Interactions between selected travel medicines and maintenance immunosuppressive therapy in solid organ transplant recipients

	Calcineurin inhibitors (CNIs)		Inhibitors of mammalian (mechanistic) target of rapamycin (mTOR inhibitors)		Mycophenolate	Prednisone, prednisolone
	Cyclosporine	Tacrolimus	Sirolimus	Everolimus	Mycophenolate	Prednisone, prednisolone
Travelers' diarrhea, self-treatment*
Azithromycin^¶	May increase cyclosporine levels; effect is usually minor. Monitor clinical status.	May increase tacrolimus levels; effect is usually minor. Monitor clinical status.	May increase sirolimus levels; effect is usually minor. Monitor clinical status.	May increase everolimus levels; effect is usually minor. Monitor clinical status.	No interaction identified.	No interaction identified.
Ciprofloxacin, levofloxacin, ofloxacin	Increased cyclosporine AUC in some studies, but not others; effect, if any, is minor. Clinical action generally not required.	Additive QTc-prolongation. Levofloxacin may increase tacrolimus AUC; effect is usually minor. Monitor clinical status.	No interaction identified.	No interaction identified.	May decrease mycophenolic acid levels (active form); effect is usually minor. Monitor clinical status.	Additive risk of tendinopathy.^Δ
Rifaximin	Increases systemic absorption of rifaximin.^◊	No interaction identified.	No interaction identified.	No interaction identified.	No interaction identified.	No interaction identified.
Malaria prophylaxis
Atovaquone-proguanil	Generally low risk of significant interactions with most maintenance immunosuppressive therapy.
Doxycycline
Mefloquine
Primaquine
Tafenoquine
Chloroquine, hydroxychloroquine	May increase cyclosporine levels; effect is usually minor. Monitor clinical status.	Additive QTc-prolongation (less with hydroxychloroquine).	No interaction identified.	No interaction identified.	No interaction identified.	No interaction identified.
High altitude illness prophylaxis
Acetazolamide^§	May increase cyclosporine levels; effect is usually minor. Monitor clinical status.	No interaction identified.	No interaction identified.	No interaction identified.	No interaction identified.	No interaction identified.

Approach to travel medicine selection in solid organ transplant recipients involves multiple considerations which may include local antimicrobial resistance patterns, adverse effects, and potential drug interactions with immunosuppressant drugs. Refer to clinical topics.
When initiating or altering drug therapy, use of a drug interactions database such as Lexicomp drug interactions, is advised. If there are any concerns about the safety of adding a medication, they should be discussed with the patient's transplant center prior to initiation.
These interactions are based on US Food and Drug Administration (FDA) guidance for classification of CYP, P-gp, and QTc-prolongation drug effects^[1-3]; other references may classify interactions differently. This is not a complete list of potential interactions.
Significant interactions between azathioprine or belatacept with travel medicines listed above have not been identified.

AUC: area under the plot of plasma concentration of a drug versus time; CYP: cytochrome P450; P-gp: P-glycoprotein.

* Loperamide, when used as an adjunct at usual doses, does not appear to interact significantly with immunosuppressive therapy.

¶ Azithromycin has a weaker effect on calcineurin and mTOR inhibitor levels than other macrolides; however, monitoring may be warranted. Azithromycin will have a stronger effect on immunosuppressive drug levels if the patient's drug list includes any CYP3A inhibitor. A table of CYP3A inhibitors is available separately in UpToDate.

Δ Baseline risk of tendinopathy is generally increased in older adults and solid organ transplant recipients.

◊ Rifaximin acts locally in the gut and is largely non-absorbed. Increased exposure may occur during cyclosporine coadministration, which could result in adverse effects and/or potential drug interactions via CYP3A or other enzyme induction; refer to drug interactions program. Additional monitoring may be warranted.

§ Acetazolamide has not been studied in solid organ transplant patients making rapid ascent to high altitudes; high altitude ascent (regardless of prophylaxis) may pose significant risks for many transplant recipients. Prior consultation with the patient's transplant team is highly advised.^[4]

References:

Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions.
US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website.
Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073161.pdf
Rosen J. Travel medicine and the solid-organ transplant recipient. Infect Dis Clin N Am. 2013; 27:429-57. [PMID23714348]

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Interactions between selected travel medicines and maintenance immunosuppressive therapy in solid organ transplant recipients