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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.

Pharmacodynamics

An exposure-response analysis encompassing doses of atomoxetine (0.5, 1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposure correlates with efficacy as measured by the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator administered and scored. The exposure-efficacy relationship was similar to that observed between dose and efficacy with median exposures at the two highest doses resulting in near maximal changes from baseline [see Clinical Studies].

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 (atomoxetine hcl) can be administered with or without food. Administration of STRATTERA (atomoxetine hcl) 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 (atomoxetine hcl) 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 (atomoxetine hcl) with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary [see STRATTERA WARNINGS AND STRATTERA PRECAUTIONS]. 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 N594 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 (atomoxetine hcl) dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation. [See STRATTERA Use In Specific Populations].

Clinical Studies

ADHD studies in Children and Adolescents

Acute Studies

The effectiveness of STRATTERA (atomoxetine hcl) in the treatment of ADHD was established in 4 randomized, double618 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.

Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for STRATTERA (atomoxetine hcl) 621 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 (atomoxetine hcl) (0.5, 1.2, or 1.8 mg/kg/day) or placebo. STRATTERA (atomoxetine hcl) 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 (atomoxetine hcl) -treated patients compared with placebo treated patients as measured on the ADHDRS scale. The 1.8 mg/kg/day STRATTERA (atomoxetine hcl) 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 (atomoxetine hcl) 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 (atomoxetine hcl) or placebo. STRATTERA (atomoxetine hcl) 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 (atomoxetine hcl) was approximately 1.3 mg/kg/day. ADHD symptoms were statistically significantly improved on STRATTERA (atomoxetine hcl) compared with placebo, as measured on the ADHDRS scale. This study shows that STRATTERA (atomoxetine hcl) 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 (atomoxetine hcl) and methylphenidate were compared with placebo. STRATTERA (atomoxetine hcl) 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 (atomoxetine hcl) dose was 2.0 mg/kg/day. The mean final dose of STRATTERA (atomoxetine hcl) for both studies was approximately 1.6 mg/kg/day. In both studies, ADHD symptoms statistically significantly improved more on STRATTERA (atomoxetine hcl) 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.

Maintenance Study

The effectiveness of STRATTERA (atomoxetine hcl) 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 4 weeks during an initial 10 week open-label treatment phase with STRATTERA (atomoxetine hcl) (1.2 to 1.8 mg/kg/day) were randomized to continuation of their current dose of STRATTERA (atomoxetine hcl) (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 a reduction of at least 25% from baseline in ADHDRS-IV-Parent:Inv total score. Patients who were assigned to STRATTERA (atomoxetine hcl) and showed continuous response for approximately 8 months during the first double-blind treatment phase were again randomized to continuation of their current dose of STRATTERA (atomoxetine hcl) (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 2 from the end of open-label phase and ADHDRS-IV-Parent:Inv total score returns to ≥ 90% of study entry score for 2 consecutive visits. In both double-blind phases, patients receiving continued STRATTERA (atomoxetine hcl) treatment experienced significantly longer times to relapse than those receiving placebo.

ADHD studies in Adults

The effectiveness of STRATTERA (atomoxetine hcl) 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 (atomoxetine hcl) or placebo. STRATTERA (atomoxetine hcl) 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 (atomoxetine hcl) for both studies was approximately 95 mg/day. In both studies, ADHD symptoms were statistically significantly improved on STRATTERA (atomoxetine hcl) , 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.

Last reviewed on RxList: 4/29/2011
This monograph has been modified to include the generic and brand name in many instances.