Drug interactions between Symbicort and Vfend

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and systemic effects of budesonide, which is primarily metabolized by the isoenzyme. According to budesonide labeling, potent inhibitors can increase the plasma levels of budesonide several fold. For example, an 8-fold increase in the systemic exposure (AUC) has been observed during coadministration of oral budesonide with ketoconazole. In a prospective study of a cystic fibrosis center patient population, 11 of 25 patients receiving high-dose itraconazole (400 to 600 mg/day) and budesonide inhalation therapy (800 to 1600 mcg/day) were found to have adrenal insufficiency (one developed Cushing's syndrome), compared to none in a group of 12 patients treated with itraconazole alone and none in a group of 30 cystic fibrosis patients retrospectively included as controls, 24 of whom had been treated with high-dose inhaled budesonide for several years. Adrenal function improved but did not normalize in 10 of the 11 patients during a follow-up of two to ten months after discontinuation of itraconazole and institution of hydrocortisone replacement therapy.

MANAGEMENT: The possibility of increased systemic pharmacologic effects of budesonide should be considered during concomitant therapy with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, voriconazole, nefazodone, protease inhibitors, and ketolide and macrolide antibiotics. Adrenal function should be monitored regularly during chronic use of these agents, and reduction of budesonide dosage may be necessary. Systemic glucocorticoid effects of budesonide during prolonged administration may include symptoms of hypercorticism (e.g., acne, easy bruising, moon face, edema, hirsutism, buffalo hump, skin striae, glucose intolerance, irregular menstruations); adrenal suppression (which reduces patient's ability to respond to stress situations); immunosuppression; and osteoporosis.

MONITOR: Beta-2 adrenergic agonists can cause dose-related prolongation of the QT interval and potassium loss. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. 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 such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). Clinically significant prolongation of QT interval and hypokalemia occur infrequently when beta-2 adrenergic agonists are inhaled at normally recommended dosages. However, these effects may be more common when the drugs are administered systemically or when recommended dosages are exceeded.

MANAGEMENT: Caution is advised if beta-2 adrenergic agonists are used in combination with other drugs that prolong the QT interval, including class IA and III antiarrhythmic agents, certain neuroleptic agents, phenothiazines, tricyclic antidepressants, quinolones, ketolide and macrolide antibiotics, and cisapride. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, or syncope.