Atomoxetine 40 mg · Hard-gelatin capsules

The precise mechanism by which atomoxetine produces its therapeutic effects in 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.

Pharmacokinetic parameters for atomoxetine and its metabolites in CYP2D6 poor metabolizers and other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate) are presented in Table 9

Abbreviations: Cmax,ss= maximum atomoxetine plasma concentration at steady state; Tmax = time to peak concentration

Specific Populations — Hepatic Impairment: Atomoxetine exposure (AUC) was increased in subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase) hepatic impairment compared to subjects with normal hepatic function in other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate) [see Dosage and Administration ( 2.4) and Use in Specific Populations (8.6)].

Renal Impairment: Patients with severe renal impairment (end stage renal disease requiring hemodialysis) had higher systemic atomoxetine exposure (about a 65% increase) than patients with normal renal function (CrCl ≥ 90 ml/minute) in other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate), but there was no difference when exposure was corrected for mg/kg dose. Thus, the differences in exposure were not clinically significant.

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

Sex: Sex did not influence atomoxetine disposition.

Ethnic Origin: Ethnic origin did not influence atomoxetine disposition.

Clinical Studies: — Strong CYP2D6 Inhibitors: Concomitant use of atomoxetine (20 mg BID for 5 days) with paroxetine (20 mg QD for 17 days), a known inhibitor of CYP2D6, in subjects who were not CYP2D6 poor metabolizers resulted in a 6.5-fold higher plasma exposure (AUC) to atomoxetine at steady state.

Concomitant use of atomoxetine (at sequential dosing of 10, 45, and 75 mg BID for up to 5 days of each dosage) with

fluoxetine (20 mg QD for 36 days) a known inhibitor of CYP2D6, in subjects who were not CYP2D6 poor metabolizers resulted in 6 to 8-fold increases of plasma atomoxetine exposure (AUC) at steady state compared to taking atomoxetine alone.

After concomitant use of atomoxetine with paroxetine or fluoxetine, the Css, max of atomoxetine was about 3-to 4-fold greater than the use of atomoxetine alone [see Drug Interactions ( 7)].

CYP3A Substrates: Concomitant use of atomoxetine (60 mg twice daily for 12 days) with midazolam (CYP3A substrate) (single dose of 5 mg), resulted in 15% increase in the midazolam AUC. This pharmacokinetic change is not clinically significant.

CYP2D6 Substrates: Concomitant use of atomoxetine (40 or 60 mg twice daily for 13 days) with desipramine, (CYP2D6 substrate) (single dose of 50 mg), did not alter the desipramine pharmacokinetics.

Drugs that Affect Gastric pH: Drugs that elevate gastric pH had no effect on atomoxetine bioavailability.

In Vitro Studies: — Drugs Highly Bound to Plasma Protein : In vitro drug-displacement studies were conducted with atomoxetine and other drugs highly bound to plasma protein at therapeutic atomoxetine concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, warfarin, acetylsalicylic acid, phenytoin, or diazepam did not affect the binding of atomoxetine to human albumin.

CYP Inhibition/induction : Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes (including CYP1A2, CYP3A, CYP2D6, and CYP2C9).