Drug Interactions between codeine / diphenhydramine / phenylephrine and eliglustat

CONTRAINDICATED: Coadministration with inhibitors of CYP450 2D6 may significantly increase the plasma concentrations of eliglustat, which is primarily metabolized by CYP450 2D6 and, to a lesser extent, CYP450 3A4. Eliglustat at substantially elevated plasma concentrations is predicted to cause prolongation of the PR, QTc and QRS cardiac intervals, which may increase the risk of bradycardia, atrioventricular block, cardiac arrest, and serious ventricular arrhythmias such as torsade de pointes. In 30 subjects who were CYP450 2D6 extensive metabolizers (EMs), eliglustat peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 7.0- and 8.0-fold, respectively, following coadministration of eliglustat (84 mg twice daily) with the potent CYP450 2D6 inhibitor paroxetine (30 mg once daily). Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that paroxetine may increase eliglustat Cmax by 2.1-fold and AUC by 2.3-fold in CYP450 2D6 intermediate metabolizers (IMs). When the moderate CYP450 2D6 inhibitor terbinafine was used, PBPK modeling predicted a 3.8-fold increase in eliglustat Cmax and 4.5-fold increase in AUC for EMs, and a 1.6-fold increase each in Cmax and AUC for IMs. The magnitude of interaction is expected to increase further with the addition of a CYP450 3A4 inhibitor like ketoconazole. Simulations using PBPK models suggest that the combination of paroxetine (30 mg once daily) and ketoconazole (400 mg once daily) may increase eliglustat Cmax by 16.7-fold and AUC by 24.2-fold in EMs given eliglustat 84 mg twice daily. For IMs, the estimated increases in eliglustat Cmax and AUC are 7.5- and 9.8-fold, respectively. When a less potent combination of CYP450 2D6 (terbinafine) and 3A4 (fluconazole) inhibitors were used, PK modeling predicted a 10.2-fold increase in eliglustat Cmax and 13.6-fold increase in AUC for EMs given eliglustat 84 mg twice daily, and a 4.2-fold increase in eliglustat Cmax and 5.0-fold increase in AUC for IMs.

MANAGEMENT: The use of eliglustat in combination with one or more drugs that may result in moderate or potent inhibition of both CYP450 2D6 and 3A4 is considered contraindicated in CYP450 2D6 intermediate metabolizers (IMs) and extensive metabolizers (EMs). In the absence of a concomitant CYP450 3A4 inhibitor, eliglustat may be prescribed at a reduced dosage of 84 mg once daily to IMs and EMs treated with a potent or moderate CYP450 2D6 inhibitor. Poor metabolizers are not affected by CYP450 2D6 inhibition (since they already have minimal functional levels of the isoenzyme) and may also receive the reduced dosage of eliglustat, so long as they are not treated with a CYP450 3A4 inhibitor. Potent and moderate CYP450 3A4 inhibitors include azole antifungal agents, protease inhibitors, aprepitant, ciprofloxacin, clarithromycin, cobicistat, conivaptan, crizotinib, delavirdine, diltiazem, dronedarone, erythromycin, fusidic acid, idelalisib, imatinib, lomitapide, mibefradil, mifepristone, nefazodone, ranolazine, telithromycin, and verapamil. Potent and moderate CYP450 2D6 inhibitors include abiraterone, bupropion, celecoxib, cimetidine, cinacalcet, clobazam, darifenacin, diphenhydramine, duloxetine, fluoxetine, givosiran, mavorixafor, methotrimeprazine, mirabegron, panobinostat, paroxetine, propoxyphene, quinidine, ranolazine, rolapitant, sertraline, stiripentol, and terbinafine. Some drugs such as abiraterone, cimetidine, mavorixafor, ranolazine, and stiripentol are dual CYP450 2D6 and 3A4 inhibitors, and they should probably not be used with eliglustat in any patient regardless of their CYP450 2D6 metabolizer status. In addition, antiarrhythmics such as amiodarone, dronedarone, flecainide, propafenone, and quinidine can inhibit CYP450 2D6 and cause significant prolongation of the QT interval. These agents should not be used with eliglustat in any patient. Depending on the elimination half-life of concomitant drugs, a considerable waiting period may also be appropriate following their discontinuation before initiating eliglustat. For example, the prolonged duration of CYP450 2D6 inhibition by the moderate CYP450 2D6 inhibitor rolapitant of at least 28 days after its administration should also be taken into account when initiating eliglustat.

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. 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: Drugs that are inhibitors of CYP450 2D6 may interfere with the analgesic effect of codeine. The mechanism is decreased in vivo conversion of codeine to morphine, a metabolic reaction mediated by CYP450 2D6. If an inhibitor is started after a stable dose of codeine is achieved, reduced analgesia and possible opioid withdrawal may result. Conversely, ceasing CYP450 2D6 inhibitor therapy may lead to increased morphine levels, increasing the risk of opioid-related adverse effects.

MANAGEMENT: The possibility of reduced or inadequate pain relief should be considered in patients receiving codeine with drugs that inhibit CYP450 2D6. An increase in the codeine dosage or a different analgesic agent may be necessary in patients requiring therapy with CYP450 2D6 inhibitors. If concurrent therapy is used and the CYP450 2D6 inhibitor is stopped, the dose of codeine may need to be reduced and the patient should be monitored for signs and symptoms of respiratory depression or sedation. In addition, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, may interfere with the analgesic effects of codeine for at least 28 days after administration of rolapitant. The manufacturer's prescribing information should be consulted for further information.