MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. The precise mechanism by which atomoxetine producesits therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD)is unknown, but is thought to be related to selective inhibition of the pre-synapticnorepinephrine transporter, as determined in ex vivo uptakeand neurotransmitter depletion studies.

STORAGE AND HANDLING SECTION.


16.2 Storage andHandling. Store at 25C (77F);excursions permitted to 15 to 30C(59 to 86F) [see USPControlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Pregnancy/Lactation Pregnant or nursingwomen should not use unless potential benefit justifies potential risk tofetus or infant. (8.1, 8.3) Hepatic Insufficiency Increased exposure(AUC) to atomoxetine thanwith normal subjects in EM subjects with moderate (Child-Pugh ClassB) (2-fold increase) and severe (Child-Pugh Class C) (4-foldincrease). (8.6) Renal Insufficiency Higher systemic exposure to atomoxetine thanhealthy subjects for EM subjects with end stage renal disease no differencewhen exposure corrected for mg/kg dose. (8.7) Patients with Concomitant Illness Doesnot worsen tics in patients with ADHD and comorbid Tourettes Disorder. (8.10) Patients with Concomitant Illness Does not worsen anxiety in patients with ADHD and comorbid Anxiety Disorders. (8.10) Pregnancy/Lactation Pregnant or nursingwomen should not use unless potential benefit justifies potential risk tofetus or infant. (8.1, 8.3) Hepatic Insufficiency Increased exposure(AUC) to atomoxetine thanwith normal subjects in EM subjects with moderate (Child-Pugh ClassB) (2-fold increase) and severe (Child-Pugh Class C) (4-foldincrease). (8.6) Renal Insufficiency Higher systemic exposure to atomoxetine thanhealthy subjects for EM subjects with end stage renal disease no differencewhen exposure corrected for mg/kg dose. (8.7) Patients with Concomitant Illness Doesnot worsen tics in patients with ADHD and comorbid Tourettes Disorder. (8.10) Patients with Concomitant Illness Does not worsen anxiety in patients with ADHD and comorbid Anxiety Disorders. (8.10) 8.1 Pregnancy. PregnancyCategory -- Pregnant rabbits were treated with up to 100 mg/kg/dayof atomoxetine by gavage throughout the period of organogenesis. At this dose,in of studies, decrease in live fetuses and an increase in early resorptionswas observed. Slight increases in the incidences of atypical origin of carotidartery and absent subclavian artery were observed. These findings were observedat doses that caused slight maternal toxicity. The no-effect dose for thesefindings was 30 mg/kg/day. The 100 mg/kg dose is approximately23 times the maximum human dose on mg/m2 basis;plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated tobe 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) thosein humans receiving the maximum human dose.Rats were treated with up to approximately 50 mg/kg/dayof atomoxetine (approximately times the maximum human dose on mg/m2 basis)in the diet from weeks (females) or 10 weeks (males) prior to mating throughthe periods of organogenesis and lactation. In of studies, decreases inpup weight and pup survival were observed. The decreased pup survival wasalso seen at 25 mg/kg (but not at 13 mg/kg).In study in which rats were treated with atomoxetine in the diet from 2weeks (females) or 10 weeks (males) prior to mating throughout the periodof organogenesis, decrease in fetal weight (female only) and an increasein the incidence of incomplete ossification of the vertebral arch in fetuseswere observed at 40 mg/kg/day (approximately times themaximum human dose on mg/m2 basis) but not at20 mg/kg/day.No adverse fetal effects were seen when pregnant rats were treated withup to 150 mg/kg/day (approximately 17 times the maximum humandose on mg/m2 basis) by gavage throughout theperiod of organogenesis.No adequate and well-controlled studies have been conducted in pregnantwomen. STRATTERA should not be used during pregnancy unless the potentialbenefit justifies the potential risk to the fetus.. 8.2 Labor and Delivery. Parturition in rats was not affected by atomoxetine.The effect of STRATTERA onlabor and delivery in humans is unknown.. 8.3 Nursing Mothers. Atomoxetine and/or its metabolites were excretedin the milk of rats. It is not known if atomoxetine isexcreted in human milk. Caution should be exercised if STRATTERA isadministered to nursing woman.. 8.4 Pediatric Use. Anyone considering the use of STRATTERA ina child or adolescent must balance the potential risks with the clinical need [seeBoxed Warning and Warnings and Precautions(5.1)].The pharmacokinetics of atomoxetine inchildren and adolescents are similar to those in adults. The safety, efficacy,and pharmacokinetics of STRATTERA inpediatric patients less than years of age have not been evaluated.A study was conducted in young rats to evaluate the effects of atomoxetineon growth and neurobehavioral and sexual development. Rats were treated with1, 10, or 50 mg/kg/day (approximately 0.2, 2, and times,respectively, the maximum human dose on mg/m2 basis)of atomoxetine given by gavage from the early postnatal period (Day 10 ofage) through adulthood. Slight delays in onset of vaginal patency (all doses)and preputial separation (10 and 50 mg/kg), slight decreasesin epididymal weight and sperm number (10 and 50 mg/kg),and slight decrease in corpora lutea (50 mg/kg) were seen,but there were no effects on fertility or reproductive performance. slightdelay in onset of incisor eruption was seen at 50 mg/kg.A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/kgand females at 50 mg/kg) and on Day 30 (females at 50 mg/kg)but not on Day 60 of age. There were no effects on learning and memory tests.The significance of these findings to humans is unknown.. 8.5 Geriatric Use. The safety, efficacy and pharmacokinetics of STRATTERA ingeriatric patients have not been evaluated.. 8.6 Hepatic Insufficiency. Atomoxetine exposure (AUC) is increased, compared with normal subjects,in EM subjects with moderate (Child-Pugh Class B) (2-foldincrease) and severe (Child-Pugh Class C) (4-foldincrease) hepatic insufficiency. Dosage adjustment is recommended for patientswith moderate or severe hepatic insufficiency [see Dosageand Administration (2.3)].. 8.7 Renal Insufficiency. EM subjects with end stage renal disease hadhigher systemic exposure to atomoxetine than healthy subjects (about 65% increase), but therewas no difference when exposure was corrected for mg/kg dose. STRATTERA cantherefore be administered to ADHD patients with end stage renal disease orlesser degrees of renal insufficiency using the normal dosing regimen.. 8.8 Gender. Gender did not influence atomoxetine disposition.. 8.9 Ethnic Origin. Ethnic origin did not influence atomoxetine disposition(except that PMs are more common in Caucasians).. 8.10 Patients with Concomitant Illness. Tics inpatients with ADHD and comorbid Tourettes Disorder --Atomoxetine administered in flexible dose range of 0.5 to 1.5 mg/kg/day(mean dose of 1.3 mg/kg/day) and placebo were compared in 148 randomized pediatric(age 7-17 years) subjects with DSM-IV diagnosis of ADHD and comorbid ticdisorder in an 18 week, double- blind, placebo-controlled study in which themajority (80%) enrolled in this trial with Tourettes Disorder (TourettesDisorder: 116 subjects; chronic motor tic disorder: 29 subjects). non-inferiorityanalysis revealed that STRATTERA did not worsen tics in these patients asdetermined by the Yale Global Tic Severity Scale Total Score (YGTSS). Outof 148 patients who entered the acute treatment phase, 103 (69.6%) patientsdiscontinued the study. The primary reason for discontinuation in both theatomoxetine (38 of 76 patients, 50.0%) and placebo (45 of 72 patients, 62.5%)treatment groups was identified as lack of efficacy with most of the patientsdiscontinuing at Week 12. This was the first visit where patients with CGI-S>=4could also meet the criteria for clinical non-responder (CGI-Sremained the same or increased from study baseline) and be eligible to enteran open-label extension study with atomoxetine.Anxiety in patients with ADHD and comorbid Anxiety Disorders In two post-marketing, double-blind, placebo-controlled trials, it has been demonstrated that treating patients with ADHD and comorbid anxiety disorders with STRATTERA does not worsen their anxiety.In 12-week double-blind, placebo-controlled trial, 176 patients, aged 8-17, who met DSM-IV criteria for ADHD and at least one of the anxiety disorders of separation anxiety disorder, generalized anxiety disorder or social phobia were randomized. Following 2-week double-blind placebo lead-in, STRATTERA was initiated at 0.8 mg/kg/day with increase to target dose of 1.2 mg/kg/day (median dose 1.30 mg/kg/day +/- 0.29 mg/kg/day). STRATTERA did not worsen anxiety in these patients as determined by the Pediatric Anxiety Rating Scale (PARS). Of the 158 patients who completed the double-blind placebo lead-in, 26 (16%) patients discontinued the study.In separate 16-week, double-blind, placebo-controlled trial, 442 patients aged 18-65, who met DSM-IV criteria for adult ADHD and social anxiety disorder (23% of whom also had Generalized Anxiety Disorder) were randomized. Following 2-week double-blind placebo lead-in, STRATTERA was initiated at 40 mg/day to maximum dose of 100 mg/day (mean daily dose 83 mg/day +/- 19.5 mg/day). STRATTERA did not worsen anxiety in these patients as determined by the Liebowitz Social Anxiety Scale (LSAS). Of the 436 patients who completed the double-blind placebo lead-in, 172 (39.4%) patients discontinued the study.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Suicidal Ideation Monitor for suicidality, clinicalworsening, and unusual changes in behavior. (5.1) Severe Liver Injury Should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury. (5.2) Serious Cardiovascular Events Sudden death, strokeand myocardial infarction have been reported in association with atomoxetinetreatment. Patients should have careful history and physical exam to assessfor presence of cardiovascular disease. STRATTERA generally should not be used in children or adolescents with known seriousstructural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities,or other serious cardiac problems that may place them at increased vulnerabilityto its noradrenergic effects. Consideration should be given to not using STRATTERA inadults with clinically significant cardiac abnormalities. (5.3) Emergent Cardiovascular Symptoms Patients shouldundergo prompt cardiac evaluation. (5.3) Effects on Blood Pressure and Heart Rate Canincrease blood pressure and heart rate; orthostasis, syncope and Raynaudsphenomenon may occur. Use with caution in patients with hypertension, tachycardia,or cardiovascular or cerebrovascular disease. (5.4). Emergent Psychotic or Manic Symptoms Considerdiscontinuing treatment if such new symptoms occur. (5.5) Bipolar Disorder Screen patients to avoid possibleinduction of mixed/manic episode. (5.6) Aggressive behavior or hostility should be monitored. (5.7) Possible allergic reactions, including angioneuroticedema, urticaria, and rash. (5.8) Effects on Urine Outflow Urinary hesitancy andretention may occur. (5.9) Priapism Prompt medical attention is requiredin the event of suspected priapism. (5.10, 17.5) Growth Height and weight should be monitoredin pediatric patients. (5.11) Concomitant Use of Potent CYP2D6 Inhibitors or Use in patients known to be CYP2D6 PMs- Doseadjustment of STRATTERA may be necessary. (5.13) Suicidal Ideation Monitor for suicidality, clinicalworsening, and unusual changes in behavior. (5.1) Severe Liver Injury Should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury. (5.2) Serious Cardiovascular Events Sudden death, strokeand myocardial infarction have been reported in association with atomoxetinetreatment. Patients should have careful history and physical exam to assessfor presence of cardiovascular disease. STRATTERA generally should not be used in children or adolescents with known seriousstructural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities,or other serious cardiac problems that may place them at increased vulnerabilityto its noradrenergic effects. Consideration should be given to not using STRATTERA inadults with clinically significant cardiac abnormalities. (5.3) Emergent Cardiovascular Symptoms Patients shouldundergo prompt cardiac evaluation. (5.3) Effects on Blood Pressure and Heart Rate Canincrease blood pressure and heart rate; orthostasis, syncope and Raynaudsphenomenon may occur. Use with caution in patients with hypertension, tachycardia,or cardiovascular or cerebrovascular disease. (5.4). Emergent Psychotic or Manic Symptoms Considerdiscontinuing treatment if such new symptoms occur. (5.5) Bipolar Disorder Screen patients to avoid possibleinduction of mixed/manic episode. (5.6) Aggressive behavior or hostility should be monitored. (5.7) Possible allergic reactions, including angioneuroticedema, urticaria, and rash. (5.8) Effects on Urine Outflow Urinary hesitancy andretention may occur. (5.9) Priapism Prompt medical attention is requiredin the event of suspected priapism. (5.10, 17.5) Growth Height and weight should be monitoredin pediatric patients. (5.11) Concomitant Use of Potent CYP2D6 Inhibitors or Use in patients known to be CYP2D6 PMs- Doseadjustment of STRATTERA may be necessary. (5.13) Figure 1. 5.1 Suicidal Ideation. STRATTERA increasedthe risk of suicidal ideation in short-term studies in children andadolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Pooledanalyses of short-term (6 to 18 weeks) placebo-controlled trialsof STRATTERA inchildren and adolescents have revealed greater risk of suicidal ideationearly during treatment in those receiving STRATTERA.There were total of 12 trials (11 in ADHD and in enuresis) involving over2200 patients (including 1357 patients receiving STRATTERA and851 receiving placebo). The average risk of suicidal ideation in patientsreceiving STRATTERA was0.4% (5/1357 patients), compared to none in placebo-treated patients.There was suicide attempt among these approximately 2200 patients, occurringin patient treated with STRATTERA. No suicides occurred in thesetrials. All reactions occurred in children 12 years of age or younger.All reactions occurred during the first month of treatment. It is unknownwhether the risk of suicidal ideation in pediatric patients extends to longer-termuse. similar analysis in adult patients treated with STRATTERA foreither ADHD or major depressive disorder (MDD) did not reveal an increasedrisk of suicidal ideation or behavior in association with the use of STRATTERA.Allpediatric patients being treated with STRATTERA should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusualchanges in behavior, especially during the initial few months of course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms have been reported with STRATTERA:anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness,impulsivity, akathisia (psychomotor restlessness), hypomania and mania. Althougha causal link between the emergence of such symptoms and the emergence ofsuicidal impulses has not been established, there is concern that such symptomsmay represent precursors to emerging suicidality. Thus, patients being treatedwith STRATTERA shouldbe observed for the emergence of such symptoms.Consideration should be given to changing thetherapeutic regimen, including possibly discontinuing the medication, in patientswho are experiencing emergent suicidality or symptoms that might be precursorsto emerging suicidality, especially if these symptoms are severe or abruptin onset, or were not part of the patients presenting symptoms.Familiesand caregivers of pediatric patients being treated with STRATTERA shouldbe alerted about the need to monitor patients for the emergence of agitation,irritability, unusual changes in behavior, and the other symptoms describedabove, as well as the emergence of suicidality, and to report such symptomsimmediately to healthcare providers. Such monitoring should include dailyobservation by families and caregivers.. 5.2 Severe Liver Injury. Postmarketing reports indicate that STRATTERA cancause severe liver injury. Although no evidence of liver injurywas detected in clinical trials of about 6000 patients, there have been rarecases of clinically significant liver injury that were considered probablyor possibly related to STRATTERA usein postmarketing experience. Because of probable underreporting, it is impossibleto provide an accurate estimate of the true incidence of these reactions. Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in the majority of cases and some patients presented with markedly elevated liver enzymes [>20 upper limit of normal (ULN)], and jaundice with significantly elevated bilirubin levels (>2 ULN), followed by recovery upon atomoxetine discontinuation.In one patient, liver injury, manifested by elevated hepatic enzymes up to40 upper limit of normal ULN and jaundice with bilirubin up to 12 ULN, recurred upon rechallenge, and was followedby recovery upon drug discontinuation, providing evidence that STRATTERA likelycaused the liver injury. Such reactions may occur several months after therapyis started, but laboratory abnormalities may continue to worsen for severalweeks after drug is stopped. The patient described above recovered from hisliver injury, and did not require liver transplant. However, severe liverinjury due to any drug may potentially progress to acute liver failure resultingin death or the need for liver transplant.STRATTERA shouldbe discontinued in patients with jaundice or laboratory evidence of liverinjury, and should not be restarted. Laboratory testing to determine liver enzymelevels should be done upon the first symptom or sign of liver dysfunction(e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, orunexplained flu like symptoms) [see Warnings and Precautions(5.12); Patient Counseling Information (17.3)].. 5.3 Serious Cardiovascular Events. SuddenDeath and Pre-existing Structural Cardiac Abnormalities or Other Serious HeartProblemsChildrenand Adolescents -- Sudden death has been reported in associationwith atomoxetine treatmentat usual doses in children and adolescents with structural cardiac abnormalitiesor other serious heart problems. Although some serious heart problems alonecarry an increased risk of sudden death, atomoxetine generallyshould not be used in children or adolescents with known serious structuralcardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities,or other serious cardiac problems that may place them at increased vulnerabilityto the noradrenergic effects of atomoxetine.Adults --Sudden deaths, stroke, and myocardial infarction have been reported in adultstaking atomoxetine atusual doses for ADHD. Although the role of atomoxetine inthese adult cases is also unknown, adults have greater likelihood than childrenof having serious structural cardiac abnormalities, cardiomyopathy, seriousheart rhythm abnormalities, coronary artery disease, or other serious cardiacproblems. Consideration should be given to not treating adults with clinicallysignificant cardiac abnormalities.AssessingCardiovascular Status in Patients being Treated with AtomoxetineChildren, adolescents, or adults who are being considered for treatmentwith atomoxetine shouldhave careful history (including assessment for family history of suddendeath or ventricular arrhythmia) and physical exam to assess for the presenceof cardiac disease, and should receive further cardiac evaluation if findingssuggest such disease (e.g., electrocardiogram and echocardiogram). Patientswho develop symptoms such as exertional chest pain, unexplained syncope, orother symptoms suggestive of cardiac disease during atomoxetine treatmentshould undergo prompt cardiac evaluation.. 5.4 Effects on Blood Pressure and Heart Rate. STRATTERA shouldbe used with caution in patients with hypertension, tachycardia, or cardiovascularor cerebrovascular disease because it can increase blood pressure and heartrate. Pulse and blood pressure should be measured at baseline, following STRATTERA doseincreases, and periodically while on therapy.In pediatric placebo-controlled trials, STRATTERA-treatedsubjects experienced mean increase in heart rate of about beats/minutecompared with placebo subjects. At the final study visit before drug discontinuation, 2.5% (36/1434)of STRATTERA-treatedsubjects had heart rate increases of at least 25 beats/minuteand heart rate of at least 110 beats/minute, compared with0.2% (2/850) of placebo subjects. There were 1.1% (15/1417) pediatric STRATTERA-treated subjects with aheart rate increase of at least 25 beats/minute and heartrate of at least 110 beats/minute on more than one occasion.Tachycardia was identified as an adverse event for 0.3% (5/1597) of these pediatric subjects compared with0% (0/934) of placebo subjects.The mean heart rate increase in extensive metabolizer (EM)patients was 5.0 beats/minute, and in poormetabolizer (PM) patients 9.4 beats/minute.STRATTERA-treatedpediatric subjects experienced mean increases of about 1.6and 2.4 mm Hg in systolic anddiastolic blood pressures, respectively compared withplacebo. At the final study visit before drug discontinuation, 4.8% (59/1226) of STRATTERA-treatedpediatric subjects had high systolic blood pressure measurements comparedwith 3.5% (26/748) of placebo subjects. High systolic bloodpressures were measured on or more occasions in 4.4% (54/1226)of STRATTERA-treatedsubjects and 1.9% (14/748) of placebo subjects. At the final studyvisit before drug discontinuation, 4.0% (50/1262) of STRATTERA-treatedpediatric subjects had high diastolic blood pressure measurements comparedwith 1.1% (8/759) of placebo subjects. High diastolic bloodpressures were measured on or more occasionsin 3.5% (44/1262) of STRATTERA-treatedsubjects and 0.5% (4/759) of placebo subjects. (High systolic anddiastolic blood pressure measurements were defined as those exceeding the95th percentile, stratified byage, gender, and height percentile National HighBlood Pressure Education Working Group on Hypertension Control in Childrenand Adolescents.)In adult placebo-controlled trials, STRATTERA-treatedsubjects experienced mean increase in heart rate of beats/minutecompared with placebo subjects. Tachycardia was identified as an adverse eventfor 1.5% (8/540) of these adult atomoxetine subjectscompared with 0.5% (2/402) of placebo subjects.STRATTERA-treatedadult subjects experienced mean increases in systolic (about 2.0 mm Hg)and diastolic (about 1.0 mm Hg)blood pressures compared with placebo. At the final study visit before drugdiscontinuation, 2.2% (11/510) of STRATTERA-treated adult subjects had systolic blood pressure measurements >=150 mm Hgcompared with 1.0% (4/393) of placebo subjects. At the final studyvisit before drug discontinuation, 0.4% (2/510) of STRATTERA-treated adult subjects had diastolic blood pressure measurements >=100 mm Hg compared with 0.5% (2/393) of placebo subjects. No adult subject hada high systolic or diastolic blood pressure detected on more than one occasion.Orthostatic hypotension and syncope have beenreported in patients taking STRATTERA.In child and adolescent trials, 0.2% (12/5596) of STRATTERA-treated patientsexperienced orthostatic hypotension and 0.8% (46/5596) experienced syncope.In short-term child and adolescent controlled trials, 1.8% (6/340)of STRATTERA-treatedpatients experienced orthostatic hypotension compared with 0.5% (1/207) ofplacebo-treated patients. Syncope was not reported during short-term childand adolescent placebo-controlled ADHD trials. STRATTERA shouldbe used with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes.Peripheralvascular effects -- There have been spontaneous postmarketingreports of Raynauds phenomenon (new onset and exacerbation of preexistingcondition).. 5.5 Emergence of New Psychotic or Manic Symptoms. Treatment emergent psychotic or manic symptoms, e.g., hallucinations,delusional thinking, or mania in children and adolescents without prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to possiblecausal role of atomoxetine, and discontinuation of treatment should be considered. In pooled analysisof multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.2% (4 patients with reactions out of 1939 exposed to atomoxetine for several weeks at usual doses) of atomoxetine-treated patients compared to out of 1056 placebo-treated patients.. 5.6 Screening Patients for Bipolar Disorder. In general, particular care should be taken intreating ADHD in patients with comorbid bipolar disorder because of concernfor possible induction of mixed/manic episode in patients at risk for bipolardisorder. Whether any of the symptoms described above represent such conversionis unknown. However, prior to initiating treatment with STRATTERA,patients with comorbid depressive symptoms should be adequately screened todetermine if they are at risk for bipolar disorder; such screening shouldinclude detailed psychiatric history, including family history of suicide,bipolar disorder, and depression.. 5.7 Aggressive Behavior or Hostility. Patients beginning treatment for ADHD shouldbe monitored for the appearance or worsening of aggressive behavior or hostility.Aggressive behavior or hostility is often observed in children and adolescentswith ADHD. In short-term controlled clinical trials, 21/1308 (1.6%) of atomoxetine patients versus 9/806 (1.1%) of placebo-treated patientsspontaneously reported treatment emergent hostility-related adverse events.Although this is not conclusive evidence that STRATTERA causesaggressive behavior or hostility, these behaviors were more frequently observedin clinical trials among children and adolescents treated with STRATTERA comparedto placebo (overall risk ratio of 1.33 [95% C.I. 0.67-2.64- not statistically significant]).. 5.8 Allergic Events. Although uncommon, allergic reactions, includingangioneurotic edema, urticaria, and rash, have been reported in patients taking STRATTERA.. 5.9 Effects on Urine Outflow from the Bladder. In adult ADHD controlled trials, the rates ofurinary retention (1.7%, 9/540) and urinary hesitation (5.6%, 30/540) were increased among atomoxetine subjectscompared with placebo subjects (0%, 0/402; 0.5%, 2/402, respectively). Two adult atomoxetine subjectsand no placebo subjects discontinued from controlled clinical trials becauseof urinary retention. complaint of urinary retention or urinary hesitancyshould be considered potentially related to atomoxetine.. 5.10 Priapism. Rare postmarketing cases of priapism, defined as painful and nonpainfulpenile erection lasting more than hours, have been reported for pediatricand adult patients treated with STRATTERA.The erections resolved in cases in which follow-up information was available,some following discontinuation of STRATTERA.Prompt medical attention is required in the event of suspected priapism.. 5.11 Effects on Growth. Data on the long-term effects of STRATTERA ongrowth come from open-label studies, and weight and height changes arecompared to normative population data. In general, the weight and height gainof pediatric patients treated with STRATTERA lagsbehind that predicted by normative population data for about the first 9-12 monthsof treatment. Subsequently, weight gain rebounds and at about yearsof treatment, patients treated with STRATTERA havegained 17.9 kg on average, 0.5 kg more thanpredicted by their baseline data. After about 12 months,gain in height stabilizes, and at years, patients treatedwith STRATTERA havegained 19.4 cm on average, 0.4 cm less thanpredicted by their baseline data (see Figure 1below). Figure 1: Mean Weight and Height PercentilesOver Time for Patients With Three Years of STRATTERA TreatmentThis growth pattern was generally similar regardlessof pubertal status at the time of treatment initiation. Patients who werepre-pubertal at the start of treatment (girls <=8 yearsold, boys <=9 years old) gained an averageof 2.1 kg and 1.2 cm less than predictedafter three years. Patients who were pubertal (girls >8 to <=13 years old, boys >9 to <=14 yearsold) or late pubertal (girls >13 years old,boys >14 years old) had average weight andheight gains that were close to or exceeded those predicted after three yearsof treatment.Growth followed similar pattern in both extensiveand poor metabolizers (EMs, PMs). PMs treated for at leasttwo years gained an average of 2.4 kg and1.1 cm less than predicted, while EMs gained an average of0.2 kg and 0.4 cm less than predicted.In short-term controlled studies (up to9 weeks), STRATTERA-treatedpatients lost an average of 0.4 kg and gained an averageof 0.9 cm, compared to gain of 1.5 kgand 1.1 cm in the placebo-treated patients. In fixed-dosecontrolled trial, 1.3%, 7.1%, 19.3%, and 29.1% of patients lost at least 3.5% oftheir body weight in the placebo, 0.5, 1.2, and 1.8 mg/kg/daydose groups.Growth should be monitored during treatment with STRATTERA.. 5.12 Laboratory Tests. Routine laboratory tests are not required.CYP2D6metabolism -- Poor metabolizers (PMs) ofCYP2D6 have 10-fold higher AUC and 5-fold higher peak concentrationto given dose of STRATTERA comparedwith extensive metabolizers (EMs). Approximately 7% of aCaucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs.The blood levels in PMs are similar to those attained by taking strong inhibitorsof CYP2D6. The higher blood levels in PMs lead to higher rate of some adverseeffects of STRATTERA [see AdverseReactions (6.1)].. 5.13 Concomitant Use of Potent CYP2D6 Inhibitors or Use in patients who are known to be CYP2D6 PMs. Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine.Dosage adjustment of STRATTERA maybe necessary when coadministered with potent CYP2D6 inhibitors (e.g., paroxetine,fluoxetine, and quinidine) or when administered to CYP2D6 PMs. [see Dosage and Administration (2.3) andDrug Interactions (7.2)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. STRATTERA(R) Capsules10 mgAtomoxetine baseequivalent.18 mg25 mg40 mg60 mg80 mg100 mgColorOpaque White,Opaque WhiteGold,Opaque WhiteOpaque Blue,Opaque WhiteOpaque Blue,Opaque BlueOpaque Blue,GoldOpaque Brown,Opaque WhiteOpaque Brown,Opaque BrownIdentificationLILLY 3227LILLY 3238LILLY 3228LILLY 3229LILLY 3239LILLY 3250LILLY 325110 mg18 mg25 mg40 mg60 mg80 mg100 mgNDCCodes:Bottlesof 300002-3227-300002-3238-300002-3228-300002-3229-300002-3239-300002-3250-300002-3251-30. 16.2 Storage andHandling. Store at 25C (77F);excursions permitted to 15 to 30C(59 to 86F) [see USPControlled Room Temperature].

ABUSE SECTION.


9.2 Abuse. In randomized, double-blind, placebo-controlled,abuse-potential study in adults comparing effects of STRATTERA andplacebo, STRATTERA wasnot associated with pattern of response that suggested stimulant or euphoriantproperties.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. Most commonadverse reactions (>=5% and at least twice the incidence of placebo patients)Child and Adolescent Clinical Trials Nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. (6.1) Adult Clinical Trials Constipation, dry mouth,nausea, fatigue, decreased appetite, insomnia, erectile dysfunction, urinaryhesitation and/or urinary retention and/or dysuria, dysmenorrhea, and hot flush. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Child and Adolescent Clinical Trials Nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. (6.1) Adult Clinical Trials Constipation, dry mouth,nausea, fatigue, decreased appetite, insomnia, erectile dysfunction, urinaryhesitation and/or urinary retention and/or dysuria, dysmenorrhea, and hot flush. (6.1) 6.1 Clinical Trials Experience. STRATTERA wasadministered to 5382 childrenor adolescent patients with ADHD and 1007 adults with ADHD in clinicalstudies. During the ADHD clinical trials, 1625children and adolescent patients were treatedfor longer than year and 2529children and adolescent patients were treatedfor over months.Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinicaltrials of drug cannot be directly compared to rates in the clinical trialsof another drug and may not reflect the rates observed in practice. Child and AdolescentClinical TrialsReasons for discontinuation of treatment due to adversereactions in child and adolescent clinical trials --In acute child and adolescent placebo-controlled trials, 3.0% (48/1613)of atomoxetine subjectsand 1.4% (13/945) placebo subjectsdiscontinued for adverse reactions. For all studies, (including open-labeland long-term studies), 6.3% of extensive metabolizer (EM)patients and 11.2% of poor metabolizer (PM)patients discontinued because of an adverse reaction. Among STRATTERA-treatedpatients, irritability (0.3%, N=5); somnolence(0.3%, N=5); aggression (0.2%, N=4); nausea (0.2%, N=4); vomiting (0.2%,N=4); abdominal pain (0.2%, N=4); constipation(0.1%, N=2); fatigue (0.1%, N=2); feeling abnormal (0.1%, N=2); and headache(0.1%, N=2) were the reasons for discontinuation reported by morethan patient.Seizures -- STRATTERA hasnot been systematically evaluated in pediatric patients with seizure disorderas these patients were excluded from clinical studies during the productspremarket testing. In the clinical development program, seizures were reportedin 0.2% (12/5073) of children whose average age was 10 years (range to 16years). In these clinical trials, the seizure risk among poor metabolizerswas 0.3% (1/293) compared to 0.2% (11/4741) for extensive metabolizers.Commonly observed adverse reactions in acute child andadolescent, placebo-controlled trials --Commonly observed adverse reactions associated with the use of STRATTERA (incidenceof 2% or greater) and not observed at an equivalent incidenceamong placebo-treated patients (STRATTERA incidence greater than placebo) are listed in Table 1.Results were similar in the BIDand the QD trial except as shown in Table 2,which shows both BID and QD results for selected adversereactions based on statisticallysignificant Breslow-Day tests. The most commonly observed adversereactions in patients treated with STRATTERA (incidenceof 5% or greater and at least twice the incidence in placebo patients, foreither BID or QD dosing) were: nausea, vomiting,fatigue, decreased appetite, abdominalpain, and somnolence (see Tables and 2).Table 1: Common Treatment-Emergent AdverseReactions Associated with the Use of STRATTERA inAcute (up to 18 weeks) Child and AdolescentTrialsAdverse ReactionPercentage of Patients Reporting ReactionSTRATTERA(N=1597)Placebo(N=934)GastrointestinalDisorders Abdominal pain 1810 Vomiting116 Nausea105GeneralDisorders and Administration Site Conditions Fatigue83 Irritability63 Therapeutic responseunexpected21Investigations Weight decreased30Metabolismand Nutritional Disorders Decreased appetite164 Anorexia31NervousSystem Disorders Headache1915 Somnolence 114 Dizziness52Skinand Subcutaneous Tissue Disorders Rash21Table 2: Common Treatment-Emergent Adverse ReactionsAssociated with the Use of STRATTERA inAcute (up to 18 weeks) Child and AdolescentTrialsAdverse ReactionPercentage of Patients Reporting Reaction from BIDTrialsPercentage of Patients Reporting Reaction from QDTrialsSTRATTERA(N=715)Placebo(N=434)STRATTERA(N=882)Placebo(N=500)GastrointestinalDisorders Abdominal pain 1713187 Vomiting118114 Nausea76134 Constipation 2110GeneralDisorders Fatigue6492PsychiatricDisorders Mood swings 2011Thefollowing adverse reactions occurred in at least 2% of PM patients and wereeither twice as frequent or statistically significantly more frequent in PMpatients compared with EM patients: insomnia (15% of PMs, 10% of EMs); weightdecreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression (7% of PMs, 4% of EMs); tremor (5%of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); conjunctivitis 3%of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening(2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs).Adult ClinicalTrialsReasons for discontinuation of treatment due to adversereactions in acute adult placebo-controlled trials --In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjectsand 3.0% (12/405) placebo subjects discontinued for adversereactions. Among STRATTERA-treatedpatients, insomnia (0.9%, N=5); nausea(0.9%, N=5); chest pain (0.6%, N=3); fatigue (0.6%, N=3);anxiety (0.4%, N=2); erectile dysfunction (0.4%, N=2);mood swings (0.4%, N=2); nervousness (0.4%, N=2);palpitations (0.4%, N=2); and urinary retention (0.4%, N=2) werethe reasons for discontinuation reported by more than patient.Seizures -- STRATTERA hasnot been systematically evaluated in adult patients with seizure disorderas these patients were excluded from clinical studies during the productspremarket testing. In the clinical development program, seizures were reportedon 0.1% (1/748) of adult patients. In these clinical trials, no poor metabolizers(0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers.Commonly observed adverse reactions in acute adult placebo-controlledtrials -- Commonly observed adverse reactions associated withthe use of STRATTERA (incidenceof 2% or greater) and not observed at an equivalent incidence among placebo-treatedpatients (STRATTERA incidencegreater than placebo) are listed in Table 3. The most commonlyobserved adverse reactions in patients treated with STRATTERA (incidenceof 5% or greater and at least twice the incidence in placebo patients) were: constipation,dry mouth, nausea, fatigue, decreased appetite, insomnia, erectile dysfunction, urinaryhesitation and/or urinary retention and/or dysuria, dysmenorrhea, and hot flush (see Table 3).Table 3: Common Treatment-Emergent Adverse ReactionsAssociated with the Use of STRATTERA inAcute (up to 25 weeks) Adult TrialsAdverse ReactionPercentage of Patients Reporting ReactionSystem Organ Class/AdverseReactionSTRATTERA(N=540)Placebo(N=402)CardiacDisorders Palpitations31GastrointestinalDisorders Dry mouth217 Nausea215 Constipation93 Abdominal pain 75 Dyspepsia42 Vomiting32GeneralDisorders and Administration Site Conditions Fatigue 94 Chills31 Therapeutic responseunexpected31 Feeling jittery20Investigations Weight decreased21Metabolismand Nutritional Disorders Decreased appetite 112NervousSystem Disorders Dizziness64 Somnolence 43 Sinus headache31 Tremor20PsychiatricDisorders Insomnia 157 Libido decreased42 Sleep disorder31Renaland Urinary Disorders Urinary hesitationand/or urinary retention 71 Dysuria30ReproductiveSystem and Breast Disorders Erectile dysfunctionBased on total numberof males (STRATTERA, N=326; placebo, N=260). 91 Dysmenorrhea Basedon total number of females (STRATTERA, N=214; placebo, N=142). 62 Ejaculation delayed and/or ejaculation disorder 31 Menstruation irregular 20Skinand Subcutaneous Tissue Disorders Hyperhidrosis41 Rash21VascularDisorders Hot flush81Male and female sexual dysfunction -- Atomoxetine appearsto impair sexual function in some patients. Changes in sexual desire, sexualperformance, and sexual satisfaction are not well assessed in most clinicaltrials because they need special attention and because patients and physiciansmay be reluctant to discuss them. Accordingly, estimates of the incidenceof untoward sexual experience and performance cited in product labeling arelikely to underestimate the actual incidence. Table above displays the incidence of sexual side effects reported by at least 2% of adult patients taking STRATTERA in placebo-controlled trials.There are no adequate and well-controlledstudies examining sexual dysfunction with STRATTERA treatment.While it is difficult to know the precise risk of sexual dysfunction associatedwith the use of STRATTERA,physicians should routinely inquire about such possible side effects.. 6.2 Postmarketing Spontaneous Reports. The following adverse reactions have beenidentified during post approval use of STRATTERA. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from population ofuncertain size, it is not always possible to reliably estimate their frequencyor establish causal relationship to drug exposure.Cardiovascular system -- QT prolongation,syncope.General disorders and administration site conditions -- Lethargy.Nervous system disorders -- Hypoaesthesia; paraesthesia in children and adolescents; sensory disturbances.Seizures -- Seizures have been reportedin the postmarketing period. The postmarketing seizure cases include patientswith pre-existing seizure disorders and those with identified risk factorsfor seizures, as well as patients with neither history of nor identifiedrisk factors for seizures. The exact relationship between STRATTERA andseizures is difficult to evaluate due to uncertainty about the backgroundrisk of seizures in ADHD patients.Urogenital system --Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.

BOXED WARNING SECTION.


WARNING: SUICIDALIDEATION IN CHILDREN AND ADOLESCENTS. STRATTERA (atomoxetine)increased the risk of suicidal ideation in short-term studies in childrenor adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD).Anyone considering the use of STRATTERA ina child or adolescent must balance this risk with the clinical need. Co-morbidities occurring with ADHD may be associated with an increase in the risk of suicidal ideation and/or behavior. Patientswho are started on therapy should be monitored closely for suicidality (suicidalthinking and behavior), clinical worsening, or unusual changes in behavior.Families and caregivers should be advised of the need for close observationand communication with the prescriber. STRATTERA is approved for ADHD in pediatric and adult patients. STRATTERA isnot approved for major depressive disorder.Pooled analysesof short-term (6 to 18 weeks) placebo-controlled trials of STRATTERA inchildren and adolescents (a total of 12 trials involving over 2200 patients,including 11 trials in ADHD and trial in enuresis) have revealed greaterrisk of suicidal ideation early during treatment in those receiving STRATTERA comparedto placebo. The average risk of suicidal ideation in patients receiving STRATTERA was0.4% (5/1357 patients), compared to none in placebo-treated patients(851 patients). No suicides occurred in these trials [seeWarnings and Precautions (5.1)].. WARNING: SUICIDALIDEATION IN CHILDREN AND ADOLESCENTSSee full prescribing information for complete boxed warning.Increased risk of suicidal ideation in childrenor adolescents (5.1)No suicides occurred in clinical trials (5.1)Patients started on therapy should be monitoredclosely (5.1). Increased risk of suicidal ideation in childrenor adolescents (5.1). No suicides occurred in clinical trials (5.1). Patients started on therapy should be monitoredclosely (5.1).

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. STRATTERA(R) is selective norepinephrine reuptake inhibitor indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). (1.1) 1.1 Attention-Deficit/Hyperactivity Disorder (ADHD). STRATTERA isindicated for the treatment of Attention-Deficit/Hyperactivity Disorder(ADHD).The efficacy of STRATTERA Capsules was established in seven clinical trials in outpatients with ADHD: four to 9-week trials in pediatric patients (ages to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages to 15) [see Clinical Studies (14)]. 1.2 Diagnostic Considerations. diagnosis of ADHD (DSM-IV)implies the presence of hyperactive-impulsive or inattentive symptomsthat cause impairment and that were present before age years.The symptoms must be persistent, must be more severe than is typically observedin individuals at comparable level of development, must cause clinicallysignificant impairment, e.g., in social, academic, or occupationalfunctioning, and must be present in or more settings, e.g., school(or work) and at home. The symptoms must not be better accounted for by anothermental disorder.The specific etiology of ADHD is unknown, andthere is no single diagnostic test. Adequate diagnosis requires the use notonly of medical but also of special psychological, educational, and socialresources. Learning may or may not be impaired. The diagnosis must be basedupon complete history and evaluation of the patient and not solely on thepresence of the required number of DSM-IV characteristics.For the Inattentive Type, at least of the following symptoms musthave persisted for at least months: lack of attention todetails/careless mistakes, lack of sustained attention, poor listener, failureto follow through on tasks, poor organization, avoids tasks requiring sustainedmental effort, loses things, easily distracted, forgetful. For the Hyperactive-ImpulsiveType, at least of the following symptoms must have persisted for at least6 months: fidgeting/squirming, leaving seat, inappropriate running/climbing,difficulty with quiet activities, on the go, excessive talking,blurting answers, cant wait turn, intrusive. For Combined Type diagnosis,both inattentive and hyperactive-impulsive criteria must be met.. 1.3 Need for Comprehensive Treatment Program. STRATTERA isindicated as an integral part of total treatment program for ADHD that mayinclude other measures (psychological, educational, social) for patients withthis syndrome. Drug treatment may not be indicated for all patients with thissyndrome. Drug treatment is not intended for use in the patient who exhibitssymptoms secondary to environmental factors and/or other primary psychiatricdisorders, including psychosis. Appropriate educational placement is essentialin children and adolescents with this diagnosis and psychosocial interventionis often helpful. When remedial measures alone are insufficient, the decisionto prescribe drug treatment medication will depend upon the physiciansassessment of the chronicity and severity of the patients symptoms.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. See FDA-approvedMedication Guide.. 17.1 General Information. Physicians should instruct their patients to read the Medication Guidebefore starting therapy with STRATTERA and to reread it each time the prescriptionis renewed.Prescribers or other health professionals shouldinform patients, their families, and their caregivers about the benefits andrisks associated with treatment with STRATTERA and should counsel them in its appropriate use. The prescriber or health professional should instruct patients, their families, and their caregiversto read the Medication Guide and should assist them in understanding its contents.Patients should be given the opportunity to discuss the contents of the MedicationGuide and to obtain answers to any questions they may have.Patients should be advised of the following issuesand asked to alert their prescriber if these occur while taking STRATTERA.. 17.2 Suicide Risk. Patients, their families, and their caregiversshould be encouraged to be alert to the emergence of anxiety, agitation, panicattacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia(psychomotor restlessness), hypomania, mania, other unusual changes in behavior,depression, and suicidal ideation, especially early during STRATTERA treatmentand when the dose is adjusted. Families and caregivers of patients shouldbe advised to observe for the emergence of such symptoms on day-to-daybasis, since changes may be abrupt. Such symptoms should be reported to thepatients prescriber or health professional, especially if they aresevere, abrupt in onset, or were not part of the patients presentingsymptoms. Symptoms such as these may be associated with an increased riskfor suicidal thinking and behavior and indicate need for very close monitoringand possibly changes in the medication.. 17.3 Severe Liver Injury. Patients initiating STRATTERA shouldbe cautioned that severe liver injury may develop. Patients shouldbe instructed to contact their physician immediately should they develop pruritus,dark urine, jaundice, right upper quadrant tenderness, or unexplained flu-likesymptoms [see Warnings and Precautions (5.2)].. 17.4 Aggression or Hostility. Patients should be instructed to call their doctoras soon as possible should they notice an increase in aggression or hostility.. 17.5 Priapism. Rare postmarketing cases of priapism, defined as painful and nonpainfulpenile erection lasting more than hours, have been reported for pediatricand adult patients treated with STRATTERA.The parents or guardians of pediatric patients taking STRATTERA andadult patients taking STRATTERA shouldbe instructed that priapism requires prompt medical attention.. 17.6 Ocular Irritant. STRATTERA isan ocular irritant. STRATTERA capsulesare not intended to be opened. In the event of capsule content coming in contactwith the eye, the affected eye should be flushed immediately with water, andmedical advice obtained. Hands and any potentially contaminated surfaces shouldbe washed as soon as possible.. 17.7 Drug-Drug Interaction. Patients should be instructed to consult physicianif they are taking or plan to take any prescription or over-the-countermedicines, dietary supplements, or herbal remedies.. 17.8 Pregnancy. Patients should be instructed to consult physicianif they are nursing, pregnant, or thinking of becoming pregnant while taking STRATTERA.. 17.9 Food. Patients may take STRATTERA withor without food.. 17.10 Missed Dose. If patients miss dose, they should be instructedto take it as soon as possible, but should not take more than the prescribedtotal daily amount of STRATTERA inany 24-hour period.. 17.11 Interference with Psychomotor Performance. Patients should be instructed to use cautionwhen driving car or operating hazardous machinery until they are reasonablycertain that their performance is not affected by atomoxetine.

LABOR & DELIVERY SECTION.


8.2 Labor and Delivery. Parturition in rats was not affected by atomoxetine.The effect of STRATTERA onlabor and delivery in humans is unknown.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis -- Atomoxetine HClwas not carcinogenic in rats and mice when given in the diet for yearsat time-weighted average doses up to 47 and 458 mg/kg/day,respectively. The highest dose used in rats is approximately and timesthe maximum human dose in children and adults, respectively, on mg/m2 basis.Plasma levels (AUC) of atomoxetine at this dose in rats are estimated to be 1.8 times (extensivemetabolizers) or 0.2 times (poor metabolizers) those in humansreceiving the maximum human dose. The highest dose used in mice is approximately39 and 26 times the maximumhuman dose in children and adults, respectively, on mg/m2 basis.Mutagenesis -- Atomoxetine HClwas negative in battery of genotoxicity studies that included reversepoint mutation assay (Ames Test), an in vitromouse lymphoma assay, chromosomal aberration test in Chinese hamster ovarycells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivomicronucleus test in mice. However, there was slight increase in the percentageof Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication(numerical aberration).The metabolite N-desmethylatomoxetine HClwas negative in the Ames Test, mouse lymphoma assay, andunscheduled DNA synthesis test.Impairmentof fertility -- Atomoxetine HCl did not impair fertility in rats when given in thediet at doses of up to 57 mg/kg/day, which is approximately6 times the maximum human dose on mg/m2 basis.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The precise mechanism by which atomoxetine producesits therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD)is unknown, but is thought to be related to selective inhibition of the pre-synapticnorepinephrine transporter, as determined in ex vivo uptakeand neurotransmitter depletion studies.. 12.2 Pharmacodynamics. An exposure-response analysis encompassingdoses of atomoxetine (0.5,1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposurecorrelates with efficacy as measured by the Attention-Deficit/HyperactivityDisorder Rating Scale-IV-Parent Version: Investigator administeredand scored. The exposure-efficacy relationship was similar to that observedbetween dose and efficacy with median exposures at the two highest doses resultingin near maximal changes from baseline [see Clinical Studies (14.2)].. 12.3 Pharmacokinetics. Atomoxetine is well-absorbed after oral administration and is minimally affectedby food. It is eliminated primarily by oxidative metabolism through the cytochromeP450 2D6 (CYP2D6) enzymatic pathway andsubsequent glucuronidation. Atomoxetine has half-life of about hours. fraction of thepopulation (about 7% of Caucasians and 2% ofAfrican Americans) are poor metabolizers (PMs) of CYP2D6metabolized drugs. These individuals have reduced activity in this pathwayresulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations,and slower elimination (plasma half-life of about 24 hours)of atomoxetine comparedwith people with normal activity [extensive metabolizers (EMs)].Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine,cause similar increases in exposure.The pharmacokinetics of atomoxetine havebeen evaluated in more than 400 children and adolescentsin selected clinical trials, primarily using population pharmacokinetic studies.Single-dose and steady-state individual pharmacokinetic data werealso obtained in children, adolescents, and adults. When doses were normalizedto mg/kg basis, similar half-life, Cmax,and AUC values were observed in children, adolescents, andadults. Clearance and volume of distribution after adjustment for body weightwere also similar.Absorptionand distribution -- Atomoxetine israpidly absorbed after oral administration, with absolute bioavailabilityof about 63% in EMs and 94% in PMs. Maximalplasma concentrations (Cmax) are reachedapproximately to hours after dosing.STRATTERA canbe administered with or without food. Administration of STRATTERA witha standard high-fat meal in adults did not affect the extent of oralabsorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in 37% lowerCmax, and delayed Tmax by hours.In clinical trials with children and adolescents, administration of STRATTERA withfood resulted in 9% lower Cmax.The steady-state volume of distributionafter intravenous administration is 0.85 L/kg indicatingthat atomoxetine distributesprimarily into total body water. Volume of distribution is similar acrossthe patient weight range after normalizing for body weight.At therapeutic concentrations, 98% of atomoxetine inplasma is bound to protein, primarily albumin.Metabolismand elimination -- Atomoxetine ismetabolized primarily through the CYP2D6 enzymatic pathway. People with reducedactivity in this pathway (PMs) have higher plasma concentrationsof atomoxetine comparedwith people with normal activity (EMs). For PMs, AUC of atomoxetine isapproximately 10-fold and Css,max is about 5-foldgreater than EMs. Laboratory tests are available to identify CYP2D6 PMs.Coadministration of STRATTERA withpotent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine,results in substantial increase in atomoxetine plasmaexposure, and dosing adjustment may be necessary [see Warnings and Precautions(5.13)]. Atomoxetine didnot inhibit or induce the CYP2D6 pathway.The major oxidative metabolite formed, regardlessof CYP2D6 status, is 4-hydroxyatomoxetine,which is glucuronidated. 4-Hydroxyatomoxetine isequipotent to atomoxetine asan inhibitor of the norepinephrine transporter but circulates in plasma atmuch lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentrationin PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine isformed at slower rate by several other cytochrome P450enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes,but has substantially less pharmacological activity compared with atomoxetine andcirculates in plasma at lower concentrations (5% of atomoxetine concentrationin EMs and 45% of atomoxetine concentrationin PMs).Mean apparent plasma clearance of atomoxetine afteroral administration in adult EMs is 0.35 L/hr/kg and themean half-life is 5.2 hours. Following oral administrationof atomoxetine toPMs, mean apparent plasma clearance is 0.03 L/hr/kg and meanhalf-life is 21.6 hours. For PMs, AUC of atomoxetine isapproximately 10-fold and Css,max is about 5-foldgreater than EMs. The elimination half-life of 4-hydroxyatomoxetine issimilar to that of N-desmethylatomoxetine (6 to hours)in EM subjects, while the half-life of N-desmethylatomoxetine ismuch longer in PM subjects (34 to 40 hours).Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide,mainly in the urine (greater than 80% of the dose) and toa lesser extent in the feces (less than 17% of the dose).Only small fraction of the STRATTERA doseis excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation.[See Use In Specific Populations(8.4,8.5,8.6, 8.7,8.8, 8.9)].

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 ADHD studies in Children and Adolescents. Acute Studies -- The effectiveness of STRATTERA inthe treatment of ADHD was established in randomized, double-blind,placebo-controlled studies of pediatric patients (ages to 18).Approximately one-third of the patients met DSM-IV criteria forinattentive subtype and two-thirds met criteria for both inattentiveand hyperactive/impulsive subtypes.Signs and symptoms of ADHD wereevaluated by comparison of mean change from baseline to endpoint for STRATTERA-and placebo-treated patients using an intent-to-treat analysisof the primary outcome measure, the investigator administered and scored ADHDRating Scale-IV-Parent Version (ADHDRS) totalscore including hyperactive/impulsive and inattentive subscales. Each texton the ADHDRS maps directly to one symptom criterion forADHD in the DSM-IV.In Study 1,an 8-week randomized, double-blind, placebo-controlled,dose-response, acute treatment study of children and adolescents aged to 18 (N=297), patients received either fixed dose of STRATTERA (0.5,1.2, or 1.8 mg/kg/day) or placebo. STRATTERA wasadministered as divided dose in the early morning and late afternoon/earlyevening. At the higher doses, improvements in ADHD symptomswere statistically significantly superior in STRATTERA-treatedpatients compared with placebo-treated patients as measured on the ADHDRSscale. The 1.8 mg/kg/day STRATTERA dosedid not provide any additional benefit over that observed with the 1.2 mg/kg/daydose. The 0.5 mg/kg/day STRATTERA dosewas not superior to placebo.In Study 2,a 6-week randomized, double-blind, placebo-controlled, acutetreatment study of children and adolescents aged to 16 (N=171),patients received either STRATTERA orplacebo. STRATTERA wasadministered as single dose in the early morning and titrated on weight-adjustedbasis according to clinical response, up to maximum dose of 1.5 mg/kg/day.The mean final dose of STRATTERA wasapproximately 1.3 mg/kg/day. ADHD symptoms were statisticallysignificantly improved on STRATTERA comparedwith placebo, as measured on the ADHDRS scale. This study shows that STRATTERA iseffective when administered once daily in the morning.In identical,9-week, acute, randomized, double-blind, placebo-controlledstudies of children aged to 13(Study 3, N=147; Study 4, N=144), STRATTERA andmethylphenidate were compared with placebo. STRATTERA wasadministered as divided dose in the early morning and late afternoon (afterschool) and titrated on weight-adjusted basis according to clinicalresponse. The maximum recommended STRATTERA dosewas 2.0 mg/kg/day. The mean final dose of STRATTERA forboth studies was approximately 1.6 mg/kg/day. In both studies,ADHD symptoms statistically significantly improved more on STRATTERA thanon placebo, as measured on the ADHDRS scale.Examination of population subsetsbased on gender and age (<12 and 12 to 17)did not reveal any differential responsiveness on the basis of these subgroupings.There was not sufficient exposure of ethnic groups other than Caucasian toallow exploration of differences in these subgroups.Maintenance Study -- The effectiveness of STRATTERA in the maintenance treatment of ADHD was established in an outpatient study of children and adolescents (ages 6-15 years). Patients meeting DSM-IV criteria for ADHD who showed continuous response for about weeks during an initial 10 week open-label treatment phase with STRATTERA (1.2 to 1.8 mg/kg/day) were randomized to continuation of their current dose of STRATTERA (N=292) or to placebo (N=124) under double-blind treatment for observation of relapse. Response during the open-label phase was defined as CGI-ADHD-S score <=2 and reduction of at least 25% from baseline in ADHDRS-IV-Parent:Inv total score. Patients who were assigned to STRATTERA and showed continuous response for approximately months during the first double-blind treatment phase were again randomized to continuation of their current dose of STRATTERA (N=81) or to placebo (N=82) under double-blind treatment for observation of relapse. Relapse during the double-blind phase was defined as CGI-ADHD-S score increases of at least from the end of open-label phase and ADHDRS-IV-Parent:Inv total score returns to >=90% of study entry score for consecutive visits. In both double-blind phases, patients receiving continued STRATTERA treatment experienced significantly longer times to relapse than those receiving placebo.. 14.2 ADHD studies in Adults. The effectiveness of STRATTERA inthe treatment of ADHD was established in randomized, double-blind,placebo-controlled clinical studies of adult patients, age 18and older, who met DSM-IV criteria for ADHD.Signs and symptoms of ADHD wereevaluated using the investigator-administered Conners Adult ADHD RatingScale Screening Version (CAARS), 30-text scale. Theprimary effectiveness measure was the 18-text Total ADHD Symptom score(the sum of the inattentive and hyperactivity/impulsivity subscales from theCAARS) evaluated by comparison of mean change from baseline to endpointusing an intent-to-treat analysis.In identical,10-week, randomized, double-blind, placebo-controlled acutetreatment studies (Study 5, N=280; Study 6,N=256), patients received either STRATTERA orplacebo. STRATTERA wasadministered as divided dose in the early morning and late afternoon/earlyevening and titrated according to clinical response in range of 60 to 120 mg/day.The mean final dose of STRATTERA forboth studies was approximately 95 mg/day. In both studies,ADHD symptoms were statistically significantly improved on STRATTERA,as measured on the ADHD Symptom score from the CAARS scale.Examination of population subsetsbased on gender and age (<42 and >=42)did not reveal any differential responsiveness on the basis of these subgroupings.There was not sufficient exposure of ethnic groups other than Caucasian toallow exploration of differences in these subgroups.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. Hypersensitivity to atomoxetine orother constituents of product. (4.1) STRATTERA use within weeks after discontinuing MAOIor other drugs that affect brain monoamine concentrations. (4.2, 7.1) Narrow Angle Glaucoma. (4.3) Hypersensitivity to atomoxetine orother constituents of product. (4.1) STRATTERA use within weeks after discontinuing MAOIor other drugs that affect brain monoamine concentrations. (4.2, 7.1) Narrow Angle Glaucoma. (4.3) 4.1 Hypersensitivity. STRATTERA iscontraindicated in patients known to be hypersensitive to atomoxetine orother constituents of the product [see Warningsand Precautions (5.7)].. 4.2 Monoamine Oxidase Inhibitors (MAOI). STRATTERA shouldnot be taken with an MAOI, or within weeks after discontinuingan MAOI. Treatment with an MAOI should not be initiated within weeksafter discontinuing STRATTERA. With other drugs that affect brain monoamine concentrations, there have beenreports of serious, sometimes fatal reactions (including hyperthermia, rigidity,myoclonus, autonomic instability with possible rapid fluctuations of vitalsigns, and mental status changes that include extreme agitation progressingto delirium and coma) when taken in combination with an MAOI. Some cases presentedwith features resembling neuroleptic malignant syndrome. Such reactions mayoccur when these drugs are given concurrently or in close proximity [seeDrug Interactions (7.1)].. 4.3 Narrow Angle Glaucoma. In clinical trials, STRATTERA usewas associated with an increased risk of mydriasis and therefore its use isnot recommended in patients with narrow angle glaucoma.

CONTROLLED SUBSTANCE SECTION.


9.1 Controlled Substance. STRATTERA isnot controlled substance.

DEPENDENCE SECTION.


9.3 Dependence. Clinical study data in over 2000 children,adolescents, and adults with ADHD and over 1200 adults withdepression showed only isolated incidents of drug diversion or inappropriateself-administration associated with STRATTERA.There was no evidence of symptom rebound or adverse reactions suggesting adrug-discontinuation or withdrawal syndrome.Animal Experience --Drug discrimination studies in rats and monkeys showed inconsistent stimulusgeneralization between atomoxetine and cocaine.

DESCRIPTION SECTION.


11 DESCRIPTION. STRATTERA(R) (atomoxetine HCl)is selective norepinephrine reuptake inhibitor. Atomoxetine HClis the R(-)isomer as determined by x-ray diffraction. The chemical designationis (-)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylaminehydrochloride. The molecular formula is C17H21NOoHCl,which corresponds to molecular weight of 291.82.The chemical structure is:Atomoxetine HClis white to practically white solid, which has solubility of 27.8 mg/mLin water.STRATTERA capsulesare intended for oral administration only.Each capsule contains atomoxetine HClequivalent to 10, 18, 25, 40, 60, 80, or 100 mgof atomoxetine.The capsules also contain pregelatinized starch and dimethicone. The capsuleshells contain gelatin, sodium lauryl sulfate, and other inactive ingredients.The capsule shells also contain one or more of the following:FD&C Blue No. 2, synthetic yellowiron oxide, titanium dioxide, red iron oxide. The capsules are imprinted withedible black ink.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Initial, Target and Maximum Daily Dose (2.1) Body WeightInitial Daily DoseTarget Total Daily DoseMaximum Total Daily DoseChildren andadolescents up to 70 kg0.5 mg/kg1.2 mg/kg1.4 mg/kgChildren andadolescents over 70 kg and adults40 mg80 mg100 mgDosing adjustment -- Hepatic Impairment, Strong CYP2D6 Inhibitor, and in patients known to be CYP2D6 poor metabolizers (PMs). (2.4, 12.3) 2.1 Acute Treatment. Dosingof children and adolescents up to 70 kg body weight -- STRATTERA shouldbe initiated at total daily dose of approximately 0.5 mg/kgand increased after minimum of days to target totaldaily dose of approximately 1.2 mg/kg administered eitheras single daily dose in the morning or as evenly divided doses in the morningand late afternoon/early evening. No additional benefit has been demonstratedfor doses higher than 1.2 mg/kg/day [see ClinicalStudies (14)].The total daily dose in children and adolescents should notexceed 1.4 mg/kg or 100 mg, whichever isless.Dosingof children and adolescents over 70 kg body weight and adults -- STRATTERA shouldbe initiated at total daily dose of 40 mg and increasedafter minimum of days to target total daily dose ofapproximately 80 mg administered either as single dailydose in the morning or as evenly divided doses in the morning and late afternoon/earlyevening. After to additionalweeks, the dose may be increased to maximum of 100 mg inpatients who have not achieved an optimal response. There are no data thatsupport increased effectiveness at higher doses [see ClinicalStudies (14)].The maximum recommended total daily dose in children and adolescentsover 70 kg and adults is 100 mg.. 2.2 Maintenance/Extended Treatment. It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The benefit of maintaining pediatric patients (ages 6-15 years) with ADHD on STRATTERA after achieving response in dose range of 1.2 to 1.8 mg/kg/day was demonstrated in controlled trial. Patients assigned to STRATTERA in the maintenance phase were generally continued on the same dose used to achieve response in the open label phase. The physician who elects to use STRATTERA for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient [see Clinical Studies (14.1)]. 2.3 General Dosing Information. STRATTERA maybe taken with or without food.STRATTERA canbe discontinued without being tapered.STRATTERA capsules are not intended to be opened,they should be taken whole [see Patient Counseling Information (17.6)]. The safety of single doses over 120 mg andtotal daily doses above 150 mg have not been systematicallyevaluated.. 2.4 Dosing in Specific Populations. Dosingadjustment for hepatically impaired patients -- For thoseADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommendedas follows: For patients with moderate HI (Child-PughClass B), initial and target doses should be reduced to 50% ofthe normal dose (for patients without HI). For patients with severe HI (Child-PughClass C), initial dose and target doses should be reducedto 25% of normal [see Use In Specific Populations(8.6)].Dosingadjustment for use with strong CYP2D6 inhibitor or in patients who are known to be CYP2D6 PMs -- In childrenand adolescents up to 70 kg body weight administered strongCYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, STRATTERA shouldbe initiated at 0.5 mg/kg/day and only increased to the usualtarget dose of 1.2 mg/kg/day if symptoms fail to improveafter weeks and the initial dose is well tolerated.In children and adolescents over 70 kg bodyweight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine,fluoxetine, and quinidine, STRATTERA shouldbe initiated at 40 mg/day and only increased to the usualtarget dose of 80 mg/day if symptoms fail to improve after4 weeks and the initial dose is well tolerated.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Each capsule contains atomoxetine HCl equivalentto 10 mg (Opaque White, Opaque White), 18 mg(Gold, Opaque White), 25 mg (Opaque Blue, Opaque White),40 mg (Opaque Blue, Opaque Blue), 60 mg(Opaque Blue, Gold), 80 mg (Opaque Brown, Opaque White),or 100 mg (Opaque Brown, Opaque Brown) of atomoxetine.. Each capsule contains atomoxetine HCl equivalentto 10, 18, 25, 40, 60, 80, or 100 mg of atomoxetine. (3, 11, 16).

DRUG ABUSE AND DEPENDENCE SECTION.


9 DRUG ABUSE AND DEPENDENCE. 9.1 Controlled Substance. STRATTERA isnot controlled substance.. 9.2 Abuse. In randomized, double-blind, placebo-controlled,abuse-potential study in adults comparing effects of STRATTERA andplacebo, STRATTERA wasnot associated with pattern of response that suggested stimulant or euphoriantproperties.. 9.3 Dependence. Clinical study data in over 2000 children,adolescents, and adults with ADHD and over 1200 adults withdepression showed only isolated incidents of drug diversion or inappropriateself-administration associated with STRATTERA.There was no evidence of symptom rebound or adverse reactions suggesting adrug-discontinuation or withdrawal syndrome.Animal Experience --Drug discrimination studies in rats and monkeys showed inconsistent stimulusgeneralization between atomoxetine and cocaine.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Monoamine Oxidase Inhibitors. (4.2, 7.1) CYP2D6 Inhibitors Concomitant use may increase atomoxetine steady-state plasma concentrations in EMs. (7.2) Pressor Agents Possible effects on bloodpressure. (7.3) Albuterol (or other beta2 agonists)- Action of albuterol on cardiovascular system can be potentiated. (7.4) Monoamine Oxidase Inhibitors. (4.2, 7.1) CYP2D6 Inhibitors Concomitant use may increase atomoxetine steady-state plasma concentrations in EMs. (7.2) Pressor Agents Possible effects on bloodpressure. (7.3) Albuterol (or other beta2 agonists)- Action of albuterol on cardiovascular system can be potentiated. (7.4) 7.1 Monoamine Oxidase Inhibitors. With other drugs that affect brain monoamineconcentrations, there have been reports of serious, sometimes fatal reactions(including hyperthermia, rigidity, myoclonus, autonomic instability with possiblerapid fluctuations of vital signs, and mental status changes that includeextreme agitation progressing to delirium and coma) when taken in combinationwith an MAOI. Some cases presented with features resembling neuroleptic malignantsyndrome. Such reactions may occur when these drugs are given concurrentlyor in close proximity [see Contraindications (4.2)].. 7.2 Effect of CYP2D6 Inhibitors on Atomoxetine. In extensive metabolizers (EMs), inhibitors ofCYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-stateplasma concentrations to exposures similar to those observed in poor metabolizers(PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine isapproximately 6- to 8-fold andCss,max is about 3- to 4-foldgreater than atomoxetine alone.In vitro studies suggest thatcoadministration of cytochrome P450 inhibitors to PMs willnot increase the plasma concentrations of atomoxetine.. 7.3 Pressor Agents. Because of possible effects on blood pressure, STRATTERA shouldbe used cautiously with pressor agents (e.g., dopamine, dobutamine).. 7.4 Albuterol. STRATTERA shouldbe administered with caution to patients being treated with systemically-administered(oral or intravenous) albuterol (or other beta2 agonists)because the action of albuterol on the cardiovascular system can be potentiatedresulting in increases in heart rate and blood pressure. Albuterol (600 mcg ivover hours) induced increases in heart rate and blood pressure.These effects were potentiated by atomoxetine (60 mg BID for days) and were most markedafter the initial coadministration of albuterol and atomoxetine.However, these effects on heart rate and blood pressure were not seen in anotherstudy after the coadministration with inhaled dose of albuterol (200-800 mcg)and atomoxetine (80 mg QD for days) in 21 healthy Asian subjects who wereexcluded for poor metabolizer status.. 7.5 Effect of Atomoxetine on P450 Enzymes. Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.CYP3A Substrate(e.g., Midazolam) -- Coadministration of STRATTERA (60 mgBID for 12 days) with midazolam, model compound for CYP3A4metabolized drugs (single dose of mg), resulted in 15%increase in AUC of midazolam. No dose adjustment is recommended for drugsmetabolized by CYP3A.CYP2D6Substrate (e.g., Desipramine) -- Coadministration of STRATTERA (40 or60 mg BID for 13 days) with desipramine,a model compound for CYP2D6 metabolized drugs (single dose of 50 mg),did not alter the pharmacokinetics of desipramine. No dose adjustment is recommendedfor drugs metabolized by CYP2D6.. 7.6 Alcohol. Consumption of ethanol with STRATTERA didnot change the intoxicating effects of ethanol.. 7.7 Methylphenidate. Coadministration of methylphenidate with STRATTERA didnot increase cardiovascular effects beyond those seen with methylphenidatealone.. 7.8 Drugs Highly Bound to Plasma Protein. In vitro drug-displacementstudies were conducted with atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine didnot affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepamto human albumin. Similarly, these compounds did not affect the binding of atomoxetine tohuman albumin.. 7.9 Drugs that Affect Gastric pH. Drugs that elevate gastric pH(magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on STRATTERA bioavailability.

GERIATRIC USE SECTION.


8.5 Geriatric Use. The safety, efficacy and pharmacokinetics of STRATTERA ingeriatric patients have not been evaluated.

LABORATORY TESTS SECTION.


5.12 Laboratory Tests. Routine laboratory tests are not required.CYP2D6metabolism -- Poor metabolizers (PMs) ofCYP2D6 have 10-fold higher AUC and 5-fold higher peak concentrationto given dose of STRATTERA comparedwith extensive metabolizers (EMs). Approximately 7% of aCaucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs.The blood levels in PMs are similar to those attained by taking strong inhibitorsof CYP2D6. The higher blood levels in PMs lead to higher rate of some adverseeffects of STRATTERA [see AdverseReactions (6.1)].

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis -- Atomoxetine HClwas not carcinogenic in rats and mice when given in the diet for yearsat time-weighted average doses up to 47 and 458 mg/kg/day,respectively. The highest dose used in rats is approximately and timesthe maximum human dose in children and adults, respectively, on mg/m2 basis.Plasma levels (AUC) of atomoxetine at this dose in rats are estimated to be 1.8 times (extensivemetabolizers) or 0.2 times (poor metabolizers) those in humansreceiving the maximum human dose. The highest dose used in mice is approximately39 and 26 times the maximumhuman dose in children and adults, respectively, on mg/m2 basis.Mutagenesis -- Atomoxetine HClwas negative in battery of genotoxicity studies that included reversepoint mutation assay (Ames Test), an in vitromouse lymphoma assay, chromosomal aberration test in Chinese hamster ovarycells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivomicronucleus test in mice. However, there was slight increase in the percentageof Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication(numerical aberration).The metabolite N-desmethylatomoxetine HClwas negative in the Ames Test, mouse lymphoma assay, andunscheduled DNA synthesis test.Impairmentof fertility -- Atomoxetine HCl did not impair fertility in rats when given in thediet at doses of up to 57 mg/kg/day, which is approximately6 times the maximum human dose on mg/m2 basis.

NURSING MOTHERS SECTION.


8.3 Nursing Mothers. Atomoxetine and/or its metabolites were excretedin the milk of rats. It is not known if atomoxetine isexcreted in human milk. Caution should be exercised if STRATTERA isadministered to nursing woman.

OVERDOSAGE SECTION.


10 OVERDOSAGE. 10.1 Human Experience. Nofatal overdoses occurred in clinical trials. There is limited clinical trialexperience with STRATTERA overdose.During postmarketing, there have been fatalities reported involving mixedingestion overdose of STRATTERA andat least one other drug. There have been no reports of death involving overdoseof STRATTERA alone,including intentional overdoses at amounts up to 1400 mg. In some cases ofoverdose involving STRATTERA, seizures have been reported. The most commonlyreported symptoms accompanying acute and chronic overdoses of STRATTERA weresomnolence, agitation, hyperactivity, abnormal behavior, and gastrointestinalsymptoms. Signs and symptoms consistent with mild to moderate sympatheticnervous system activation (e.g., mydriasis, tachycardia,dry mouth) have also been observed. Less commonly, there have been reportsof QT prolongation and mental changes, including disorientation and hallucinations.. 10.2 Management of Overdose. Anairway should be established. Monitoring of cardiac and vital signs is recommended,along with appropriate symptomatic and supportive measures. Gastric lavagemay be indicated if performed soon after ingestion. Activated charcoal maybe useful in limiting absorption. Because atomoxetine ishighly protein-bound, dialysis is not likely to be useful in the treatmentof overdose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


STRATTER 18MG LABEL IMAGE STRATTER 18MG LABEL IMAGE.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Anyone considering the use of STRATTERA ina child or adolescent must balance the potential risks with the clinical need [seeBoxed Warning and Warnings and Precautions(5.1)].The pharmacokinetics of atomoxetine inchildren and adolescents are similar to those in adults. The safety, efficacy,and pharmacokinetics of STRATTERA inpediatric patients less than years of age have not been evaluated.A study was conducted in young rats to evaluate the effects of atomoxetineon growth and neurobehavioral and sexual development. Rats were treated with1, 10, or 50 mg/kg/day (approximately 0.2, 2, and times,respectively, the maximum human dose on mg/m2 basis)of atomoxetine given by gavage from the early postnatal period (Day 10 ofage) through adulthood. Slight delays in onset of vaginal patency (all doses)and preputial separation (10 and 50 mg/kg), slight decreasesin epididymal weight and sperm number (10 and 50 mg/kg),and slight decrease in corpora lutea (50 mg/kg) were seen,but there were no effects on fertility or reproductive performance. slightdelay in onset of incisor eruption was seen at 50 mg/kg.A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/kgand females at 50 mg/kg) and on Day 30 (females at 50 mg/kg)but not on Day 60 of age. There were no effects on learning and memory tests.The significance of these findings to humans is unknown.

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. An exposure-response analysis encompassingdoses of atomoxetine (0.5,1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposurecorrelates with efficacy as measured by the Attention-Deficit/HyperactivityDisorder Rating Scale-IV-Parent Version: Investigator administeredand scored. The exposure-efficacy relationship was similar to that observedbetween dose and efficacy with median exposures at the two highest doses resultingin near maximal changes from baseline [see Clinical Studies (14.2)].

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Atomoxetine is well-absorbed after oral administration and is minimally affectedby food. It is eliminated primarily by oxidative metabolism through the cytochromeP450 2D6 (CYP2D6) enzymatic pathway andsubsequent glucuronidation. Atomoxetine has half-life of about hours. fraction of thepopulation (about 7% of Caucasians and 2% ofAfrican Americans) are poor metabolizers (PMs) of CYP2D6metabolized drugs. These individuals have reduced activity in this pathwayresulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations,and slower elimination (plasma half-life of about 24 hours)of atomoxetine comparedwith people with normal activity [extensive metabolizers (EMs)].Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine,cause similar increases in exposure.The pharmacokinetics of atomoxetine havebeen evaluated in more than 400 children and adolescentsin selected clinical trials, primarily using population pharmacokinetic studies.Single-dose and steady-state individual pharmacokinetic data werealso obtained in children, adolescents, and adults. When doses were normalizedto mg/kg basis, similar half-life, Cmax,and AUC values were observed in children, adolescents, andadults. Clearance and volume of distribution after adjustment for body weightwere also similar.Absorptionand distribution -- Atomoxetine israpidly absorbed after oral administration, with absolute bioavailabilityof about 63% in EMs and 94% in PMs. Maximalplasma concentrations (Cmax) are reachedapproximately to hours after dosing.STRATTERA canbe administered with or without food. Administration of STRATTERA witha standard high-fat meal in adults did not affect the extent of oralabsorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in 37% lowerCmax, and delayed Tmax by hours.In clinical trials with children and adolescents, administration of STRATTERA withfood resulted in 9% lower Cmax.The steady-state volume of distributionafter intravenous administration is 0.85 L/kg indicatingthat atomoxetine distributesprimarily into total body water. Volume of distribution is similar acrossthe patient weight range after normalizing for body weight.At therapeutic concentrations, 98% of atomoxetine inplasma is bound to protein, primarily albumin.Metabolismand elimination -- Atomoxetine ismetabolized primarily through the CYP2D6 enzymatic pathway. People with reducedactivity in this pathway (PMs) have higher plasma concentrationsof atomoxetine comparedwith people with normal activity (EMs). For PMs, AUC of atomoxetine isapproximately 10-fold and Css,max is about 5-foldgreater than EMs. Laboratory tests are available to identify CYP2D6 PMs.Coadministration of STRATTERA withpotent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine,results in substantial increase in atomoxetine plasmaexposure, and dosing adjustment may be necessary [see Warnings and Precautions(5.13)]. Atomoxetine didnot inhibit or induce the CYP2D6 pathway.The major oxidative metabolite formed, regardlessof CYP2D6 status, is 4-hydroxyatomoxetine,which is glucuronidated. 4-Hydroxyatomoxetine isequipotent to atomoxetine asan inhibitor of the norepinephrine transporter but circulates in plasma atmuch lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentrationin PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine isformed at slower rate by several other cytochrome P450enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes,but has substantially less pharmacological activity compared with atomoxetine andcirculates in plasma at lower concentrations (5% of atomoxetine concentrationin EMs and 45% of atomoxetine concentrationin PMs).Mean apparent plasma clearance of atomoxetine afteroral administration in adult EMs is 0.35 L/hr/kg and themean half-life is 5.2 hours. Following oral administrationof atomoxetine toPMs, mean apparent plasma clearance is 0.03 L/hr/kg and meanhalf-life is 21.6 hours. For PMs, AUC of atomoxetine isapproximately 10-fold and Css,max is about 5-foldgreater than EMs. The elimination half-life of 4-hydroxyatomoxetine issimilar to that of N-desmethylatomoxetine (6 to hours)in EM subjects, while the half-life of N-desmethylatomoxetine ismuch longer in PM subjects (34 to 40 hours).Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide,mainly in the urine (greater than 80% of the dose) and toa lesser extent in the feces (less than 17% of the dose).Only small fraction of the STRATTERA doseis excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation.[See Use In Specific Populations(8.4,8.5,8.6, 8.7,8.8, 8.9)].

PREGNANCY SECTION.


8.1 Pregnancy. PregnancyCategory -- Pregnant rabbits were treated with up to 100 mg/kg/dayof atomoxetine by gavage throughout the period of organogenesis. At this dose,in of studies, decrease in live fetuses and an increase in early resorptionswas observed. Slight increases in the incidences of atypical origin of carotidartery and absent subclavian artery were observed. These findings were observedat doses that caused slight maternal toxicity. The no-effect dose for thesefindings was 30 mg/kg/day. The 100 mg/kg dose is approximately23 times the maximum human dose on mg/m2 basis;plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated tobe 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) thosein humans receiving the maximum human dose.Rats were treated with up to approximately 50 mg/kg/dayof atomoxetine (approximately times the maximum human dose on mg/m2 basis)in the diet from weeks (females) or 10 weeks (males) prior to mating throughthe periods of organogenesis and lactation. In of studies, decreases inpup weight and pup survival were observed. The decreased pup survival wasalso seen at 25 mg/kg (but not at 13 mg/kg).In study in which rats were treated with atomoxetine in the diet from 2weeks (females) or 10 weeks (males) prior to mating throughout the periodof organogenesis, decrease in fetal weight (female only) and an increasein the incidence of incomplete ossification of the vertebral arch in fetuseswere observed at 40 mg/kg/day (approximately times themaximum human dose on mg/m2 basis) but not at20 mg/kg/day.No adverse fetal effects were seen when pregnant rats were treated withup to 150 mg/kg/day (approximately 17 times the maximum humandose on mg/m2 basis) by gavage throughout theperiod of organogenesis.No adequate and well-controlled studies have been conducted in pregnantwomen. STRATTERA should not be used during pregnancy unless the potentialbenefit justifies the potential risk to the fetus.

RECENT MAJOR CHANGES SECTION.


Warning and Precautions, Severe Liver Injury (5.2) 06/2009Warnings and Precautions, Effects on Blood Pressure and Heart Rate (5.4) 09/2008Boxed Warning 07/2008Warnings and Precautions, Suicidal Ideation (5.1), Effects on Blood Pressure and Heart Rate (5.4), Effects on Urine Outflow from the Bladder (5.9) 07/2008.

SPL MEDGUIDE SECTION.


MEDICATIONGUIDE STRATTERA(R) (Stra-TAIR-a)(atomoxetine hydrochloride)Read the Medication Guide that comes with STRATTERA(R) beforeyou or your child starts taking it and each time you get refill. There maybe new information. This Medication Guide does not take the place of talkingto your doctor about your treatment or your childs treatment with STRATTERA.What is the most important information should know about STRATTERAThe followinghave been reported with use of STRATTERA:1.Suicidal thoughts and actions in children and teenagers:Children andteenagers sometimes think about suicide, and many report trying to kill themselves.Results from STRATTERA clinicalstudies with over 2200 child or teenage ADHD patients suggest that some childrenand teenagers may have higher chance of having suicidal thoughts or actions. Althoughno suicides occurred in these studies, out of every 1000 patients developedsuicidal thoughts. Tell your child or teenagers doctor if your childor teenager (or there is family history of):has bipolar illness (manic-depressive illness)had suicide thoughts or actions before starting STRATTERAThe chance forsuicidal thoughts and actions may be higher:early during STRATTERA treatmentduring dose adjustmentsPrevent suicidalthoughts and action in your child or teenager by:paying close attention to your child or teenagersmoods, behaviors, thoughts, and feelings during STRATTERA treatmentkeeping all follow-up visits with your child orteenagers doctor as scheduledWatch for thefollowing signs in your child or teenager during STRATTERA treatment:anxietyagitationpanic attackstrouble sleepingirritabilityhostilityaggressivenessimpulsivityrestlessnessmaniadepressionsuicide thoughtsCall your childor teenagers doctor right away if they have any of the above signs,especially if they are new, sudden, or severe. Your child or teenagermay need to be closely watched for suicidal thoughts and actions or need achange in medicine.2.Severe liver damage:STRATTERA cancause liver injury in some patients. Call your doctor right away if you or your child has thefollowing signs of liver problems:itchingright upper belly paindark urineyellow skin or eyesunexplained flu-like symptoms3.Heart-related problems:suddendeath in patients who have heart problems or heart defectsstrokeand heart attack in adultsincreasedblood pressure and heart rateTell your doctor if you or your child has any heart problems, heartdefects, high blood pressure, or family history of these problems. Yourdoctor should check you or your child carefully for heart problems beforestarting STRATTERA.Your doctor should check your blood pressure or your childs bloodpressure and heart rate regularly during treatment with STRATTERA.Call your doctorright away if you or your child has any signs of heart problems such as chestpain, shortness of breath, or fainting while taking STRATTERA.4.New mental (psychiatric) problems in children and teenagers:new psychotic symptoms (such as hearing voices,believing things that are not true, being suspicious) or new manic symptomsCall your childor teenagers doctor right away about any new mental symptoms becauseadjusting or stopping STRATTERA treatmentmay need to be considered.What Is STRATTERASTRATTERA isa selective norepinephrine reuptake inhibitor medicine. It is used for thetreatment of attention deficit and hyperactivity disorder (ADHD). STRATTERA mayhelp increase attention and decrease impulsiveness and hyperactivity in patientswith ADHD. STRATTERA shouldbe used as part of total treatment program for ADHD that may include counselingor other therapies. STRATTERA hasnot been studied in children less than years old.Who should not take STRATTERASTRATTERA shouldnot be taken if you or your child:are taking or have taken within the past 14 daysan anti-depression medicine called monoamine oxidase inhibitor or MAOI.Some names of MAOI medicines are Nardil(R) (phenelzinesulfate), Parnate(R) (tranylcypromine sulfate)and Emsam(R) (selegiline transdermal system).have an eye problem called narrow angle glaucomaare allergic to anything in STRATTERA.See the end of this Medication Guide for complete list of ingredients.STRATTERA maynot be right for you or your child. Before starting STRATTERA tellyour doctor or your childs doctor about all health conditions (or afamily history of) including:have or had suicide thoughts or actionsheart problems, heart defects, irregular heartbeat, high blood pressure, or low blood pressuremental problems, psychosis, mania, bipolar illness,or depressionliver problemsTell your doctor if you or your child is pregnant, planning to becomepregnant, or breastfeeding.Can STRATTERA betaken with other medicinesTell your doctorabout all the medicines that you or your child takes including prescription and nonprescriptionmedicines, vitamins, and herbal supplements. STRATTERA andsome medicines may interact with each other and cause serious side effects.Your doctor will decide whether STRATTERA canbe taken with other medicines.Especially tellyour doctor if you or your child takes:asthma medicinesanti-depression medicines including MAOIsblood pressure medicinescold or allergy medicines that contain decongestantsKnow the medicines that you or your child takes. Keep list of yourmedicines with you to show your doctor and pharmacist.Do not startany new medicine while taking STRATTERA withouttalking to your doctor first.How should STRATTERA betakenTake STRATTERA exactlyas prescribed. STRATTERA comesin different dose strength capsules. Your doctor may adjust thedose until it is right for you or your child.Donot chew, crush, or open the capsules. Swallow STRATTERA capsuleswhole with water or other liquids. Tell your doctor if you or your child cannotswallow STRATTERA whole.A different medicine may need to be prescribed.Avoid touching broken STRATTERA capsule.Wash hands and surfaces that touched an open STRATTERA capsule.If any of the powder gets in your eyes or your childs eyes, rinse themwith water right away and call your doctor.STRATTERA canbe taken with or without food.STRATTERA is usually taken once or twice day. Take STRATTERA at the same time each day to help you remember. If you miss dose of STRATTERA,take it as soon as you remember that day. If you miss day of STRATTERA,do not double your dose the next day. Just skip the day you missed.From time to time, your doctor may stop STRATTERA treatmentfor while to check ADHD symptoms.Your doctor may do regular checks of the blood,heart, and blood pressure while taking STRATTERA. Children should have their height and weight checked often while taking STRATTERA. STRATTERA treatmentmay be stopped if problem is found during these check-ups.Ifyou or your child takes too much STRATTERA oroverdoses, call your doctor or poison control center right away, or get emergencytreatment.What are possible side effects of STRATTERASee What is the most important informationI should know about STRATTERA for information on reported suicidal thoughts and actions, othermental problems, severe liver damage, and heart problems.Other seriousside effects include:serious allergic reactions (call your doctor ifyou see swelling, hives, or experience other allergic reactions)slowing of growth (height and weight) in childrenproblems passing urine includingtrouble starting or keeping urine streamcannot fully empty the bladderCommon sideeffects in children and teenagers include:upset stomachdecreased appetitenausea or vomitingdizzinesstirednessmood swingsCommon sideeffects in adults include:constipationdry mouthnauseadecreased appetitedizzinesstrouble sleepingsexual side effectsmenstrual crampsproblems passing urineOther informationfor children, teenagers, and adults:Erections that wont go away (priapism) haveoccurred rarely during treatment with STRATTERA. If you have an erection that lasts more than hours, seek medical helpright away. Because of the potential for lasting damage, including the potentialinability to have erections, priapism should be evaluated by doctor immediately.STRATTERA mayaffect your ability or your childs ability to drive or operate heavymachinery. Be careful until you know how STRATTERA affects you or your child.Talk to your doctor if you or your child has sideeffects that are bothersome or do not go away. This is not complete list of possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store STRATTERAStore STRATTERA ina safe place at room temperature, 59 to 86F (15 to 30C).Keep STRATTERA andall medicines out of the reach of children.General information about STRATTERAMedicines are sometimes prescribed for purposes other than those listedin Medication Guide. Do not use STRATTERA fora condition for which it was not prescribed. Do not give STRATTERA toother people, even if they have the same condition. It may harm them.This Medication Guide summarizes the most important information about STRATTERA.If you would like more information, talk with your doctor. You can ask yourdoctor or pharmacist for information about STRATTERA thatwas written for healthcare professionals. For more information about STRATTERA call1-800-Lilly-Rx (1-800-545-5979) or visitwww.strattera.com.What are the ingredients in STRATTERAActiveingredient: atomoxetine hydrochloride.Inactiveingredients: pregelatinized starch, dimethicone, gelatin, sodiumlauryl sulfate, FD&C Blue No. 2, synthetic yellow ironoxide, titanium dioxide, red iron oxide, and edible black ink.Nardil(R) is registeredtrademark of Pfizer Inc.Parnate(R) is registered trademark ofGlaxoSmithKline.Emsam(R) is registered trademark of SomersetPharmaceuticals Inc.ThisMedication Guide has been approved by the US Food and Drug Administration.Patient Information revised July 23, 2008Eli Lilly and CompanyIndianapolis, IN 46285,USAwww.strattera.comCopyright (C) 2003, 2008, Eli Lilly and Company. All rights reserved.PV 5854 AMP. has bipolar illness (manic-depressive illness). had suicide thoughts or actions before starting STRATTERA. early during STRATTERA treatment. during dose adjustments. paying close attention to your child or teenagersmoods, behaviors, thoughts, and feelings during STRATTERA treatment. keeping all follow-up visits with your child orteenagers doctor as scheduled. anxiety. agitation. panic attacks. trouble sleeping. irritability. hostility. aggressiveness. impulsivity. restlessness. mania. depression. suicide thoughts. itching. right upper belly pain. dark urine. yellow skin or eyes. unexplained flu-like symptoms. suddendeath in patients who have heart problems or heart defects. strokeand heart attack in adults. increasedblood pressure and heart rate. new psychotic symptoms (such as hearing voices,believing things that are not true, being suspicious) or new manic symptoms. are taking or have taken within the past 14 daysan anti-depression medicine called monoamine oxidase inhibitor or MAOI.Some names of MAOI medicines are Nardil(R) (phenelzinesulfate), Parnate(R) (tranylcypromine sulfate)and Emsam(R) (selegiline transdermal system).. have an eye problem called narrow angle glaucoma. are allergic to anything in STRATTERA.See the end of this Medication Guide for complete list of ingredients.. have or had suicide thoughts or actions. heart problems, heart defects, irregular heartbeat, high blood pressure, or low blood pressure. mental problems, psychosis, mania, bipolar illness,or depression. liver problems. asthma medicines. anti-depression medicines including MAOIs. blood pressure medicines. cold or allergy medicines that contain decongestants. Take STRATTERA exactlyas prescribed. STRATTERA comesin different dose strength capsules. Your doctor may adjust thedose until it is right for you or your child.. Donot chew, crush, or open the capsules. Swallow STRATTERA capsuleswhole with water or other liquids. Tell your doctor if you or your child cannotswallow STRATTERA whole.A different medicine may need to be prescribed.. Avoid touching broken STRATTERA capsule.Wash hands and surfaces that touched an open STRATTERA capsule.If any of the powder gets in your eyes or your childs eyes, rinse themwith water right away and call your doctor.. STRATTERA canbe taken with or without food.. STRATTERA is usually taken once or twice day. Take STRATTERA at the same time each day to help you remember. If you miss dose of STRATTERA,take it as soon as you remember that day. If you miss day of STRATTERA,do not double your dose the next day. Just skip the day you missed.. From time to time, your doctor may stop STRATTERA treatmentfor while to check ADHD symptoms.. Your doctor may do regular checks of the blood,heart, and blood pressure while taking STRATTERA. Children should have their height and weight checked often while taking STRATTERA. STRATTERA treatmentmay be stopped if problem is found during these check-ups.. Ifyou or your child takes too much STRATTERA oroverdoses, call your doctor or poison control center right away, or get emergencytreatment.. serious allergic reactions (call your doctor ifyou see swelling, hives, or experience other allergic reactions). slowing of growth (height and weight) in children. problems passing urine includingtrouble starting or keeping urine streamcannot fully empty the bladder. trouble starting or keeping urine stream. cannot fully empty the bladder. upset stomach. decreased appetite. nausea or vomiting. dizziness. tiredness. mood swings. constipation. dry mouth. nausea. decreased appetite. dizziness. trouble sleeping. sexual side effects. menstrual cramps. problems passing urine. Erections that wont go away (priapism) haveoccurred rarely during treatment with STRATTERA. If you have an erection that lasts more than hours, seek medical helpright away. Because of the potential for lasting damage, including the potentialinability to have erections, priapism should be evaluated by doctor immediately.. STRATTERA mayaffect your ability or your childs ability to drive or operate heavymachinery. Be careful until you know how STRATTERA affects you or your child.. Talk to your doctor if you or your child has sideeffects that are bothersome or do not go away. Store STRATTERA ina safe place at room temperature, 59 to 86F (15 to 30C).. Keep STRATTERA andall medicines out of the reach of children.

SPL UNCLASSIFIED SECTION.


1.1 Attention-Deficit/Hyperactivity Disorder (ADHD). STRATTERA isindicated for the treatment of Attention-Deficit/Hyperactivity Disorder(ADHD).The efficacy of STRATTERA Capsules was established in seven clinical trials in outpatients with ADHD: four to 9-week trials in pediatric patients (ages to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages to 15) [see Clinical Studies (14)].