Atomoxetine (Page 5 of 9)

8.5 Geriatric Use

The safety, efficacy and pharmacokinetics of atomoxetine in geriatric patients have not been evaluated.

8.6 Hepatic Insufficiency

Atomoxetine exposure (AUC) is increased, compared with normal subjects, in EM subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase) hepatic insufficiency. Dosage adjustment is recommended for patients with moderate or severe hepatic insufficiency [see Dosage and Administration (2.3)].

8.7 Renal Insufficiency

EM subjects with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. Atomoxetine can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen.

8.8 Gender

Gender did not influence atomoxetine disposition.

8.9 Ethnic Origin

Ethnic origin did not influence atomoxetine disposition (except that PMs are more common in Caucasians).

8.10 Patients with Concomitant Illness

Tics in patients with ADHD and comorbid Tourette’s Disorder — Atomoxetine administered in a flexible dose range of 0.5 to 1.5 mg/kg/day (mean dose of 1.3 mg/kg/day) and placebo were compared in 148 randomized pediatric (age 7 to 17 years) subjects with a DSM-IV diagnosis of ADHD and comorbid tic disorder in an 18 week, double-blind, placebo-controlled study in which the majority (80%) enrolled in this trial with Tourette’s Disorder (Tourette’s Disorder: 116 subjects; chronic motor tic disorder: 29 subjects). A non-inferiority analysis revealed that atomoxetine did not worsen tics in these patients as determined by the Yale Global Tic Severity Scale Total Score (YGTSS). Out of 148 patients who entered the acute treatment phase, 103 (69.6%) patients discontinued the study. The primary reason for discontinuation in both the atomoxetine (38 of 76 patients, 50.0%) and placebo (45 of 72 patients, 62.5%) treatment groups was identified as lack of efficacy with most of the patients discontinuing at Week 12. This was the first visit where patients with a CGI-S≥4 could also meet the criteria for “clinical non-responder” (CGI-S remained the same or increased from study baseline) and be eligible to enter an open-label extension study with atomoxetine. There have been postmarketing reports of tics [see Adverse Reactions (6.2)].

Anxiety in patients with ADHD and comorbid Anxiety Disorders

In two post-marketing, double-blind, placebo-controlled trials, it has been demonstrated that treating patients with ADHD and comorbid anxiety disorders with atomoxetine does not worsen their anxiety.

In a 12-week double-blind, placebo-controlled trial, 176 patients, aged 8-17, who met DSM-IV criteria for ADHD and at least one of the anxiety disorders of separation anxiety disorder, generalized anxiety disorder or social phobia were randomized. Following a 2-week double-blind placebo lead-in, atomoxetine was initiated at 0.8 mg/kg/day with increase to a target dose of 1.2 mg/kg/day (median dose 1.30 mg/kg/day +/- 0.29 mg/kg/day). Atomoxetine did not worsen anxiety in these patients as determined by the Pediatric Anxiety Rating Scale (PARS). Of the 158 patients who completed the double-blind placebo lead-in, 26 (16%) patients discontinued the study.

In a separate 16-week, double-blind, placebo-controlled trial, 442 patients aged 18-65, who met DSM-IV criteria for adult ADHD and social anxiety disorder (23% of whom also had Generalized Anxiety Disorder) were randomized. Following a 2-week double-blind placebo lead-in, atomoxetine was initiated at 40 mg/day to a maximum dose of 100 mg/day (mean daily dose 83 mg/day +/- 19.5 mg/day). atomoxetine did not worsen anxiety in these patients as determined by the Liebowitz Social Anxiety Scale (LSAS). Of the 413 patients who completed the double-blind placebo lead-in, 149 (36.1%) patients discontinued the study. There have been postmarketing reports of anxiety [see Adverse Reactions (6.2)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Atomoxetine is not a controlled substance.

9.2 Abuse

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

9.3 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 atomoxetine. 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.

10 OVERDOSAGE

10.1 Human Experience

There is limited clinical trial experience with atomoxetine overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine and at least one other drug. There have been no reports of death involving overdose of atomoxetine alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations [see Clinical Pharmacology (12.2)].

10.2 Management of Overdose

Consult with a Certified Poison Control Center for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.

11 DESCRIPTION

Atomoxetine is a selective norepinephrine reuptake inhibitor. Atomoxetine hydrochloride is the R (-) isomer as determined by x-ray diffraction. The chemical designation is (-)-N -Methyl-3-phenyl-3-(o- tolyloxy)-propylamine hydrochloride. The molecular formula is C17 H21 NO•HCl, which corresponds to a molecular weight of 291.82. The chemical structure is:

Atomoxetine capsules
(click image for full-size original)

Atomoxetine hydrochloride is a white to practically white solid, which has a solubility of 27.8 mg/mL in water.

Each atomoxetine capsule intended for oral administration contains atomoxetine hydrochloride equivalent to atomoxetine 18 mg or 25 mg or 40 mg or 60 mg or 80 mg or 100 mg. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, gelatin, pregelatinized starch, sodium lauryl sulfate and titanium dioxide. Additionally each 18 mg capsule shell contains: iron oxide yellow, each 25 mg and 40 mg capsule shell contains: FD & C blue # 2, each 60 mg capsule shell contains: FD & C blue # 2 and iron oxide yellow and each 80 mg and 100 mg capsule shell contains: iron oxide red and iron oxide yellow. The capsule is printed with black pharmaceutical ink which contains following ingredients: black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac and strong ammonia solution.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies.

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