What medications should not be combined due to CYP450 (Cytochrome P450) interactions?

Critical CYP450 Drug Combinations to Avoid

Strong CYP3A4 inducers (rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's wort) are contraindicated with most protease inhibitors, direct-acting antivirals, and many CYP3A4 substrates due to severe reduction in drug levels and loss of efficacy. 1, 2

Life-Threatening Cardiac Arrhythmia Combinations

Absolutely contraindicated combinations that cause torsades de pointes:

• Ketoconazole, itraconazole, clarithromycin, erythromycin, or nefazodone with terfenadine, astemizole, cisapride, or pimozide - these CYP3A4 inhibitors dramatically increase levels of QT-prolonging drugs, causing fatal ventricular arrhythmias 2, 3, 4
• Fluconazole with erythromycin - this combination should be avoided due to additive QT prolongation and sudden cardiac death risk 5
• Ketoconazole with dofetilide, quinidine, methadone, disopyramide, dronedarone, or ranolazine - contraindicated due to life-threatening dysrhythmias 3

Anticoagulant Contraindications

Direct oral anticoagulants (DOACs) should never be combined with strong dual inhibitors of both CYP3A4 and P-glycoprotein - this causes severe bleeding risk 2, 6

Specific high-risk combinations:

• Dabigatran with P-gp inhibitors in renal impairment - contraindicated due to excessive bleeding risk 2, 6
• Rivaroxaban with combined strong CYP3A4/P-gp inhibitors (ketoconazole, itraconazole, ritonavir) - avoid this combination 6
• Edoxaban requires switching to warfarin when strong P-gp inhibitors are needed, especially with CrCl <50 mL/min 2

Statin-Related Contraindications

Simvastatin with strong CYP3A4 inhibitors causes rhabdomyolysis:

• Maximum simvastatin 10 mg daily with verapamil, diltiazem, or dronedarone 2
• Maximum simvastatin 20 mg daily with amiodarone, amlodipine, or ranolazine 2
• Rosuvastatin is absolutely contraindicated with sofosbuvir/velpatasvir/voxilaprevir due to 19-fold increase in exposure 6
• Any statin with potent CYP3A4 inhibitors (itraconazole, ketoconazole, clarithromycin, ritonavir) increases rhabdomyolysis risk 4, 7

Antiretroviral and Tuberculosis Drug Combinations

Rifampin is contraindicated with all protease inhibitors - rifampin induces CYP3A4 and dramatically lowers protease inhibitor levels, causing treatment failure 1

Alternative approaches:

• Rifabutin at reduced doses (150 mg 2-3 times weekly) can be used with ritonavir-containing regimens 1
• Rifabutin at standard dose (300 mg daily) is acceptable with saquinavir soft-gel capsule 1
• Rifabutin dose must be increased (450-600 mg daily) when combined with efavirenz due to CYP3A4 induction 1
• Bedaquiline and delamanid require extreme caution with CYP3A4 modulators (efavirenz, nevirapine, protease inhibitors) 2

Hepatitis C Direct-Acting Antiviral Contraindications

Sofosbuvir/velpatasvir cannot be combined with potent P-gp or CYP inducers:

• Rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's wort are absolutely contraindicated - these cause loss of antiviral efficacy 1, 6
• Moderate inducers like modafinil are not recommended with sofosbuvir/velpatasvir 1
• Lopinavir/ritonavir should not be combined with CYP3A-metabolized tyrosine kinase inhibitors 6

Warfarin Management with CYP450 Modulators

When initiating strong CYP2C9 inhibitors (amiodarone, fluconazole), reduce warfarin dose by 25% and monitor INR closely 2, 5

When starting CYP450 inducers, increase warfarin dose by 50% with close INR follow-up 2

The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation due to long half-life, requiring extended monitoring 5

Chemotherapy Drug Interactions

Aprepitant is contraindicated with pimozide, terfenadine, astemizole, and cisapride due to serious cardiac arrhythmias 2

Use caution when combining aprepitant with CYP3A4-metabolized chemotherapy agents (docetaxel, paclitaxel, etoposide, irinotecan, imatinib, vincristine) - dose adjustments may be necessary 2

Benzodiazepine and Sedative Interactions

Strong CYP3A4 inhibitors cause excessive sedation with midazolam, triazolam, alprazolam, and diazepam 4

Avoid combining these benzodiazepines with ketoconazole, itraconazole, clarithromycin, ritonavir, or nefazodone - consider alternative anxiolytics not metabolized by CYP3A4 (lorazepam, oxazepam, temazepam) 4

Other Critical Contraindications

Carbamazepine with CYP3A4 inhibitors causes ataxia - avoid this combination 4

Ergotamine with CYP3A4 inhibitors causes ergotism (severe vasoconstriction, ischemia) - contraindicated 4

Sildenafil with strong CYP3A4 inhibitors causes symptomatic hypotension - reduce sildenafil dose or avoid combination 4

Abrocitinib with fluconazole - avoid concomitant use due to excessive systemic exposure 5

Alfentanil with fluconazole requires dose reduction due to prolonged half-life 5

Critical Management Principles

Renal impairment exacerbates DOAC drug interactions more than warfarin interactions - always assess creatinine clearance before combining DOACs with CYP/P-gp modulators 2

Screen for antiplatelet agents and NSAIDs when prescribing any anticoagulant - add proton pump inhibitor protection when appropriate 2

The magnitude of mechanism-based inhibition cannot be prevented by separating administration times - unlike competitive inhibition, these interactions persist until new enzyme is synthesized 8

When potentially interacting drugs must be used together, adjust dosages based on specific interaction profiles and monitor for adverse effects with drug levels when available 2, 6