Drug Interactions between budesonide / formoterol and fexinidazole

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the systemic bioavailability of budesonide, which undergoes extensive first-pass and systemic metabolism via intestinal and hepatic CYP450 3A4. In pharmacokinetic studies, 6- to 8-fold increases in budesonide systemic exposure (AUC) have been observed during coadministration of the potent CYP450 3A4 inhibitor ketoconazole with different oral formulations of budesonide. When ketoconazole was administered 12 hours after budesonide in one study, the AUC increase was approximately half that reported during simultaneous administration. 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 oral inhalation therapy (800 to 1600 mcg/day) were found to have adrenal insufficiency, including one who developed Cushing's syndrome, compared to none in a group of 12 patients treated with itraconazole alone. There was also no adrenal insufficiency 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. Limited pharmacokinetic data indicate that itraconazole (200 mg once daily) may increase the plasma levels of budesonide by about 4-fold following inhalation of a single 1000 mcg dose, which may be mainly due to increased bioavailability of the swallowed portion of the dose.

MANAGEMENT: The possibility of increased systemic adverse effects of budesonide should be considered during coadministration with CYP450 3A4 inhibitors. If concomitant use cannot be avoided, the dosing times between budesonide and the CYP450 3A4 inhibitor should be separated by as much as possible. In addition, the lowest effective dosage of budesonide should be prescribed, and further adjustments made as necessary according to therapeutic response and tolerance. Patients should be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and menstrual disorders. Other systemic glucocorticoid effects may include adrenal suppression, immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents.

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 additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. 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 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 recommended if beta-2 agonists are used in combination with other drugs that can prolong the QT interval. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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.