What medications interact with grapefruit?

Grapefruit and Common Medication Interactions

Patients must completely avoid grapefruit and grapefruit juice when taking certain medications, as the interaction is irreversible and long-lasting—timing separation does not solve the problem. 1

Mechanism of Interaction

Grapefruit inhibits cytochrome P450 3A4 (CYP3A4) enzyme in the intestinal wall through mechanism-based inhibition by furanocoumarins, leading to decreased first-pass metabolism and dramatically increased blood levels of affected medications. 2 The inhibition is irreversible, meaning the effect persists long after consumption, making it insufficient to simply avoid concurrent ingestion. 1 Grapefruit also inhibits P-glycoprotein transport and OATP uptake transporters, further increasing drug concentrations. 3, 2

Medications Requiring Absolute Grapefruit Avoidance

Cardiovascular Medications

Calcium Channel Blockers:

• Verapamil is contraindicated with grapefruit juice due to CYP3A4 inhibition and P-glycoprotein effects, which can cause dangerous hypotension, bradycardia, and atrioventricular conduction disorders. 1
• Diltiazem should avoid grapefruit juice to prevent similar cardiovascular complications. 1
• Felodipine, nitrendipine, and nisoldipine show the most marked interactions with median AUC increases exceeding 70%. 4

Antiarrhythmic Agents:

• Amiodarone must not be combined with grapefruit juice because grapefruit increases amiodarone AUC by 50% and peak concentration by 84%, risking severe toxicity including QT prolongation, torsades de pointes, and hepatotoxicity. 1
• Class I and III antiarrhythmics (flecainide, propafenone, quinidine) are particularly high-risk due to their low therapeutic index and potential for torsades de pointes. 5

Other Cardiac Medications:

• Ivabradine is absolutely contraindicated with grapefruit juice per American Heart Association guidelines. 6, 1
• Digoxin requires caution as verapamil (which interacts with grapefruit) can increase digoxin levels and cause toxicity. 1

Lipid-Lowering Agents (Statins)

High-Risk Statins (Complete Avoidance Required):

• Simvastatin and lovastatin require complete avoidance of grapefruit as grapefruit juice increases blood levels by approximately 260% when taken simultaneously (90% when taken 12 hours apart). 3, 7
• Lomitapide must avoid grapefruit juice as it is a CYP3A4 substrate with significant drug exposure increases. 6, 3

Moderate-Risk Statins (Limit Consumption):

• Atorvastatin blood levels increase by approximately 80% with grapefruit juice consumption, regardless of timing. 3, 8, 7 The FDA label notes that excessive grapefruit consumption (≥750 mL to 1.2 liters per day) can increase AUC up to 2.5-fold and Cmax up to 1.71-fold. 8
• Patients on atorvastatin should limit grapefruit consumption or discuss dose adjustment with their healthcare provider. 3

Safe Alternatives (No Significant Interaction):

• Pravastatin, rosuvastatin, fluvastatin, and pitavastatin have minimal interaction with grapefruit juice as they are not significantly metabolized by CYP3A4. 3 These are the preferred alternatives for patients who regularly consume grapefruit. 3

Immunosuppressive Medications

• Cyclosporine requires complete avoidance of grapefruit and grapefruit juice because the CYP3A4 inhibition in both gut and liver causes variable but potentially marked increases in blood levels. 1
• Since cyclosporine has a narrow therapeutic index, small changes markedly influence both efficacy and toxicity. 1
• The effect is long-lasting, so patients must completely avoid grapefruit, not just avoid concurrent ingestion. 1
• Tacrolimus also requires increased monitoring and appropriate dose adjustments. 5

Protease Inhibitors and Antivirals

• Grapefruit should be avoided with protease inhibitors including boceprevir, telaprevir, simeprevir, tipranavir, saquinavir, darunavir, fosamprenavir, and nelfinavir, as it acts as a CYP3A4 inhibitor leading to increased drug levels. 5, 8
• The interaction can result in overdose and increased side effects. 5

Benzodiazepines and Sedatives

• Oral midazolam is contraindicated with grapefruit juice due to significant increases in drug levels and sedation risk. 5
• Triazolam shows possibly relevant concentration increases. 4

Other High-Risk Medications

• Ergot derivatives (dihydroergotamine, ergotamine) can lead to serious risks when combined with grapefruit. 5
• Sildenafil requires caution due to CYP3A4 metabolism. 5
• Cisapride is contraindicated. 5
• Disopyramide and quinidine (Class IA antiarrhythmics) should avoid grapefruit due to CYP3A4 metabolism and QT prolongation risk. 5

Medications with Minimal or No Interaction

The following medications do not require grapefruit avoidance:

• Buprenorphine, methadone, tenofovir, and esomeprazole show no significant interactions. 5
• Pravastatin, rosuvastatin, fluvastatin, and pitavastatin (statins not metabolized by CYP3A4). 3

Clinical Management Algorithm

Step 1: Identify if the patient is taking any CYP3A4 substrate medications

• Review the patient's complete medication list for drugs metabolized by CYP3A4, particularly those with low bioavailability and narrow therapeutic index. 9

Step 2: Assess grapefruit consumption patterns

• Ask specifically about grapefruit juice, fresh grapefruit, and grapefruit-containing products. 3
• Determine frequency and volume of consumption. 8

Step 3: For high-risk medications (absolute contraindications)

• Advise complete avoidance of all grapefruit products for verapamil, diltiazem, amiodarone, ivabradine, simvastatin, lovastatin, lomitapide, cyclosporine, and oral midazolam. 6, 1, 3
• Explain that timing separation does not eliminate risk due to irreversible enzyme inhibition. 1

Step 4: For moderate-risk medications (atorvastatin)

• Recommend limiting grapefruit consumption or switching to pravastatin, rosuvastatin, fluvastatin, or pitavastatin. 3
• If switching statins, ensure equivalent dosing for lipid-lowering effect. 3

Step 5: For patients who cannot avoid grapefruit

• Switch to alternative medications without grapefruit interactions whenever possible. 9
• For statins: use pravastatin, rosuvastatin, fluvastatin, or pitavastatin. 3
• For calcium channel blockers: consider amlodipine (minimal interaction per FDA data). 8

Critical Pitfalls to Avoid

• Do not assume timing separation solves the problem: The CYP3A4 inhibition is irreversible and long-lasting, so avoiding concurrent ingestion is insufficient. 1
• Failing to ask about grapefruit consumption when prescribing high-risk medications (particularly simvastatin and lovastatin) is a common error. 3
• Assuming all statins have the same level of interaction is incorrect—pravastatin, rosuvastatin, fluvastatin, and pitavastatin are safe alternatives. 3
• Underestimating the magnitude of interaction: Excessive grapefruit consumption (≥750 mL to 1.2 liters per day) can increase drug levels by 2.5-fold or more. 8
• Forgetting that the effect applies to all grapefruit products: Fresh grapefruit, grapefruit juice, and grapefruit-containing foods all cause the interaction. 1

Special Considerations

Risk factors for increased toxicity include:

• Age >65 years, small body frame and frailty, multisystem disease, multiple medications, and higher drug doses. 3
• These patients require particularly careful counseling about grapefruit avoidance. 3

Alternative citrus fruits:

• Patients may consume other types of citrus fruits (oranges, tangerines, lemons) to avoid the interaction while maintaining dietary variety. 9