openFDA text is shown for search and cross-checking; DailyMed SPL is canonical.
Adverse reactions sections page 1 of 3 · 9 matching rows.
adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.1) Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions (5.2) ] Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis [see Warnings and Precautions 5.3 ] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions 5.4 ] Metabolic changes (hyperglycemia, dyslipidemia, weight gain) [see Warnings and Precautions 5.5 ] Tardive dyskinesia [see Warnings and Precautions 5.6 ] Hypotension [see Warnings and Precautions 5.7 ] Increases in blood pressure (children and adolescents) [see Warnings and Precautions 5.8 ] Leukopenia, neutropenia and agranulocytosis [see Warnings and Precautions 5.9 ] Cataracts [see Warnings and Precautions 5.10 ] QT Prolongation [see Warnings and Precautions 5.11 ] Seizures [see Warnings and Precautions 5.12 ] Hypothyroidism [see Warnings and Precautions 5.13 ] Hyperprolactinemia [ see Warnings and Precautions 5.14 ] Potential for cognitive and motor impairment [see Warnings and Precautions 5.15 ] Body temperature regulation [see Warnings and Precautions 5.16 ] Dysphagia [see Warnings and Precautions 5.17 ] Discontinuation Syndrome [see Warnings and Precautions 5.18 ] Most common adverse reactions (incidence ≥ 5% and twice placebo): Adults:somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain,postural hypotension, pharyngitis, weight gain, lethargy, ALT increased,dyspepsia (6.1) Childrenand Adolescents: somnolence, dizziness, fatigue, increased appetite, nausea,vomiting, dry mouth, tachycardia, weight increased (6.1) To report SUSPECTED ADVERSE REACTIONS, contactAscend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Study Experience Becauseclinicalstudiesareconductedunderwidely varyingconditions,adversereactionratesobservedintheclinical studiesof adrugcannotbedirectlycompared toratesin theclinicalstudies ofanotherdrugand maynotreflecttheratesobservedin practice. Adu lt s : Theinformationbelow isderivedfroma clinicaltrialdatabaseforquetiapineconsistingofover4300 patients.This databaseincludes 698patientsexposedtoquetiapine forthetreatmentofbipolardepression,405patientsexposedto quetiapinefor the treatmentofacutebipolarmania (monotherapyand adjunct therapy),646 patientsexposedto quetiapinefor the maintenancetreatmentofbipolarIdisorderasadjunct therapy, and approximately2600patientsand/ornormalsubjectsexposedto1 ormoredosesofquetiapine for the treatmentofschizophrenia. Of theseapproximately4300subjects,approximately 4000(2300 inschizophrenia,405 inacutebipolarmania,698 inbipolardepression,and 646forthe maintenancetreatmentofbipolarIdisorder)werepatientswhoparticipated inmultipledose effectivenesstrials,andtheirexperiencecorresponded toapproximately2400 patient-years.Theconditionsand durationoftreatmentwith quetiapinevaried greatlyandincluded(inoverlappingcategories)open-labelanddouble-blindphases ofstudies,inpatientsandoutpatients,fixed-dose and dose-titrationstudies,andshort-termorlonger-termexposure. Adversereactions wereassessedbycollectingadverse events,results ofphysicalexaminations,vitalsigns,weights,laboratoryanalyses,ECGs, andresultsofophthalmologic examinations. Thestated frequenciesofadverse reactions represent theproportion ofindividualswho experienced, atleastonce,a treatment-emergent adversereactionofthe typelisted. AdverseReactions Associated with Discontinuation ofTreatment inShort-Term, Placebo-ControlledTrials Schizophrenia: Overall,therewaslittledifferencein the incidenceofdiscontinuationdueto adversereactions(4%forquetiapine vs. 3% for placebo)ina poolofcontrolledtrials. However,discontinuationsdueto somnolence(0.8%quetiapinevs. 0%placebo) andhypotension(0.4%quetiapinevs.0%placebo)wereconsideredtobedrugrelated [see Warningsand Precautions (5.7 and 5.18 )]. BipolarDisorder: Mania: Overall,discontinuations dueto adverse reactions were5.7%for quetiapinevs. 5.1% for placeboin monotherapyand 3.6%forquetiapinevs. 5.9% forplacebo in adjuncttherapy. D epression: Overall, discontinuationsduetoadverse reactionswere12.3%forquetiapine300 mg vs. 19.0% forquetiapine 600 mgand5.2% for placebo. CommonlyObserved AdverseReactionsin Short-Term,Placebo-Controlled Trials: Inthe acutetherapyofschizophrenia(upto 6weeks)and bipolarmania (upto12weeks) trials,the mostcommonlyobserved adversereactionsassociated withtheuseofquetiapinemonotherapy(incidenceof5%orgreater)andobserved atarateon quetiapine at least twicethatofplacebo were somnolence (18%),dizziness(11%),drymouth (9%),constipation(8%), ALT increased(5%),weightgain (5%),and dyspepsia (5%). AdverseReactionsOccurringatanIncidenceof2%orMoreAmong quetiapineTreated Patientsin Short-Term, Placebo-ControlledTrials: Theprescriber shouldbe awarethat the figuresinthetablesand tabulationscannotbe usedtopredict the incidence ofsideeffectsinthe courseofusualmedical practicewherepatientcharacteristicsandotherfactors differfromthose thatprevailedin theclinical trials. Similarly,thecitedfrequenciescannotbecompared withfiguresobtainedfromotherclinicalinvestigationsinvolvingdifferenttreatments,uses, and investigators.Thecited figures,however, doprovide the prescribingphysicianwithsomebasisforestimatingtherelative contributionofdrugandnondrugfactorstothe side effectincidenceinthepopulationstudied. Table9enumeratestheincidence,roundedtothenearestpercent,ofadversereactionsthatoccurred duringacutetherapyofschizophrenia(upto6 weeks)andbipolarmania(upto12 weeks) in2%ormoreofpatientstreated withquetiapine(dosesrangingfrom75to 800mg/day)wheretheincidencein patientstreatedwith quetiapinewasgreaterthanthe incidenceinplacebo-treatedpatients. Table9:AdverseReactionIncidencein3-to12-WeekPlacebo-ControlledClinicalTrialsfortheTreatmentofSchizophreniaandBipolarMania(Monotherapy) Preferred Term Quetiapine (n=719) PLACEBO (n=404) Headache 21% 14% Agitation 20% 17% Somnolence 18% 8% Dizziness 11% 5% Dry Mouth 9% 3% Constipation 8% 3% Pain 7% 5% Tachycardia 6% 4% Vomiting 6% 5% Asthenia 5% 3% Dyspepsia 5% 1% Weight Gain 5% 1% ALT Increased 5% 1% Anxiety 4% 3% Pharyngitis 4% 3% Rash 4% 2% Abdominal Pain 4% 1% Postural Hypotension 4% 1% Back Pain 3% 1% AST Increased 3% 1% Rhinitis 3% 1% Fever 2% 1% Gastroenteritis 2% 0% Amblyopia 2% 1% Intheacuteadjuncttherapyofbipolarmania(upto3weeks)studies,themostcommonlyobservedadversereactionsassociated withtheuseof quetiapine(incidenceof 5%or greater)andobserved atarateonquetiapineatleasttwice thatofplacebo weresomnolence(34%),drymouth (19%),asthenia(10%), constipation (10%), abdominalpain (7%),posturalhypotension (7%),pharyngitis (6%),andweightgain (6%). Table10enumeratestheincidence,rounded tothenearestpercent, ofadversereactionsthatoccurredduringtherapy(upto 3 weeks)ofacutemaniain 2%ormoreofpatientstreated with quetiapine(dosesrangingfrom100 to 800 mg/day)usedasadjuncttherapytolithiumanddivalproexwheretheincidencein patientstreated with quetiapinewasgreater thantheincidenceinplacebo-treatedpatients. Table10:AdverseReactionIncidencein3-WeekPlacebo-ControlledClinicalTrialsfortheTreatmentofBipolarMania(AdjunctTherapy) Preferred Term Quetiapine (n=196) PLACEBO (n=203) Somnolence 34% 9% Dry Mouth 19% 3% Headache 17% 13% Asthenia 10% 4% Constipation 10% 5% Dizziness 9% 6% Tremor 8% 7% Abdominal Pain 7% 3% Postural Hypotension 7% 2% Agitation 6% 4% Weight Gain 6% 3% Pharyngitis 6% 3% Back Pain 5% 3% Hypertonia 4% 3% Rhinitis 4% 2% Peripheral Edema 4% 2% Twitching 4% 1% Dyspepsia 4% 3% Depression 3% 2% Amblyopia 3% 2% Speech Disorder 3% 1% Hypotension 3% 1% Hormone Level Altered 3% 0% Heaviness 2% 1% Infection 2% 1% Fever 2% 1% Hypertension 2% 1% Tachycardia 2% 1% Increased Appetite 2% 1% Hypothyroidism 2% 1% Incoordination 2% 1% Thinking Abnormal 2% 0% Anxiety 2% 0% Ataxia 2% 0% Sinusitis 2% 1% Sweating 2% 1% Urinary Tract Infection 2% 1% Inbipolardepression studies(upto8 weeks), themostcommonlyobserved treatmentemergentadversereactions associatedwiththeuseofquetiapine(incidenceof5%orgreater)and observedatarateonquetiapine atleasttwice thatofplacebo weresomnolence(57%),drymouth (44%),dizziness(18%),constipation(10%),and lethargy (5%). Table11 enumeratestheincidence,rounded tothenearestpercent, ofadversereactionsthatoccurredduringtherapy(upto 8 weeks)ofbipolardepressionin 2% ormoreofpatientstreatedwith quetiapine(doses of300and600mg/day) wheretheincidenceinpatientstreatedwithquetiapinewasgreaterthantheincidencein placebo-treatedpatients. Table11: AdverseReactionIncidencein8-WeekPlacebo-ControlledClinicalTrialsfortheTreatmentofBipolarDepression Preferred Term Quetiapine (n=698) PLACEBO (n=347) Somnolence 3 57% 15% Dry Mouth 44% 13% Dizziness 18% 7% Constipation 10% 4% Fatigue 10% 8% Dyspepsia 7% 4% Vomiting 5% 4% Increased Appetite 5% 3% Lethargy 5% 2% Nasal Congestion 5% 3% Orthostatic Hypotension 4% 3% Akathisia 4% 1% Palpitations 4% 1% Vision Blurred 4% 2% Weight increased 4% 1% Arthralgia 3% 2% Paraesthesia 3% 2% Cough 3% 1% Extrapyramidal Disorder 3% 1% Irritability 3% 1% Dysarthria 3% 0% Hypersomnia 3% 0% Sinus Congestion 2% 1% Abnormal Dreams 2% 1% Tremor 2% 1% Gastroesophageal Reflux Disease 2% 1% Pain in Extremity 2% 1% Asthenia 2% 1% Balance Disorder 2% 1% Hypoaesthesia 2% 1% Dysphagia 2% 0% Restless Legs Syndrome 2% 0% 3. Somnolencecombinesadversereactiontermssomnolenceand sedation Explorationsfor interactionsonthe basis of gender, age,andracedid notrevealanyclinicallymeaningfuldifferencesin theadversereactionoccurrenceon thebasisofthesedemographicfactors. DoseDependencyofAdverseReactionsinShort-Term,Placebo-ControlledTrials D ose-relatedAdverseReactions: Spontaneouslyelicited adversereactiondatafroma studyof schizophreniacomparing fivefixeddosesof quetiapine (75 mg,150mg, 300 mg, 600mg,and 750 mg/day)to placebo wereexploredfordose- relatednessofadversereactions. Logisticregression analysesrevealed apositivedoseresponse(p<0.05)forthefollowingadversereactions:dyspepsia, abdominalpain,and weightgain. AdverseReactionsinclinicaltrialswith quetiapineandnotlistedelsewherein thelabel: Thefollowingadversereactionshavealso beenreportedwithquetiapine:nightmares, hypersensitivityandelevationsinserumcreatine phosphokinase (notassociatedwithNMS), galactorrhea,bradycardia(whichmayoccur atornearinitiationof treatmentandbeassociated withhypotensionand/orsyncope) decreasedplatelets,somnambulism(and otherrelated events),elevationsingamma-GTlevels,hypothermia, and priapism. ExtrapyramidalSymptoms (EPS): D ystonia C l assEffect: Symptomsofdystonia,prolonged abnormalcontractionsofmuscle groups,mayoccur insusceptible individuals duringthefirstfewdaysoftreatment. Dystonicsymptoms include:spasmoftheneckmuscles,sometimesprogressingtotightness ofthethroat,swallowingdifficulty,difficultybreathing, and/orprotrusionofthe tongue. Whilethesesymptomscanoccuratlowdoses, theyoccurmore frequentlyand with greaterseveritywith highpotencyand at higher dosesoffirstgeneration antipsychoticdrugs.Anelevated riskof acutedystoniaisobserved inmales and younger agegroups. FourmethodswereusedtomeasureEPS:(1)Simpson-Angus totalscore(meanchangefrombaseline)whichevaluatesParkinsonismand akathisia,(2) BarnesAkathisiaRatingScale (BARS) GlobalAssessmentScore,(3)incidence ofspontaneouscomplaintsofEPS (akathisia,akinesia, cogwheelrigidity,extrapyramidalsyndrome, hypertonia, hypokinesia, neckrigidity, and tremor),and (4) use ofanticholinergicmedicationstotreatemergentEPS. Adults: Datafromone6-weekclinicaltrialofschizophreniacomparingfive fixeddosesofquetiapine(75,150, 300, 600,750 mg/day) providedevidenceforthelackof treatment-emergentextrapyramidalsymptoms(EPS)anddose- relatednessforEPS associated with quetiapine treatment. ThreemethodswereusedtomeasureEPS:(1)Simpson- Angustotalscore(meanchangefrombaseline)whichevaluatesParkinsonismandakathisia,(2) incidenceofspontaneouscomplaintsofEPS (akathisia,akinesia,cogwheelrigidity,extrapyramidalsyndrome,hypertonia,hypokinesia,neck rigidity, and tremor),and (3)useof anticholinergicmedicationstotreatemergentEPS. InTable 12,dystoniceventincludednuchalrigidity, hypertonia,dystonia,musclerigidity,oculogyration;parkinsonism includedcogwheelrigidity,tremor,drooling, hypokinesia;akathisiaincludedakathisia, psychomotoragitation;dyskinetic event includedtardive dyskinesia, dyskinesia,choreoathetosis;andotherextrapyramidaleventincludedrestlessness,extrapyramidaldisorder,movementdisorder. Table12: AdversereactionsassociatedwithEPS inashort-term,placebo-controlledmultiplefixed-dosePhaseIIIschizophreniatrial (6weeksduration) Preferred Term Quetiapine75 mg/day (N=53) Quetiapine 150 mg/day (N=48) Quetiapine 300 mg/day (N=52) Quetiapine 600 mg/day (N=51) Quetiapine 750 mg/day (N=54) Placebo (N=51) n % n % n % n % n % n % Dystonic event 2 3.8 2 4.2 0 0.0 2 3.9 3 5.6 4 7.8 Parkinsonism 2 3.8 0 0.0 1 1.9 1 2.0 1 1.9 4 7.8 Akathisia 1 1.9 1 2.1 0 0.0 0 0.0 1 1.9 4 7.8 Dyskinetic event 2 3.8 0 0.0 0 0.0 1 2.0 0 0.0 0 0.0 Other extrapyramidal event 2 3.8 0 0.0 3 5.8 3 5.9 1 1.9 4 7.8 Parkinsonismincidenceratesas measured bythe Simpson-Angus totalscoreforplaceboandthefivefixeddoses(75,150, 300,600,750mg/day)were:-0.6;-1.0,-1.2;-1.6;-1.8and-1.8.Therateofanticholinergicmedicationusetotreat emergentEPS forplacebo and thefivefixeddoses was:14%;11%;10%;8%;12%and 11%. Insix additionalplacebo-controlled clinicaltrials(3inacutemaniaand3 inschizophrenia)using variabledosesof quetiapine, therewerenodifferences between the quetiapineand placebotreatmentgroupsintheincidence ofEPS,as assessed bySimpson-Angustotalscores, spontaneouscomplaintsof EPSand the useof concomitantanticholinergicmedicationsto treatEPS. Intwoplacebo-controlled clinicaltrialsforthetreatmentofbipolardepressionusing300 mgand 600 mgofquetiapine, theincidenceofadverse reactions potentiallyrelatedtoEPS was 12% inbothdose groups and 6%inthe placebo group. Inthese studies, theincidenceoftheindividual adversereactions(akathisia,extrapyramidaldisorder,tremor,dyskinesia, dystonia,restlessness, musclecontractionsinvoluntary, psychomotor hyperactivityand musclerigidity)were generallylowand did notexceed 4%inanytreatmentgroup. The3 treatmentgroups weresimilarin meanchange inSAS totalscoreandBARS GlobalAssessmentscore at the endoftreatment.Theuseofconcomitant anticholinergicmedicationswasinfrequentandsimilaracrossthethreetreatment groups. Childrenand Adolescents Theinformationbelow isderivedfroma clinicaltrialdatabaseforquetiapineconsistingofover1000 pediatricpatients. Thisdatabase includes 677patientsexposedto quetiapinefor the treatmentofschizophrenia and393childrenand adolescents(10to 17 yearsold) exposedto quetiapineforthetreatmentofacutebipolarmania. AdverseReactions Associated with Discontinuation ofTreatment inShort-Term,Placebo-ControlledTrialsSchizophrenia:Theincidence ofdiscontinuationduetoadversereactionsfor quetiapine-treated andplacebo-treated patients was8.2%and2.7%, respectively.Theadverse eventleadingtodiscontinuationin 1%or moreofpatientson quetiapineand ata greaterincidence than placebowas somnolence (2.7%and 0%forplacebo). BipolarIMania:The incidenceofdiscontinuation dueto adversereactionsforquetiapine-treated andplacebo-treatedpatientswas11.4% and4.4%, respectively.Theadverse reactionsleadingto discontinuationin 2%ormoreofpatientson quetiapineand ata greaterincidence than placebowere somnolence(4.1% vs.1.1%)andfatigue (2.1%vs.0). CommonlyObservedAdverseReactions inShort-Term,Placebo-ControlledTrials Intherapyforschizophrenia(upto6weeks),themostcommonlyobservedadversereactionsassociatedwiththeuseof quetiapinein adolescents(incidenceof 5%orgreaterand quetiapine incidenceatleasttwicethatfor placebo) weresomnolence(34%), dizziness(12%),drymouth (7%),tachycardia(7%). Inbipolarmaniatherapy(up to3 weeks) the mostcommonlyobservedadversereactionsassociatedwiththeuse of quetiapineinchildrenand adolescents(incidenceof5%or greater andquetiapineincidenceatleast twicethatfor placebo)weresomnolence(53%),dizziness(18%),fatigue(11%),increasedappetite(9%),nausea(8%), vomiting(8%), tachycardia(7%),drymouth (7%),and weight increased (6%). Adverse Reactions Occurring at an Incidenceof ≥ 2% Among quetiapine Treated Patients in Short-Term, Placebo-ControlledTrials Schizophrenia (Adolescents,13 to 17 yearsold) Thefollowingfindingswerebasedona6-weekplacebo-controlledtrialinwhichquetiapinewasadministered ineither dosesof 400 or800 mg/day. Table13 enumeratestheincidence,roundedto the nearestpercent,oftreatment-emergent adverse reactionsthatoccurred duringtherapy(up to 6 weeks)ofschizophreniain2%ormoreofpatientstreatedwithquetiapine (doses of400 or800 mg/day)where the incidence inpatientstreatedwithquetiapine was atleast twice the incidence inplacebo-treated patients. Adverse eventsthatwere potentiallydose-relatedwithhigher frequencyinthe800mg group comparedtothe400 mg group includeddizziness(8%vs. 15%), drymouth(4% vs. 10%), and tachycardia(6% vs.11%). Table13: AdverseReactionIncidenceina6-WeekPlacebo-ControlledClinicalTrial fortheTreatment ofSchizophreniainAdolescentPatients Preferred Term Quetiapine 400 mg (n=73) Quetiapine 800 mg (n=74) Placebo (n=75) Somnolence 1 33% 35% 11% Dizziness 8% 15% 5% Dry Mouth 4% 10% 1% Tachycardia 2 6% 11% 0% Irritability 3% 5% 0% Arthralgia 1% 3% 0% Asthenia 1% 3% 1% Back Pain 1% 3% 0% Dyspnoea 0% 3% 0% Abdominal Pain 3% 1% 0% Anorexia 3% 1% 0% Tooth Abscess 3% 1% 0% Dyskinesia 3% 0% 0% Epistaxis 3% 0% 1% Muscle Rigidity 3% 0% 0% 1. Somnolencecombinesadversereactiontermssomnolenceand sedation. 2. Tachycardiacombinesadversereactiontermstachycardiaand sinustachycardia. B i p olarIMania(Childrenand Adolescents 10to17 years old) Thefollowingfindingswerebased on a3-weekplacebo-controlledtrialinwhichquetiapinewasadministeredin eitherdosesof 400 or600 mg/day. CommonlyObservedAdverseReactions Inbipolarmaniatherapy(upto3weeks) themostcommonlyobservedadversereactionsassociatedwiththeuseofquetiapinein children andadolescents(incidenceof5%or greater andquetiapineincidence atleast twicethatfor placebo)weresomnolence(53%),dizziness(18%),fatigue(11%),increasedappetite(9%),nausea(8%), vomiting(8%), tachycardia(7%),drymouth(7%), andweight increased(6%). Table14 enumeratestheincidence,rounded tothenearestpercent, oftreatment-emergent adverse reactionsthatoccurredduringtherapy(up to3 weeks) of bipolar maniain2%ormore of patientstreatedwithquetiapine (doses of400 or600 mg/day)where the incidence inpatientstreatedwithquetiapinewasgreaterthan theincidenceinplacebo-treated patients. Adverseeventsthatwerepotentiallydose-relatedwithhigher frequencyinthe600mg group comparedtothe400 mg group includedsomnolence(50%vs.57%), nausea(6% vs.10%) and tachycardia(6% vs.9%). Table14:AdverseReactionsina3-WeekPlacebo-ControlledClinicalTrial fortheTreatment ofBipolar Maniain ChildrenandAdolescentPatients Preferred Term Quetiapine 400 mg (n=95) Quetiapine 600 mg (n=98) Placebo (n=90) Somnolence 1 50% 57% 14% Dizziness 19% 17% 2% Nausea 6% 10% 4% Fatigue 14% 9% 4% Increased Appetite 10% 9% 1% Tachycardia 2 6% 9% 1% Dry Mouth 7% 7% 0% Vomiting 8% 7% 3% Nasal Congestion 3% 6% 2% Weight Increased 6% 6% 0% iritability 3% 5% 1% Pyrexia 1% 4% 1% Aggression 1% 3% 0% Musculoskeletal Stiffness 1% 3% 1% Accidental Overdose 0% 2% 0% Acne 3% 2% 0% Arthralgia 4% 2% 1% Lethargy 2% 2% 0% Pallor 1% 2% 0% Stomach Discomfort 4% 2% 1% Syncope 2% 2% 0% Vision Blurred 3% 2% 0% Constipation 4% 2% 0% Ear Pain 2% 0% 0% Paraesthesia 2% 0% 0% Sinus Congestion 3% 0% 0% Thirst 2% 0% 0% 1. Somolencecombinesadversereactionstermssomnolenceand sedation. 2. Tachycardiacombinesadversereactiontermstachycardiaand sinustachycardia. ExtrapyramidalSymptoms: Inashort-termplacebo-controlledmonotherapytrialinadolescentpatientswithschizophrenia(6-weekduration),theaggregatedincidenceofextrapyramidalsymptomswas 12.9%(19/147) for quetiapineand 5.3%(4/75)forplacebo, though theincidenceoftheindividualadverseevents (akathisia,tremor,extrapyramidaldisorder,hypokinesia, restlessness,psychomotorhyperactivity, musclerigidity,dyskinesia)didnotexceed 4.1%in anytreatmentgroup. Ina short-termplacebo-controlledmonotherapytrialinchildrenand adolescentpatientswithbipolarmania(3-weekduration),the aggregatedincidence ofextrapyramidalsymptomswas3.6% (7/193) orquetiapine and 1.1%(1/90)forplacebo. Table15 presentsalistingofpatientswith adversereactionspotentiallyassociated withextrapyramidalsymptoms in the short-termplacebo-controlledmonotherapytrialinadolescentpatientswithschizophrenia(6-weekduration). InTables15– 16dystonicevent includednuchalrigidity,hypertonia,andmusclerigidity;parkinsonismincluded cogwheelrigidityandtremor;akathisiaincludedakathisiaonly; dyskinetic event includedtardive dyskinesia,dyskinesia,andchoreoathetosis;andotherextrapyramidaleventincludedrestlessnessandextrapyramidaldisorder. T able15: AdverseReactionsAssociatedwith ExtrapyramidalSymptomsinthePlacebo-controlled TrialinAdolescentPatientswithSchizophrenia (6-weekduration) Preferred Term Quetiapine 400 mg/day (N=73) Quetiapine 800 mg/day (N=74) All Quetiapine (N=147) Placebo (N=75) n % n % n % n % Dystonic event 2 2.7 0 0.0 2 1.4 0 0.0 Parkinsonism 4 5.5 4 5.4 8 5.4 2 2.7 Akathisia 3 4.1 4 5.4 7 4.8 3 4.0 Dyskinetic event 2 2.7 0 0.0 2 1.4 0 0.0 Other Extrapyramidal Event 2 2.7 2 2.7 4 2.7 0 0.0 Table16 presentsa listingofpatientswith adversereactions associatedwithextrapyramidalsymptoms in a short-termplacebo-controlled monotherapytrialin childrenand adolescentpatientswith bipolarmania (3-weekduration). Table16: AdverseReactionsAssociatedwithExtrapyramidalSymptomsinaPlacebo-ControlledTrialinChildrenandAdolescentPatientswithBipolarI Mania(3-weekduration) Preferred Term1 Quetiapine 400 mg/day (N=95) Quetiapine 600 mg/day (N=98) All Quetiapine (N=193) Placebo (N=90) n % n % N % N % Parkinsonism 2 2.1 1 1.0 3 1.6 1 1.1 Akathisia 1 1.0 1 1.0 2 1.0 0 0.0 Other Extrapyramidal Event 1 1.1 1 1.0 2 1.0 0 0.0 1. Therewerenoadverseexperienceswith thepreferredtermofdystonicor dyskineticevents. O t herAdverseReactionsObservedDuringthePre-MarketingEvaluationofquetiapine FollowingisalistofCOSTARTterms thatreflecttreatment-emergentadversereactionsasdefinedin the introductiontothe ADVERSE REACTIONS sectionreportedbypatientstreatedwithquetiapine atmultipledoses >75mg/dayduring anyphaseofatrialwithinthe premarketingdatabase ofapproximately2200 patientstreatedfor schizophrenia. Allreported reactionsareincludedexceptthosealreadylistedinthetablesorelsewhereinlabeling,thosereactionsforwhich a drugcause wasremote,and those reaction termswhich weresogeneralastobeuninformative. It is importantto emphasize that, although the reactionsreported occurredduringtreatmentwithquetiapine, theywerenotnecessarilycaused byit. Reactionsarefurthercategorizedbybodysystemandlistedinorderofdecreasingfrequencyaccordingtothefollowingdefinitions:frequentadverse reactionsare those occurringin at least1/100 patients(onlythosenotalreadylistedin thetabulatedresultsfromplacebo-controlledtrialsappearin thislisting); infrequentadverse reactionsarethose occurringin 1/100to 1/1000patients;rare reactions arethoseoccurringinfewerthan1/1000patients. NervousSystem: Infrequent: abnormaldreams,dyskinesia, thinkingabnormal, tardive dyskinesia,vertigo, involuntary movements,confusion,amnesia, psychosis,hallucinations,hyperkinesia,libido increased2,urinaryretention, incoordination,paranoidreaction, abnormalgait, myoclonus,delusions, manicreaction, apathy,ataxia, depersonalization, stupor,bruxism,catatonicreaction,hemiplegia; Rare: aphasia, buccoglossalsyndrome, choreoathetosis, delirium,emotionallability,euphoria, libido decreased2,neuralgia, stuttering,subduralhematoma. Bodyas aWhole: Frequent: flusyndrome; Infrequent: neckpain, pelvicpain2suicideattempt,malaise,photosensitivity reaction, chills,face edema,moniliasis; Rare: abdomen enlarged. D i gestiveSystem: Frequent: anorexia; Infrequent: increasedsalivation,increasedappetite, gammaglutamyltranspeptidase increased, gingivitis, dysphagia, flatulence,gastroenteritis,gastritis,hemorrhoids,stomatitis,thirst,toothcaries,fecalincontinence,gastroesophagealreflux,gumhemorrhage, mouthulceration,rectalhemorrhage, tongueedema; Rare: glossitis, hematemesis,intestinalobstruction, melena,pancreatitis. CardiovascularSystem: Infrequent: vasodilatation,QTintervalprolonged,migraine, bradycardia,cerebralischemia, irregularpulse,Twaveabnormality,bundlebranchblock,cerebrovascularaccident,deep thrombophlebitis,Twaveinversion; Rare: anginapectoris, atrialfibrillation,AV blockfirstdegree,congestiveheartfailure, STelevated,thrombophlebitis,Twaveflattening, STabnormality,increased QRS duration. RespiratorySystem: Frequent: cough increased,dyspnea; Infrequent: pneumonia, epistaxis,asthma; Rare: hiccup, hyperventilation. MetabolicandNutritionalSystem: Infrequent: weightloss, alkalinephosphataseincreased,hyperlipemia,alcohol intolerance, dehydration, hyperglycemia, creatinineincreased,hypoglycemia; Rare: glycosuria,gout, handedema, hypokalemia, waterintoxication. Skin andAppendages System: Infrequent: pruritus,acne,eczema,contactdermatitis,maculopapularrash,seborrhea,skin ulcer; Rare: exfoliativedermatitis,psoriasis,skindiscoloration. U rogenitalSystem: Infrequent: dysmenorrhea2,vaginitis2,urinaryincontinence,metrorrhagia2,impotence2,dysuria,vaginalmoniliasis2,abnormalejaculation2,cystitis,urinary frequency, amenorrhea2,femalelactation2,leukorrhea2, vaginalhemorrhage2,vulvovaginitis2,orchitis2; Rare: gynecomastia2,nocturia,polyuria,acutekidneyfailure. SpecialSenses: Infrequent: conjunctivitis, abnormalvision, dryeyes, tinnitus,taste perversion, blepharitis, eyepain; Rare: abnormalityof accommodation,deafness, glaucoma. M usculoskeletalSystem: Infrequent: pathologicalfracture,myasthenia, twitching, arthralgia,arthritis,leg cramps,bone pain. H emic and LymphaticSystem: Infrequent: leukocytosis, anemia, ecchymosis,eosinophilia, hypochromicanemia;lymphadenopathy, cyanosis; Rare: hemolysis,thrombocytopenia. EndocrineSystem: Infrequent: hypothyroidism, diabetesmellitus; Rare: hyperthyroidism. 2Adjustedfor gender. Laboratory, ECGand vitalsignchanges observed in clinicalstudies LaboratoryChanges: NeutrophilCounts Adults :Inplacebo-controlledmonotherapyclinicaltrials involving3368patientsonquetiapinefumarateand 1515 on placebo,theincidenceofatleastone occurrence ofneutrophilcount<1.0x 109/Lamongpatientswith a normalbaselineneutrophilcountandatleastoneavailablefollowuplaboratorymeasurementwas0.3%(10/2967)inpatientstreatedwithquetiapinefumarate,comparedto 0.1% (2/1349)inpatientstreatedwithplacebo. [seeWarningsand Precautions (5.9)]. TransaminaseElevations Adults :Asymptomatic, transientandreversibleelevationsinserumtransaminases(primarilyALT)havebeenreported. Inschizophreniatrials inadults, theproportions ofpatientswithtransaminase elevationsof> 3times the upper limitsofthe normalreferencerangein apoolof3-to6-weekplacebo-controlledtrialswere approximately6%(29/483)for quetiapine compared to1% (3/194)for placebo.In acutebipolarmaniatrialsinadults,theproportionsof patientswithtransaminaseelevations of> 3 times theupper limitsof thenormalreferencerangein apoolof 3-to12-weekplacebo- controlledtrialswere approximately1%forboth quetiapine (3/560) andplacebo(3/294).These hepatic enzyme elevationsusuallyoccurredwithin thefirst3weeksofdrugtreatmentand promptlyreturned topre-studylevelswithongoingtreatmentwith quetiapine. In bipolardepression trials,theproportionsof patientswithtransaminaseelevations of>3timestheupperlimitsofthenormalreferencerangeintwo8-weekplacebo-controlledtrialswas1%(5/698)for quetiapine and 2% (6/347) forplacebo. DecreasedHemoglobin Adults :Inshort-termplacebo-controlled trials, decreases inhaemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasionoccurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2 %(219/3536) of patients treated with placebo. In a database of controlled anduncontrolled clinical trials, decreases in haemoglobin to ≤ 13 g/dL males, ≤ 12g/dL females on atleast one occasion occurred in 11% (2277/20729) of quetiapinetreated patients. InterferencewithUrineDrugScreens Therehavebeenliteraturereportssuggestingfalse positive resultsinurine enzyme immunoassaysformethadoneand tricyclic antidepressants inpatientswhohave takenquetiapine. Cautionshouldbeexercisedinthe interpretation of positive urinedrugscreen resultsforthesedrugs, andconfirmation byalternativeanalyticaltechnique(e.g., chromatographic methods)shouldbe considered. ECGChanges Adults: Between-group comparisonsforpooled placebo-controlledtrialsrevealed no statisticallysignificant quetiapine/placebo differencesintheproportionsofpatientsexperiencingpotentiallyimportantchangesinECGparameters,includingQT,QTc,andPR intervals.However,the proportions ofpatientsmeetingthe criteriafor tachycardia werecomparedinfour 3-to 6-weekplacebo-controlled clinicaltrials for the treatmentofschizophrenia revealinga 1%(4/399) incidenceforquetiapine compared to0.6%(1/156)incidence forplacebo. Inacute (monotherapy) bipolar maniatrials the proportions ofpatientsmeetingthe criteriafortachycardia was0.5%(1/192)for quetiapine compared to0% (0/178)incidence forplacebo. In acutebipolarmania(adjunct)trialstheproportionsof patientsmeetingthesamecriteriawas 0.6%(1/166)for quetiapine compared to0%(0/171)incidenceforplacebo. Inbipolardepressiontrials, nopatientshadheart rateincreases to> 120beatsperminute.Quetiapine use wasassociatedwitha meanincrease inheartrate, assessedbyECG,of 7 beats per minutecompared toa mean increaseof1beatper minute amongplacebopatients.Thisslighttendencytotachycardiainadultsmay be relatedtoquetiapine'spotential forinducingorthostaticchanges [see Warnings andPrecautions( 5.7 )] . Childrenand Adolescents: Intheacute(6 week)schizophreniatrialinadolescents, increases inheartrate(>110 bpm)occurredin 5.2%(3/73)ofpatientsreceivingquetiapine400 mgand 8.5%(5/74)ofpatientsreceivingquetiapine 800 mgcomparedto0%(0/75)of patientsreceivingplacebo. Mean increasesinheartratewere3.8bpmand 11.2bpmfor quetiapine 400 mgand800 mg groups, respectively,compared toa decreaseof3.3 bpmin theplacebogroup [seeWarningsand Precautions ( 5.7 )] . In theacute(3 week)bipolarmania trialinchildrenand adolescents,increasesinheartrate (>110bpm) occurredin 1.1%(1/89)ofpatientsreceivingquetiapine400 mgand 4.7% (4/85)ofpatientsreceivingquetiapine600 mg compared to 0%(0/98)ofpatients receivingplacebo.Meanincreases inheartratewere12.8bpmand 13.4 bpmforquetiapine400 mgand 600 mg groups,respectively,compared to a decrease of1.7 bpminthe placebogroup [seeWarningsandPrecautions ( 5.7 )] . 6.2 Post Marketing Experience The following adverse reactions were identified during post approval of quetiapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).