                                                                            Based on relative ratio of inhibitory constant for
Elimination        half-life (days)                                                                                         noradrenaline reuptake to the inhibitory constant
-Parent          compound                                                2to3                             1                 for serotonin reuptake

Elimination        half-life (days)                     I.

TActive metabolite                                                       7to9                      2to4
Serotonin selectivity’
(higher value denotes
greater selectivity)                                                                                   1)O

In vitro activity does not necessiiilv                       imply clink ii cffect

                                                                                                                             Relieves          associated                                  #{149}



                                      Decreases Associated                                                                   anxiety          symptoms                                 :            #{149}   #{149}

                                       Anxiety Symptoms
                                                                I         L\ ii           0                                ...with        minimal                  agitation
       Mcdo                                                          Iniipt       inui             nO
                                                                     PLichn                   1:.) 1                         Incidence    of dclItli                           )   1
      Fi   tot
                                                                                                                             conpar(1L)Ie    to

                       !
                   #{149}




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                                                  000    ht of otminir              \    ‘t    III 1        I
                                                                                                        #{149}   hot   n     1       #{149}              #
                                                                                                                                                    #{149} {149}
 ____________ONCE-DAILY

                                                                                                                                         A Cii&i Rniw

 PAROXET/NE/-ICI
Safety established
in patients 18 to 96 years of age
More than 200,000 patients treated worldwide
Effective 20 mg once-daily dosage*
4Maximum daily dose: 50 mg (40 mg/day in elderly and/or patients with severe renal or hepatic imi
if titration is required, use increases of 10 mg/day at weekly intervals

 References: I . Data from controlled clinical trials. On file, SmithKline Beecham Pharmaceuticals.
 2. De Wilde J, Spiers R,Mertens c, et al. ActaPsychiatrScand. 1993;87:141-145. 3. Physicians’DeskReference5. 47th ed. Montvale, NJ: Medical Economics Data,
 a division of MedicalEconomics coinc; 1993. 4. Johnson AM.(n: FeighnerJP, BoyerWF, eds. SelectiveSerotoninRe-uptakelnhibitors:       TheCllnicalUseofCitalopram.
 Fluoxetine, Fluvoxamine, Paroxetine, andSertraline. Perspectives in Psychiatry, vol 1. chichester, England: John Wiley &Sons Ltd; 1991:37-70. 5. DunbarGc, cohn JB,
 Fabre LF, et al. BrJPsychiatry. 1991;1 59:394-398.

 PAXIL’ (brand              of p.rox.tin.            hydrochiodd.)                                        Pr.gnancy         Cat.gory          B. Reproduction            studies performed             in    ischemia, pallor, phlebitis, pulmonaryembolus,                        supraventricular
                                                                                                          rats and rabbits at doses up to 50 and 6 times the maximum                                         extrasystoles,        thrombosis,         varicose vein, vascular headache,
 S..      compi.t.             pr..cribing            inform.tlon              in Smithkiin.              recommended              human dose have revealed no evidence of                                   ventricular       extrasystoles.           Dlgsstiv.         Systsm:          infrequent:
 Bscham            Pharmaceuticals                litersturs          or PD Th. follow-                   teratogenic       effects or of selective toxicity to the fetus. How-                              bruxism, dysphagia, eructation,                   gastritis, glossitis, increased
 ing Is a brlof summary.                                                                                  ever, there are no adequate and well-controlled                                studies in          salivation,     liver function         tests abnormal,             mouth ulceration,
 INbIcATI0Ns                AND USAGE: Paxi! s indicated for the treat-                                   pregnantwomen.             Paxi!should be used in pregnancy only if the                            rectal hemorrhage;           rare:aphthous          stomatitis.       bloody diarrhea.
 ment of depression.                                                                                      benefits outweigh the risks. The effect of Paxilon labor and                                       bulimia, colitis, duodenitis, esophagitis,                  fecal impactions,            fecal
 ONTRAINDlCATlONS:                           Concomitant              use in patients taking              delivery in humans is unknown.                         Paroxetine        is secreted in            incontinence.       gastritis, gastroenteritis,           gingivitis, hematemesis.
 monoamine              oxidase inhibitors              (MAOist          is contraindicated.              human milk; exercise caution when administering                                 Paxil to a         hepatitis, ileus, jaundice, melena, peptic ulcer, salivary gland
 (See WARNINGS.)                                                                                          nursing woman.                                                                                     enlargement,         stomach ulcer. stomatitis,               tongue edema. tooth
 WARNINGS:                lrrt.ractlons         with MAOIs may occur. Giv.n                               Safety and effectiveness                  in children have not been estab-                         caries. Endocrine            Systsm:          rare: diabetes          mellitus,       hyper-
 th.fstalint.ractlonsr.port.dwith                                 concomitantorlmm.-                      lished.                                                                                            thyroidism. hypothyroidism,               thyroiditis. H.mlcandLymphatic
 diatoly cons.cutlv.                   administration               of MAOIS and oth.r                    in worldwide         Paxi/clinical trials, 17% of Paxi/-treated patients                           Systsms:       infrequent: anemia, (eukopenia. lymphadenopathy,
 SSRls, do not usi Pa.iI in combination                                     with a MAOI or                were 65 years of age. Pharmacokinetic                             studies revealed a               purpura; rare:abnormalerythrocytes,                    eosinophilia, leukocytosis,
 within2w.iksofdlscontlnuing                               MAOItr..tm.nt.                 AIIOWIt         decreased clearance in the elderly; however, there were no                                         lymphedema,           abnormal lymphocytes,                 lymphocytosis.            micro-
 losst2 w.ks              sft.rstopplng             Paxil bifor             starting       a MAOI.        overall differences          in the adverse event profile between older                            cytic anemia, monocytosis,                   normocytic         anemia. Mitabolic
 PRECAUTIONS:                   As with all antidepressants,                      use Paxi! cau-          and younger patients.                                                                              and Nutritional:          frequent: edema, weight gain, weight loss;
 tious(y in patients with a history of mania.                                                             ADVERSE          REACTiONS:              incidsecs         in Controlisd          Trials-          infrequent:         hyperglycemia,            peripheral       edema, thirst; rare:
 Use Paxil cautiously                 in patients with a history of seizures.                             Commonly          Obs.rv#{149}dAdv..i#{149} Evrsts              in Controlled          Clini-      alkaline phosphatase              increased,        bilirubinemia,         dehydration,
 Discontinue           it in any patient who develops seizures.                                           cal THaI& The most commonly                           observed        adverse events               gout, hypercholesteremia,               hypocalcemia,          hypoglycemia,           hypo-
 The possibilityof             suicideattempt            is inherent in depression and                    associated       with the use of Paxil(incidence                     of 5% or greater              kalemia, hyponatremia,                SGOT increased.               SGPT increased.
 may persist until significant                  remission occurs. Close supervi-                          and incidencefor          Paxilatleast         twice thatforplacebo):             asthenia         Musculosk.IstalSystsm:                   infrequent:arthralgia,           arthritis; rare:
 sion othigh-risk patientsshou(daccompany                                 initial drugtherapy.            (15% vs. 6%(, sweating 111 % vs. 2%l, nausea 126% vs. 9%),                                         arthrosis, bursitis, myositis,               osteoporosis,          tetany. Nsrvous
 Write Paxi! prescriptions                  for the smallest quantity of tablets                          decreased appetite 16% vs. 2%), somnolence                              (23% vs. 9%),              Syst.m:      frequent: amnesia, CNS stimulation,                         concentration
 consistent        with good patient management                            in order to reduce             dizziness 113% vs. 6%), insomnia (13% vs. 6%l, tremor (8%                                          impaired, depression,              emotional       lability, vertigo; infrequent:
 the risk of overdose.                                                                                    vs. 2%), nervousness                 15% vs. 3%l, ejaculatory               disturbance            abnormal       thinking,      akinesia, alcohol abuse, ataxia. convul-
 Reversible hyponatremia                     has been reported, mainly in elderly                         113% vs. 0%) and other male genital disorders 110% vs. 0%).                                        sions. depersonalization,              hallucinations,         hyperkinesia.          hyper-
 patients, patients taking diuretics or those who were other-                                             Twenty-one        percent 1881/4,126) of Paxil patients in worldwide                               tonia, incoordination,          lack ofemotion,          manic reaction, paranoid
 wise volume depleted.                                                                                    clinical trials discontinued            treatment        due to an adverse event.                  reaction; rare:abnormalelectroencephalogram,                             abnormalgait,
 Clinical experience                with Paxil in patients with concomitant                               The most           common             events         l1 %) associated                   with       antisocial      reaction,        choreoathetosis,             delirium,        delusions,
 systemic        illness is limited. Use cautiously                           in patients with            discontinuation          and considered             to be drug related include:                    diplopia, drug dependence.                  dysarthria.       dyskinesia.         dystonia,
 diseases or conditions that could affect metabolism                                      or hemo-        somnolence,           insomnia,        agitation,      tremor, anxiety, nausea,                    euphoria,       fasciculations,          grand mal convulsion.                    hostility,
 dynamic responses.                   Observe the usual cautions in cardiac                               diarrhea, dry mouth, vomiting, asthenia, abnormal ejaculation,                                     hyperalgesia.        hypokinesia,         hysteria, libido increased,                 manic-
 patients. In patients with severe renal impairment                                     (creatinine       sweating.       The following adverse events occurred in 6-week                                    depressivereaction,           meningitis, myelitis, neuralgia. neuropathy,
 clearance <30 mL/min.lor                     severe hepatic impairment.                     a lower      placebo-controlled            trials of similar design at a frequency                         of   nystagmus,         paralysis, psychosis,             psychotic         depression,           re-
 starting dose 110 mgI should be used.                                                                     1 % or more.                                                                                      flexes increased. stupor, withdrawal                      syndrome.        Rssplrstory
 Caution patients about operating                             hazardous          machinery,         in-   Body as a Whole: headache, asthenia, abdominal pain, fever,                                        Systsm: frequent:cougn               increased, rhinitis; infrequent:asthma,
 cluding automobiles,                 until they are reasonably sure that Paxil                           chest pain, trauma, back pain. Cardiovascular                                 palpitation,         bronchitis,      dyspnea. epistaxis, hyperventilation,                       pneumonia,
 therapydoes            notaffect       theirabilitytoengage                 in suchactivities.           vasodilation,       postural hypotension.               D.rmstOIOgIC            sweating,          respiratory flu, sinusitis; rare: carcinoma of lung, hiccups, lung
 Tell patients 1) to continue therapy as directed; 2) to inform                                           rash. Gastrolnt.stinal:               nausea, dry mouth, constipation,                    diar-    fibrosis, sputum increased. Skin and                                            : frequent:
 physicians about other medications                            they are taking or plan to                 rhea, decreased            appetite,        flatulence,        vomiting,      oropharynx           pruritus;    infrequent:         acne, alopecia,             ry skin, ecchymosis,
 take; 31 to avoid alcohol while taking Paxit 41 to notify their                                          disorder,     dyspepsia,           increased        appetite.       Musculoslislstal:              eczema, furunculosis,               urticaria;     rare: angioedema,                 contact
 physicians         if they become pregnant                          or intend to become                  myopathy,        myalgia, myasthenia.                 Nervous        Systsm:         somno-        dermatitis,       erythema        nodosum,         maculopapular            rash, photo-
 pregnant during therapy, or if they’re nursing.                                                          lence, dizziness,           insomnia,          tremor,        nervousness,          anxiety,       sensitivity, skindiscoloration.              skin melanoma. Sp.cislSsns.s:
 Concomitant           use of Paxilwith tryptophan is not recommended.                                    paresthesia,         libido decreased.              agitation,       drugged        feeling,       infrequent:abnormality              ofaccommodation,               ear pain. eye pain,
 Use cautiously             with warfarin. When administering                            Paxilwith        myoclonus,        CNS stimulation,             confusion. Riaplratlon:               respire-      mydriasis, otitis media, taste loss, tinnitus;                        rare: amblyopia,
 cimetidine,        dosage adjustment                  of Paxilafter the 20 mg start-                     tory disorder,          yawn, pharyngitis.                         I Sins.s           blurred      cataract, conjunctivitis,          cornealulcer,         exophthalmos.            eye hem-
 ing dose should be guided by clinical effect. When co-admin-                                             vision, taste perversion. Urogsnltai                         ystsm: ejaculatory dis-               orrhage. glaucoma. hyperacusis,                    otitis externa, photophobia.
 istering Paxil with phenobarbital                       or phenytoin,            no initial Paxil        turbance,       other male genital disorders,                      urinary frequency,              UrogsnftalSyst.m:               infrequent:abortion,            amenorrhea,           breast
 dosage adjustment                   is needed; base subsequent                            changes        urination disorder, female genital disorders.                                                      pain, cystitis, dysmenorrhea,                 dysuria. menorrhagia,               nocturia.
 on clinicaleffect.            Concomitant           use of Paxilwith drugs metabo-                       Studies show a clear dose dependency                           for some of the more                polyuria, urethritis,          urinary incontinence,               urinary retention,
 lized by cytochrome                      P4llD6          lantidepressants                such as         common adverse events associated with Paxiluse. There was                                          urinary urgency, vaginitis; rare: breast atrophy. breast card-
 nortriptyiine,           amitriptyline,          imipramine,              desipramine            and     evidenceofadaptation                tosomeadverse              eventswith       continued          noma, breast neoplasm, female lactation, hematuria,                                   kidney
 fluoxetine;         phenothiazines              such as thioridazine;                    Type 1C          Paxi! therapy (e.g., nausea and dizziness). Significant weight                                    calculus.     kidney function             abnorm&.          kidney pain, mastitis.
 antiarrhythmicssuch                 as propafenone,              fecaunideand encainidel                 loss may be an undesirable result of Paxiltreatment                               for some         nephritis. oliguna. prostatic carcinoma. vaginal moniliasis.
 or with drugs that inhibit this enzyme (e.g.. quinidinel                                        may      patients     but on average, patients                       in controlled       trials had         Non-U.S. Postmark.tlng                   Rsports
 require lower doses than usually prescribed for either Paxilor                                           minimal (about 1 IbI loss. In placebo-controlled                           clinical trials,        Voluntary reports of adverse events that have been received
 the other drug; approach concomitant                               use cautiously. Admin-                 PaxiI-treated patients exhibited abnormal values on liver func-                                   since market introduction              and may have no causal relationship
 istration of Paxilwith               another tightly protein-bound                      drug may         tion tests no more frequently                   than placebo-treated            patients.          with Paxil include elevated                   liver function         tests (the most
 shift plasma concentrations,                    resulting in adverse effects from                        Othir Evsnts Obs.ry.d                   During di. Pr.m.rk.tlng                     Evalus-        severe case was a death due to liver necrosis, and one other
 either drug. Concomitant                  use of Paxi/andalcohol                  in depressed           tlonofPaxM          During premarketingassessment,                        multipledoses            case involvinggrosslyelevatedtransaminasesassociatedwith
 patients is not advised. Undertake                            concomitant           use of Paxil         of Paxilwere administered                 to4,126 patients, and thefollowing                       severe liver dysfunction).
 and lithium or digoxin cautiously.                        If adverse effects are seen                    adverse events were reported.                         Note: frequent             =    events       DRUG ABUSE AND DEPENDENCE:                                 Controllsd        Substanos
 when co-administering                     Paxil with procyclidine,                   reduce the          occurring      in at least 1/100 patients; ‘infrequenf=                            1/100 to        class: Paxil is not a controlled substance. Evaluate patients
 procyclidine          dose.                                                                               1/1000 patients; ‘rare’ = less than 1/1000 patients. Events are                                   carefully for history of drug abuse and observe such patients
 in 2-year studies, a significantly                   greater number of male rats in                      classified within body system categories                          and enumerated              in   closely for signs of Paxil misuse or abuse (e.g., development
 the 20 mg/kg/day groupdeveloped                             reticulum cell sarcomasvs.                   order of decreasing frequency using the following definitions.                                     oftolerance,       incrementations            ofdose, drug-seeking               behaviorl.
 animals given doses of 1 or 5 mg/kg/day.                                  There was also a               It is important to emphasize that although the events occurred
 significantly        increased linear trend across dose groups for the                                   during Paxiltreatment,              they were not necessarily caused by it.                        BRS-PX:L4
 occurrence          of lymphoreticular              tumors in male rats. Although                        BodyasaWhoia:               frequent:chills,          malaise; infrequent:allergic
 there was a dose-related                   increase in the number of tumors in                           reaction, carcinoma, face edema, moniliasis,                           neck pain; rare.
 mice, there was no drug-related                            increase in the number of                     abscess, adrenergic              syndrome.         cellulitis, neck rigidity, pelvic
 mice with tumors. The clinical significance
 unknown. There is no evidence of mutagenicity
                                                                         of these findings is
                                                                                    with Paxil.
                                                                                                          pain, peritonitis,
                                                                                                          hypertension,
                                                                                                                                     ulcer. Cardiovascular
                                                                                                                                 syncope, tachycardia;
                                                                                                                                                                            Syst.m:
                                                                                                                                                                     infrequent:
                                                                                                                                                                                            frequent:
                                                                                                                                                                                      bradycardia,           Su          SmithKhn.        Bscthan
 Serotonergic            compounds            are known to affect reproductive                            conduction          abnormalities,              electrocardiogram              abnormal,                       P’t’iarrnaceuticals
 function in animals. Impaired reproductivefunction                                    in rats (i.e.,     hypotension,         migraine, peripheral vascular disorder; rare: an-
 reduced pregnancy rate, increased pre- and post-implantation                                             gina pectciris, arrhythmia, atrialfibrillation,                  bundlebranch           block,
 losses, decreased viability of pups) was found at Paxildoses                                             cerebral schemia, cerebrovascular                      accident, congestive              heart
 15 or more times the highest recommended                                       human dose.               failure, low cardiac output,                    myocardial        infarct      myocardial          Philadelphia, PA 19101                          © SmithKline Beecham, 1993
                                                                                                                                 AT



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                         THE                    AMERICAN                                               JOURNAL                                                         OF PSYCHIATRY


                                                                                                                     EDITOR

                                                                                          Nancy          C. Andreasen,                              M.D.,              Ph.D.

                                                                                                      DEPUTY                          EDITORS

                                                                Arnold           M.       Cooper,             M.D.                             Jack              M.        Gorman,               M.D.


EDITORIAL                    STAFF                                                                   EDITOR                      EMERITUS                                                                            STATISTICAL                    EDITORS
Managing               Editor                                                                       John        C. Nemiah,                              M.D.                                                              Stephan         Arndt,          Ph.D.
Sandra            L. Patterson
                                                                                                                                                                                                                          JohnJ.         Bartko,          Ph.D.
Assistant           Managing              Editor                                                   ASSOCIATE                             EDITORS
                                                                                                                                                                                                                          FORMER               EDITORS
Linda         A. Loy
                                                                                                  Paul        S. Appelbaum,                                   M.D.                                                    Amariah          Brigham,              M.D.
Senior        Assistant            Editors                                                                                                                                                                                          1844-1849
                                                                                            Daniel            G. Blazer,                  M.D.,                  Ph.D.
Laura M. Little                                                                                                                                                                                                          T. Romeyn             Beck,        M.D.
Jane Weaver                                                                                    Gabrielle                 A. Carison,                           M.D.
                                                                                                                                                                                                                                    1849-1854
                                                                                                   Kenneth                 L. Davis,                         M.D.                                                          John       P. Gray,            M.D.
Assistant           Editor
                                                                                                    Judith               H.       Gold,              M.D.                                                                           1854-1886
Marjorie            M. Henry
                                                                                                                                                                                                                         G. Alder         Blumer,           M.D.
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Production              Editor                                                                                                                                                                                                      1886-1894
Beverly           M. Sullivan                                                                       Roger            E. Meyer,                          M.D.                                                              Richard         Dewey,           M.D.
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Production              Assistant                                                                                                                                                                                         Henry       M. Hurd,             M.D.
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                                                                                                                                                                                                                                    1897-1904
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Administrative                    Assistant
Dawn          Baldwin                                                                              Carol         Tamminga,                                   M.D.                                                             1904-1931
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Editorial  Secretaries                                                                                                                                                                                                        193 1-1 965
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A6
       The cr


a major conL
   of psychiatric corn
   seroton ink
A8
                      NEW

 THE FIRSTTHERAPEUTIC AGENT FOR
THE TREATMENT OF MILD-TO-MODERATE
       ALZHEIMER’S DISEASE




          INTRODUCING



     Cognex#{174}
                             HO
                         TACRNECAPSULES                                              a
                                                                          0mg20mg30mg, nd40mg
           Please see brief summary   of full prescribing   information    on last page   of this advertisement.
    Cocmex#{174}
             HO
      “TACRNE CAPSULES
                                                                           2 30mg.
                                                                        0mg, 0mg. and40mg

                PROVEN EFFECTIVE IN
              TWO WELL-CONTROLLED
                     STUDIES1’2
.   The effects               of COGNEX               vs placebo       were demonstrated
    in patients              with mild-to-moderate               Alzheimer’s        disease     in
    12-and             30-week          trials

.   In both studies,                  statistically     significant      effects   were
    achieved                on the primary            efficacy      measures:

    -An          oblective,           performance-based                test of cognitive
        function            that examines             aspects    of memory,        attention,
         reason,            language,            and the ability      to perform      simple
        tasks

    -A        clinician-rated              global      evaluation       of change      vs
         baseline

.   Caregiver                global      evaluations        were      positive


    COGNEX presumably          acts by elevating acetylcholine       concentrations
    in the cerebral cortex by slowing the degradation          of acetylcholine
    released by still intact cholinergic    neurons. If this theoretical     mecha-
    nism of action is correct, the effects of COGNEX          may lessen as the
    disease process advances and fewer cholinergic            neurons remain
    functionally   intact. There is no evidence that COGNEX            alters the
    course of the underlying      dementing    process.




    © 1993 Worner-lambert   Company
See full prescribing                   information           for COGNEX               dosing       and administration   and the complete
protocol          for managing               ALT elevations.

*   Investigational    new drug.

    Alanine    aminotransferase,      also known as SGPT.

Please    see brief summary        of full prescribing   information   on last page   of this advertisement.
   @cmex
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                                                                                                                                                                                                  REFERENS
                                                                                                                                                                                                  1. Far)ow     M, Grocon      SC, Hershey       LA, et ol A contro))ed            trio) of
                                                                                                                                                                                                     tacrine in Alzheimer’s disease. JAMA.                  1992;268:2523.2529.
   ©1993         Warner’tombert             Company                                                                                                                                               2. Dab on file, Porke.Oavis.




COGNEX       is a registered         frodemark            of Wamer-tambert                  Company.                                         C..)     Pnnted         on Recycled   Paper                                                           PD-102-JA-8623-B1 (014) 410020
                                                            The American                                      Psychiatric                      Association
                                                                        1400       K Street,               N. W.,     Washington,              D.C.       20005


               OFFICERS                 1993-1        994                                                 BOARD       OF TRUSTEES                                        MEDICAL                 DIRECTOR’S               OFFICE
          President:            John       S. McIntyre                                                     Elissa P. Benedek                                        Medical          Director:       Melvin           Sabshin
 President-Elect:               Jerry   M. Wiener                                                          Harvey Bluestone
  Vice-President:                Lewis   L. Judd                                                           Daniel B. Borenstein                                         Senior    Deputy
  Vice-President:                Martha    J. Kirkpatrick                                                                                                          Medical     Director:             Carolyn           B. Robinowitz
                                                                                                           Charles   L. Bowden
           Secretary:            Steven          S. Sharfstein
          Treasurer:             Mary       Jane       England                                             Marian   I. Butterfield
                                                                                                                                                                                      Deputy
                                                                                                           Joseph T. English                                      Medical          Directors:        Robert       T.M.    Phillips
                                                                                                           Gladys   R. Gregory                                                                       Harold        A. Pincus
                                                                                                           Lawrence      Hartmann                                                                    James       Scully
                                ASSEMBLY
                                                                                                           Abram    M. Hostetter
            Speaker:             Richard           M. Bridburg                                             Merlin   H. Johnson
   Speaker-Elect:                Norman            A. Clemens
                                                                                                           Benjamin     Liptzin
          Recorder:              Richard           K. Harding
                                                                                                           Robert   J. McDevitt
                                                                                                           Steven   M. Mirin
                                                                                                           Rodrigo     A. Munoz
                                                                                                           Herbert    S. Sacks




                                 CHAIRPERSONS                      OF    COUNCILS,                      COMMISSIONS,                  COMMITTEES,                    AND           TASK          FORCES

CONSTITUTIONAL                            COMMITTEES                                                                        JCAHO         Standards        for Hospital-Based,
Budget                                                                                 Donald    J. Scherl                        Hospital-Related            Services                                        Boris      M. Astrachan
Constitution/Bylaws                                                                   Barry   B. Perlman                    Managed         Care                                                               J eremy     A. Lazarus
Elections                                                                Eliza      Wright    Menninger                     Occupational           Psychiatry                                                           Peter L. Brill
Ethics                                                                                      Donna         E. Frick          Private     Practice                                                                   Peter D. Kramer
Ioint Reference                                                                            Jerry      M. Wiener             Prospective         Payment        Issues                                           Joseph      T. English
Membership                                                                                         Aron  S. Wolf             Q uality Assurance                                                                Marlin     R. Mattson
                                                                                                                             Universal      Access      to Health      Care                                       Herbert      S. Sacks
Strategic      Membership                 Plan                                      G. Pirooz Sholevar
Nominating                                                                           Joseph T. English
Resource        Development                                                             Doyle I. Carson                     COUNCIL   ON INTERNAL
Tellers                                                                                        Oscar       Legault             ORGANIZATION                                                                   Thelissa      A. Harris
                                                                                                                            Advertising                                                                               Harold      I. Eist
                                                                                                                            Headquarters                                                                          Lucy D. Ozarin
COUNCIL    ON ADDICTION
   PSYCHIATRY                                                                      Charles        E. Riordan
                                                                                                                            History       and Library                                                   Martha       J. Kirkpatrick
                                                                                                                            Human          Resources                                                         Jack W. Bonner            III
Psychiatric          Services                                                                  Sheila    Blume              Information           Systems                                                   Zebulon        C. Taintor
Training       and      Education                                                            Marc     Galanter              Special      Benefit       Programs                                              Eva Veronica           Ebin
                                                                                                                            Telemedical           Services                                                      Frank W. Brown
COUNCIL            ON AGING                                                           Burton            V. Reifler          Exhibits        Advisory                                                Joseph      H.B. Honnigford
Education        and Training          in Geriatric                                                                         Local      Arrangements                                                        James      M. Delaplane
     Psychiatry                                                                  Charles           A. Shamoian              Advertisers         and Exhibitors                                                Maurice       J. Martin
Ethnic      Minority                                                      Kenneth             Mark        Sakauye           Scientific       Program                                                           John M. Oldham
Geriatric       Psychiatry        in the Public     Mental                                                                  Film and Video                                                              Edward        K. Rynearson
      Health      Sector                                                            Barry           Steven   Fogel          Grants       and Awards                                                         Mary       Jane England
Long-Term           CareTl’reatment         for the Elderly                                           Ira R. Katz           APA Award             for Research                                            Nancy       C. Andreasen
Reimbursement              for Elderly     Mentally     Ill                    Howard               H. Goldman              APA Award             and Fellowship            for    Psychiatric
Senior     Psychiatrists                                                           Hugo             Van Dooren                    Services       Research                                                            Carl Salzman
White      House       Conference        on Aging                               Sanford             Irwin Finkel            H&CP         Achievement            Awards                                              Don R. Lipsitt
                                                                                                                            McGavin           Award                                                           Mina   Karen     Dulcan
COUNCIL  ON CHILDREN,                                   ADOLESCENTS,                                                         Vestermark          Award                                                                   Jerald     Kay
                                                                                                                            Friends       ofthe      APA                                                           Linda    Logsdon
   AND THEIR FAMILIES                                                                        David        B. Pruitt
 Chronically         Ill and Emotionally            Handicapped
       Children                                                                      Kendon     W. Smith                    COUNCiL            ON       INTERNATIONAL
 Day Care for Preschool                Children                                     Shahla   S. Chehrazi                            AFFAIRS                                                                   Eugene        B. Feigelson
Family        Violence      and Sexual       Abuse                                   Cynthia    R. Pfeffer                  Bilateral      Exchange       With       Eastern         Europe                               John Talbott
Ittleson      Award                                                                 Donald    Jay Cohen                     Human         Rights                                                                      Carlos    E. Sluzki
I uvenile Justice          Issues                                                    Richard   A. Ranier                    International        Abuse     and      Misuse
Psychiatric         Aspects       of New     Reproductive                                                                         of Psychiatry                                                        D. Raymond                Freebury
       Technologies                                                              Miriam             B. Rosenthal            International        Education                                                   Normund                 Wong
Psychiatry         and Mental         Health     in Schools                                        David   Fassler
 Use and Abuse            of Hospitalization                                                                                COUNCIL            ON       MEDICAL          EDUCATION                  AND
       of Adolescents                                                               Elizabeth           B. Weller                   CAREER        DEVELOPMENT                                                         J ames     H. Shore
                                                                                                                            Administrative          Psychiatry                                                 Michael          J. Vergare
COUNCIL             ON ECONOMIC                          AFFAIRS                              Paul J. Fink                  APA/Burroughs             Wellcome        Fellowship                                              Roger    Peele
Codes      and Reimbursement                                              Chester       W. Schmidt,       Jr.               APA/CMHS             Minority      Fellowship
Financing         and Marketing                                                       Robert    0. Friedel                       Program                                                                               Ruth L. Fuller
Harvard        RBRVS                                                                   Donald     J. Scherl                 APA/Mead          Johnson        Fellowship                                                Stuart   L. Keill
Interprofessional        Affairs                                                      John S. McIntyre                      Communication               Between      APA          and    ABPN                  Rodrigo       A. Munoz




                                                                                                                                                                                                                                       A13
Consultation-Liaison                 Psychiatry     and                                                   Psychiatry      in U.S. Territories                                                  Jeffrey L. Geller
      Primary        Care Education                                               Fawzy     I. Fawzy      State and      Community       Psychiatry           Systems                            Steven E. Katz
Continuing           Education                                                  Pauline     Langsley      Veterans’      Affairs                                              Frederick         G. Guggenheim
Diagnostic          Education                                            Michael      A. Fauman
Early     Career       Psychiatrists                                             Mary  Ellen Foti         COUNCIL           ON PSYCHIATRY                    AND        LAW          Paul S. Appelbaum
Graduate          Education                                              Daniel   K. Winstead             Confidentiality                                                           Renee Leslie Binder
Impaired         Physician                                                 Gordon    L. Moore             Consent         to Voluntary     Hospitalization                            Francine  Coumos
Medical        Student       Education                                  Carol   Ann Bernstein             Peer Review          on Expert      Testimony                             Kathleen   M. Quinn
Model        Curricular        Material       on Medical/                                                 Sexually        Dangerous      Offenders                                      Howard   Zonana
      Psychiatric         Ethics                                                    Allan   Tasman        Manfred          S. Guttmacher       Award                              W. Walter Menninger
PKSAP-VI                                                            Gordon       Darrow       Strauss     Isaac Ray Award                                                                  Alan A. Stone
Recertification                                                     Gordon       Darrow       Strauss
Residents         and Fellows                                                 Marilynn      J. Peters                                                                                                  Pardes
                                                                                                          COUNCIL           ON RESEARCH                                                     Herbert
                                                                                                          Biographical          Directory                                                 Lorrin M. Koran
COUNCIL             ON NATIONAL                     AFFAIRS                          Fred Gottlieb        DSM-IV                                                                           Allen J. Frances
Abuse      and Misuse            ofPsychiatry           in U.S.        William        M. Womack           Electroconvulsive             Therapy                                        Richard      D. Weiner
American         Indian,       Alaska       Native       and                                              Nicotine       Dependence                                                 John Russell Hughes
      Native       Hawaiian          Psychiatrists                       Albert   F. Samuelson            Psychiatric        Diagnosis       and Assessment                              Layton McCurdy
Asian-American              Psychiatrists                                  Jambur    V. Ananth            Psychosocial          Treatment       Research                                 John P. Docherty
Black      Psychiatrists                                                Robert       T.M.    Phillips     Research        on Psychiatric        Treatments                              Alan J. Gelenberg
Gay,      Lesbian,       and Bisexual            Issues                   Rochelle     L. Klinger         Research        Training                                                      Ronald 0. Rieder
Hispanic        Psychiatrists                                        Fernando      Jose Milanes           Steering      Committee          on Practice     Guidelines                    John S. McIntyre
Homelessness                                                         Stephen       M. Goldfinger          Traumatic         Brain     Injury                                          Stuart C. Yudofsky
International           Medical        Graduates                                    Richard     Balon
Psychological            Aspects       of Nuclear         Issues                   Vamik      Volkan
                                                                             Richard      J. Thurrell     SPECIAL        COMPONENTS
Religion       and Psychiatry
                                                                               Gail E. Robinson           Commission         on AIDS                                                       Marshall           Forstein
Women
                                                                                                          Commission         on Judicial      Action                                      J.
                                                                                                                                                                                          Richard    Ciccone
                                                                                                          Commission         on Subspecialization                                        James    M. Trench
COUNCIL             ON     PSYCHIATRIC                 SERVICES                 James     T. Barter
                                                                                  J. Frank James          Consultation        Service    Board                                        Stephen Alan Green
APA       Public      Psychiatry         Consortium
Chronic        Mental        Illness                                                Ezra S. Susser
                                                                                                          Distinguished        Service    Award      Committee                            Jack D. Barchas
Clinician        Safety                                                     William       R. Dubin        Ethics     Appeals     Board                                                Steven S. Sharfstein
Disability        and Rehabilitation                                   Kenneth       G. Terkelsen         Executive Compensation                 Committee                                Pete C. Palasota
Marie      H. Eldredge            Award                                      Anita      L. Gerhard        Joint   Commission          on Government               Relations            Ronald A. Shellow
Family/Systems             Therapy                                                  Fred Gottlieb         Joint   Commission          on Public   Affairs                                   Edward   Hanin
H&CP         Service                                                             Leah Dickstein           Long-Range Planning Committee                                                    RobertO.            Pasnau
Institute      on H&CP                                                           Alan M. Elkins           Medical Necessity and Reimbursement
Practice       of Psychotherapy                                             William       H. Sledge             Criteria                                                                        Edward          Hanin
Psychiatric         Services       in Jails and Prisons                  Henry       C. Weinstein         Minority       Research     Training      in Psychiatry                     M. Jeanne Spurlock
Psychiatric         Services       for Mentally         Retarded/                                         Strategic      Planning                                                       Joseph T. English
       Developmentally               Disabled       Adults             Ludwik S. Szymanski                Work       Group      on Federal      Government
Psychiatric         Services       in the Military                         Kenneth S. Hoyle                     Organizational        Structure                                                 J.    Frank     James




                                                       Coming                 in the            February                1 994            issue               of

                                  THE                AMERICAN                               JOURNAL                      OF PSYCHIATRY

                              Electroconvulsive                                     Therapy               of Acute   Manic                                   Episodes:
                                             A Review                                 ofSO              Years’ Experience
          By Sukdeb                             Mukherjee,                        Harold                A. Sackeim,                      and David                            B. Schnur




A14
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       For more information                   call
       1-800-292-GATE.
       GATE Pharmaceuticals,
GATE   Sellersville, PA 18960
       © 1993.   GATE Pharmaceuticals




                                                     A1S
                                                                                                                            Calendar

For     free       listing              of     your       organization                 ‘s official         annual           or    regional             meeting,              please     send       us      the      following             information:          sponsor,
location,              inclusive                dates,      type           and     number            of    continuing              education              credit            (if available),          and the name, address,                              and telephone
number             of the person                         or group             to contact             for more           information.               In order                 for an event           to appear in our listing,                             all notices and
changes            must            be        received           at    least      6 months              in advance            of    the       meeting          and           should      be     addressed              to     Calendar,           American         Journal
of Psychiatry,                     1400           K St.,        NW,           Washington,                 DC     20005;           202-682-6026                     (tel),       202-682-6016                     (fax).     Because          of space       limitations,
only        listings         of     meetings               of        the    greatest        interest           to Journal           readers            will       be     included.




                                                                                                                                                   March     12-1 9, conference,            “Health       Care Organization,”         Rose
MARCH                                                                                                                                              Medical       Center,        Park      City,     Utah.     Contact:      Bernard      A.
                                                                                                                                                   Karshmer,      Ph.D.,       Rose Medical          Center    Conference       Program,
March         1-6,   annual   meeting       and review         course,      “Creative
                                                                                                                                                   800 Clermont          St.-#330,         Denver,      CO 80220;        303-333-3321
Care for the 90s” (36 hours category                 I CME credit),         American
                                                                                                                                                   (tel), 303-333-4224             (fax).
Society       for Adolescent    Psychiatry,        Scottsdale,       Ariz. Contact:
Karen       Artis,   ASAP,   4330     East West         Highway,         Suite    I 117,
Bethesda,          MD 20814-4408;           301-718-6502           (tel), 301-656-                                                                 March     1 7-1 8, “Alzheimer’s      Disease    Conference:      Advances     in
                                                                                                                                                   Treatment       1994,”   University     of California,      San Diego,    Alz-
0989      (fax).
                                                                                                                                                   heimer’s     Disease   Research     Center,   San Diego.       Contact:   Cass
March      2-5,    annual     meeting,      Association        for Academic         Psy-                                                           J ones,             Professional            Conference                  Management,                Inc., 791 6 Con-
chiatry,    “Enhancing         Professional        Development         in a Time of                                                                voy Court,                   San    Diego,           CA         92111;         619-565-9921                (tel),   619-
Change,”        Tucson,     Ariz. Contact:         AAP Executive         Office,      De-                                                          565-9954                   (fax).
partment       of Psychiatry,       Wyman       2, Mount        Auburn      Hospital,
Cambridge,         MA 02238;         617-499-5198.                                                                                                 March      1 7-20,     14th National     Conference        of the Anxiety     Dis-
                                                                                                                                                   orders     Association       of America,       “Getting      Well and Staying
March      4-5,      conference,      “Treating     the Addictions,”           Cam-                                                                Well:     Working        Toward      a Broader       Understanding,”        Santa
bridge    HospitalfHarvard            Medical    School,      Boston.     Contact:                                                                 Monica,       Calif.    Contact:     Jan J. Ross, Conference           Director,
Judy    Reiner      Platt,    Ed.D.,   Cambridge       Hospital,      1493     Cam-                                                                6000 Executive          Blvd, Suite 513, Rockville,           MD 20852;      301-
bridge   St., Cambridge,            MA 02139;     617-864-6165          (tel), 617-                                                                231-5484.
876-9760        (fax).
                                                                                                                                                   March      1 8-20,      “Clinical       Neurology         for Psychiatrists”            (30
March      5-6,    1 9-20,   3 1 st Annual        Introductory         Course    in Clini-                                                         hours category        I CME credit),          Montefiore        Medical     Center/Al-
cal Hypnosis          for Physicians,          Dentists,     and Psychologists          (28                                                        bert Einstein      College      of Medicine,       New York.         Contact:      Office
hours     category        I CME       credit),      San Francisco          Academy         of                                                      of Continuing        Medical         Education,       Montefiore        Medical      Cen-
Hypnosis,       Berkeley,      Calif.     Contact:       Verna     Carter,    SFAH,      29                                                        ter, 1 1 1 East 210th          St., Bronx,      NY 10467;          1-800-626-8519
Pinto Ave., San Francisco,               CA 94132;           415-239-4104.                                                                         (tel), 718-798-2336            (fax).

March     5-12,   conference,         “Minding        the Body-Mending              the                                                            March       19, 1st International         Meeting,      Spiritual     Approach         in
Mind,”      Rose Medical         Center,     Vail, Cob.       Contact:      Bernard                                                                Psychiatry,       “Meditation         and Psychotherapy,”            Lyon,   France.
A. Karshmer,       Ph.D.,     Rose Medical            Center   Conference        Pro-                                                              Contact:      Jean-Marc       Mantel,     M.D.,    P0 Box 131, 30300            Atlit,
gram,   800 Clermont        St.-#330,         Denver,      CO 80220;      303-333-                                                                 Israel;    972-4-842812        (tel), 972-4-842663            (fax).
3321   (tel), 303-333-4224            (fax).
                                                                                                                                                   March       19-20,      “HealthCare                                Ethics    Forum   ‘94,”     American
March       10-12,     “Critical     Issues      in the Treatment          of Affective                                                            Association        of Critical-Care                             Nurses     and the Society    of Critical
Disorders,”        European       Decade       of Brain Research,           Paris. Con-                                                            Care Medicine,           Washington,                                D.C. Contact:     AACN-Critical
tact: Nicoletta        Brunello,       Scientific      Secretariat,      International                                                             Care,     101 Columbia,            Aliso                        Viejo,    CA 92656;     800-899-2226
Academy         for Biomedical           and      Drug     Research,        Institute       of                                                     (tel), 714-362-2020             (fax).
Pharmacological            Sciences,       Via Balzaretti           9, 20133         Milan,
Italy; 39-2-20488331/332              (tel), 39-2-29404961/2048821                   1 (fax).                                                      March    19-22,     1 ith Annual     National       Disease    Prevention        and
                                                                                                                                                   Health    Promotion       Meeting,      “PREVENTION                 94: Science,
March       10-13,      20th Annual         Meeting        of the Association           for                                                        Skills and Strategies,”      American       College      of Preventive      Medi-
Gerontology           in Higher        Education,         “Aging       Reconsidered:                                                               cine and Association         of Teachers         of Preventive         Medicine,
Challenges         to Inquiry       and Education,”           Cleveland.       Contact:                                                            Atlanta.   Contact:      PREVEN11ON             94, 1015        15th    St., NW,
Dr. Jim McAuley,             AGHE       Program        Chair,    Center     for Geron-                                                             Suite 403, Washington,          DC 20005-2605;            202-789-0006.
tology,     Virginia       Polytechnic       Institute      and State University,
Blacksburg,         VA 24061-0426;            703-231-7657.                                                                                        March    20-25,     International      Symposium      on Dementia     in Park-
                                                                                                                                                   inson’s   Disease,     Jerusalem.      Contact:  Professor   Amos     D. Kor-
March     1 2, conference,  “Understanding        and Treating      Children,”                                                                     czyn, P0 Box 50006,             Tel Aviv 61500,    Israel; 972-3-5140014
Cambridge        Hospital, Cambridge.        Contact:   Judy Reiner         Platt,                                                                 (tel), 972-3-5175674            (fax).
Ed.D., Cambridge       Hospital,      1493 Cambridge        St., Cambridge,
MA 02139;     617-864-6165          (tel), 617-876-9760         (fax).                                                                                                                                                                   (Continued         on page    A22)




A16
TheFirstino
New Chemical      Class of                                                              2
Non-benzodiazepine                                                             a                z
Sleep Agents                                                                        z
                                                                                            z




                                                                     NTM
                  DEMTARIRATE)
              (ZOLH
                                                  5-MG   & 10-MG     TABLETS

              . AMBIEN-an       imidazopyridine,   chemically      unrelated   to
                benzodiazepines    or any other sleep agent
              . AMBIEN-.indicated        for short-term management        of
                insomnia    (generally   limited to 7 to 10 days)
              #{149}
                 Extensive clinical experience-over      500 million doses
                 prescribed throughout    Europe’
                                                                                                                             Refersocex: 1. Data on file, Searle. 2. Merlofli L Roehrs 1, Koshorek 6, et al. The doseeffects olzolpidem on the sep of healthy
                                                                                                                             normals. JClinPsychopharmacol.      1989;9:9-14. 3. VogeiG W, ScharlM,WaIshJ, etai Effectsofchronicallyadministeredzolpidem
                                                                                                                             on the sleep of healthy insomniacs. Sleep Research. 1989;18:80. Abstract. 4 SCltarf MB, Mayleben DW, Kaffeman M, et al. Dose

                        AMREN                                                                                                respooseeffectsofzolpidem    in normalgenatnic subjects. JCIinPsyr/satry    1991;52:77-83. 5. WalshJK, SchweitzerPK, Sugerman
                                                                                                                             JLSIOL hottest nsomnaassodetedwtha3-hourphaseadvanceofsleeptmeasdtreatmentw©ztipdem.                      JOin Psycitoptwmaco/
                                                                                                                             1990;1O:184-189. 6. Oswald I, Adam K. A new look at short-acting hypnotics. In: Sauvanet JP, Lunger SZ, Morselh PL, edo.
                        (ZODEM                  TARIRATE)#{128}                                                              lmidazopyndinesinSleepD,sordeis.      New York, NY: Raven Press; 1988:253-259.


BRIEF              SUMMARY
                                                                                                                 seen in 4/100           rats 13 males, 1 female) receiving 80 mg/kg/day                                    and a            Incidence     of Treatment-Emergent            Adverse        Experiences                          in
                          INDICATIONS          AND USAGE                                                         renal hpoma was observed                      in one male rat at the 18 mg/kg/day                          dose.                Long-term     Placebo-Controlled          Clinical     Trials (Cont’d)
Ambien    Izolpidem    tsrtratel   is indicated    for the short-term      treatment of                          Incidence rates of lipoma and liposarcoma                              for zolpidem were compa-                                              (Percentage      of patients     reportingl
insomnia.    Hypnotics      should   generally     be limited   to 7 to 10 days of
                                                                                                                 rable to those seen in historical controls and the tumor findings are                                                                                                                         Zolpidem
use, and reevaluation        of the patient is recommended           if they are to be
                                                                                                                 thought to be a spontaneous                       occurrence.
taken for more than 2 to 3 weeks.                                                                                                                                                                                                      Body System/                                                           ( 10 mg)                    Placebo
                                                                                                                 Mutag.nesis:              Zolpidem          did not have mutagenic                     activity in several              Adverse Event                                                         lN152l                     lN=161)
   Ambien    should not be prescnbed            in quantities exceeding a 1-month
                                                                                                                 tests including the Ames test, genotosicity                              in mouse lymphoma                    cells
supply (see #{188}rnings).                                                                                                                                                                                                             Respiratory        System
                                                                                                                 in vitro, chromosomal                    aberrations         in cultured         human lymphocytes.
                                    CONTRAINDICATUONS                                                            unscheduled           DNA synthesis in rat hepatocytes                           in vitro, and the mi-                   Upper       respiratory       infection                                     5                        6
None     known.                                                                                                  cronucleus         test in mice.                                                                                         Sinusitis                                                                   4                        2
                                                WARNINGS                                                         Impain’n.nt           of fw’tility:         In a rat reproduction                study. the high dose                   Pharyngitis                                                                  3                        1
                                                                                                                 1100 mg base/kg) of zolpidem resulted in irregular estrus cycles and                                                    Rhinitis                                                                     1                        3
Since sleep disturbances                    may be the presenting                manifestation         of a
physical and/or psychiatric                  disorder.     symptomatic         treatment       of insom-         prolonged precoital intervals, but there was no effect on male or female                                              Skin and Appendages
nia should be initiated only after a careful evaluation                                of the patient.           fertility after daily oral doses of 4 to 100 mg base/kg or 5 to 130                                                     Rash                                                                         2                        1
The failure of insomnia to remit after 7 to 10 days of treatment                                        may      times the recommended                       human dose in mg/m#{176}.No effects                         on any        Urogenital    System
indicate      the presence             of a primary psychiatric and/or medical illness                           other fertility parameters                 were noted.                                                                  Urinary tract infection                                                      2                        2
which should be evaluated.                     Worsening        of insomnia or the emergence                     Pregnancy                                                                                                              Events      reported        by at least       1% of patients            treated      with     Ambien.
of new thinking             or behavior abnormalities               may be the consequence                 of    Category         B. Studies to assess the effects of zolpidem                                      on human
an unrecognized               psychiatric       or physical disorder. Such findings have                         reproduction          and development               have not been conducted.                                          There is evidence            from dose comparison              trials suggesting         a dose
emerged durin9 the course of treatment                           with sedative/hypnotic             drugs.          Teratology         studies were conducted                   in rats and rabbits.                                   relationship      for many of the adverse events associated                     with zolpidem
including       Ambien.         Because some of the important                     adverse      effects     of       In rats, adverse maternal and fetal effects occurred at 20 and 100                                                 use. particularly        for certain CNS and gastrointestinal               adverse events.
Ambeen appear to be dose related lsee Precautions                                   and Dosage and               mg bese/kg            and included dose-related                    maternal         lethargy and ataxia                  Adverse events are further classified                  and enumerated            in order of
Administratsonl,             it is important        to use the smallest            possible      effective       and a dose-related              trend to incomplete              ossification        of fetal skull bones.            decreasing       frequency      using the following        definitions:     frequent adverse
dose, especially in the elderly.                                                                                    In rabbits, dose-related                maternal sedation and decreased weight gain                                events are defined as those occurring in greater than 1/ 100 subjects;
   A variety of abnormal thinking and behavior changes have been                                                 occurred       at all doses tested.               At the high dose, 16 mg base/kg,                          there     infrequent      adverse events are those occurring                   in 1/100      to 1/1.000
reported        to occur in association with the use of sedative/hypnotics.                                      was an increase in postimplantation                         fetal loss and underossification                     of   patients; rare events are thoxe occurring in less than 1/1,000                          patients.
Some of these changes may be characterized                                 by decreased         inhibition       sternebrae         in viable fetuses.                                                                                 Frequent:        abdominal pain, amnesia,              ataxia,     confusion.      depression,
leg, aggressiveness                 and extroversion          that seemed out of characterl.                        This drug should be used during pregnancy                                 only if clearly needed.                  diarrhea, diplopia, dizziness, dreaming abnormal,                      drowsiness,      drugged
similar     to effects produced                 by alcohol and other CNS depressants.                             Nont.ratog.nic              effcts:         Studies to assess the effects on children                                feeling, dry mouth, dyspepsia,              euphoria,     fatigue,     headache,      insomnia,
Other      reported         behavioral         changes       have included          bizarre     behavior.        whose mothers took zolpidem                          during pregnancy              have not been con-                 lethargy, lightheadedness,            myalgia. nausea, upper respiratory               infection,
agitation,        hallucinations,          and depersonalization.              Amnesia        and other          ducted.       However,         children       born of mothers              taking sedative/hypnotic                   vertigo,    vision abnormal,         vomiting.
neuropsychiatric             symptoms          may occur unpredictably.               In primarily de-           drugs may be at some risk for withdrawal                                 symptoms            from the drug            Infrequent:         agitation,    allergy, anorexia,       anxiety, arthralgia,         arthritis,
pressed       patients.        worsening        of depression.        including      suicidal thinking.          during the postnatal                period.      In addition,       neonatal         flaccidity      has been         asthenia, back pain. bronchitis,               cerebrovascular         disorder, chest pain,
has been reported                in association        with the use of sedative/hypnotics.                       reported        in infants born of mothers                     who received sedative/hypnotic                         constipation,   coughing, cystitis. decreased cognition, detached, diffi-
   It can rarely            be determined             with certainty         whether        a particular         drugs dunng pregnancy.                                                                                                culty concentrating,   dysarthria, dysphagia, dyspnea, edema, emotional
instance       of the abnormal                behaviors      listed above are drug induced,                      Labor       and delivery:             Ambien         has no established                 use in labor and              lability. eye irritation,         falling,     fever, flatulence,            gastroenteritis,           halluci-
spontaneous            in origin. or a result of an underlying psychiatric or physical                           delivery.                                                                                                             nation, hiccup, hyperglycemia.                    hypertension,           hypoaesthesia,            infection,
disorder. Nonetheless. the emergence                           of any new behavioral               sign or       Nursing        mothers:          Studies in lactating mothers indicate that between                                   influenza-like       symptoms,           malaise,       menstrual          disorder,       migraine,         ncr-
symptom          of concern          requires     careful and immediate             evaluation.                  0.004       and 0.019%           of the total administered               dose is excreted into milk,                  vousness,        pallor, palpitation,           paresthesia.        pharyngitis,          postural hypo-
   Following          the rapid dose decrease                    or abrupt discontinuation                 of    but the effect of zolpidem on the infant is unknown.                                                                  tension,       pruritus,    rash, rhinitis, scleritis,              SGPT increased,                  sinusitis,
sedative/hypnotics.                there have been reports of signs and symptoms                                    The use of Ambien in nursing mothers is not recommended.                                                           sleep disorder, sleeping (after daytime dosing),                                 stupor, sweating               in-
similar to those associated with withdrawal from other CNS-depressant                                               Safety and effectiveness                    in children below the age of 18 have not                               creased, tachycardia,            taste perversion,           tinnitus, tooth disorder, trauma,
drugs (see Drug Abuse and Dependencel.                                                                           been established.                                                                                                     tremor, unnary incontinence,                   urinary tract infection, vaginitis.
   Ambien,         like other          sedative/hypnotic           drugs.     has CNS-depressant                                                                                                                                       Rare: abdominal            body sensation,              abscess,        acne, acute renal failure,
                                                                                                                                                       ADVERSE            REACTIONS
effects.      Due to the rapid onset of action. Ambien                                should only be                                                                                                                                   aggressive        reaction, allergic reaction, allergy aggravated,                            anaphylactic
                                                                                                                 Associated           with      discontinuation             of treatment:              Approximately            4%
ingested       immediately pnor to going to bed. Patients should be cau-                                         of 1.701 patients who received zolpidem at all doses                                        1.25 to 90 mg)            shock, anemia, appetite increased,                       arrhythmia,         arteritis, arthrosis,             bil-
tioned against engaging in hazardous occupations                                 requiring complete
                                                                                                                 in U.S. premarketing                 clinical trials discontinued               treatment         because of          irubinemia,       breast fibroadenosis,              breast neoplasm,              breast pain female,
mental alertness              or motor coordination               such as operating           machinery                                                                                                                                bronchospasm,            bullous       eruption,       BUN increased,                circulatory        failure,
                                                                                                                 an adverse           clinical event. Events most commonly                                 associated          with
or driving a motor vehicle after ingesting the drug. including potential                                                                                                                                                               corneal      ulceration,      delusion,        dementia,        depersonalization,                dermatitis,
impairment          of the performance of such activities that may occur the                                     discontinuation            from U.S. trials were deytime                           drowsiness           (0.5%).
                                                                                                                 dizziness fO.4%), headache (0.5%), nausea 10.6%), and vomiting 10.5%).                                                dysphasia,        dysuria, edema periorbital,                  enteritis, epistaxis,              eructation,
day following            ingestion       of Ambien.        Ambien        showed additive effects                    Approximately             6% of 1.320 patients                  who received             zolpidem        at all    esophagospasm,             ESR increased,            extrasystoles,           eye pain, face edema,
when combined                 with alcohol and should not be taken with alcohol.                                                                                                                                                       feeling strange. flushing, furunculosis,                     gastritis, glaucoma,               gout, hem-
Patients       should also be cautioned                   about possible           combined        effects       doses 15 to 50 mgI in similar foreign trials discontinued                                           treatment
                                                                                                                 because of an adverse event. Events most commonly                                          associated         with    orrhoids,      hepatic function abnormal,                 herpes simplex. herpes zoster, hot
with other CNS-depressant                      drugs. Dosage adjustments                  may be nec-                                                                                                                                  flashes,       hyparcholesteremia.                hyperhemoglobinemia,                    hyperlipidemia,
essary when Ambien is administered                          with such agents because of the                      discontinuation            from these trials were daytime                          drowsiness             1.6%),
                                                                                                                 amnesia )0 6%), dizziness 10.6%), headache                              0.6%). and nausea 0.6%).                      hypertension          aggravated.          hypotension,          hypotonia,          hypoxia,        hysteria,
potentially       additive effects                                                                                                                                                                                                     illusion, impotence.           injection site inflammation,                    intestinal obstruction,
                                                                                                                 Incidence         in controlled           clinical trials
                                                                                                                 Mosncommoniyobserwdadverse                                  events in controiledtriais:                  During       intoxicated feeling, lacrimation                   abnormal,        laryngitis,        leg cramps,            leu-
Gnir.I                              PRECAUTIONS                                                                                                                                                                                        kopenia, libido decreased, lymphadenopathy,                             macrocytic anemia, manic
U.. in tip. #{149}Id#{149}dy
                        and/or d.bilitated        patiavits:    Impaired motor arid/                             short-term         treatment          up to 10 nights) with Ambien at doses up to 10
                                                                                                                 mg. the most commonly                      observed adverse events associated                          with the       reaction, micturition frequency, muscle weakness,                               myocardial infarction,
or cognitive performance         after repeated exposure or unusual sensitivity                                                                                                                                                        neuralgia,       neuritis, neuropathy,              neurosis,      otitis esterna,            otitix media,
to sedative/hypnotic         drugs is a concern        in the treatment       of elderly                         use of zolpidem              and seen at statistically                significant        differences         from
                                                                                                                                                                                                                                       pain, panic attack,           paresis,       personality        disorder,        phlebitis,       photopsia,
and/or debilitated    patients. Therefore.      the recommended            Ambien dos-                           placebo-treated            patients were drowsiness                  (reported by 2% of zolpidem
                                                                                                                                                                                                                                       photosensitivity         reaction,      pneumonia,          polyuria,        pulmonary         edema, pul-
age is 5 mg in such patients              lsee Dosage        and Administration)       to                        patients).       dizziness         1%), and diarrhea (1%). During longer’term                               treat-
                                                                                                                 ment 28 to 35 nights) with zolpidem at doses up to 10 mg. the most                                                    moriary       embolism,        purpura,        pyelonephritis,           rectal hemorrhage,                 renal
decrease     the possibility      of side effects.      These     patients   should    be                                                                                                                                              pain. restless legs, rigors, saliva altered,                           sciatica,       SGOT increased,
closely monitored.                                                                                               commonly           observed adverse events associated                           with the use of zolpi-
                                                                                                                                                                                                                                       somnambulism,            suicide attempt, syncope, tendinitis, tenesmus,                                tetany,
Us. in patients      with concomitant          illness: Clinical experience with                                 dem and seen at statistically                         significant differences from placebo-                           thinking abnormal, thirst, tolerance increased, tooth caries, urinary
Ambien in patients with concomitant                       systemic illness is limited. Caution                   treated patients were dizziness                       5%) and drugged feelings                     3%).
                                                                                                                                                                                                                                       retention,      urticaria. varicose veins, ventricular                      tachycardia,         weight de-
 is advisable in using Ambien in patients with diseases                                  or conditions                   Incidence        of Treatment’Emergent                     Adverse          Experiences           in          crease, yawning.
 that could affect metabolism                   or hemodynamic             responses            Although                           Short-term            Placebo-Controlled                Clinical       Trials
 preliminary        studies     did not reveal respiratory                depressant           effects     at                                                                                                                                                    DRUG ABUSE                AND DEPENDENCE
                                                                                                                                               IPercentage          of patients reporting)                                             Controlled         substance:         Schedule        IV.
 hypnotic      doses of Ambien            in normals.       precautions        should be observed
 if  Ambien is prescribed                to patients        with compromised                 respiratory                                                                                 Zolpidem                                      Abuse and dependence:                       Studies of abuse potential                    in former d
 function. since sedative/hypnotics                   have the capacity to depress respi-                        Body System/                                                           ( 10 mg)                   Placebo             abusers found that the effects of single doses of zolpidem                                       tartrate
 ratory drive. Data in end-stage                 renal failure patients repeatedly                  treated         Adverse        Event                                                 )N685)                    )N473)              mg were similar. but not identical, to diazepam 20 mg, while zolpidem
 with Ambien did not demonstrate                       drug accumulation             or alterations         in                                                                                                                         tartrate 10 mg was difficult                 to distinguish        from placebo.
                                                                                                                 Central and Peripheral   Nervous                    System                                                                Sedative/hypnotics            have produced            withdrawal           signs and symptoms
pharmacokinetic            parameters.        No dosage adlustment               in renally impaired                Headache                                                                   7                         6
 patients     is required;       however.       these patients        should be closely               moni-                                                                                                                            following      abrupt discontinuation.              These reported            symptoms           range from
                                                                                                                    Drowsiness                                                                 2                         -
                                                                                                                                                                                                                                       mild dysphoria           and insomnia             to a withdrawal                syndrome           that may
 tored Ieee Pt-,armacokinerics)                A study in sublects with hepatic impair-                             Dizziness                                                                  1                         -
 ment did reveal prolonged elimination in this group; therefore. treatment                                                                                                                                                             include abdominal            and muscle cramps, vomiting,                          sweating,         tremors,
                                                                                                                 Gastrointestinal  System                                                                                              and convulsions.           The U.S. clinical trial experience                    from zolpidem does
 should be initiated with 5 mg in patients with hepatic compromise.                                                 Nausea                                                                      2                        3
and they should be closely                  monitored                                                                                                                                                                                  not reveal any clear evidence for withdrawal                              syndrome.          Nevertheless,
                                                                                                                    Diarrhea                                                                    1                        -
                                                                                                                                                                                                                                       the following adverse events included in DSM-IIl-R                                  criteria for uncom-
 Use in daprsaion:                As with other sedative/hypnotic                     drugs. Ambien              Pikjsculoskeletal System
 should be administered                with caution to patients                exhibiting        signs or                                                                                                                              plicated sedative/hypnotic                  withdrawal        were reported              at an incidence
                                                                                                                    Myalgia                                                                     1                        2             of       1% during U.S. clinical trials following placebo substitution                                   occur-
 symptoms         of depression.         Suicidal tendencies           may be present in such
 patients      and protective         measures         may be required.             Intentional        over-      tvents      reported        by at least        1% of Ambien             patients      are included.                  ring within 48 hours following                  last zolpidem         treatment:         fatigue, nausea,
 dosage is more common                  in this group of patients; therefore.                    the least                                                                                                                             flushing, lightheadedness,              uncontrolled crying, emexis, stomach cramps,
 amount of drug that is feasible should be prescribed                              for the patient at                   Incidence         of Treatment-Emergent                     Adverse      Experiences                 in        panic attack, nervousness,                  and abdominal           discomfort.
any one time                                                                                                                        Long-term      Placebo-Controlled                   Clinical    Trials                                 Individuals      with a history of addiction                    to, or abuse of, drugs or
 Infomaticn          rpatienta:          Patient information         is printed in the complete                                              )Percentage    of patients              reporting)                                        alcohol are at risk of habituation and dependence;                                 they should be under
 prescribing        information       and is available           in pads for distribution                  to                                                                                                                          careful surveillance when receiving any hypnotic.
                                                                                                                                                                                         Zolpidem
 patients.                                                                                                       Body System/                                                            ( 10 mgI                   Placebo                                           OVERDOSAGE
 Laboratory        tests: There are no specific laboratory tests recommended.                                      Adverse Event                                                          )N=152)                   )N=161)            Signs and symptoms:       In European postmarketing        reports of overdose
 Drug interactions                                                                                                                                                                                                                     with zolpidem alone, impairment         of consciousness       has ranged from
                                                                                                                 Autonomic          Nervous System                                                                                     somnolence    to light coma, with one case each of cardiovascular             and
 CNS-actiw            drugs:     Ambien        was evaluated          in healthy volunteers                 in     Dry mouth                                                                   3                             1
 single-dose       interaction      studies for several CNS drugs. A study involving                                                                                                                                                   respiratory compromise.     Individuals   have fully recovered    from zolpidem
haloparidol         and zolpidem           revealed      no effect       of haloperidol            on the        Body as a Whole                                                                                                       tartrate overdoses up to 400 mg 40 times the maximum                                         recommended
pharmacokinetics              or pharmacodynamics               of zolpidem.            Imipramine          in     Allergy                                                                     4                         1             dose). Overdose        cases involving multiple CNS-depressant          agents, in-
combination           with zolpidem          produced       no pharmacokinetic                interaction          Back pain                                                                   3                         2             cluding zolpidem.       have resulted in more severe symptomatology,             in-
other than a 20% decrease in paak levels of imipramine.                                 but there was              Influenza-like     symptoms                                                 2                         -             cluding fatal outcomes.
an additive effect of decreased                    alertness.     Similarly.     chlorpromazine            in      Chest pain                                                                   1                        -             Recommended          treatment:      General symptomatic    and supportive     mea-
combination          with zolpedem produced                 no pharmacokinetic              interaction,           Fatigue                                                                     1                         2             sures should be used along with immediate                  gastric  lavage where
but there was an additive effect of decreased                            alertness        and psycho-            Cardiovascular      System                                                                                            appropriate     Intravenous      fluids should be administered         as needed.
motor parformance.               The lack of a drug interaction                    following         single-       Palpitation                                                                 2                         -             Flumazenil may be useful. Respiration,          pulse, blood pressure, and other
 dose administration                does not predict              a lack following                chronic        Central and Peripheral Nervous                      System                                                            appropriate   signs should be monitored            and general supportive      mea-
administration.                                                                                                    Heedache                                                                   19                       22              suies employed.       Sedating drugs should be withheld following zolpidem
    An additive effect on psychomotor                        performance           between         alcohol         Drowsiness                                                                  8                        5              overdosage     Zolpidem      is not dialyzable.
and zolpidem           was demonstrated.                                                                           Dizziness                                                                   5                         1                The possibility of multiple drug ingestion should be considered.
    Since the systematic               evaluations        of Ambien          in combination             with       Lethargy                                                                    3                         1             Caution        Federal       law prohibits        dispensing         without       prescription.
other CNS-active            drugs have been limited. careful consideration                           should        Drugged feeling                                                             3                         -

be given to the pharmacology                    of any CNS-active          drug to be used with                    Lightheadedness                                                             2                             1                                                                                                              5/27/93
zolpidem.        Any drug with CNS-depressant                        effects       could potentially               Depression                                                                  2                             1
enhance the CNS-depressant                    effects of zolpidem                                                  Abnormal       dreams                                                       1                         -
                                                                                                                                                                                                                                       Manufactured      and distributed                by
 Other      drugs:      A study involving cimetidine/zolpidem                         and ranitidine/              Amnesia                                                                     1                         -
                                                                                                                                                                                                                                       G.D Scene & Co.
zolpidem combinations                revealed no effect of either drug on the phar-                                Anxiety                                                                     1                         1             Chicago.    IL 60680
macokinetics           or pharmacodynamics                 of zolpidem          Zolpidem           had no          Nervousness                                                                 1                         3             by agreement       with
effect on digoxin kinetics and did not affect prothrombin                                    time when             Sleep disorder                                                              1                         -
                                                                                                                                                                                                                                       Lorex Pharmaceuticals
given with warfarin in normal sublects                         Zolpidem’s         sedative/hypnotic              Gastrointestinal      System                                                                                          Skokie,   IL
effect was reversed by flumazenil; however, no significant alterations                                             Nausea                                                                      6                         6
in zolpidem pharmacokinetics                   were found.                                                         Dyspepsia                                                                   5                         6             Address medical inquiries     to
Drug/Laboratory             test interactions:           Zolpidem is not known to interfere                        Diarrhea                                                                    3                         2             GD. Scathe & Co.
with commonly             employed       clinical laboratory        tests.                                         Abdominal       pain                                                        2                         2             Medical & Scientific Information                      Department
                                                                                                                    Constipation                                                               2                          1            4901 Searle Parkway
Carcinogen.sis,             mutagenesis,            impairment        of fertility
                                                                                                                   Anorexia                                                                     1                        1             Skokie, IL 60077
Cercinogn.aia:               Zolpidem       was administered            to rats and mice for 2                     Vomitjng                                                                     1                        1
years at dietary dosages                of 4. 18. and 80 mg/kg/day.
doses are 26 to 520 times or 2 to 35 times the maximum
                                                                                       In mice. these
                                                                                                     10-mg
                                                                                                                 Immunologic
                                                                                                                   Infection
                                                                                                                                 System
                                                                                                                                                                                                1                            1
                                                                                                                                                                                                                                       S E.4RLE                                      Box 5110
human dose on a mg/kg                    or mg/m’         basis. respectively            In rats these
doses are 43 to 876 times or 6 to 115 times the maximum                                              10-mg       Musculoskeletal     System                                                                                                                                          Chicago,         IL 60680-5110
human dose on a mg/kg or mg/rn’ basis, respectively.                                  No evidence of               Myalgia                                                                     7                         7
                                                                                                                   Arthralgia                                                                  4                         4
carcinogenic         potential     was observed          in mice Renal liposarcomas                    were                                                                                                                            Ambien        is a trademark           of Synthelabo.                          P93AB8676T
TheFirstina
New Chemical      Class of                                                                  2
Non-benzodiazepine                                                                 a                Z
Sleep Agents                                                                            z       z




                                               .JNTM
                  DEMTARIRATE)
              (ZOLH         C
                                                    5-MG    & 10-MG      TABLETS
              . AMBIEN-an           imidazopyridine,   chemically     unrelated    to
                  benzodiazepines      or any other sleep agent
              . AMBIEN-indicated           for short-term management         of
                  insomnia    (generally   limited to 7 to 10 days)
              S   Extensive clinical experience-over        500 million doses
                  prescribed throughout    Europe’
  TheFirstina
  New Chemical Class of
  Nonbenzodiazepine
  Sleep Agents



                                                                                              NTM
          T      #{128}
  (ZOLPIDEMARIRATE)                                            5-MG         & 10-MG             TABLETI




  With AMBIEN, Patients Fall Asleep                                                                       With AMBIEN, Patients                                              Awaken
  Fast and Get a Full Night’s Sleep                                                                       Refreshed and Alert
  . Rapid onset of action-sleep                                    generally           induced            . A short half-life             -      mean 2.5 hours, with
          within       30 minutes’-4                                                                        no active metabolites
  . AMBIEN significantly                             increases          duration                          . No evidence of significant                             daytime
          of sleep”2’4’5                                                                                    sedation         or psychomotor                       impairment”2’5’6
                                                                                                            Although AMBIEN is generally not associated with
  AMBIEN Generally Preserves                                                                                next-day effects, until your patients know how they will
                                                                                                            react to this sleep agent, they should not engage in
  Normal Sleep Physiology25                                                                                 activities requiring mental alertness or motor
  Mean       Percentage          ofTinie       in Each Sleep Stage2                                         coordination    after taking AMBIEN (eg, driving or
                                                                                                            operating hazardous       machinery).     Potential impairment
                                                                                                            ofthe performance       of such activities may occur the day
AMBIEN                                                                                                      following ingestion of AMBIEN.

Natural
  Sleep

  No statistically       significant    difference from natural    sleep (at baseline)       for all
  sleep stages,     in a double-blind,         controlled study of 12 healthy    volunteers.
  The clinical     significance      is unknown.




                                                                                                               Please
  SE.4RLE                                                                                                               see references   and   briefsummary
                                                                                                                                                        on last
                                                                                                                                                                    ofprescribing
                                                                                                                                                                   page ofthis
                                                                                                                                                                                        information
                                                                                                                                                                                    advertisement.



          © 1993 Searle
A Favorable           Safety       Profile                        Recommended                   Dosage:
. No rebound   insomnia in studies of up to                       For adults:                                  one    lO-mg tablet
  35 nights at recommended    doses’4
. No evidence   oftolerance   in sleep latency                    For elderly/debilitated   patients:           one    S-mg tablet
  in studies of up to 35 nights”3
                                                                  Patients should take AMBIEN right before going to bed
. A low incidence       of adverse     events
                                                                  and when ready for sleep.
  In short-term treatment    (up to 10 nights) with AMBIEN
  at doses 10 mg, the adverse events seen at statistically       S     Prescriptions  for AMBIEN should not exceed
  significant differences from placebo were: drowsiness (2%),          a 1-month supply. Hypnotics should generally
  dizziness (1%), and diarrhea (1%); and in longer-term
  treatment (28 to 35 nights): dizziness (5%) and drugged
                                                                       be limited to 7 to 10 days of use, and
  feelings (3%).                                                       reevaluation   of the patient is recommended
                                                                       if they are taken for more than 2 to 3 weeks.
. Because of additive effects, AMBIEN should
  not be combined with alcohol. Dosage                           . In patients    with hepatic dysfunction,
  adjustments  may be necessary when                                   dosage should be reduced and appropriate
  AMBIEN is coadministered     with CNS                                monitoring instituted.
  depressants.


                                                           TARTRATE)C
                                                   (ZOLPIDEM     5MG   4 10MG   TABLETS



                The First in a New Chemical                Class ofNon-benzodiazepine                   Sleep Agents
                                                                                                                                  References: 1. DaIs on file, Seurle. 2, Merlotti L Rosho 1. Koxhorek G, et al. The dose effects ofzolpidem on the sleep of heathy
                                                                                                                                  normals. JClinPsychopltarrriacol.    1989;9:9’14. 3.VogelGW, SCharI M. WalxhJ,etal. Effectxofchronicallyadminislered     zolpidem
                                                                                                                                  on the sleep of healthy insomniacs. Sleep Research. 1989;18:80. Abslract. 4 Scharf MB, Mayleben DW, Kaffeman M, el a). Dose

                           AN                                                                                                     Tesponoeeffeclsofzolpldem     in normalgenalnicxublects.  JChnPoychiatry. 1991;52:77-83. 5. WalshJK, SchweitzerPK,Sugerman
                                                                                                                                  JLetal. Transient inoomnaassooatedwitha3-hourphaseadvanceofsleepnmeandtreaonenlwithzolpiije,n.            JCIinPSyChOpPiamnXOI.
                                                                                                                                  199t,lt:184-189.     6. Oswald I, Adam K. A new look at short-acting hypnolics. In: Sauvanet JP, Lunger SZ, Morxelli PL, edo.
                           (ZOIHDEM TARIRATE)#{128}                                                                               lmida.zopyndinesinSleepDisordeis.      NewYork, NY: Raven Press; 1988:253’259.

 BRIEF               SUMMARY
                           INDICATIONS          AND USAGE                                                              seen in 4/100        rats 13 males, 1 female) receiving 80 mg/kg/day               and a                       Incidence     of Treatment-Emergent           Adverse       Experiences                               in
 Amble,,   )zolpidem    tartrate)   is indicated for the short-term       treatment    of                              renal lipoma was observed            in one male rat at the 18 mg/kg/day           dose.                           Long-term     Placebo-Controlled        Clinical     Trials (Cont’d)
 insomnia.    Hypnotics      should generally      be limited  to 7 to 10 days of                                      Incidence rates of hpoma and liposarcoma                  for zolpidem      were compa-                                         IPercentage    of patients     reporting)
 use, and reevaluation        of the patient is recommended         if they are to be                                  rable to those seen in historical controls and the tumor findings are
                                                                                                                       thought     to be a spontaneous          occurrence.                                                                                                                             Zolpidem
 taken for more than 2 to 3 weeks.                                                                                                                                                                                             Body System/                                                            ) 10 mg)                     Placebo
    Ambien should not be prescribed             in quantities exceeding      a 1-month                                 Mutag.n.sis:          Zolpidem     did not have mutagenic            activity in several
                                                                                                                                                                                                                                 Adverse EventS                                                          )N=152)                    )N=161)
 supply )see Warnings).                                                                                                tests including the Ames test, genotoxicity                in mouse lymphoma        cells
                                                                                                                       in vitro, chromosoma)            aberrations      in cultured    human lymphocytes,                     Respiratory    System
                                       CONTRAINDICATIONS                                                               unscheduled        DNA synthesis        in rat hepatocytes        in vitro, and the mi-                    Upper respiratory              infection                                      5                       6
 None      known.                                                                                                      cronucleus      test in mice.                                                                              Sinusitis                                                                     4                       2
                                                WARNINGS                                                               Impalement         of fertility:   In a rat reproduction         study, the high dose                      Pharyngitis                                                                   3                        1
 Since sleep disturbances                 may be the presenting manifestation                      of a                )100 mg bese/kg)          of zolpidem      resulted   in irregular    estrus cycles and                    Rhinitis                                                                      1                       3
 physical and/or psychiatric disorder, symptomatic                         treatment       of insom-                   prolonged precoital intervals, but there was no effect on male or female                                Skin and Appendages
 nia should be initiated              only after a careful evaluation               of the patient.                    fertility  after datly oral doses of 4 to 100 mg base/kg or 5 to 130                                       Rash                                                                          2                       1
 The failure of insomnia to remit after 7 to 10 days of treatment                                  may                 times the recommended              human dose in mg/os2. No effects on any                              Urogenital        System
 indicate    the presence           of a primary        psychiatric      and/or medical illness                        other fertility parameters        were noted.                                                              Urinary       tract infection                                                 2                       2
 which should be evaluated.                 Worsening        of insomnia or the emergence                              Pregnancy                                                                                                Events      reported         by at least       1% of patients               treated     with    Ambien.
 of new thinking or behavior abnormalities                      may be the consequence                of               Category       B. Studies        to assess       the   effects      of zolpidem       on human
 an unrecognized            psychiatric      or physical disorder. Such findings have                                  reproduction        and development have not been conducted.                                            There is evidence               from dose comparison                    trials suggesting               a dose
 emerged during the course of treatment                       with sedative/hypnotic           drugs.                     Teratology       studies were conducted in rats and rabbits.                                         relationship       for many of the adverse                   events associated               with zolpidem
 including     Ambien. Because some of the important                          adverse effects of                          In rats, adverse maternal and fetal effects occurred                       at 20 and 100             use, particularly         for certain CNS and gastrointestinal                          adverse events.
 Ambien      appear to be dose related 15cc Precautions                          and Dosage         and                mg base/kg         and included dose-related              maternal     lethargy and ataxia                   Adverse events are further classified                         and enumerated                 in order of
 Administration),          it is important        to use the smallest possible effective                               and a dose-related        trend to incomplete           ossification    of fetal skull bones.           decreasing        frequency         using the following             definitions:         frequent       adverse
dose, especially          in the elderly.                                                                                 In rabbits, dose-related        maternal      sedation      and decreased       weight gain          events are defined as those occumng                            in greater than 1/ 100 subjects;
    A variety        of abnormal         thinking and behavior             changes       have been                     occurred     at all doses tested          At the high dose. 16 mg base/kg.                  there        infrequent      adverse        events are those occurring                      in 1/100         to 1/1,000
reported      to occur in association               with the use of sedative/hypnotics                                 was an increase in postimplantation                 fetal loss and underossification            of       patients;    rare events are those occurring                     in less than 1/1,000                patients.
Some of these changes may be characterized                             by decreased         inhibition                 sternebrae      in viable fetuses.                                                                       Frequent:        abdominal          pain. amnesia,             ataxia,      confusion,          depression,
leg, aggressiveness              and extroversion          that seemed         out of character),                         This drug should be used during pregnancy                       only if clearly needed.              diarrhea,      diplopia,     dizziness,         dreaming       abnormal,         drowsiness,           drugged
similar to effects produced                  by alcohol and other CNS depressants.                                     Nont.ratog.nic          #{149}ffects: Studies     to assess        the effects     on children          feeling, dry mouth, dyspepsia,                       euphoria, fatigue. headache,                   insomnia,
Other reported            behavioral        changes      have included bizarre behavior,                               whose mothers took zolpidem                  during pregnancy          have not been con-               lethargy, lightheadedness,                   myalgia. nausea, upper respiratory                      infection,
agitation,      hallucinations,         and depersonalization.             Amnesia        and other                    ducted.     However,     children      born of mothers           taking sedative/hypnotic               vertigo,     vision abnormal,              vomiting.
neuropsychiatric           symptoms         may occur unpredictably.               In primarily de-                    drugs may be at some risk for withdrawal                        symptoms       from the drug             Infrequent:         agitation,       allergy,       anorexia,      anxiety.        arthralgia.        arthritis,
pressed      patients, worsening             of depression,        including suicidal thinking,                        during the postnatal period In addition, neonatal flaccidity has been                                   asthenia,       back pain, bronchitis,                 cerebrovascular            disorder,       chest pain,
has been reported             in association        with the use of sedative/hypnotics.                                reported      in infants born of mothers              who received        sedative/hypnotic             constipation.         coughing,          cystitis,     decreased        cognition,          detached,         diffi-
    It can rarely be determined                    with certainty         whether      a particular                    drugs during pregnancy.                                                                                 culty concentrating,             dyxarthria,         dysphagia,      dyspnea,          edema, emotional
instance      of the abnormal              behaviors      listed above are drug induced.                               Labor and delivery:            Ambien       has no established            use in labor and              lability, eye irritation,           falling, fever, flatulence,               gastroenteritis,           halluci-
spontaneous          in origin. or a result of an underlying psychiatnc or physical                                    delivery                                                                                                nation, hiccup, hyperglycemia,                      hypertension,         hypoaesthesia,             infection,
disorder.     Nonetheless,           the emergence          of any new behavioral             sign or                  Nursing      mothers:      Studies in lactating mothers indicate that between                           influenza-like        symptoms,            malaise,       menstrual         disorder,        migraine,         ncr-
symptom        of concern requires careful and immediate                        evaluation.                            0.004    and 0.019%        of the total administered           dose is excreted into milk,              vousness,        pallor, palpitation,              paresthesia,      pharyngitis,           postural hypo.
    Following       the rapid dose decrease                   or abrupt discontinuation               of               but the effect of zolpidem            on the infant is unknown.                                         tension,      pruritus,       rash, rhinitis, scleritis,              SGPT increased,                 sinusitis,
sedative/hypnotics,             there have been reports of signs and symptoms                                             The use of Ambien             in nursing mothers         is not recommended.                         sleep disorder, sleeping after daytime dosing), stupor, sweating in-
similar to those associated               with withdrawal        from other CNS-depressant                                Safety and effectiveness               in children below the age of 18 have not                      creased, tachycardia.              taste perversion,           tinnitus, tooth disorder, trauma,
drugs )see Drug Abuse and Dependence).                                                                                 been established.                                                                                       tremor, urinary incontinence,                    urinary tract infection, vaginitis.
    Ambien,       like other sedative/hypnotic                 drugs.     has CNS-depressant                                                                                                                                   Rare: abdominal             body sensation,               abscess,       acne, acute renal failure,
effects.     Due to the rapid onset of action, Ambien                             should only be                                                        ADVERSE          REACTIONS
                                                                                                                       Associated        with     discontinuation           of treatment:          Approximately         4%    aggressive        reaction, allergic reaction, allergy aggravated,                              anaphylactic
ingested immediately               prior to going to bed. Patients should be cau-                                                                                                                                              shock, anemia, appetite                  increased,        arrhythmia,        arteritis,      arthrosis,        bil-
tioned against engaging in hazardous                       occupations       requiring complete                        of 1,701 patients         who received         zolpidem     at all doses          1.25 to 90 mgI
                                                                                                                       in U.S. premarketing            clinical trials discontinued           treatment       because of       irubinemia,       breast fibroadenosis,                breast neoplasm,              breast pain female,
mental alertness            or motor coordination             such as operating          machinery                                                                                                                             bronchospasm,             bullous        eruption,       BUN increased,               circulatory         failure,
or driving a motor vehicle after ingesting the drug. including potential                                               an adverse clinical event. Events most commonly                                 associated       with
                                                                                                                       discontinuation        from      U.S trials were daytime                  drowsiness         0.5%).     corneal ulceration,             delusion,         dementia,       depersonalization,               dermatitis,
impairment        of the performance             of such activities         that may occur the                                                                                                                                 dysphasia,        dysuria, edema periorbital,                   enteritis,       epistaxis,        eructation,
day following          ingestion of Ambien.             Ambien       showed additive effects                           dizziness p.4%),        headache (0.5%), nausea 10.6%), and vomiting                         10.5%).
                                                                                                                          Approximately         6% of 1,320 patients who received zolpidem at all                              esophagospasm,              ESR increased,             extrasystoles,          eye pain, face edema,
when combined              with alcohol and should not be taken with alcohol                                                                                                                                                   feeling strange. flushing, furunculosis,                       gastritis,      glaucoma,          gout, hem-
Patients     should also be cautioned                  about     possible      combined       effects                  doses 15 to 50 mg) in similar foreign trials discontinued                                treatment
                                                                                                                       because of an adverse event. Events most commonly                                associated      with   orrhoids,      hepatic function abnormal,                   herpes simplex, herpes zoster, hot
with other CNS-depressant                   drugs.    Dosage       adlustments        may be nec-                                                                                                                              flashes,       hypercholesteremia,                  hyperhemoglobinemia,                    hyperlipidemia,
essary when Ambien                is administered        with such agents because of the                               discontinuation        from these trials were daytime                     drowsiness         11.6%),
                                                                                                                       amnesia lO.6%l. dizziness 0.6%), headache 10.6%), and nausea 10.6%).                                    hypertension          aggravated.            hypotension,         hypotonia,           hypoxia, hysteria,
potentially     additive effects.                                                                                                                                                                                              illusion, impotence,             injection site inflammation,                   intestinal obstruction,
                                                                                                                       Incidence in controlled              clinical trials
                                                                                                                       Moatcommonly             observedadi,rse             events in controildtrials:               During    intoxicated       feeling, lacrimation               abnormal,       laryngitis,        leg cramps,            lee’
 General                                     PRECAUTIONS
                                                                                                                       short-term treatment up to 10 nightsl with Ambien at doses up to 10                                     kopenia, libido decreased,                  lymphadenopathy,            macrocytic           anemia, manic
  Us. in th .lderly              and/or dbilitated               patients:         Impaired       motor and/
 or cognitive performance                 after repeated exposure or unusual sensitivity                               mg, the most commonly                 observed     adverse events associated               with the     reaction, micturition            frequency, muscle weakness,                         myocardial      infarction,
                                                                                                                       use of zolpidem and seen at statistically                     significant differences           from    neuralgia.      neuritis,      neuropathy,           neurosis,     otitis externa,          otitis media,
 to sedative/hypnotic                drugs is a concern               in the treatment               of elderly
 and/or debilitated            patients. Therefore,             the recommended                 Ambien dos-            placebo-treated        patients     were drowsiness          (reported       by 2% of zolpidem          pain, panic attack,            paresis,       personality       disorder,       phlebitis,       photopsia,
                                                                                                                       patients). dizziness )1%), and diarrhea                   1%). During longer-term              treat-   photosensitivity          reaction,       pneumonia.         polyuria,      pulmonary         edema, pal’
 age is 5 mg in such patients                          see Dosage              and Administration)                to
                                                                                                                       meet (28 to 35 nights) with zolpidem at doses up to 10 mg, the most                                     monary embolism,                purpura. pyelonephritis,                 rectal hemorrhage,               renal
 decrease       the possibility            of side effects             These         patients       should       be
 closely monitored.                                                                                                    commonly        observed      adverse       events associated          with the use of zolpi-           pain, restless         legs. rigors,           saliva altered,        sciatica,       SCOT increased,
                                                                                                                       dem and seen at statistically                  significant     differences         from placebo-        somnambulism,             suicide attempt.            syncope,     tendinitis,       tenesmus,         tetany,
  Us. In patients             with      concomitant           illness:        Clinical experience             with                                                                                                             thinking     abnormal,          thirst,     tolerance       increased,         tooth      caries,      unnary
 Ambien in patients with concomitant                        systemic         illness is limited          Caution       treated patients       were dizziness          (5%) and drugged            feelings     3%).
                                                                                                                                                                                                                               retention,     urticaria,      varicose        veins, ventricular          tachycardia,        weight de-
 is advisable        in using Ambien in patients with diseases or conditions                                                 Incidence    of Treatment-Emergent           Adverse      Experiences                        in   crease, yawning.
 that could affect metabolism                      or hemodynamic                 responses.          Although                       Short-term       Placebo-Controlled      Clinical    Trials
 preliminary        studies       did not reveal respiratory                     depressant          effects      at                                                                                                                                     DRUG ABUSE AND DEPENDENCE
                                                                                                                                                Percentage    of patients  reporting)
 hypnotic doses of Ambien in normals,                           precautions          should be observed                                                                                                                        Controlled       substance:             Schedule IV.
 if Ambien         is prescribed           to patients          with compromised                   respiratory                                                                           Zolpidem                              Abuse and dependence:                       Studies       of abuse potential             in former        dru
 function,     since sedative/hypnotics                  have the capacity              to depress          respi-     Body System/                                                  l      10 mgI           Placebo           abusers found that the effects of single doses of zolpidem                                     tartrate     4
 ratory drive. Data in end-stage                    renal failure patients             repeatedly        treated         Adverse EventS                                                  )N=685)             )N473)            mg were similar, but not identical,                     to diazepam         20 mg, while zolpidem
 with Ambien           did not demonstrate               drug accumulation                 or alterations         in                                                                                                           tartrate    10 mg was difficult               to distinguish       from placebo.
                                                                                                                       Central and Peripheral  Nervous              System
 pharmacokinetic            parameters.         No dosage adlustment                   in renally impaired                                                                                                                         Sedative/hypnotics             have produced withdrawal                   signs and symptoms
                                                                                                                         Headache                                                            7                        6
 patients is required; however,                    these patients should be closely moni-                                                                                                                                      following    abrupt discontinuation.                  These reported symptoms                  range from
                                                                                                                         Drowsiness                                                          2                        -
 toted Ieee Pharmacokinetics).                    A study in subjects with hepatic impair-                                                                                                                                     mild dysphoria            and insomnia              to a withdrawal             syndrome          that may
                                                                                                                         Dizziness                                                           1                    -
 ment did reveal prolonged elimination in this group; therefore, treatment                                                                                                                                                     include abdominal             and muscle cramps,                 vomiting,         sweating,        tremors,
                                                                                                                       Gastrointestinal System                                                                                 and convulsions.            The U.S. clinical trial experience                   from zolpidem does
 should be initiated             with 5 mg in patients                  with hepatic            compromise,              Nausea                                                              2                        3
 and they should be closely monitored                                                                                                                                                                                          not reveal any clear evidence for withdrawal syndrome. Nevertheless,
                                                                                                                         Diarrhea                                                            1                    -
                                                                                                                                                                                                                               the following adverse events included in DSM-III-R criteria for uncom-
 Us. In depression:                As with other sedative/hypnotic                          drugs, Ambien              Musculoskeletal  System
 should be administered                   with caution to patients                   exhibiting        signs or                                                                                                                plicated   sedative/hypnotic    withdrawal      were reported    at an incidence
                                                                                                                         Myalgia                                                              1                   2            of      1% during U.S. clinical trials following    placebo   substitution  occur-
 symptoms         of depression.            Suicidal tendencies               may be present in such
 patients     and protective             measures        may be required                  Intentional        over-      Events    reported      by at least      1% of Ambien            patients    are included.             ring within 48 hours following last zolpidem treatment: fatigue. nausea,
 dosage is more common in this group of patients; therefore.                                           the least                                                                                                               flushing,  lightheadedness, uncontrolled crying, emesis, stomach cramps,
 amount of drug that is feasible should be prescribed                                    for the patient at                  Incidence       of Treatment-Emergent           Adverse      Experiences                     in   panic attack, nervousness, and abdominal discomfort.
 any one time.                                                                                                                           Long’term      Placebo-Controlled       Clinical    Trials                               Individuals        with     a history        of addiction           to.     or abuse of,          drugs or
 Information         lbrpatients:          Patient information             is pnnted in the complete                                               Percentage    of patients reporting)                                        alcohol are at risk of habituation  and dependence;                               they should        be under
 prescnbing         information          and is available            in pads for distribution                    to                                                                                                            careful surveillance  when receiving   any hypnotic
                                                                                                                                                                                      Zolpidem
 patients.                                                                                                             Body System/                                                  ) 10 mg)                Placebo                                            OVERDOSAGE
 Laboratory       tests:       There are no specific laboratory tests recommended                                        Adverse Event                                                 )N=152)               )N=161)           Signs and symptoms:         In European postmarketing reports of overdose
 Drug interactions                                                                                                                                                                                                             with zolpidem alone, impairment            of consciousness    has ranged from
 CNS-act.Ive          drugs: Ambien              was evaluated              in healthy         volunteers         in   Autonomic   Nervous            System                                                                   somnolence     to light coma, with one case each of cardiovascular            and
 single-dose       interaction        studies for several CNS drugs A study involving                                    Dry mouth                                                           3                        1        respiratory compromise.       Individuals have fully recovered    from zolpidem
 haloperidol        and zolpidem             revealed       no effect of haloperidol                     on the        Body as a Whole                                                                                         tartrate overdoses    up to 400 mg (40 times the maximum          recommended
pharmacokinetics               or pharmacodynamics                   of zolpidem.             Imipramine          in     Allergy                                                             4                    1            dose). Overdose      cases involving multiple CNS-depressant          agents, in-
combination           with zolpidem            produced         no pharmacokinetic                 interaction           Back pain                                                           3                    2            cluding zolpidem,     have resulted      in more severe symptomatology,        in-
other than a 20% decrease in peak levels of imipramine.                                       but there was              Influenza-like      symptoms                                        2                    -            cluding fatal outcomes.
an additive effect of decreased                      alertness        Similarly. chlorpromazine                   in     Chest pain                                                          1                    -            Recommended            treatment:       Genera) symptomatic        and supportive      mea-
combination          with zolpidem            produced         no pharmacokinetic                 interaction,           Fatigue                                                             1                    2            sures should be used along with immediate                        gastric    lavage where
but there was an additive effect of decreased                                   alertness       and psycho-            Cardiovascular        System                                                                            appropriate       Intravenous       fluids   should     be administered        as needed.
motor performance.                 The lack of a drug interaction                        following        single-        Palpitation                                                         2                    -            Flumazenil   may be useful. Respiration,            pulse, blood pressure,         and other
 dose administration                  does not predict                 a lack following                 chronic        Central and Peripheral Nervous               System                                                     appropriate     signs should be monitored               and general      supportive    mea-
administration                                                                                                           Headache                                                           19                  22             sures employed. Sedating drugs should be withheld following zolpidem
    An additive          effect on psychomotor                   performance             between         alcohol         Drowsiness                                                          8                   5             overdosage.      Zolpidem is not dia)yzable.
and zolpidem was demonstrated.                                                                                           Dizziness                                                           5                    1               The possibility       of multiple drug ingestion        should be considered.
    Since the systematic evaluations of Ambien in combination                                                 with       Lethargy                                                            3                    1
                                                                                                                                                                                                                               Caution:      Federal        law prohibits        dispensing         without         prescription.
other CNS-active            drugs have been limited, careful consideration                                should         Drugged feeling                                                     3                    -

be given to the pharmacology                      of any CNS-active               drug to be used with                   Lightheadedness                                                     2                        1                                                                                                              5/27/93
zolpidem.        Any drug with CNS-depressant                             effects       could potentially                Depression                                                          2                        1
enhance the CNS-depressant                       effects of zolpidem                                                     Abnormal       dreams                                               1                    -
                                                                                                                                                                                                                               Manufactured   and distributed                   by
Oth#{149}s’drugs:        A study involving cimetidine/zolpidem                              and ranitidine/              Amnesia                                                             1                    -
                                                                                                                                                                                                                               G 0 Searle & Co.
zolpidem       combinations            revealed       no effect of either drug on the phar-                              Anxiety                                                             1                    1            Chicago, IL 60680
macokinetics           or pharmacodynamics                   of zolpidem              Zolpidem          had no           Nervousness                                                         1                    3            by agreement   with
effect on digoxin             kinetics     and did not affect prothrombin                         time when              Sleep disorder                                                      1                    -
                                                                                                                                                                                                                               Lorex Pharmaceuticals
given with warfarin in normal sublects.                           Zolpidem’s           sedative/hypnotic               Gastrointestinal     System                                                                             Skokie, IL
effect was reversed by flumazenil;                        however, no significant alterations                            Nausea                                                              6                    6
in zolpidem        pharmacokinetics              were found                                                              Dyspepsia                                                           5                    6            Address medical inquiries to
Drug/Laboratory              test interactions:            Zolpidem is not known to interfere                            Diarrhea                                                            3                    2            G 0 Searle & Co.
with commonly             employed         clinical laboratory           tests                                           Abdominal     pain                                                  2                    2            Medical & Scientific Information                      Department
Carcinogensis,               mutagenesis,             impairment            of fertility                                 Constipation                                                        2                    1            4901 Searle Parkway
                                                                                                                         Anorexia                                                            1                    1            Skokie, IL 60077
C.rclnog.n.als:              Zolpidem         was administered                to rats and mice for 2
years at dietary dosages                  of 4, 18. and 80 mg/kg/day
doses are 26 to 520 times or 2 to 35 times the maximum
                                                                                             In mice, these
                                                                                                          10-mg
                                                                                                                         Vomiting
                                                                                                                       Immunologic
                                                                                                                         Infection
                                                                                                                                       System
                                                                                                                                                                                             1

                                                                                                                                                                                             1
                                                                                                                                                                                                                  1

                                                                                                                                                                                                                      1
                                                                                                                                                                                                                               S E4RLE                                       Box     110
human dose on a mg/kg or mg/m2 basis, respectively                                             In rats these
doses are 43 to 876 times or 6 to 115 times the maximum                                                   10-mg        Musculoskeletal     System                                                                                                                            Chicago,         IL 60680-5110
human dose on a mg/kg or mg/m                             basis, respectively.              No evidence of               Myalgia                                                             7                    7
carcinogenic         potential was observed in mice. Renal liposarcomas                                     were         Arthralgia                                                          4                    4
                                                                                                                                                                                                                               Ambien       is a trademark           of Synthelabo.                            PQtRR7T
                                                                                                     Calendar


(Continued          from page A16)



March    21-23,            8th Annual               Symposium          on Psychiatric               Medi-       April 17-30,    “Creativity     and Madness:           Psychological    Studies of
cine  (22 hours              category              I CME      credit),     Florida               Hospital       Art and Artists”      (22 hours      category        I CME credit),    American
Center        for      Psychiatry,             Orlando.           Contact:         Dottie        Manley,        Institute  of Medical       Education,        Paris,     Brussels,   Amsterdam,
Medical         Director’s           Office,     Florida   Hospital    Center     for                   Psy-    Cannes         (August           1-5, Santa Fe, N.Mex.; September     17-30,
chiatry,       601 East           Rollins    St., Orlando,      FL; 407-897-1801.                               Athens).        Contact:           AIME, 2625 W Alameda    Ave., Suite 504,
                                                                                                                Burbank,            CA 91505;         800-348-8441                (tel),     818-789-9857               (fax).
March     23-25,   4th International           Conference          on “Innovations
in Community       Psychiatry,”       Internationallnstitute              of Commu-                             April      20-30,         conference,       “Women,”                          Cambridge                Hospi-
nity Psychiatry,     York,      U.K. Contact:        International         Institute     of                     tal/Harvard            Medical      School,   Boston.                      Contact:     Judy           Reiner
Community        Psychiatry,        P0 Box B135,              Huddersfield           HD1                        Platt, Ed.D.,           Cambridge             Hospital,         1493         Cambridge            St., Cam-
1YG, UK; 0484-532102                (tel), 484-425699
                                           0                       (fax).                                       bridge,       MA       02139;        617-864-6165                 (tel),     617-876-9760                  (fax).


March   24-25,  “The Dementias:       Diagnosis       and Implications                                          April      21-23,         21st      Annual           Conference              on     Dyslexia,           Orton
for Management,       Rotman     Research
                                  “            Institute   of Baycrest                                          Dyslexia         Society,        New       York.       Contact:             New       York       Branch          of
Centre and the University    of California,     Los Angeles,     Alzhei-                                        the Orton           Dyslexia       Society,         71 West        23rd       St., Suite       1500,       New
mer’s    Disease      Center,                Toronto.           Contact:         Education           Dept.,     York,       NY 10010;              212-691-1930.
Baycrest       Centre      for               Geriatric          Care,        3560     Bathurst           St.,
                                                                                                                April   21-23,           Jazz Fest            Program,           “Pain         and Pain Manage-
Toronto,           Ont.,     Canada           M6A        2E1;     416-789-5131              ext.     2365.
                                                                                                                ment,”   Tulane            University          Medical         Center,         New Orleans.    Con-
                                                                                                                tact:  Pamala             Schmidt,            Tulane          University          Medical   Center,
March         27-31,          “Folk         Medicine        of Portugal            and      Spain”       (17
                                                                                                                Office      of Continuing                Education,            1440        Canal      St., Suite        1611,
hours      category        I CME            credit),     Southern          California       Neuropsy-
                                                                                                                New       Orleans,        LA 70112-2750;                   504-588-5466.
chiatric   Institute,  Lisbon. Contact:                           Ann      McCormick,              SCNPI,
6794     La Jolla Blvd, La Jolla,   CA                          92037;      619-454-2102              (tel),
                                                                                                                April      28-30,       National          Student         Research           Forum,        University            of
619-454-2104               (fax).
                                                                                                                Texas       Medical         Branch,        Galveston.            Contact:           National          Student
                                                                                                                Research   Forum,    Room                     G-210        Ashbel           Smith Building,             Route
                                                                                                                M-17,    UTMB,    Galveston,                     TX       77550;           409-772-3762.

APRIL
April      7-10,       European             Congress       ofPsychophysiology,                     Federa-
tion of European               Psychophysiology                   Societies,      Barcelona.           Con-
                                                                                                                MAY
tact: Professor     T. Sagal#{233}s,Hospital                       General        Universitari          Vall    May      5-8,     12th      Annual     Symposium,          American                             College          of
d’Hebron,       Pg. Vall d’Hebron          s/n,                    Barcelona         08035,          Spain;     Forensic      Psychiatry,       Montreal.     Contact:      American                             College         of
34-3-2191018        (tel), 34-3-2848753                            (fax).                                       Forensic      Psychiatry,       P0 Box 5870, Balboa Island,                                    CA 92662;
                                                                                                                714-831-0236            (tel), 714-675-1107         (fax).
April      9, conference,            “The    Process      of Psychotherapy,”         Cam-
bridge       Hospital,            Cambridge.         Contact:     Judy      Reiner    Plait,                    May        1 1-13,       Middle           East      Regional              Meeting        of     the     Royal
EcLD.,      Cambridge             Hospital,    1493 Cambridge           St., Cambridge,                         College         of      Psychiatrists,               Cairo.         Contact:           Nasser           Loza,
MA       02139; 617-864-6165                                6
                                                       (tel), 17-876-9760                (fax).                 M.R.C.Psych.,              Behman             Hospital,          El Marsad               St.-Helwan,
                                                                                                                Cairo,    Egypt;         202-780-477              (tel),      202-960-999               (fax).
April     1 3-1 6, 52nd     Annual    Meeting    of the American   Psycho-
somatic       Society,  Boston.    Contact:   Carol Ann Kiner,   Associate                                      May 20-21,         2nd Annual         Meeting,      American       Psychiatric       Elec-
Director,       APS, 6728       Old McLean     Village  Dr., McLean,       VA                                   trophysiology          Association,        Philadelphia.        Contact:        Nashaat
22101; 703-556-9222.                                                                                            Boutros,      Secretary,      APEA,      Ohio      State University,          473 West
                                                                                                                 12th Ave., Columbus,               OH 43210;        614-293-8211.
April     15-16,      1 ith Annual        Psychopharmacology              Update     (12
hours      category        I CME      credit),      Tufts  University       School     of                       May       21-26,       147th     Annual             Meeting     of the American       Psychi-
Medicine,        Boston.     Contact:      Tufts University        School     of Mcdi-                          atric     Association,       Philadelphia.             Contact:    George   Campbell,       Di-
cine,   Office      of Continuing            Education,      136 Harrison          Ave.,                        rector,      Meetings           Management,                APA,       1400        K St., NW,           Wash-
Boston,      MA 02111;         617-956-6579.                                                                    ington,       DC      20005;        202-682-6193                 (tel),     202-682-6114                (fax).

April 1 7, 6th Annual     Symposium     on Treatment                                     of Headaches           May 3 1-June       2, inaugural      symposium,         Centre      for Studies     of
and Facial    Pain,   New    York   Headache     Center,                                   New     York.        Children    at Risk,     “Improving       the Life Quality            of Children:
Contact:   Alexander      Mauskop,     M.D.,    Director,                                   New     York        Options   and Evidence,”        Hamilton.       Contact:      Peggy McAlpine,
Headache            Center,           301     East       66 St., New           York,       NY      10021;       Dept. of Psychiatry,       Chedoke-McMaster              Hospitals,      Box 2000,
212-794-3550.                                                                                                   Hamilton,     Ont., Canada        L8N 3Z5; 905-521-2100,                 ext. 7358.




A22
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    Join the Celebration
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                       IDEAS & INFORMATION                                         FOR
                       APA ‘S SESQUICENTENNIAL!
Order  this new 28-page    booklet    filled   with   ideas   to help you celebrate          our 1 50th   anniver-
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                                                                                                                     A23
                                                 Reprinted          for      the     information         of the    readers   of The      American            Journal       of Psychiatry



                                                 THE                BRITISH                            JOURNAL                       OF PSYCHIATRY
                                                                                              December            1993,      Volume              163




      Papers                                                                                                                   hospitals            in Denmark               from        1969       to 1991.
                                                                                                                               P. ]ensen,  S.A. S#{248}rensen,K. Fenger                                   and
      Soviet  special   psychiatric                             hospitals. Where                                               T.G. Bolwig                                                                       790
        the system    was criminal                               and the inmates
        were         sane.          N. Adler              and S. Gluzman                                     713             Psychosis           and     cannabis             abuse   in The              Gam-
                                                                                                                               bia. A case-control                        study.    M. Rolfe,
      Childhood               sexual              abuse        and        mental             health                            C.M.       Tang, S. Sabally, J.E. Todd,
        in adult            life.     P.E.          Mullen,           J.L.         Martin,                                     E.B.      Sam and A.B. Hatib N’]ie                                                798
        J.C.     Anderson,                   S.E.       Romans
                                                                                                             72 1            Psychiatric            morbidity              in sentenced            segre-
        and      G.P.         Herbison
                                                                                                                               gated I-IIV-positive      prisoners.                         A. Dorman,
      Otago          women’s                health           survey           30-month                                         A. O’Connor,         E. Hardiman,                           A. Freyne
        follow-up.        I: Onset    patterns     of non-psy-                                                                 and H. O’Neill                                                                    802
        chotic     psychiatric     disorder.     S.E. Romans,
                                                                                                                             Stress      among       police    body handlers.                        A long-
        V.A. Walton,           B. McNoe,       G.P. Herbison
                                                                                                                                term      follow-up.        D.A. Alexander                                       806
        and P.E. Mullen                                                                                      733
      Otago     women’s       health    survey      30-month                                                                 The       Current         literature
        follow-up.      II: Remission        patterns     of non-
                                                                                                                             Jobst    et al’s “Detection        in life of confirmed
        psychotic    psychiatric      disorder.      S.F. Romans,
                                                                                                                                Alzheimer’s      disease    using a simple       meas-
        V.A. Walton,        B. McNoe,          G.P. Herbison
        and P.E. Mullen
                                                                                                             739                urement      of medial    temporal      lobe atrophy
                                                                                                                                by computed        tomography.”         M. Philpot
      Do psychosocial                        factors           influence              outcome                                  and A. Burns                                                                      809
        in severely                 depressed                female          psychiatric
        in-patients?                 B. Andrew,                  K. Hawton,                                                  Brief      Reports
       I.     Fagg      and          D.      Westhrook                                                       747
                                                                                                                             Poppy        tea dependence.                    S. Unnithan
      Self-esteem       in recovered     bipolar    and unipo-                                                                 and].        Strang                                                               813
        tar out-patients.        D. Pardoen,      F. Bauwens,
        A. Tracy,      F. Martin     and].     Mendlewicz                                                    755             Treatment          of cocaine      abuse                  with      mono-
                                                                                                                               amine        oxidase    inhibitors.                   C. Brewer                   815
      The role of gender       in understanding        the
        familial  transmission      of schizoaffective                                                                       Treatment             of hysterical       aphonia      with hypno-
        disorder.   ].M. Goldstein,       S. V. Faraone,                                                                       sis and          prokaletic       therapy.     ]. Neeleman
        W.J. Chen and M.T.          Tsuang                                                                   763               andA.H.Mann                                                                       816

      Negative    features,     retrieval     processes                                                                      Hyponatraemia                     and inappropriate                    secretion
        and verbal      fluency     in schizophrenia.                                                                          of antidiuretic                 hormone     associated                  with
        H.A. Allen,       P.F. Liddle      and C.D.                                     Frith                769               the use of imipramine.                             R. Colgate                     819
      Negative    symptoms                           as a risk factor        for                                             Clozapine            in the treatment               of psychotic
        tardive  dyskinesia                          in schizophrenia.                                                         refractory            depression.              D. Dassa, A. Kalad-
        P.F. Liddle,    T.R.E.                         Barnes,    J. Speller                                                   jian,     ].M.       Azorin          and      S.    Giudicelli                    822
        and D. Kibel                                                                                         776
                                                                                                                             Cyclic       psychosis  associated with the                                 men-
      The effect of activation                              procedures                  on                                     strual      cycle. D. Stein, A. Hanukoglu,
        neuroleptic-induced                               akathisia.                                                           S. Blank           and A. Elizur                                                  824
        W. W. Fleischhacker,                                 C.H.         Miller,
                                                                                                                             A case of delayed                   post-traumatic                  stress
        C. Barnas,                  K. Bergmann,                      R. Perovich,
                                                                                                                               disorder   with               ‘organic  memories’                    accompa-
       ].Ma.].          Alvir,            J.A.       Lieberman                 and
                                                                                                                               nying therapy.                  A.C. Briggs                                       828
       ].M.          Kane                                                                                    781
                                                                                                                             Automatism                and       post-traumatic                 stress
      Personality    disorders      in patients      with
                                                                                                                               disorder.          ].I. Bisson                                                    830
        somatisation      disorder.      A controlled                                         study.
        I. Stern, M. Murphy           and C. Bass                                                            785
                                                                                                                             Columns
      A study          of psychiatric                     morbidity                 in patients                              Correspondence                                                                      833
        with Huntington’s        disease,                               their relatives,                                     A hundred  years                   ago. H. Rollin                                   840
        and controls.     Admissions                                  to psychiatric                                         Book Reviews                                                                        841




A24
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                                                                                                                                            is seizure.        For more information,              see fu)) presCribing      information.
                                                                                                                                            See    brief summary ofprescribing                       information on next page.

References:      1. Fabre LF, Brodie HKH, Garner D. Zung WWK. A multicenter                       evaluation     of bupropion     versus placebo in hospitalized         depressed      patients. J CAn Psychiatry.      1983;44:88-94.2. Lineberry CG,
Johnston    JA, Raymond        RN, et al. A fixed-dose       (300 mg) efficacy       study of bupropion      and placebo      in depressed      outpatients.    J C/in Psychiatry.    1990;51: 194-1 99. 3. Data on file, Burroughs Wel/come Co.
4. Feighner   J, Hendrickson       G, Miller L Stem W. Double-blind             comparison      of doxepin versus bupropion           in outpatients     with a major depressive       disorder.    J C/in Psychopharmaco/.     1986;6:27-32.     5. Gardner
EA. Johnston     JA. Bupropion-an          antidepressant       without   sexual pathophysiological         action. J C/in Psychophannaco/.             1985;5:24-29.6. Jacobsen FM. Fluoxetine-induced                sexual dysfunction     and an open tnal
of yohimbine.     J C/in Psychiatry.    1992;53:1     19-122. 7. Segraves        RT. Sexual dysfunction         complicating     the treatment      of depression.    J C/in Psychiatry      Monograph.     1992;10(1):75-79.   8. Fems AM. Cooper BR.
Mechanism      of antidepressant      activity   of bupropion.      J C/in Psychiatry     Monograph.      1993;11(1):2-14.
                                                                                                                                                       Pediatric Use: The safety and effectiveness of Wellbutrin in individuals under 18 years old have not been
WELLBUTRIN#{174}(BUPROPION                                                     HYDR0cHL0RDE)Tablets                                                    established.
                                                                                                                                                       Use in the Elderly: Wellbutrin has not been systematically evaluated in older patients.
Before prescribing, please consult complete product information, a summary of which follows:                                                           ADVERSE REACTIONS: (See also WARNINGS and PRECAUTIONS)                  Adverse events commonly encountered
INDICATiONS AND USAGE: Wellbutnn is indicated for the treatment of depression. A physician considenng                                                  in patients treated with We/Ibutrin are agitation, dry mouth, insomnia, headache/migraine, nausealvomiting,
the initiation of Wellbutrin should be aware that the drug may cause generalized seizures with an                                                      constipation. and tremor.
approximate incidence of O.4x/x (4/1000).          This incidence may exceed that of other antidepressants as much                                     Adverse        evenls     were    sufficiently          troublesome         to cause       discontinuation       of Wel/butrin        treatment          in
as fourfold. This relative nsk is only an approximation since no direct comparative studies have been conducted.                                       approximately ten percent ofthe 2400 patients and volunteers who participated in clinical trials during the
CONTRAINDICATIONS:               Wellbutnn is contraindicated in patients with a seizure disorder; with a current or                                   product’s initial development The more common events causing discontinuation      include neuropsychiatnc
pnor diagnosis of bulimia or anoreoia nervosa, because ofa higher incidence of seizures noted in such patients;                                        disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances
who have shown an allergic response to it; or who are currently being treated wilh an MAO inhibitor. At/east                                           (2.1%), pnmanly         nausea and vomiting;              neurological      disturbances        1.7%), pnmanly     seizures,       headaches,          and
 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with                                                    sleep disturbances; and dermatologic problems )l.4x/x), primarily rashes. It is importantto      note, however,
Wellbutrin.                                                                                                                                            that many ofthese events occurred at doses that exceed the recommended daily dose.
WARNINGS: SEIZURES: WelIbutrin is associated with seizures in approximately O.4%(4/1000)of                           patients                          The table below is presented solely to indicate the relative frequency of adverse events reported in
treated at doses up to 450 mg/day. This incidence of seizures may exceed that of other marketed                                                        representative controlled clinical studies conducted to evaluate the safety and efficacy of Wellbutrin
antidepressants       by as much as fourfold. This relative risk is only an approximate estimate because                                               under relatively similar conddions of daily dosage )300’600 mg), setting, and duration (3.4 weeks). The figures
 no direct comparative studies have been conducted. The estimated seizure incidencefor                            Wellbutrin                           cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical
 increases almost tenfold between 450 and 600 mg/day, which is twice the usually required daily dose                                                   practice where patient characteristics and other factors must differ from those which prevailed in the
( mg)and one and one4hlrd the maximum recommended daily doee(450 mg Given the wide variability                                                         clinicaltrials. These incidence figures also cannot be compared with those obtained from other clinical studies
among Individuals and their capacity to metabolize and eliminate drugs, this disproportionate                                                          involving related drug products as each group of drug lnals is conducted under a different set of conditions.
 Increase in seizure incidence with dose incrementation calls for caution in dosing.                                                                   Finally, it is impottantto  emphasize   thatthe tabulation does not reflectthe relalive severity and/or clinical
 During the Initial development,             25 among approximately             2400 patients treated with Wellbutrin                                  importance of the events. A beSet perspecbve on the senous adverse events assooated with the use of Weibutnn
experienced seizures. At the time of seizure, 7 patIents were receiving daily doses of 450 mg or below,                                                is provided      in the WARNINGS            and PRECAUTIONS                   sections.
for an incidence of 0.33% (3/1000) within the recommended dose range. Twelve (12) patients                                                              TREATMENT         EMERGENT ADVERSE EXPERIENCE                           INCIDENCE iN PLACEBO-CONTROLLED CLINICAL TRlAL$
experienced seizures at 600 mg per day (2.3% Incidence); 6 additional patients had seizures at daily                                                                                          (Percentol                         Patients Reporting)
doses between 600 and 900 mg (2.8% incidence).
A separate, prospective study wee conducted to determine the incidence of seizure during an 8 week                                                                                                Wellbutrin            PlaceIo                                                Wellbutrin              Placebo
treatment exposure in approximately               3200 additional patients who received daily doses of up to 450                                                                                   Patients             Patients                                                PatIents               Patients
mq. Patients were permitted to continue treatment beyond 8 weeks If clinically indicated. Eight (8)                                                        Adverse Experience                      (n 323)             (n x l5)            Adverse Experience                   (n x 323)             (n 185)
seizures occurred during the Initial 8 week treatment period and 5 seizures were reported in
patients continuing treatment beyond 8 weeks, resulting                      in a total seizure incidence of 0.4%.                                     CARDIOVASCULAR                                                                      Dry Mouth                             27 6                 18.4
The risk of seizure appears to be strongly suociated                    with dose and the presence       of predisposing                                   Cardiac Arrhythmias                        53                 4.3               Excessive Sweating                    22.3                 14.6
factors. A signifIcant predlsposing            factor(e.g.,     history of head trauma or prIor seizure, CNS tumor,                                        Dizziness                                 22.3               16.2               Headache/Migraine                     25.7                 22.2
concomitant medications thatlower seizure threshold,                     etc.) was present in approximately one-haN                                        Hypertension                               4.3                1.6               Impaired Sleep Quality                 4.0                   1.6
of the patients experiencing a selzur Sudden end large kicrements in dose may contribute to increased                                                    Hypotension                                  2.5                2.2              Increased Salivary Flow                 3.4                  3.8
rIsk. While many seizures occurred early In the course oftreatment,                       some seizures did occur after                                  Palpitations                                 3.7                2.2              Insomnia                               18.6                 15.7
several weeks affixed dose.                                                                                                                              Syncope                                      1.2                0.5              Muscle Spasms                           1.9                  3.2
R.ecommendstions forreducing 11w,lsk ofselzure:Retrospectlve                       analysis of clinical experience gained                                Tachycardia                                 10.8                8.6              Pseudoparkinsonism                      1.5                  1.6
during the development of Weilbutrin suggests that the ri#{225}kseizureTmay be minimized ft(1)thi
                                                                             of                                           total                        DERMATOLOGIC                                                                       Sedation                               19.8                 19.5
daily dose ofWellbutrin does notexceed 450 mc, (2)the daily dose Is administered                          t.i.d., with each                              Pruntus                                        2.2              0.0              Sensory Disturbance                     4.0                  3.2
single dose not to exceed 150 mg to avoid high peak concentrations of buproplon and/or its                                                               Rash                                           80               6.5              Tremor                                 21.1                  7.6
metsbolltes,     and (3) the rate ofincrementation             of dose is very gradual. Extreme caution should be                                      GASTROINTESTINAL                                                                 NEUROPSYCHIATRIC
used when Weilbutrin         ls(1)administered        to patients with a history of seizure, cranial traum or other                                      Anorexia                                    18.3               18.4               Agitation                             31.9                 22.2
predisposition(s)       toward seizure, or (2) prescrIbed with other agents (e.g., sntlpsychotics, other                                                 Appetite Increase                            3.7                2.2               Anxiety                                 3.1                 1.1
antidepressants,      etc.)or treatment       regimens      (e.g., abrupt discontinuation      of a benzodiazepine)that                                  Constipation                                26.0               17.3               Confusion                               8.4                 4.9
lower seizure threshold.                                                                                                                                   Diarrhea                                     6.8              8.6               DecreasedLibido                         3.1                 1.6
Potentlalfor     Hepatotoxicity:      In rats receiving large doses of bupropion chronically, there was an increase                                        Dyspepsia                                    3.1              2.2               Delusions                               1.2                 1.1
in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large                                                       NauseaNomiting                            22.9              18.9               Disturbed Concentration                  3.1                 3.8
doses of bupropson chronically, venous helologic thanges were seen e the liver, and laboratory tests suggesting                                            Weight Gain                               13.6              22.7               Euphoria                                 1.2                 0.5
mild hepatocellular injury were noted. Although scattered abnormalities in liverfunction tests were detected                                               Weight Loss                               23.2              23.2               Hostility                                5.6                 3.8
in patients participating in clinical trials, there is no clinical evidence that bupropion acts as a hepatotoxin                                       GENITOURINARY                                                     31             NONSPECIFIC                                50                  86
in humans.
PRECAUTIONS: General:                                                                                                                                    Menstrual Complaints                           4.7              1.1               Fever/Chills                            12                  0
Agftaticn    andlnson,nia: A substantial propottion of patients treated with We)lbutnn expenence some degree                                             Unnary Frequency                               2.5              2.2                                                          .

of increased       restlessness,       agitation,    ansiet’,    and insomnia,        especially         shortly   after initiation    of treatment.     Unnary Retention                               1 .9             2.2            RESPIRATORY
In clinical studies, these symptoms were sometimes of sufficient magnitude to require treatment with                                                   MUSCULOSKELETAL                                                                    Upper Respiratory
sedative/hypnotic drugs. In approximately 2% ot patients, symptoms were sufficiently severe to require                                                   Arthritis                                      3.1              2.7               Complaints                              5.0                11.4
discontinuation of Wellbutrin treatment.                                                                                                               NEUROLOGICAL                                                                     SPECIAL SENSES
Psychosis, Confusion, and Other Neuropsychiatric         Phenomena: Patients treated with Wellbutrin                                                     Akathisia                                      1.5              1.1              Auditory Disturbance                    5.3                  3.2
have been         reported    to show       a variety      of neuropsychiatnc           signs      and symptoms            including     delusions,        Akinesia/Bradykinesia                        8.0              8.6              Blurred Vision                         14.6                 10.3
hallucinations, psychotic episodes, confusion, and paranoia. Because ofthe uncontrolled nature of many                                                     Cutaneous Temperature                                                          Gustatory Disturbance                   3.1                  1.1
studies, it is imposaibie to provide a precise estimate ofthe extent of mit imposed by treatment with Wellbutnn.                                             Disturbance                                1.9              1.6
In several cases, neuropsychiatric phenomena abated upon dose reduction and/or withdrawal of treatment
Activation      of Psychosis and/or Mania: Anlidepressants         can precipitate  manic episodes    in Bipolar
                                                                                                                                                        Events reported by at least 1% of Wellbutrin patients are included.
Manic Depressive patients during the depressed phase of their illness and may activate latent psychosis in                                             Other Events Observed During the Development of Wellbutrin: The conditions and duration of
other susceptible        patients.     Wellbutnin       is expected     to pose similar         risks.                                                 exposure to Wellbutne varied greatly and a substantial proportion of the expenence was gained in open and
AlferedAppefiteand      Weight: A weight loss of greeter than 5 pounds occurred in 28% of Wellbutnn patients.                                          uncontrolled   clinical settings. Dunngthis     experience, numerous adverse events were reported; however,
This incidence is approximately double that seen in comparable patients treated with tncyc)ics or placebo.                                             without appropriate controls, it is impossibleto determine with certainty which events were or were not caused
Furthermore,    while 34.5% of patients receiving     tricyclic antidepressants  gained weight, only 9.4% of                                           by Weffbutnn. The following enumeration        a organized by organ system and describes events in terms of their
patients treated eath Wetbulnn id. Consequently, it weqnt kiss a a major presenteig sqn cit a patienfs depressive                                      relative frequency of reporting in the data base. Events of major clinical importance are also described       in
illness,   the anorectic      and/or     weight     reducing     potential     otWellbutnin        should      be considered.                          the WARNINGS            and PRECAUTIONS                   sections      of the labeling.
Sedc:     The possibility ota decide attempt ia aherent in depression and may persist untit sigeificant remission                                      The following definitions otfrequency are used: Frequent adverse events are defined as those occurring in
occurs. Accordingly,     prescriptions for Wellbutrin  should be wntten for the smallest number of tablets                                             at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while tare
consistent with good patient management.                                                                                                               events are those occurring in less than 1/1000 patients.
Use In Patients with Systemic Illness: There is no clinical experience establishing the safety of Wellbutnn                                            Cardiovascular:     Frequent was edema; infrequent were chest pain, EKG abnormalities (premature beats
in patients      with a recent history       of myocardial        infarction    or unstable       heart disease.        Therefore,      care should    and nonspecific ST.T changes), and shortness of breath/dyspnea; rare were flushing, pallor, phlebitis and
be exercised if it is used in these groups.                                                                                                            myocardial       infarction.
Because bupropion HCI and its metabolites are almost completely excreted through the kidney and                                                        D.rmatologic:         Frequent were nonspecific      rashes; infrequent    were alopecia       and dry skin; rare were
metabolites are likely to undergo conjugation in the liver pnorto unnary excretion, treatment of patients with                                         change in hair color, hirsutism and acne.
renis or hepatic kntsitmerit should be Abated at reisced dosage as bttropson and its metaboittes may acoumulate                                        Endocrine:       Infrequent was gynecomastia; rare were glycosuria and hormone level change.
in such patients beyond concentrations    expected in patients without renal or hepatic impairment   The patient                                       Gsstrointesfinal:       Infrequentwere dysphagia, thirstdisturbance,     and liver damage/jaundice; rare were rectal
should be dosely mondored tot possdIe toxic effects of elevated blood and tissue tenets of drug and tnetattohtes.                                      complaints, colitis, G.I. bleeding, intestinal perforation and stomach ulcer.
Information for Patients: Consult complete product information.                                                                                        Genitourinary:        Frequent was nocturia; infrequent     were vaginal irritation, testicular swelling, urinary tract
Drug Interactions:      No systematic data have been collected on the consequences of the concomitant                                                                                                                             enuresis, unnary incontinence, menopause,
                                                                                                                                                       infection, paxiftit erection, and retarded ejaculation; rare were dysu#{241}
administration       of Wellbutnin       and other drugs.                                                                                              ovanan disorder, pelvic infection, cystitis, dyspareunia, and painful ejaculation.
However, animal data suggestthat       Wellbutrin may be an inducer of drug metabolizing enzymes. This may                                             Hematologic/Oncologic:            Rare were lymphadenopathy, anemia and pancytopenia.
be of potential clinical importance because the blood levels of co’administered      drugs may be altered.                                             Musculoskeletal:         Rare was musculoskeletal chest pain.
Alternatively, because bupropion is extensively metabokzed, the coadministration ofother drugs may affect                                              Neurologftal:(see         WARNINGS) Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and
its clinical activity. In particular, care should be exercised when administering drugs known to affect                                                dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were EEG abnormality, abnormal
hepatic drug metabolizing enzyme systems (e.g., carbamazepine, cimetidine, phenobarbital, phenytoin).                                                  neurological exam, impaired attention, sciatica and aphasia.
Studies in animals demonstrate that the acute toxicity of bupropEoe a enhanced by the MAO mhibdor phenelane                                            N.uropsychiatric:(see          PRECAUTIONS) Frequent were mania/hypomania, increased libido, hallucinations,
(see CONTRAINDICATIONS).                                                                                                                               decrease in sexual function, and depression; infrequent were memory impairment, depersonalization, psychosis,
Limited clinical data suggest a higher incidence of adverse expenences in patients receiving concurrent                                                dysphoria, mood instability, paranoia, formal thought disorder, and frigidity; rare was suicidal ideation.
administration     of Wellbutrin and Ldopa. Administration       of Wellbutrin to patients receiving L.dopa                                            Oral Complaints:       Frequentwas stomatibs; infrequent were toothache, bruxism, gum irritation, and oral edema;
concurrently should be undertaken with caution, using small initial doses and small gradual dose increases.                                            rare was glossitis.
Concurrent administration of Wellbutrin and agents which lower seizure threshold should be undertaken only                                             Respiratory: lnfrequentwere         bronchitis and shortness of breath/dyspnea;     rare were epistaxis, rate or rhythm
with extreme caution (see WARNINGS). Low dais dosing and small graduid dose increases should be employed.                                              disorder,     pneumonia        and pulmonary            embolism.
Carcinogenesis,       Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity   studies were performed                                          Sp.ciaIS.naes:   Infrequent was visual disturbance; rare was diplopia.
in rats and mice         at doses       up to 300 and           150 mg/kg/day,
                                                                            respectively. In the rat study there was an                                Nonspecific: Frequent were ftulike symptoms; infrequent was nonapecifo: pan; rare were body odor, surgically
increase in nodular proliferative            lesions ofthe liver at doses of 100 to 300 mg/kg/day; lower doses were not                                related     pain, infection,     medication         reaction     and overdose.
tested.    The question of whether or not such lesions may be precursors of neoplasms of the liver is                                                  Postintroduction          Reports: Voluntary reports of adverse events temporally associated with Wellbutrin that
currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant                                             have been received         since market introduction and which may have no causal relationship with the drug include
tumors of the liver and other organs was seen in either study.                                                                                         the following:
Bupropion produced a borderline positive response (2.3 times control mutation rate) in some strains in the                                             Cardiovascular:     orthostatic hypotension, third degree hearfblock
Ames bactenal mutagemoty test. and a lagh otis dose)300, but no) 100 or200 rneg) pruduced a low incidence                                              Endocrine: syndrome of inappropriate antidiuretic hormone secretion
of chromosomal aberrations in rats. The relevance of these results in estimating the risk of human                                                     Gastrointestinal:    esophagitis, hepatitis
exposure to therapeutic doses is unknown.                                                                                                              Hemic and Lymphatic: ecchymosis, leukocytosis, leukopenia
A fertility study was performed in rats; no evidence of impairment of fertility was encountered at oral                                                Musculoakeletal:      arthralgia, mya)gia, muscle rigidity/fever/rhabdomyolysis
doses up to 300 mg/kg/day.                                                                                                                             Nervous: coma, delirium, dream abnormalities, paresthesia, unmasking ottardive dyskinesia
Pregnancy: Teratognic        Effects: Pregnancy Category B: Reproduction        studies have been performed     in                                     Skin andAppendages:          Stevens’Johnson  syndrome.      angioedema.   exfoliative dermatitis, urticaria
rabbits and rats at doses up to 15.45 timex the human daily dose and have revealed no definitive evidence                                              Special Senaes:tinnitus
of impaired fertility or harm to the fetus due to bupropion. (In rabbits, a slightly increased incidence of fetal                                                                                                                              October 1992         646033
abnormalities was seen in two studies, butthere was no increase in any specific abnormality). There are no
adequate and we)l.controlled    studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed
Labor and Delivery: The effect of Wellbutrin on labor and delivery in humans is unknown.                                                                                Burroughs Wellcome Co.
Nursing Mothers: Because ofthe potential for senous adverse reactions in nursing infants from Wellbutrin,                                              Welceme          Research Triangle Park, NC 27709
a decision should be made whetherto discontinue nursing Otto discontinue the drug. taking into account the
importance of he drug In the mother.                                                                                                                   Copr C 1992 Burroughs Wellcome Co                              All righfs reserved.
                                                                                                                                                       Printed in U.S.A WB.Y05409                                                                                               PrntadovRacycedPape

				
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