Strattera - Clinical Pharmacology

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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 4 th 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.

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.

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, ie, 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 should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).