CNS Drugs 2004; 18 (6): 397-401ADIS SPOTLIGHT 1172-7047/04/0006-0397/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Spotlight on Atomoxetine in Adultswith Attention-Deficit HyperactivityDisorder1

Dene Simpson and Greg L Plosker

Adis International Limited, Auckland, New Zealand

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3971. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3982. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3983. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3994. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4005. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400

Atomoxetine (Strattera™) is a selective noradrenaline (norepinephrine) reuptakeAbstractinhibitor and nonstimulant that has shown greater efficacy than placebo inattention-deficit hyperactivity disorder (ADHD) in adults. In two large, wellcontrolled, 10-week trials in adults with ADHD, improvements in ADHD symp-toms, as assessed by investigator- and patient-rated scores, were greater with oralatomoxetine (60, 90 or 120 mg/day) than with placebo. Mean reductions in thetotal ADHD symptom score on the investigator-rated Conners’ Adult ADHDRating Scale (CAARS) in atomoxetine versus placebo recipients were 28.3%versus 18.1% and 30.1% versus 19.6%, respectively. Mean reductions in thescores on the Clinician Global Impression of Severity Scale, patient-rated CAARSand Wender-Reimherr Adult Attention Deficit Disorder Scale were also signifi-cantly greater with atomoxetine than with placebo. Continued efficacy wasdemonstrated in a noncomparative, 34-week extension phase.

Atomoxetine was generally well tolerated in clinical trials; withdrawal ratesdue to adverse events in atomoxetine- versus placebo-treated patients participat-ing in the two major trials were 7.8% versus 4.3% and 9.3% versus 2.4% (p < 0.05for the latter trial). Adverse events reported significantly more frequently withatomoxetine than placebo included dry mouth, insomnia, nausea, decreasedappetite, constipation, dizziness, sweating, dysuria, sexual problems and palpita-tions. Modest increases in heart rate and blood pressure were well tolerated andgradually decreased on cessation of treatment. Atomoxetine was not associatedwith QT interval prolongation.

1 This Spotlight is derived from abstract and summary text of an Adis Drug Evaluation originally published in full inDrugs 2003; 64 (2): 205-222. Reviewers of the original full text article are listed in the Acknowledgments section.

398 Simpson & Plosker

Atomoxetine can be administered once or twice daily. Its subjective-effectsprofile is different to that of methylphenidate and atomoxetine is not associatedwith abuse or diversion; it is therefore not a controlled substance in the US. Thisalso means repeat prescriptions during long-term treatment can be more conve-niently processed.Conclusion: Atomoxetine is an effective and generally well tolerated treatmentfor adults with ADHD. It is a nonstimulant and is the first ADHD treatment to beapproved specifically for adult use based on its efficacy in well controlled adulttrials. It can be administered as a single daily dose or split into two evenly divideddoses. It carries negligible risk of abuse or diversion and is not a controlledsubstance. Atomoxetine is a valuable new treatment option for adults with ADHDand is particularly useful in patients who are at risk for substance abuse or who donot wish to take a controlled substance.

1. Pharmacodynamic Properties subcortical areas may indicate a low potential foratomoxetine to produce tics,[5] have psychomimeticeffects or lead to abuse.[1,5]

The mechanism of action of atomoxetine (Strat-Atomoxetine had no appreciable affinity for vari-tera™)2 in attention-deficit hyperactivity disorder

ous neurotransmitter receptors in the rat or human(ADHD) is thought to be related to its selectivebrain, suggesting that it has a low potential forinhibition of noradrenaline (norepinephrine) reup-adverse effects and/or drug interactions.[3,5,7]take.[1-8] The dissociation constant (Ki) for atomoxe-

There were modest increases in heart rate andtine inhibition of radioligand binding in animal andsystolic blood pressure (BP) and no QT intervalhuman cell membranes transfected with human nor-prolongation in atomoxetine recipients in the pivotaladrenaline transporters was 5 nmol/L comparedtrials.[10] Small but statistically significant increaseswith 77 and 1451 nmol/L for binding to serotoninfrom baseline in heart rate, BP and bodyweight wereand dopamine transporters.[5]

observed during the 34-week extension phase.[11]Atomoxetine has demonstrated selective inhibi-

The subjective-effects profile of atomoxetine istion of the presynaptic uptake of noradrenaline indistinct from that of methylphenidate.[12] Atomoxe-adrenergic neurons in animals.[9] A study in humanstine was rated significantly higher than placebo forshowed marked inhibition of noradrenaline uptake‘bad’ and ‘sick’ effects, which indicates that it is(p = 0.054 vs placebo).[9] Atomoxetine demonstra-unlikely to be associated with abuse.[12] Methyl-ted selectivity, as serotonin uptake into plateletsphenidate was rated higher than placebo for stimu-isolated from study participants was unaffected.[9]

lant effects and dysphoric or psychomimetic ef-In the prefrontal cortex of the rat brain, atomoxe-fects.[12]

tine increased extracellular levels of noradrenalineand dopamine (but not serotonin) and in the subcor- 2. Pharmacokinetic Profiletical areas it increased extracellular noradrenalinebut not dopamine.[5] Increased noradrenaline trans- The oxidative metabolism of atomoxetine to itsmission in these areas may play a role in the efficacy major active metabolite, 4-hydroxyatomoxetine, isof atomoxetine in ADHD and may indicate the via the genetically polymorphic cytochrome P450potential for the alleviation of symptoms of comor- (CYP) 2D6 pathway.[13,14] Two subpopulations ofbid depression and anxiety by atomoxetine.[5] The metabolisers have been identified[13] and, althoughlack of increase in dopamine transmission in the dosages in clinical practice are not adjusted for

2 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2004 Adis Data Information BV. All rights reserved. CNS Drugs 2004; 18 (6)

Spotlight on Atomoxetine 399

genotype, most pharmacokinetic data are available approximately 0.036 L/h/kg for PMs versus 0.373 L/as distinct values for each metaboliser subtype (ex- h/kg for EMs.[14]

tensive metabolisers [EMs] and poor metabolisers Atomoxetine is eliminated from the body mainly[PMs]). via excretion of its glucuronidated metabolites in the

urine (>80%) with approximately 13–22% andAtomoxetine is rapidly absorbed from the gastro-1–2% eliminated in the faeces of PMs and EMs,intestinal tract after oral administration and has anrespectively.[14] Less than 3% is eliminated as un-absolute bioavailability of 94% in PMs and 63% inchanged drug.[13]

EMs.[13] The median time to reach maximum plasmaAlthough the Cmax of atomoxetine was not in-concentrations (Cmax) at steady state was approxi-

creased in patients with hepatic impairment, theremately 1–2 hours in both groups.[13,14] Food slowedwas increased systemic exposure in that populationthe rate, but not the extent, of absorption of atomox-due to decreased atomoxetine clearance, necessitat-etine and the drug can be administered with oring dosage adjustment.[15] Higher exposure towithout food.[13] At steady state, the Cmax foratomoxetine was observed in patients with end-atomoxetine was almost 6-fold higher in PMs thanstage renal disease, but there was no differencein EMs and mean area under the plasma concentra-when the exposure was corrected for mg/kg dose.[13]tion-time curve was approximately 8-fold higher.[14]

Selective CYP2D6 inhibitors (paroxetine,[16]The steady-state volume of distribution of

fluoxetine[13] or quinidine[13]) increase the exposureatomoxetine after intravenous administration is 0.85to atomoxetine. The pharmacokinetic values forL/kg and is similar for PMs and EMs.[13] The appar-atomoxetine in EMs concomitantly receiving aent volume of distribution was 1.02 L/kg in PMs andCYP2D6 inhibitor are, predictably, similar to those2.33 L/kg in EMs.[14] At therapeutic concentrations,observed in PMs.[13,16]

98% of atomoxetine is bound to plasma protein(principally to albumin).[13]

3. Therapeutic EfficacyThe same metabolites of atomoxetine are formed

(4-hydroxyatomoxetine and N-desmethylatomoxe- Orally administered atomoxetine (60, 90 or 120tine) regardless of CYP2D6 status, but the pro- mg/day) has shown efficacy in two well controlledportions of circulating metabolites differ according 10-week trials in adults with ADHD (n = 267 andto the metabolic status of individuals.[13,14] In EMs, 248 in the intention-to-treat analyses of study I andatomoxetine and 4-hydroxyatomoxetine (equipotent II).[10] Eighty percent of patients in study I and 75%with atomoxetine for noradrenaline transporter inhi- in study II received 90 or 120 mg/day (approximate-bition) are the principal circulating compounds.[14]

ly equal numbers receiving each dosage).[10] MeanBecause in PMs the rate of formation of 4-hydroxy- reductions in total ADHD symptom score on theatomoxetine is slower, the principal circulating investigator-rated Conners’ Adult ADHD Ratingcompounds are atomoxetine and N-desmethy- Scale (CAARS) [primary endpoint] in atomoxetinelatomoxetine (a relatively inactive metabolite).[13]

versus placebo recipients were 28.3% versus 18.1%The exposure of PMs to atomoxetine is, however, in study I and 30.1% versus 19.6% in study II (p <approximately 8- to 10-fold that of EMs, which is 0.01 for both).[10] Mean reductions in the patient-primarily due to the slower rate of formation of rated CAARS total ADHD symptom score were4-hydroxyatomoxetine, but also the reduced overall 19.4% versus 11.5% in study I and 20.9% versusrate of plasma clearance of atomoxetine.[13,14]

14.5% in study II (p < 0.01 for both).[10]

Plasma elimination half-life (t1/2) of atomoxetine Emotional dysregulation (indicated by at leastin PMs is approximately 4-fold longer than in EMs moderate scores for temper, affective lability and(20 vs 5 hours) indicating increased systemic expo- emotional over-reactivity on the Wender-Reimherrsure to atomoxetine in PMs.[14] The mean apparent Adult Attention Deficit Disorder Scale) was evidentplasma clearance of atomoxetine at steady state was at baseline in one-third of patients in the major

© 2004 Adis Data Information BV. All rights reserved. CNS Drugs 2004; 18 (6)

400 Simpson & Plosker

studies and showed a greater improvement with 5. Dosage and Administrationatomoxetine than with placebo (42% vs 19% im-

The starting dosage recommended in the pub-provement; p = 0.001).[17]

lished prescribing information for atomoxetine inAn open-label extension phase (mean 34 weeks) adults with ADHD is 40mg orally once daily in the

of the pivotal trials demonstrated continued efficacy morning (or as an evenly divided dose twice daily),of atomoxetine, and improved clinical responses which can then be increased to a target dosage of 80with higher bodyweight-based dosages.[11,18]

mg/day or a maximum of 100 mg/day if neces-sary.[13]No head-to-head comparisons of atomoxetine

Atomoxetine should be used with caution in pa-with any of the stimulants or other effective treat-tients with hypertension, tachycardia or cerebral orments for ADHD have been conducted.cardiovascular disease. Dosage adjustment may benecessary for patients with hepatic impairment[13,15]

4. Tolerability or those receiving CYP2D6 inhibitors (paroxe-tine,[16] fluoxetine or quinidine[13]). The concomitant

Atomoxetine was generally well tolerated in use of atomoxetine and monoamine oxidase inhibi-10-week clinical trials and no serious treatment- tors is contraindicated and the drug is not recom-related adverse events were reported.[10] The adverse mended in patients with narrow angle glaucoma.[13]

effect-related withdrawal rates for atomoxetine ver-Acknowledgementssus placebo recipients from the two major trials

were 7.8% versus 4.3% (study I) and 9.3% versusThe full text article in Drugs 2003; 64 (2): 205-222 was

2.4% [p < 0.05] (study II).[10] Treatment-related reviewed by: P.J. Ambrosini, Eastern Pennsylvania Psychiat-withdrawals (reported by more than one patient) ric Institute, Drexel University College of Medicine, Phila-

delphia, Pennsylvania, USA; J. Elia, Department of Psychia-among the 270 atomoxetine-treated patients weretry, University of Pennsylvania, Philadelphia, Pennsylvania,due to insomnia (n = 3), chest pain (n = 2), palpita-USA; J.H. Newcorn, Department of Psychiatry, Mount Sinai

tions (n = 2) and urinary retention (n = 2).[13] Hypo- Medical Center, New York, New York, USA; F. Reimherr,tension and hypertension were among events re- Department of Psychiatry, University of Utah Health Sci-

ences Center, Salt Lake City, Utah, USA; M. Weiss, Chil-sponsible for one withdrawal each.[19]

dren’s and Women’s Health Centre of British Columbia,The most common adverse events that were re- Vancouver, British Columbia, Canada.

ported significantly more frequently with atomoxe-tine than placebo included dry mouth (21.2% vs References6.8%), insomnia (20.8% vs 8.7%), nausea (12.3% vs 1. Stahl SM. Neurotransmission of cognition, part 2. Selective

NRIs are smart drugs: exploiting regionally selective actions4.9%), decreased appetite (11.5% vs 3.4%), consti-on both dopamine and norepinephrine to enhance cognition. J

pation (10.8% vs 3.8%), dizziness (6.3% vs 1.9%), Clin Psychiatry 2003 Feb; 64 (2): 110-12. Gehlert DR, Schober DA, Gackenheimer SL. Comparison ofsweating (5.2% vs 0.8%), dysuria (5% vs 0.4%),

(R)-[3H]tomoxetine and (R/S)-[3H]nisoxetine binding in ratpalpitations (3.7% vs 0.8%) and sexual prob- brain. J Neurochem 1995 Jun; 64 (6): 2792-800

3. Wong DT, Penny G, Threlkeld KL, et al. A new inhibitor oflems.[10,11,20]

norepinephrine uptake devoid of affinity for receptors in ratThere was a modest but significant increase in brain. J Pharmacol Exp Ther 1982 Jul; 222 (1): 61-5

4. Bolden-Watson C, Richelson E. Blockade by newly-developedheart-rate and systolic BP with atomoxetine versusantidepressants of biogenic amine uptake into rat brain

placebo but these increases were generally well tol- synaptosomes. Life Sci 1993; 52 (12): 1023-95. Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine in-erated and gradually decreased on cessation of treat-

creases extracellular levels of norepinephrine and dopamine inment.[10,19] The incidence of tachycardia was not prefrontal cortex of rat: a potential mechanism for efficacy in

attention deficit/hyperactivity disorder. Neuropsychopharma-significantly greater in atomoxetine recipients thancology 2002 Nov; 27 (5): 699-711in placebo recipients.[19] Atomoxetine was not asso- 6. Gehlert DR, Gackenheimer SL, Robertson DW. Localization of

ciated with QT interval prolongation.[19] rat brain binding sites for [3H] tomoxetine an enantiomerically

© 2004 Adis Data Information BV. All rights reserved. CNS Drugs 2004; 18 (6)

Spotlight on Atomoxetine 401

pure ligand for norepinephrine reuptake sites. Neurosci Lett 15. Chalon SA, Desager JP, Desante KA, et al. Effect of hepatic1993 Jul 23; 157 (2): 203-6 impairment on the pharmacokinetics of atomoxetine and its

metabolites. Clin Pharmacol Ther 2003 Mar; 73 (3): 178-917. Cusack B, Nelson A, Richelson E. Binding of antidepressants tohuman brain receptors: focus on newer generation compounds. 16. Belle DJ, Ernest CS, Sauer JM, et al. Effect of potent CYP2D6Psychopharmacology (Berl) 1994 May; 114 (4): 559-65

inhibition by paroxetine on atomoxetine pharmacokinetics. J8. Fuller RW, Hemrick-Leucke SK. Antagonism by tomoxetine of Clin Pharmacol 2002 Nov; 42 (11): 1219-27

the depletion of norepinephrine and epinephrine in rat brain by17. Reimherr FW, Strong RE, Dawson WH, et al. Emotionala-methyl-m-tyrosine. Res Commun Chem Pathol Pharmacol

dysregulation in ADHD and response to atomoxetine [abstract1983 Jul; 41 (1): 169-72no. NR640]. American Psychiatric Association 2003 Annual9. Zerbe RL, Rowe H, Enas GG, et al. Clinical pharmacology ofMeeting; New Research Abstracts, 156th Annual Meeting;tomoxetine, a potential antidepressant. J Pharmacol Exp Ther

1985 Jan; 232 (1): 139-43 2003 May 17-22; San Francisco

10. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults 18. Adler LA, Spencer TJ, Reimherr FW, et al. Efficacy and safetywith ADHD: two randomized, placebo-controlled studies. Biol of atomoxetine in long-term, open-label treatment of adultsPsychiatry 2003 Jan 15; 53 (2): 112-20 with ADHD [abstract no. NR645 plus poster]. American Psy-

11. Adler L, Spencer T, Sutton V, et al. Dose and time response of chiatric Association 2003 Annual Meeting; New Researchatomoxetine use in adult ADHD [poster]. American Academy Abstracts, 156th Annual Meeting; 2003 May 17-22; Sanof Child and Adolescent Psychiatry (AACAP); 2003 Oct

Francisco14-19; Miami19. Wernicke FJ, Faries D, Girod D, et al. Cardiovascular effects of12. Heil SH, Holmes HW, Bickel WK, et al. Comparison of the

atomoxetine in children, adolescents, and adults. Drug Safsubjective, physiological, and psychomotor effects of atomox-2003; 26 (10): 729-40etine and methylphenidate in light drug users. Drug Alcohol

Depend 2002 Jul 1; 67 (2): 149-56 20. Eli Lilly and Company, 2003. (Data on file)13. Eli Lilly and Company. Indianapolis. Strattera (R) (atomoxetine

HCl) [online]. Available from URL: http://www.strattera.com[Accessed 2003 Jul 28] Correspondence: Dene Simpson, Adis International Limited,

14. Sauer JM, Ponsler GD, Mattiuz EL, et al. Disposition and 41 Centorian Drive, Private Bag 65901, Mairangi Bay,metabolic fate of atomoxetine hydrochloride: the role of

Auckland 1311, New Zealand.CYP2D6 in human disposition and metabolism. Drug MetabDispos 2003 Jan; 31 (1): 98-107 E-mail: demail@adis.co.nz

© 2004 Adis Data Information BV. All rights reserved. CNS Drugs 2004; 18 (6)