Drugs Known to Prolong QTc-Interval: Onbrez Breezhaler, as other β2-adrenergic agonists, should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants or drugs known to prolong the QT-interval, as any effect of these on the QT-interval may be potentiated. Drugs known to prolong the QT-interval may increase the risk of ventricular arrhythmia (see Precautions).
Sympathomimetic Agents: Concomitant administration of other sympathomimetic agents (alone or as part of combination therapy) may potentiate the undesirable effects of Onbrez Breezhaler (see Precautions).
Hypokalemia: Concomitant treatment with methylxanthine derivatives, steroids or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of β2-adrenergic agonists (see Precautions).
Beta-Adrenergic Blockers: β-adrenergic blockers may weaken or antagonise the effect of β2-adrenergic agonists. Therefore, Onbrez Breezhaler should not be given together with β-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. Where required, cardioselective β-adrenergic blockers should be preferred, although they should be administered with caution.
Metabolic- and Transporter-Based Drug Interaction: Inhibition of the key contributors of indacaterol clearance, cytochrome (CYP) 3A4 and P-gp, has no impact on safety of therapeutic doses of Onbrez Breezhaler. Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (ie, ketoconazole, erythromycin and verapamil). Verapamil was used as the prototypic inhibitor of P-gp and resulted in 1.4- to 2-fold increase in AUC and 1.5-fold increase in Cmax. Co-administration of erythromycin with Onbrez Breezhaler resulted in an increase of 1.4- to 1.6-fold for AUC and 1.2-fold for Cmax. Combined inhibition of P-gp and CYP3A4 by the very strong dual inhibitor ketoconazole caused a 2-fold and 1.4-fold increase in AUC and Cmax, respectively. Taken together, the data suggest that systemic clearance is influenced by modulation of both P-gp and CYP3A4 activities and that the 2-fold AUC increase caused by the strong dual inhibitor ketoconazole reflects the impact of maximal combined inhibition. The magnitude of exposure increases due to drug interactions does not raise any safety concerns given the safety experience of treatment with Onbrez Breezhaler in clinical trials of up to 1 year at doses 2- to 4-fold the recommended therapeutic doses.
Onbrez Breezhaler has not been shown to cause drug interactions with co-medications. In vitro investigations have indicated that indacaterol has negligible potential to cause metabolic interactions with medications at the systemic exposure levels achieved in clinical practice.