What medication combinations should be avoided due to cytochrome P450 (CYP450) interactions?

Medication Combinations to Avoid Due to Cytochrome P450 Interactions

Strong CYP3A4 inhibitors should never be combined with medications that are CYP3A4 substrates with narrow therapeutic windows, as this can lead to dangerous increases in drug concentrations and serious adverse effects including death. 1, 2

Most Critical CYP450-Based Drug Interactions to Avoid

Strong CYP3A4 Inhibitors with CYP3A4 Substrates

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, ritonavir) should not be combined with medications metabolized by CYP3A4 3, 1
• Specific dangerous combinations include:
  • Lovastatin/simvastatin with strong CYP3A4 inhibitors - can cause fatal rhabdomyolysis 3, 4
  • Antiarrhythmics (amiodarone, dronedarone, flecainide, propafenone, quinidine) with ritonavir - risk of cardiac arrhythmias 1
  • Benzodiazepines metabolized by CYP3A4 (alprazolam, triazolam, brotizolam, midazolam) with azole antifungals or macrolide antibiotics 5

P-glycoprotein (P-gp) Interactions

• Sofosbuvir (hepatitis C medication) should not be administered with P-gp inducers such as rifampin, carbamazepine, phenytoin, or St. John's wort 6
• Direct oral anticoagulants (DOACs) are P-gp substrates and should not be combined with strong P-gp inhibitors or inducers 6, 7
• Dabigatran should not be co-administered with P-gp inhibitors in patients with renal impairment 6

Strong CYP Inducers with Medications Requiring Stable Levels

• Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, phenobarbital, St. John's wort) significantly decrease levels of many medications 6
• Avoid combining with:
  • Direct-acting antivirals for hepatitis C 6
  • DOACs (rivaroxaban, apixaban) 6
  • Immunosuppressants 6

Specific High-Risk Combinations by Drug Class

Anticoagulants

• Rivaroxaban should not be combined with strong inhibitors of both CYP3A4 and P-gp 6
• Apixaban dose should be reduced by 50% when combined with strong CYP3A4 inhibitors 6
• Edoxaban is primarily affected by P-gp inhibitors rather than CYP3A4 6

Statins

• Lovastatin is contraindicated with strong CYP3A4 inhibitors including ketoconazole, itraconazole, posaconazole, voriconazole, erythromycin, clarithromycin, HIV protease inhibitors, and cobicistat-containing products 3
• Simvastatin and lovastatin should not be combined with gemfibrozil due to increased risk of myopathy 4
• Rosuvastatin is contraindicated with sofosbuvir/velpatasvir/voxilaprevir due to 19-fold increase in plasma exposure 6

Antiviral Medications

• Lopinavir/ritonavir should not be combined with:
  • CYP3A-metabolized tyrosine kinase inhibitors 6
  • QT-prolonging medications (many TKIs, doxorubicin, ondansetron) 6
  • Immune checkpoint inhibitors (risk of autoimmune hepatitis and pancreatitis) 6

Anticonvulsants

• Carbamazepine, phenytoin, and phenobarbital (strong CYP3A4 inducers) should not be combined with:
  • Apremilast (reduced efficacy) 6
  • Sofosbuvir (reduced efficacy) 6
  • DOACs (reduced anticoagulant effect) 6

Immunosuppressants

• Cyclosporine inhibits CYP3A4, P-gp, and OATP1B1, significantly increasing statin concentrations 4
• Avoid combination with sofosbuvir/velpatasvir/voxilaprevir as voxilaprevir plasma exposure increases 19-fold 6

Monitoring and Management Strategies

• When potentially interacting drugs must be used together:
  • Adjust dosages based on specific interaction profiles 6
  • Monitor for adverse effects and drug levels when available 6
  • Consider staggering administration times for P-gp substrate interactions 6
  • Choose alternative medications with less interaction potential when possible 6

Common Pitfalls to Avoid

• Failing to recognize that herbal supplements (especially St. John's wort) can cause significant CYP450 interactions 6, 1
• Overlooking the role of P-gp transporters in addition to CYP450 enzymes 6, 7
• Not accounting for the compounding effect of renal impairment on drug interactions, particularly with medications eliminated renally 6
• Assuming all drugs within a class have similar interaction profiles (e.g., statins, DOACs) 6, 4