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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 Bibliographical information, includingcontributory unpublished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
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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.
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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
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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
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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
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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]
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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
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(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.
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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.
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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.
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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
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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.
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(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
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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
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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]
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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
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(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
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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]
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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
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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
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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
Atomoxetine: A Review 22
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Changes resulting from any comments received were made on the basis of
scientific and editorial merit.
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Correspondence: Karly P. Garnock-Jones, Wolters Kluwer Health | Adi
41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 075
Auckland, New Zealand.
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