Critical CYP450 Drug Interactions to Avoid
Contraindicated Combinations
Strong CYP3A4 inhibitors must never be combined with simvastatin due to severe myopathy and rhabdomyolysis risk. 1 These contraindicated combinations include azole antifungals (itraconazole, ketoconazole, posaconazole, voriconazole), macrolide antibiotics (erythromycin, clarithromycin), HIV protease inhibitors (nelfinavir, ritonavir, darunavir/ritonavir), HCV protease inhibitors (boceprevir, telaprevir), cobicistat-containing products, and nefazodone. 1 If treatment with a strong CYP3A4 inhibitor is unavoidable, suspend simvastatin entirely during the course of treatment. 1
Aprepitant is contraindicated with pimozide, terfenadine, astemizole, and cisapride because these combinations may cause serious or life-threatening cardiac arrhythmias. 2 These CYP3A4 substrates can accumulate to dangerous levels when combined with aprepitant's moderate CYP3A4 inhibition, leading to QT prolongation and torsades de pointes. 2
Ketoconazole must not be combined with methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids, or irinotecan. 3 The potential increase in plasma concentrations when coadministered with ketoconazole may increase the risk of serious cardiovascular events including QT prolongation and torsades de pointes, ergotism with vasospasm potentially leading to cerebral ischemia, or potentially fatal adverse events with irinotecan. 3
High-Risk Anticoagulant Interactions
Direct oral anticoagulants (DOACs) should not be combined with strong dual inhibitors of both CYP3A4 and P-glycoprotein. 2 For rivaroxaban specifically, avoid concomitant use with strong CYP3A4 and P-gp inhibitors such as ketoconazole, ritonavir, and cobicistat, as these significantly increase rivaroxaban exposure and bleeding risk. 2, 4
Dabigatran should not be co-administered with P-gp inhibitors in patients with renal impairment. 4 Dronedarone, a strong P-gp inhibitor, can double dabigatran plasma concentrations when administered simultaneously, increasing bleeding risk substantially. 2
For edoxaban, switch to warfarin instead of continuing therapy when strong P-gp inhibitors are required, especially with renal impairment (CrCl < 50 mL/min). 2 P-gp inhibition increases edoxaban exposure by greater than 2.3-fold for peak concentration and 1.7-fold for overall exposure. 2
Statin-Specific Restrictions
Simvastatin is also contraindicated with cyclosporine, danazol, and gemfibrozil due to extreme myopathy risk. 1 Gemfibrozil may cause myopathy when given alone, and the combination dramatically increases rhabdomyolysis risk. 1
Limit simvastatin to maximum 10 mg daily when combined with verapamil, diltiazem, or dronedarone. 1 For amiodarone, amlodipine, or ranolazine, do not exceed simvastatin 20 mg daily. 2, 1 The SEARCH trial identified 8 cases of myopathy and 7 cases of rhabdomyolysis in patients on simvastatin 80 mg with amiodarone versus zero cases on simvastatin 20 mg (relative risk 8.8; 95% CI 4.2-18.4). 2
Rosuvastatin is contraindicated with sofosbuvir/velpatasvir/voxilaprevir due to 19-fold increase in plasma exposure. 4
Antiretroviral and Tuberculosis Drug Combinations
Bedaquiline and delamanid (TB drugs metabolized by CYP3A4) should be used cautiously with antiretrovirals that either induce (efavirenz, etravirine, nevirapine) or inhibit (protease inhibitors, cobicistat) CYP450 metabolism. 2 These combinations create overlapping risks for QT prolongation when combined with fluoroquinolones, bedaquiline, delamanid, or clofazimine. 2
Lopinavir/ritonavir should not be combined with CYP3A-metabolized tyrosine kinase inhibitors. 4
Strong CYP3A4 Inducers to Avoid
Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, phenobarbital, St. John's wort) significantly decrease levels of many medications and should be avoided with most CYP3A4 substrates. 4, 5 These inducers can reduce drug efficacy to the point of treatment failure. 4
For brexpiprazole, increase dosage when combined with strong CYP3A4 inducers, but avoid St. John's wort entirely as it decreases drug levels unpredictably. 5
Sofosbuvir (hepatitis C medication) should not be administered with P-gp inducers such as rifampin, carbamazepine, phenytoin, or St. John's wort. 4
Apremilast should not be combined with carbamazepine, phenytoin, or phenobarbital due to reduced efficacy. 4
Warfarin Management with CYP450 Modulators
Reduce warfarin dose by 25% when initiating strong CYP2C9 inhibitors (amiodarone, fluconazole). 2 For metronidazole, reduce warfarin by 33%. 2
Increase warfarin dose by 50% with close follow-up when CYP450 enzyme inducers are started. 2 Full induction of CYP450 enzymes occurs in 2-4 weeks after initiation and persists up to 2-4 weeks after discontinuation. 2
Monitor INR more frequently when CYP3A4 inhibitors or inducers are added to warfarin therapy. 2 Strong CYP2C9 and CYP3A4 inducers are particularly problematic for vitamin K antagonists. 2
Chemotherapy Drug Interactions
Exercise caution when using aprepitant with chemotherapeutic agents metabolized by CYP3A4 (docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, vincristine). 2 Aprepitant simultaneously acts as a substrate, moderate inducer, and moderate inhibitor of CYP3A4, creating complex bidirectional interactions. 2
Aprepitant decreases oral contraceptive efficacy; use alternative birth control methods during treatment and for 1 month after the last dose. 2
Benzodiazepine and Sedative Interactions
Ketoconazole is contraindicated with oral midazolam, triazolam, and alprazolam as coadministration may cause several-fold increases in plasma concentrations of these drugs, leading to excessive sedation. 3, 6 Intravenous midazolam requires caution but is not contraindicated. 3
Critical Management Principles
Mechanism-based inhibition cannot be prevented by separating administration times of interacting drugs. 7 This type of inhibition occurs when a substrate forms a reactive intermediate creating a stable enzyme-intermediate complex that irreversibly reduces enzyme activity. 7 Drugs causing mechanism-based inhibition include omeprazole, paroxetine, macrolide antibiotics, and mirabegron. 7
Renal impairment exacerbates DOAC drug interactions to a greater extent than warfarin interactions. 2 A moderate CYP3A4 and P-gp inhibitor like erythromycin increased rivaroxaban exposure by 76% and 99% in mild and moderate renal impairment respectively. 2
Screen for antiplatelet and NSAID use when prescribing any anticoagulant, and add proton pump inhibitor protection when appropriate. 2 This reduces additive bleeding risk from pharmacodynamic interactions. 2
When potentially interacting drugs must be used together, adjust dosages based on specific interaction profiles and monitor for adverse effects. 4 When appropriate, measure plasma drug concentrations. 3