`
`1
`
`
`
`
`STRATTERA®
`(atomoxetine HCl)
`WARNING
`Suicidal Ideation in Children and Adolescents — STRATTERA (atomoxetine) increased
`the risk of suicidal ideation in short-term studies in children or adolescents with
`Attention-Deficit/Hyperactivity Disorder (ADHD). Anyone considering the use of
`STRATTERA in a child or adolescent must balance this risk with the clinical need.
`Patients who are started on therapy should be monitored closely for suicidality (suicidal
`thinking and behavior), clinical worsening, or unusual changes in behavior. Families and
`caregivers should be advised of the need for close observation and communication with the
`prescriber. STRATTERA is approved for ADHD in pediatric and adult patients.
`STRATTERA is not approved for major depressive disorder.
`Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of STRATTERA
`in children and adolescents (a total of 12 trials involving over 2200 patients, including 11
`trials in ADHD and 1 trial in enuresis) have revealed a greater risk of suicidal ideation
`early during treatment in those receiving STRATTERA compared to placebo. The average
`risk of suicidal ideation in patients receiving STRATTERA was 0.4% (5/1357 patients),
`compared to none in placebo-treated patients (851 patients). No suicides occurred in these
`trials. (See WARNINGS and PRECAUTIONS, Pediatric Use).
`
`DESCRIPTION
`STRATTERA® (atomoxetine HCl) is a selective norepinephrine reuptake inhibitor.
`Atomoxetine HCl is the R(-) isomer as determined by x-ray diffraction. The chemical
`designation is (-)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride. The molecular
`formula is C17H21NO•HCl, which corresponds to a molecular weight of 291.82. The chemical
`structure is:
`
`
`Atomoxetine HCl is a white to practically white solid, which has a solubility of 27.8 mg/mL in
`water.
`STRATTERA capsules are intended for oral administration only.
`Each capsule contains atomoxetine HCl equivalent to 10, 18, 25, 40, 60, 80, or 100 mg of
`atomoxetine. The capsules also contain pregelatinized starch and dimethicone. The capsule shells
`
`

`

`
`
`2
`
`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 yellow iron oxide, titanium
`dioxide, red iron oxide. The capsules are imprinted with edible black ink.
`CLINICAL PHARMACOLOGY
`Pharmacodynamics and Mechanism of Action
`The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-
`Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective
`inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and
`neurotransmitter depletion studies.
`Human Pharmacokinetics
`Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is
`eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6)
`enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about
`5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are
`poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity
`in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and
`slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with 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 have been evaluated in more than 400 children and
`adolescents in selected clinical trials, primarily using population pharmacokinetic studies.
`Single-dose and steady-state individual pharmacokinetic data were also obtained in children,
`adolescents, and adults. When doses were normalized to a mg/kg basis, similar half-life, Cmax,
`and AUC values were observed in children, adolescents, and adults. Clearance and volume of
`distribution after adjustment for body weight were also similar.
`Absorption and distribution — Atomoxetine is rapidly absorbed after oral administration, with
`absolute bioavailability of about 63% in EMs and 94% in PMs. Maximal plasma concentrations
`(Cmax) are reached approximately 1 to 2 hours after dosing.
`STRATTERA can be administered with or without food. Administration of STRATTERA with
`a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine
`(AUC), but did decrease the rate of absorption, resulting in a 37% lower Cmax, and delayed Tmax
`by 3 hours. In clinical trials with children and adolescents, administration of STRATTERA with
`food resulted in a 9% lower Cmax.
`The steady-state volume of distribution after intravenous administration is 0.85 L/kg indicating
`that atomoxetine distributes primarily into total body water. Volume of distribution is similar
`across the patient weight range after normalizing for body weight.
`At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily
`albumin.
`Metabolism and elimination — Atomoxetine is metabolized primarily through the CYP2D6
`enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma
`concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC
`of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. Laboratory
`tests are available to identify CYP2D6 PMs. Coadministration of STRATTERA with potent
`inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial
`
`

`

`
`
`3
`
`increase in atomoxetine plasma exposure, and dosing adjustment may be necessary (see
`Drug-Drug Interactions). Atomoxetine did not inhibit or induce the CYP2D6 pathway.
`The major oxidative metabolite formed, regardless of CYP2D6 status, is
`4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is equipotent to
`atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much
`lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine
`concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs,
`4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes.
`N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has
`substantially less pharmacological activity compared with atomoxetine and circulates in plasma
`at lower concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine
`concentration in PMs).
`Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is
`0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to
`PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs,
`AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. The
`elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to
`8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much 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 to a lesser extent in the feces (less than 17% of the
`dose). Only a small fraction of the STRATTERA dose is excreted as unchanged atomoxetine
`(less than 3% of the dose), indicating extensive biotransformation.
`Special Populations
`Hepatic insufficiency — Atomoxetine exposure (AUC) is increased, compared with normal
`subjects, in EM subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe
`(Child-Pugh Class C) (4-fold increase) hepatic insufficiency. Dosage adjustment is
`recommended for patients with moderate or severe hepatic insufficiency (see DOSAGE AND
`ADMINISTRATION).
`Renal insufficiency — EM subjects with end stage renal disease had higher systemic exposure
`to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when
`exposure was corrected for mg/kg dose. STRATTERA can therefore be administered to ADHD
`patients with end stage renal disease or lesser degrees of renal insufficiency using the normal
`dosing regimen.
`Geriatric — The pharmacokinetics of atomoxetine have not been evaluated in the geriatric
`population.
`Pediatric — The pharmacokinetics of atomoxetine in children and adolescents are similar to
`those in adults. The pharmacokinetics of atomoxetine have not been evaluated in children under
`6 years of age.
`Gender — Gender did not influence atomoxetine disposition.
`Ethnic origin — Ethnic origin did not influence atomoxetine disposition (except that PMs are
`more common in Caucasians).
`Drug-Drug Interactions
`CYP2D6 activity and atomoxetine plasma concentration — Atomoxetine is primarily
`metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs, inhibitors of CYP2D6
`increase atomoxetine steady-state plasma concentrations to exposures similar to those observed
`
`

`

`
`
`4
`
`in PMs. Dosage adjustment of STRATTERA in EMs may be necessary when coadministered
`with CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine (see Drug-Drug Interactions
`under PRECAUTIONS). In vitro studies suggest that coadministration of cytochrome P450
`inhibitors to PMs will not increase the plasma concentrations of atomoxetine.
`Effect of atomoxetine on P450 enzymes — Atomoxetine did not cause clinically important
`inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6,
`and CYP2C9.
`Albuterol — Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood
`pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most
`marked after the initial coadministration of albuterol and atomoxetine (see Drug-Drug
`Interactions under PRECAUTIONS).
`Alcohol — Consumption of ethanol with STRATTERA did not change the intoxicating effects
`of ethanol.
`Desipramine — Coadministration of STRATTERA (40 or 60 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 recommended for drugs
`metabolized by CYP2D6.
`Methylphenidate — Coadministration of methylphenidate with STRATTERA did not increase
`cardiovascular effects beyond those seen with methylphenidate alone.
`Midazolam — Coadministration of STRATTERA (60 mg BID for 12 days) with midazolam, a
`model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase
`in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A.
`Drugs highly bound to plasma protein — In vitro drug-displacement studies were conducted
`with atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine did
`not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human
`albumin. Similarly, these compounds did not affect the binding of atomoxetine to human
`albumin.
`Drugs that affect gastric pH — Drugs that elevate gastric pH (magnesium hydroxide/aluminum
`hydroxide, omeprazole) had no effect on STRATTERA bioavailability.
`CLINICAL STUDIES
`The effectiveness of STRATTERA in the treatment of ADHD was established in 6
`randomized, double-blind, placebo-controlled studies in children, adolescents, and adults who
`met Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD (see
`INDICATIONS AND USAGE).
`Children and Adolescents
`The effectiveness of STRATTERA in the treatment of ADHD was established in 4
`randomized, double-blind, placebo-controlled studies of pediatric patients (ages 6 to 18).
`Approximately one-third of the patients met DSM-IV criteria for inattentive subtype and
`two-thirds met criteria for both inattentive and hyperactive/impulsive subtypes (see
`INDICATIONS AND USAGE).
`Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline
`to endpoint for STRATTERA- and placebo-treated patients using an intent-to-treat analysis of
`the primary outcome measure, the investigator administered and scored ADHD Rating
`Scale-IV-Parent Version (ADHDRS) total score including hyperactive/impulsive and inattentive
`subscales. Each item on the ADHDRS maps directly to one symptom criterion for ADHD in the
`DSM-IV.
`
`

`

`
`
`5
`
`In Study 1, an 8-week randomized, double-blind, placebo-controlled, dose-response, acute
`treatment study of children and adolescents aged 8 to 18 (N=297), patients received either a fixed
`dose of STRATTERA (0.5, 1.2, or 1.8 mg/kg/day) or placebo. STRATTERA was administered
`as a divided dose in the early morning and late afternoon/early evening. At the 2 higher doses,
`improvements in ADHD symptoms were statistically significantly superior in STRATTERA-
`treated patients compared with placebo-treated patients as measured on the ADHDRS scale. The
`1.8-mg/kg/day STRATTERA dose did not provide any additional benefit over that observed with
`the 1.2-mg/kg/day dose. The 0.5-mg/kg/day STRATTERA dose was not superior to placebo.
`In Study 2, a 6-week randomized, double-blind, placebo-controlled, acute treatment study of
`children and adolescents aged 6 to 16 (N=171), patients received either STRATTERA or
`placebo. STRATTERA was administered as a single dose in the early morning and titrated on a
`weight-adjusted basis according to clinical response, up to a maximum dose of 1.5 mg/kg/day.
`The mean final dose of STRATTERA was approximately 1.3 mg/kg/day. ADHD symptoms
`were statistically significantly improved on STRATTERA compared with placebo, as measured
`on the ADHDRS scale. This study shows that STRATTERA is effective when administered once
`daily in the morning.
`In 2 identical, 9-week, acute, randomized, double-blind, placebo-controlled studies of children
`aged 7 to 13 (Study 3, N=147; Study 4, N=144), STRATTERA and methylphenidate were
`compared with placebo. STRATTERA was administered as a divided dose in the early morning
`and late afternoon (after school) and titrated on a weight-adjusted basis according to clinical
`response. The maximum recommended STRATTERA dose was 2.0 mg/kg/day. The mean final
`dose of STRATTERA for both studies was approximately 1.6 mg/kg/day. In both studies,
`ADHD symptoms statistically significantly improved more on STRATTERA than on placebo, as
`measured on the ADHDRS scale.
`Examination of population subsets based 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 to allow exploration of differences in these
`subgroups.
`Adults
`The effectiveness of STRATTERA in the treatment of ADHD was established in 2
`randomized, double-blind, placebo-controlled clinical studies of adult patients, age 18 and older,
`who met DSM-IV criteria for ADHD.
`Signs and symptoms of ADHD were evaluated using the investigator-administered Conners
`Adult ADHD Rating Scale Screening Version (CAARS), a 30-item scale. The primary
`effectiveness measure was the 18-item Total ADHD Symptom score (the sum of the inattentive
`and hyperactivity/impulsivity subscales from the CAARS) evaluated by a comparison of mean
`change from baseline to endpoint using an intent-to-treat analysis.
`In 2 identical, 10-week, randomized, double-blind, placebo-controlled acute treatment studies
`(Study 5, N=280; Study 6, N=256), patients received either STRATTERA or placebo.
`STRATTERA was administered as a divided dose in the early morning and late afternoon/early
`evening and titrated according to clinical response in a range of 60 to 120 mg/day. The mean
`final dose of STRATTERA for both 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.
`
`

`

`
`
`6
`
`Examination of population subsets based 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 to allow exploration of differences in these subgroups.
`INDICATIONS AND USAGE
`STRATTERA is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder
`(ADHD).
`The effectiveness of STRATTERA in the treatment of ADHD was established in 2 placebo-
`controlled trials in children, 2 placebo-controlled trials in children and adolescents, and 2
`placebo-controlled trials in adults who met DSM-IV criteria for ADHD (see CLINICAL
`STUDIES).
`A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive
`symptoms that cause impairment and that were present before age 7 years. The symptoms must
`be persistent, must be more severe than is typically observed in individuals at a comparable level
`of development, must cause clinically significant impairment, e.g., in social, academic, or
`occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at
`home. The symptoms must not be better accounted for by another mental disorder. For the
`Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months:
`lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to
`follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses
`things, easily distracted, forgetful. For the Hyperactive-Impulsive Type, at least 6 of the
`following symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat,
`inappropriate running/climbing, difficulty with quiet activities, “on the go,” excessive talking,
`blurting answers, can’t wait turn, intrusive. For a Combined Type diagnosis, both inattentive and
`hyperactive-impulsive criteria must be met.
`Special Diagnostic Considerations
`The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate
`diagnosis requires the use not only of medical but also of special psychological, educational, and
`social resources. Learning may or may not be impaired. The diagnosis must be based upon a
`complete history and evaluation of the patient and not solely on the presence of the required
`number of DSM-IV characteristics.
`Need for Comprehensive Treatment Program
`STRATTERA is indicated as an integral part of a total treatment program for ADHD that may
`include other measures (psychological, educational, social) for patients with this syndrome. Drug
`treatment may not be indicated for all patients with this syndrome. Drug treatment is not
`intended for use in the patient who exhibits symptoms secondary to environmental factors and/or
`other primary psychiatric disorders, including psychosis. Appropriate educational placement is
`essential in children and adolescents with this diagnosis and psychosocial intervention is often
`helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment
`medication will depend upon the physician’s assessment of the chronicity and severity of the
`patient’s symptoms.
`Long-Term Use
`The effectiveness of STRATTERA for long-term use, i.e., for more than 9 weeks in child and
`adolescent patients and 10 weeks in adult patients, has not been systematically evaluated in
`controlled trials. Therefore, the physician who elects to use STRATTERA for extended periods
`
`

`

`
`
`7
`
`should periodically reevaluate the long-term usefulness of the drug for the individual patient (see
`DOSAGE AND ADMINISTRATION).
`CONTRAINDICATIONS
`
`Hypersensitivity
`STRATTERA is contraindicated in patients known to be hypersensitive to atomoxetine or
`other constituents of the product (see WARNINGS).
`Monoamine Oxidase Inhibitors (MAOI)
`STRATTERA should not be taken with an MAOI, or within 2 weeks after discontinuing an
`MAOI. Treatment with an MAOI should not be initiated within 2 weeks after discontinuing
`STRATTERA. With other drugs that affect brain monoamine concentrations, there have been
`reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus,
`autonomic instability with possible rapid fluctuations of vital signs, and mental status changes
`that include extreme agitation progressing to delirium and coma) when taken in combination
`with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome.
`Such reactions may occur when these drugs are given concurrently or in close proximity.
`Narrow Angle Glaucoma
`In clinical trials, STRATTERA use was associated with an increased risk of mydriasis and
`therefore its use is not recommended in patients with narrow angle glaucoma.
`WARNINGS
`
`Suicidal Ideation
`STRATTERA increased the risk of suicidal ideation in short-term studies in children and
`adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Pooled analyses of
`short-term (6 to 18 weeks) placebo-controlled trials of STRATTERA in children and adolescents
`have revealed a greater risk of suicidal ideation early during treatment in those receiving
`STRATTERA. There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over
`2200 patients (including 1357 patients receiving STRATTERA and 851 receiving placebo). The
`average risk of suicidal ideation in patients receiving STRATTERA was 0.4% (5/1357 patients),
`compared to none in placebo-treated patients. There was 1 suicide attempt among these
`approximately 2200 patients, occurring in a patient treated with STRATTERA. No suicides
`occurred in these trials. All events occurred in children 12 years of age or younger. All events
`occurred during the first month of treatment. It is unknown whether the risk of suicidal ideation
`in pediatric patients extends to longer-term use. A similar analysis in adult patients treated with
`STRATTERA for either ADHD or major depressive disorder (MDD) did not reveal an increased
`risk of suicidal ideation or behavior in association with the use of STRATTERA.
`All pediatric patients being treated with STRATTERA should be monitored closely for
`suicidality, clinical worsening, and unusual changes in behavior, especially during the initial few
`months of a course of drug therapy, or at times of dose changes. Such monitoring would
`generally include at least weekly face-to-face contact with patients or their family members or
`caregivers during the first 4 weeks of treatment, then every other week visits for the next
`4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by
`telephone may be appropriate between face-to-face visits.
`The following symptoms have been reported with STRATTERA: anxiety, agitation, panic
`attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
`restlessness), hypomania and mania. Although a causal link between the emergence of such
`
`

`

`
`
`8
`
`symptoms and the emergence of suicidal impulses has not been established, there is a concern
`that such symptoms may represent precursors to emerging suicidality. Thus, patients being
`treated with STRATTERA should be observed for the emergence of such symptoms.
`Consideration should be given to changing the therapeutic regimen, including possibly
`discontinuing the medication, in patients who are experiencing emergent suicidality or symptoms
`that might be precursors to emerging suicidality, especially if these symptoms are severe or
`abrupt in onset, or were not part of the patient’s presenting symptoms.
`Families and caregivers of pediatric patients being treated with STRATTERA should be
`alerted about the need to monitor patients for the emergence of agitation, irritability, unusual
`changes in behavior, and the other symptoms described above, as well as the emergence of
`suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring
`should include daily observation by families and caregivers.
`Screening Patients for Bipolar Disorder — In general, particular care should be taken in
`treating ADHD in patients with comorbid bipolar disorder because of concern for possible
`induction of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
`symptoms described above represent such a conversion is unknown. However, prior to initiating
`treatment with STRATTERA, patients with comorbid depressive symptoms should be
`adequately screened to determine if they are at risk for bipolar disorder; such screening should
`include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and
`depression.
`Severe Liver Injury
`Postmarketing reports indicate that STRATTERA can cause severe liver injury in rare cases.
`Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there
`have been two reported cases of markedly elevated hepatic enzymes and bilirubin, in the absence
`of other obvious explanatory factors, out of more than 2 million patients during the first two
`years of postmarketing experience. In one patient, liver injury, manifested by elevated hepatic
`enzymes (up to 40 X upper limit of normal (ULN)) and jaundice (bilirubin up to 12 X ULN),
`recurred upon rechallenge, and was followed by recovery upon drug discontinuation providing
`evidence that STRATTERA caused the liver injury. Such reactions may occur several months
`after therapy is started, but laboratory abnormalities may continue to worsen for several weeks
`after drug is stopped. Because of probable underreporting, it is impossible to provide an accurate
`estimate of the true incidence of these events. The patients described above recovered from their
`liver injury, and did not require a liver transplant. However, in a small percentage of patients,
`severe drug-related liver injury may progress to acute liver failure resulting in death or the need
`for a liver transplant.
`STRATTERA should be discontinued in patients with jaundice or laboratory evidence of liver
`injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be
`done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice,
`right upper quadrant tenderness, or unexplained “flu-like” symptoms). (See also Information
`for Patients under PRECAUTIONS.)
`Serious Cardiovascular Events
`Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart
`Problems
`Children and Adolescents — Sudden death has been reported in association with atomoxetine
`treatment at usual doses in children and adolescents with structural cardiac abnormalities or other
`serious heart problems. Although some serious heart problems alone carry an increased risk of
`
`

`

`
`
`9
`
`sudden death, atomoxetine generally should not be used in children or adolescents with known
`serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or
`other serious cardiac problems that may place them at increased vulnerability to the
`noradrenergic effects of atomoxetine.
`Adults — Sudden deaths, stroke, and myocardial infarction have been reported in adults taking
`atomoxetine at usual doses for ADHD. Although the role of atomoxetine in these adult cases is
`also unknown, adults have a greater likelihood than children of having serious structural cardiac
`abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or
`other serious cardiac problems. Consideration should be given to not treating adults with
`clinically significant cardiac abnormalities.
`Assessing Cardiovascular Status in Patients being Treated with Atomoxetine
`Children, adolescents, or adults who are being considered for treatment with atomoxetine
`should have a careful history (including assessment for a family history of sudden death or
`ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and
`should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram
`and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained
`syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should
`undergo a prompt cardiac evaluation.
`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 a prior history of psychotic illness or mania can be
`caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to
`a possible causal role of atomoxetine, and discontinuation of treatment should be considered. In a
`pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in
`about 0.2% (4 patients with events out of 1939 exposed to atomoxetine for several weeks at
`usual doses) of atomoxetine-treated patients compared to 0 out of 1056 placebo-treated patients.
`Allergic Events
`Although uncommon, allergic reactions, including angioneurotic edema, urticaria, and rash,
`have been reported in patients taking STRATTERA.
`PRECAUTIONS
`
`General
`Effects on blood pressure and heart rate — STRATTERA should be used with caution in
`patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease because it
`can increase blood pressure and heart rate. Pulse and blood pressure should be measured at
`baseline, following STRATTERA dose increases, and periodically while on therapy.
`In pediatric placebo-controlled trials, STRATTERA-treated subjects experienced a mean
`increase in heart rate of about 6 beats/minute compared with placebo subjects. At the final study
`visit before drug discontinuation, 3.6% (12/335) of STRATTERA-treated subjects had heart rate
`increases of at least 25 beats/minute and a heart rate of at least 110 beats/minute, compared with
`0.5% (1/204) of placebo subjects. No pediatric subject had a heart rate increase of at least
`25 beats/minute and a heart rate of at least 110 beats/minute on more than one occasion.
`Tachycardia was identified as an adverse event for 1.5% (5/340) of these pediatric subjects
`compared with 0.5% (1/207) of placebo subjects. The mean heart rate increase in extensive
`metabolizer (EM) patients was 6.7 beats/minute, and in poor metabolizer (PM) patients
`10.4 beats/minute.
`
`

`

`
`
`10
`
`STRATTERA-treated pediatric subjects experienced mean increases of about 1.5 mm Hg in
`systolic and diastolic blood pressures compared with placebo. At the final study visit before drug
`discontinuation, 6.8% (22/324) of STRATTERA-treated pediatric subjects had high systolic
`blood pressure measurements compared with 3.0% (6/197) of placebo subjects. High systolic
`blood pressures were measured on 2 or more occasions in 8.6% (28/324) of STRATTERA-
`treated subjects and 3.6% (7/197) of placebo subjects. At the final study visit before drug
`discontinuation, 2.8% (9/326) of STRATTERA-treated pediatric subjects had high diastolic
`blood pressure measurements compared with 0.5% (1/200) of placebo subjects. High diastolic
`blood pressures were measured on 2 or more occasions in 5.2% (17/326) of
`STRATTERA-treated subjects and 1.5% (3/200) of placebo subjects. (High systolic and diastolic
`blood pressure measurements were defined as those exceeding the 95th percentile, stratified by
`age, gender, and height percentile - National High Blood Pressure Education Working Group on
`Hypertension Control in Children and Adolescents.)
`In adult placebo-controlled trials, STRATTERA-treated subjects experienced a mean increase
`in heart rate of 5 beats/minute compared with placebo subjects. Tachycardia was identified as an
`adverse event for 3% (8/269) of these adult atomoxetine subjects compared with 0.8% (2/263) of
`placebo subjects.
`STRATTERA-treated adult subjects experienced mean increases in systolic (about 3 mm Hg)
`and diastolic (about 1 mm Hg) blood pressures compared with placebo. At the final study visit
`before drug discontinuation, 1.9% (5/258) of STRATTERA-treated adult subjects had systolic
`blood pressure measurements ≥150 mm Hg compared with 1.2% (3/256) of placebo subjects. At
`the final study visit before drug discontinuation, 0.8% (2/257) of STRATTERA-treated adult
`subjects had diastolic blood pressure measurements ≥100 mm Hg compared with 0.4% (1/257)
`of placebo subjects. No adult subject had a high systolic or diastolic blood pressure detected o