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Clinical Trials Experience

STRATTERA (atomoxetine hcl) was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Child and Adolescent Clinical Trials

Reasons for discontinuation of treatment due to adverse reactions in child and adolescent clinical trials — In acute child and adolescent placebo-controlled trials, 3.0% (48/1613) of atomoxetine subjects and 1.4% (13/945) placebo subjects discontinued for adverse reactions. For all studies, (including open-label and long-term studies), 6.3% of extensive metabolizer (EM) patients and 11.2% of poor metabolizer (PM) patients discontinued because of an adverse reaction. Among STRATTERA (atomoxetine hcl) -treated patients, irritability (0.3%, N=5); somnolence (0.3%, N=5); aggression (0.2%, N=4); nausea (0.2%, N=4); vomiting (0.2%, N=4); abdominal pain (0.2%, N=4); constipation (0.1%, N=2); fatigue (0.1%, N=2); feeling abnormal (0.1%, N=2); and headache (0.1%, N=2) were the reasons for discontinuation reported by more than 1 patient.

Seizures — STRATTERA (atomoxetine hcl) has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies during the product's premarket testing. In the clinical development program, seizures were reported in 0.2% (12/5073) of children whose average age was 10 years (range 6 to 16 years). In these clinical trials, the seizure risk among poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4741) for extensive metabolizers.

Commonly observed adverse reactions in acute child and adolescent, placebo-controlled trials — Commonly observed adverse reactions associated with the use of STRATTERA (atomoxetine hcl) (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (STRATTERA (atomoxetine hcl) incidence greater than placebo) are listed in Table 1. Results were similar in the BID and the QD trial except as shown in Table 2, which shows both BID and QD results for selected adverse reactions based on statistically significant Breslow-Day tests. The most commonly observed adverse reactions in patients treated with STRATTERA (atomoxetine hcl) (incidence of 5% or greater and at least twice the incidence in placebo patients, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 1 and 2).

Table 1: Common Treatment–Emergent Adverse Reactions Associated with the Use of STRATTERA (atomoxetine hcl) in Acute (up to 18 weeks) Child and Adolescent Trials

Table 2: Common Treatment-Emergent Adverse Reactions Associated with the Use of STRATTERA (atomoxetine hcl) in Acute (up to 18 weeks) Child and Adolescent Trials

The following adverse reactions occurred in at least 2% of PM patients and were either twice as frequent or statistically significantly more frequent in PM patients compared with EM patients: insomnia (15% of PMs, 10% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression¹ (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); conjunctivitis (3% of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs).

¹Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria.

Adult Clinical Trials

Reasons for discontinuation of treatment due to adverse reactions in acute adult placebo-controlled trials — In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3.0% (12/405) placebo subjects discontinued for adverse reactions. Among STRATTERA (atomoxetine hcl) -treated patients, insomnia (0.9%, N=5); nausea (0.9%, N=5); chest pain (0.6%, N=3); fatigue (0.6%, N=3); anxiety (0.4%, N=2); erectile dysfunction (0.4%, N=2); mood swings (0.4%, N=2); nervousness (0.4%, N=2); palpitations (0.4%, N=2); and urinary retention (0.4%, N=2) were the reasons for discontinuation reported by more than 1 patient.

Seizures — STRATTERA (atomoxetine hcl) has not been systematically evaluated in adult patients with a seizure disorder as these patients were excluded from clinical studies during the product's premarket testing. In the clinical development program, seizures were reported on 0.1% (1/748) of adult patients. In these clinical trials, no poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers.

Commonly observed adverse reactions in acute adult placebo-controlled trials — Commonly observed adverse reactions associated with the use of STRATTERA (atomoxetine hcl) (incidence of 2% or greater) and not observed at an equivalent incidence among placebo338 treated patients (STRATTERA (atomoxetine hcl) incidence greater than placebo) are listed in Table 3. The most commonly observed adverse reactions in patients treated with STRATTERA (atomoxetine hcl) (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, fatigue, decreased appetite, insomnia, erectile dysfunction, urinary hesitation and/or urinary retention and/or dysuria, dysmenorrhea, and hot flush (see Table 3).

Table 3: Common Treatment-Emergent Adverse Reactions Associated with the Use of STRATTERA (atomoxetine hcl) in Acute (up to 25 weeks) Adult Trials

Male and female sexual dysfunction — Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. Table 3 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking STRATTERA (atomoxetine hcl) in placebo-controlled trials.

There are no adequate and well-controlled studies examining sexual dysfunction with STRATTERA (atomoxetine hcl) treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of STRATTERA (atomoxetine hcl) , physicians should routinely inquire about such possible side effects.

Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post approval use of STRATTERA (atomoxetine hcl) . Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular system — QT prolongation, syncope.

General disorders and administration site conditions — Lethargy.

Nervous system disorders — Hypoaesthesia; paraesthesia in children and adolescents; sensory disturbances; tics.

Psychiatric disorders — Depression and depressed mood; anxiety.

Seizures — Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between STRATTERA (atomoxetine hcl) and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.

Skin and subcutaneous tissue disorders — Hyperhidrosis.

Urogenital system — Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.

Monoamine Oxidase Inhibitors

With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see STRATTERA CONTRAINDICATIONS].

Effect of CYP2D6 Inhibitors on Atomoxetine

In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css,max is about 3- to 4-fold greater than atomoxetine alone.

In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine.

Pressor Agents

Because of possible effects on blood pressure, STRATTERA (atomoxetine hcl) should be used cautiously with pressor agents (e.g., dopamine, dobutamine).

Albuterol

STRATTERA (atomoxetine hcl) should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200-800 mcg) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status.

Effect of Atomoxetine on P450 Enzymes

Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

CYP3A Substrate (e.g., Midazolam) — Coadministration of STRATTERA (atomoxetine hcl) (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A.

CYP2D6 Substrate (e.g., Desipramine) — Coadministration of STRATTERA (atomoxetine hcl) (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6.

Alcohol

Consumption of ethanol with STRATTERA (atomoxetine hcl) did not change the intoxicating effects of ethanol.

Methylphenidate

Coadministration of methylphenidate with STRATTERA (atomoxetine hcl) did not increase cardiovascular effects beyond those seen with methylphenidate alone.

Drugs Highly Bound to Plasma Protein

In vitro drug-displacement studies were conducted with atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, these compounds did not affect the binding of atomoxetine to human albumin.

Drugs that Affect Gastric pH

Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on STRATTERA (atomoxetine hcl) bioavailability.

Drug Abuse And Dependence

Controlled Substance

STRATTERA (atomoxetine hcl) is not a controlled substance.

Abuse

In a randomized, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of STRATTERA (atomoxetine hcl) and placebo, STRATTERA (atomoxetine hcl) was not associated with a pattern of response that suggested stimulant or euphoriant properties.

Dependence

Clinical study data in over 2000 children, adolescents, and adults with ADHD and over 1200 adults with depression showed only isolated incidents of drug diversion or inappropriate self-administration associated with STRATTERA (atomoxetine hcl) . There was no evidence of symptom rebound or adverse reactions suggesting a drug-discontinuation or withdrawal syndrome.

Animal Experience — Drug discrimination studies in rats and monkeys showed inconsistent stimulus generalization between atomoxetine and cocaine.

Last reviewed on RxList: 4/29/2011
This monograph has been modified to include the generic and brand name in many instances.