Digoxin-Clarithromycin Interaction: Well-Reported Yet Oft-Forgotten

Timothy H. Self, PharmD
Ryan E. Owens, PharmD, BCPS
Volume 55 - Issue 9 - September 2015

While digoxin is often added as adjunctive therapy for atrial fibrillation and heart failure, the narrow therapeutic index of the drug may cause some practitioners to shy away from its use. Drug interactions coupled with other risk factors (eg, decreased renal function) place patients at high risk of developing potentially life-threatening toxicity. 

Toxicity Manifestations

Digoxin toxicity can be separated into acute and chronic toxicity, with both phases sharing some similar symptoms. Table 1 lists the characteristics of digoxin toxicity.1,2 Digoxin toxicity due to clarithromycin commonly presents acutely with symptoms of nausea, vomiting, confusion, bradycardia, and arrhythmias.2 Malaise may also be a common complaint of elderly patients experiencing toxicity.1-3 While digoxin toxicity is typically associated with levels >2 ng/mL, some patients may present with manifestations of toxicity with normal digoxin levels, especially those with other risk factors.

Risk Factors

The most notable risk factor of digoxin toxicity is impaired renal function, as digoxin undergoes significant renal elimination as unchanged drug.1,2 Elderly patients are at heightened risk of experiencing digoxin toxicity due to age-related decline in renal function and decrease in volume of digoxin distribution.3 Therefore, monitoring renal function is essential not only upon initiation, but periodically throughout therapy as well. 

Electrolyte imbalances, including hypokalemia, hypomagnesaemia, and hypercalcemia, also place patients at increased risk of toxicity.1 Supplementation to correct electrolyte levels is prudent to prevent toxicity development. Drug interactions play a large role in predisposing patients to digoxin toxicity as well. While this article is focusing specifically on clarithromycin, many other agents (eg, verapamil and amiodarone) have also been well-documented in the literature to interact with digoxin as well.1,2  

Mechanism of Interaction

While the exact mechanism of the digoxin-clarithromycin interaction is unknown, several theories have been proposed. Two such theories relate to the effects of clarithromycin on the GI tract. In a small subset of the population, gut bacteria accounts for a large percentage of digoxin metabolism.4,5 Macrolides eliminate Eubacterium lentum in the gut through their antimicrobial effects which thereby may decrease digoxin metabolism, increasing its bioavailability.4,5 Macrolides also serve as prokinetic agents in the gut via stimulation of motilin receptors which may cause GI disturbance.6 Sutton et al found that erythromycin’s ability to increase gastric emptying resulted in increased oral bioavailability as well as plasma concentrations of digoxin.7 

The main mechanism of interaction is thought to be due to strong P-glycoprotein inhibition by clarithromycin, as digoxin is a P-glycoprotein substrate. Through this inhibition, digoxin’s intestinal drug absorption is increased and inactive tubular secretion in the kidneys is decreased.8,9 Both of these altered transport effects lead to increased plasma concentrations. Tsutsumi et al concluded that this mechanism is more predominately seen with oral digoxin therapy rather than intravenous therapy.10 

Management

Despite many case reports and case series describing this interaction, no specific recommendations for managing this interaction are available other than monitoring digoxin levels during concurrent therapy with clarithromycin.11-21 Specific details of selected case reports are shown in Table 2.11-14 A profound effect can be seen even with short courses of clarithromycin. The management strategies in these reports ranged from temporary digoxin dose reduction to holding digoxin completely until the course of clarithromycin therapy was completed.11-21 It is important to note that no patients required administration of digoxin specific antigen binding fragments. Digoxin specific antigen binding fragments should be reserved for severe or life-threatening arrhythmias, as its use may unmask symptoms of congestive heart failure, atrial fibrillation, or atrial flutter during the reversal process.1,2 

Ideally, this interaction could be avoided via selecting an alternative antibiotic when possible. However, alternative agents are sometimes neither available nor ideal. If clarithromycin must be used, it is essential to monitor digoxin levels and patient clinical status. However, with the body of evidence available indicating toxicity development, it would be prudent to pre-emptively decrease the digoxin dose temporarily upon initiation of clarithromycin rather than doing so after toxicity develops.11-21

Other Macrolides 

While erythromycin and azithromycin are weak P-glycoprotein inhibitors compared to clarithromycin, interactions with digoxin still exist.22-26 However, Gomes et al reported that digoxin toxicity is 4 times higher with clarithromycin than either erythromycin or azithromycin.27 Association between antibiotic use and hospitalization for digoxin toxicity was determined and adjusted odds ratios were: 14.83 clarithromycin, 3.69 erythromycin, and 3.71 azithromycin.27 Therefore, interactions with digoxin should be viewed as a class effect for macrolides, with clarithromycin as the most clinically significant. If a macrolide is required, azithromycin is preferred due to less risk of digoxin toxicity.

Key Points For Your Practice: 

Digoxin-macrolide interactions are serious and can result in hospitalization and potentially death, with clarithromycin documented as the worst offender. Alternative antibiotics should be chosen for patients receiving concomitant digoxin therapy to avoid this interaction. If alternative agents are unavailable, practitioners should remain vigilant in monitoring digoxin levels and decreasing or holding digoxin doses accordingly during macrolide concurrent therapy. Practitioners should also ensure that patients are well-versed in the signs and symptoms of digoxin toxicity in order to quickly recognize and alert prescribers.

Ryan E. Owens, PharmD, is a PGY2 internal medicine pharmacy resident at Methodist University Hospital and the University of Tennessee Health Science Center, both in Memphis, TN.

Timothy H. Self, PharmD, is a professor of clinical pharmacy at the University of Tennessee Health Science Center and program director of the PGY2 internal medicine pharmacy residency at Methodist University Hospital, both in Memphis, TN.

References:

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