Juice interactions: What patients need to know
How to counsel patients about potential interactions
More than 85 medications are known to interact with grapefruit juice, and approximately one-half of these interactions have the potential to cause serious adverse events. In addition, many medications can interact with other juices, such as orange, apple, and cranberry. For example, the Drug Facts label of OTC fexofenadine (Allegra—Sanofi) states not to consume the drug with fruit juices.
Many patients are unaware that fruit juices can cause significant drug interactions. Pharmacists must educate patients about this fact to decrease the likelihood of these events.
The irreversible inhibition of intestinal cytochrome P450 (CYP)3A4 enzymes by grapefruit juice is the most commonly identified mechanism mediating grapefruit drug interactions. CYP3A4 metabolizes furanocoumarins found in grapefruit to reactive intermediates that then bond covalently to the active site of the enzyme, causing irreversible inactivation. This leads to increased bioavailability of administered medications that are substrates for intestinal CYP3A4 and creates the potential for toxic effects.
Since grapefruit primarily targets intestinal CYP3A4, not liver CYP3A4, I.V. medications are usually not affected. Grapefruit products also interact with the efflux transporter P-glycoprotein and uptake transporters such as organic anion-transporting polypeptides (OATPs).
Seville oranges, limes, and pomelos produce drug interactions similar to grapefruit by inhibiting intestinal CYP-3A4. Other juices, such as orange and apple, appear to inhibit OATPs, which aid in drug absorption. OATP inhibition results in reduced absorption and potentially decreased serum levels of drugs transported by OATP.
Drug interactions with cranberry juice have also been reported. These interactions have primarily occurred with warfarin, and the exact mechanism is unknown. According to one mechanism proposed by researchers, cranberry flavonoids interact with CYP450 enzymes, resulting in reduced warfarin metabolism. Others have attributed cranberry–warfarin interactions to the presence of salicylic acid in cranberries, which results in an increased bleeding risk.
High-risk patients and likely interactions
All forms of grapefruit, including freshly squeezed juice, frozen concentrate, and whole fruit, can reduce the activity of intestinal CYP3A4. As little as 200 mL of grapefruit juice, the amount in a whole grapefruit, may be sufficient to cause clinically relevant increased systemic drug concentrations and subsequent adverse events. In addition, since administration of grapefruit causes irreversible inactivation, the effects of consuming these products can last as long as 72 hours. Therefore, separation of medications and grapefruit products by a few hours is usually not helpful.
For OATP-mediated fruit juice interactions, the magnitude of the effects of orange and apple juices on OATP appear to be similar and can be significant with a 200-mL serving. Currently, there is minimal to no evidence that eating these fruits causes clinically significant OATP-mediated drug interactions. The inhibition of OATP appears to dissipate over a shorter time period than inhibition of intestinal CYP3A4. These types of interactions may be avoided by separating medication and juice consumption by at least 4 hours.
Patients older than 45 years have been noted as a key patient group vulnerable to grapefruit drug interactions in the literature. This patient population is most likely to purchase grapefruits and to have comorbidities which require multiple medications. Older patients are also at high risk for clinically significant fruit juice interactions because pharmacokinetics are different in patients older than 70 years, and in general, the body’s compensatory mechanisms do not work as effectively as one ages.
David Bailey, PhD, and colleagues published an updated list of drugs that interact with grapefruit, their predicted interaction risk (e.g., very high, high, or intermediate), and potential dose-related adverse events in the Canadian Medication Association Journal in November 2012. A summary of drugs in the very high and high risk categories is presented in Tables 1 and 2, respectively; these tables are not all inclusive.
Table 1. Medications with a very high grapefruit interaction risk
|Interacting drugs (generic name)||Dose-related adverse events|
|Maraviroc||Postural hypotension, syncope|
|Dronedarone||Torsades de pointes|
|Oral ketamine||Respiratory depression|
|Lurasidone||Torsades de pointes, orthostatic hypotension, syncope|
Source: Bailey DG et al. Grapefruit–medication interactions: forbidden fruit or avoidable consequences [published online ahead of print November 26, 2012]? CMAJ.
Table 2. Medications with a high grapefruit interactions risk
|Interacting drugs (generic name)||Dose-related adverse events|
|Crizotinib||Torsades de pointes, myelotoxicity|
|Dasatinib||Torsades de pointes, myelotoxicity|
|Lapatinib||Torsades de pointes, myelotoxicity|
|Nilotinib||Torsades de pointes, myelotoxicity|
|Pazopanib||Torsades de pointes, myelotoxicity|
|Sunitinib||Torsades de pointes, myelotoxicity|
|Vandetanib||Torsades de pointes, myelotoxicity|
|Erythromycin||Torsades de pointes|
|Quinine||Torsades de pointes|
|Rilpivirine||Torsades de pointes|
|Amiodarone||Torsades de pointes|
|Clopidogrel||Loss of efficacy|
|Eplerenone||Hyperkalemia, serious arrhythmias|
|Ticagrelor||Gastrointestinal or kidney bleeding|
|Verapamil||Complete heart block|
|Central nervous system agents|
|Oral fentanyl||Respiratory depression|
|Pimozide||Torsades de pointes|
|Ziprasidone||Torsades de pointes|
|Cisapride||Torsades de pointes|
Source: Bailey DG et al.
Researchers have described OATP-mediated fruit juice interactions with grapefruit, orange, and apple juices in other publications as well. A summary of select medications involved in these types of interactions is presented in Table 3. The absorption of some medications is decreased by less than 10%, which is not thought to be clinically significant in most patients.
Table 3. OATP-mediated fruit juice interactions
|Drug||Decrease in absorption|
Abbreviation used: OATP, organic anion-transporting polypeptide.
Source: Cupp M. OATP fruit juice interactions. Pharmacist's Letter/Prescriber's Letter. June 2011.
Patient counseling pearls
FDA has released an educational piece listing tips for patients regarding potential fruit juice interactions (www.fda.gov/ForConsumers/ConsumerUpdates/ucm292276.htm). These informational points include the following:
- Educate patients to ask a pharmacist or other health care provider if they can drink grapefruit and other juices with prescribed medications.
- Encourage patients to read the Medication Guide or patient information sheet that comes with prescription medications to identify any fruit juice interactions.
- Encourage patients to review the Drug Facts labels on nonprescription medications for fruit juice interactions.
- If patients must avoid certain fruit juices, educate them to check the labels of flavored drinks to ensure that they do not contain those juices.
- Educate patients on other fruits that should be avoided, such as Seville oranges and tangelos, with medications known to interact with grapefruit.
Pharmacists and health professionals who properly screen for and educate patients about potential fruit juice interactions can help minimize their occurrence and reduce the likelihood of adverse events.