Tomoxetine

The Food and Drug Administration (FDA) approved the use of atomoxetine (Strattera) in November 2002-the first new medication in 30 years for attention deficit hyperactivity disorder (ADHD) treatment. Individuals with ADHD exhibit problems with control of attention and impulsivity (see Table: "Symptoms of ADHD"). Behaviors such as fidgeting, interrupting others, making careless mistakes, and excessive talking are commonly seen in children and adolescents. These behaviors may result in dysfunctional learning, and can affect relationships with peers, teachers, and family members. Although adult ADHD is not well defined, symptoms may include lack of organization, daydreaming, irritability, and lack of motivation.1

Traditional treatment modalities focus on behavioral and pharmacological interventions (see Table: "Current Treatment Modalities for ADHD"). Drug therapy combined with psychological interventions is associated with superior symptom reduction when compared with psychosocial interventions alone.2 Historically, pharmacological agents that affect dopaminergic and noradrenergic neurotransmission have improved ADHD symptoms. Stimulants, such as methylphenidate and d-amphetamine, were the only FDA-approved medications for ADHD, and are still the most often prescribed.3 Despiramine and bupropion are additional nonstimulant medications that are clinically effective for ADHD.4-6

The traditional stimulant medications are safe and efficacious, but some patients are intolerant of them or fail to respond. There may also be concerns for the patient and prescriber associated with these medications because they are controlled substances.

* Pharmacokinetics

Although originally called tomoxetine, the name was changed to atomoxetine to avoid drug-dispensing confusion with tamoxifen. Atomoxetine is a potent reuptake inhibitor of norepinephrine by the presynaptic neuron, but has minimal affinity for other neurotransmitter receptors, inhibitors, or other noradrenergic receptors. Atomoxetine's exact pharmacodynamic mechanism of action in producing therapeutic effects in ADHD patients is unknown. However, selective inhibition of presynaptic norepinephrine reuptake is believed to be related to its observed effects.7

Atomoxetine is minimally affected by food and is rapidly absorbed after oral administration. Maximum plasma concentrations are achieved in approximately 1 to 2 hours after ingestion. Food, especially high-fat meals, may increase the time of absorption but has minimal effect on the final plasma concentration. The drug is bound to protein, mostly albumin, in the plasma.

The half-life of atomoxetine is approximately 5 hours and is eliminated by oxidative metabolism in the cytochrome P450 2D6 enzymatic pathway. A small percentage of the population (7% Caucasians and 2% African Americans) has reduced metabolism in this enzyme pathway. "Poor metabolizers" using atomoxetine have slower elimination (half-life to 24 hours) and higher plasma concentrations (five times) compared with people with normal enzymatic metabolism.7 Other medications that use this same enzymatic pathway, such as fluoxetine, paroxetine, and quinidine may inhibit atomoxetine metabolism, creating higher plasma concentrations and longer elimination times of each drug. Dosage adjustment may be necessary in patients using both atomoxetine and one of the above-mentioned drugs.

Elimination of atomoxetine is primarily through excretion in the urine (>80%) and minimally through the feces (

* Clinical Trials

Atomoxetine was approved based on results of six randomized, double-blind, placebo-controlled studies in children, adolescents, and adults with ADHD.

In one 8-week study of ADHD patients (N=297) age 8 to 18, fixed doses of atomoxetine (0.5, 1.2, or 1.8 mg/kg/day) or placebo were administered in divided twice-a-day doses to evaluate symptom improvement based on dosage.8 The 1.2 mg/kg/day dose offered a statistically significant improvement in ADHD symptoms. The highest dose did not provide additional symptom improvement, and the lowest dose was not significantly different than the placebo.

A second study of patients (N=171) age 6 to 16 looked at the efficacy of once-daily dosing.9 Results in this study indicated once daily morning dosing of 1.3 mg/kg/day was effective in significantly improving ADHD symptoms in comparison to a placebo.

Two other studies with patients ages 7-13 (N=147 and N=144) evaluated ADHD symptom response using atomoxetine, methylphenidate, and placebo. Patients who received atomoxetine demonstrated statistically significant symptom improvement in comparison to patients given a placebo.

Two identical studies specifically addressed the efficacy of atomoxetine in the treatment of ADHD in adults.10 Each adult group (N=280 and N=256) received either a divided dose of placebo or atomoxetine, titrated from 60 to 120 mg/day. Statistically significant improvement in ADHD symptoms was seen in the atomoxetine groups with a final mean dose of 95 mg/day.

These clinical trials exhibited appropriate methodologies and statistical analyses. The conclusions were appropriate for the results identified and limitations of the studies were adequately delineated and addressed. However, the manufacturer of atomoxetine, Eli Lilly and Company, funded the majority of the clinical studies for this medication.

* Practitioner Considerations

Pharmacological interventions should be a part of an integrated treatment program for ADHD. Psychological, social, and educational interventions should also be addressed, and may eliminate the need for drug use in some ADHD patients. Atomoxetine is approved and indicated only for the treatment of ADHD. Diagnostic criteria for ADHD include the presence of hyperactive-impulsive or inattentive symptoms causing impairment and observed before age 7. Symptoms must persist, be more severe than those found in individuals of a comparable developmental level, and result in social, academic, or occupational dysfunction in two or more settings (e.g., home, school). Diagnosis of ADHD is derived from a thorough history and evaluation; no laboratory or imaging tests are indicated.

Atomoxetine is contraindicated in any patient with hypersensitivity to this drug or other product constituents. Atomoxetine should not be used by anyone currently taking, or within 2 weeks of discontinuing, a monoamine oxidase inhibitor. The use of this medication in patients with narrow angle glaucoma is also contraindicated.

Practitioners prescribing atomoxetine should monitor growth parameters of children or adolescents. During short-term clinical trials, minimal weight loss (average 0.4 kg) was noted in atomoxetine groups. No studies have evaluated the effect of long-term use of atomoxetine on growth, and drug therapy should be discontinued if weight or height parameters seem to be adversely affected.

Blood pressure and heart rate may increase slightly in patients on atomoxetine. These parameters should be carefully monitored in patients with a history of hypertension, tachycardia, and cardiovascular or cerebrovascular disease. These medical conditions are less common in pediatric patients and not likely to be a contraindication for the use of atomoxetine in this population. However, all patients, especially poor metabolizers, should have their vital signs regularly evaluated for drug-induced changes.

Urinary retention and hesitancy was noted in 3% of the adult ADHD patients taking atomoxetine during clinical trials. New complaints of these symptoms in patients after initiating atomoxetine therapy should be considered potentially related to the drug.

Atomoxetine therapy does not require the practitioner to monitor any routine laboratory or other diagnostic tests. Based on testing in rats and mice, there is no indication of atomoxetine-induced carcinogenesis or mutagenesis, and no fertility impairment. Atomoxetine is classified as Pregnancy Category C and the drug is not recommended for use during pregnancy. No studies have examined whether atomoxetine is excreted in human milk and the practitioner should be cautious in prescribing this medication to nursing mothers.

Important drug-drug interactions to consider include albuterol, monoamine oxidase inhibitors, certain cytochrome P450 inhibitors, and pressor agents. Albuterol's (and other beta^sub 2^ agonists') cardiovascular effects maybe potentiated by atomoxetine. Certain drugs may affect the cytochrome P450 inhibitors, specifically the CYP2D6 enzymes, and if taken concurrently with atomoxetine may potentiate its effects. Patients using paroxetine, fluoxetine, and quinidine may need dosage adjustments, as these are medications known to inhibit the CYP2D6 enzymes. Due to atomoxetine's potential to affect blood pressure, patients taking antihypertensive medications should be carefully monitored for increases in blood pressure.

Common adverse reactions observed in the child and adolescent study participants included: dyspepsia, nausea, vomiting, fatigue, decreased appetite, dizziness, and mood swings. In the adult study subjects, commonly reported adverse reactions included: constipation, dry mouth, nausea, decreased appetite, dizziness, insomnia, decreased libido, impotence, urinary hesitation and retention, and dysmenorrhea. Poor metabolizers were more likely to experience an increase in adverse reactions.

Unlike other ADHD stimulant medications, atomoxetine is not a controlled substance and no evidence of withdrawal, stimulant, or euphoric properties was observed during clinical trials. Thus, the drug is considered unlikely to be abused or lead to physiological dependence. The effects of atomoxetine overdose are unknown and no specific antidote is available.

Atomoxetine is available in 10, 18, 25, 40, and 60 mg capsules.

Current dosing for atomoxetine is as follows:

Children and adolescents

Adults or younger patients > 70 kg: Start with a 40 mg daily dose and increase after 3 days to a target dose of 80 mg administered either as a single morning dose or divided dose in morning and late afternoon/early evening. The dose may be increased to 100 mg if optimal response is not seen after 2 to 4 weeks.

Dosage adjustments may be necessary in patients with hepatic impairment, poor metabolizers, and those using a strong CYP2D6 inhibitor (see package insert for detailed adjustments). Atomoxetine may be discontinued without tapering.

Atomoxetine represents a new class of medication demonstrated in clinical trials to be effective in treating the symptoms of ADHD in both children and adults. Combined with psychological, social, and educational interventions, it may offer new options in the treatment regimen of ADHD patients. Further information for patients or health care professionals is available at http://www. strattera.com.

ACKNOWLEDGEMENT

The authors would like to gratefully acknowledge the preparation of "Current Treatment Modalities of ADHD by Sena Hitt-Laustsen: Project Coordinator for Colorado study: "Attentional and Learning Difficulties in College Students" (Erik G. Willcutt, PhD, Principal Investigator).

REFERENCES

1. U.S. Food and Drug Administration. FDA approves non-stimulant ADHD drug. In: FDA Talk Paper 2002. Retrieved July 21, 2003, from FDA.gov: http://fda.gov/bbs/topics/ANSWERS/ 2002/ANS01177.html

2. MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1999;56: 1073-1086.

3. Popper CW: Pharmacologic alternatives to psychostimulants for the treatment of attention-deficit/hyperactivity disorder. Child & Adolescent Psychiatric Clinics of North America 2000;9(3): 605-646.

4. Wilens TE, Biederman J, Abrantes AM, et al: A naturalistic assessment of protriptyline for attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1996;35: 1485-1490.

5. Wender PH, Reimherr FW: Bupropion treatment of attention-deficit hyperactivity disorder in adults. Am J Psychiatry 1990;147:1018-1020.

6. Higgins ES: A comparative analysis of antidepressants and stimulants for the treatment of adults with attention-deficit hyperactivity disorder. J Fam Pract 1999;48:15-20.

7. Eli Lilly and Company. Strattera [Drug Insert] 2002. Indianapolis, Ind.

8. Michelson D, Paries D, Wernicke J, 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), 1-9.

9. Michelson D, Allen AJ, Busner J, 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(11), 1896-1901.

10. Kratochvil CJ, Heiligenstein JH, Dittman R, et al: Atomoxetine and methylphenidate treatment in children with ADHD: A prospective, randomized, open-label trial. Journal of the American Academy of Child & Adolescent Psychiatry 2002;41; 776-784.

11. Michelson D, Adler L, Spencer T, et al: Atomoxetine in adults with ADHD: Two randomized, placebo-controlled studies. Society of Biological Psychiatry 2003;53; 112-120.

12. Lilienfeld SO, Lynn SJ (Eds.): Science and pseudoscience in clinical psychology. New York, NY, US: Guilford Press. 2003.

13. Wilens TE, Biederman, J, Spencer TJ: Attention deficit/ hyperactivity disorder across the lifespan. Ann Rev Med 2002,53, 113-31.

Lynn Wimett RN, ANP, EdD

Gary Laustsen RN, PhDc, CFNP

Drug News Co-Editors

Copyright Springhouse Corporation Dec 2003
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