Drug Interactions between dexamethasone / moxifloxacin and lefamulin

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 and/or P-glycoprotein (P-gp) may significantly decrease the plasma concentrations of lefamulin, which is a substrate of both the isoenzyme and efflux transporter. When oral lefamulin was administered with oral rifampin, a potent CYP450 3A4/P-gp inducer, mean lefamulin peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 57% and 72%, respectively. Coadministration of intravenous lefamulin with oral rifampin reduced mean lefamulin Cmax and AUC by 8% and 28%, respectively. Reduced therapeutic efficacy may occur.

MANAGEMENT: Concomitant use of lefamulin with potent or moderate inducers of CYP450 3A4 and/or P-gp should be avoided unless the benefit outweighs the risks. Monitor for reduced efficacy of lefamulin if coadministration is necessary.

GENERALLY AVOID: Lefamulin may cause dose-related prolongation of the QT interval. 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 two randomized, double-blind, double-dummy, active-controlled (moxifloxacin 400 mg once daily) studies, a concentration-dependent QTc prolongation effect of lefamulin was observed. The mean change from baseline QTcF around Tmax on day 3 or 4 was 13.6 msec for lefamulin 150 mg administered twice daily by infusion and 9.3 msec for lefamulin 600 mg administered twice daily orally, compared to 16.4 msec for moxifloxacin 400 mg administered once daily by infusion and 11.6 msec for moxifloxacin 400 mg administered once daily orally. 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).

MANAGEMENT: Coadministration of lefamulin with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Patients should have electrocardiograms (ECGs) and electrolyte levels assessed during treatment as appropriate based on individual risk factors. The recommended dosage and infusion rate of lefamulin should not be exceeded, as the magnitude of QT prolongation may increase with increasing concentrations of the drug or increasing the rate of infusion. 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.