Common drug interactions in travel medicine

Whether or not you provide pre-travel consultation services, all pharmacists are responsible for ensuring drug therapy provided to patients is safe and effective. This includes an assessment for drug interactions. This column reviews some drug interactions to be aware of with com- monly-prescribed medications in travel medicine, and strategies to address them. As this is not a comprehensive review of all potential drug interactions with each agent, pharmacists are encouraged to confirm the potential for interactions using interaction-checking software inte- grated with dispensary software, product monographs, or subscription-based services (e.g., LexiComp, Micromedex). This is particularly important for patients on medications frequently implicated in drug interactions, such as antiretrovirals, macrolide antibiotics, azole antifungals and antiepileptics.1 Drugs for travellers’ diarrhea Azithromycin–Due to concerns of increasing resistance to fluoroquinolones worldwide,2-4 azithromycin is the preferred antibiotic for the standby treatment of moderate to severe travellers’ diarrhea.5 Dispensary software may alert pharmacists on potential CYP3A4 interactions with azithromycin; however, azithromycin does not have an appreciable interaction with the CYP3A4 pathway and such alerts are generally assigned to all drugs in the macrolide class.6 Be aware of mixed evidence related to the potential for elevations in INR in patients on warfarin due to concurrent use with azithromycin.7-9 However, given the short treatment period for azithromycin (often a single dose is sufficient for travellers’ diarrhea)5 and lower magnitude of azithromycin’s interaction with warfarin compared to other macrolide antibiotics,6 modification of therapy is likely not required for travellers dispensed azithromycin for standby purposes. Despite this, it would be wise to counsel patients to monitor for signs of bleeding should azithromycin be used abroad. The potential for QTc-interval pro- longation is another common concern with azithromycin use. Unpublished data included in the Zithromax product monograph report mean increases in QTc of 5–9 msec, which is significantly less than the 60 msec threshold most associated with the development of drug- induced torsades de pointes (TdP).10 Azithromycin should be avoided in patients with a history of TdP or congenital long QT syndrome. Patient assessment for risk of clinically significant QTc-pro- longation should consider the potentially interacting drug (those at highest risk of interaction include amiodarone, chlor- promazine, disopyramide, methadone, procainamide, quinidine, quinine and ziprasidone, among others),11 the dose of the interacting drug, and the presence of multiple minor risk factors for drug-induced QTc including advanced age, female sex, hypokalemia, hypocal- cemia or hypomagnesemia.10 The use of standby azithromycin in a healthy adult on citalopram, for example, is unlikely to be of clinical concern, despite this interaction being flagged by interaction software. Professional judgment and patient assessment are required when considering the risk of QTc prolongation. Additional information on drugs and conditions that may prolong the QTc can be found at www.crediblemeds.org or the QT prolongation module at www.pharmacy5in5.ca. Ciprofloxacin–If ciprofloxacin is selected as the antibiotic for standby treatment of travellers’ diarrhea, remember that concurrent administration with foods (e.g., dairy), supplements (e.g., multivitamins) or drugs (e.g., antacids, sucralfate) containing minerals such as calcium, magnesium, iron, zinc or aluminum can decrease quinolone bioavailability. As with azithromycin, the potential for interactions with warfarin and QTc-prolonging drugs must be considered, and management is similar. Individuals with diabetes receiving oral hypoglycemics should be advised to monitor for changes in blood glucose (either hypo- or hyperglycemia) following ciprofloxacin use; hypoglycemia is more likely, as quinolones initially stimulate insulin release12 and ciprofloxacin use for traveller’s diarrhea is likely to be only short-term. As a weak CYP3A4 inhibitor,13 ciprofloxacin may increase serum levels of drugs metabolized by this enzyme, including propranolol, clozapine, carbamazepine, theophylline and zolpidem;13, 14 however, adjustment of therapy is generally not required.13 An exception is ciprofloxacin use with the skeletal muscle relaxant, tizanidine; this combination is contraindicated, as ciprofloxacin use has been associated with a seven-fold increase in maximum serum concentrations of tizanidine15 and case reports of hypotension, drowsiness and dizziness as a result of the interaction have been published.16, 17 Drugs for malaria prophylaxis Atovaquone–proguanil–The product monograph of Malarone indicates that enhanced INR monitoring is recommended for patients on warfarin who are prescribed atovaquone–proguanil, due to the proguanil component potentiating the effect of warfarin.18, 19 A case report suggests that atovaquone may interact similarly,20 which some attribute to plasma protein displacement.20, 21 While little is known on the mechanism or magnitude of this interaction, it may be prudent to consider a trial of atovaquone–proguanil prior to travel with INR monitoring to determine the potential impact on the patient. If this interaction is problematic and atovaquone–proguanil use will be long-term, a novel oral anticoagulant can be considered as an alternative to warfarin, if indicated.22 Another notable potential drug interaction is with metoclopramide, which may significantly reduce atovaquone plasma concentrations,23 potentially reducing its effective- ness in preventing malaria. Little information on the magnitude or mechanism of this interaction exists; the combination is only advised if an alternative to metoclopramide is unavailable.24 Doxycycline–As with ciprofloxacin, separation from minerals such as calcium, iron and magnesium is required to ensure complete absorption, as well as separation from bismuth subsalicylate, which may be used for the prevention or treatment of traveller’s diarrhea.25 Doxycycline use is contraindicated with retinoic acid derivatives such as isotretinoin due to risk of intracranial hypertension.25 Phenytoin, carbamazepine and barbiturates may decrease the half-life of doxycycline,(22) by an unknown mech- anism.25 An alternate agent (e.g., atovaquone–proguanil) may be preferred. Like all tetracyclines, doxycycline may also enhance the anticoagulant effect of war- farin;25 a pre-travel trial of doxycycline with monitoring of INR may be advisable. Chloroquine–As with azithromycin and ciprofloxacin, chloroquine has the potential to prolong the QTc interval; this inter- action should be managed as discussed above. Since chloroquine is metabolized via CYP3A4, drugs that are both CYP3A4 inhibitors and have QTc-prolonging potential (e.g., clarithromycin) should be avoided in patients prescribed chloroquine.26 Other CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) should also be avoided.(22) Chloroquine should be spaced at least four hours apart from ant- acids containing calcium, magnesium or aluminum due to the risk of reduced bio-availability of chloroquine.27 Chloroquine should not be used with cimetidine, due to decreased clearance of chloroquine by up to 53%.28 As chloroquine is an inhibitor of CYP2D6, patients should monitor for adverse effects from drugs metabolized by this enzyme (e.g., metoprolol, propranolol, fluoxetine, paroxetine).22 An interaction with ciprofloxacin may result in either hyper- or hypoglycemia;26 caution and increased monitoring is advised for those with diabetes. Azithromycin would be a preferred option for treating traveller’s diarrhea in this population. Finally, chloroquine may increase serum levels of digoxin; patients on digoxin should have increased monitoring of serum digoxin levels upon initiation and discontinuation of chloroquine.26 Drugs for prophylaxis of altitude illness Acetazolamide–Acetazolamide alkalinizes the urine, which can increase the excretion rate of some drugs (e.g., barbiturates, salicylates, lithium) and decrease the excretion of others (e.g., dextroamphetamine, anticholinergics, quinidine).22 It should be avoided in patients on other drugs in the carbonic anhydrase inhibitor class, including ophthalmic products (e.g., brinzola- mide, dorzolamide) due to potential for acid-base disorders and the formation of kidney stones.31 Acetazolamide should also be avoided in those on topiramate, as topiramate also inhibits some isoenzymes of carbonic anhydrase.31 Elevated serum carbamazepine levels may occur following acetazolamide initiation; patients should be monitored closely.32 Interaction soft- ware may flag a concern with metformin and acetazolamide due to theoretical additive risk of lactic acidosis. However, a study of more than 200 patients on metformin found no cases of metabolic acidosis when used in combination with topiramate, another carbonic anhydrase inhibitor, as described above.33 Dexamethasone–Dexamethasone has a number of drug-drug and drug-disease interactions, but it is rarely used as prophylaxis for altitude illness, unless an individual has a history of altitude illness. Most patients with a prescription for dexamethasone for travel to altitude are receiving it for standby treatment should illness occur. The use of dexamethasone to prevent and treat high-altitude cerebral or pulmonary edema is often life-saving. While it may be prudent to counsel patients on separating dexamethasone from mineral-containing antacids, or to monitor for increases in blood glucose among individuals with diabetes, this only applies to prophylactic use and treatment should not be delayed in the event of altitude illness. Take-home message Drug interactions in travel medicine are common and require clinical judgment to interpret and manage. While inter- action-checking software is a valuable tool to detect potential interactions, pharmacists should be aware that many of these interactions reflect drug classes and may not adequately capture exceptions (e.g., azithromycin and CYP3A4 interactions) or consider the often short-term or standby nature of medications prescribed to travellers. As experts in pharmacology and therapeutics, pharmacists are relied on by patients and prescribers to identify and mitigate any potential drug inter- actions. Whether you are the person pre- scribing the drugs, or are determining the appropriateness of a drug prescribed by another healthcare professional, individual patient assessment and consideration of the nature and duration of travel should be part of any interaction assessment. Sherilyn Houle, BSP, PhD, is an assistant professor, School of Pharmacy, University of Waterloo, ON, and a pharmacist at the International Travel & Immunizations Clinic, Centre for Family Medicine in Kitchener, ON. She has her Certificate in Travel Health from the International Society of Travel Medicine. REFERENCES Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007;76:391- 6. https://www.aafp.org/afp/2007/0801/p391.html (accessed September 24, 2021). Mendez Arancibia E, Pitart C, Ruiz J, et al. Evolution of antimicrobial resistance in enteroaggregative Escherichia coli and enterotoxigenic Escherichia coli causing traveller’s diarrhoea. J Antimicrob Chemother 2009;64:343-7. Hoge CW, Gambel JM, Srijan A, et al. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998;26(2):341-5. Pandey P, Bodhidatta L, Lewis M, et al. 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