Digoxin (digoxin)

Digoxin has a narrow therapeutic index; therefore, cautious dosage determination is essential and dosage must be carefully individualized based on clinical assessment and therapeutic drug monitoring. Dosage guidelines provided are based upon average patient response and substantial patient variation can be expected. When selecting an appropriate dosage, the patient's renal function, body weight, age, concomitant disease states, concurrent drugs, and other factors likely to alter serum concentrations of digoxin should be considered. Because the distribution of digoxin is proportional to lean body weight, lean body weight should be used for dosage calculations. Serum digoxin concentrations can be used to guide dosing, but should always be interpreted in the overall clinical context.

Digoxin dosage may be initiated with or without a loading dose depending on whether rapid titration or a more gradual titration is desired; the different approaches vary in dosage and frequency of administration but achieve the same total amount of digoxin accumulated in the body.

Loading doses of digoxin are administered in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose and additional fractions (usually 25%) usually administered every 6-8 hours with careful assessment of the patient's clinical response (including possible toxicity) before each additional dose. If a change from the calculated loading dose is required, then the maintenance dosage should be calculated based upon the amount (i.e., total loading dose) actually administered.

More gradual attainment of digoxin concentrations can be achieved by initiating therapy with a maintenance dosage without a loading dose. Steady-state serum digoxin concentrations will be achieved in about 5 half-lives of the drug for the individual patient; depending on the patient's renal function, this may take approximately 1-3 weeks.

Differences in the bioavailability of parenteral and oral preparations of digoxin should be considered when patients are switched from one dosage form to another. Because the absolute bioavailability of digoxin tablets and solution are similar, equivalent dosages may be used. When switching from oral to IV therapy, dosage of digoxin should be reduced by about 20-25%.

Since daily maintenance digoxin dosage is a replacement of daily digoxin loss from the body, an alternative dosing method has been used where the maintenance dosage for a particular patient is estimated by multiplying the daily percentage loss by the peak body stores (i.e., loading dose) that produced a satisfactory response. The percentage of digoxin eliminated from the body daily can be estimated by the following equation:

Digoxin usually is administered orally. When oral therapy is not feasible or when rapid therapeutic effect is necessary, the drug may be administered parenterally. Although digoxin may be given IM or IV, the IV route of administration is preferred because IM injection can cause severe pain at the site of injection. If the drug must be administered by the IM route, injections should be made deep into the muscle followed by massage of the injection site, and no more than 2 mL of the drug should be injected at a single site in adult and pediatric patients.

Because digoxin has a narrow therapeutic window, increased monitoring of serum digoxin concentrations and for possible clinical manifestations of digoxin toxicity is necessary when initiating, adjusting, or discontinuing therapy with any drugs that may interact with digoxin. Clinicians should also consult the prescribing information for any drugs that are concurrently administered with digoxin for potential drug interaction information.

Concomitant use of certain drugs may increase serum concentrations of digoxin by interfering with absorption of the cardiac glycoside via P-glycoprotein (P-gp) interaction or other mechanisms. Drugs that have been shown to increase serum digoxin concentrations by more than 50% include amiodarone, captopril, clarithromycin, dronedarone, gentamicin, erythromycin, itraconazole, lapatinib, propafenone, quinidine, ranolazine, ritonavir, tetracycline, and verapamil. Serum digoxin concentrations should be measured prior to initiating these drugs and the dosage of digoxin should be adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency and continuing monitoring.

Drugs that have been shown to increase digoxin concentrations by less than 50% include atorvastatin, carvedilol, conivaptan, diltiazem, indomethacin, mirabegron, nefazodone, nifedipine, propantheline, quinine, rabeprazole, spironolactone, telmisartan, ticagrelor, tolvaptan, and trimethoprim. Serum digoxin concentrations should be measured prior to initiating these drugs and dosage of digoxin should be adjusted by either decreasing the dose by approximately 15-30% or modifying the dosing frequency and continuing monitoring.

Drugs that have been shown to increase serum digoxin concentrations with an unclear magnitude include alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, and omeprazole. Serum digoxin concentrations should be measured prior to initiating these drugs; monitoring should be continued and the dosage of digoxin should be reduced as necessary.

Drugs or therapies that have been shown to decrease serum digoxin concentrations include acarbose, albuterol, antacids, certain chemotherapy or radiation therapy, cholestyramine, colestipol, exenatide, kaolin-pectin, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John's wort (Hypericum perforatum), sucralfate, and sulfasalazine. Serum digoxin concentrations should be measured prior to initiating these drugs or therapies; monitoring should be continued and dosage of digoxin should be increased by approximately 20-40% as necessary.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Digoxin; Etoposide/Adagrasib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib may increase the absorption of digoxin and etoposide by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may result in elevated levels of and toxicity from digoxin and etoposide.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias. Etoposide toxicity may include hematologic and gastrointestinal toxicities.

PREDISPOSING FACTORS: The interaction magnitude may be greater in patients receiving oral etoposide, or with impaired renal or hepatic function.

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that concurrent administration of sensitive narrow therapeutic index P-glycoprotein substrates (e.g. digoxin, etoposide) with adagrasib should be avoided.(1)

DISCUSSION: Concurrent adagrasib (600 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.5-fold and 1.9-fold, respectively.(1)

Selected Antiarrhythmics/Arbutamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Arbutamine may have additive or synergistic effects on the proarrhythmic effects of these agents.(1)

CLINICAL EFFECTS: Concurrent use may result in precipitation or exacerbation of supraventricular and ventricular arrhythmias.(1)

PREDISPOSING FACTORS: Possibly a history of sustained supraventricular or ventricular arrhythmias.(1)

PATIENT MANAGEMENT: The manufacturer of arbutamine states that arbutamine should not be administered with Class I antiarrhythmics such as flecainide, lidocaine, and quinidine or with digoxin.(1)

DISCUSSION: Because arbutamine may precipitate or exacerbate supraventricular or ventricular arrhythmias, the manufacturer of arbutamine states that it should not be administered with proarrhythmic agents such as Class I antiarrhythmics such as flecainide, lidocaine, or quinidine.(1) The manufacturer of arbutamine also states that it should not be administered with digoxin.(1) There is no published documentation for this interaction.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Cause Bradycardia/Camizestrant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Camizestrant may cause symptomatic bradycardia. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1)

CLINICAL EFFECTS: Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of camizestrant recommends avoiding concurrent use of camizestrant and other agents known to cause bradycardia.(1) If combination therapy is unavoidable, monitor heart rate and blood pressure regularly. Monitor heart rate more frequently during the first 30 days of treatment with camizestrant in patient with bradycardia (heart rate less than 60 beats per minute (bpm)) and those on concomitant medications known to lower heart rate.(1) If bradycardia occurs, symptomatic or Grade 2 or above, withhold camizestrant until symptoms resolve. Obtain an ECG to evaluate the etiology of the symptomatic bradycardia. If a contributing concomitant medication is identified, modify the dosage or discontinue the medication as appropriate until bradycardia symptoms resolve and then resume camizestrant. Consider reassessing the heart rate after restarting camizestrant. Permanently discontinue camizestrant for persistent bradycardia.(1) The manufacturer of camizestrant recommends performing an ECG prior to initiating camizestrant, then every week for the first 2 weeks of treatment, and periodically during treatment as clinically indicated.(1)

DISCUSSION: In a clinical trial, bradycardia occurred in 8% of patients on camizestrant. The mean heart rate decrease from baseline was approximately 13 beats per minute with camizestrant, with the maximum decrease observed on Day 15. The median time to onset of adverse reaction was 17 days (range 13 to 283 days) after starting camizestrant. Bradycardia led to dose interruption of camizestrant in 3.9% of patients.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin, and moxonidine.

Agents That Cause Bradycardia/Crizotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Crizotinib may cause symptomatic bradycardia. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1)

CLINICAL EFFECTS: Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of crizotinib recommends avoiding concurrent use of crizotinib and other agents known to cause bradycardia to the extent possible. If combination therapy is required, monitor heart rate and blood pressure regularly. If bradycardia occurs, withhold crizotinib until heart rate recovers to 60 bpm or above, or patient is asymptomatic. Re-evaluate the use of the concomitant medication. If the concomitant medication is discontinued or its dose is reduced, resume crizotinib at the previous dose upon patient's recovery. If the concomitant medication is not discontinued or dose adjusted, resume crizotinib at a reduced dose upon patient's recovery. If life-threatening bradycardia occurs, discontinue or reduce the dose of the concomitant medication. Upon the patient's recovery, lower the dose of crizotinib to 250 mg daily. Monitor blood pressure and heart rate frequently.(1)

DISCUSSION: Across clinical trials, bradycardia occurred in 13 % of patients on crizotinib, and grade 3 syncope occurred in 2.4 % of patients on crizotinib compared with 0.6 % on chemotherapy.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin, and moxonidine.(1)

Agents That Cause Bradycardia/Etrasimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Initiation of etrasimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. The first dose has also been associated with heart block. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1)

CLINICAL EFFECTS: The heart rate lowering effect of etrasimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to etrasimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to etrasimod.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The prescribing information for etrasimod treatment states that advice from a cardiologist should be sought before initiating etrasimod treatment in patients currently taking additional agents that cause bradycardia or in patients with preexisting heart and cerebrovascular conditions, with resting heart rate of less than 50 bpm, history of symptomatic bradycardia, recurrent cardiogenic syncope, severe untreated sleep apnea, or history of Mobitz type 1 second-degree AV block (unless has functioning pacemaker).(1) Monitor blood pressure during treatment.(1)

DISCUSSION: Initiation of etrasimod treatment has been associated with transient atrioventricular (AV) conduction delays. The AV conduction delays manifested as first or second degree AV block (prolonged PR interval on ECG), which occurred in 0.7% of etrasimod treated patients in UC-1 and in 0.8% of patients in UC-2 and UC-3 compared to 0% for placebo in all studies.(1)

Agents That Cause Bradycardia/Fexinidazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Fexinidazole has been shown to prolong the QTc interval. Concurrent use with agents that cause bradycardia may increase the risk of QTc prolongation.(1)

CLINICAL EFFECTS: Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fexinidazole recommends avoiding concurrent use of fexinidazole and other agents known to cause bradycardia.(1) Avoid use of fexinidazole in patients who have a baseline QTcF interval greater than 470 msec, a history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death, or uncorrected hypokalemia.(1) If patients are, or need to be, treated with drugs known to induce bradycardia or prolong the QTc interval do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs). Do not start such drugs until fexinidazole therapy is eliminated (allow a washout period of 7 days).(1)

DISCUSSION: Bradycardia increases the risk of QTc interval prolongation and torsade de pointes.(1) In clinical studies, fexinidazole was associated with a concentration-dependent QTcF prolongation. At recommended therapeutic doses, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec). The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, clonidine, digoxin and moxonidine.(1)

Agents That Cause Bradycardia/Ponesimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Initiation of ponesimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 2-4 hours. The first dose has also been associated with heart block. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1)

CLINICAL EFFECTS: The heart rate lowering effect of ponesimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The prescribing information states ponesimod treatment should generally not be initiated in patients who are on concurrent therapy with additional agents that cause bradycardia. If treatment with ponesimod is considered, advice from a cardiologist should be sought regarding switching to non-heart rate lowering drugs or monitoring during treatment initiation. Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of ponesimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, ponesimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of ponesimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1)

DISCUSSION: Initiation of ponesimod treatment has been associated with transient atrioventricular (AV) conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. The AV conduction delays manifested in most of the cases as first-degree AV block (prolonged PR interval on ECG), which occurred in 3.4% of ponesimod treated patients and in 1.2% of patients receiving teriflunomide in Study 1. Second-degree or third-degree AV blocks have not been reported in patients in clinical trials. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, and did not require discontinuation of ponesimod treatment.(1)

Agents That Cause Bradycardia/Siponimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Initiation of siponimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 3-4 hours. The first dose has also been associated with heart block. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1)

CLINICAL EFFECTS: The heart rate lowering effect of siponimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The prescribing information states siponimod treatment should generally not be initiated in patients who are concurrent therapy with additional agents that cause bradycardia. If treatment with siponimod is considered, advice from a cardiologist should be sought regarding switching to non-heart rate lowering drugs or recommendations for monitoring for treatment initiation. Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of siponimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, siponimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of siponimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1)

DISCUSSION: Initiation of siponimod treatment has been associated with transient atrioventricular (AV) conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. The AV conduction delays manifested in most of the cases as first-degree AV block (prolonged PR interval on ECG), which occurred in 5.1% of siponimod treated patients and in 1.9 % of patients receiving placebo in Study 1. Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time of treatment initiation with siponimod in less than 1.7% of patients in clinical trials. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, rarely required treatment with atropine, and did not require discontinuation of siponimod treatment.(1)

Beta-Blockers; Av Node Blockers/Fingolimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Initiation of fingolimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block. Beta-blockers or agents which slow AV node conduction further increase the risk for symptomatic bradycardia or heart block.

CLINICAL EFFECTS: The heart rate lowering effect of fingolimod is biphasic with an initial decrease usually within 6 hours, followed by a second decrease 12 to 24 hours after the first dose. Symptomatic bradycardia and heart block have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes. The cause of death in a patient who died within 24 hour after taking the first dose of fingolimod was not conclusive; however a link to fingolimod or a drug interaction with fingolimod could not be ruled out. Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol. AV Node Blocking agents are:digoxin, diltiazem, flecainide, ivabradine, propafenone and verapamil.

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to fingolimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to fingolimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)

PATIENT MANAGEMENT: Fingolimod is contraindicated in patients with Class III/IV heart failure or in patients who have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA) or decompensated heart failure within the past six months.(1) Patients with pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, or a prolonged QTc interval prior to fingolimod initiation should receive cardiologist consultation to evaluate the risks of fingolimod therapy. Patients receiving agents linked to this monograph should have their physician evaluate the possibility of a switch to agents which do not slow heart rate or cardiac conduction. If fingolimod is initiated, the patient should stay overnight in a medical facility with continuous ECG monitoring after the first dose. Correct hypokalemia or hypomagnesemia prior to starting fingolimod. US monitoring recommendations in addition to continuous ECG with overnight monitoring: Check blood pressure hourly. If heart rate (HR) is < 45 beats per minute (BPM) or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, the first dose monitoring strategy should be repeated for the second dose of fingolimod. If, within the first two weeks of treatment one or more fingolimod doses is missed, then first dose procedures are recommended upon resumption. If during weeks 3 and 4 of fingolimod treatment dose is interrupted more than 7 days, then first dose procedures are recommended upon resumption. United Kingdom recommendations(3): Obtain a 12-lead ECG prior to initiating fingolimod therapy. Consult a cardiologist for pretreatment risk-benefit assessment if patient has a resting heart rate less than 55 bpm, history of syncope, second degree or greater AV block, sick-sinus syndrome, concurrent therapy with beta-blockers, Class Ia, or Class III antiarrhythmics, heart failure or other significant cardiovascular disease. Perform continuous ECG monitoring, measure blood pressure and heart rate every hour, and perform a 12-lead ECG 6 hours after the first dose. Monitoring should be extended beyond 6 hours if symptomatic bradycardia or new onset of second degree AV block, Mobitz Type II or third degree AV block has occurred at any time during the monitoring period. If heart rate 6 hours after the first dose is less than 40 bpm, has decreased more than 20 bpm compared with baseline, or if a new onset second degree AV block, Mobitz Type I (Wenckebach) persists, then monitoring should also be continued. If fingolimod treatment is discontinued for more than two weeks, the effects on heart rate and conduction could recur. Thus, first dose monitoring precautions should be followed upon reintroduction of fingolimod.

DISCUSSION: After the first dose of fingolimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 6 hours followed by a second decrease 12 to 24 hours after the first dose. The second dose may further decrease heart rate, but the magnitude of change is smaller than the first dose. With continued, chronic dosing, heart rate gradually returns to baseline in about one month.(1,2) Diurnal variation in heart rate and response to exercise are not affected by fingolimod treatment.(2) In a manufacturer sponsored study, fingolimod and atenolol 50 mg daily lowered heart rate 15% more than fingolimod alone. However, additional heart rate lowering was not seen with the combination of extended release diltiazem and fingolimod compared with fingolimod alone.(1)

Digitalis Glycosides/Amiodarone; Dronedarone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Multiple mechanisms appear to be involved in the interaction between amiodarone and digitalis glycosides. Amiodarone decreases renal and nonrenal clearance of the digitalis glycosides, reduces digitalis glycoside volume of distribution, and increases digitalis glycoside bioavailability. In addition, digitalis glycosides depress the sinus node, producing bradycardia. Dronedarone increases digoxin levels by inhibiting the P-glycoprotein transporter. Digoxin also potentiates the electrophysiologic effects of dronedarone.

CLINICAL EFFECTS: Concurrent amiodarone or dronedarone may result in elevated levels of and effects from digitalis glycosides. The magnitude of the interaction between amiodarone and digitalis glycosides is dependent on the route of administration of the digitalis glycoside and proportional to the amiodarone dose and serum level. Concurrent use of dronedarone and digoxin may increase the risk of arrhythmic or sudden death. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor serum digitalis glycoside levels and observe the patient for symptoms of digitalis toxicity. Upon adding amiodarone or dronedarone, digitalis dosages should first be decreased in anticipation of an interaction, then adjusted accordingly. The dosage of oral digitalis glycoside may need to be decreased by 30-50%, or the frequency of administration may be reduced. For IV or IM digitalis glycoside, the dosage may need to be decreased by 15-30%, or the dosing frequency may be reduced.

DISCUSSION: Plasma digitalis glycoside concentrations may increase several fold after adding amiodarone to the treatment regimen. The effect appears related to the dose of amiodarone, with higher doses of amiodarone being associated with the greatest increases. A study in 12 patients controlled on digitalis found that the addition of amiodarone for arrhythmias resulted in a 75.42% increase in digitalis plasma levels at initiation of amiodarone. At the mid-point of combination therapy, digitalis serum levels were elevated by 52.1%. Three patients experienced digitalis-related toxicity. In a study in 6 healthy volunteers, a 7-day course of amiodarone increased the maximum concentration (Cmax) of a single dose of digoxin (0.50 mg) from 2.92 ng/ml to 5.87 ng/ml. Digoxin area-under-curve (AUC) increased from 30.71 ng x h/mL to 40.63 ng x h/ml. Four out of the 6 subjects showed a decrease in the time to Cmax (Tmax) of digoxin. Concurrent use of amiodarone with IV or IM digoxin increased the digoxin AUC by 40%.(28) Increased serum digitalis glycoside levels with accompanying toxicity have been reported during concomitant administration of amiodarone and digoxin, digitalis, and digitoxin. Torsades de pointes has been reported. The subjects suffered torsades de pointes within 48 hours of amiodarone loading. Concurrent dronedarone and digoxin (dosages not stated) increased digoxin exposure 2.5-fold. In the ANDROMEDA and PALLAS trials, baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in dronedarone-treated patients when compared to the use of digoxin plus placebo. In patients not taking digoxin, there was no difference in sudden risk of death between dronedarone and placebo. In the ANDROMEDA trial, baseline digoxin use was reported in 6 of 16 dronedarone patients versus 1 of 16 placebo patients who died of arrhythmia. In the PALLAS trial, baseline digoxin therapy was reported in 11 of 13 patients who died of arrhythmia, versus none of the 4 patients in the placebo group who died of arrhythmia. Concomitant administration of dronedarone and oral digoxin increased the digoxin AUC by 150%.(29)

Digitalis Glycosides/Amphotericin B

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Amphotericin B may cause hypokalemia which can predispose patients to digitalis toxicity.

CLINICAL EFFECTS: Possible potentiation of digitalis effects. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor potassium levels carefully in patients using these agents concomitantly. Correct potassium deficits promptly.

DISCUSSION: Amphotericin B induced hypokalemia is a well known drug side effect.

Digitalis Glycosides/Intravenous Calcium Products

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of action of digitalis glycosides involves its ability to cause an increase in excitation-contraction coupling mediated through the effects of calcium. Excitable tissues in the heart experience inhibition of sodium/potassium ATPase (the membrane "sodium pump") by digitalis glycosides and so attain relatively higher intracellular sodium and lower potassium concentrations. Higher intracellular sodium concentrations facilitate exchange of extracellular calcium ions and the inward and internal flux of calcium results in modified transmembrane potentials and stronger contractions of cardiac muscle. Elevated extracellular concentrations of calcium after parenteral calcium salts further facilitate these inward calcium fluxes.

CLINICAL EFFECTS: Rapid administration of calcium via the intravenous route may result in digitalis toxicity, including arrhythmias.(1)

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: In patients maintain on a digitalis glycosides, administer intravenous calcium slowly and with caution. If cardiac toxicity develops, supportive measures without additional antiarrhythmics may be sufficient.

DISCUSSION: Effects of digitalis glycosides on the heart are increased by elevated extracellular concentrations of ionic calcium. Intravenous administration of calcium salts during digitalis therapy may result in altered cardiac electrophysiologic activity such as tachycardia or arrhythmias. Oral calcium carbonate has not been shown to affect the bioavailability of oral digitalis.

Digitalis Glycosides/Quinidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Quinidine may inhibit the transport of digoxin by P-glycoprotein (P-gp).

CLINICAL EFFECTS: Concurrent quinidine may result in digoxin toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: In patients receiving concurrent quinidine, monitor serum digoxin levels and for signs and symptoms of digoxin toxicity. The dosage of digoxin may need to be adjusted by 30% to 50% or its frequency of administration adjusted if quinidine is initiated or discontinued. Consider therapy with an agent which has not been shown to interact with digoxin.

DISCUSSION: In a study of six subjects, quinidine sulfate (300 mg every 6 hours) was given orally for 3 days prior to an injection of digoxin (1 mg) and then continued for 5 more days. Systemic clearance of digoxin was reduced by 45%, the renal clearance reduced by 33%, and the nonrenal clearance reduced by 60% with all values being statistically significant. In another study of 101 subjects receiving digoxin alone and 20 subjects receiving digoxin and quinidine together, the addition of quinidine was found to decrease digoxin clearance by 26%. In addition, 10 of the 20 subjects (50%) receiving digoxin and quinidine together were confirmed to have digitalis toxicity, whereas only 5 of the 101 subjects (4.9%) receiving digoxin alone were confirmed to have digitalis toxicity. The authors concluded that quinidine caused an increase in digoxin toxicity even in the therapeutic serum digoxin levels(2). In a clinical pharmacokinetic in vitro study, a portion of the jejunum was taken from seven healthy subjects with a multilumen perfusion catheter. A portion of the jejunal segment was added with digoxin alone while another portion had administered digoxin with quinidine. The results indicated that when digoxin was added alone 22.3%(+/-8.9%) was absorbed; the addition of quinidine to the jejunal segment caused an increase in the fraction of absorbed digoxin by 55.8%(+/-21.2%)(p<0.05). Also, the Cmax for digoxin alone was 1.0ng/ml/mg(+/-0.4) while digoxin administered with quinidine caused a Cmax increase to 3.8ng/ml/mg(+/-1.2) (P<0.001)(3). Concomitant administration of quinidine and digoxin increased the digoxin serum concentration 100%. (17)

Digoxin, Oral/Macrolide Antibiotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Macrolides may alter the bacterial flora in the GI tract, increasing the bioavailability of digoxin. Some macrolides may inhibit the transport of digoxin by p-glycoprotein in the intestines and kidneys.

CLINICAL EFFECTS: Digoxin serum levels may be elevated (up to 2-fold), producing increased therapeutic and adverse effects. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias. The effects of macrolides on the GI flora may persist for several months.

PREDISPOSING FACTORS: The increase in serum levels is greatest with those digoxin products with the lowest bioavailability and may not be clinically significant in patients taking digoxin elixir. Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin serum levels during concurrent macrolide therapy and adjust the dose as needed. The dosage of digitalis glycoside may need to be decreased by 30-50% or the frequency of administration may be reduced.

DISCUSSION: In a retrospective review, azithromycin, clarithromycin, and erythromycin use were associated with a 3.7-fold, 7.9-fold, and 3.7-fold increased risk of digoxin toxicity.(1) In a retrospective review, clarithromycin prescription at 7, 14, and 30 days prior was associated with a 4.36-fold, 5.07-fold, and 2.98-fold increase in risk of hospitalization for digoxin toxicity.(2) In a clinical trial in 12 healthy males, clarithromycin (250 mg twice daily for 3 days) increased the area-under-curve (AUC) of a single oral dose of digoxin by 1.7-fold. Clarithromycin increased the AUC of intravenous digoxin by 1.2-fold.(3) In a study in 7 patients with congestive heart failure, clarithromycin therapy increased digoxin levels by 70%.(4) In a study in elderly patients taking digoxin, clarithromycin decreased digoxin renal clearance by 56-60%.(5) In a study in 9 healthy males, clarithromycin and erythromycin had no effect on levels of intravenous digoxin.(6) In a study in 3 subjects, erythromycin increased serum digoxin concentrations 2-fold.(7) Telithromycin has been shown to increase digoxin maximum concentration (Cmax) and trough levels (Cmin) by 73% and 21%, respectively.(8) Elevated digoxin levels and toxicity have been reported during concurrent therapy with azithromycin,(9) clarithromycin,(10-25) erythromycin,(26-30) josamycin,(31) roxithromycin,(32) and telithromycin.(33) Approximately 10% of the patients receiving digoxin excrete significant amounts of inactive digoxin metabolites.(7) Since bacterial flora in the GI tract are involved with the conversion of cardioactive digoxin to the inactive metabolite, administration of macrolides as well as other antibiotics may alter the bacterial flora, interfering with the conversion process. These 10% of the patients are at additional risk of elevated digoxin levels due to the drug interaction. Concomitant administration of erythromycin and digoxin caused digoxin serum concentration to increase 100%. (34)

Digoxin/Belumosudil

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Belumosudil may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of belumosudil may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Avoid coadministration of belumosudil with P-gp substrates such as digoxin. If coadministration cannot be avoided, monitor serum digoxin concentrations before initiating belumosudil. When the digoxin concentration is expected to be increased by greater than 50%, the manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations. Continue monitoring and reduce digoxin dose as necessary.(2)

DISCUSSION: Coadministration of belumosudil increased dabigatran (P-gp substrate) area-under-curve (AUC) and maximum concentration (Cmax) by 2-fold.(1)

Digoxin/Cyclosporine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cyclosporine may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).

CLINICAL EFFECTS: The pharmacological effects of digoxin may be increased resulting in toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: In patients receiving digoxin, monitor serum digoxin level when treatment with cyclosporine is instituted, increased, decreased or discontinued. Adjust the dose of digoxin accordingly.

DISCUSSION: Digoxin toxicity has been reported in two patients following the addition of cyclosporine to their treatment schedule. In two additional patients, the apparent volume of distribution and the plasma clearance of digoxin decreased by 71% and 53% respectively during concurrent administration of cyclosporine.

Digoxin/Hydroxychloroquine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, hydroxychloroquine may reduce the renal and non-renal clearance of digoxin.

CLINICAL EFFECTS: Plasma digoxin concentrations may be elevated, increasing the toxic effects of digoxin. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum digoxin concentrations and observe the patient for signs of toxicity when starting or stopping hydroxychloroquine. Adjust the dose of digoxin as needed.

DISCUSSION: Two patients stabilized on digoxin therapy experienced an increase in serum digoxin levels when hydroxychloroquine was added to their treatment. Plasma digoxin levels decreased when hydroxychloroquine was discontinued.

Digoxin/Itraconazole; Ketoconazole; Posaconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of digoxin at the levels of intestinal absorption, renal tubular secretion, and biliary-intestinal secretion.(1) Itraconazole, ketoconazole, and posaconazole are P-gp inhibitors.

CLINICAL EFFECTS: Concurrent use of itraconazole, ketoconazole, or posaconazole may result in increased digoxin levels and signs of digoxin toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin levels in patients receiving concurrent therapy with itraconazole, ketoconazole, or posaconazole. The dosage of digoxin may need to be adjusted, possibly by as much as a 30% to 75% decrease during concurrent therapy. Alternatively, the frequency of administration may be decreased.

DISCUSSION: Digoxin is a known substrate of P-gp. Inhibitors of P-gp may increase toxicity of digoxin.(1) In a double-blind, randomized, cross-over study in 10 healthy subjects, itraconazole (200 mg daily for 5 days) increased the area-under curve (AUC) of a single dose of digoxin (0.5 mg on Day 3) by 50%. The renal clearance of digoxin decreased by 20%. Increases in digoxin maximum concentration (Cmax) and half-life were not statistically significant. In a double-blind, randomized, cross-over study in 10 healthy subjects, itraconazole (200 mg daily for 10 days) increased the AUC of digoxin (0.25 mg daily for 20 days) by 80%. There are several published case reports of increased digoxin levels and signs of digoxin toxicity in patients receiving concurrent therapy with itraconazole. In four of these reports, it was documented that there were no changes in serum creatinine or potassium to account for the increased digoxin levels and toxicity observed. In two patients, a reduction in digoxin dosage by 75% resulted in therapeutic levels during concurrent therapy. In contrast to these reports, itraconazole (200 mg daily) was administered for 36 months with concurrent digoxin (0.125 mg daily) with no changes in digoxin levels. In a double-blind, randomized, cross-over study in healthy subjects, voriconazole (200 mg twice daily Days 11-22) had no effect on digoxin levels (0.5 mg twice daily, Day 1; 0.25 mg twice daily Day 2; 0.25 mg daily Days 3-22). Concomitant administration of itraconazole and digoxin increased the digoxin serum concentration by 80%. There are case reports of elevated digoxin levels during concurrent ketoconazole therapy.

Digoxin/Propafenone;Flecainide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Uncertain, but decreases in volume of distribution as well as renal and metabolic clearance of digoxin have been observed.

CLINICAL EFFECTS: Digoxin plasma concentrations may increase, producing toxicity. Signs of digitalis toxicity include nausea, vomiting and ECG changes like bradycardia, ventricular ectopy and shortening of the QT interval. Propafenone use may have resulted in a digoxin-induced fatal ventricular fibrillation (1).

PREDISPOSING FACTORS: Propafenone should be used with caution in patients with serious structural heart disease as it may cause or aggravate life-threatening arrhythmias. Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor serum digoxin glycoside levels and observe the patient for symptoms of digitalis toxicity. Upon adding propafenone or flecainide, digoxin dosages should first be decreased in anticipation of an interaction, then adjusted accordingly. The dosage of oral digoxin may need to be decreased by 30-50%, or the frequency of administration may be reduced. For IV or IM digoxin, the dosage may need to be decreased by 15-30%, or the dosing frequency may be reduced.

DISCUSSION: Clinical studies have shown that coadministration of propafenone and digoxin may result in an increase in serum digoxin levels of 30-60%. Symptoms of digitalis toxicity have been reported. An interaction has been demonstrated in both adult and pediatric patients. Concurrent administration of flecainide and digoxin resulted in a small but significant increase of 13% in plasma digoxin concentration. A significant prolongation of the PR interval in six of 15 subjects was noted. Two studies have documented that encainide therapy does not affect digoxin pharmacokinetics. Concomitant administration of propafenone and oral digoxin increased the digoxin area-under-the-curve (AUC) 60-270%.(14) Concurrent use of propafenone with IV or IM digoxin increased the digoxin AUC by 29%.(15)

Digoxin/Tepotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tepotinib may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of tepotinib may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Avoid coadministration of tepotinib with P-gp substrates such as digoxin.(1) If coadministration cannot be avoided, monitor serum digoxin concentrations before initiating tepotinib. When the digoxin concentration is expected to be increased by greater than 50%, the manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations. Continue monitoring and reduce digoxin dose as necessary.(2)

DISCUSSION: Coadministration of tepotinib increased dabigatran (P-gp substrate) area-under-curve (AUC) and maximum concentration (Cmax) by 50% and 40%, respectively.(1)

Digoxin/Trimethoprim

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Trimethoprim may inhibit the renal tubular clearance of digoxin.(1-3)

CLINICAL EFFECTS: Concurrent use of trimethoprim may result in elevated levels of and toxicity from digoxin.(1,2) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: The manufacturer of digoxin states if concurrent therapy is warranted, monitor serum digoxin levels before initiating concurrent trimethoprim therapy and observe the patient for symptoms of digoxin toxicity. Upon adding trimethoprim, digoxin should first be decreased by approximately 15-30% of the current dose or by modifying the dosing frequency in anticipation of interaction. Continue monitoring digoxin levels and further adjust the dosing as necessary.(1)

DISCUSSION: In a study of nine patients (median age 78 years, range 62-92) treated with a constant oral dosage of digoxin (0.125-0.25 mg daily), trimethoprim (200 mg twice daily) increased serum digoxin concentrations by 22% during concurrent therapy (p < 0.05).(3) In a single dose study of 6 healthy subjects (median age 29 years, range 24-31) treated with trimethoprim and digoxin (1 mg intravenous), trimethoprim (200 mg twice daily) administration did not affect total body clearance of digoxin. The renal clearance of digoxin decreased by 17% (p < 0.05) and the extrarenal clearance of digoxin increased by 14%.(3) In a retrospective, population-based cohort study of 47,961 patients receiving digoxin (median age 80 years, range 74-86) and initiated on trimethoprim-sulfamethoxazole (TMP-SMX) (n=10,273) or amoxicillin (n=37,688), the 30-day risk of a hospital encounter with digoxin toxicity was nearly 6 times higher in older adults who were prescribed TMP-SMX versus amoxicillin, although the absolute risk difference was low (0.4%). Of 10,273 patients co-prescribed digoxin and TMP-SMX, 492 (5%) had evidence of a digoxin dose reduction when the prescription for TMP-SMX was started. A hospital encounter with digoxin toxicity occurred in 49/10,273 (0.48%) patients treated with TMP-SMX versus 32/37,688 (0.08%) in those treated with amoxicillin (weighted risk ratio, 5.71 (95% confidence interval, 3.9 to 10.24)).(4)

Digoxin/Vemurafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Vemurafenib may increase the absorption of digoxin by inhibiting P-glycoprotein.(1)

CLINICAL EFFECTS: Concurrent vemurafenib may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Avoid concurrent use of vemurafenib with digoxin. If concurrent use is unavoidable, consider dose reduction of digoxin. Monitor patients receiving concurrent therapy with digoxin and vemurafenib(1) for symptoms of toxicity, including anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

DISCUSSION: In vitro studies suggest that vemurafenib is a substrate and an inhibitor of P-glycoprotein. (1) In a study in 26 cancer patients, administration of vemurafenib (960 mg twice daily) for 22 days increased digoxin AUC by 1.8 fold (90%CI:1.6, 2.0) and Cmax by 1.5-fold (90%CI:1.3, 1.7) after concomitant administration of a single dose of digoxin (0.25 mg).

Digoxin/Verapamil; Mibefradil

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Verapamil may reduce the clearance of digoxin and may displace digoxin from its tissue binding sites.

CLINICAL EFFECTS: May observe increased digoxin toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal or hepatic function, low heart rate, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor serum digoxin levels and observe the patient for symptoms of digitalis toxicity. Upon adding verapamil, digoxin dosages should first be decreased in anticipation of an interaction, then adjusted accordingly. The dosage of oral digoxin may need to be decreased by 30-50%, or the frequency of administration may be reduced. For IV or IM digoxin, the dosage may need to be decreased by 15-30%, or the dosing frequency may be reduced. Concurrent therapy in patients with low heart rates may unmask sick sinus syndrome. Consider therapy with an agent which has not been shown to interact with digoxin.

DISCUSSION: Serum digoxin concentrations are increased 50% to 70% during concurrent therapy of oral digoxin and verapamil. The increased concentrations occur within seven days of initiation of verapamil. The clinical and toxic effects of digoxin have been increased. The manufacturer of mibefradil states that concurrent use of mibefradil and digoxin in patients with low heart rates may result in the unmasking of sick sinus syndrome. Concomitant administration of verapamil and oral digoxin increased the digoxin serum concentration by 50-75%.(15) Concurrent use of verapamil with IV or IM digoxin increased digoxin area-under-curve (AUC) by 24%.(16)

Digoxin/Vimseltinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Vimseltinib may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of vimseltinib may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before initiating concomitant use with vimseltinib and continue monitoring serum digoxin concentrations as recommended in the prescribing information for digoxin.(1-2) The manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations.(2) The manufacturer of vimseltinib recommends avoiding concomitant use with P-gp substrates.(1)

DISCUSSION: In a clinical model, vimseltinib (30 mg twice weekly) increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dabigatran (a P-gp substrate) by 2- to 3-fold. Dabigatran Cmax and AUC are predicted to increase up to 1.3-fold if administered 4 hours after administration of vimseltinib 30 mg twice weekly.(1)

Oral Digoxin/Oral Rolapitant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Rolapitant may increase the absorption of digoxin by inhibiting P-glycoprotein.(1)

CLINICAL EFFECTS: Concurrent us of rolapitant may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Avoid concurrent use if possible. If concurrent use cannot be avoided, monitor patients for increased digoxin levels.(1) Monitor patients receiving concurrent therapy for symptoms of digoxin toxicity, including anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

DISCUSSION: A single dose of rolapitant was found to increase the maximum concentration (Cmax) and area-under-curve (AUC) of digoxin (0.5 mg single dose) by 70% and 30%, respectively.(1)

Selected P-Glycoprotein (P-Gp) Substrates/Lorlatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lorlatinib is an inducer of the P-glycoprotein (P-gp) system. The absorption of P-gp substrates with a narrow therapeutic index may be decreased.(1)

CLINICAL EFFECTS: Concurrent use of lorlatinib with narrow therapeutic index P-gp substrates may result in decreased levels and effectiveness of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lorlatinib states that the concurrent use of narrow therapeutic index P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the dosage of the narrow therapeutic index P-gp substrate should be increased according to the substrate prescribing information.(1)

DISCUSSION: In a study, lorlatinib 100 mg daily for 15 days decreased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose fexofenadine 60 mg (a P-gp substrate) by 67% and 63%, respectively.(1) Selected narrow therapeutic index P-gp substrates include: digoxin, everolimus, pazopanib, sirolimus, and topotecan.(1,2)

Selected P-Glycoprotein (P-Gp) Substrates/Venetoclax

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Venetoclax is an inhibitor of the P-glycoprotein (P-gp) system and may increase the absorption of P-gp substrates.(1)

CLINICAL EFFECTS: Concurrent use of venetoclax with P-gp substrates may result in elevated levels and toxicities of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of venetoclax states that the concurrent use of P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the P-gp substrate should be taken at least 6 hours before venetoclax.(1) If concurrent therapy with afatinib is unavoidable and not tolerated, the US manufacturer of afatinib states that the afatinib dose should be reduced by 10 mg. Resume the previous dose of afatinib if venetoclax is discontinued.(2) The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant when coadministered with P-gp inhibitors. The initial dose of ubrogepant should not exceed 50 mg. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(8)

DISCUSSION: In vitro data suggests venetoclax is a P-gp inhibitor at therapeutic doses in the gut.(1) Administration of a single venetoclax 100 mg dose with digoxin increased the maximum concentration (Cmax) and area-under-the-curve of digoxin by 35% and 9%, respectively.(1) Selected P-gp substrates linked to this monograph include: afatinib, aliskiren, betrixaban, bilastine, cyclosporine, dabigatran, digoxin, edoxaban, everolimus, loperamide, sirolimus, talazoparib, topotecan, and ubrogepant.(1-9)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Digitalis Glycosides, Oral/Cholestyramine; Colestipol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Digitalis glycosides bind to cholestyramine and colestipol in the gastrointestinal tract reducing digitalis absorption and enterohepatic recirculation.

CLINICAL EFFECTS: Reduced therapeutic response to digitalis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration times of the two drugs by at least two hours, or more if possible. Adjust the digitalis dose as needed based on serum drug levels and patient response. The dosage of digoxin may need to be increased by 20% to 40%.

DISCUSSION: Documentation supports routine monitoring of this interaction. Serum concentrations may increase when the cholesterol lowering resin is discontinued. Because of the longer half-life of digitoxin over that of digoxin, the extent of the interaction may be more profound in digitoxin.

Digitalis Glycosides/Hydantoins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Phenytoin may inhibit the absorption of the digitalis glycosides by inducing P-glycoprotein.

CLINICAL EFFECTS: Concurrent or recent use of hydantoins may result in decreased levels of digitalis glycosides and possible decreased clinical effectiveness.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Digitalis glycoside levels should be monitored in patients receiving concurrent therapy or when concurrent therapy is discontinued. The dosage of digoxin may need to be increased by 20% to 40% when therapy is initiated. Hydantoins have been used to treat digitalis-induced arrhythmias.

DISCUSSION: Two studies have documented that concurrent administration of phenytoin and digoxin result in decreased digoxin levels and half-life. With appropriate safeguards, phenytoin does appear to be a useful adjunct in the management of digitalis-induced supraventricular arrhythmias.

Digitalis Glycosides/Kaluretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Potassium-losing diuretics may result in potassium depletion which can predispose patients to digitalis toxicity.

CLINICAL EFFECTS: May observe increased arrhythmias, resulting from an increase in the cardiac response to digitalis. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor serum potassium status and give potassium replacements as needed.

DISCUSSION: This interaction is well documented. Most patients taking diuretics do not develop significant potassium depletion if they are on low doses of diuretics and have adequate potassium intake.

Digitalis Glycosides/Rifamycins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifamycins may inhibit the absorption of digitalis glycosides by inducing P-glycoprotein.(1-2)

CLINICAL EFFECTS: Concurrent or recent use of rifamycins may result in decreased levels and effectiveness of digitalis glycosides.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor digoxin levels if a rifamycin is initiated or discontinued. The dosage of digoxin may need to be increased by 20% to 40%.(2)

DISCUSSION: In a study in 18 healthy volunteers, rifampin (300 mg BID for 7 days) decreased the maximum concentration (Cmax), 3-hour area-under-curve (AUC), and 24-hour AUC by 38.5%, 30.4%, and 24.6%, respectively.(1) Case reports also document decreased digoxin(3-5) and digitoxin(6-7) levels with rifampin.

Digoxin, Oral/Acarbose

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Acarbose may alter the absorption of digoxin.(1)

CLINICAL EFFECTS: Concurrent use of acarbose with digoxin may result in decreased levels and effectiveness of digoxin.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor digoxin levels if acarbose is initiated or discontinued. The dosage of digoxin may need to be increased by 20% to 40%.(2)

DISCUSSION: In a randomized cross-over study in healthy subjects, the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of digoxin (0.5 mg) was significantly lower when digoxin was administered 30 minutes after a single dose of acarbose (200 mg) or 30 minutes after the tenth dose of acarbose (100 mg TID) when compared to the administration of digoxin alone.(1) In a randomized cross-over study in healthy subjects, there were no effects on digoxin AUC when a single dose of digoxin (0.75 mg) was administered 60 minutes after acarbose (50 mg TID for 8 days). Digoxin Cmax increased 28%.(3) There are several case reports of digoxin levels decreasing to subtherapeutic levels following the addition of acarbose to therapy.(4-6)

Digoxin, Oral/Aminoglycosides, Oral

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aminoglycosides appears to inhibit gastrointestinal absorption of digoxin but the precise mechanism is unknown.

CLINICAL EFFECTS: Therapeutic effects of digoxin may be decreased. However, in a minority of patients (10%) gut flora inactivates digoxin. In these patients, due to an aminoglycoside-induced reduction in GI bacteria, serum digoxin concentrations may be increased. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: None Determined.

PATIENT MANAGEMENT: If both drugs are administered, monitor serum digoxin levels when initiating, discontinuing or changing the dose of the aminoglycoside. Measure serum digoxin concentrations before initiating gentamicin. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. (3)

DISCUSSION: Separating the administration times of digoxin and the aminoglycoside is not likely to prevent this interaction. Digoxin levels were found to be decreased when neomycin was taken 3 or 6 hours before digoxin. Additionally, serum digoxin concentrations may increase when the aminoglycoside is stopped. Concomitant administration of gentamicin and digoxin caused an increase in digoxin serum concentration of 129-212%. (3)

Digoxin, Oral/Antineoplastics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Decreased gastrointestinal digoxin absorption.

CLINICAL EFFECTS: The pharmacologic effects of digoxin may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum digoxin concentrations and observe the patient for a decrease in pharmacologic activity. Adjust the dose of digoxin accordingly. Substituting digitoxin or digoxin capsules for digoxin tablets may circumvent this interaction.

DISCUSSION: There are a number of factors affecting the outcome of this interaction. The effects of antineoplastic therapy on the gastrointestinal absorption of digoxin have only been studied with certain chemotherapeutic agents or regimens (e.g., bleomycin, carmustine, cyclophosphamide, cytarabine, doxorubicin, methotrexate, procarbazine, vincristine). The interaction appears to occur with the administration of oral digoxin tablets as opposed to digoxin capsules. The gastrointestinal absorption of digitoxin does not seem to be altered by antineoplastic therapy.

Digoxin/Boceprevir; Ritonavir; Telaprevir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Boceprevir(1), ritonavir, and telaprevir(2) inhibit the P-glycoprotein (P-gp) system, which may increase digoxin levels.

CLINICAL EFFECTS: Concurrent use of boceprevir, ritonavir, or telaprevir may result in elevated levels and toxicity from digoxin. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: When initiating digoxin in patients maintained on boceprevir, ritonavir, or telaprevir, use the lowest dose possible.(1,2) Monitor patients receiving concurrent therapy for elevated digoxin levels and adjust the dose accordingly.(1,2) The manufacturer of digoxin states to reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency.(3)

DISCUSSION: In a study in healthy subjects, boceprevir (800 mg TID for 61 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of digoxin (0.25 mg) by 18% and 19%, respectively.(1) In a study of 12 healthy subjects, ritonavir (200 mg twice daily for 14 days) increased the AUC of digoxin (0.4 mg orally) by 29%.(4) In another study of 12 healthy subjects, ritonavir (300 mg twice daily for 11 days) increased the AUC of digoxin (0.5 mg IV) by 86%.(3-5) In a study in healthy subjects, telaprevir (750 mg every 8 hours for 11 days) increased the Cmax and AUC of a single dose of digoxin (2 mg) by 50% and 85%, respectively.(2,6)

Digoxin/Conivaptan

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Conivaptan may inhibit the metabolism of digoxin via P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of conivaptan and digoxin may result in an increased concentration of digoxin, which may lead to increased clinical effects and toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.(1)

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Dosage of digoxin may need to be altered based on the individual patient response. Monitor for signs and symptoms of digoxin toxicity and adjust dose accordingly.(1) The manufacturer of digoxin recommends reducing digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency of digoxin.(2)

DISCUSSION: Conivaptan is a P-gp inhibitor. Digoxin is a P-glycoprotein substrate. Coadministration of conivaptan (80 mg/day) and digoxin (0.5 mg) resulted in a 30% decrease in the clearance, 79% increase in the maximum concentration (Cmax), and a 43% increase in the area under the curve (AUC) of digoxin.(1)

Digoxin/Daclatasvir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but daclatasvir may inhibit the transport of digoxin by p-glycoprotein.

CLINICAL EFFECTS: Concurrent use of daclatasvir may result in increased digoxin levels and signs of digoxin toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin levels in patients receiving concurrent therapy with daclatasvir. If patient is already receiving daclatasvir and initiating digoxin, initiate treatment using the lowest appropriate digoxin dosage and adjust digoxin doses as necessary. If the patient is already receiving digoxin prior to initiating daclatasvir, reduce digoxin dosage by approximately 15-30% or by modifying the dosing frequency.(1)

DISCUSSION: In a study, concomitant administration of digoxin (0.125 mg once daily) and daclatasvir (60 mg once daily) increased digoxin's minimum concentration (Cmin) and area under the curve (AUC) by 65% and 27%.

Digoxin/Eliglustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Digoxin is a substrate for P-glycoprotein (P-gp). P-gp in the gastrointestinal tract limits systemic absorption of digoxin. Eliglustat inhibition of P-gp may lead to increased absorption of digoxin.(1)

CLINICAL EFFECTS: Concurrent eliglustat may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, heart block (first, second or third-degree) or other arrhythmias, visual disturbances, confusion, weakness, malaise, headache, anxiety, depression, delirium, disorientation or hallucinations.(2)

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.(2)

PATIENT MANAGEMENT: Measure serum digoxin concentrations before starting eliglustat. Reduce digoxin dose by 30% and continue monitoring.(1) Counsel patients to assure they are aware of signs or symptoms of digoxin toxicity such as nausea, vomiting, persistent diarrhea, confusion, weakness, or visual disturbances as these could be signs that the digoxin dose may need to be lowered.

DISCUSSION: Multiple doses of eliglustat at higher than presently recommended doses - 127 mg twice daily in CYP2D6 extensive or intermediate metabolizers, or 84 mg twice daily in CYP2D6 poor metabolizers, increased systemic exposure to digoxin. The mean digoxin maximum concentration (Cmax) increased 1.7 fold and area-under-curve (AUC) increased 1.5 fold.(1)

Digoxin/Ezogabine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The N-acetyl metabolite of ezogabine (NAMR) is a P-glycoprotein (P-gp) inhibitor and may inhibit P-gp mediated renal elimination of digoxin.(1)

CLINICAL EFFECTS: Concurrent use of ezogabine may lead to elevated digoxin levels and risk for toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.(2)

PREDISPOSING FACTORS: Based upon in vitro studies (1), risk for clinically significant inhibition of digoxin is greater at ezogabine total daily doses greater than or equal to 900 mg per day. Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: For digoxin patients newly started on ezogabine, evaluate prior digoxin measurements then monitor and adjust dose accordingly.(3) As low ezogabine doses may have less effect on digoxin levels, monitoring should continue until a stable ezogabine maintenance dose has been achieved.(1) When initiating digoxin in patients maintained on ezogabine, lower than expected digoxin doses may be required. Monitor digoxin levels as recommended.(2)

DISCUSSION: Based upon manufacturer sponsored in vitro testing, NAMR may reduce P-gp mediated transport activity for digoxin by approximately 30 to 50 %.(1)

Digoxin/Flibanserin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Flibanserin may increase the absorption of digoxin by inhibiting P-glycoprotein.(1)

CLINICAL EFFECTS: Concurrent flibanserin may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Closely monitor digoxin concentration and adjust dose as required to assure levels are in the therapeutic range.(1) Counsel patients receiving concurrent therapy to assure they get digoxin levels checked and are aware of symptoms of digoxin toxicity, including anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

DISCUSSION: In a study in 24 healthy men and women, administration of flibanserin 100 mg daily for 5 days followed by a single dose of digoxin, increased digoxin AUC by 2.0-fold and Cmax by 1.5-fold compared to digoxin alone.(1)

Digoxin/Fostamatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fostamatinib may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of fostamatinib may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before and during the administration of fostamatinib. The manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations.(2)

DISCUSSION: A 100 mg twice daily dose of fostamatinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin (0.25 mg once daily, sensitive P-gp substrate) by 37% and 70%, respectively.(1) In a clinical study, subjects received oral digoxin (loading dose of 0.25 mg twice daily on day 1 and 0.25 mg once daily on days 2 to 8) followed by oral digoxin (0.25 mg once daily) with oral fostamatinib (100 mg twice daily) on days 9 to 15. Concurrent use with fostamatinib increased the Cmax and AUC of digoxin by 1.7-fold and 1.27-fold, respectively.(3)

Digoxin/Ibuprofen; Indomethacin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism of this interaction is unknown, but it may involve decreased digoxin renal excretion.

CLINICAL EFFECTS: Increased levels of digoxin which may result in digoxin toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Digoxin levels should be monitored and patients should be monitored for signs of digoxin toxicity during concurrent therapy. The dosage of digoxin may need to be decreased by 15-30% or the frequency of administration may be reduced.

DISCUSSION: Although the documentation for this interaction is conflicting, caution is warranted. One study in 12 patients reported that serum digoxin levels were significantly increased (mean 59%) after concurrent administration of ibuprofen (1600 to 1800 mg/day) for seven days. However, there was no significant difference in digoxin levels after 28 days of concomitant therapy. In another study in eight patients, there was no significant change in digoxin serum concentration during concurrent administration of ibuprofen. Indomethacin-induced digoxin toxicity in three premature infants has been reported in one study. In another study, administration of indomethacin to 11 preterm infants who received intravenous digoxin followed by oral maintenance doses of digoxin resulted in a significant increase of digoxin serum concentration by 40.6% with a significant decrease in urine output by 47.7%. The digoxin half-life increased 125.5%. This study recommended decreasing the digoxin dosage by 50% when indomethacin is added to digoxin therapy in preterm infants until further assessments of urine output and digoxin levels are obtained. There are two case reports of digoxin toxicity in neonates following the addition of indomethacin to therapy. Administration of indomethacin to ten patients maintained on digoxin resulted in a 39.7% increase in digoxin concentrations. In contrast, the concurrent administration of indomethacin and digoxin in six healthy adults did not result in a significant pharmacokinetic or pharmacodynamic interaction. However, indomethacin did tend to elevate serum digoxin levels, strengthen the digoxin-induced decrease in ECG parameters and heart rate, and reduce the positive inotropic action of digoxin. In another study involving six healthy adults, the administration of indomethacin for three days followed by a single infusion of digoxin (750 mcg) did not affect any pharmacokinetic or pharmacodynamic parameters of digoxin.

Digoxin/Isavuconazonium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Isavuconazonium inhibits the P-glycoprotein (P-gp) system, which may increase digoxin levels.(1)

CLINICAL EFFECTS: Concurrent use of isavuconazonium may result in elevated levels and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin levels when initiating and discontinuing isavuconazonium. The dosage of digoxin may need to be adjusted.(1) Instruct patients to report symptoms of digoxin toxicity such as anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

DISCUSSION: Isavuconazonium increased the maximum concentration (Cmax) and area-under-curve (AUC) of digoxin (0.5 mg) by approximately 1.25-fold.(1)

Digoxin/Lapatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lapatinib may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of lapatinib may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before and during the administration of lapatinib. If digoxin serum concentration is greater than 1.2 ng/ml, reduce the dosage of digoxin by one-half during concurrent therapy.(1) The manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 30-50% or by modifying the dosing frequency to reduce digoxin concentrations.(2)

DISCUSSION: Concurrent lapatinib increased the area-under-curve (AUC) of oral digoxin by 2.8-fold.(1) Concurrent lapatinib administration increased digoxin AUC 180%. (2)

Digoxin/Mavorixafor

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Mavorixafor may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of mavorixafor may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: The manufacturer of mavorixafor recommends monitoring digoxin concentrations before initiation of mavorixafor. Monitor digoxin concentrations during concurrent use with mavorixafor as recommended by the digoxin labeling.(1) The manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations.(2)

DISCUSSION: In a study in healthy subjects, concomitant use of a single oral dose of 0.25 mg of digoxin with mavorixafor dosed to steady state (400 mg/day) increased the digoxin maximum concentration (Cmax) by 1.5-fold and the area-under-curve (AUC) by 1.6-fold.(1)

Digoxin/Metoclopramide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Metoclopramide stimulates the smooth muscle in the gastrointestinal tract to increase peristalsis. This action may reduce the time digoxin is at the absorption site, causing less drug to be absorbed since digoxin absorption is dissolution rate-limited.(1-3) Metoclopramide may alter digoxin levels by increasing digoxin biliary excretion.(4)

CLINICAL EFFECTS: Concurrent use of metoclopramide with digoxin may result in decreased levels and effectiveness of digoxin.(5-7)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration time of metoclopramide and digoxin by as much time as possible. Monitor digoxin levels if metoclopramide is initiated or discontinued. The dosage of digoxin may need to be increased by 20% to 40%.

DISCUSSION: Steady-state serum digoxin concentrations were reduced by approximately one-third in a group of elderly female patients receiving metoclopramide. When metoclopramide was discontinued, digoxin concentrations returned to previous levels.(8) In a study, 6 healthy subjects received digoxin (0.25 mg twice daily) for for 1 week alone and during concurrent metoclopramide (10 mg 3 times daily). Metoclopramide decreased digoxin maximum concentration (Cmax) and AUC by 27% and 19%, respectively. Metoclopramide prolonged time to reach Cmax (Tmax) by 35%.(9) In a study involving 16 healthy subjects who received digoxin (two 0.25 mg tablets), a single dose of metoclopramide reduced digoxin's area-under-curve (AUC) and cumulative urinary digoxin excretion as compared to digoxin alone. However, metoclopramide did not affect the same parameters for the soft gelatin capsule form of digoxin (two 0.2 mg capsules). Metoclopramide reduced digoxin Tmax for both dosage forms.(10) In a study in 10 healthy subjects, a single dose of metoclopramide (10 mg) given 30 minutes before a single dose of digoxin (two standard Lanoxin 0.25 mg tablets) decreased digoxin urinary excretion by 8%.(11)

Digoxin/Mirabegron

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Mirabegron may inhibit the metabolism of digoxin via P-glycoprotein.(1)

CLINICAL EFFECTS: Concurrent use of mirabegron and digoxin may result in an increased concentration of digoxin, which may lead to increased clinical effects and toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Dosage of digoxin may need to be altered based on the individual patient response. Monitor for signs and symptoms of digoxin toxicity and adjust dose accordingly. The manufacturer of mirabegron recommends initiating the lowest dose of digoxin in combination with mirabegron.(1) The manufacturer of digoxin recommends reducing digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency of digoxin. Monitor serum digoxin concentrations before initiation of mirabegron and monitor levels closely during concurrent therapy.(2)

DISCUSSION: When given in combination, 100 mg mirabegron increased digoxin maximum concentration (Cmax) by 29% and area-under curve (AUC) by 27%.(1)

Digoxin/Osimertinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Osimertinib may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of osimertinib may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before and during the administration of osimertinib. The manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations.(2)

DISCUSSION: Osimertinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of fexofenadine (a P-gp substrate) by 56% and 76% after a single dose of osimertinib, respectively, and by 27% and 25% at steady-state of osimertinib, respectively.(1)

Digoxin/P-Glycoprotein (P-Gp) Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of digoxin at the levels of intestinal absorption, renal tubular secretion, and biliary-intestinal secretion.(1)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels and toxicities of digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before initiating concomitant use with P-gp inhibitors and continue monitoring serum digoxin concentrations as recommended in the prescribing information for digoxin.(1) When digoxin levels are expected to be increased by over 50%, the manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 30-50% or by modifying the dosing frequency to reduce digoxin concentrations.(1) When digoxin levels are expected to be increased by less than 50%, the manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Digoxin is a known substrate of P-gp. Inhibitors of P-gp may increase toxicity of digoxin.(1) In a clinical study, elacestrant increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.1-fold and 1.3-fold, respectively.(3,4) In another clinical study, imlunestrant increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.4-fold and 1.6-fold, respectively.(5) In another clinical study, maribavir increased the AUC and Cmax of digoxin by 1.2-fold and 1.25-fold, respectively.(6) Inhibitors of P-gp linked to this monograph include: abrocitinib, aumolertinib, capmatinib, daraxonrasib, elacestrant, enzalutamide, imlunestrant, maribavir, selpercatinib, sparsentan, sotorasib, vepdegestrant, and vibegron.(2-8)

Digoxin/Pacritinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Pacritinib may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of Pacritinib may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before initiating concomitant use with pacritinib and continue monitoring serum digoxin concentrations as recommended in the prescribing information for digoxin.(1-2) The manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations.(2)

DISCUSSION: Pacritinib (200 mg twice daily at steady state) increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of digoxin (0.25 mg) by 29% and 15%, respectively.(1)

Digoxin/Penicillamine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Serum digoxin concentrations may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum digoxin concentrations and observe the patient for a decrease in pharmacologic activity when concurrent treatment with penicillamine is started or stopped. Adjust the dose of digoxin accordingly. The dosage of digoxin may need to be increased by 20% to 40%.

DISCUSSION: Penicillamine administration to adults or children has been shown to decrease serum concentrations. The decrease occurred whether digoxin was given orally or intravenously.

Digoxin/Pirtobrutinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Pirtobrutinib may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of pirtobrutinib may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before and during the administration of pirtobrutinib. The manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations.(2)

DISCUSSION: A single 200 mg dose of pirtobrutinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin (sensitive P-gp substrate) by 17% and 51%, respectively. Multiple doses of pirtobrutinib (200 mg daily) further increased the AUC and Cmax of digoxin (sensitive P-gp substrate) up to 35% and 55%, respectively.(1)

Digoxin/Quinine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Reduced clearance of digoxin and possible displacement of digoxin from its tissue binding sites.

CLINICAL EFFECTS: May observe increased digoxin toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal and/or hepatic function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor serum digoxin levels and observe the patient for signs and symptoms of digoxin toxicity. The dosage of digoxin may need to be decreased by 15-30% or the frequency of administration may be reduced.(6) Consider therapy with an agent which has not been shown to interact with digoxin.

DISCUSSION: This interaction is well documented. Concomitant administration of digoxin and quinine resulted in a 33% increase in digoxin area-under-the-curve (AUC).(6)

Digoxin/Ranolazine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ranolazine may increase the absorption of digoxin by inhibiting P-glycoprotein.(1,2)

CLINICAL EFFECTS: Concurrent ranolazine may result in elevated levels of and toxicity from digoxin.(1,2) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with digoxin and ranolazine. The dosage of digoxin may need to be adjusted by 30% to 50% or the frequency of administration may need to be reduced.(1-3)

DISCUSSION: In healthy subjects, ranolazine (1000 mg twice daily) increased plasma levels of digoxin (0.125 mg daily) by 1.5-fold.(1,2) In healthy subjects, digoxin (0.125 mg daily) had no effect on ranolazine levels.(1) Concomitant administration of ranolazine with digoxin increased the digoxin serum concentration 50%.(3)

Digoxin/Selected Antacids; Kaolin; Sucralfate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The aluminum or magnesium salts may bind digoxin in the gastrointestinal tract, preventing the absorption of digoxin.

CLINICAL EFFECTS: Concurrent administration may result in decreased digoxin concentrations and possible decreased clinical effectiveness of digoxin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with digoxin and aluminum and/or magnesium hydroxide, magnesium trisilicate, or sucralfate should be monitored for signs of decreased effects of digoxin. Digoxin concentrations should be monitored. The administration of digoxin and aluminum and/or magnesium hydroxide or magnesium trisilicate should be separated by at least one to two hours. The administration of digoxin and sucralfate should be separated by at least two hours. The separation of administration times may not be effective in all patients. The dosage of digoxin may need to be increased by 20% to 40% or the antacid or sucralfate may need to be discontinued. Some vitamin preparations may contain sufficient quantities of magnesium salts with antacid properties to interact as well.

DISCUSSION: Sucralfate was shown to decrease the mean digoxin area-under-curve (AUC) by 19% in a study in 12 healthy males. This difference was not seen when digoxin and sucralfate administration was separated by two hours.(1) In a case report, a patient developed intermittent pressure-like chest pain, shortness of breath, and a generalized feeling of fatigue during concurrent administration of digoxin and sucralfate, despite sucralfate administration being separated from digoxin administration by two hours.(2) The simultaneous administration of oral antacids containing magnesium trisilicate, magnesium hydroxide, and aluminum hydroxide or kaolin with digoxin tablets has been shown to decrease the gastrointestinal absorption of digoxin.(3-7) There is some evidence that digoxin capsules may not be affected;(5) however, additional information is needed.

Digoxin/Selected Calcium Channel Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Calcium channel blockers may inhibit the renal clearance of digoxin through an unknown mechanism.

CLINICAL EFFECTS: Plasma digoxin concentrations may be elevated. In addition, the negative chronotropic effects of digoxin and bepridil are additive, resulting in a cumulative decrease in heart rate. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor serum digoxin levels and observe the patient for symptoms of digoxin toxicity. Upon adding a calcium channel blocker, digoxin should first be decreased in anticipation of interaction, then adjust the dosage accordingly. The dosage of digoxin may need to be decreased by 15-50% or the frequency of administration may be reduced.

DISCUSSION: The effect of bepridil on steady-state serum digoxin levels was studied in a randomized, double-blind investigation. Concurrent administration of bepridil and digoxin produced a 34% increase in serum digoxin levels compared to administration of digoxin alone. Concomitant administration of both drugs was associated with additive negative chronotropic effects. Information on the effects of diltiazem on digoxin concentrations are conflicting. Several studies have reported that concurrent use of digoxin and diltiazem led to an increased steady state digoxin level as well as an increased digoxin area-under-curve (AUC) and decreased renal clearance, and reduced volume of distribution. However, one of these studies reported no significant change in digoxin half-life, peak concentration (Cmax), time to Cmax (Tmax), or volume of distribution, and seven other studies reported no effect of diltiazem on serum digoxin concentrations or renal digoxin clearance. Concomitant isradipine administration significantly decreased (by 9%) the the digoxin volume of distribution and increased (by 25%) digoxin Cmax; however, the digoxin steady state serum concentration, AUC, and renal clearance were not affected. In patients with congestive heart failure on digoxin therapy, the addition of felodipine resulted in a significant increase in digoxin Cmax attained following oral administration. This increase was most notable in patients with high felodipine serum concentrations. Digoxin trough levels and six hour post-dose levels were unaffected; as were digoxin AUC measurements. There is one case report of an interaction between nifedipine and digoxin; however, a study in 28 patients found no effect of nifedipine on digoxin. A study in ten subjects showed that nisoldipine increased digoxin levels by 15%. Information on the effects of nicardipine on digoxin kinetics is conflicting. One study in twenty patients showed no effect of nicardipine on digoxin. One study in ten subjects showed a significant increase in digoxin levels: however, this was seen in only one subject. Concurrent nitrendipine has been shown to increase digoxin serum levels by 57% and digoxin AUC by 15%. Concurrent diltiazem has been shown to increase digoxin serum concentration by 20%. Concurrent nifedipine has been shown to increase digoxin serum concentration by 45%.

Digoxin/Selected Hepatitis C Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ledipasvir,(1) ombitasvir-paritaprevir-ritonavir,(2,3) velpatasvir(4,5), and glecaprevir-pibrentasvir (8) inhibit intestinal P-glycoprotein (P-gp) transport, which may increase digoxin bioavailability. Glecaprevir-pibrentasvir also inhibits OATP1B3.

CLINICAL EFFECTS: Concurrent use of ledipasvir,(1) or ombitasvir-paritaprevir-ritonavir,(2,3) or velpatasvir,(4,5) or glecaprevir-pibrentasvir may result in elevated levels and toxicity from digoxin. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with ledipasvir for elevated digoxin levels and adjust the dose accordingly.(1) The manufacturer of ombitasvir-paritaprevir-ritonavir recommends a digoxin dose reduction of 30-50% with follow-up digoxin monitoring in patients not also receiving concomitant dasabuvir therapy.(2) In contrast, monitoring but no automatic dose adjustment is recommended in patients receiving ombitasvir-paritaprevir-ritonavir with dasabuvir.(2,3) During concomitant therapy, the manufacturer of sofosbuvir-velpatasvir recommends digoxin therapeutic concentration monitoring and digoxin dose adjustment based upon digoxin prescribing information modifications for concentration increases less than 50%.(4) During concomitant therapy, the manufacturer of sofosbuvir-velpatasvir-voxilaprevir recommends digoxin therapeutic concentration monitoring and digoxin dose adjustment based upon digoxin prescribing information modifications for concentration increases with unclear magnitude.(5) The manufacture of glecaprevir-pibrentasvir recommends a digoxin dose reduction of 50% or modification of the dosing frequency with follow-up digoxin monitoring in patients.(8)

DISCUSSION: In an interaction study, the combination of ombitasvir-paritaprevir-ritonavir increased exposure (area-under-curve, AUC) to a single dose of digoxin by 36% (range: 21 - 54%).(2) In a second evaluation, the combination of ombitasvir-paritaprevir-ritonavir and dasabuvir with digoxin increased digoxin 16% (range: 9 - 23%).(6) In an interaction study in 21 subjects, velpatasvir (100 mg) increased the Cmax and AUC of digoxin (0.25 mg single dose) by 88% and 34%, respectively.(4,5) Concomitant administration of ritonavir and digoxin increased the digoxin AUC 86%.(7) In an interaction study in 12 subjects, glecaprevir-pibrentasvir (400/120 mg daily) increased the Cmax and AUC of digoxin (0.5 mg single dose) by 72% and 48%, respectively.(8)

Digoxin/Selected Hmg-Coa Reductase Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but may involve competitive inhibition of P-glycoproteins.(1)

CLINICAL EFFECTS: Concurrent use of digoxin and a HMG-CoA reductase inhibitor may result in rhabdomyolysis.(1) Concurrent use of atorvastatin(2) or simvastatin(3) may result in increased levels of digoxin. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity. The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with digoxin and a HMG-CoA reductase inhibitor should be closely monitored for rhabdomyolysis and instructed to report any symptoms of myopathy.(1) Patients receiving concurrent atorvastatin(2) or simvastatin(3) should be monitored for elevated digoxin levels and instructed to report any symptoms of digoxin toxicity. The dosage of digoxin may need to be decreased by 15-30% or the frequency of administration may be reduced.(4)

DISCUSSION: A retrospective review examined all reports of HMG-CoA reductase inhibitor-induced rhabdomyolysis submitted to the Food and Drug Administration (FDA) between November, 1997 and March, 2000. There were 601 unique cases of rhabdomyolysis, with 26 cases involving concurrent use of digoxin. There were 5 reports involving concurrent atorvastatin/digoxin, 7 reports with cerivastatin/digoxin, 1 report with fluvastatin/digoxin, 2 with lovastatin/digoxin, 2 with pravastatin/digoxin, and 9 with simvastatin/digoxin.(5) Concurrent use of atorvastatin (80 mg daily for 14 days) with digoxin (0.25mg daily for 20 days) increased digoxin maximum concentration (Cmax) and area-under-curve (AUC) by 20% and 15%, respectively.(2) In a study in 18 subjects, concurrent fluvastatin had no effect on digoxin AUC but digoxin Cmax increased 11%.(6) Concurrent use of lovastatin had no effect on digoxin levels.(7) In a study in 18 subjects, concurrent pravastatin had no effect on digoxin levels.(8) Concurrent use of rosuvastatin had no effect on digoxin levels.(9) Concurrent simvastatin slightly increased the concentration of a single dose of digoxin by less than 0.3 ng/ml.(3)

Digoxin/Spironolactone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Spironolactone may decrease the renal clearance of digoxin. Spironolactone may also interfere with some digoxin assays.

CLINICAL EFFECTS: Concurrent spironolactone may result in elevated levels of and toxicity from digoxin. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias. Spironolactone may also interfere with some digoxin assays, resulting in falsely elevated levels.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Concurrent administration of spironolactone and digoxin should be closely monitored, and potassium and digoxin concentrations should be measured frequently. Patients should be monitored for changes in therapeutic effects. The dosage of digoxin may need to be decreased by 15-30% or the frequency of administration may be reduced.(8)

DISCUSSION: Simultaneous administration of spironolactone and digoxin has been shown to decrease in digoxin's volume of distribution, plasma clearance, and renal clearance, with corresponding increases in the plasma digoxin concentration. Although the influence of spironolactone on digoxin's pharmacodynamic effects has not been as extensively evaluated as its pharmacokinetic effects, in two studies the inotropic action of digoxin was reduced during spironolactone administration as measured by preejection period index. However, one study reported that in patients for whom potassium depletion may lead to digoxin toxicity, a potassium-sparing diuretic may safely be used to reduce potassium excretion and thereby reduce the risk of arrhythmias. Spironolactone has been reported to interfere with some digoxin assays. Concomitant administration of spironolactone and digoxin increased the digoxin serum concentration 25%. (8)

Digoxin/St. John's Wort

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: St. John's wort may induce P-glycoprotein, which mediates the intestinal absorption, distribution, and renal excretion of digoxin.(1)

CLINICAL EFFECTS: The concurrent administration of digoxin and St. John's wort may result in decreased levels and clinical effects of digoxin.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with digoxin and St. John's wort should be monitored for decreased levels and clinical effects of digoxin. The dosage of digoxin may need to be adjusted if St. John's wort is added to or removed from concurrent therapy with digoxin. The dosage of digoxin may need to be increased by 20% to 40%.

DISCUSSION: A single-blind study in 25 subjects compared the concurrent administration of digoxin (0.25 mg daily) with hypericum (300 mg dried hypericum extract) to the administration of digoxin with placebo. Administration of a single dose of hypericum had no effect on digoxin pharmacokinetics. After 7 and 10 days of concurrent administration, digoxin trough values decreased by 19% and 33%, respectively, when compared to the placebo group. Digoxin area-under-curve (AUC) decreased 33% after 10 days of concurrent administration. Within the hypericum group, digoxin maximum concentration (Cmax) and AUC decreased 26% and 28%, respectively, following 10 days of concurrent administration.(1) St. John's wort is a common name for the flowering plant Hypericum perforatum. Other common names include klamath weed, amber touch-and-heal, goatweed, rosin rose, and millepertuis.

Digoxin/Tucatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tucatinib may increase the absorption of digoxin by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of tucatinib may result in elevated levels of and toxicity from digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before and during the administration of tucatinib. If digoxin serum concentration is greater than 1.2 ng/ml, reduce the dosage of digoxin by one-half during concurrent therapy.(1) The manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 30-50% or by modifying the dosing frequency to reduce digoxin concentrations.(2)

DISCUSSION: Concurrent tucatinib (300 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of oral digoxin by 1.5-fold and 2.4-fold, respectively.(1)

*Ventricular fibrillation.

*Known hypersensitivity to digoxin or other digitalis preparations.

• Ventricular fibrillation

• Acute myocardial infarction
• Amyloid heart muscle disease
• Atrioventricular block
• Chronic kidney disease stage 2 (mild) GFR 60-89 ml/min
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Constrictive pericarditis
• Cor pulmonale
• Digitalis toxicity
• Hypercalcemia
• Hypertrophic cardiomyopathy
• Hypokalemia
• Hypomagnesemia
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Myocarditis
• Restrictive cardiomyopathy
• Sick sinus syndrome
• Sinus bradycardia
• Wolff-parkinson-white pattern

• Myxedema

Overall, adverse effects have been reported in 5-20% of patients; 15-20% of these reported adverse effects were considered serious. Cardiac toxicity accounted for about 50% of these reactions, followed by GI disturbances for about 25%, and CNS and other toxicities for 25%.

Less Frequent

• Sinus bradycardia

Rare or Very Rare

• Abnormal ECG
• Allergic dermatitis
• Anorexia
• Atrioventricular block
• Delirium
• Diarrhea
• Digitalis toxicity
• Heart block
• Intestinal ischemic necrosis
• Skin rash
• Tachyarrhythmia
• Thrombocytopenic disorder
• Ventricular fibrillation
• Ventricular premature beats
• Ventricular tachycardia
• Visual halos

More Frequent

• Gynecomastia

Less Frequent

• Nausea

Rare or Very Rare

• Accidental fall
• Acute abdominal pain
• Acute cognitive impairment
• Anticholinergic toxicity
• Blurred vision
• Depression
• Dizziness
• General weakness
• Hallucinations
• Headache disorder
• Indifference
• Maculopapular rash
• Symptoms of anxiety
• Vomiting

No enhanced messaging available.

Safety and efficacy of digoxin in controlling ventricular rate have not been established in pediatric patients with atrial fibrillation.

The manufacturer states that safety and efficacy of digoxin in pediatric patients with heart failure have not been established in adequate and well-controlled studies; however, improvements in hemodynamics and clinical manifestations have been reported in pediatric patients with heart failure of various etiologies in the published literature.

Neonates exhibit considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the drug, and dosage must be reduced and individualized according to maturity. The adverse effect profile of digoxin differs in infants and children, particularly in regard to initial signs of toxicity. Cardiac arrhythmias, including sinus bradycardia, usually occur earliest and most frequently. In children, any arrhythmia can occur. Therefore, any arrhythmia or alteration in cardiac conduction in a child should be considered a sign of toxicity.

Available data from retrospective clinical studies, case reports, and clinical experience over several decades have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal and fetal effects with digoxin. However, the untreated underlying maternal condition (e.g., heart failure, atrial fibrillation) may increase the risk of adverse pregnancy outcomes. Animal reproduction studies have not been conducted with the drug.

Heart failure during pregnancy increases the risk of preterm birth. Additionally, atrial fibrillation increases the risk of delivering a low-birth-weight infant. Heart disease or atrial fibrillation may worsen with pregnancy and can lead to maternal or fetal death.

Dosage requirements for digoxin may increase during pregnancy and decrease during the postpartum period; serum digoxin concentrations should be monitored during pregnancy and the postpartum period.

Because digoxin crosses the placenta and is found in amniotic fluid, neonates should be monitored for signs and symptoms of digoxin toxicity (e.g., vomiting, cardiac arrhythmias).

Because the risk of arrhythmias can increase during labor and delivery, patients should receive continuous monitoring.

Although digoxin is distributed into human milk, the quantities present (up to 4% of the neonatal maintenance dosage) are unlikely to be clinically important. The effects of digoxin on the breast-fed infant or on milk production are not known.

Dosage of digoxin should be selected carefully in geriatric patients since they are more likely to have impaired renal function. Lower dosages (125 mcg (0.125 mg) daily or every other day) are recommended for the management of heart failure in geriatric patients >70 years of age.

Most clinical experience with digoxin has been in the geriatric patient population, and has not identified any differences in clinical efficacy or adverse effects between geriatric patients and younger adults. However, digoxin is primarily excreted by the kidneys; therefore, the risk of toxic reactions may be increased in patients with compromised renal function. Geriatric patients may also exhibit a smaller volume of distribution due to age-related decreases in lean muscle mass. Because of the greater likelihood of compromised renal function in geriatric patients, care should be taken with dosage selection based on renal function. Additionally, it may be useful to monitor renal function during therapy in geriatric patients.