7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Treatment with digoxin: Initial dosing, monitoring, and dose modification : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA : Brian Olshansky, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 16, 2022. INTRODUCTION Cardiac glycosides have important positive inotropic, neurohormonal, and electrophysiologic actions, which are the basis for its use in two clinical situations: heart failure due to systolic dysfunction, and in certain supraventricular tachyarrhythmias. The ability of digoxin to reduce sympathetic activation has also been recognized. For maximal early benefits in treating tachyarrhythmias, digoxin requires loading doses, which can be administered intravenously or orally. While two cardiac glycosides (digoxin and digitoxin) were previously used, digitoxin has not been widely available since the 1980s. As digoxin is now the only cardiac glycoside available in most countries, the method of initiating therapy with digoxin for patients with atrial fibrillation is presented here. Recommendations regarding the use of digoxin in the management of heart failure or arrhythmias are discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) INITIATION OF THERAPY The electrolyte and renal status of each patient should be ascertained prior to initiating treatment and periodically thereafter. Hypokalemia or hypomagnesemia, for example, may https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 1/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate promote the development of digoxin-induced arrhythmias, while impaired renal function may result in higher than anticipated serum drug levels. (See 'Dose adjustments' below.) The initiation of digoxin therapy has been divided into rapid and slow digitalization followed by the maintenance digoxin dose, and the proposed regimens vary considerably. The following principles should be viewed as a general guide to the use of digoxin for its inotropic or electrophysiologic effects, which must be modified according to clinical circumstances. Patients receiving digoxin for ventricular rate control in atrial fibrillation or flutter will usually require more rapid loading than those treated with digoxin for heart failure, in whom a loading dose is typically not required. The use of digoxin primarily for heart failure is discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Slow digoxin loading Slow oral digitalization, generally preferred for most patients, can be achieved by starting a maintenance dose of 0.125 to 0.25 mg daily. A steady state will be achieved after five cycles of the drug half-life (T1/2 ), which is approximately 7 to 10 days in the average subject. Rapid digoxin loading Rapid intravenous and oral digitalization can be used to control the ventricular response in atrial fibrillation and flutter. However, other drugs may be more effective and/or have a more rapid onset of action on the ventricular response in these arrhythmias; therefore, rapid digitalization is rarely needed unless alternative drugs are contraindicated or have not been effective. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Control of ventricular rate in atrial flutter", section on 'Rate control with drugs'.) The total loading dose with digoxin varies from patient to patient but is usually between 0.75 to 1.5 mg with intravenous administration and 1 to 1.5 mg with oral administration. (See 'Dose adjustment in kidney disease' below and 'Patients with low body weight' below.) Intravenous loading For ventricular rate control in atrial fibrillation and flutter, the most rapid means of digitalization is the intravenous route. An initial intravenous dose of 0.25 to 0.5 mg of digoxin is given over several minutes, followed by 0.25 mg every 6 hours for a total loading dose of 0.75 to 1.5 mg (10 to 12 mcg/kg lean body weight) (calculator 1 and calculator 2). Intravenous digoxin begins to act in 15 to 30 minutes with a peak effect in 1 to 5 hours. Oral loading Rapid oral digitalization can be accomplished by giving 0.5 mg initially followed by 0.25 mg every six hours for a total loading dose of 0.75 to 1.5 mg. https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 2/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Loading dose adjustments Patients who are hypokalemic, hypomagnesemic, hypercalcemic, hypoxic, or with hypothyroidism are more sensitive to the effects of digoxin. If these issues persist at the time of digoxin loading, an initial loading dose in the lower range (eg, 0.75 mg or less) should be considered. Digoxin distributes widely to skeletal muscle, cardiac, and other lean tissue and has a large volume of distribution (ie, 4 to 7 L/kg) in normal subjects, which is decreased in patients who are older, have low skeletal muscle mass, or severe renal impairment. Digoxin serum concentrations relative to the administered loading dose may be proportionally increased among persons with low muscle mass and/or renal impairment, and a reduced loading dose should be considered. Renal impairment The digoxin loading dose should be reduced by approximately one-third to one-half (or more) in the setting of severe chronic renal insufficiency [1-3]. For most patients with chronic renal insufficiency not on dialysis, the reduced loading dose may be supplemented after six hours if clinical response is inadequate, in absence of toxicity. For patients with stage 5 chronic kidney disease (glomerular filtration rate [GFR] <15 mL/minute), or for those on hemodialysis, chronic ambulatory peritoneal dialysis, or continuous renal replacement therapy, alternative agents (eg, beta blockers or nondihydropyridine calcium channel blockers) may be preferred for heart rate control; however, if digoxin will be used, a reduced loading dose of 3 to 5 mcg/kg (0.25 to 0.375 mg) is recommended, followed by a maintenance dose of 0.0625 mg every 48 hours. (See 'Dose adjustment in kidney disease' below.) Lean body weight In general, it is reasonable to select an initial loading dose in the lower range (ie, 0.75 to 1 mg) for patients of low to average lean body weight (eg, 45 to 70 kg) and in the upper part of the dose range (ie, 1 to 1.5 mg) for patients of average to above average lean body weight (eg, 71 to 90 kg) (calculator 1 and calculator 2). Patients with low body weight Patients with body weight of less than 45 kg should receive 50 percent of the normal loading dose. Patients who are obese Compared with normal weight subjects, neither volume of distribution nor clearance of digoxin are consistently altered by changes in body composition associated with obesity [4-6]. Therefore, normal (non-weight based) loading doses should be used. However, if a weight based dose is used, it should be based upon estimated lean body weight (calculator 1 and calculator 2). Maintenance digoxin dosing For most patients, the maintenance dose of digoxin will be between 0.125 mg and 0.25 mg daily. The daily maintenance dose will vary depending on the indication for digoxin therapy, with patients receiving digoxin for heart failure often requiring lower doses than those who are taking digoxin for ventricular rate control. Additionally, the https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 3/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate maintenance dose is affected by renal function, body weight, and the presence or absence of other medications which are known to alter the metabolism of digoxin [7]. (See 'Dose adjustments' below.) Ventricular rate control For patients taking digoxin for ventricular rate control in the setting of atrial arrhythmias, the typical maintenance dose is between 0.125 and 0.25 mg daily. In contrast to digoxin use for heart failure, there is no particular serum digoxin level which is targeted, as the medication should be adjusted to maintain optimal ventricular rate control. However, serum digoxin levels higher than 1 ng/mL (1.3 nmol/L) should be avoided to reduce the risk of digoxin toxicity. Heart failure The approach to maintenance digoxin dosing in patients with heart failure is discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Dose adjustments Bioavailability is between 70 and 80 percent for conventional digoxin tablets and between 75 and 85 percent for digoxin elixir, and the T1/2 of digoxin ranges from 33 to 50 hours when renal function is normal. Unlike certain other drugs (eg, furosemide), the bioavailability of the oral dose forms of digoxin does not appear to be affected by heart failure. Dose adjustments of digoxin are necessary in patients with renal dysfunction, patients with low body weight, and with the concomitant use of certain medications. The effect of digoxin in patients with heart failure and the need for dose adjustments in such patients are discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Dose adjustment in kidney disease Approximately 70 to 80 percent of digoxin is eliminated unchanged in the urine, leading to prolongation of the half-life in patients with renal insufficiency. Renal insufficiency also decreases the extravascular volume of distribution of digoxin, another effect that can elevate plasma drug levels. As a result, both the initial loading dose and the maintenance dose must be reduced in patients with underlying kidney disease. In end-stage kidney disease, for example, the loading dose should be one-half to two-thirds normal. The adjustment of the digoxin loading dose is discussed above. (See 'Renal impairment' above.) The initial maintenance dose (for congestive heart failure) adjusted for ideal body weight and renal function (except stage 5 chronic kidney disease or receiving renal replacement therapy) is presented in the table ( table 1). (See 'Patients requiring hemodialysis' below https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 4/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Patients requiring hemodialysis For patients on intermittent hemodialysis (IHD), chronic ambulatory peritoneal dialysis (CAPD), and continuous renal replacement therapy (CRRT), the dosing recommendation is 0.0625 mg every 48 hours, or approximately 10 to 25 percent of the usual dose for patients with normal renal function given every 48 hours [8,9]. No supplemental dose for dialysis is required because renal replacement therapies (eg, IHD, CAPD, CRRT) remove only insignificant amounts of digoxin from the body due to digoxin's large volume of distribution. Serum digoxin concentrations should be monitored. The same dose recommendation is used for stage 5 chronic kidney disease patients (GFR <15 mL/minute) who are not currently receiving dialysis. (See 'Monitoring serum digoxin' below.) Dose adjustment with hepatic disease Hepatic disease has little influence on digoxin metabolism or clearance; therefore, no dose adjustment is necessary. Dose adjustment with concomitant medications There are a number of important drug interactions with digoxin. Some examples are provided below; in addition, specific interactions of digoxin with medications may be determined using the Lexicomp drug interactions program included within UpToDate (Lexicomp drug interactions). Inhibitors of P-glycoprotein efflux transporters (eg, amiodarone, dronedarone, propafenone, quinidine, and verapamil) can increase serum digoxin levels. With concurrent dronedarone administration, for example, the digoxin dose should be reduced by one-half if digoxin cannot be discontinued [10-12] (see "Clinical uses of dronedarone", section on 'Metabolism and drug interactions'). A list of medicines that inhibit P-glycoprotein is provided separately ( table 2). Inducers of P-glycoprotein (eg, phenytoin, rifampin, etc), on the other hand, can decrease serum digoxin levels. A list of medicines that induce P-glycoprotein is provided separately ( table 2). Cholestyramine and antacids can decrease the intestinal absorption of digoxin by 20 to 35 percent, necessitating an increase in the daily dose. To avoid these interactions, digoxin should be dosed one hour before or two to three hours after the administration of the antacids or cholestyramine. Bupropion, an antidepressant that is also frequently prescribed to aid in smoking cessation, can decrease digoxin levels by 60 percent; monitor serum digoxin levels and clinical status [13-15]. https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 5/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Diuretics may increase digitalis toxicity as a result of a decrease in the glomerular filtration rate and the development of electrolyte abnormalities, especially hypokalemia. Tetracycline and erythromycin can interfere with the sequential hydrolysis pathway of digoxin metabolism (which begins in the stomach and is responsible for less than 15 percent of the metabolism in most patients but which can be significantly more active in a minority of patients). As such, these drugs increase digoxin levels in approximately 10 percent of patients in whom this pathway is a significant component of the drug's metabolism. High doses of biotin (vitamin B7) can increase the measured serum concentration of digoxin by as much as 0.25 ng/mL (0.3 nmol/L) when measured using the luminescent oxygen channeling immunoassay (LOCI) [16]. This does not represent a true increase in serum digoxin concentration but an interaction between biotin and the measurement assay, resulting in the artificial appearance of increased serum digoxin levels. Digoxin in pregnancy Digoxin crosses the placenta and has been used for both fetal and maternal cardiac indications without report of fetal harm or teratogenicity [17]. As such, there is no contraindication for using digoxin during pregnancy or during lactation. Digoxin in patients with amyloidosis The inotropic effects of digoxin are not generally beneficial in patients with amyloidosis. Moreover, because digoxin binds avidly to amyloid fibrils, patients with amyloidosis who take digoxin may be at an increased risk of digoxin toxicity [18]. Additionally, as a result of the binding of digoxin to myocardial amyloid fibrils, cardiac digoxin concentration may be higher than serum digoxin concentration, leading to toxicity in the setting of "therapeutic" serum digoxin levels. However, in a patient with atrial fibrillation with a rapid ventricular response, careful digoxin administration is usually safe and effective for reducing the ventricular rate [19]. (See "Amyloid cardiomyopathy: Treatment and prognosis".) MONITORING SERUM DIGOXIN Monitoring Given the relatively narrow therapeutic window of digoxin, with substantial overlap between so-called therapeutic and toxic levels, patients taking digoxin require monitoring of the serum digoxin concentration, with the "optimal" level varying with the clinical setting. Monitoring the serum digoxin level is particularly important in persons with chronic renal dysfunction or rapidly changing renal function, as significantly decreased renal function can lead to accumulation of digoxin and its metabolites and predispose to digoxin toxicity. Additionally, patients with electrolyte disturbances, particularly hypokalemia and hypomagnesemia, which may be related to diuretic therapy or other medications, are at https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 6/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate increased risk for digoxin-associated arrhythmias and should undergo monitoring of the serum digoxin level until serum potassium level and magnesium concentration return to the normal range [20]. (See 'Dose adjustments' above and "Cardiac arrhythmias due to digoxin toxicity", section on 'Plasma digoxin levels associated with toxicity'.) Monitoring the serum digoxin concentration is most important when digoxin is used in the treatment of heart failure with systolic dysfunction, whereas levels are only checked when used in patients with atrial fibrillation if toxicity is suspected. Blood samples should be obtained at least 6 hours, but optimally 12 hours, after administration of digoxin to ensure completion of distribution from the blood to the tissues. In patients with advanced kidney disease or who are on hemodialysis, the digoxin level should be checked at least 12 to 24 hours after the prior dose. Serum digoxin concentrations measured prior to these times may be falsely elevated. Adjusting the digoxin dose Assuming that the digoxin level was drawn at the correct time, at steady state, and under conditions of stable renal function, there is a linear relationship between digoxin dose and serum concentration. As an example, a steady state concentration is measured and returns at 1.6 ng/mL (2.05 nmol/L) in a patient taking a daily maintenance dose (for this example, 0.25 mg daily). Assuming the desired serum concentration is 0.8 ng/mL (1.0 nmol/L), the dose should be reduced by 50 percent (to 0.125 mg daily in this example). The same linear relationship is true for patients whose serum concentration is lower than desired in whom a dose increase is needed. Heart failure The monitoring of serum digoxin levels in patients with heart failure is discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Atrial fibrillation Digoxin is generally less effective for rate control of atrial fibrillation (AF) than beta blockers or calcium channel blockers, is less likely to control the ventricular rate during exercise (when vagal tone is low and sympathetic tone is high), has little or no ability to terminate the arrhythmia, and often does not slow the heart rate with recurrent AF. Thus, patients frequently require the addition of a beta blocker or calcium channel blocker for optimal rate control. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) When digoxin is used strictly for ventricular rate control in AF, serum digoxin levels should be monitored periodically, although the drug concentration often does not correlate with ventricular rate control and is used more as a guide to toxicity than to therapy. Junctional escape beats (as detected by the equality of all the longest observed R-R intervals on the electrocardiogram) are common when digitalis has successfully slowed the ventricular rate. https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 7/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Giving more digoxin in this setting will increase the degree of AV nodal block and produce periods of regular junctional rhythm. The change from single junctional escapes to periodic junctional rhythm usually signifies the development of digoxin toxicity. (See "Cardiac arrhythmias due to digoxin toxicity", section on 'Junctional rhythm, tachycardia, and bradycardia'.) Relation to digoxin toxicity Digoxin-related cardiac arrhythmias and extracardiac symptoms can occur when the serum digoxin concentration is in the therapeutic or even subtherapeutic range; as a result, the presence of digoxin toxicity or excess is often a clinical diagnosis irrespective of circulating levels (unless of course the value is zero). (See "Cardiac arrhythmias due to digoxin toxicity".) SUMMARY AND RECOMMENDATIONS Indications Cardiac glycosides such as digoxin have positive inotropic, neurohormonal, and electrophysiologic actions which are the basis for its use in two clinical situations: heart failure with reduced ejection fraction, and in certain supraventricular tachyarrhythmias, primarily atrial fibrillation (AF) and atrial flutter. (See 'Introduction' above.) Slow digoxin loading This approach is preferred for most patients. A slow digoxin load is achieved by starting a maintenance oral dose of 0.125 to 0.25 mg daily, which results in a steady state serum level of drug in approximately 7 to 10 days in the average subject. (See 'Slow digoxin loading' above.) Rapid digoxin loading This approach can be used to control the ventricular response in AF and atrial flutter (see 'Rapid digoxin loading' above): Initial intravenous doses of 0.25 to 0.5 mg of digoxin are given over several minutes, followed by 0.25 mg every six hours for a total dose of 0.75 to 1.5 mg with appropriate dosing adjustments for kidney disease and the concomitant use of certain medications. (See 'Dose adjustment in kidney disease' above and 'Dose adjustment with concomitant medications' above.) Rapid oral digoxin loading can be accomplished by giving 0.5 mg initially followed by 0.25 mg every six hours for a total loading dose of 0.75 to 1.5 mg. Monitoring considerations Narrow therapeutic window Given the relatively narrow therapeutic window of digoxin and substantial overlap between therapeutic and toxic levels, patients taking https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 8/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate digoxin require monitoring of the serum digoxin concentration. The optimal level of digoxin varies according to clinical setting. Monitoring the serum digoxin level is particularly important in persons with chronic kidney disease, rapidly changing kidney function, or electrolyte disturbances (eg, hypokalemia, hypomagnesemia). (See 'Monitoring serum digoxin' above.) Dose adjustments Assuming that the digoxin level was drawn at the correct time, at steady state, and under conditions of stable kidney function, there is a linear relationship between digoxin dose and serum concentration that should be followed for any necessary dose adjustments. (See 'Adjusting the digoxin dose' above.) When digoxin is used strictly for ventricular rate control in AF, serum digoxin levels should be monitored periodically, although the drug concentration often does not correlate with ventricular rate control and is used more as a guide to toxicity than to therapy. (See 'Atrial fibrillation' above.) Patients with kidney disease Approximately 70 to 80 percent of digoxin is eliminated in the urine; thus, the half-life of digoxin is prolonged in patients with kidney disease. Kidney disease also decreases the extravascular volume of distribution of digoxin, another effect that can elevate plasma drug levels. As a result, we reduce both the initial loading dose and the maintenance dose in patients with kidney disease ( table 1). (See 'Dose adjustment in kidney disease' above.) Patients with concomitant medications Quinidine, verapamil, and amiodarone (medications that inhibit P-glycoprotein efflux transporters) can increase serum digoxin levels, thereby requiring a reduction in the daily digoxin dose ( table 2). Inducers of P- glycoprotein (eg, phenytoin, rifampin, etc), on the other hand, can decrease serum digoxin levels. Cholestyramine and antacids can decrease the intestinal absorption of digoxin. This necessitates spacing of the doses or an increase in the daily digoxin dose. Specific interactions of digoxin with other medications may be determined using the Lexicomp drug interactions program (Lexicomp drug interactions) included within UpToDate. (See 'Dose adjustment with concomitant medications' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 9/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate The UpToDate editorial staff acknowledges Lynne Sylvia, PharmD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Aronson JK. Clinical pharmacokinetics of cardiac glycosides in patients with renal dysfunction. Clin Pharmacokinet 1983; 8:155. 2. Cheng JW, Charland SL, Shaw LM, et al. Is the volume of distribution of digoxin reduced in patients with renal dysfunction? Determining digoxin pharmacokinetics by fluorescence polarization immunoassay. Pharmacotherapy 1997; 17:584. 3. Matzke GR, Frye RF. Drug administration in patients with renal insufficiency. Minimising renal and extrarenal toxicity. Drug Saf 1997; 16:205. 4. Ewy GA, Groves BM, Ball MF, et al. Digoxin metabolism in obesity. Circulation 1971; 44:810. 5. Abernethy DR, Greenblatt DJ. Drug disposition in obese humans. An update. Clin Pharmacokinet 1986; 11:199. 6. Erstad BL. Dosing of medications in morbidly obese patients in the intensive care unit setting. Intensive Care Med 2004; 30:18. 7. DiDomenico RJ, Bress AP, Na-Thalang K, et al. Use of a simplified nomogram to individualize digoxin dosing versus standard dosing practices in patients with heart failure. Pharmacotherapy 2014; 34:1121. 8. Caroline Ashley and Aileen Dunleavy. Digoxin. In: The Renal Drug Handbook: The Ultimate P rescribing Guide for Renal Practitioners, 5th edition, CRC Press, Boca Raton 2018. p.330. 9. Mooradian AD. Digitalis. An update of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations. Clin Pharmacokinet 1988; 15:165. 10. Vallakati A, Chandra PA, Pednekar M, et al. Dronedarone-induced digoxin toxicity: new drug, new interactions. Am J Ther 2013; 20:e717. 11. Dorian P. Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation. J Cardiovasc Pharmacol Ther 2010; 15:15S. 12. Dronedarone tablet. US Food & Drug Administration (FDA) approved product information. R evised March, 2014. US National Library of Medicine. Available online at http://www.dailyme d.nlm.nih.gov/. 13. Kirby BJ, Collier AC, Kharasch ED, et al. Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 10/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate rifampin, or bupropion. Drug Metab Dispos 2012; 40:610. 14. He J, Yu Y, Prasad B, et al. Mechanism of an unusual, but clinically significant, digoxin- bupropion drug interaction. Biopharm Drug Dispos 2014; 35:253. 15. Bupropion US prescribing information (revision May 10, 2017) https://www.accessdata.fda.g ov/drugsatfda_docs/label/2017/020711s045s046s047lbl.pdf. 16. Rodriguez JJ, Acosta F, Bourgeois L, Dasgupta A. Biotin at High Concentration Interferes with the LOCI Digoxin Assay but the PETINIA Phenytoin Assay Is Not Affected. Ann Clin Lab Sci 2018; 48:164. 17. Hauptman PJ, Kelly RA. Digitalis. Circulation 1999; 99:1265. 18. Rubinow A, Skinner M, Cohen AS. Digoxin sensitivity in amyloid cardiomyopathy. Circulation 1981; 63:1285. 19. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005; 112:2047. 20. Broeren MA, Geerdink EA, Vader HL, van den Wall Bake AW. Hypomagnesemia induced by several proton-pump inhibitors. Ann Intern Med 2009; 151:755. Topic 1051 Version 50.0 https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 11/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate GRAPHICS Initial digoxin maintenance dose for adult patients with heart failure targeting a serum concentration of 0.5 to 0.9 nmol/L Creatinine clearance (mL/minute) Digoxin oral dose per day (mg) Ideal body weight (kg)* 45 to 50 15 to 60 0.0625 >60 0.125 51 to 60 15 to 45 0.0625 46 to 110 0.125 >110 0.25 61 to 70 15 to 35 0.0625 36 to 110 0.125 >110 0.25 20 71 to 80 0.0625 21 to 80 0.125 >80 0.25 81 to 90 15 to 70 0.125 >70 0.25 This table provides initial dose recommendations based upon a nomogram tested at a single center in nondialysis patients. Dose adjustment(s) according to clinical response and serum digoxin concentration(s) at steady state (ie, after 7 to 10 days of therapy) may be necessary. NOTE: This nomogram is not for use in patients with stage 5 chronic kidney disease and/or receiving renal replacement therapy . Dosing recommendations are provided separately in the clinical topic discussion. Alternative renal dose adjustment recommendations are available in the Lexicomp digoxin drug monograph included in UpToDate. A calculator to determine ideal body weight is available in UpToDate. A calculator to estimate creatinine clearance according to Cockcroft and Gault equation is available in UpToDate. 0.0625 mg daily dose can alternatively be given as 0.125 mg every other day. Patients with unstable renal function or stage 5 renal disease requiring renal replacement therapy, pregnant patients, and patients who were receiving medications known to significantly interact with https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 12/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate digoxin (eg, amiodarone, quinidine, verapamil, or macrolide antibiotics) were excluded from the population in which this nomogram was validated. Adapted from DiDomenico RJ, Bress AP, Na-Thalang K, et al. Use of a simpli ed nomogram to individualize digoxin dosing versus standard dosing practices in patients with heart failure. Pharmacotherapy 2014. Graphic 90157 Version 15.0 https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 13/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- containing coformulations Neratinib Lorlatinib Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- Tamoxifen* ivacaftor Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole (isavuconazonium sulfate) Verapamil Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 14/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. These classifications are based upon US FDA guidance. [1,2] Other sources may use a different classification system resulting in some agents being classified differently. Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 15/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 16/16