Pharmacology Update: Atomoxetine HCl — New Drug for ADHD
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA has approved Atomoxetine (previously named tomoxetine), the first nonstimulant/noncontrolled drug to be approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). Unlike previous drugs for this indication, atomoxetine is a selective inhibitor of the presynaptic norepinephrine transporter. Atomoxetine is marketed by Eli Lilly as "Strattera."
Indications
Atomoxetine is indicated for the treatment of ADHD in children, adolescents, and adults.
Dosage
The initial dose in children and adolescents up to 70 kg in body weight is 0.5 mg/kg. The dose may be increased after a minimum of 3 days up to 1.2 mg/kg. It may be given as a single dose in the morning or divided into morning and late-afternoon/early evening doses. Total dose should not exceed 1.4 mg/kg or 100 mg. For patients over 70 kg and adults, the initial dose is 40 mg/d, with increases up to 80 mg/d after a minimum of 3 days. The dose may be increased to 100 mg/d if an optimal response has not been achieved in 2-4 weeks. The maximum dose is 100 mg/d.1
Atomoxetine may be taken without regard to meals. Dosage should be reduced for those with hepatic impairment and those taking CYP2D6 isoform inhibitors.1
Atomoxetine is available in 10-mg, 18-mg, 25-mg, 40-mg, and 60-mg capsules.
Potential Advantages
Atomoxetine, a nonstimulant, differs from the commonly used drugs for this indication, such as methylphenidate and amphetamines. It does not appear to share the same abuse potential and is not a Scheduled (controlled) drug.2
Potential Disadvantages
In short-term studies, weight loss and slower increase in height have been reported in children. About 19% of patients on 1.2 mg/kg/d and 29% on 1.8 mg/kg/d lost at least 3.5% of their body weight. In addition, atomoxetine-treated patients had an average growth of 0.9 cm compared to 1.1 cm for those treated with placebo. In patients treated for at least 18 months, mean weight percentile decreased from 68 to 60 and mean height percentile from 54 to 50.1 Common side effects include increase in heart rate and blood pressure. The mean increase in heart rate was 5-6 beats/min. The frequencies of tachycardia were 1.5% in the pediatric population and 3% in the adult population compared to 0.5% and 0.8%, respectively, for placebo-treated patients. The frequencies of high systolic BP (vs placebo) in pediatric studies were 6.8% vs 3%, and high diastolic BP were 2.8% vs 0.5%. In adults systolic BP ³ 150 mm Hg and diastolic BP ³ 100 mm Hg were 1.9% vs 1.2% and 0.8% vs 0.4%, respectively. Urinary retention or hesitancy has been reported in adults with an incidence of 3% for each compared to 0% for placebo. Erectile disturbance (7% vs 1%), impotence (3% vs 0%), and abnormal orgasm ( 2% vs 1%) have been reported in placebo-controlled studies. In a small comparative study, atomoxetine appeared to have a higher incidence of vomiting and somnolence than methylphenidate.3 Atomoxetine is metabolized by CYP2D6. Dose adjustments may be necessary in patients taking drugs that inhibit this enzyme (ie, fluoxetine, paroxetine, quinidine).1 Atomoxetine is not recommended during pregnancy due to lack of safety data.
Comments
Atomoxetine differs from commonly used drugs for ADHD. It does not release norepinephrine but blocks norepinephrine reuptake by inhibiting the norepinephrine transporter in the brain. It does not appear to have any significant effect on other noradrenergic receptors or neurotransmitters. The effectiveness of atomoxetine has been demonstrated in 4 studies involving pediatric patients (n = 759) and 2 studies involving adults (n = 536). These studies were randomized, double-blind, and placebo-controlled, and 6 to 10 weeks in duration.1,3,4,5 Patients had ADHD based on DSM-IV criteria, and pediatric patients had inattentive subtypes or hyperactive/inattentive subtypes. Primary effectiveness was based on an investigator-administered and scored ADHD Rating Scale-IV-Parent Version total score (pediatrics) or Conners Adult ADHD Rating Scale Screening Version (adults). A small percent of patients (7%) are slow metabolizers of atomoxetine, and these patients may achieve therapeutic effect with a lower dose and may be more sensitive to side effects such as increase in heart rate.1,4 In a small study of pediatric patients who were randomized to atomoxetine (n = 144) or methylphenidate (n = 44), similar effectiveness and tolerability was reported.3 Most study subjects were males. However, atomoxetine was also reported to be effective and well tolerated involving a subset (n = 51) of girls aged 7-13.6 The long-term effectiveness and safety is not known as controlled studies were up to 10 weeks in duration.
All strengths of atomoxetine are priced the same, $2.50 per capsule. The cost for a 50-kg child is $2.50 per day and $5.00 for the 100-mg maximum dose.
Clinical Implications
ADHD is believed to affect 6-10% of school-aged children and often continues into adulthood. Current therapy includes stimulants such as methylphenidate and amphetamines. Atomoxetine provides a nonstimulant and nonscheduled alternative for treatment both in pediatrics and adults who are not responsive to or are intolerant of current therapy. However, long-term safety of atomoxetine and effectiveness remain to be established.
References
1. Strattera Product Information. Eli Lilly and Company. November 2002.
2. Heil SH, et al. Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users. Drug Alcohol Depend. 2002;67(2):149-156.
3. Kratochvil CJ, et al. Atomoxetine and methylphenidate treatment in children with ADHD: A prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry. 2002;41(7):776-784.
4. Michelson D, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: A randomized, placebo-controlled, dose-response study. Pediatrics. 2001;108(5):E83.
5. Michelson D, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: A randomized, placebo-controlled study. Am J Psychiatry. 2002;159:1896-1901.
6. Biederman J, et al. Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder. Pediatrics. 2002;110(6):e75.
Dr. Elliott is Chair
of the Formulary Committee, Northern California Kaiser Permanente and Assistant
Clinical Professor of Medicine at the University of California-San Francisco.
Dr. Chan is Pharmacy Quality and Outcomes Manager at Kaiser Permanente in Oakland,
CA.
The FDA has approved Atomoxetine (previously named tomoxetine), the first nonstimulant/noncontrolled drug to be approved for the treatment of attention-deficit/hyperactivity disorder (ADHD).
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