Drug Interactions between dextromethorphan / quinidine and eliglustat

GENERALLY AVOID: Coadministration with potent CYP450 2D6 inhibitors (e.g., quinidine, terbinafine) may significantly increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Studies in humans have shown an increase in systemic exposure of dextromethorphan of up to 43-fold when given concurrently with quinidine. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. However, this interaction has also been used clinically, with dextromethorphan in combination with quinidine indicated by some authorities for the treatment of pseudobulbar affect. Data evaluating the impact of this interaction in patients who are poor metabolizers of CYP450 2D6 are limited; most studies include extensive metabolizers of this isoenzyme. It is expected that poor metabolizers would have elevated dextromethorphan levels without concurrent quinidine

MANAGEMENT: The combination of dextromethorphan with potent CYP450 2D6 inhibitors should be generally avoided. Some manufacturers consider the concomitant use of dextromethorphan and selective serotonin reuptake inhibitors contraindicated. If use is considered necessary, the patient should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.

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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, methotrimeprazine, mirabegron, panobinostat, paroxetine, propoxyphene, quinidine, ranolazine, rolapitant, sertraline, stiripentol, and terbinafine. Some drugs such as abiraterone, cimetidine, 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.

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MONITOR: Coadministration with CYP450 2D6 inhibitors may increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. Coadministration of dextromethorphan (60 mg orally, once) with the CYP450 2D6 inhibitor panobinostat (20 mg orally once a day on days 3, 5, and 8) in 14 patients with advanced cancer had a highly variable effect on dextromethorphan levels, increasing the peak plasma concentration (Cmax) of dextromethorphan by 20% to 200%, and total systemic exposure (AUC 0 to infinity) by 20% to 130%, compared to dextromethorphan given alone. In addition, multiple doses of the potent CYP450 2D6 inhibitor cinacalcet (50 mg daily), increased the AUC of a single 30 mg dextromethorphan dose by 11-fold in extensive metabolizers of this isoenzyme. The moderate CYP450 2D6 inhibitor asunaprevir, given at 200 mg twice daily, also increased Cmax and AUC of a single 30 mg dose of dextromethorphan by 2.7- and 3.9-fold, respectively, in 17 study subjects.

MANAGEMENT: Caution should be exercised if these drugs must be used together. Patients should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.

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