As a nutrition support pharmacist, you will see more alerts for drug and grapefruit interactions. More than 85 of these interactions are now identified and about 40 have the potential to cause a serious reaction. Several are just newly recognized. For example, grapefruit can increase GI bleeding risk with ticagrelor (Brilique, Brilinta), increase arrhythmia risk with Amiodarone (Cordarone), or increase hyperkalemia risk with eplerenone (Eraloner, Eplorefix, etc), for more (see Table 2).
It only takes one grapefruit or one cup of juice to cause a clinically significant drug interaction. And separating the ingestion of grapefruit and a daily drug usually does NOT prevent the interaction. To understand why, you need to know how these interactions work. Grapefruit permanently inactivates CYP3A4 enzymes in the GUT, and it takes 48 to 72 hours for them to be replaced. Therefore, grapefruit is most likely to increase levels of drugs that are metabolized by CYP3A4 AND have very low oral absorption. In this case, a small change in enzyme activity can have a big change in total absorption.
| Table (1). Grapefruit-Drug Interactions and Alternative Therapies | |||
|---|---|---|---|
| DRUG CLASS | DRUGS POTENTIALLY AFFECTED BY GRAPEFRUIT | EFFECTS OF INTERACTION | ALTERNATIVE TREATMENTS |
| Antiarrhythmics | Amiodarone (Cordarone), disopyramide, quinidine | Increased plasma concentrations of amiodarone may cause thyroid or pulmonary toxicity, liver injury, QTc prolongation, proarrhythmic disorders, and bradycardia. | Digoxin (Lanoxin), diltiazem, verapamil Beta blockers |
| Increased plasma concentration of quinidine and disopyramide may be cardiotoxic causing torsades de pointes. | |||
| Calcium channel blockers | Felodipine (Plendil), nicardipine, nifedipine, nimodipine (Nimotop) | Increased plasma concentration may lead to flushing, peripheral edema, headaches, tachycardia, symptomatic hypotension, and myocardial infarction in rare cases. | Amlodipine (Norvasc), diltiazem (Altiazem), verapamil |
| Statins | Atorvastatin (Lipitor), lovastatin (Mevacor), simvastatin (Zocor) | Increased plasma concentration may cause headaches, gastrointestinal complaints, hepatic inflammation, and myopathies (e.g., rhabdomyolysis). | Fluvastatin (Lescol), pravastatin, rosuvastatin (Crestor) Fibric acids, nicotinic acid, or bile acid sequestrants |
| Immunosuppressants | Cyclosporine (Sandimmune, Neoral), tacrolimus (Prograf) | Increased drug exposure without effects on peak concentration may cause increased adverse events or toxicity evidenced by renal toxicity, hepatic toxicity, and increased immunosuppression. | No alternatives available |
| Protease inhibitors | Saquinavir (Fortovase) | Increased plasma concentrations may cause increased side effects such as headache, fatigue, insomnia, and anxiety. | Amprenavir (Agenerase), atazanavir (Reyataz), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfinavir (Viracept), ritonavir (Norvir) |
| Information from, Am Fam Physician. 2006 Aug 15;74(4):605-608. | |||
Advise patients taking interacting medications (see Table 1) to avoid grapefruit or switch them to another drug. For example, use pravastatin (Lipostat) or rosuvastatin (Crestor) instead of simvastatin (Zocor) or lovastatin (Lowchol). When patients ask, explain they do NOT need to worry as much about other fruits. It's true that similar interactions might also occur with limes, pomelos, or Seville sour oranges, but not too many of your patients will consume enough of these to cause an interaction. Also point out that lemons and sweet oranges are okay.
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REMEMBER!
Keep in mind a DIFFERENT interaction, sweet oranges inhibit OATP enzymes and can LOWER levels of fexofenadine (Telfast), atenolol (Blokium, Ateno), and others.
| Table (2). Potential Drug Interactions with Grapefruit | ||
|---|---|---|
| DRUGS OR DRUG CLASS | FINDINGS | IMPLICATIONS |
| Amiodarone (Cordarone) | 50% increase in AUC and 84% increase in peak. | Prescribing information advises to avoid grapefruit. |
| Apixaban (Eliquis) | Potential to interact based on the drug’s pharmacokinetics. | Potential for bleeding. Avoid grapefruit in elderly. |
| Benzodiazepines, oral: Diazepam Midazolam |
Increase in AUC and peak. No interaction seen with IV midazolam. Alprazolam does not appear to interact. | Potential for increased sedation. U.S. prescribing information for midazolam syrup advises avoiding grapefruit. |
| Budesonide | Increase in oral absorption. | Potential hypercorticism. Product labeling advises avoiding grapefruit. |
| Buspirone (BuSpar) | Increase in absorption and plasma concentrations. | Potential for dizziness, sedation. Avoid grapefruit in elderly. Product labeling advises against consuming large amounts of grapefruit. |
| Calcium Channel Blockers: Amlodipine (Norvasc) Diltiazem (Altiazem) Felodipine (Plendil) Nifedipine (Adalat) Verapamil (Isopten) |
Increase in AUC and serum concentration. Some references dispute the clinical relevance of the interactions with amlodipine, diltiazem, and verapamil. However, there is considerable interindividual variability in the effect of grapefruit on drug metabolism. | Potential for flushing, headache, tachycardia, and hypotension. U.S. prescribing information advises avoiding grapefruit in patients on nisoldipine, nifedipine capsules, and Adalat. Caution with felodipine. Per Canadian monograph, avoid grapefruit with felodipine, nifedipine, nimodipine, and verapamil. |
| Carbamazepine (Tegretol) |
Increase in AUC, peak, and trough plasma concentrations. |
Avoid grapefruit. |
| Carvedilol |
Increase in bioavailability of a single dose by 16%. |
The clinical significance of this interaction is not known. |
| Cilostazol (Pletal) |
Increase in peak. Case report of purpura in patient also taking aspirin. Resolved with grapefruit discontinuation. | Avoid grapefruit, especially in patients taking other antithrombotics. |
| Cisapride |
Increase in AUC. | Contraindicated with grapefruit. |
| Clarithromycin | Slight delay in absorption. | Not likely significant. |
| Clomipramine (Anafranil) | Increase in plasma concentrations. | Potential for increased side effects, such as dry mouth, somnolence, dizziness, fatigue. |
| Clopidogrel (Plavix) |
Potential to interact based on the drug’s pharmacokinetics (i.e., inhibited conversion to active metabolite). | Potential for loss of efficacy. |
| Colchicine (Colcrys) | Potential increase in peak and AUC by more than 50%. | Product labeling advises avoiding grapefruit. |
| Cyclosporine (Neoral, Sandimmune) | Increase in AUC and serum concentrations. | Watch for signs of toxicity, such as nephrotoxicity, hepatotoxicity, and increased immunosuppression. Monitor levels. Product labeling advises avoiding grapefruit. |
| Darifenacin | Potential to interact based on the drug’s pharmacokinetics. | Potential for urinary retention, constipation. |
| Dextromethorphan | Increased AUC. | Potential for drowsiness, hallucinations. Avoid grapefruit in elderly. |
| Digoxin (Lanoxin) | Slight increase in AUC. | Unlikely significant with occasional consumption of a glass of juice. |
| Domperidone | Potential to interact based on pharmacokinetics. | Potential for torsades. Avoid grapefruit in elderly. Consider metoclopramide. |
| Eplerenone | Small increase (25%) in exposure. | Potential for hyperkalemia, serious arrhythmias. Avoid grapefruit in elderly. Consider spironolactone. Not likely significant per Canadian product labeling. |
| Erythromycin | Increase in AUC and peak. | Potential for torsades. Avoid grapefruit in elderly. Consider clarithromycin. |
| Estrogens |
Increased absorption and plasma concentrations of 17-beta-estradiol and ethinyl estradiol. | Not likely significant. |
| Etoposide (e.g., Vepesid) | Impaired absorption. Mechanism unknown. | Given that this is a chemotherapeutic agent, decreased AUC is concerning. Avoid combination. |
| Everolimus (e.g., Afinitor) |
Potential to interact based on the drug’s pharmacokinetics. | Potential for myelotoxicity, nephrotoxicity. Product labeling advises avoiding grapefruit. |
| Fentanyl (oral, transmucosal) |
Potential to interact based on the drug’s pharmacokinetics. Delay in time to peak effect documented. | Potential for respiratory depression. Ensure correct use of product to minimize swallowing. Prescribing information advise to avoid grapefruit. |
| Fexofenadine | Decrease in AUC by about 40%. Due to inhibition of organic anion transporting polypeptide (OATP). |
Clinical significance unknown. U.S. labeling recommends taking fexofenadine with water. Separate by four hours to be safe. Consider desloratadine as alternative. No data for loratadine. |
| HMG-CoA Reductase Inhibitors: Atorvastatin (Lipitor) Simvastatin (Zocor) |
Increase in absorption and plasma concentrations. | Potential for headache, GI complaints, and muscle pain. Lovastatin and simvastatin (Zocor) prescribing information advise avoiding grapefruit. Experts also suggest avoiding grapefruit with atorvastatin (Lipitor). Consider pravastatin (Pravachol) (not affected), rosuvastatin (Crestor), or fluvastatin (Lescol) as alternatives (not metabolized by CYP3A4). |
| Itraconazole (Sporanox) |
Increase or decrease in AUC. OATP may be involved. | Clinical significance unknown. |
| Levothyroxine |
11% decrease in AUC. Due to inhibition of organic anion transporting polypeptide (OATP). |
Separate by four hours. |
| Losartan (Cozaar) |
Possible decrease in AUC of losartan’s major active metabolite (i.e., inhibited conversion to active metabolite). | Potential for reduced losartan efficacy. Further studies are needed to determine significance. |
| Lurasidone | Potential to interact based on the drug’s pharmacokinetics. | Potential for torsades, orthostatic hypotension. Canadian product labeling advises avoiding grapefruit. |
| Methylprednisolone |
Increase in plasma concentration and half-life. | Consumption of large amounts of grapefruit might increase the risk of adverse effects. Consider prednisone or prednisolone. |
| Montelukast (Singulair) |
No effect. | None. |
| Omeprazole (Losec) | No significant effect. | None. |
| Phenytoin | No effect. | None. |
| Progesterone | Increase in AUC. | Clinical significance unknown. |
| Quetiapine (e.g., Seroquel) |
Potential to interact based on the drug’s pharmacokinetics. | Potential for dizziness, drowsiness. Avoid grapefruit in elderly. |
| Quinidine | Decrease in clearance, prolonged half-life, and delayed absorption. Mechanism other than gut CYP3A4 inhibition may be involved. | Potential for torsades. |
| Quinine | Potential to interact based on the drug’s pharmacokinetics. No effect in single-dose study. Case report in patient with long QT syndrome. | Potential for torsades. Avoid grapefruit in elderly. |
| Rivaroxaban (Xarelto) |
Potential to interact based on the drug’s pharmacokinetics. | Potential for bleeding. |
| Scopolamine (oral) |
Increase in absorption and plasma concentrations. | Avoid. |
| Sertraline | Increase in serum concentrations. | Not likely significant. |
| Sildenafil (e.g., Viagra) |
Increase in AUC. | Adverse events not seen in study, but decreased blood pressure and increased heart rate could occur in some patients. Interaction could theoretically occur with tadalafil (Cialis) and vardenafil. (Avoid grapefruit per Canadian Levitra product labeling). |
| Silodosin | Potential to interact based on the drug’s pharmacokinetics. | Potential for orthostatic hypotension. Canadian product labeling advises caution with grapefruit. |
| Sirolimus | Potential to interact based on the drug’s pharmacokinetics. | Potential for myelotoxicity, nephrotoxicity. Product labeling advises avoiding grapefruit. |
| Solifenacin (Vesicare) |
Potential to interact based on the drug’s pharmacokinetics. | Potential for torsades. |
| Sunitinib (Sutent) |
11% increase in AUC. | Potential for torsades, myelotoxicity. Product labeling advises avoiding grapefruit. |
| Tacrolimus (Prograf) |
Increase in trough concentration. | Potential for nephrotoxicity. Watch for symptoms of toxicity, such as hypertension, tremor, headache, insomnia. Product labeling advises to avoid grapefruit. |
| Tamsulosin | Potential to interact based on the drug’s pharmacokinetics. | Potential for orthostatic hypotension. |
| Theophylline | Conflicting studies. Decrease in AUC and peak, and delay in time to peak, or no effect. Mechanism unknown. | Monitor levels or avoid. |
| Ticagrelor (Brilique) |
Approximate doubling of peak and AUC. | Potential for bleeding. Avoid. |
| Warfarin (Coumadin) |
No effect of up to three glasses (24 oz) daily. Case report of increased INR associated with 50 oz daily. | Limit grapefruit juice intake to three glasses daily. |
REFERENCES
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Bailey DG, Dresser G, Arnold JM. Grapefruit-medication interactions: forbidden fruit or avoidable consequences? CMAJ. 2013 Mar 5;185(4):309-16. Available at: https://www.cmaj.ca/content/185/4/309
Hanley MJ, Cancalon P, Widmer WW, Greenblatt DJ. The effect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol. 2011 Mar;7(3):267-86. Available at: https://www.tandfonline.com/doi/abs/10.1517/17425255.2011.553189?journalCode=iemt20
Reddy P, Ellington D, Zhu Y, Zdrojewski I, Parent SJ, Harmatz JS, Derendorf H, Greenblatt DJ, Browne K Jr. Serum concentrations and clinical effects of atorvastatin in patients taking grapefruit juice daily. Br J Clin Pharmacol. 2011 Sep;72(3):434-41. Available at: https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2011.03996.x
Farkas D, Greenblatt DJ. Influence of fruit juices on drug disposition: discrepancies between in vitro and clinical studies. Expert Opin Drug Metab Toxicol. 2008 Apr;4(4):381-93. Available at: https://www.tandfonline.com/doi/abs/10.1517/17425255.4.4.381?journalCode=iemt20