Drug Interactions between formoterol / mometasone and levoketoconazole

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.

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MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of mometasone, which is primarily metabolized by the isoenzyme. In healthy subjects coadministered mometasone (400 mcg inhaled twice daily for 9 days) with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally twice daily on days 4 to 9), 4 out of 12 subjects had peak plasma concentrations of mometasone increase from less than 150 pcg/mL on day 3 before the addition of ketoconazole to more than 200 pcg/mL afterwards. Serum cortisol AUC also decreased slightly after ketoconazole was added. The clinical significance of these findings is unknown.

MANAGEMENT: The possibility of increased systemic adverse effects of mometasone should be considered during coadministration with potent CYP450 3A4 inhibitors. Some authorities advise against concomitant use unless the potential benefit outweighs the risk. If the combination cannot be avoided, the dosing times between mometasone and the CYP450 3A4 inhibitor should be separated by as much as possible. In addition, the lowest effective dosage of mometasone should be prescribed, and further adjustments made as necessary according to therapeutic response and tolerance. Alternatively, a less potent, less lipophilic, and/or shorter-acting agent such as beclomethasone may be considered. Beclomethasone is also less dependent on CYP450 3A4 metabolism. 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.

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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.

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