Drug Interactions between budesonide / formoterol and donepezil

MONITOR: Concomitant use of acetylcholinesterase inhibitors and corticosteroids or adrenocorticotropic agents may result in severe muscle weakness in patients with myasthenia gravis. The mechanism of the interaction is unknown. It has been suggested that corticosteroids at high doses have a direct effect on neuromuscular transmission. Marked deterioration in muscle strength has been reported in patients with myasthenia gravis shortly after the initiation of corticosteroid therapy, particularly when high dosages were used. The use of cortisone appears to be associated with the highest rate of myasthenia gravis exacerbation, with an intermediate rate for prednisone and the lowest rate for methylprednisolone. In most cases, the decline in muscular function was relatively refractory to acetylcholinesterase inhibitors. However, clinical improvement generally occurs during prolonged corticosteroid therapy when administered properly.

MANAGEMENT: Caution and monitoring for muscle weakness is recommended with the use of corticosteroids or adrenocorticotropic agents in combination with acetylcholinesterase inhibitors in the treatment of patients with myasthenia gravis. Prednisone or prednisolone are often considered part of the standard treatment for this condition. Recommendations in the medical literature have advised that corticosteroid therapy should be instituted at relatively low dosages and in a controlled setting in patients with myasthenia gravis. Respiratory support should be available, and the dosage should be increased stepwise as tolerated. Dose reductions of the acetylcholinesterase inhibitor may be required as symptoms improve, which often may be delayed and gradual. However, according to some manufacturers of the corticosteroids dexamethasone and triamcinolone, anticholinesterase agents should be discontinued at least 24 hours before initiating corticosteroid therapy in patients with myasthenia gravis. Other management recommendations in the medical literature suggest avoiding the use of corticosteroids at high doses; however, if high doses are required, consider pre-treatment with intravenous immunoglobulin or plasmapheresis. Local protocols and/or the manufacturer's product labeling should be consulted for specific guidance.

MONITOR: Acetylcholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes, which occasionally manifest as bradycardia or heart block (<2%). Because bradycardia is a risk factor for torsade de pointes, a theoretical risk exists when combined with agents that prolong the QT interval. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors including, but not limited to congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation may vary depending on the dosage(s) and specific drug(s) involved.

MANAGEMENT: Caution is advised when acetylcholinesterase inhibitors are used with drugs that can prolong the QT interval. Patients should be monitored for bradycardia, atrioventricular block and syncope, and advised to seek medical attention if they experience dizziness, lightheadedness, fainting, shortness of breath, or slow or irregular heartbeat.

Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the potential significance is unknown. Patients who are receiving systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be at a greater risk of developing hypokalemia.