Onbrez Breezhaler Drug Interactions

Medicinal products known to prolong QTc interval: As with other beta₂ agonists, there is a theoretical risk that medicinal products known to prolong the QTc interval may cause a pharmacodynamic interactions with indacaterol and increase the potential risk of ventricular arrhythmia. Examples of such medicinal products are certain antihistamines (e.g. terfenadine, mizolastine), certain antiarrhythmic agents (e.g. quinidine), phenothiazines, erythromycin, ritonavir and tricyclic antidepressants. Concomitant administration of sympathomimetic agents may exacerbate adverse cardiovascular effects. Caution is required when giving Onbrez Breezhaler to patients receiving treatment with MAO inhibitors or tricyclic antidepressants since the action of beta₂-stimulants on the cardiovascular system may be potentiated.
Concomitant administration of levodopa, levothyroxine and oxytocin may have a negative impact on cardiac tolerance to beta₂-sympathomimetic agents.
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 hypokalemic effect of beta₂-adrenergic agonists (see PRECAUTIONS).
Beta-adrenergic blockers: Beta-adrenergic blockers may weaken or antagonise the effect of beta₂-adrenergic agonists. Therefore Onbrez Breezhaler should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. Where required, cardioselective beta-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, CYP3A4 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 (i.e., ketoconazole, erythromycin, verapamil and ritonavir). Verapamil was used as the prototypic inhibitor of P-gp and resulted in 1.4- to two-fold increase in AUC and 1.5-fold increase in C_max. 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 C_max. 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 C_max, respectively. Concomitant treatment with ritonavir, another dual inhibitor of CYP3A4 and P-gp, resulted in a 1.6- to 1.8-fold increase in AUC whereas C_max was unaffected. 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 one year at doses two- to four-fold the recommended therapeutic doses.
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.