CYP3A4 Medication List
CYP3A4 is involved in the metabolism of approximately 50% of marketed drugs, and clinically significant interactions occur with strong inhibitors (ketoconazole, clarithromycin, ritonavir), moderate inhibitors (diltiazem, verapamil, erythromycin), and inducers (rifampin, carbamazepine, phenytoin) that can lead to life-threatening toxicity or treatment failure. 1, 2
Strong CYP3A4 Inhibitors
These agents can more than double plasma concentrations of substrate drugs and may cause serious or life-threatening reactions: 1, 3
- Azole antifungals: Ketoconazole, itraconazole 4, 3
- Macrolide antibiotics: Clarithromycin (strong inhibitor), erythromycin (moderate-to-strong inhibitor) 4, 5, 6, 3
- HIV protease inhibitors: Ritonavir (very potent inhibitor), delavirdine 3, 7, 2
- Grapefruit juice: Clinically important inhibitor 3, 8
Moderate CYP3A4 Inhibitors
These cause less pronounced but still clinically significant increases in substrate drug levels: 1
- Calcium channel blockers: Verapamil, diltiazem 4, 5, 2
- Antidepressants: Nefazodone, fluoxetine, fluvoxamine 3, 2
CYP3A4 Inducers
These agents decrease substrate drug concentrations and can lead to treatment failure: 4, 2
- Rifamycins: Rifampin (rifampicin) - decreases substrate AUC by 31-66% 4, 9, 2
- Anticonvulsants: Carbamazepine, phenytoin 4, 2
- Herbal products: St. John's wort (Hypericum perforatum) 4
Major CYP3A4 Substrate Drugs
Chemotherapeutic Agents
The National Comprehensive Cancer Network identifies these chemotherapy drugs as CYP3A4 substrates requiring caution with inhibitors/inducers: 4
- Docetaxel, paclitaxel 4
- Etoposide, irinotecan, ifosfamide 4
- Imatinib 4
- Vinca alkaloids: vinorelbine, vinblastine, vincristine 4
Cardiovascular Drugs
- Calcium channel blockers: Amlodipine, nifedipine, verapamil, diltiazem - risk of hypotension and acute kidney injury with strong inhibitors 5, 9
- Statins: Simvastatin, lovastatin, atorvastatin - risk of rhabdomyolysis with strong inhibitors 5, 6, 3
Anticoagulants
The American Heart Association and American College of Cardiology provide specific guidance for direct oral anticoagulants: 4, 1
- Apixaban: Reduce dose by 50% when combined with strong CYP3A4 inhibitors if on 5-10mg twice daily; avoid use with strong inducers 4, 1
- Rivaroxaban: Avoid concomitant use with strong CYP3A4 inhibitors or inducers 4, 1
- Edoxaban: Minimally affected by CYP3A4 interactions 4
- Warfarin: Partially metabolized by CYP3A4; requires closer INR monitoring with inhibitors/inducers 4
Psychotropic Medications
- Benzodiazepines: Midazolam, triazolam, alprazolam, diazepam - risk of excessive sedation with inhibitors 3, 8
- Other sedatives: Zopiclone, buspirone, brotizolam 3, 8
Antiemetics
- Aprepitant: Acts as substrate, moderate inducer, AND moderate inhibitor of CYP3A4 simultaneously 4
Contraindicated Combinations
The FDA contraindicates these combinations due to risk of serious or life-threatening reactions: 4, 5
- With strong CYP3A4 inhibitors: Pimozide, terfenadine, astemizole, cisapride (risk of torsades de pointes) 4, 3
- With clarithromycin: Lomitapide (risk of elevated transaminases), simvastatin, lovastatin (risk of rhabdomyolysis) 5
- With erythromycin: Simvastatin, lovastatin (risk of rhabdomyolysis) 6
Clinical Management Strategies
For Strong CYP3A4 Inhibitors
- Avoid combination with contraindicated drugs entirely 5, 6
- Reduce substrate drug dose by 50% for apixaban 5-10mg twice daily regimens 4, 1
- Suspend therapy with lovastatin or simvastatin during clarithromycin treatment 5
- Limit atorvastatin to ≤20mg daily and pravastatin to ≤40mg daily if clarithromycin cannot be avoided 5
- Consider alternative antibiotics (e.g., azithromycin, which only inhibits P-gp) when treating patients on CYP3A4 substrates 4
For Strong CYP3A4 Inducers
- Avoid combination with direct oral anticoagulants due to reduced efficacy 4, 1
- Monitor closely and anticipate need for increased substrate drug doses 4
- Allow 2-4 weeks for full enzyme induction after starting and for washout after stopping inducers 4
For Moderate Inhibitors
- No empiric dose reduction recommended for apixaban with moderate CYP3A4 inhibitors 4
- Stagger administration by 2 hours when possible to minimize interaction (e.g., with dabigatran and P-gp inhibitors) 4
Special Populations
The American College of Clinical Pharmacology emphasizes that elderly patients (≥65 years) are at higher risk for CYP3A4 interaction-related adverse events, particularly acute kidney injury with calcium channel blockers and QT prolongation 4, 5, 6
Renal impairment magnifies the effect of CYP3A4 inhibitors for drugs with renal clearance, potentially tripling drug exposure 4