Drug Interactions between mavorixafor and MKO Melt Dose Pack

MONITOR CLOSELY: Coadministration of ketamine with other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. In addition, opioid analgesics, barbiturates, and benzodiazepines may prolong the time to complete recovery from anesthesia.

MANAGEMENT: During concomitant use of ketamine with other CNS depressants, including alcohol, close monitoring of neurologic status and respiratory parameters, including respiratory rate and pulse oximetry, is recommended. Dosage adjustments should be considered according to the patient's clinical situation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: Coadministration with mavorixafor may increase the plasma concentrations of drugs that are substrates of the isoenzyme CYP450 2D6, isoenzyme CYP450 3A4, and/or the efflux transporter P-glycoprotein (P-gp). It is important to determine if the isoenzyme in question is responsible for drug clearance or drug activation as these situations may result in either a potential increase in adverse effects or reduction in efficacy, respectively. When mavorixafor (400 mg) was used concurrently with the sensitive CYP450 2D6 substrate dextromethorphan in healthy subjects, dextromethorphan's peak plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 6- and 9-fold, respectively. On the other hand, when mavorixafor (400 mg) was used concurrently with the sensitive CYP450 3A4 substrate midazolam in healthy subjects, the Cmax and AUC increased by only 1.1- and 1.7-fold, respectively. Likewise, when a single dose of a transporter cocktail containing P-gp substrate digoxin (0.25 mg) was administered to healthy subjects on mavorixafor (400 mg/day at steady state), digoxin's Cmax and AUC increased by 1.5- and 1.6-fold, respectively. Data for less sensitive substrates or drugs metabolized and/or transported by multiple routes are unavailable.

MANAGEMENT: Caution is advised if mavorixafor is used concurrently with medications that are substrates of the P-gp efflux transporter and/or undergo metabolism via CYP450 2D6 and/or 3A4. This may be particularly important in cases where minimal concentration changes may result in serious adverse reactions from the substrate(s) in question. Dose adjustments and/or increased monitoring may be required. For example, digoxin's serum concentrations should be measured before initiating concomitant use with mavorixafor and as clinically indicated during coadministration. The labeling for the substrate(s) in question should be consulted for more specific recommendations.

MONITOR: Coadministration with mavorixafor may increase the plasma concentrations of drugs that are substrates of the isoenzyme CYP450 2D6, isoenzyme CYP450 3A4, and/or the efflux transporter P-glycoprotein (P-gp). It is important to determine if the isoenzyme in question is responsible for drug clearance or drug activation as these situations may result in either a potential increase in adverse effects or reduction in efficacy, respectively. When mavorixafor (400 mg) was used concurrently with the sensitive CYP450 2D6 substrate dextromethorphan in healthy subjects, dextromethorphan's peak plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 6- and 9-fold, respectively. On the other hand, when mavorixafor (400 mg) was used concurrently with the sensitive CYP450 3A4 substrate midazolam in healthy subjects, the Cmax and AUC increased by only 1.1- and 1.7-fold, respectively. Likewise, when a single dose of a transporter cocktail containing P-gp substrate digoxin (0.25 mg) was administered to healthy subjects on mavorixafor (400 mg/day at steady state), digoxin's Cmax and AUC increased by 1.5- and 1.6-fold, respectively. Data for less sensitive substrates or drugs metabolized and/or transported by multiple routes are unavailable.

MANAGEMENT: Caution is advised if mavorixafor is used concurrently with medications that are substrates of the P-gp efflux transporter and/or undergo metabolism via CYP450 2D6 and/or 3A4. This may be particularly important in cases where minimal concentration changes may result in serious adverse reactions from the substrate(s) in question. Dose adjustments and/or increased monitoring may be required. For example, digoxin's serum concentrations should be measured before initiating concomitant use with mavorixafor and as clinically indicated during coadministration. The labeling for the substrate(s) in question should be consulted for more specific recommendations.

MONITOR: Mavorixafor may increase the concentration of CYP450 3A4 and/or P-glycoprotein (P-gp) substrates via inhibition of the isoenzyme and/or the efflux transporter. It is important to determine if CYP450 3A4 is responsible for drug clearance or drug activation as these situations could result in a potential increase in adverse effects or reduction in efficacy, respectively. When mavorixafor (400 mg) was used concurrently with the sensitive CYP450 3A4 substrate midazolam in healthy subjects, midazolam's peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.1- and 1.7-fold (with an upper bound of the 90% confidence interval of 2.1-fold), respectively. Likewise, when a single dose of a transporter cocktail containing P-gp substrate digoxin (0.25 mg) was administered to healthy subjects on mavorixafor (400 mg/day at steady state), digoxin's Cmax and AUC increased by 1.5- and 1.6-fold, respectively. Data for less sensitive substrates are unavailable.

MONITOR: Mavorixafor can cause dose-related prolongation of the QT interval. Theoretically, coadministration with agents that can also prolong the QT interval may result in additive effects including torsade de pointes, other serious arrhythmias, and sudden death. In a thorough QT study completed in healthy volunteers following the administration of mavorixafor (800 mg), the maximum mean increase in the QTc interval (QT interval corrected for heart rate) was 15.6 ms, with an upper bound of the 90% confidence interval of 19.8 ms. The concentration-QT analysis demonstrated a concentration-dependent increase in the QTc interval. 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 including, but not limited to, congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation may vary depending on the dosage(s) and specific drug(s) involved.

MANAGEMENT: Caution and close clinical monitoring are recommended if mavorixafor is used in combination with a CYP450 3A4 and/or P-glycoprotein (P-gp) substrate that is also capable of QT prolongation, particularly if the QT prolongation is concentration-dependent. If coadministration is necessary, monitoring for an increase in adverse effects (if the medication is cleared by CYP450 3A4 and/or P-gp) or a reduction in efficacy (if the medication is activated by CYP450 3A4) is advised. Due to the risk of QT prolongation from both drugs, modifiable risk factors for QT prolongation (such as electrolyte abnormalities) should be corrected. The QTc interval should be assessed at baseline and during treatment as clinically indicated. A dose reduction, treatment pause, or discontinuation of one or both drugs may be required if changes are observed in the patient's electrocardiogram (ECG). The labeling for both medications should be consulted for more specific recommendations.