Drug Interaction Report

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.

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.

ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir. The mechanism is unknown. When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state. Darunavir exposure was similar for the range of meals studied. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food. The type of food is not important.