Drug Therapy

Atomoxetine
Jeeson C. Unni hydroxyatomoxetine, is glucuronidated and excreted in the urine. Clinical trials Atomoxetine has demonstrated a statistically significant reduction in core ADHD symptoms and improvement in social and family functioning compared with the placebo group(6,7) in randomized, placebo-controlled trials in children and adolescents 8 to 18 years of age. Another study has demonstrated the positive impact of atomoxetine on health related quality of life (HRQL) in children with ADHD(8). Atomoxetine was compared with methylphenidate in a randomized, open-label trial(9) in children with ADHD during a 10week study period. Significant improvements were noticed in inattentive and hyperactive/ impulsive symptom domains with both medications to a comparable extent. Atomoxetine has a slower onset to action than do stimulants; thus, effects may not be seen until the end of the first week of treatment. However, it seems to have a longer duration of action after once-a-day dose with suggestions of symptom relief during the evening and early-morning hours. The treatment effect for core ADHD symptoms is similar when oncedaily dosing is compared with twice-daily dosing; parent ratings document a sustained effect late in the day(10). Treatment with atomoxetine is preferred over stimulants in patients with psychiatric comorbidities, contraindications to stimulants, or relatively heavy use of behavioral health care(11). Further, it is the drug of choice in adolescent ADHD associated with substance abuse disorder because it has a lower risk of abuse potential(12). In children and
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Atomoxetine is a non-stimulant drug licensed by the Food and Drug Administration in November 2002 for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents(1). Hitherto, ADHD was treated with stimulant drugs, e.g., methylphenidate. Several other non-stimulants are also shown to be efficacious in ADHD(2-5), but their doseresponse and safety profile is not well established in children. Mode of Action Atomoxetine is a selective inhibitor of the presynaptic norepinephrine transporter in the central nervous system. It increases both norepinephrine and dopamine levels, especially in the prefrontal cortex. Pharmacokinetics Atomoxetine is well absorbed after oral administration. It is metabolized through the cytochrome P450 2D6 (CYP 2D6) pathway and has a plasma half-life of approximately 4 hours in CYP 2D6 extensive metabolisers and 19 hours in CYP 2D6 poor metabolisers. The slow metabolisers have 10-fold higher area under curves (AUCs) and 5-fold higher plasma concentrations. The active metabolite, 4Correspondence to: Dr. Jeeson C. Unni, Editor-inchief, IAP Drug Formulary, Dr. Kunhalu’s Nursing Home, T D Road, Kochi 682 011, India. E- mail: jeeson @asianetindia.com
INDIAN PEDIATRICS

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in the early phase of treatment. such as methylphenidate and dextroamphetamine. Atomoxetine treatment was associated with small but statistically significant increase in mean systolic pressure in adults and diastolic pressure in children and adolescents(15). painful menstrual periods. it can cause drowsiness(9). Other documented side effects mentioned are dizziness. Rather. vomiting. 2006 . with the exception that atomoxetine does not cause or worsen insomnia though. for moderate and severe hepatic dysfunction. sweating and hot flushes have also been reported(16). Discontinuation because of cardiovascular-related events did not occur in the child/adolescent group. and returned toward baseline after drug discontinuation. Caution should be exercised while administering the drug to lactating mothers. headache. difficulty falling asleep or staying asleep. Side effects Adverse effects of atomoxetine are similar to that of methylphenidate (appetite suppression. excessive tiredness. crying. atomoxetine does not exacerbate the tic symptoms. Heartburn. Dose Dosing of atomoxetine. is not straightforward because of the potential for excessive dosing in patients who are slow metabolizers. Clinically significant drug interactions also exist with antiarrhythmics. selective serotonin reuptake inhibitors. The drug has not been evaluated in children less than 6 years of age. resting their feet on the floor for a few minutes before standing up. constipation. paroxetine. weight loss. loss of appetite. Atomoxetine should not be coadministered with a MAO inhibitor or within 2 weeks of discontinuing one(17). Caution is needed in patients with hypertension. Blood pressure and pulse tended to increase early in therapy. upset stomach. Contraindications Atomoxetine should be avoided in children with narrow angle glaucoma due to increased risk of mydriasis. beta-blockers and sympathomimetics. children are advised to get out of bed slowly. fever. Dose should be reduced by 25% and 50%.. It does not appear to be habit forming and is not a controlled substance and therefore it does not require observance of the stringent prescribing rules necessary for Schedule X drugs. unfortunately. Dosage adjustment of atomoxetine may be necessary when co-administered with CYP2D6 inhibitors.g. It is not known if atomoxeine is secreted in human milk. decreased sex drive or ability. light-headedness. It is also effective for the treatment of ADHD in patients with comorbid oppositional defiant behavior (ODD) though it did not significantly reduce the severity of ODD symptoms(14). tachycardia. Atomoxetin has caused severe INDIAN PEDIATRICS liver damage in some patients(16). then stabilized. and fainting when you get up too quickly from a lying position(16). respectively.DRUG THERAPY adolescents with ADHD and co-morbid tic disorders. Children and adolescents may be started at 0. irritability. To avoid this problem. The drug needs to be used carefully in any condition that may predispose to hypotension. muscle pain. chills. e. there was some evidence of reduction in tic severity(13). difficulty urinating. mood swings. dry mouth. There was no significant difference as revealed by electrocardiogram between atomoxetine and placebo groups in change in QT interval for all study populations.5 mg/kg/day and dose may be increased after 604 VOLUME 43__JULY 17. initial weight loss). fluoxetine and quinidine. Dose changes are not necessary in patients with endstage renal disease. cardiovascular or cerebrovascular disease.

Brand name .Rs 65 25 mg . Do not exceed 1. Agitation. Sympathetic nervous system stimulation may occasionally manifest as mydriasis causing blurring of vision.thus. Since atomoxetine is highly protein-bound. Patients with psychiatric comorbidities. Substance abuse disorder . 2006 .contraindicated 7. 18. Schedule X drug 2. REFERENCES 1.10 tabs .10 tabs .3 to 6 hours with immediate release tabs and 5-10 hrs with the long and very long acting tabs which are not available in India 6. Sleep disturbances Atomoxetin Non-scheduled drug Non-stimulant drug Does not cause or worsen insomnia but in the early phase can cause drowsiness Slower onset to action . Price .4 mg/kg/ day or 100 mg/day(16). tachycardia and dryness of INDIAN PEDIATRICS mouth.79p a minimum of 3 days to a target dose of 1. 25 and 40mg 18 mg . dialysis is not likely to be useful in the treatment of overdose. Onset of action . Stimulant drug 3. These children and adolescents should be monitored carefully and given supportive care.10 tabs . given once daily or in 2 divided doses in the morning and late afternoon(16). No specific information is available on the treatment of overdose. Kratochvil CJ. Presentation . Overdose The most common symptom of acute and chronic overdose is somnolence. Gastric emptying and repeated doses of activated charcoal may prevent systemic absorption. 4: 1165 -1174. Burke WJ.Addwise (Sun Pharma) 9.2 mg/kg/day(7). Harrington MJ.DRUG THERAPY TABLE–Comparison of Methylphenidate and Atomoxetine in Treatment of ADHD Methylphenidate 1. Duration of action .2 mg/ kg/day. 40p Tomoxetin (Torrent) Tab 10.Rs 89. Expert Opin Pharmacother 2003. Atomoxetine: A selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder. effects may not be seen until the end of the first week of treatment Longer duration of action after a once-a-day dose with suggestions of symptom relief during the evening and early-morning hours Drug of choice Preferred drug 4.Rs 88. No additional benefit is seen in doses more than 1. Vaughan BS. contraindications to stimulants and those requiring frequent use of behavioral care services 8. VOLUME 605 43__JULY 17. hyperactivity.Tab 10 mg 10.within 20 to 60 minutes of dose 5. abnormal behavior and gastrointestinal symptoms may also occur.

Drug Saf 2003. et al. Kratochvil CJ. 26: 729 -740 Unni JC (2005). 25: 264-271. Kurian RM. Am J Psychiatry 1990. Higgins ES. Dunn D. Harder D. 147: 1018-1020. Gao H. 11. Biederman J. Am J Psychiatry 2002. Abrantes AM. 159: 1896-1901. Biederman J.DRUG THERAPY Key Message • Atomoxetine is a promising. Allen AJ. Sallee FR. J Am Acad Child Adolesc Psychiatry 1993. Kratochvil CJ. Kelsey D. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: A randomized. 12. Faries DE. Lynch T. 65: 1941-1949. Wilens TE. Sterling KL. West S. Publication of Indian Academy of Pediatrics. Pediatrics 2001. A naturalistic assessment of protriptyline for attention-deficit hyperactivity disorder. Busner J. Wernicke J. 32: 205210 Michelson D. 68: 1827-1828. Wilens T. et al. Girod D. INDIAN PEDIATRICS 606 VOLUME 43__JULY 17. et al. Evidencebased pharmacotherapy for attention-deficit hyperactivity disorder. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized. Am Fam Physician 2003. Available at: www. adolescents and adults. et al. A comparative analysis of antidepressants and stimulants for the treatment of adults with attention-deficit hyperactivity disorder. Geist D. 7: 77-97. et el. 48: 15-20. Pharmacotherapy 2005. Van Brunt DL. Sumner CR. Steingard R. placebo-controlled study. open-label trial. Wender PH. 6. Cardiovascular effects of atomoxetine in children. J Fam Pract 1999. 7. Kelsey D. Linder SL. Efficacy and safety of atomoxetine in childhood attentiondeficit/hyperactivity disorder with comorbid oppositional defiant disorder. Kaplan S. Mumbai. 19: 643-655. Atomoxetine and methylphenidate treatment in children with ADHD: A prospective. J Dev Behav Pediatr 2004. Brown J. Wernicke J. 10. 8. CNS Drugs 2005. 9. Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders. 14. Reimherr FW. Spencer T. Casat C. Dittmann R. 2006 . Schubiner H. dose-response study. J Am Acad Child Adolesc Psychiatry 2002. Kendrick K. 4. randomized. 2nd edn. Neurology 2005. 4: 776 -784. Faries D. non-stimulant. Spencer T. Allen AJM. Spencer TJ. Heiligenstein J. Wilens T. Pohl GM. 108. Improvement in health-related quality of life in children with ADHD: An analysis of placebo controlled studies of atomoxetine.org/cgi/content/full/108/5/e83 Biederman J. 15. Johnston JA. Perwien AR. 8: 45-52. et al. 35: 1485-1490. In: IAP Drug Formulary Web Update 2005 with IAP recommendations on Drug Therapy in Pediatric Illnesses. Wernicke JF. Allen AJ. Gilbert DL. Faries D. 13. Nortriptyline treatment of children with attention-deficit hyperactivity disorder and tic disorder or Tourette’s syndrome. placebo-controlled. Dittmann R. Michelson D. Busner J. Bupropion treatment of attention-deficit hyperactivity disorder in adults. Int J Neuro-psychopharmacol 2004. 5. Predictors of selecting atomoxetine therapy for children with attention-deficit-hyperactivity disorder. J Atten Disord 2004. Ye W. Coffey BJ. Substance abuse in patients with attention-deficit hyperactivity disorder: therapeutic implications. Biederman J. Kelsey DK. Atomoxetine. 17. 25: 1541-1549. 3. et al. Kratochvil C.pediatrics. Spencer TJ. Sun PJ. J Am Acad Child Adolesc Psychiatry 1996. 16. non-schedule drug now available for treatment of children with attention deficit hyperactivity disorder 2. Heiligenstein JH. Atomoxetine for ADHD [STEPS]. Lewis DW.

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