Cytochrome P450 Enzymes: Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6 and CYP2C9. Using in vitro preparations, atomoxetine and N-desmethylatomoxetine are predicted to inhibit the activities of cytochrome P450 enzymes CYP2D6, CYP3A and CYP2C9 (predicted inhibition is 65%, 73% and 16% at maximum dose, respectively). However, in clinical studies evaluating the co-administration of atomoxetine with desipramine, a model compound for CYP2D6 metabolised drugs, or midazolam, a model compound for CYP3A4 metabolised drugs, atomoxetine did not significantly alter the pharmacokinetics of these model compounds. Atomoxetine is principally metabolised by the CYP2D6 pathway. In CYP2D6 EMs, inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in CYP2D6 PMs. In EMs, selective inhibitors of CYP2D6 increased atomoxetine steady-state plasma concentrations to exposures less than or similar to those observed in PMs. This pharmacokinetic interaction did not result in an increased sensitivity to Strattera.
In vitro studies suggest that several CYP isoforms are involved in the formation of 4-hydroxyatomoxetine in CYP2D6 PMs (including CYP2B6, CYP2C19 and CYP2E1) and therefore co-administration of cytochrome P450 inhibitors may not markedly increase the circulating plasma concentration of atomoxetine.
Fluoxetine, Paroxetine or Quinidine: Administration of Strattera to patients taking fluoxetine, paroxetine or quinidine, known inhibitors of CYP2D6, resulted in a higher plasma exposure to atomoxetine. 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 post-marketing reports, QT prolongation has been very rarely reported amongst patients taking Strattera in overdose, and in conjunction with CYP2D6 inhibitors such as fluoxetine, paroxetine or quinidine. Concomitant administration of Strattera with drugs that prolong QT interval, drugs that cause electrolyte disturbance and drugs that inhibit CYP2D6 is cautioned (See Pharmacology: Pharmacodynamics: Clinical Trials: Cardiac Electrophysiology under Actions).
Dosage adjustment of Strattera may be necessary in those patients who are also taking CYP2D6 inhibitor drugs (see CYP2D6 inhibitors under Dosage & Admnistration).
Methylphenidate: Co-administration of methylphenidate with Strattera did not increase cardiovascular effects beyond those seen with methylphenidate administration alone.
Midazolam: Co-administration of Strattera with midazolam resulted in small increases in midazolam plasma concentrations. These changes were smaller than those caused by weak inhibitors of CYP3A and therefore, no dose adjustment is recommended for drugs metabolised by CYP3A.
Monoamine Oxidase Inhibitors: (see Contraindications).
Anti-hypertensive drugs and Pressor Agents: Because of possible effects on blood pressure, Strattera should be used cautiously with anti-hypertensive drugs and pressor agents or other drugs that increase blood pressure.
Drugs that Affect Noradrenaline: Drugs that affect noradrenaline such as α1 agonists or those that inhibit the reuptake of noradrenaline should be used cautiously when co-administered with Strattera because of the potential for additive or synergistic pharmacological effects.
Beta-Adrenergic Receptor Agonists: Strattera should be administered with caution to patients being treated with systemically-administered (oral or intravenous) salbutamol (or other beta2 agonists) because the action of salbutamol on the cardiovascular system can be potentiated.
Tricyclic Antidepressants: Strattera can increase the adverse cardiovascular effects of tricyclic antidepressants if co-administered.
Desipramine (a tricyclic antidepressant) pharmacokinetics, which is dependent on CYP2D6 metabolism, were not altered by steady-state atomoxetine concentrations. However these drugs should not be used in combination because one of desipramine's effects is to block noradrenaline reuptake.
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 plasma protein binding of acetylsalicylic acid, desipramine or warfarin to human plasma proteins. However, atomoxetine increased the fraction of unbound diazepam (by 60%), paroxetine (by 19%) and phenytoin (by 11%). Desipramine, diazepam, paroxetine, phenytoin, midazolam and warfarin did not change the fraction of atomoxetine bound to plasma proteins. High concentrations of acetylsalicylic acid (≥ 300 μg/mL) caused up to a 3-fold increase in the unbound fraction of Strattera.
Drugs that Affect Gastric pH: Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on Strattera bioavailability.
Alcohol: Consumption of ethanol with Strattera did not change the intoxicating effects of ethanol.