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AtomoxetineA Review of its Use in Attention-Deficit Hyperactivity Disorder in

Children and Adolescents

Karly P. Garnock-Jones and Gillian M. Keating

Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Philadelphia,

Pennsylvania, USA

Various sections of the manuscript reviewed by: J. Graham, Department of Psychiatry, University of Dundee, Dundee, UK; D.E. Greydanus, Department of Pediatrics and HumanDevelopment, Michigan State University, Kalamazoo, Michigan, USA; F. Levy, School of Psychiatry, University of New South Wales, Sydney,

New South Wales, Australia.

Data SelectionSources: Medical literaturepublishedin anylanguagesince 1980on ‘atomoxetine’,identifiedusing MEDLINEand EMBASE,supplementedby AdisBase (a proprietary databas

of WoltersKluwerHealth | Adis). Additionalreferences were identified from the reference lists of publishedarticles. Bibliographical information, includingcontributory unpublished

data, was also requested from the company developing the drug.Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘atomoxetine’ and [(‘attention deficit hyperactivity disorder’ or ‘ADHD’) and (‘infants’ or ‘children’ o

‘adolescents’)]. Searches were last updated 10 February 2009.Selection: Studies in pediatric patients with attention-deficit hyperactivity disorder who received atomoxetine. Inclusion of studies was based mainly on the methods sectiono

the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also

included.Index terms: Atomoxetine, attention-deficit hyperactivity disorder, ADHD, children, adolescents, pharmacoeconomics, pharmacodynamics, pharmacokinetics, therapeutic

use, tolerability.

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

2. Pharmacodynamic Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

2.1 Effects on Neurotransmitter Transporters and Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

2.2 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

3. Pharmacokinetic Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

3.2 Metabolism and Elimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

3.3 Special Populations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2083.4 Drug Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

4. Therapeutic Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

4.1 Comparisons with Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

4.1.1 Short-Term Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

4.1.2 Longer Term Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

4.1.3 In Stimulant-Naive Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

4.2 Comparisons with Stimulants or Standard Current Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

4.3 In Patients with Co-Morbid Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

5. Tolerability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

5.1 Specific Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

6. Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

ADIS DRUG EVALUATION Pediatr Drugs 2009; 11 (3): 203-2

1174-5878/09/0003-0203/$49.9

ª 2009 Adis Data Information BV. All rights reserve



7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

8. Place of Atomoxetine in the Management of Attention-Deficit Hyperactivity Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Summary

Abstract Atomoxetine (Strattera) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not clas-

sified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder

(ADHD).

Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and

standard current therapy and does not differ significantly from or is noninferior to immediate-release

methylphenidate; however, it is significantly less effective than the extended-release methylphenidate for-

mulation OROS methylphenidate (hereafter referred to as osmotically released methylphenidate) and

extended-release mixed amfetamine salts.

Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a

negligible risk of abuse or misuse, and is not a controlled substance in the US. Atomoxetine is particularlyuseful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do

not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in

children and adolescents.

PharmacologicProperties

The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of

presynaptic norepinephrine reuptake in the prefrontal cortex.Atomoxetine hasa high affinity andselectivity

for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. Atomox-

etine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and

studies have shown that it preferentially binds to areas of known high distributionof noradrenergic neurons,

such as the fronto-cortical subsystem.

Atomoxetine was generally associated with statistically, but not clinically, significant increases in both

heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected

height andweightamong atomoxetine recipients, this eventuallyreturned to normal in the longer term. Datasuggest that atomoxetine is unlikely to have any abuse potential. Atomoxetine appeared less likely than

methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD.

Atomoxetine is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It

undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP)

2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination

of atomoxetine than extensive metabolizers.

Patients withhepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as

paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among

poor CYP2D6 metabolizers.

Therapeutic Efficacy Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and

adolescents, as observed in several well designed placebo-controlled trials. Atomoxetine also demonstrated

efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into

the evening, and discontinuation of atomoxetine was not associated with symptom rebound. Atomoxetine

efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded

well to atomoxetine treatment.

Atomoxetine did not differ significantly from or was noninferior to immediate-release methylphenidate in

children and adolescents with ADHD with regard to efficacy, and was significantly more effective than

standard current therapy (any combination of medicines [excluding atomoxetine] and/ or behavioral

counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically re-

leased methylphenidate and extended-release mixed amfetamine salts.

The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and

symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration.

204 Garnock-Jones & Keatin

ª 2009 Adis Data Information BV. All rights reserved. Pediatr Drugs 2009; 11



Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and

long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy.

Tolerability Atomoxetine was generally well tolerated in children and adolescents with ADHD. Common adverse events

included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients

discontinued atomoxetine treatment because of adverse events. Atomoxetine discontinuation appeared to

be well tolerated, with a low incidence of discontinuation-emergent adverse events. Atomoxetine appeared

better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers.

Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both im-

mediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and

insomnia appeared more common among stimulant recipients.

A black-box warning for suicidal ideation has been published in the US prescribing information, based on

findings from a meta-analysis showing that atomoxetine is associatedwith a significantly higher incidence of

suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; post-

marketing data show that three patients have had liver-related adverse events deemed probably related to

atomoxetine treatment.

PharmacoeconomicEvaluation:

Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms in-

volving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants,

or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The

incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as

shown in several Markov model analyses conducted from the perspective of various European countries,

with a time horizon of 1 year.

1. Introduction

Attention-deficit hyperactivity disorder (ADHD) is a neuro-

behavioral disorder, characterized by one or both of its subtypes

(inattention and hyperactivity/ impulsiveness).[1,2] Symptoms may

manifest as early as 3 years of age; however, most diagnoses occur

when the patient is aged 7–10 years.[3] Approximately half of

childhood ADHD patients show symptomatic features continuing

into adulthood.[1]ADHD has a prevalence of 3–9% in children and

adolescents in the US,[1] and 4–8% worldwide.[4] European rates

appear lower than US rates; however, this has been described as an

effect of using diagnostic criteria based on the International

Classification of Diseases (ICD), as opposed to Diagnostic and

Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)[5]

criteria.[1] Male sex, low socioeconomic status, and young age are

all associated with a higher prevalence of ADHD.[6]

Co-morbid psychiatric disorders are common among patients

with ADHD, including oppositional defiant disorder (ODD),

conduct disorders, mood disorders, and anxiety disorders.[2,6]

More than two-thirds of children with ADHD have a co-morbid

condition.[2]

The etiology and pathophysiology of ADHD are, thus far,

unknown; however, genetic and developmental factors have been

implicated, as have, to a smaller degree, environmental and social

factors.[2,4,6] Dopamine and norepinephrine (noradrenalin

abnormalities are believed to be associated with ADHD, as aralterations in regional cerebral volumes and reduced metabo

lism in the prefrontal cortex and striatal regions. [2,4,6]

It has been demonstrated that ADHD patients use sig

nificantly more health services than children without ADHD

both before and after diagnosis.[7] The total financial burden o

ADHD to patients and their families in the year 2000 in the U

was estimated to be $US31.6 billion.[2]

Currently, where pharmacologic treatment is deemed ap

propriate, recommended ADHD treatments include methy

phenidate, dexamfetamine, and atomoxetine (Strattera).

Lisdexamfetamine is also approved for the treatment oADHD.[9] Of these, methylphenidate, dexamfetamine, and lis

dexamfetamine are all CNS stimulants.[8,9] There are severa

concerns with stimulant use, including the risk of growth re

tardation, development of tics, and sudden cardiac death, a

well as a potential for abuse or misuse.[2]

Atomoxetine is an orally administered selective norepinephrin

reuptake inhibitor that is approved for the treatment of ADHD i

various countries including the US[10] and the UK.[11] It is no

classified as a stimulant, and is not a controlled substance in th

US. This article reviews the pharmacologic properties and clinic

Atomoxetine: A Review 20




profile of oral atomoxetine in children and adolescents with

ADHD.

2. Pharmacodynamic Properties

Atomoxetine is a (-) isomer of an ortho-methylphenoxy ana-

logof nisoxetine, andis a derivative of phenoxypropylamine.[12]

Its mechanism of action in the treatment of ADHD is unclear,

but is thought to be related to its selective inhibition of pre-

synaptic norepinephrine reuptake in the prefrontal cortex, re-

sulting in increased noradrenergic transmission, important for

attention, learning, memory, and adaptive response.[13,14]

2.1 Effects on Neurotransmitter Transporters

and Receptors

Atomoxetine has a high affinity and selectivity for norepine-

phrine transporters, as demonstrated in radioligand binding stu-

dies in rat brain synaptosomes,[12,15] as well as in clonal cell lines

transfected with human neurotransmitter transporters.[16] The af-

finity constant (Ki) values for atomoxetine inhibition of nor-

epinephrine, serotonin, and dopamine transporters (in MDCK

and HEK 293 cells) were 5, 77, and 1451 nmol/ L.[16] Atomox-

etine was associated with a much lower affinity (K i >1 mmol/ L)

for choline, GABA, and adenosine transporters,[16] as well as

many other neurotransmitter receptors, ion channels, second

messengers, and brain/ gut peptides.[16]

In vitro radioligand binding studies of atomoxetine in the

human brain have demonstrated that it has little or no affinity

for various neurotransmitter receptors.[17] Ki values for ato-

moxetine binding to muscarinic, a-adrenergic, histamine H1,

and serotonergic (5-HT1A and 5-HT2) receptors were

940–10 900nmol/ L; for atomoxetine binding to dopamine D2

receptors the Ki was >35000 nmol/ L.[17]

When norepinephrine and serotonin depletion was induced

in the rat brain in vivo, using the transporter-specific neurotox-

insp-CA andDSP-4, atomoxetinewas shown to inhibit thedeple-

tion of norepinephrine, but not serotonin, in a dose-dependent

manner.[16] Methylphenidate did not inhibit either transporter,leading to normal depletion of both neurotransmitters.[16]

Localization studies, using quantitative autoradiography in

the rat brain, suggest that atomoxetine preferentially binds to

areas of known high distribution of noradrenergic neurons,

such as the fronto-subcortical system, which controls attention

and motor behavior.[18,19]

In rats, intraperitoneal atomoxetine significantly (p< 0.025)

increased extracellular norepinephrine and dopamine levels in the

prefrontal cortexby up to 290%and 323%of basal levels;serotonin

levels did not significantly differ from baseline.[16] Extracellular

dopamine levels in the nucleus accumbens and striatum remaine

constant. Methylphenidate significantly (p< 0.05) increased extra

cellular norepinephrine and dopamine levels in the prefrontal co

tex, and dopamine levels in the nucleus accumbens and striatumindicating a potential difference from atomoxetine in mechanism

of action.[16] It was hypothesized that the inhibition of dopamin

uptake in the prefrontal cortex, but not in the dopamine tran

porter-rich nucleus accumbens and striatum, was due to baselin

nonselective dopamine uptake by norepinephrine transporters i

the prefrontal cortex.[16] The absence of extracellular dopamin

accumulation in the nucleus accumbens and striatum suggests th

atomoxetine is unlikely to produce tics or have abuse potential.[1

Atomoxetine also selectively inhibits norepinephrine uptak

in humans.[20] Four healthy male volunteers received atomox

etine 20 mg twice daily for 1 week, following a week of placeb

administration. When an infusion of norepinephrine wa

administered, the mean pressor response for atomoxetin

versus placebo was 12.4 versus 5.2 mmHg per microgram o

norepinephrine per minute (p= 0.054).[20] The increase wit

atomoxetine on day 1 was 261% greater than that observed wit

placebo.[20] There was a significant correlation between th

pressor response to norepinephrine and the plasma con

centration of atomoxetine (p= 0.002).[20] In contrast, when a

infusion of tyramine was administered, the mean pressor re

sponse for atomoxetine versus placebo treatment was 4.5 versu

7.9 mmHg per milligram of tyramine per minute (p= 0.003

and the increase with atomoxetine on day 1 was 70% of thaobserved with placebo.[20] Serotonin uptake into platelets wa

not affected by atomoxetine administration in this study. [20]

A randomized, double-blind, crossover study using tran

scranial magnetic stimulation in nine healthy volunteers de

monstrated that both atomoxetine 60 mg and methylphenida

30 mg significantly (p < 0.05) decreased cortical inhibition an

increased cortical facilitation to extents that did not sig

nificantly differ between treatments, indicating the possibilit

of a shared cortical target for ADHD treatment.[21]

2.2 Other Effects

Atomoxetine was associated with modest increases in hear

rate and BP in children and adolescents with ADHD, accordin

to the results of a pooled analysis of clinical trial data. [22] In th

short term (up to 9 weeks’ therapy), significantly greater increas

in mean heart rate (+7.8 vs +1.5 beats/ minute [bpm]; p <0.00

and mean diastolic BP (DBP;+2.1 vs-0.5 mmHg; p= 0.002) wer

seen with atomoxetine than with placebo; there was no signif

cant between-group difference in the change in systolic BP (SBP

Patients receivingatomoxetinefor‡1 year hadincreases in mea





heart rate of <10 bpm and mean increases in BP that were small

and not considered to be of clinical significance.[22] The in-

cidence of abnormally high heart rate or BP in atomoxetine

recipients is discussed in section 5.1. Atomoxetine treatment wasnot associated with QT prolongation in these clinical trials.[22]

Heart rate appears to increase to a greater extent among

atomoxetine recipients compared with stimulant recipients (sec-

tion 4.2). In a study comparing the efficacy of atomoxetine with

that of the extended-release methylphenidate formulation OROS

methylphenidate (hereafter referred to as osmotically released

methylphenidate), recipients of atomoxetineshowed a significantly

greater change in heart rate (+6.4 vs +3.0 bpm; p<0.05).[23]

Another study demonstrated a greater increase in heart rate among

atomoxetine versus immediate-release methylphenidate recipients

(+

8.51 vs+

4.76 bpm; p=

0.005).

[24]

Where reported in other activecomparator trials, atomoxetine did not differ significantly from

immediate-release methylphenidate[25] or extended-release mixed

amfetamine salts[26] with regard to the increase in heart rate.

Atomoxetine is unlikely to lead to abuse.[27,28] A rando-

mized, double-blind, crossover trial in 16 healthy volunteers

who were nondependent light drug users compared the effects

of placebo, atomoxetine 20, 45, or 90 mg and methylphenidate

20 or 40 mg on subjective, physiologic, and psychomotor

measures.[27] Results demonstrated that atomoxetine did not

significantly differ from placebo in perceptions of stimulant

and euphoric effects, but methylphenidate was associated with

significantly higher perceptions of these effects than placebo

(p< 0.05). Atomoxetine 90 mg was associated with ‘bad’ and

‘sick’ feelings, differing significantly from placebo in these

measures (p< 0.05).[27] Data from a study involving six healthy

volunteers with a recent history of nontherapeutic stimulant

abuse who received methylphenidate 5–30 mg, atomoxetine

15–90 mg, dexamfetamine 2.5–15 mg, triazolam 0.06–0.375 mg,

and placebo suggest that, while behavioral effects of atomox-

etine overlap somewhat with psychomotor stimulants, it has a

low abuse potential.[28] This conclusion is potentially supported

by the lack of extracellular increase of dopamine in the nucleus

accumbens and striatum (section 2.1).[16]Atomoxetine recipients demonstrated an initial loss in both

expected weight and height, although these shortfalls peaked at

15 and 18 months, respectively, and returned to expected measure-

ments by 36 and 24 months, according to the interim results of a

long-term, open-label extension study.[29] Persistentdecreases from

the expected measurements appeared to occur in patients who

were taller or heavier than average before treatment. [29] The

study involved pediatric patients (n= 1312; 5-year data n= 61)

who were enrolled in one of 13 clinical atomoxetine trials and

who subsequently received long-term atomoxetine treatment.

Sexual development did not appear to be affected by atomoxe

tine treatment in an analysis (available as an abstract) o

15 months’ treatment with atomoxetine compared with placebo i

children and adolescents with ADHD using Tanner staging.[3

Children with ADHD receiving atomoxetine 1–1.8 mg/ kg/ da

had a smaller increase in sleep-onset latencies than those receivin

methylphenidate 0.9–1.8mg/ kg/ day (12.06 vs 39.24 minute

p< 0.001), according to results from a randomized, double-blin

crossover study.[31] Other actigraphy measures demonstrated tha

atomoxetine recipients worsened to a significantly lesser exten

than methylphenidate recipients, with regard to total sleep interv

(p= 0.004) and assumed sleep time (p = 0.016), although methy

phenidate recipients showed an improved interrupted sleep tim

compared with a worsened interrupted sleep time among atomox

tine recipients (p=

0.025), as well as the number of sleep interruptions worsening to a significantly (p = 0.011) greater extent amon

atomoxetine recipients than among methylphenidate recipients.[3

When monoamine oxidase inhibitors (MAOIs) have bee

administered concomitantly with other drugs that affect brai

monoamine concentrations, reports of serious, sometimes fata

reactions have occurred. Thus, coadministration of atomox

etine and MAOIs is contraindicated.[10,11] Other drugs tha

interact with atomoxetine include pressor agents (e.g. dopa

mine), with subsequent effects on blood pressure, and high

dose nebulized[11] or systemically administered[10,11]b2-agonis

(e.g. albuterol [salbutamol]), with possible effects on heart rat

and blood pressure.[10,11] Atomoxetine should therefore b

coadministered with caution with pressor agents orb2-agonist

Atomoxetine made no difference to the intoxicating effects o

ethanol or the cardiovascular effects of methylphenidate.[10]

The UK prescribing information states that atomoxetin

should also be used with caution with drugs that affect no

epinephrine levels (such as antidepressants or certain decong

stants), as there is a potential for additive or synergistic effect

caution is also advised with drugs that lower the seizure threshol

(e.g. antidepressants, antipsychotics), as there is a potential risk o

seizures with atomoxetine.[11] When atomoxetine is administere

with QT-prolonging drugs (e.g. antipsychotics or class IA and IIantiarrhythmics), drugs that cause an imbalance in electrolyt

(e.g. thiazide diuretics), or drugs that inhibit cytochrome P45

(CYP) 2D6, there is a potential for an increased risk of QT pro

longation, according to the UK prescribing information.[11] Thes

precautions are not specified in the US prescribing information.[1

3. Pharmacokinetic Properties

This section focuses, where possible, on results from an open

label pharmacokineticstudy conducted in children and adolescen





aged 7–14 years with a DSM-IV diagnosis of ADHD who

received either a single 10 mg dose of oral atomoxetine (n = 7)

or atomoxetine 20–45 mg twice daily for 11 weeks (n = 16)

[dosage was not adjusted for weight].[32] Most doses were notadministered within 1 hour of a meal. Although it was not a

requirement, all patients were extensive metabolizers of

CYP2D6 substrates (extensive metabolizers). The vast majority

of the general population are extensive metabolizers, with 7%of

Caucasians and 2% of African-Americans being poor meta-

bolizers of CYP2D6 substrates (poor metabolizers);[10] some

pharmacokinetic data are available for pediatric poor meta-

bolizers.[33] Dosage adjustments are recommended in the poor

metabolizer population (section 7).

Atomoxetine pharmacokinetics have been demonstrated to

be similar for adults and children or adolescents, once weight isadjusted for.[32] Therefore, some data presented in this section

are from studies in adult subjects, when no pediatric data are

available. These data were obtained from a review article[34] and

from the US prescribing information.[10]

While there are few published pediatric data for poor me-

tabolizers, it has been demonstrated in adult poor metabolizers

that values for the area under the plasma concentration-time

curve (AUC) and maximum plasma concentration (Cmax) are

10- and 50-fold higher than in extensive metabolizers, and that

atomoxetine elimination is slower, with a plasma half-life (t1=2)

of »24 hours.[10]

A population pharmacokinetic, one-compartment model

was constructed, using data from five studies in pediatric pa-

tients receiving dosages of atomoxetine 10–90 mg/ day, ad-

ministered twice daily.[33] This model demonstrated that drug

clearance among pediatric poor metabolizers is 9-fold lower

than that among extensive metabolizers.

3.1 Absorption and Distribution

Oral atomoxetine is rapidly absorbed; Cmax (144 ng/ mL) was

reached in 2 hours among children and adolescents with

ADHD (all of whom were extensive metabolizers) receiving asingle dose of atomoxetine 10 mg.[32] The AUC from time zero

to infinity (AUC1) was 645 ng

h/ mL.

Corresponding data for children and adolescents with ADHD

receiving multiple doses of 40–90 mg/ day are 537 ng/ mL (Cmax at

steady state), 1.73 hours, and 2250 ng

h/ mL.[32]

Adult studies demonstrated an absolute oral bioavailability of

»63% in extensive metabolizers and»94% in poormetabolizers.[10]

Atomoxetine demonstrated dose-proportional increases in plas-

ma exposure.[32] When administered with food, atomoxetine was

absorbed at a slower rate, with a 9% lower Cmax in children and

adolescents; however, atomoxetine may be administered with o

without food.[10] The steady-state volume of distributio

(2.25 L/ kg[32]) indicates that atomoxetine primarily distribut

into total body water.[10] Plasma protein binding (mainly to abumin) of atomoxetine was 98% at therapeutic concentrations.[1

3.2 Metabolism and Elimination

Atomoxetine undergoes extensive biotransformation.[10] I

extensive metabolizers, it is mainly metabolized via the CYP2D

enzymatic pathway, in which atomoxetine is oxidated to form

4-hydroxyatomoxetine (the major metabolite), which is the

glucuronidated to form 4-hydroxyatomoxetine-O-glucuronid

the main excreted metabolite (accounting for >80% and <17% o

the total dose in urine and feces); <3% of the total atomoxetin

dose is excreted as unchanged drug.[10,34] Poor metabolizers arunable to metabolize as efficiently using the CYP2D6 pathway

metabolism in these individuals occurs mainly via the CYP2C1

pathway, forming N -desmethylatomoxetine.[10,34] Several othe

CYP isoforms are able to form 4-hydroxyatomoxetine an

N -desmethylatomoxetine; thus, 4-hydroxyatomoxetine is still th

most common metabolite, even in poor metabolizers.[10,34]

4-Hydroxyatomoxetine has similar pharmacologic activity t

atomoxetine (although, unlike atomoxetine, it does have rela

tively high affinity for the human serotonin transporter),[34] bu

circulates in plasma at lower concentrations (e.g. at 1% of ato

moxetine concentrations in extensive metabolizers).[10]

Conversely, N -desmethylatomoxetine has much less pharmacolog

activity than atomoxetine and 4-hydroxyatomoxetine,[34] but als

circulates at lower concentrations.[10]

Atomoxetine has a short half-life (just over 3 hours); th

explains the low amount of atomoxetine accumulation (mea

9% in pediatric patients) observed at steady state. [32]

Time-invariant pharmacokinetics were indicated by the pe

diatric study; t1=2, apparent clearance, and apparent volume o

distribution were all similar after a single dose (3.12 hour

0.455 L/ h/ kg, and 1.96 L/ kg, respectively) and at steady stat

(3.28 hours, 0.477 L/ h/ kg, and 2.25 L/ kg).[32]

3.3 Special Populations

Extensive metabolizers with moderate (Child-Pugh class B

or severe (Child-Pugh class C) hepatic insufficiency have in

creased atomoxetine exposure compared with healthy volun

teers.[10] Therefore, dosage reduction is recommended in thes

patients (section 7).[10,11] Following a single dose of atomox

etine 20 mg, AUC1 was significantly higher in adults wit

moderate (n= 6) or severe (n= 4) hepatic impairment than i

healthy volunteers (1.59 vs 0.85 mg

h/ mL; p< 0.05).[35]





Extensive metabolizers with end-stage renal disease showed no

significant difference from healthy volunteers when exposure was

corrected for dosage.[10] Atomoxetine pharmacokinetics were not

influenced by sex or ethnicorigin(other than Caucasians having ahigher likelihood of being poor metabolizers).[10]

3.4 Drug Interactions

Atomoxetine was not associated with clinically important in-

hibition or induction of CYP isoenzymes, including CYP1A2,

CYP3A, CYP2D6, and CYP2C9.[10] No dosage adjustment is

considered necessary for drugs metabolized by CYP3A or

CYP2D6.[10]

Healthy extensive metabolizers receiving both atomoxetine

20 mg twice daily and paroxetine 20 mg once daily, a potent

CYP2D6 inhibitor, demonstrated pharmacokinetic parametersforatomoxetinethat were similar to those seen among poor meta-

bolizers.[36] Coadministration of paroxetine with atomoxetine

was associated with 3.5-, 6.5-, and 2.5-fold increases in atomox-

etine steady-state Cmax, AUC from time 1 to 12 hours, and t1=2,

respectively.[36] Dosage adjustment is recommended for pediatric

patients receiving potent CYP2D6 inhibitors (see section 7).[10] In

vitro studies suggest that CYP2D6 inhibitors have no effect on

atomoxetine pharmacokinetics among poor metabolizers.[10]

Atomoxetine had no effect on the binding of warfarin, aspirin

(acetylsalicylic acid), phenytoin, or diazepam to human albumin,

or vice versa, according to results from in vitro drug-displacement

studies.[10] Gastric pH-elevating drugs(e.g. antacids, omeprazole)

had no effect on the bioavailability of atomoxetine.[10]

4. Therapeutic Efficacy

The focus of this section is on data from large (n >100), fully

published, randomized, controlled trials investigating the efficacy

of atomoxetine in children and adolescents with ADHD. It

should be noted that the vast majority of atomoxetine clinical

trials included dosages that were potentially higher than the

maximum approved dosage of 1.4mg/ kg/ day or 100 mg/ day. For

definitions of some of the rating scale abbreviations and de-scriptions of rating scales referred to in this section, see table I.

4.1 Comparisons with Placebo

The efficacy of oral atomoxetine was compared with that of

placebo in the treatment of children and adolescents with ADHD

in eight 6- to 9-week, randomized, double-blind, multicenter,

short-term, fully published trials;[37-43,58] one multinational

study with two randomized, double-blind, placebo-controlled

phases has investigated longer term results.[46,47] Two rando-

mized, double-blind, multicenter trials of 10[59] and 12[60] weeks’

duration investigated the efficacy of atomoxetine versus placeb

in a stimulant-naive population.

4.1.1 Short-Term Treatment

Patients in the short-term trials were randomized to receiv

once-[38,40-43] or twice-daily[37,39] atomoxetine or placebo. One fixed

dose trial titrated patients to a target dosage of atomoxetine 0.5, 1

or 1.8 mg/ kg/ day.[37] Three other trials titrated patients to a targe

dosage of atomoxetine 1.0[38] or 1.2[42,43] mg/ kg/ day, although th

dosage could be further increased to 1.5[38] or 1.8[42,43] mg/ kg/ day

required. The remaining four trials titrated patients according t

therapeutic response; permitted atomoxetine dosages we

0.8–1.8,[41]£1.8,[40] or£2[39] mg/ kg/ day. Where specified, final mea

atomoxetine dosages were 1.3,[38,41-43] 1.4,[40] and 1.5[39] mg/ kg/ da

Eligible patients aged 6–18 years in the short-term trials hadDSM-IV diagnosis of ADHD, as confirmed by the Kiddie Sched

ule for Affective Disorders and Schizophrenia for School-Ag

Children-Present and Lifetime version (K-SADS-PL),[37,38,41-4

the K-SADS-Epidemiologic version (K-SADS-E; Chinese ve

sion),[40] or an unspecified version of K-SADS.[39] Most patien

were required to have a minimum ADHD-RS total score of 25 fo

boys and 22 for girls (or 12 for the inattentive or hyperactive

impulsive score),[40] or ADHD-RS total or inattentive or hyper

active/ impulsive subscale scores ‡1[42] or 1.5[37-39,43] SD above ag

and sex norms. Exclusion criteria included below-average intell

gence levels,[37,39-42] use of other psychotropic medication,[37-4

weight <25[39,41] or <20[40] kg or >60[40] kg, or a history of or cu

rent psychosis,[37-41,43] bipolar disorder,[37-41,43] or serious medica

illness.[37,38,40,42,43] Two trials also excluded patients who wer

poor metabolizers.[39]

The primary endpoint for all short-term placebo-controlle

trials was the change in the investigator-administered ADHD-R

total score (parent[37-40,43] or teacher[41,42] version) from baselin

to endpoint.

Additional endpoints included scores on the inattentive an

hyperactive/ impulsive subscales of the ADHD-RS,[37-40,42,43] re

ponse rate (see table II for definitions of response),[38,39,41-43] an

CPRS,[37-42]CTRS,[38,40] CGI-ADHD-S,[39,40,43]and CGI-S[37,38,4

scores; as well as health-related quality of life (HR-QOL), rated o

the CHQ psychosocial summary score.[37,41] Two studies[38,4

specifically investigated morning and evening efficacy usin

the DPREMB, both original[38] and revised (DPREMB-R)[4

versions.

The majority of patients in treatment groups were diagnose

with the combined subtype(55–81%); inattentive and hyperactiv

impulsive subtype proportions ranged from 19% to41% and from

0% to 4%, respectively.[37-43] The mean patient age ranged from

9.1 to 11.5 years.[37-43] The majority of patients were ma





(70–90%),[37-43] and 48–61% had received previous stimulant

treatment.[38,40-43]

The most common (‡10% of patients) co-morbid disorders

included ODD,[37-43] learning disorders,[41,42] elimination dis-

orders,[39] and phobias.[39]

Assessments were based on the modified intention-to-treat

(mITT) population[37-43] using last-observation-carried-for-

ward (LOCF) imputation.[37-41,43] Between-group differences

in baseline characteristics within each trial were not significant,

except for in a combined analysis of two studies,[39] which

showed a significantly (p < 0.05) higher mean Wechsler In-

telligence Scale Intelligence Quotient (WISC-IQ) score among

placebo than atomoxetine recipients; this was shown to have n

effect on the efficacy conclusions.Once- or twice-daily atomoxetine was effective in the shor

term treatment of ADHD in children and adolescents (table II

The mean improvement from baseline in ADHD-RS total scor

(primary endpoint) was significantly greater among atomox

etine than placebo recipients in all eight short-term tria

(reduction of 10.3–17.3 vs 5.0–9.3; all p < 0.05)[37-43] [table II]

In addition, results from the trials reporting inattentive an

hyperactive/ impulsive subscale scores[37-40,42,43] demonstrate

that these scores also improved to a significantly greater exten

after atomoxetine versus placebo administration (table II). Of th

Table I. Definition of efficacy rating scale abbreviations and description of rating scales used in clinical studies[23-26,37-57]

Rating scale Range Description

ADHD-Rating Scale (ADHD-RS) 0–54 18-item rating scale, each item corresponding to a symptom contained in the DSM-

ADHD diagnosis. Each item is scored from 0 (never or rarely) to 3 (very often). It

includes the subscales ‘inattentive’ and ‘hyperactive/ impulsive’. Parent and teacher

versions are both available

Child Health and Illness Profile-Child,

Adolescent or Parental Edition (CHIP-CE,

CHIP-AE or CHIP-PRF)

NA 76-item parent- or patient-rated quality-of-life rating scale. The total score is the mea

score of the five domains (satisfaction, comfort, resilience, risk avoidance, and

achievement), which is then standardized to a t-score (a mean –SD of 50–10, base

on norms of a sample of US children). A higher score implies a higher quality of life

Children’s Health Questionnaire (CHQ) 0–100 50-item parent-rated quality-of-life rating scale, measuring 14 physical and

psychosocial concepts. A higher score implies a higher quality of life

Clinical Global Impressions-Improvement

scale (CGI-I)

1–7 7-point scale for rating the improvement of mental illness, taking into account the tot

clinical experience. Rating is from 1 (very much improved), through to 4 (nochange),

7 (very much worsened)

Clinical Global Impressions-ADHD-Severityscale (CGI-ADHD-S)

1–7 7-point scale for rating the severity of ADHD, taking into account the total clinicalexperience. Rating is from 1 (normal) to 7 (extremely ill)

Clinical Global Impressions-Severity scale

(CGI-S)

1–7 7-point scale for ratingthe severityofmentalillness,takingintoaccount the total clinic

experience. Rating is from 1 (normal) to 7 (extremely ill)

Conners’ Parent/ Teacher Rating Scale

(CPRS/ CTRS)

0–3 per item Parent- orteacher-ratedADHD ratingscalewith directlinksto the DSM-IV. Eachitem

scoredfrom0 (never) to 3 (very often). Studies variedin thenumberof items included

their analyses

Daily Parent Ratings of Evening and

Morning Behavior scale (DPREMB)

0–52 13-item parent-completed questionnaire, examining behavior in the morning and

evening. Each item is scored from 0 (not present) to 4 (extremely problematic)

Daily Parent Ratings of Evening and

Morning Behavior-Revised scale

(DPREMB-R)

0–33 11-item parent-completed questionnaire, examining behavior in the morning (3 item

and evening (8 items). Revised version of the DPREMB. Each item is scored from

0 (no difficulty) to 3 (a lot of difficulty)

Pediatric Quality of Life Inventory (PedsQL) 0–100 4-subscale quality-of-life rating scale. A higher score implies a higher quality of life

Swanson, Kotkin, Agler, M-Flynn, and

Pelham behavioral rating scale (SKAMP)

0–6 per item 13-item rating scale representing classroom behavior (6 deportment items, 7 attention

items). Each item is scoredfrom0 (normal)to 6 (maximum impairment).The deportment an

attention subscale scores are acquired by calculating the mean of the items in each scale

Swanson, Nolan, and Pelham Rating

Scale-Revised (SNAP-IV)

0–3 per item 26-item ratingscale(18 items for ADHDsymptoms,9 items for ODD symptoms).Eac

item is scored from 0 (not at all) to 3 (very much). Scores are yielded in three domain

inattention, hyperactivity/ impulsivity, and oppositional

ADHD =attention-deficit hyperactivity disorder; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th edition; NA =not applicab

ODD =oppositional defiant disorder.





six trials reporting response rates, five[38,39,41,43] reported sig-

nificantly higher response rates among atomoxetine than placebo

recipients (59–60% vs 25–40%; a l l p< 0.05); the remaining trial[42]

reported no significant difference (69% vs 43%) [table II].The two studies investigating HR-QOL, rated on the CHQ

psychosocial summary score, reported differing results. One

study[41] reported no significant difference between atomoxetine

and placebo recipients in the change from baseline in the CHQ

psychosocial summary score (+7.1 vs+3.7; baseline scores of 32.5

and 32.1). The other study[37] reported significant differences

between patients receiving any of the three dosages of atomox

etine (0.5, 1.2, and 1.8 mg/ kg/ day) and placebo recipients for th

change from baseline in the CHQ psychosocial summary scor

(+4.4, +6.0, and +9.1 vs -0.9; all p< 0.05 vs placebo) [baselinscores of 32.9, 35.4, 31.3, and 35.2, respectively].

Other efficacy measures, including CPRS,[37-42] CTRS,[38,4

CGI-S,[38,42]and CGI-ADHD-S[39,40,43]scores, werealsosignificant

(p< 0.05) improved among atomoxetineversus placebo recipient

Two studies specifically investigating evening efficacy of

single morning dose of atomoxetine found that it had a positiv

Table II. Efficacy of oral atomoxetine (ATO) in the short-term treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD

Results from eight randomized, double-blind, placebo (PL)-controlled, multicenter trials in patients (pts) aged 6–18 years. [37-43] The primary endpoint in a

studies was the ADHD-Rating Scale (ADHD-RS) total score

Study Treatmentduration

(wk)

Age of pts(y)

Treatment

a

(mg/ kg/ day)No. of pts Mean ADHD-

RSb total score

at baseline

Mean change from baseline inADHD-RSb score

Response

c

ra(% pts)

total inattentive hyperactive/

impulsive

Brown et al.[41] 7 8–12 ATO 0.8–1.8d 99 65.6e-10.3***e 66**

PL 51 64.4e-5.0e 36

Gau et al.[40] 6 6–16 ATO £1.8d 69 36.7 -17.3**-8.7*

-8.7***

PL 29 37.1 -9.3 -5.2 -4.1

Kelsey et al.[43] 8 6–12 ATO 1.2d 126 42.1 -16.7*-8.3*

-8.5* 63***

PL 60 42.3 -7.0 -4.1 -2.9 33

Michelson et al.[37]f 8 8–18 ATO 1.2d 84 39.2 -13.6*-7.0*

-6.6*

ATO 1.8

d

82 39.7 -

13.5

*-

6.8

*-

6.7

*

PL 83 38.3 -5.8 -2.5 -3.2

Michelson et al.[38] 6 6–16 ATO 1.0d 84 37.6 -12.8***-7.1***

-5.7*** 60***

PL 83 36.7 -5.0 -2.9 -2.1 31

Spencer et al.[39]g 9 7–12 ATO £2.0d 64 41.2 -15.6***-7.5***

-8.0*** 64***

(Study 1) PL 61 41.4 -5.5 -3.0 -2.5 25

Spencer et al.[39]g 9 7–12 ATO £2.0d 63 37.8 -14.4***-7.6***

-6.9** 59*

(Study 2) PL 60 37.6 -5.9 -3.0 -2.9 40

Weiss et al.[42] 7 8–12 ATO 1.2d 100 38.9 -14.5***-7.5*

-7.0*** 69

PL 51 36.7 -7.2 -4.3 -3.0 43

a Treatment was administered either once daily in the morning[38,40-43] or in divided doses twice daily, in the morning and early evening.[37,39]

b Investigator-administered parent[37-40,43]

or teacher[41,42]

version.

c Defined as‡25% reduction frombaseline in ADHD-RStotal score;[38,39,43] anendpointt-scoreusing chi-square analysesthatwas no worsethan1 SDbelo

age and sex norms;[41] or ‡20% reduction from baseline in ADHD-RS total score. [42]

d Of the four fixed-dose trials, one titrated patients to a target dosage of ATO 0.5, 1.2, or 1.8 mg/ kg/ day,[37] and three titrated patients to a target dosage o

ATO 1.0[38] or 1.2[42,43] mg/ kg/ day, although the dosage could be further increased to 1.5[38] or 1.8[42,43] mg/ kg/ day if required. The remaining four tria

titrated patients according to therapeutic response; permitted ATO dosages were 0.8–1.8,[41] £1.8,[40] or £2[39] mg/ kg/ day.

e The ADHD-RS total score was standardized to a t-score (a mean–SD of 50–10, based on norms of a sample of children) in this study.

f An additional ATO treatment group (ATO 0.5mg/ kg/ day) wasincluded, butresults have notbeen reported as this group wasonly present to show any dos

dependent effect and was not included in the primary analysis.

g Methylphenidate treatment group was included as a positive control, but the data are not reported.

* p<0.05, ** p<0.01, *** p£0.001 vs PL.





effect compared with placebo. One study[43] reported significant

improvement on an overall evening parent-rated scale (p< 0.05 vs

placebo), as well as on five of the eight evening subscale scores

(all p<0.05 vs placebo). The other study[38] reported significantimprovement on two of the nine evening items (both p < 0.05 vs

placebo), but did not report an overall evening result.

Of the six trials[37,38,40-43] that did not exclude poor meta-

bolizers, only one reported efficacy results in this popula-

tion.[37] However, a pooled analysis of four randomized,

double-blind studies[37-39] reported that significantly (p =0.002)

greater reductions from baseline in mean ADHD-RS-IV total

scores were observed among poor metabolizers (-20.9; n= 30)

than among extensive metabolizers (-14.1; n= 559).[61] Baseline

mean ADHD-RS-IV total scores were 38.9 and 40.3 in this

pooled analysis. Response rates (percentage of patients with a‡25% decrease from baseline in ADHD-RS-IV total score)

were also significantly higher among poor metabolizers than

among extensive metabolizers (80% vs 59%; p= 0.033).

Atomoxetine efficacy does not appear to differ between

children and adolescents, but it does appear more effective

among older children than younger children. A meta-analysis

of six trials, involving children aged 6–11 years (n = 510 ato-

moxetine, n= 341 placebo) and adolescents aged 12–17 years

(n= 107 atomoxetine, n= 69 placebo) receiving atomoxetine or

placebo for 6–8 weeks, revealed no significant differences in the

effects on ADHD symptoms (rated on the ADHD-RS, the

CGI-S, and the CPRS), response rates, or time to response. [44]

Another meta-analysis of six 6- to 9-week trials compared

atomoxetine efficacy versus placebo among young children

(6–7 years; n =184 atomoxetine, n = 96 placebo) versus older

children (8–12 years; n =544 atomoxetine, n= 316 placebo).[62]

It found that, while both age groups showed a significantly

greater improvement in ADHD-RS scores and response rates

among atomoxetine versus placebo recipients (p< 0.05), older

children had significantly (p< 0.05) greater improvements in

ADHD-RS scores than younger children, regardless of whether

they were receiving atomoxetine or placebo.[62]

Discontinuation of atomoxetine does not appear to be as-sociated with symptom rebound. A prospective pooled analysis

of two »9-week randomized, double-blind, placebo-controlled

trials involving a total of 194 (102 atomoxetine £2 mg/ kg/ day

and 92 placebo recipients) children aged 7–12 years with

ADHD was carried out.[45] The trial demonstrated that among

patients originally administered atomoxetine, ADHD-RS total

scores, while worsening on treatment discontinuation (p< 0.001

vs original placebo recipients), did not return to pretreatment

levels after a 1-week discontinuation phase, during which all

patients received placebo in a single-blind manner.

4.1.2 Longer Term Treatment

A multicenter study has investigated longer term atomoxetin

administration in this population. This study was in two phase

the first[47] investigated 9-month relapse prevention in responder(response defined as a decrease of ‡25% in ADHD-RS total scor

and a CGI-S score of 1 or 2) to an initial 12-week period of open

label atomoxetine treatment; the second[46] was a re-randomize

6-month extension phase in recipients of atomoxetine in the fir

phase. Patients were aged 6–15 years and had a DSM-IV diagnos

of ADHD confirmed by K-SADS-PL, and a symptom severity o

‡1.5 SD above US age and sex norms. Exclusion criteria include

bipolar or psychotic disorders, unstable medical illness, and con

comitant psychotropic medication (other than atomoxetine).

The primary endpoint for both phases was time to relaps

(defined as an increase in ADHD-RS total score to 90%

of thbaseline score plus an increase in CGI-S score by ‡

points).[46,47] Additional endpoints included relapse rate[46,4

and ADHD-RS total,[46,47] CGI-S,[47] CHQ,[46,47] CPRS,[46,4

and CTRS[46,47] scores.

Of the 604 patients who entered the initial 12-week atomox

etine treatment period (target dosage 1.2mg/ kg/ day [as two equ

doses in the morning and evening], maximum 1.8 mg/ kg/ day

416 responded to treatment and were randomized in a double

blind manner to 9 months of atomoxetine (at the same dosag

n= 292) or placebo (n= 124) treatment. Of the atomoxetine re

cipients, 163 were re-randomized to a further 6 months of ato

moxetine (n= 81) or placebo (n= 82) treatment. The mean fina

atomoxetine dosages were 1.56 mg/ kg/ day forthe 9-month perio

and 1.55 mg/ kg/ day for the subsequent 6-month period.[46,47]

The only common (‡10% of patients) co-morbid disorder i

this study was ODD. The mean patient age ranged from 10.1 t

11.0 years, and 89–90% of patients were male.[46,47] Combine

and inattentive subtype proportions in treatment groups ran

ged from73% to74% and from 21% to23%; 5%of patients wer

hyperactive/ impulsive.[46,47] A total of 50–54% of patients i

one phase had previously received stimulant therapy.[47]

Assessments were based on the mITT population usin

LOCF imputation. Between-group differences in baselincharacteristics within each phase were not significant.

Atomoxetine was effective in the longer term treatment o

ADHD in children and adolescents. Among responders, ato

moxetine wasassociatedwith a significantly longermean time t

relapse than placebo in both the 9-month (217.7 vs 146.1 days

p< 0.001)[47] and 6-month (160.5 vs 130.8 days; p = 0.008)[4

periods. Relapse rates for atomoxetine and placebo recipien

were 22% and38% (p< 0.01)[47] in the 9-month, and 3% and 12%

(relative risk ratio for relapse with placebo vs atomoxetine 5.6

95% CI 1.2, 25.6)[46] in the 6-month periods.





Mean total ADHD scores increased to a significantly smaller

extent among atomoxetine compared with placebo recipients in

both periods (9-month:+6.8 vs+12.3, p< 0.001; 6-month: +1.7 vs

+7.8, p< 0.001); mean inattentive and hyperactive/ impulsivesymptom scores also increased to a significantly smaller extent

among atomoxetine versus placebo recipients (all p< 0.01).[46,47]

Other efficacy endpoints revealed differing results in the two

phases. In the first,[47] both CGI-S and CPRS scores increased to a

significantly (p<0.05) lesser extent among atomoxetine versus

placebo recipients; however, the change in CTRS scores did not

significantly differ between treatment groups. In the second phase,

however, CTRS score improved to a significantly greater extent

among atomoxetine than placebo recipients, and CPRS score

changes did not significantly differ between treatment groups.[46]

Atomoxetine recipients demonstrated a significantly smallerdecline in HR-QOL compared with placebo recipients, as

assessed by mean CHQ psychosocial summary scores, in the

9-month (-5.6 vs -9.5; p= 0.016)[47] but not the 6-month (-0.9

vs -2.9)[46] period.

Atomoxetine appears to maintain efficacy for at least 2 years

with no evidence of drug tolerance. Two meta-analyses of 13

trials each, one in 219 adolescents (aged 12–18 years)[49] andone

in 97 young children (aged 6–7 years)[48] with ADHD who were

treated with atomoxetine for a minimum of 2 years, showed

that atomoxetine retained significant (p< 0.001) improvement

at endpoint versus baseline in ADHD-RS scores. [48,49] Dosage

escalation was not required.[49]

4.1.3 In Stimulant-Naive Patients

Two randomized, double-blind, placebo-controlled, multi-

center trials have investigated the efficacy of atomoxetine in

stimulant-naive patients aged 6–15[60] or 7–15[59] years with a

K-SADS-PL-confirmed DSM-IV diagnosis of ADHD.[59,60]

Some additional efficacy data forthe 12-week study[60]were taken

from an abstract.[63] Patients were randomized to treatment with

atomoxetine (n= 49[59] and 99[60]) or placebo (n = 50[59,60] ) for

10[59] or12[60] weeks. The atomoxetine dosage, taken in the morn-

ing, was 0.5mg/ kg/ day (40 mg/ kg in patients weighing >70kg[59])for the first 1[59] or 2[60] weeks and increased to a target[60] dosage

of 1.2 mg/ kg/ day (80 mg/ day in patients weighing >70kg[59]) for

the rest of the treatment period.[59,60]

Eligible patients had an ADHD-RS total score of ‡1.5 stan-

dard deviations above the US[59] age[59,60] and sex[59] norms for

their diagnostic subtype, were stimulant-naive,[59,60] and were

newly diagnosed.[60] Exclusion criteria included impaired in-

tellect;[59,60] serious medical illness;[59] a history of psychosis,[59,60]

bipolar disorder[59,60] or pervasive developmental disorder;[60]

alcohol or drug abuse[59,60] within the past 3 months;[59] use of

psychoactive medication;[59,60] a need for immediate pharm

cotherapy;[59] and psychotherapy.[59,60]

Primary endpoints were the change from baseline in tota

ADHD-RS score[60] and HR-QOL, rated on the CHIP-Cachievement domain (primary endpoint data not available from

this study).[59] Other endpoints included ADHD-RS total,[5

inattention,[59,60] and hyperactivity/ impulsivity[59,60] score

CGI-S[59] or CGI-ADHD-S[60] scores, CGI-I scores,[59] respons

rates (the proportions of patients with a ‡25% or ‡40% im

provement from baseline in ADHD-RS total score),[59] an

CHIP-CE, -AE and -PRF.[60]

Most patients in both studies were male (81%[59] and 80%[60]

with a mean age of 12[59] or 10[60] years. A total of 78%[59] an

63%[60] had the combined ADHD subtype; 4%[59,60] had the hy

peractive subtype, and 18%[59]

and 33%[60]

had the inattentive subtype. The most common co-morbid disorder was ODD (20%[5

and 26%[60]); other common (‡10% of patients) co-morbiditie

included tics (14%[59] and 17%[60]) and anxiety disorders (13%[60]

Assessments were based on the mITT population,[59,60] usin

LOCF imputation.[59] No differences were reported betwee

groups in baseline characteristics.[59,60]

Atomoxetine was effective in stimulant-naive pediatric pa

tients with ADHD. ADHD-RS total scores decreased to

significantly (p< 0.001)[59,63] greater extent with atomoxetin

than with placebo (-19.0 vs -6.3[59] and -12.8 vs -4.7[60]

baseline scores in atomoxetine and placebo recipients were 38.

and 39.5[59] and 39.1 and 39.5.[60]

Atomoxetine was associated with an increased efficacy re

lated to a longer treatment duration. After 12 weeks, th

ADHD-RS total score was significantly improved compare

with after 6 weeks of atomoxetine treatment (p = 0.0132).[63]

Where reported,[59] other endpoints support the efficacy o

atomoxetine. ADHD-RS inattention and hyperactivit

impulsivity subscale scores, as well as CGI-S and -I scores, were a

significantly (p< 0.001) improved among atomoxetine versus pla

cebo recipients.[59] Significantly (p< 0.001) more atomoxetine tha

placebo recipients had a ‡25% (71% vs 29%) or ‡40% (63% v

14%) improvement in ADHD-RS total scores.[59]HR-QOL was significantly improved with regard to risk avoid

ance and achievement among atomoxetine versus placebo recip

ents; no significant difference was noted between treatment group

in theother three domains (satisfaction, comfort, and resilience).[6

When rated on the CHIP-PRF, risk avoidance and achievemen

improved to a greater extent with atomoxetine than with placeb

(+7.89 vs -0.64 [p<0.001] and +4.94 vs +1.55 [p= 0.042]); bas

line scores were 31.7 and 34.1 for risk avoidance and 33.2 an

33.1 for achievement.[60] When rated on the CHIP-CE/ A

(combined), risk avoidance again improved to a greater exten





with atomoxetine than with placebo (+3.60 vs +0.03; p= 0.006)

from baseline scores of 47.6 and 49.1; however, no significant

treatment difference was noted for achievement on this scale.[60]

4.2 Comparisons with Stimulants or Standard

Current Therapy

The efficacy of oral atomoxetine compared with other ADHD

medication in the treatment of children and adolescents aged

6–16 years with ADHD has been evaluated in six randomized

open-label[25,50,51] or double-blind,[23,24,26] multicenter, fully pub

lished trials lasting 3–10 weeks (table III).[23-26,50,51] Active com

parators included immediate-release methylphenidate,[24,2

osmotically released methylphenidate,[23,51] extended-releas

mixed amfetamine salts (this study was conducted in a laborator

school setting),[26] and standard current therapy (any combinatio

of medicines [excluding atomoxetine] and/ or behavioral counse

ing, or no treatment).[50] It should be noted that two of these tria

Table III. Efficacy of atomoxetine (ATO) vs other attention-deficit hyperactivity disorder (ADHD) medication in the treatment of children and adolescents wi

ADHD. Results from six randomized, open-label[25,50,51] or double-blind,[23,24,26] multicenter trials comparing the efficacy of ATO with immediate-releas

methylphenidate (MPH),[24,25] osmotically released MPH (OR MPH),[23,51] extended-release mixed amfetamine salts (MAS)[26] or standard current therap

(SCT)

[50]

in patients (pts) aged 6–16 yearsStudy Treatment

duration

(wk)

Age of pts

(y)

Treatmenta No.

of

pts

Mean ADHD-RSb

total score

Mean CHIP-CE

total t-score

Mean SKAMP

deportment score

Response

ratec

(% pts)baseline change baseline endpoint baseline change

Kemner et al.[51] 3 6–12 ATOd 850 38.6 -16.0e 69

(FOCUS) OR MPHd 473 39.9 -20.2**e 80**

Kratochvil et al.[25] 10 7–15 (boys) ATO £2 mg/ kg/ dayf 178 39.4 -19.4e

7–9 (girls) MPH 5–60mg/ day 40 37.6 -17.8e

Newcorn et al.[23] 6 6–16 ATO 0.8–1.8 mg/ kg/ day 222 40.9 -14.4 45ze

OR MPH 18–54 mg/ day 220 40.0 -16.9* 56*zzg,e

PL 74 41.7 -7.3 24e

Prasad et al.[50] 10 7–15 ATO 0.5–1.8 mg/ kg/ day 104 45.5 23.5-h 23.2 38.4-e 79-/ 65-i

(SUNBEAM) SCT j 97 45.6 33.7h 23.9 30.8e 48/ 35i

Wang et al.[24] 8 6–16 ATO 0.8–1.8 mg/ kg/ day 162 38.6 -21.1 77e,k

MPH 0.2–0.6 mg/ kg/ day 164 37.4 -21.6 82e

Wigal et al.[26] 3 6–12 ATO 0.5–1.4 mg/ kg/ day 101 1.63 -0.13e 38/ 28l

(StART) MAS 10–30 mg/ day 102 1.44 -0.56**e 70**/ 68**l

a ATO wasadministered eitheroncedaily,[24,26,51] in divided doses twice daily,[23,25] orone ortheother.[50] MPH was administeredeither twice daily[24] oron

of once, twice or three times daily. [25] OR MPH and MAS were both administered once daily.[23,26,51]

b Studies used an investigator-administered version of the parent[24,25] or an unspecified[23,50,51] version of ADHD-RS.

c Defined as a ‡25%[50,51] and/ or ‡40%[23,24,50] reduction from baseline in ADHD-RS total score; or a ‡25% improvement on the SKAMP deportment

attention scales.[26]

d Dosage was individually tailored to simulate clinical practice, on the basis of clinical judgment and the US FDA-approved prescribing information.e Primary endpoint.

f Cytochrome P450 2D6 poor metabolizers received ATO 0.2–1.0 mg/ kg/ day.

g ATO did not demonstrate noninferiority to OR MPH.

h Presented as value at endpoint, not change from baseline.

i Data presented as ‡25%/ ‡40% response rate.

j SCT included any combination of medicines (excluding atomoxetine) and/ or behavioral counseling, or no treatment.

k ATO was noninferior to MPH.

l SKAMP deportment/ attention scale response rate.

ADHD-RS =ADHD-Rating Scale; CHIP-CE=Child Health and Illness Profile-Child Edition; FOCUS =Formal Observation of Concerta versUs Stratter

PL =placebo; SKAMP =Swanson, Nolan, and Pelham Rating Scale; StART =Strattera/ Adderall Randomized Trial; SUNBEAM=Study into the broad

efficacy of atomoxetine; *

p<

0.05, **

p<

0.001 vs ATO; -

p<

0.001 vs SCT; z

p=

0.003, zz

p£

0.001 vs placebo.





(comparing atomoxetine with extended-release mixed amfetamine

salts[26] and osmotically released methylphenidate[51]) were of only

3 weeks’ duration; full benefits of atomoxetine often take several

weeks (potentially up to 8 weeks)[8] to occur.[2,64] Additionally, oneof the studies comparing atomoxetine with immediate-release me-

thylphenidate reported preliminary results only, from a study in-

vestigating relapse prevention, and was not powered for

comparisons between the two drugs;[25] despite this, statistical

comparisons were still reportedandare included in this section. One

trial titrated atomoxetine recipients to a target dosage of atomox-

etine 1.2 mg/ kg/ day (maximum permitted dosage was 1.4 mg/ kg/

day); the extended-release mixed amfetamine salt dosage was in-

creased in 10mg increments at 1-week intervals to a final dosage of

30mg/ day.[26] One trial administered atomoxetine or osmotically

released methylphenidate with an individually tailored dosage, tosimulate the clinical setting.[51] The remaining trials titrated patients

according to therapeutic response, with permitted atomoxetine

dosages of £2,[25] 0.8–1.8,[23,24] 0.5–1.8[50] mg/ kg/ day, immediate-

release methylphenidate dosages of 5–60mg/ day[25] or 0.2–0.6 mg/

kg/ day,[24] and osmotically released methylphenidate dosages of

18–54 mg/ day.[23] Where stated, the mean final dosages were

1.08,[51] 1.40 (among extensive metabolizers only),[25] 1.45,[23] 1.5,[50]

and 1.37[24] mg/ kg/ day for atomoxetine, and were 31.3 mg/ day[25]

and 0.52 mg/ kg/ day[24] for immediate-release methylphenidate and

1.01[51] and 1.16[23] mg/ kg/ day for osmotically released methylphe-

nidate. Certain limitations of these trials are discussed in section 8.

In the trial comparing atomoxetine with standard current

therapy, at baseline 75.3% of patients in the SCT arm received

only pharmacotherapy, 3.1% received simple behavioural

counselling, and 10.3% received both pharmacotherapy and

simple behavioural counselling; 11.3% received no treat-

ment.[50] Pharmacotherapy included immediate-release me-

thylphenidate (37.3%), extended-release methylphenidate

(47.0%), clonidine (3.6%), or combinations thereof (12%).

Eligible patients met DSM-IV criteria for ADHD (any sub-

type[23-25,50,51] or either combined or hyperactive/ impulsive sub-

types[26]), confirmed by K-SADS-PL[23,24,50] or an unspecified

K-SADS version,[25] and had to have an investigator-administeredADHD-RS total score of ‡24,[51] ‡25 for boys and ‡22 for girls,[24]

‡1.5 SD above age and/ or sex norms,[23,25,50] or >12 for a specific

subtype.[24] One trial required a CGI-S score of ‡4,[51] another

a CGI-ADHD-S score of ‡4.[24] Exclusion criteria included

other psychiatric disorders (except ODD;[51] e.g. depression,[26]

bipolar disorders,[23-26,50] anxiety disorders,[23,24,26] psychotic dis-

orders[23-26,50]); a history of seizure,[23,26,50,51] tic disorder,[23-26,51]

mental retardation[51] or developmental disorder;[23,24,26,50,51]

Tourette’s syndrome;[24-26,51] use of concomitant psychotropic

medication;[24,26,50,51] and serious medical illness.[25,50] Three

studies excluded patients who had not responded to previou

ADHD treatment.[23,25,51]

Primary endpoints were ADHD-RS investigator-admini

tered total score (parent[25] or unspecified[51] version), CHIP-Ctotal t-score,[50] SKAMP deportment score,[26] and respons

(defined as a ‡40% reduction from baseline in ADHD-RS tota

score) rate.[23,24] Additional endpoints included response rat

(see table III for definitions),[26,50,51] and ADHD-RS,[23,24,50,5

CPRS,[23-25] CGI-ADHD-S,[23-25] CGI-S,[50] and SKAMP a

tention[26] scores. Two studies[23,26] also investigated HR-QOL

using the PedsQL[26] or CHQ.[23]

Theproportions of patients in treatment groupswith ADHD o

the combined, inattentive and hyperactive/ impulsive subtype

ranged from 57% to 100%, from 0% to 39% and from 0% to 13%

respectively.

[23-26,50,51]

The most common co-morbid disorde(‡10%of patients) were ODD[23-25,50] and elimination disorders.[2

Mean patient age ranged from 8.6 to 11.1 years,[23-26,50,51] an

69–100% of patients were male.[23-26,50,51] A total of 23–67% o

patients had received prior ADHD treatment.[23,24,51]

Where stated, assessments were based on the mITT popu

lation[23-26,50] using LOCF imputation.[23-25,50] Between-grou

differences in baseline characteristics within each trial were e

ther not significant[23,26] or accounted for in the analyses,[50,5

except for one significant (p < 0.05) difference in sex propor

tions[25] and another (p<0.05) in patient age.[24] Two trials wer

noninferiority studies; noninferiority of atomoxetine to im

mediate-release methylphenidate[24] or osmotically release

methylphenidate[23] was established if the lower limit of the 95%

confidence interval (CI) for the difference between groups i

response rate was greater than -18%[24] or -15%.[23]

Atomoxetine did not differ significantly from[25] or was non

inferior to[24] immediate-release methylphenidate, with regard t

the primary endpoints (change from baseline in ADHD-RS tot

score[25] and response rate[24]) in children and adolescents wit

ADHD (table III). In terms of response rate, the lowerlimit of th

95% CI for the difference between atomoxetine and immediate

release methylphenidate was -11.7%.[24] Recipients of atomox

etine did not differ significantly from those receiving immediaterelease methylphenidate in the mean change from baseline o

ADHD inattention (-11.3 vs -12.0[24] and -9.9 vs -9.3[25]) o

hyperactivity/ impulsivity (-9.7 vs -9.5[24] and -9.5 vs -8.5[25

subscale scores, although both treatment groups showed score

significantly lower than baseline (both p<0.001).[24,25] Othe

additional endpoints (CPRS and CGI-ADHD-S scores) did no

differ significantly between groups.[24,25]

Atomoxetine was significantly less effective than osmoticall

released methylphenidate[51] and extended-release mixed amfe

tamine salts,[26] both controlled-release formulations of stimu





lants, in the change from baseline in ADHD-RS total score[51]

and SKAMP deportmentscore[26] (tableIII). In terms of response

rate, atomoxetine was not noninferior to osmotically released

methylphenidate (lower limit of the 95% CI for between-groupdifference of -21%); the response rate was subsequently shown to

be significantly higher in osmotically released methylphenidate

recipients than in atomoxetine recipients (table III).[23] In addi-

tion, response rates were significantly higher with osmotically

released methylphenidate[51] or extended-release mixed amfeta-

mine salts[26] than with atomoxetine in two other trials (table III).

Mean SKAMPattention score improvement was also significant-

ly lower among atomoxetine than extended-release mixed

amfetamine salt recipients (-0.08 vs -0.49; p<0.001),[26] and ato-

moxetine recipients demonstrated a significantly (p < 0.01) lower

improvement on the CPRS and CGI-ADHD-S scales comparedwith recipients of osmotically released methylphenidate.[23]

In a subanalysis, the response rates among stimulant-ex-

posed patients (n = 301) receiving atomoxetine versus osmoti-

cally released methylphenidate were significantly different

(37% vs 51%; p = 0.03) and only osmotically released methyl-

phenidate differed significantly from placebo (23%; p= 0.002);

however, among stimulant-naive patients (n= 191), the two

active treatment groups did not differ significantly from each

other (57% vs 64%) and both differed significantly from pla-

cebo (25%; p= 0.004 and p £ 0.001, respectively).[23]

When compared with standard current therapy, atomoxetine

had a significantly greater positive impact on HR-QOL, as

assessed by the mean CHIP-CE total t-score at endpoint[50]

(table III). Atomoxetine was also significantly moreeffective than

standard current therapy in terms of ADHD-RS total score and

response rate at endpoint (table III), as well as on the ADHD-RS

subscale scores (inattention 12.1 vs 17.3; p< 0.001; hyperactivity/

impulsivity 11.3 vs 16.3; p< 0.001).[50] Atomoxetine was asso-

ciated with a significant improvement versus standard current

therapy with regard to CGI-S score (p < 0.001).[50]

4.3 In Patients with Co-Morbid Conditions

While most of the major efficacy trials investigating atomox-

etine have allowed the inclusion of patients with co-morbid

ODD, other disorders are also common in patients with ADHD,

and were either not permitted in these trials or patient numbers

with theseco-morbid disorderswere low. Therefore, randomized,

double-blind, placebo-controlled trials,[52-57] mainly of multi-

center design,[52-55,57] have been conducted in patients with co-

morbid anxiety disorders,[52,53] depressive disorders,[53,55] tic dis-

orders (including Tourette’s syndrome),[57] and autism spectrum

disorders (including Asperger’s syndrome).[56] An additional trial

in patients with ADHD and co-morbid ODD has also bee

conducted.[54]

Eligible patients were children or adolescents (aged 5–18 year

mean9.3–14.6 years)[52-57] with a DSM-IVdiagnosis of ADHD[52-5

and a total or subscale ADHD-RS score of ‡1.5 SD above ag

and sex norms,[52,55,57] and/ or a Children’s Depression Ratin

Scale-revised total score >36[53] or ‡40.[55] Patients were also re

quired to have a DSM-IV diagnosis of an anxiety disorder,[52,5

depressive disorder,[53] major depression,[55] Tourette’s syn

drome,[57] tic disorders,[57] autism spectrum disorder,[5

or ODD.[54] Diagnoses were confirmed using the K-SADS

PL.[52-55,57] One study[52] focused on patients who did no

respond during the placebo lead-in period, based on a £25%

reduction in Pediatric Anxiety Rating Scale (PARS) scor

Patient numbers ranged from 16

[56]

to 226,

[54]

with most studieinvolving between 100 and 200 patients.[52,53,55,57]

Not all primary endpoints related to efficacy with regard t

ADHD (most focused on both ADHD and the co-morbi

condition,[52,54-57] one focused on tolerability[53]); the mai

ADHD endpoints of each trial (ADHD-RS total,[52,53,55,5

DSM-IV ADHD symptoms,[56] and SNAP-IV ADHD sub

scale[54] scores) are focused on in this section.

Patients did not receive concomitant psychotropic treatmen

for their co-morbid conditions in most studies;[52,54-57] the on

exception[53] involved all patients receiving atomoxetine an

being randomized to fluoxetine or placebo.

The efficacy of atomoxetine does not appear to be affected b

the presence of co-morbid disorders, and symptoms of th

co-morbid disorders were either not adversely affected or im

proved in these studies.[52-57] Atomoxetine was more effectiv

than placebo in the treatment of ADHD in patients with co

morbid anxiety disorders (mean change in ADHD-RS total scor

of -10.5 vs -1.4; p< 0.001),[52] major depression (mean change i

ADHD-RS total score of -13.3 vs-5.1; p< 0.001),[55] tic disorde

(including Tourette’s syndrome) [mean change in ADHD-R

total score of -10.9 vs -4.9; p< 0.01],[57] autism spectrum di

orders (mean DSM-IV ADHD hyperactive/ impulsive symptom

score at endpoint of 10.4 vs 14.5; p< 0.01; no significant betweengroup difference in inattentive symptom score),[56] and ODD

(mean change in SNAP-IV ADHD hyperactive/ impulsive sub

scale score of -4.6 vs-2.2; p< 0.01; change in inattentive subsca

score of -5.0 vs -2.2; p< 0.001).[54]

In general, symptoms of co-morbid conditions were not wor

ened by the use of atomoxetine;[54,55,57] for example, in childre

with co-morbid tic disorder Yale Global Tic Severity Scale tota

scores in atomoxetine recipients did not differ significantly from

those in placebo recipients (-5.5 vs -3.0) and Tic Symptom Sel

Report total scores were -4.7 and -2.9, while Clinical Globa





Impressions tic/ neurologic severity scale scores were significantly

improved with atomoxetine (-0.7 vs -0.1; p= 0.002).[57]

In addition, in some trials[52,56] the co-morbid conditions

were improved by treatment with atomoxetine; for example, inpatients with anxiety disorders Pediatric Anxiety Rating Scale

scores in atomoxetine recipients were significantly improved

with respect to placebo (-5.5 vs -3.2; p< 0.012).[52]

When administered alone, atomoxetine did not significantly

differ from atomoxetine plus fluoxetine with regard to ADHD

(mean change in ADHD-RS total score of -20.5 vs -24.0) or

anxiety symptoms (mean change in Multidimensional Anxiety

Scale for Children score of -11.3 vs -13.4).[53] Depression

measures were inconclusive in this study: there was a significant

difference between groups in favor of combination treatment in

the change in mean Children’s Depression Inventory score(-5.4 vs -8.8; p= 0.43), but no significant difference was found

in the change in mean Children’s Depression Rating Scale-

Revised score (-17.6 vs -20.4).

5. Tolerability

This section focuses primarily on data from the US prescrib-

ing information,[10] supplemented by data from two meta-

analyses[65,66] and the trials reported in section 4.[23-26,37-43,46,47,50-57]

Oral atomoxetine was generally well tolerated in children and

adolescents with ADHD. Common (‡5% of atomoxetine recipi-ents and reported by numerically more atomoxetine than placebo

recipients) adverse events from placebo-controlled trials of £18

weeks’ duration are shown in figure 1, and included headache,

abdominal pain, decreased appetite, vomiting, somnolence, and

nausea.[10]

In individual placebo-controlled trials, significantly (p< 0.05

more atomoxetine than placebo recipients reported decrease

appetite (18–36% vs 4–17%),[38-40,42,43] somnolence (15–17% v

2–4%),[42,43] vomiting (15% vs 1%),[38] nausea (12–17% v0–2%),[38,40] asthenia (11% vs 1%),[38] fatigue (10% vs 2%),[43] an

dyspepsia (9% vs 0%).[38]

Where reported, the severity of adverse events among ato

moxetine recipients was generally classified as mild[51] or mil

to moderate.[24,26,50,55] Most studies either did not report the in

cidenceof serious adverse events[23,25,37,38,40,41,43,46,47,52-54] or state

that there were none among atomoxetine recipients.[26,39,42,50,55,5

Where reported, serious adverse events included aggressive beha

vior,[56] partial seizure,[24] and prolonged crying (fear of death),[5

and had a low incidence.

A total of 3%

of atomoxetine recipients (48 of 1613) versu1% of placebo recipients (13 of 945) discontinued treatmen

because of adverse events in short-term studies, with advers

events leading to discontinuation including irritability, som

nolence, aggression, nausea, vomiting, abdominal pain, con

stipation, fatigue, feeling abnormal, and headache.[10]

Atomoxetine appears better tolerated among extensive me

tabolizers than poor metabolizers. The US prescribing in

formation reported that adverse events occurring in ‡5% o

poor metabolizers and either twice as frequently or significant

(p-value not stated) more frequently among poor metabolizer

than extensive metabolizers included tremor (5% vs 1%), de

pression (7% vs 4%), constipation (7% vs 4%), decreased weigh

(7% vs 4%), and insomnia (15% vs 10%).[10] A pooled analys

of 14 studies reported significant differences between poo

(n= 237) and extensive (n= 3017) metabolizers receiving ato

moxetine in the incidence of decreased appetite (24% vs 17%

p =0.008), insomnia (11% vs 7%; p= 0.035), abrasion (5% v

2%; p = 0.012), and tremor (5% vs 1%; p< 0.001).[61]

Atomoxetine appears generally well tolerated in the long

term treatment of children and adolescents with ADHD. Dis

continuations due to adverse events in long-term placebo

controlled trials among atomoxetine versus placebo recipient

occurred in 3%[47]

and 1%[46]

versus 1%[47]

and1%.[46]

A total o66% atomoxetine versus 54% placebo recipients reported a

least one new or worsened adverse event.[47] Common advers

events included headache (10% atomoxetine vs 9% placeb

recipients) and nasopharyngitis (8% vs 9%).[46]

Atomoxetine appears associated with weight loss to varyin

degrees in comparison with other ADHD medication. Overall, i

placebo-controlled trials the incidence of weight loss was 3% o

atomoxetine vs 0% of placebo recipients.[10] Long-term placebo

controlled trials demonstrated that a switch to placebo was a

sociated with a greater increase in weight than atomoxetin

0 5 10 15 20

Headache

Abdominal pain

Decreased appetite

Vomiting

Somnolence

Nausea

Fatigue

Irritability

Dizziness

Incidence (% patients)

ATO

PL

Fig. 1. Tolerability of oral atomoxetine (ATO) in pediatric patients with

attention-deficit hyperactivity disorder. Incidence of common (‡5% of ATO

recipients [n =1597] and reported by numerically more ATO recipients than

placebo [PL] recipients [n=934]) treatment-emergent adverse events asso-

ciated with ATO and PL. Data from trials of £18 weeks’ duration.[10]





continuation (weight +3.3 vs +1.2kg; p< 0.001;[47] weight per-

centile +9.9 vs +0.72; p< 0.001[46]). Of the active comparator

studies, one[24] found significantly (p< 0.001) greater weight loss

among atomoxetine versus immediate-release methylphenidaterecipients (-1.2 vs -0.4 kg), and one[23] found significantly lower

weight loss among atomoxetine versus osmotically released me-

thylphenidate recipients (-0.6 vs -0.9kg; p< 0.05). Where re-

ported in the other active comparator trials, weight loss did not

differ significantly between treatment groups.[25,50] Longer term

weight data (£5 years) are presented in section 2.2, and imply that

this weight loss is not permanent.

Where reported, no clinically significant changes in labora-

tory test values occurred in any of the short-[23-25,40,42,43] or

long-[46,47] term trials.

Atomoxetine was associated with a significantly (p<

0.05)greater incidence of somnolence (11–26% vs 0–4%),[24,25] nausea

(20% vs 10%),[24] vomiting (12% vs 0–4%),[24,25] anorexia (37% vs

25%),[24] and dizziness (15% vs 7%)[24] compared with immediate-

release methylphenidate. Immediate-release methylphenidate

was associated with a significantly (p < 0.05) greater incidence of

abnormal thinking than atomoxetine (5% vs 0%).[25] One study

found that the incidence of discontinuation due to adverse events

did not differ significantly between groups;[25] another showed

significantly (p< 0.05) more atomoxetine than immediate-release

methylphenidate recipients discontinued because of treatment-

emergent adverse events (11% vs 4%), and had an overall sig-

nificantly (p< 0.001) greater incidence of treatment-emergent

adverse events (87% vs 68%).[24]

In one study comparing atomoxetine with osmotically released

methylphenidate and placebo,[23] recipients of atomoxetine had a

significantly (p< 0.05) greater incidence of somnolence compared

withosmotically released methylphenidate but not placebo (6%vs

2% and 4%), whereas osmotically released methylphenidate was

associated with a significantly (p< 0.05) greater incidence of in-

somnia compared with atomoxetine and placebo (13% vs 7%

and 1%).[23] Both atomoxetine and osmotically released methyl-

phenidate were associated with a significantly higher incidence of

decreased appetite compared with placebo (14% and 17% vs 3%),but did not differ significantly from each other. Atomoxetine was

associated with a significantly higher rate of any treatment-emer-

gent adverse events than placebo (67% vs 54%); osmotically re-

leased methylphenidate did not differ from either other treatment

group in this measure (67%).[23] In the other study comparing ato-

moxetine to osmotically released methylphenidate, adverse events

included somnolence (4% of atomoxetine vs 1% of osmotically

released methylphenidate recipients), nausea (5% vs 1%), fatigue

(3% vs 0%), insomnia (2% vs 6%), and decreased appetite (3% vs

6%).[51] Atomoxetine and osmotically released methylphenidate

recipients did not differ significantly in overall incidence of ad

verse events, the incidence of treatment-related adverse events, o

the incidence of discontinuations due to adverse events.

In the trial comparing atomoxetine with extended-releamixed amfetamine salts, the most commonly occurring trea

ment-related adverse events among atomoxetine recipients wer

somnolence (19% of patients), decreased appetite (18%), uppe

abdominal pain (15%), and headache, and among extended

release mixed amfetamine recipients were insomnia (28% of pa

tients), decreased appetite (28%), upper abdominal pain (19%

and anorexia (17%).[26] In this study, a total of 73% of atomox

etine versus 85% of extended-release mixed amfetamine salt r

cipients reported treatment-emergent adverse events, 65% versu

74% reported a study medication-related adverse event, and 4%

and 7%

discontinued treatment because of adverse events.

[26]

A pooled analysis using data from two open-label atomox

etine studies demonstrated that the initiation of therapy using

twice-daily divided dose regimen compared with a once-dai

regimen could potentially decrease the risk of adverse event

within the first few weeks of treatment.[67] The incidence o

decreased appetite in the first 2 weeks was significantly highe

among once-daily than among twice-daily atomoxetine r

cipients (14% vs 8%; p = 0.036), as was somnolence (14% vs 4%

p <0.001). The incidence of headache was, however, lowe

among once-daily recipients (7% vs 17%; p = 0.003).

Discontinuation of atomoxetine appears to be well tolerated

A prospective pooled analysis of two 9- to 10-week trials i

children aged 7–12 years with ADHD demonstrated that after

1-week discontinuation phase, during which all patients receive

placebo in a single-blind manner, there was a low incidence o

discontinuation-emergent adverse events, and no significant di

ferences were observed between patients previously receivin

atomoxetine and those receiving placebo throughout.[45]

5.1 Specific Adverse Events

The US prescribing information carries a black-box warnin

regarding suicidal ideation in children and adolescents; it appeato be more common among atomoxetine than placebo recip

ents.[10] A meta-analysis including 14 pediatric clinical tria

(12 placebo-controlled and 5 including a methylphenidate trea

ment arm) was conducted investigating the suicidality of patient

aged 6–18 yearsreceiving atomoxetine.[66]No suicides occurred i

the trials included in the meta-analysis. The frequency of suicida

ideation was greater among atomoxetine (n= 1357) than placeb

(n= 851) recipients (0.37% vs 0%; incidence difference 0.46; 95%

CI 0.09, 0.83; p = 0.016), but did not differ significantly betwee

atomoxetine (n= 558) and methylphenidate (n=464) recipien





(0.18% vs 0.22%; incidence difference -0.12; 95%CI-0.62, +0.38).

All patients with suicidal ideation in placebo-controlled trials

were male and aged between 7 and 12 years. With atomoxetine,

the number needed to harm for an additional suicide-relatedevent was 227; the number needed to treat for achievement of

remission of ADHD symptoms was 5.[66] Patients starting atomox-

etine therapy should be closely monitored for suicidal thinking

and behavior, clinical worsening, or unusual changes in behavior.[10]

Rarely, atomoxetine may be associated with severe liver in-

jury.[10] A retrospective study investigated the incidence of liver-

related adverse events in pediatric and adult patients treated with

atomoxetine in clinical trials, as well as among spontaneous post-

marketing reports of adverse events.[65] Among recipients of

atomoxetine in clinical trials, 41 of 7961 (0.5%) had hepatobiliary

events that were considered possibly related to atomoxetine; mostof these were mild increases in ALT or AST levels. [65] Four years

after the market launch of atomoxetine, a total of 351 liver-

related adverse events had been reported (among a total of

4 328 000 recipients of atomoxetine; <0.01%). Of these, 69 were

explainable by factors unrelatedto atomoxetine, 146 hadtoo little

information to assess fully, 133 had possible confounding factors

and were deemed possibly atomoxetine-related, and 3 found

atomoxetine to be probably related. These three patients all re-

covered after atomoxetine discontinuation.[65] Patients who have

jaundice or laboratory evidence of liver injury should discontinue

atomoxetine treatment; treatment should not be re-initiated.[10]

There is the potential for cardiovascular effects with ato-

moxetine administration. Both the US[10] and the UK[11] prescrib-

ing information include precautions regarding cardiovascular

effects. Caution should be used when prescribing atomoxetine to

children and adolescents with serious structural cardiac ab-

normalities[10,11] (a cardiac specialist should be consulted in these

patients)[11] or other serious heart problems,[10] as sudden death

has been reported in these patients;[10,11] caution should also be

used in patients with congenital long QT interval, acquired long

QT interval, or a family history of QT prolongation. [11] There

have been post-marketing spontaneous reports of prolonged QT

intervals during atomoxetine administration.[10,11]In a pooled analysis of placebo-controlled trials, 2.5% (36 of

1434 patients) of atomoxetine and 0.2% (2 of 850) of placebo

recipients demonstrated a heart rate of at least 110 bpm plus an

increase in heart rate of ‡25 bpm at endpoint.[10] A total of4.8%

(59 of 1226) of atomoxetine and 3.5% (26 of 748) of placebo had

high SBP at endpoint; corresponding proportions of patients

with high DBP at endpoint were 4.0% (50 of 1262) and 1.1%

(8 of 759).[10] Caution should be used when administering

atomoxetine in patients with hypertension,[11] tachycardia,[11]

other conditions associated with abrupt heart rate or BP

changes,[10] cardiovascular disease,[11] or cerebrovascular di

ease,[11] as well as in patients with hypotension.[10,11]

A study conducted by FDA officials indicates that atomox

etine use (as well as other ADHD medication use) is potentiallassociated with hallucinations and other psychotic symptoms.[6

In a pooled analysis from 49 randomized, placebo-controlle

clinical trials of extended-release mixed amfetamine salts (fou

trials), dexmethylphenidate (seven trials), extended-relea

methylphenidate (tablets [four trials] and capsules [four trials]

long-acting extended-release methylphenidate (three trials), me

thylphenidate transdermal system (eight trials), modafinil (fiv

trials), and atomoxetine (14 trials), the rate of psychosis/ man

events per 100 person-years was 1.48 in the drug group compare

with 0 in the placebo group. Of the eleven psychosis/ mania even

occurring in the pooled drug group, four occurred among atomoxetine recipients.[68]

There have been post-marketing spontaneous reports o

seizures.[10,11] No fatal overdoses occurred in clinical trials, an

there have been no post-marketing reports of death by overdos

with atomoxetine alone.[10]

6. Pharmacoeconomic Considerations

This section provides a brief overview of recent pharmaco

economic analyses of atomoxetine in the treatment of chi

dren[69-72] and adolescents[70] with ADHD. The cost effectivenes

of atomoxetine compared with other treatments (immediate- o

extended-release methylphenidate,[69-72] dexamfetamine, [69,71] tr

cyclic antidepressants,[71] or no medication[69,70,72]), as a cos

utility analysis, has been investigated in one fully publishe

paper[69] and three abstracts with attached posters[70-72] (table IV

All four analyses used a Markov model, incorporating 10,[7

14,[70] 18,[69] or 22[71] health states, to estimate the costs and ben

efits of the treatment strategies, and estimated the incrementa

cost per quality-adjusted life-year (QALY) gained with atomox

etine versus the comparator strategies.[69-72] A surveyof 83 paren

of children with ADHD provided utility values for all four stu

dies, and efficacy andsafety of theinvolved treatments were baseon a review of controlled clinical trials and other clinical litera

ture.[69-72] Costs and outcomes were estimated using a Mon

Carlo simulation, with a time horizon of 1 year;[69-72] costs wer

estimated from the perspective of the National Health Service i

England and Wales,[69] Dutch society,[71] the German health se

vice,[72] and the Norwegian healthcare system.[70] All four studie

included direct costs[69-72] (two studies only included study dru

costs[69,72] ), with one study also including indirect costs.[71]

All four studies divided patients into three groups: stimulan

naive, stimulant-failure, and stimulant-contraindicated.[69-72]Th





fully published study also included stimulant-averse patients

(results for this group are not reported here), and further split the

stimulant-contraindicated patients into stimulant-naive and -ex-

posed.[69] Treatment algorithms differed slightly between studies,

but involved an atomoxetine-based algorithm versus a com-

parator algorithm, with numbers of treatments in each algorithm

ranging from two to five for stimulant-naive patients, one to four

for stimulant-failed patients, and one to three for stimulant-

contraindicated patients.

Initial atomoxetine treatment algorithms appear cost effective

versus algorithms involving initial methylphenidate (immediate-

or extended-release), dexamfetamine, tricyclic antidepressants, or

no treatment in stimulant-naive, -failed, and -contraindicated

children and adolescents with ADHD (table IV).[69-72] The in-

cremental cost per QALY gained was below commonly accepted

cost-effectiveness thresholds.[69-72] Sensitivity analyses demon-

strated that the models were robust to changes in most variables;

however, utility values were shown to be important indicators of

cost effectiveness.[69-72]

An additional study (available as a poster) investigating the

cost effectiveness of atomoxetine versus placebo with regard to

societal costs in Sweden found that placebo was dominated byatomoxetine.[73] Costs were taken from 2005 databases, with an

exchange rate of h1= 9.2 Swedish kronor, and included both in-

direct and direct costs. Stimulant-naive patients with ADHD

(aged 7–15 years) were randomized to 10 weeks of treatment with

atomoxetine or placebo; both groups received additional parental

training. Atomoxetine was associated with a significantly greater

least squares mean change from baseline in ADHD-RS score

(-19.0 vs -6.3; p<0.001), and total cost (excluding costs due to

loss of leisure time) decreased among atomoxetine recipients and

increased among placebo recipients (-h349 vs +h246; p= 0.002).

Pharmacoeconomic analyses of atomoxetine, in common wit

all pharmacoeconomic analyses, are subject to a number of lim

itations. Pharmacoeconomic analyses based on clinical trials ex

trapolate the results of such trials to the general population

however, patient populations, rates of compliance, and majo

outcomes in clinical trials may differ from those observed in rea

life practice. Modeled analyses, such as those presented in th

section, rely on a number of assumptions and use data from

variety of sources. Results of pharmacoeconomic analyses ma

not be applicable to other geographical regions because of di

ferences in healthcare systems, medical practice, and unit costs

7. Dosage and Administration

Atomoxetine is indicated in various countries including th

US[10] and the UK[11] for the treatment of children and ado

lescents with ADHD;[10,11] atomoxetine is approved for use i

children aged ‡6 years in the UK.[11]

Table IV. Pharmacoeconomic evaluation of atomoxetine vs other or no medication in children [69-72] and adolescents[70] with attention-deficit hyperactivi

disorder (ADHD). Incremental cost per quality-adjusted life-year (QALY) gained, estimated using a Markov model with a time horizon of 1 year

Study Perspective Year of Incremental cost per QALY gained

costing stimulant-naive pts stimulant-failed pts stimulant-contraindicated pts

IM MPH ER MPH DA IR no med TCA no med

Cottrell et al.[69] NHS in England and Wales 2004 d15224 d13241 d14945 d11523/ 12370a

Diamantopoulos et al.[72]b German health service NR h18227 h7778 h14385 h14916

Laing et al.[71]b Dutch societal NR h18831 h22804 h13 120 Dominant

Tilden et al.[70]b Norwegian healthcaresystem 2005 h25463ch19162c

h21497ch22385c

a Stimulant-naive/ -exposed patients.

b Available as abstract plus poster.

c Converted from Norwegian kroner (NOK) using the exchange rate as at 13/ 10/ 2005 of NOK1 =h0.12784.

DA IR =dexamfetamine immediate release; ER MPH =extended-release methylphenidate; IM MPH = immediate-release methylphenidate; N HS=Nation

Health Service; no med=no medication; NR =not reported; pts =patients; TCA = tricyclic antidepressants.

Table V. Summary of recommended atomoxetine dosage and administrtion in pediatric patients according to bodyweight.a Local prescribing i

formation should be consulted for further details

Atomoxetine

dosage

£70kg

(mg/ kg/ day)

>70kg

(mg/ day

Initial dosage 0.5 40

Target dosageb 1.2 80

Maximum dosage 1.4 (US) 100

a According to both US[10] and UK[11] labeling unless otherwise specified

b The minimum periodbefore thefirst dose incrementis 3 days in theUS[1

or 7 days in the UK.[11]





Recommended atomoxetine dosages and the administration

schedule are presented in table V. No additional benefit has been

shown for atomoxetine dosages exceeding 1.2 mg/ kg/ day.[10,11]

Atomoxetine can be taken with or without food, and can bediscontinued without tapering.[10,11] Capsules should be taken

whole.[10] Atomoxetine can be administered either as a single

daily dose in the morning, or as evenly divided doses in the

morning and late afternoon or early evening.[10]

The US prescribing information contains a black-box

warning regarding suicidal ideation (section 5).[10]

Initial and target atomoxetine dosages should be halved in

patients with moderate hepatic impairment (Child-Pugh class B)

and reduced by three-quarters in patients with severe hepatic im-

pairment (Child-Pugh class C).[10,11] No dosage adjustment is re-

quired for patients with end-stage renal disease or lesser degreesof renal insufficiency.[10,11] In the UK, in patients who are known

to be poor metabolizersor whoare receivingconcomitant CYP2D6

inhibitors, such as paroxetine, a lower starting dose and slower

dosage up-titration than extensive metabolizers should be con-

sidered.[11] In the US, patients who are either poor metabolizers

or who are receiving concomitant strong CYP2D6 inhibitors are

recommended to initiate treatment at the normal dosage, but

only increase to the normal target dosage if no response has oc-

curred after 4 weeks and if the initial dosage is well tolerated.[10]

Local prescribing information should be consulted for con-

traindications, precautions and warnings, drug interactions,

dosage modifications, and patient monitoring requirements.

8. Place of Atomoxetine in the Management of

Attention-Deficit Hyperactivity Disorder

The main aim of therapy for ADHD patients is to improve

psychologic functioning (including academic, family, and social

functioning),[74] i.e. thecore symptoms of ADHD. Both behavioral

and pharmacologic therapies, as well as psychoeducation, are re-

commended.[74] Current treatment guidelines recommend the

first-line use of psychostimulants (e.g. methylphenidate) and/ or

psychosocial intervention for the treatment of children (aged over6 years) and adolescents with ADHD, particularly if no co-morbid

condition is present.[64,74,75] Second-line therapies include a dif-

ferent stimulant or atomoxetine.[64,75] In the case of patients with

ADHD and co-morbid anxiety, first-line treatment is either ato-

moxetine (to treat both disorders) or a stimulant (to treat the

ADHD) plus a serotonin reuptake inhibitor (to treat the anxi-

ety).[64,74] Atomoxetine may also be a first-line therapy for patients

with co-morbid tics.[74] Patients unable to take stimulants because

of an active substance abuse disorder or previous adverse effects

are advised to take atomoxetine as a first-line therapy.[74,76] Other

potential (but not US FDA-approved) therapies include bupro

pion, tricyclic antidepressants, and a-adrenergic agonists.[74]

While the immediate-release formulations of methylphen

date and amfetamines have been shown to be effective iADHD, they require multiple daily doses to achieve the optim

effect, and can potentially be associated with abuse or mi

use.[77] Longer acting, once daily, extended-release formula

tions of stimulants are just as effective as immediate release, an

are easier to administer; however, they may be associated wit

pharmacokinetic variability, as they rely on pH and gastro

intestinal transit time for delivery of the active ingredient.[77]

Atomoxetine is the first drug not classified as a stimulant to b

approved for ADHD, and, unlike stimulants, is not a controlle

substance.[78] It also has low to no abuse or misuse potential.[7

The issue of stimulant abuse is, however, controversial. It habeen stated that patients who are being administered therapeut

dosages of stimulants for the treatment of ADHD do not nor

mally have a problem with abuse; in fact, there is the possibilit

that stimulant treatment may reduce the chance of substanc

abuse in ADHD patients.[79] More emphasis is placed on the ris

of diversion of immediate-release stimulants for recreation o

performance enhancement (extended-release formulations can b

used, but it is more difficult to extract the drug).[79]

In well designed clinical trials of 6–9 weeks’ duration, ato

moxetine was effective in pediatric patients (including stimulan

naive patients) with ADHD, demonstrating greater improvemen

from baseline in efficacy measures than placebo (sections 4.1.1 an

4.1.3). Atomoxetine was also effective in preventing relapse i

longer term trials; its efficacy was maintained for at least 2 year

(section 4.1.2). Atomoxetine, despite a half-life of just over 3 hour

shows efficacy into the evening if given as a single morning dos

(section 4.1.1), and can be administered either as a single dose o

two evenly divided doses (section 7).[10] However, a recent stud

has shown that the risk of some adverse events may be lower

atomoxetine is initiated as a twice-daily regimen (section 5).[6

Prospective trials are required to confirm this possibility.

Co-morbid disorders (such as anxiety disorders, depressiv

disorders, tic disorders, and autism spectrum disorders), commoin ADHD patients, were either not affected or improved on ad

ministration of atomoxetine, and efficacy with regard to ADHD

was not affected by the presence of co-morbidities (section 4.3

However, four[53,54,56,57] of the six[52-57] trials in patients with co

morbid disordersdid not have ADHD symptom measures as the

primary endpoints, and thus definitive conclusions with regard t

the efficacy of atomoxetine cannot be drawn from these studies

Comparisons with other ADHD medications reveale

mixed results with regard to primary efficacy measure

Atomoxetine appeared more effective than standard curren





therapy (any combination of medicines [immediate- or extended-

release methylphenidate or clonidine] and/ or behavioral coun-

seling, or no treatment) and as effective as, or noninferior to,

immediate-release methylphenidate, but less effective than os-motically released methylphenidate or extended-release mixed

amfetamine salts (section 4.2). However, the extended-release

mixed amfetamine salts study[26] and one of the osmotically

released methylphenidate studies[51] were of only3 weeks’ du-

ration; full benefits of atomoxetine often take several weeks

(potentially up to 8 weeks)[8] to occur.[2,8,63,64] Studies involving

a longer treatment period are required before conclusions can

be drawn in these comparisons. Also, one of the immediate-

release methylphenidate studies[25] was not powered for a direct

comparison, and should only be used as supporting data for the

other immediate-release methylphenidate study.

[24]

The studies had other potential limitations. Three of the

active comparator trials were open-label,[25,50,51] and only one

was placebo controlled.[23] The comparison of atomoxetine

with extended-release mixed amfetamine salts[26] was con-

ducted in a laboratory classroom, and thus different from a

‘normal’ classroom atmosphere; all children had ADHD (ra-

ther than a small proportion), and the number of observers and

staff was higher than in an average non-laboratory classroom.

This study also excluded patients with the inattentive subtype

of ADHD, thus not allowing comparison in these patients.[26]

The two studies investigating atomoxetine versus osmotically

released methylphenidate both excluded, for ethical reasons,

patients with no response to previous methylphenidate treat-

ment, thus introducing a possible methylphenidate-slanted

bias.[23,51] Patients with tic[23,51] or anxiety disorders[23] were

also excluded, again for ethical reasons, which would also po-

tentially bias results in favor of methylphenidate (which is

contraindicated in these disorders), as atomoxetine may po-

tentially be more beneficial in these populations.

Interestingly, the significant difference in efficacy observed

between atomoxetine and osmotically released methylphenidate

was not present when only the stimulant-naive patients in the

population of one study were investigated;[23] stimulant-exposedpatients still demonstrated a significant treatment difference

(section 4.2). This may reflect study design, as the trial excluded

patients with no responseto previous methylphenidate treatment.

Overall, the impact of atomoxetine treatment on HR-QOL

appears positive. In shorter term, placebo-controlled trials,

HR-QOL either stayed constant or was improved, and longer

term, placebo-controlled trials also demonstrated positive ef-

fects (sections 4.1.1, 4.1.2, and 4.1.3). HR-QOL was also im-

proved to a greater extent with atomoxetine than with standard

current therapy (section 4.2).

Pharmacoeconomic analyses suggest that initial atomox

etine treatment appears cost effective compared with initia

methylphenidate (both immediate- and extended-release

dexamfetamine, tricyclic antidepressants or no treatment (section 6), demonstrating a cost per QALY that was below com

monly accepted cost-effectiveness thresholds.

Several of the most commonly occurring adverse events wit

atomoxetine administration were generally consistent with in

creased noradrenergic tone (e.g. somnolence, vomiting) [section 5

other common adverse events included headache and decrease

appetite. Adverse events were generally classified as mild o

moderate, and serious adverse events were rare. An increase i

suicidal ideation among atomoxetine versus placebo recipients le

to a black-box warning for children and adolescents (section 5.1

Rarely, severe liver injury may also occur in atomoxetine rcipients, with three reports of liver-related adverse events deeme

probably related to atomoxetine treatment in the 4 years followin

its market launch. There have also been reports of sudden death i

patients with serious structural cardiac abnormalities and othe

serious heart problems receiving atomoxetine. Discontinuation o

atomoxetine is well tolerated, with a low incidence of di

continuation-emergent adverse events and no evidence of symp

tom rebound (sections 4.1.1 and 5). In contrast, there has bee

some anecdotal evidence of symptom rebound and discontinua

tion-emergent adverse events following withdrawal of stimulant

with dexamfetamine potentially causing more rebound tha

methylphenidate.[80]

Slight differences were noted in the adverse events profiles o

atomoxetine and extended-release stimulants, probably reflectin

differences in their mechanisms of action (e.g. atomoxetine ap

peared more commonly associated with somnolence, osmoticall

released methylphenidate with insomnia). The adverse even

profile of atomoxetine also differed somewhat to that of im

mediate-release methylphenidate; for example, atomoxetine wa

associated with a significantly higher incidence of somnolence

nausea, vomiting, anorexia, and dizziness (section 5).

In contrast, stimulants are commonly associated with appeti

suppression, stomach pain, insomnia, and weight loss.[4] There also a possible potential for tic disorders and growth effects, a

well as potential cardiovascular problems; the US prescribin

information for mixed amfetamine salts includes a black-bo

warning regarding cardiovasculardisorders, and otherstimulan

carry contraindications and warnings for patients with cardio

vascular conditions.[4] However, with stimulants only two non

fatal adverse cardiovascular events occur per millio

prescriptions, and less than one death occurs per million.[80] St

mulant treatment effects on growth is controversial.[80] Ther

is evidence that growth is affected by many factors, and thus it





possible that differences in height and weight are the result of

other causes; however, the possibility cannot be ruled out that

stimulants are associated with significantly stunted growth, as

several meta-analyses and trials appear to demonstrate.[80]

Statistically, but not clinically, significant increases in heart

rate and BP occur with atomoxetine administration (section 2.2),

with few patients experiencing increases in heart rate or BP to

abnormal levels (section 5.1); however, additional longer term

data would be of use in expanding our knowledge of the cardiac

effects of atomoxetine. There is also an initial loss in expected

weight and height among atomoxetine recipients, although both

measures return to expected measurements after a period of time

(section 2.2). However, it has been suggested that a weakness of

this study was that growth was only monitored sporadically.[80]

As atomoxetine is mainly metabolized via the CYP2D6 en-zymatic pathway, it remains in the system of poor metabolizers

of CYP2D6 substrates for longer than extensive metabolizers,

and at higher concentrations (section 3); thus, these patients are

more prone than extensive metabolizers to the adverse events

associated with atomoxetine (section 5). However, this can be

managed satisfactorily by decreasing the dosage administered

to these patients (section 7). A recent study has, interestingly,

shown that genotyping is not necessary to safely administer

atomoxetine: investigators in the trial were able to administer

atomoxetine to similar efficacy and safety levels regardless of

metabolizer status, without prior knowledge of whether the

patients were extensive or poor metabolizers.[81]

A common co-morbid problem among pediatric patients

with ADHD is disordered sleep, specifically reduced sleep time

and more total interrupted sleep time, as well as more daytime

sleepiness and difficulty getting up, compared with healthy

controls.[82] Atomoxetine appears less likely than methylphe-

nidate to exacerbate disordered sleep in pediatric patients with

ADHD (section 2.2).

Higher dosages of atomoxetine are not associated with a

greater improvement in efficacy, and thus there appears to be no

advantage to increasing atomoxetine dosages beyond the current

guidelines. Two randomized, double-blind studies involvingatomoxetine nonresponders aged 6–16 years demonstrated no

significant difference in ADHD-RS total scores between re-

cipients of atomoxetine 1.2 or 1.8 mg/ kg/ day (usual dosage) and

those receiving the increased dosage of 3.0 or 2.4 mg/ kg/ day.[83]

The potential for lower (off-label) target dosages in the

longer term treatment of ADHD has been investigated. In two

studies, responders to short-term atomoxetine treatment were

randomized to lower (0.5[84] or 0.8[85] mg/ kg/ day) versus higher

(1.2–1.8[84] or 1.4[85] mg/ kg/ day) dosages of atomoxetine. Both

showed that the mean change in ADHD-RS total score from

baseline did not significantly differ between groups after »8[8

and 10[85] months’ therapy.[84,85] However, a significan

(p= 0.017) loss of benefit (in terms of ADHD-RS total score

versus baseline was shown in patients receiving a lower dosagepatients receiving a higher atomoxetine dosage did not diffe

significantly from baseline in this measure.[84]

Very young children (aged under 6 years) with ADHD hav

not been extensively studied.[3] The majority of methylphenida

studies have included school-age children; very few have involve

preschoolers, and, despite an FDA warning against administra

tion to children under the age of 6 years, methylphenidate is ofte

prescribed off-label for these patients.[3] Atomoxetine appear

potentially effective in this patient group. One noncomparativ

pilot study involving 22 children with ADHD, aged 5–6 year

demonstrated that atomoxetine to a maximum dosage o1.8 mg/ kg/ day was generally effective with regard to core ADHD

symptoms.[86] A large, randomized, placebo-controlled study o

atomoxetine is ongoing in children with ADHD aged 5–6 years.

Although atomoxetine has been extensively researched, add

tional data are needed. Of interest would be a well designed, long

term safety study, prospectively investigating, for example, th

weight and height differences of atomoxetine recipients com

pared with placebo and active comparators. A greater number o

trials to augment the discoveries in patients with co-morbid di

orders would also be desirable, in particular trials specifyin

ADHD symptom measures as their primary endpoint, as woul

more studies of atomoxetine in very young patients.

In conclusion, atomoxetine is an effective and generally we

tolerated option for the treatment of ADHD in children an

adolescents, and is not classified as a stimulant. Atomoxetin

showed efficacy in children and adolescents with ADHD in we

designed placebo-controlled trials, with mixed results seen i

active comparator trials; atomoxetine did not differ significantl

from or was noninferior to immediate-release methylphenidat

and was significantly less effective than osmotically release

methylphenidate or extended-release mixed amfetamine salts. I

can be administered either as a single daily dose or split into tw

evenly divided doses, has a negligible risk of abuse or misuse, anis not a controlled substance in the US. Atomoxetine is particu

larly useful for patients at risk of substance abuse or misuse, a

well as those who have co-morbid anxiety or tics, or who do no

wish to take a controlled substance. Thus, atomoxetine is a usefu

option in the treatment of ADHD in children and adolescents.

Disclosure

The preparation of this review was not supported by any extern

funding. During the peer review process, the manufacturer of the agen

under review was offered an opportunity to comment on this articl





Changes resulting from any comments received were made on the basis of

scientific and editorial merit.

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