Atomoxetine Hydrochloride (Page 5 of 8)

8.5 Geriatric Use

The safety, efficacy and pharmacokinetics of atomoxetine hydrochloride 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 hydrochloride 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 hydrochloride 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%) 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)]

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Atomoxetine hydrochloride is not a controlled substance.

9.2 Abuse

In a randomized, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of atomoxetine hydrochloride and placebo, atomoxetine hydrochloride 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 hydrochloride. 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

No fatal overdoses occurred in clinical trials. There is limited clinical trial experience with atomoxetine hydrochloride overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine hydrochloride and at least one other drug. There have been no reports of death involving overdose of atomoxetine hydrochloride alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine hydrochloride, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine hydrochloride 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.

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 hydrochloride is a selective norepinephrine reuptake inhibitor. Atomoxetine HCl 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:

atomoxine-chemical-structure

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

Atomoxetine hydrochloride capsules are intended for oral administration only.

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.

12.2 Pharmacodynamics

An exposure-response analysis encompassing doses of atomoxetine (0.5, 1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposure correlates with efficacy as measured by the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator administered and scored. The exposure-efficacy relationship was similar to that observed between dose and efficacy with median exposures at the two highest doses resulting in near maximal changes from baseline [see Clinical Studies (14.2)].

12.3 Pharmacokinetics

Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity [extensive metabolizers (EMs)]. Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure.

The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and adolescents in selected clinical trials, primarily using population pharmacokinetic studies. Single-dose and steady-state individual pharmacokinetic data were also obtained in children, adolescents, and adults. When doses were normalized to a mg/kg basis, similar half-life, Cmax , and AUC values were observed in children, adolescents, and adults. Clearance and volume of distribution after adjustment for body weight were also similar.

Absorption and distribution— Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Maximal plasma concentrations (Cmax ) are reached approximately 1 to 2 hours after dosing.

Atomoxetine hydrochloride can be administered with or without food. Administration of atomoxetine hydrochloride with a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in a 37% lower Cmax , and delayed Tmax by 3 hours. In clinical trials with children and adolescents, administration of atomoxetine hydrochloride with food resulted in a 9% lower Cmax .

The steady-state volume of distribution after intravenous administration is 0.85 L/kg indicating that atomoxetine distributes primarily into total body water. Volume of distribution is similar across the patient weight range after normalizing for body weight.

At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin.

Metabolism and elimination — Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs . Laboratory tests are available to identify CYP2D6 PMs. Coadministration of atomoxetine hydrochloride with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary [see Warnings and Precautions (5.13)]. Atomoxetine did not inhibit or induce the CYP2D6 pathway.

The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in plasma at lower concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs).

Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs . The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).

Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O -glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction of the atomoxetine hydrochloride dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation.

[See Use In Specific Populations (8.4, 8.5, 8.6, 8.7, 8.8, 8.9)].

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