Digoxin

Pharmacologic Category

Antiarrhythmic Agent, Miscellaneous; Cardiac Glycoside

Dosing: Adult

Note: When changing from oral (tablets or liquid) to IV therapy, dosage may be reduced by 20% to 25%. Periodically monitor digoxin concentrations as appropriate for the condition being treated, especially if renal impairment occurs. Toxicity may occur even at therapeutic concentrations in some settings (eg, hypokalemia).

Atrial fibrillation or atrial flutter, rate control (alternative agent): Note: Some experts reserve digoxin for patients whose rate has not adequately been controlled with other agents or interventions (Ganz 2018; Giardina 2018). Additionally, digoxin is not effective for rate control during high-adrenergic states (eg, exercise); a beta-blocker is preferred. Do not use in patients with preexcitation associated with an accessory pathway, as this can lead to ventricular arrhythmias (AHA/ACC/HRS [January 2014]).

Total digitalizing dose (TDD): Initial:

IV: 0.25 to 0.5 mg over several minutes, with repeat doses of 0.25 mg every 6 hours to a maximum of 1.5 mg over 24 hours (AHA/ACC/HRS [January 2014]; Giardina 2018)

or

IV: A total of 8 to 12 mcg/kg (use lean body weight) (not to exceed 0.75 to 1.5 mg) administered by giving 50% of TDD over 5 minutes and the remaining 50% as 2 doses of 25% of TDD at 4- to 8-hour intervals after the initial dose (ACLS [Neumar 2010]).

Note: follow either of these TDD regimens with an oral maintenance regimen (Giardina 2018).

Maintenance dose: Oral: 0.125 to 0.25 mg once daily (AHA/ACC/HRS [January 2014]).

Fetal supraventricular tachyarrhythmia, sustained (maternal administration for transplacental transfer to the fetus) (off-label use): Note: These patients should be managed by a highly experienced fetal arrhythmia team. Due to decreased placental transfer, maternal administration of digoxin may be less effective when fetal hydrops is present (AHA [Donofrio 2014]; Alsaied 2017; Jaeggi 2011; Levine 2019). The lowest effective dose should be used to avoid maternal adverse events (Moatassim 2018). Prior to use, evaluate appropriateness of therapy to the mother (eg, maternal electrolytes, renal function, ECG).

Maternal dose:

Loading dose (may be given oral or IV):

IV: 1.2 to 1.5 mg over 24 hours given in divided doses every 8 hours; follow with oral maintenance regimen (AHA [Donofrio 2014]). Some experts do not recommend IV administration (Levine 2019).

Oral: 1 to 2 mg given over 24 to 48 hours in divided doses (eg, 0.5 mg followed by 0.25 mg, then 0.25 mg over the first 18 to 24 hours with subsequent additional doses as needed to achieve target levels); follow with an oral maintenance regimen (Alsaied 2017; Jaeggi 2011; Levine 2019).

Maintenance dose: Oral: 0.375 mg to 0.75 mg per day given in divided doses every 8 to 12 hours. Adjust dose to maintain a target maternal blood level between 0.7 and 2 ng/mL (AHA [Donofrio 2014]). Some experts recommend dividing into 3 times daily dosing to ensure adequate drug levels (Levine 2019).

Heart failure with reduced ejection fraction (HFrEF): Note: Some experts reserve use of digoxin for patients with persistent New York Heart Association functional class III or IV symptoms despite optimal guideline-directed medical therapy (ACCF/AHA [Yancy 2013]; Colucci 2019).

Maintenance dose (loading dose not recommended): Oral: 0.125 to 0.25 mg once daily; higher daily doses are rarely necessary. If patient is >70 years of age, has impaired renal function, or has a low lean body mass, low doses (eg, 0.125 mg daily or every other day) should be used initially (ACCF/AHA [Yancy 2013]). A dosing nomogram is also available based on lean body weight and CrCl (DiDomenico 2014).

Supraventricular tachycardia (eg, atrioventricular nodal reentrant tachycardia), rate control (alternative agent) (off-label use):

Total digitalizing dose: Initial:

Oral: 0.5 mg loading dose, with additional 0.125 to 0.25 mg doses administered at 6- to 8-hour intervals until evidence of adequate effect (maximum total dose over 24 hours: 8 to 12 mcg/kg [use lean body weight], not to exceed 0.75 to 1.5 mg) (ACC/AHA/HRS [Page 2015]; Giardina 2018).

IV: 0.25 to 0.5 mg bolus; may repeat 0.25 mg administered at 6- to 8-hour intervals until evidence of adequate effect (maximum total dose over 24 hours: 8 to 12 mcg/kg [use lean body weight], not to exceed 0.75 to 1.5 mg) (ACC/AHA/HRS [Page 2015]; Giardina 2018).

Maintenance dose: Oral: 0.125 to 0.25 mg once daily (ACC/AHA/HRS [Page 2015]).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Dose is based on assessment of lean body mass and renal function. Elderly patients with low lean body mass may experience higher digoxin concentrations due to reduced volume of distribution (Cheng 2010). Decrease dose in patients with decreased renal function (see Dosing in Renal Impairment).

Atrial fibrillation: Avoid as first-line therapy; if used, do not exceed 0.125 mg/day in patients ≥65 years (Beers Criteria [AGS 2019]).

Heart failure: If patient is >70 years of age, low doses (eg, 0.125 mg daily or every other day) should be used (ACCF/AHA [Yancy 2013]). Avoid as first-line therapy; if used, do not exceed 0.125 mg/day in patients ≥65 years (Beers Criteria [AGS 2019]).

Dosing: Renal Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Periodically monitor digoxin concentrations as appropriate for the condition being treated. Toxicity may occur even at therapeutic concentrations in some settings (eg, hypokalemia).

Altered kidney function:

Atrial fibrillation/flutter, supraventricular tachycardia:

IV, Oral:

Loading dose: Note: Use with caution and only when rapid ventricular rate control is necessary.

CrCl >15 mL/minute: No dosage adjustment necessary.

CrCl ≤15 mL/minute: Administer 50% of usual dose (Cheng 1997; Ohnhaus 1980; expert opinion).

Maintenance dose (Golightly 2013; expert opinion):

Note: Patients with low lean body weight may require lower doses. Doses of 0.0625 mg once daily may be given as 0.125 mg every other day.

CrCl ≥60 mL/minute: No dosage adjustment necessary.

CrCl 45 to <60 mL/minute: 0.0625 to 0.125 mg once daily.

CrCl 30 to <45 mL/minute: 0.0625 mg once daily.

CrCl <30 mL/minute: 0.0625 mg every 48 hours or consider alternative agent.

Heart failure:

Oral:

Hemodialysis, intermittent (thrice weekly): Not dialyzable (Mooradian 1988):

Oral, IV:

Note: Avoid use if possible; use in end-stage renal disease is associated with increased mortality (Chan 2010).

Atrial fibrillation/flutter, supraventricular tachycardia:

Loading dose: Use with caution and only when rapid ventricular rate control is necessary. Reduce to 50% of usual dose (Cheng 1997; Foote 1998; expert opinion).

Maintenance dose: 0.0625 mg every 48 hours or 3 times/week may be considered (Golightly 2013; expert opinion).

Heart failure: Maintenance dose: 0.0625 mg every 48 hours or 3 times/week may be considered (Li 2014; expert opinion).

Peritoneal dialysis: Not dialyzable (Mooradian 1988):

Oral, IV:

Note: Avoid use if possible (expert opinion).

Atrial fibrillation/flutter, supraventricular tachycardia:

Loading dose: Use with caution and only when rapid rate control is necessary. Reduce to 50% of usual dose (Foote 1998; expert opinion).

Maintenance dose: 0.0625 mg every 48 hours may be considered (Golightly 2013).

Heart failure: Maintenance dose: 0.0625 mg every 48 hours may be considered (Golightly 2013).

CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Close monitoring of response, serum drug concentrations, and adverse reactions (eg, arrhythmias) due to drug accumulation is important.

Oral, IV:

Note: Avoid use if possible (expert opinion).

Atrial fibrillation/flutter, supraventricular tachycardia:

Loading dose: Reduce to 50% of usual dose (expert opinion). Use with caution and only when rapid rate control is necessary.

Maintenance dose: 0.0625 to 0.125 mg every 48 hours may be considered (Benken 2013, Golightly 2013).

Heart failure: Maintenance dose: 0.0625 to 0.125 mg every 48 hours may be considered (Benken 2013, Golightly 2013).

PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Close monitoring of response, serum drug concentrations, and adverse reactions (eg, arrhythmias) due to drug accumulation is important.

Oral, IV:

Note: Avoid use if possible (expert opinion).

Atrial fibrillation/flutter, supraventricular tachycardia:

Loading dose: Reduce to 50% of usual dose (expert opinion). Use with caution and only when rapid rate control is necessary.

Maintenance dose: 0.0625 to 0.125 mg every 48 hours may be considered (Benken 2013; Golightly 2013).

Heart failure: Maintenance dose: 0.0625 mg every 48 hours may be considered (expert opinion).

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary.

Dosing: Pediatric

Note: Dosage must be individualized due to substantial individual variation and must take into account renal function. Doses should be based on lean body weight. When changing from oral solution to IV therapy, dosage should be reduced by 20% to 25%.

Heart failure: Injection, Oral: Infants, Children, and Adolescents: The dosage tables below list dosage recommendations for normal renal function and are based upon average patient response; lower doses are needed for patients with renal impairment.

Digitalizing dose, initial regimen (optional): Total digitalizing dose should be divided (see below); digitalizing dose (loading dose) may not be necessary; consider use if rapid titration is desired. To avoid toxicity, consider doses at lower end of the recommended range; dosage should be individualized based on patient response (eg, clinical response, serum drug levels).

Dosage Recommendations for Digitalizing DoseA (Optional)

Tachyarrhythmias, treatment: Limited data available (Escudero 2012): Injection, Oral: Infants, Children, and Adolescents:

Initial (digitalizing dose):

IV: 10 to 12 mcg/kg/dose every 8 hours for 3 doses

Oral: 13 to 17 mcg/kg/dose every 8 hours for 3 doses

Maintenance: Oral: 8 to 10 mcg/kg/day divided once or twice daily (Escudero 2012); use twice daily dosing in infants and young children (O'Sullivan 1995)

Dosing: Renal Impairment: Pediatric

Infants, Children, and Adolescents: Oral, IV:

Digitalizing (loading) dose: There are no dosage adjustments provided in the manufacturer's labeling for digitalizing dose; however, 50% to 70% of a digoxin dose is excreted unchanged in the urine. The following adjustments have been recommended in adults with end-stage renal disease (ESRD): Reduce usual dose by 50% (Aronoff 2007).

Maintenance dose:

Manufacturer's labeling: Dosage reductions and close monitoring recommended; see product labeling for CrCl-specific dosage recommendation

Alternate dosing: The following adjustments have been recommended (Aronoff 2007):

GFR >50 mL/minute/1.73 m2: No dosage adjustment necessary

GFR: 30 to 50 mL/minute/1.73 m2: Administer 75% of normal dose at normal intervals

GFR: 10 to 29 mL/minute/1.73 m2: Administer 50% of normal dose at normal intervals or administer normal dose every 36 hours

GFR: <10 mL/minute/1.73 m2: Administer 25% of normal dose at normal intervals or administer normal dose every 48 hours

Intermittent hemodialysis: Nondialyzable (0% to 5%). Administer 25% of normal dose at normal intervals or administer normal dose every 48 hours

Peritoneal dialysis (PD): Administer 25% of normal dose at normal intervals or administer normal dose every 48 hours

Continuous renal replacement therapy (CRRT): Administer 75% of normal dose at normal intervals; titrate to desired effect; monitor serum concentrations

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Creatinine Clearance by Jelliffe
• Creatinine Clearance by Sanaka
• Glomerular Filtration Rate by Abbreviated MDRD
• Glomerular Filtration Rate by Abbreviated MDRD (SI units)
• Glomerular Filtration Rate by MDRD
• Glomerular Filtration Rate by MDRD (IDMS-Traceable SCr)
• Glomerular Filtration Rate by MDRD (SI units)
• Glomerular Filtration Rate by Schwartz
• Glomerular Filtration Rate Estimate in African Americans by AASK Equation

Use: Labeled Indications

Atrial fibrillation or atrial flutter, rate control: Control of ventricular response rate in adults with chronic atrial fibrillation.

Heart failure with reduced ejection fraction (HFrEF): Treatment of mild to moderate (or stage C as recommended by the ACCF/AHA) heart failure in adults; to increase myocardial contractility in pediatric patients with heart failure

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Fetal supraventricular tachyarrhythmia, sustained (maternal administration for transplacental transfer to the fetus)Level of Evidence [C, G]

Data from retrospective studies of fetuses with tachycardia with or without hydrops suggest that digoxin via maternal administration may be beneficial for the treatment of fetal tachycardia Ref.

Based on the American Heart Association Scientific Statement for the Diagnosis and Treatment of Fetal Cardiac Disease, digoxin may be considered for the in utero management of fetal supraventricular tachycardia (SVT) or atrial flutter with hydrops or ventricular dysfunction. Digoxin may also be considered for SVT without hydrops or ventricular dysfunction if heart rate is ≥200 bpm, atrial flutter, or other rare tachycardias with an average heart rate of ≥200 bpm Ref.

Supraventricular tachycardia (eg, atrioventricular nodal reentrant tachycardia), rate controlLevel of Evidence [G]

Based on the American College of Cardiology/American Heart Association/Heart Rhythm Society guideline for the management of adult patients with supraventricular tachycardia, digoxin may be a reasonable alternative therapeutic option for the ongoing management of symptomatic SVT (eg, atrioventricular nodal reentrant tachycardia [AVNRT]) if preferred therapies fail in patients who are not candidates for, or prefer not to undergo, catheter ablation.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Arrhythmias:

AATS, “2014 AATS Guidelines for the Prevention and Management of Perioperative Atrial Fibrillation and Flutter for Thoracic Surgical Procedures,” June 2014

ACC/AHA/HRS, “Guideline for the Management of Adult Patients with Supraventricular Tachycardia” 2015

AHA/ACC/HRS, "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation," January 2019

AHA/ACC/HRS, "2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation," March 2014

Canadian Cardiovascular Society, "2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation," 2016

Coronary Artery Bypass Graft Surgery:

“2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery,” November 2011

Heart Failure:

ACCF/AHA, “2013 ACCF/AHA Guideline for the Management of Heart Failure,” June 2013

Canadian Cardiovascular Society, “2012 Heart Failure Management Guidelines Update: Focus on Acute and Chronic Heart Failure,” 2012

“HFSA 2010 Comprehensive Heart Failure Practice Guideline,” July 2010

Administration: IM

IV route preferred. If IM injection necessary, administer by deep injection followed by massage at the injection site. Inject no more than 2 mL per injection site. May cause intense pain.

Administration: IV

May be administered undiluted or diluted. Inject slowly over ≥5 minutes

Vesicant; ensure proper needle or catheter placement prior to and during administration; avoid extravasation.

Extravasation management: If extravasation occurs, stop IV administration immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity.

When used for the management of fetal tachycardia ( off-label use), IV doses are administered to the mother for transplacental transfer to the fetus (AHA [Donofrio 2014]).

Administration: Injectable Detail

pH: 6.8 to 7.2 (0.25 mg/mL undiluted solution)

Administration: Oral

When used for the management of fetal tachycardia (off-label use), oral doses are administered to the mother for transplacental transfer to the fetus (AHA [Donofrio 2014]).

Administration: Pediatric

Neonatal, Infants, Children, and Adolescents:

Oral: Administer consistently with relationship to meals; avoid concurrent administration (ie, administer digoxin 1 hour before or 2 hours after) with meals high in fiber or pectin and with drugs that decrease oral absorption of digoxin.

Oral solution: Only the calibrated manufacturer-provided dropper or a calibrated oral syringe should be used to measure the dose. For doses <0.2 mL the manufacturer-provided dropper is not accurate and should not be used; use a calibrated oral syringe.

Parenteral:

IV: May be slowly administered IV over ≥5 minutes (usually 5 to 10 minutes); avoid rapid IV infusion since this may result in systemic and coronary arteriolar vasoconstriction.

Vesicant; ensure proper needle or catheter placement prior to and during administration; avoid extravasation. If extravasation occurs, stop IV administration immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity.

IM: Not usually recommended due to local irritation, pain, and tissue damage; if necessary, administer by deep injection followed by massage at the injection site. May cause intense pain.

FETAL: IM: Administer into FETAL buttock or thigh under direct ultrasound guidance.

Vesicant/Extravasation Risk

Vesicant

Dietary Considerations

Maintain adequate amounts of potassium in diet to decrease risk of hypokalemia (hypokalemia may increase risk of digoxin toxicity).

Storage/Stability

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect elixir, injection, and tablets from light.

Preparation for Administration: Adult

IM: No dilution required.

IV: May be administered undiluted or diluted fourfold in D5W, NS, or SWFI for direct injection. Less than fourfold dilution may lead to drug precipitation.

Preparation for Administration: Pediatric

Parenteral:

IV: May be administered undiluted or diluted at least fourfold in D5W, D10W, NS, or SWFI; less than fourfold dilution may lead to drug precipitation.

IM: No dilution required.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat heart failure (weak heart).

• It is used to treat a certain type of abnormal heartbeat (atrial fibrillation).

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache

• Abdominal pain

• Injection site pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe dizziness

• Passing out

• Nausea

• Vomiting

• Severe diarrhea

• Vision changes

• Seeing halos or bright colors around lights

• Weight loss

• Lack of appetite

• Loss of strength and energy

• Black, tarry, or bloody stools

• Vomiting blood

• Confusion

• Slow heartbeat

• Fast heartbeat

• Abnormal heartbeat

• Sensing things that seem real but are not

• Behavioral changes

• Mood changes

• Enlarged breasts

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

High alert medication:

Geriatric Patients: High-Risk Medication:

International issues:

Contraindications

Hypersensitivity to digoxin, other forms of digitalis, or any component of the formulation; ventricular fibrillation

Warnings/Precautions

Concerns related to adverse effects:

• Digoxin toxicity: Signs and symptoms of digoxin toxicity include anorexia, nausea, vomiting, visual changes, and cardiac arrhythmias; toxicity is usually associated with digoxin levels >2 ng/mL, although symptoms may occur at lower levels. Patients at increased risk for digoxin toxicity include those with low body weight, advanced age, renal impairment, hypokalemia, hypercalcemia, or hypomagnesemia.

• Extravasation: IV administration: Vesicant; ensure proper needle or catheter placement prior to and during administration; avoid extravasation.

• Proarrhythmic effects: Monitor for proarrhythmic effects (especially with digoxin toxicity)

Disease-related concerns:

• Accessory bypass tract (eg, Wolff-Parkinson-White [WPW] syndrome): During an episode of atrial fibrillation or flutter in patients with an accessory bypass tract or pre-excitation syndrome, use has been associated with increased anterograde conduction down the accessory pathway leading to ventricular fibrillation; avoid use in such patients (ACLS [Neumar 2010]; AHA/ACC/HRS [January 2014]).

• Acute coronary syndrome: Use with caution in patients with an acute MI; may increase myocardial oxygen demand and lead to ischemia. During an acute coronary syndrome, digoxin administered IV may be used to slow a rapid ventricular response and improve left ventricular (LV) function in the acute treatment of atrial fibrillation associated with severe LV function and heart failure or hemodynamic instability (AHA/ACC/HRS [January 2014]).

• Atrial fibrillation: When used for rate control in patients with atrial fibrillation, monitor serum concentrations closely; may be associated with an increased risk of mortality especially when serum concentrations are not properly controlled (Vamos 2015).

• Beri beri heart disease: Patients with beri beri heart disease may fail to adequately respond to digoxin therapy; treat underlying thiamine deficiency concomitantly.

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy; toxicity may occur despite therapeutic digoxin concentrations (eg, <2 ng/mL). Hypercalcemia may increase the risk of digoxin toxicity and hypocalcemia can nullify the effects of digoxin; maintain normocalcemia.

• Heart failure: Digoxin should be considered for use only in heart failure (HF) with reduced ejection fraction (HFrEF) when symptoms remain despite guideline-directed medical therapy. It may also be considered in patients with both HF and atrial fibrillation; however, beta blockers may offer better ventricular rate control than digoxin (ACCF/AHA [Yancy 2013]). Withdrawal of digoxin in clinically stable patients with HF may lead to recurrence of HF symptoms (Packer 1993). Monitor serum concentrations closely; may be associated with an increased risk of mortality especially when serum concentrations are not properly controlled (Vamos 2015).

• Hypermetabolic states: Atrial arrhythmias associated with hypermetabolic (eg, hyperthyroidism) or hyperdynamic (hypoxia, arteriovenous shunt) states are very difficult to treat; treat underlying condition first. If digoxin is used, ensure digoxin toxicity does not occur.

• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Outflow obstruction may worsen due to the positive inotropic effects of digoxin; avoid use unless used to control ventricular response with atrial fibrillation. Digoxin is potentially harmful in the treatment of dyspnea in patients with HCM in the absence of atrial fibrillation (ACCF/AHA [Gersh 2011]).

• Myocarditis: In a murine model of viral myocarditis, digoxin in high doses was shown to be detrimental (Matsumori 1999). If used in humans, therefore, digoxin should be used with caution and only at low doses (Frishman 2007). The manufacturer recommends avoiding the use of digoxin in patients with myocarditis.

• Preserved left ventricular function: Decreased cardiac output may occur in patients with preserved left ventricular systolic function, including restrictive or hypertrophic cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale; in general, the manufacturer recommends to avoid use unless used to control ventricular response with atrial fibrillation.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment needed.

• Sinus node disease and atrioventricular (AV) block: Because digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. Digoxin may cause severe sinus bradycardia or sinoatrial block particularly in patients with preexisting sinus node disease. Avoid use in patients with second- or third-degree heart block (except in patients with a functioning artificial pacemaker) (ACCF/AHA [Yancy 2013]); incomplete AV block (eg, Stokes-Adams attacks) may progress to complete block with digoxin administration. In such patients, if treatment with digoxin is necessary, consider the insertion of a pacemaker before treatment.

• Thyroid disease: Use with caution in patients with hypothyroidism, higher digoxin concentrations may result due to significant reduction in digoxin clearance (Burk 2010). In patients with hyperthyroidism, lower digoxin concentrations may result due to an increase in renal clearance of digoxin. No significant differences in absorption were seen in either thyroid condition compared with those with normal thyroid function (Burk 2010). Note: New-onset atrial fibrillation or exacerbation of ventricular arrhythmias should prompt evaluation of thyroid status.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Infants: Newborn infants display considerable variability to their tolerance to digoxin; premature and immature infants are particularly sensitive to the effects of digoxin.

• Low body weight: Patients with decreased body weight are at an increased risk of drug-related toxicity.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007).

Other warnings/precautions:

• Elective electrical cardioversion: It is not necessary to routinely reduce or hold digoxin therapy prior to elective electrical cardioversion for atrial fibrillation; however, exclusion of digoxin toxicity (eg, clinical and ECG signs) is necessary prior to cardioversion. If signs of digoxin excess exist, withhold digoxin and delay cardioversion until toxicity subsides (AHA/ACC/HRS [January 2014]).

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Digitalis preparations (primarily digoxin) are frequently used to treat common cardiac diseases in the elderly (heart failure, atrial fibrillation). Elderly are at risk for toxicity due to age-related changes; volume of distribution is diminished significantly; half-life is increased as a result of decreased total body clearance. Additionally, elderly frequently have concomitant diseases which affect the pharmacokinetics in digitalis glycosides; hypo- and hyperthyroidism and renal function decline will affect clearance of digoxin. Exercise in elderly will reduce serum concentrations of digoxin due to increased skeletal muscle uptake. Therefore, a knowledge of the physical activity of elderly helps interpret serum assays. Must be observant for noncardiac signs of toxicity in elderly such as anorexia, vision changes (blurred), confusion, and depression. Changes in dose may be necessary with declining renal function with age; monitor closely.

Warnings: Additional Pediatric Considerations

Children are more likely to experience cardiac arrhythmia as a sign of excessive dosing. The most common are conduction disturbances or tachyarrhythmia (atrial tachycardia with or without block) and junctional tachycardia. Ventricular tachyarrhythmias are less common. In infants, sinus bradycardia may be a sign of digoxin toxicity. Any arrhythmia seen in a child on digoxin should be considered as digoxin toxicity. The gastrointestinal and central nervous system symptoms are not frequently seen in children.

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Shehab 2009).

Pregnancy Considerations

Digoxin crosses the placenta.

Available guidelines note experience with digoxin in pregnancy is extensive (ESG [Regitz-Zagrosek 2018]). Based on available data, an increased risk of adverse pregnancy outcomes has not been observed. However, untreated maternal heart failure and atrial fibrillation may increase the risk of preterm birth and low birth weight, respectively. The manufacturer recommends monitoring neonates for signs and symptoms of digoxin toxicity following in utero exposure.

Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of digoxin may be altered. Close monitoring of maternal serum digoxin is recommended (Hebert 2008; Luxford 1983; Martin-Suarez 2017); dose adjustments may be required during pregnancy and postpartum.

Heart failure and atrial fibrillation may worsen during pregnancy. Digoxin is recommended as a first-line agent for the chronic treatment of highly symptomatic supraventricular tachycardia (SVT) in pregnancy; the lowest effective dose is recommended (ACC/AHA/HRS [Page 2015]). Digoxin may be considered for long-term rate control of maternal atrial tachycardia or atrial fibrillation when preferred agents fail (ESG [Regitz-Zagrosek 2018]). Monitor for an increased risk of maternal arrhythmias during labor and delivery.

Digoxin may be considered for the in utero management of fetal SVT or atrial flutter with hydrops or ventricular dysfunction. Digoxin may also be considered for SVT without hydrops or ventricular dysfunction if heart rate is ≥200 bpm, atrial flutter, or other rare tachycardias with an average heart rate of ≥200 bpm (AHA [Donofrio 2014]).

Breast-Feeding Considerations

Digoxin is present in breast milk.

The manufacturer reports the relative infant dose (RID) of digoxin to be 1% to 7% of a weight-adjusted maternal dose or ~ 0.2% to 4% of a neonatal maintenance dose.

In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).

The RID of digoxin was calculated by the manufacturer using milk concentrations of 0.4 to 1 ng/mL, providing an estimated daily infant dose via breast milk of 0.03 to 0.16 mcg/kg/day. This milk concentration was obtained following maternal administration of digoxin 0.25 mg once daily to 13 lactating women. Higher milk concentrations (<12 ng/mL) were obtained following an IV bolus dose of 500 mcg to 1 breastfeeding woman; however, digoxin levels rapidly decreased to ~1 ng/mL ~2 hours after the injection. This study found milk concentrations declined in parallel to maternal serum concentrations following either oral or IV dosing (Reinhardt 1982). Digoxin can be detected in the serum of breastfed infants (Finley 1979).

The amount of digoxin available to the infant via breast milk is not likely to be clinically significant. The World Health Organization considers digoxin to be compatible with breastfeeding (WHO 2002).

Briggs' Drugs in Pregnancy & Lactation

• Digoxin

Adverse Reactions

Incidence not always reported.

Cardiovascular: Accelerated junctional rhythm, asystole, atrial tachycardia with or without block, AV dissociation, first-, second- (Wenckebach), or third-degree heart block, facial edema, PR prolongation, PVCs (especially bigeminy or trigeminy), ST segment depression, ventricular tachycardia or ventricular fibrillation

Central nervous system: Dizziness (6%), mental disturbances (5%), headache (4%), apathy, anxiety, confusion, delirium, depression, fever, hallucinations

Dermatologic: Rash (erythematous, maculopapular [most common], papular, scarlatiniform, vesicular or bullous), pruritus, urticaria, angioneurotic edema

Gastrointestinal: Nausea (4%), vomiting (2%), diarrhea (4%), abdominal pain, anorexia

Neuromuscular & skeletal: Weakness

Ophthalmic: Visual disturbances (blurred or yellow vision)

Respiratory: Laryngeal edema

<1%, postmarketing, and/or case reports (limited to important or life-threatening): Asymmetric chorea, gynecomastia, thrombocytopenia, palpitation, intestinal ischemia, hemorrhagic necrosis of the intestines, vaginal cornification, eosinophilia, sexual dysfunction, diaphoresis

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Digitalis Glycoside Allergy

Toxicology

• Digoxin

Metabolism/Transport Effects

Substrate of CYP3A4 (minor), P-glycoprotein/ABCB1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

5-Aminosalicylic Acid Derivatives: May decrease the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Acarbose: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy

Adenosine: Digoxin may enhance the adverse/toxic effect of Adenosine. Risk C: Monitor therapy

Aminoglycosides: May decrease the serum concentration of Cardiac Glycosides. This effect has only been demonstrated with oral aminoglycoside administration. Exceptions: Amikacin (Systemic); Arbekacin; Isepamicin; Plazomicin; Streptomycin; Tobramycin (Systemic). Risk C: Monitor therapy

Aminoquinolines (Antimalarial): May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Amiodarone: May increase the serum concentration of Cardiac Glycosides. Management: Reduce the dose of cardiac glycosides by 30% to 50% or reduce the frequency of administration when initiating concomitant amiodarone therapy. Monitor for increased serum concentrations and toxic effects of cardiac glycosides. Risk D: Consider therapy modification

Amphotericin B: May enhance the adverse/toxic effect of Cardiac Glycosides. Risk C: Monitor therapy

Anagliptin: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Anthracyclines: Cardiac Glycosides may diminish the cardiotoxic effect of Anthracyclines. Anthracyclines may decrease the serum concentration of Cardiac Glycosides. The effects of liposomal formulations may be unique from those of the free drug, as liposomal formulation have unique drug disposition and toxicity profiles, and liposomes themselves may alter digoxin absorption/distribution. Risk C: Monitor therapy

Antithyroid Agents: May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Asunaprevir: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

AtorvaSTATin: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Barnidipine: May enhance the adverse/toxic effect of Digoxin. Risk C: Monitor therapy

Benidipine: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Beta-Blockers: May enhance the bradycardic effect of Cardiac Glycosides. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Cardiac Glycosides. Exceptions: Colesevelam. Risk C: Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy

Bretylium: May enhance the adverse/toxic effect of Cardiac Glycosides. Management: Bretylium should only be used in digitalis-treated patients when other antiarrhythmic options are ineffective and when arrhythmia is not suspected to be related to digitalis toxicity. Bretylium is contraindicated in digitalis-induced arrhythmias. Risk D: Consider therapy modification

Brimonidine (Topical): May enhance the bradycardic effect of Digoxin. Risk C: Monitor therapy

BuPROPion: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the AV-blocking effect of Cardiac Glycosides. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Calcium Polystyrene Sulfonate: May enhance the adverse/toxic effect of Cardiac Glycosides. Risk C: Monitor therapy

Calcium Salts: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Canagliflozin: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Carvedilol: Digoxin may enhance the bradycardic effect of Carvedilol. Carvedilol may increase the serum concentration of Digoxin. Risk C: Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Exceptions are discussed in separate monographs. Risk D: Consider therapy modification

CloNIDine: May enhance the AV-blocking effect of Cardiac Glycosides. Sinus node dysfunction may also be enhanced. Risk C: Monitor therapy

Cobicistat: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Colchicine: Digoxin may enhance the adverse/toxic effect of Colchicine. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

CycloSPORINE (Systemic): May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Daclatasvir: May increase the serum concentration of Digoxin. Management: See full interaction monograph for details. Risk D: Consider therapy modification

Diacerein: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Disulfiram: May enhance the adverse/toxic effect of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid combination

Dronedarone: Digoxin may enhance the AV-blocking effect of Dronedarone. Digoxin may also enhance the other electrophysiologic effects of Dronedarone. Dronedarone may increase the serum concentration of Digoxin. Management: Avoid concurrent use of digoxin when possible. If concurrent use is necessary, reduce adult digoxin dose by 50%, monitor digoxin concentration closely, and increase monitoring for both clinical response to therapy and the occurrence of adverse effects. Risk D: Consider therapy modification

Edrophonium: May enhance the AV-blocking effect of Cardiac Glycosides. Risk C: Monitor therapy

Elagolix: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Elagolix, Estradiol, and Norethindrone: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Elexacaftor, Tezacaftor, and Ivacaftor: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Eliglustat: May increase the serum concentration of Digoxin. Management: In patients receiving digoxin, measure digoxin serum concentrations prior to initiating eliglustat. Preemptively reduce digoxin doses by 30% and continue monitoring following eliglustat initiation. Risk D: Consider therapy modification

EPHEDrine (Nasal): Cardiac Glycosides may enhance the arrhythmogenic effect of EPHEDrine (Nasal). Risk C: Monitor therapy

EPHEDrine (Systemic): May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Epoprostenol: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy

Etravirine: May increase the serum concentration of Digoxin. Management: Monitor serum digoxin concentrations and adjust dose as needed. In patients initiating a regimen of digoxin with etravirine, digoxin should be initiated at the lowest dose. Risk C: Monitor therapy

Fexinidazole [INT]: May increase the serum concentration of Products Containing Propylene Glycol. Risk X: Avoid combination

Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. Risk X: Avoid combination

Flecainide: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Flibanserin: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Fostamatinib: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Glecaprevir and Pibrentasvir: May increase the serum concentration of Digoxin. Management: Measure serum digoxin concentrations before initiating glecaprevir/pibrentasvir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 50% or by modifying the dosing frequency; continue monitoring during concomitant therapy. Risk D: Consider therapy modification

Glycopyrrolate (Systemic): May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Ibrutinib: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Isavuconazonium Sulfate: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Istradefylline: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Itraconazole: May increase the serum concentration of Cardiac Glycosides. Management: Consider preemptive cardiac glycoside dose adjustments with initiation / changes / discontinuation of itraconazole. Risk D: Consider therapy modification

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy

Ivacaftor: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Kaolin: May decrease the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk X: Avoid combination

Lenalidomide: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Levosulpiride: May enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, levosulpiride may diminish symptoms of cardiac glycoside-related toxicity. Risk C: Monitor therapy

Licorice: May enhance the adverse/toxic effect of Cardiac Glycosides. Risk C: Monitor therapy

Loop Diuretics: May enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of loop diuretics. Risk C: Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of Digoxin. Lumacaftor and Ivacaftor may increase the serum concentration of Digoxin. Risk C: Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Cardiac Glycosides. Exceptions: Fidaxomicin; Roxithromycin; Spiramycin. Risk C: Monitor therapy

Metaraminol: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Methotrimeprazine: Products Containing Ethanol may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, CNS depressant effects may be increased. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid combination

MetroNIDAZOLE (Systemic): May enhance the adverse/toxic effect of Products Containing Propylene Glycol. A disulfiram-like reaction may occur. Risk X: Avoid combination

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

MiFEPRIStone: May increase the serum concentration of Digoxin. Management: Measure serum digoxin concentration 1-2 weeks following mifepristone initiation, and in accordance with normal clinical practice thereafter, adjusting dose as needed. Risk C: Monitor therapy

Milnacipran: May enhance the adverse/toxic effect of Digoxin. The risk of postural hypotension and tachycardia may be increased, particularly with IV digoxin. Management: Avoid concurrent use of intravenous (IV) digoxin in patients receiving milnacipran. Use caution when using oral digoxin and milnacipran together, monitoring closely for possible postural hypotension and tachycardia. Risk D: Consider therapy modification

Mirabegron: May increase the serum concentration of Digoxin. Management: Consider using the lowest dose of digoxin when initiating concurrent mirabegron. Monitor serum digoxin concentrations closely to help guide digoxin dosing. Risk D: Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Nefazodone: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Neratinib: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Neuromuscular-Blocking Agents: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

NIFEdipine: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Octreotide: May enhance the bradycardic effect of Digoxin. Octreotide may increase the serum concentration of Digoxin. Risk C: Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of Digoxin. Management: When initiating the ombitasvir/paritaprevir/ritonavir combination product in patients taking digoxin, decrease the digoxin dose by 30% to 50% and monitor serum digoxin levels to determine further dose adjustments. Risk D: Consider therapy modification

Parathyroid Hormone: May enhance the adverse/toxic effect of Cardiac Glycosides. More specifically, Parathyroid Hormone-related hypercalcemia may predispose to digitalis toxicity. Risk C: Monitor therapy

Paricalcitol: May enhance the adverse/toxic effect of Digoxin. Risk C: Monitor therapy

PenicillAMINE: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

Polyethylene Glycol 3350: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy

Polyethylene Glycol 4000: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy

Posaconazole: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Potassium-Sparing Diuretics: May diminish the therapeutic effect of Cardiac Glycosides. In particular, the inotropic effects of digoxin appear to be diminished. Potassium-Sparing Diuretics may increase the serum concentration of Cardiac Glycosides. This particular effect may be unique to Spironolactone. Risk C: Monitor therapy

Propafenone: May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

QuiNIDine: May increase the serum concentration of Cardiac Glycosides. Management: Upon quinidine initiation, consider reducing cardiac glycoside dose by 25% to 50%, with continued monitoring of glycoside serum concentrations and clinical response until the quinidine reaches steady state (5-10 days). Risk D: Consider therapy modification

QuiNINE: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Ranolazine: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Regorafenib: May enhance the bradycardic effect of Digoxin. Risk C: Monitor therapy

Reserpine: May enhance the adverse/toxic effect of Cardiac Glycosides. Risk C: Monitor therapy

Ritonavir: May increase the serum concentration of Digoxin. Management: Reduce the digoxin dose by approximately 30% to 50%, or reduce the dosing frequency, when these agents are combined. Monitor digoxin levels closely and adjust digoxin dose as needed. Risk D: Consider therapy modification

Roxithromycin: May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Risk C: Monitor therapy

Sarecycline: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Simeprevir: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Risk D: Consider therapy modification

SITagliptin: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Sodium Polystyrene Sulfonate: May enhance the adverse/toxic effect of Digoxin. Risk C: Monitor therapy

Spironolactone: May increase the serum concentration of Digoxin. Spironolactone (and/or its metabolites) may also interfere with the assays used to determine Digoxin concentrations, falsely increasing or decreasing Digoxin concentrations. Risk C: Monitor therapy

St John's Wort: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy

Sucralfate: May decrease the serum concentration of Digoxin. Specifically, sucralfate may decrease the absorption of digoxin. Management: Administer digoxin at least 2 hours before sucralfate. Concomitant administration should be avoided. Monitor for decreased digoxin levels/effects with initiation of sucralfate therapy. Risk D: Consider therapy modification

Telmisartan: May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Tezacaftor and Ivacaftor: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of thiazide diuretics. Risk C: Monitor therapy

Thyroid Products: May decrease the serum concentration of Cardiac Glycosides. Specifically, returning to a euthyroid state from a hypothyroid state may decrease the serum concentration of cardiac glycosides. Risk C: Monitor therapy

Ticagrelor: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Tolvaptan: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Trimethoprim: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Valbenazine: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Vandetanib: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Velpatasvir: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Vemurafenib: May increase the serum concentration of Digoxin. Management: Avoid coadministration of vemurafenib and digoxin when possible. If concomitant use cannot be avoided, consider digoxin dose reduction. Risk D: Consider therapy modification

Venetoclax: May increase the serum concentration of Digoxin. Management: Avoid concomitant use of venetoclax and digoxin if possible. If combined, administer digoxin at least 6 hours before venetoclax to minimize the potential for an interaction. Risk D: Consider therapy modification

Vilazodone: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Vitamin D Analogs: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Food Interactions

Digoxin peak serum concentrations may be decreased if taken with food. Meals containing increased fiber (bran) or foods high in pectin may decrease oral absorption of digoxin.

Test Interactions

Spironolactone may interfere with digoxin radioimmunoassay.

Genes of Interest

• P-Glycoprotein

Monitoring Parameters

Heart rate and rhythm should be monitored along with periodic ECGs to assess desired effects and signs of toxicity; baseline and periodic serum creatinine. Periodically monitor serum potassium, magnesium, and calcium especially if on medications where these electrolyte disturbances can occur (eg, diuretics), or if patient has a history of hypokalemia or hypomagnesemia. Observe patients for noncardiac signs of toxicity, confusion, and depression.

When to draw serum digoxin concentrations: Digoxin serum concentrations are monitored because digoxin possesses a narrow therapeutic serum range; the therapeutic endpoint is difficult to quantify and digoxin toxicity may be life-threatening. Digoxin serum concentrations should be drawn at least 6 to 8 hours after last dose, regardless of route of administration (optimally 12 to 24 hours after a dose). Note: Serum digoxin concentrations may decrease in response to exercise due to increased skeletal muscle uptake; a period of rest (eg, ~2 hours) after exercise may be necessary prior to drawing serum digoxin concentrations.

Initiation of therapy:

If a loading dose is given: Digoxin serum concentration may be drawn within 12 to 24 hours after the initial loading dose administration. Concentrations drawn this early may confirm the relationship of digoxin plasma concentrations and response but are of little value in determining maintenance doses.

If a loading dose is not given: Digoxin serum concentration should be obtained after 3 to 5 days of therapy.

Maintenance therapy:

Trough concentrations should be followed just prior to the next dose or at a minimum of 6 to 8 hours after last dose.

Digoxin serum concentrations should be obtained within 5 to 7 days (approximate time to steady-state) after any dosage changes. Continue to obtain digoxin serum concentrations 7 to 14 days after any change in maintenance dose. Note: In patients with end-stage renal disease, it may take 15 to 20 days to reach steady-state.

Patients who are receiving electrolyte-depleting medications such as diuretics, serum potassium, magnesium, and calcium should be monitored closely.

Digoxin serum concentrations should be obtained whenever any of the following conditions occur:

Questionable patient compliance or to evaluate clinical deterioration following an initial good response

Changing renal function

Suspected digoxin toxicity

Initiation or discontinuation of therapy with drugs (eg, amiodarone, quinidine, verapamil) which potentially interact with digoxin.

Any disease changes (eg, thyroid disease)

Reference Range

Digoxin therapeutic serum concentrations:

Heart failure: 0.5 to 0.9 ng/mL (SI: 0.6 to 1.2 nmol/L) (ACCF/AHA [Yancy 2013])

Adults: 0.8 to 2 ng/mL (SI: 1.0 to 2.6 nmol/L); <0.5 ng/mL (SI: <0.6 nmol/L) probably indicates underdigitalization unless there are special circumstances. A serum concentration ≥1.2 ng/mL (SI: 1.5 nmol/L) may be associated with increased all-cause mortality in patients with atrial fibrillation (regardless of heart failure) (Lopes 2018).

Toxic: Risk increases with serum concentrations >2 ng/mL (>2.6 nmol/L), but toxicity can occur at any time and may occur at lower levels in the setting of hypokalemia, hypomagnesemia, or hypothyroidism (ACCF/AHA [Yancy 2013]).

Digoxin-like immunoreactive substance (DLIS) may cross-react with digoxin immunoassay. DLIS has been found in patients with renal and liver disease, heart failure, neonates, and pregnant women (third trimester).

Advanced Practitioners Physical Assessment/Monitoring

Assess results of laboratory tests when beginning or changing dosage, especially with IV administration. Monitor for signs of digoxin toxicity. IV: Monitor ECG continuously. Oral: Monitor apical pulse before administering any dose.

Nursing Physical Assessment/Monitoring

Monitor laboratory tests when beginning or changing dosage, especially with IV administration. IV: Monitor ECG continuously. Oral: Monitor apical pulse before administering any dose. Teach patient to report noncardiac signs of toxicity (eg, anorexia, blurred vision, "yellow" vision, confusion).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection:

Lanoxin: 0.25 mg/mL (2 mL) [contains alcohol, usp, propylene glycol]

Lanoxin Pediatric: 0.1 mg/mL (1 mL) [contains alcohol, usp, propylene glycol]

Generic: 0.25 mg/mL (2 mL)

Solution, Oral:

Generic: 0.05 mg/mL (60 mL)

Tablet, Oral:

Digitek: 125 mcg [scored; contains fd&c yellow #10 aluminum lake]

Digitek: 250 mcg [scored]

Digox: 125 mcg [scored; contains fd&c yellow #10 aluminum lake]

Digox: 250 mcg [scored]

Lanoxin: 62.5 mcg [contains corn starch, fd&c yellow #6 (sunset yellow)]

Lanoxin: 125 mcg [DSC] [contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Lanoxin: 125 mcg [scored; contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Lanoxin: 187.5 mcg, 250 mcg [DSC]

Lanoxin: 250 mcg [scored]

Generic: 125 mcg, 250 mcg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Elixir, Oral:

Toloxin: 0.05 mg/mL (115 mL) [contains alcohol, usp, fd&c yellow #10 (quinoline yellow), methylparaben, propylene glycol]

Solution, Injection:

Lanoxin: 0.25 mg/mL (2 mL) [contains alcohol, usp]

Generic: 0.05 mg/mL ([DSC]); 0.25 mg/mL (2 mL)

Tablet, Oral:

Lanoxin: 62.5 mcg [DSC] [contains fd&c yellow #6 (sunset yellow)]

Lanoxin: 125 mcg [DSC] [contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Lanoxin: 250 mcg [DSC]

Toloxin: 62.5 mcg [contains fd&c yellow #6 (sunset yellow)]

Toloxin: 125 mcg [contains fd&c yellow #10 (quinoline yellow)]

Toloxin: 250 mcg

Generic: 62.5 mcg, 125 mcg, 250 mcg

Anatomic Therapeutic Chemical (ATC) Classification

• C01AA05

Generic Available (US)

Yes

Pricing: US

Solution (Digoxin Injection)

0.25 mg/mL (per mL): $3.30 - $3.74

Solution (Digoxin Oral)

0.05 mg/mL (per mL): $2.48 - $2.80

Solution (Lanoxin Injection)

0.25 mg/mL (per mL): $65.70

Solution (Lanoxin Pediatric Injection)

0.1 mg/mL (per mL): $131.40

Tablets (Digitek Oral)

125 mcg (per each): $2.30

250 mcg (per each): $2.30

Tablets (Digox Oral)

125 mcg (per each): $2.30

250 mcg (per each): $2.30

Tablets (Digoxin Oral)

125 mcg (per each): $1.42 - $4.56

250 mcg (per each): $1.42 - $4.56

Tablets (Lanoxin Oral)

62.5 mcg (per each): $16.32

125 mcg (per each): $16.32

250 mcg (per each): $16.32

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Heart failure: Inhibition of the sodium/potassium ATPase pump in myocardial cells results in a transient increase of intracellular sodium, which in turn promotes calcium influx via the sodium-calcium exchange pump leading to increased contractility. May improve baroreflex sensitivity (Gheorghiade 1991).

Supraventricular arrhythmias: Direct suppression of the AV node conduction to increase effective refractory period and decrease conduction velocity - positive inotropic effect, enhanced vagal tone, and decreased ventricular rate to fast atrial arrhythmias. Atrial fibrillation may decrease sensitivity and increase tolerance to higher serum digoxin concentrations.

Pharmacodynamics/Kinetics

Onset of action: Heart rate control: Oral: 1 to 2 hours; IV: 5 to 60 minutes

Peak effect: Heart rate control: Oral: 2 to 8 hours; IV: 1 to 6 hours; Note: In patients with atrial fibrillation, median time to ventricular rate control in one study was 6 hours (range: 3 to 15 hours) (Siu 2009)

Duration: Adults: 3 to 4 days

Absorption: By passive nonsaturable diffusion in the upper small intestine; food may delay, but does not affect extent of absorption

Distribution:

Normal renal function: 6 to 7 L/kg

Vd: Extensive to peripheral tissues, with a distinct distribution phase which lasts 6 to 8 hours; concentrates in heart, liver, kidney, skeletal muscle, and intestines. Heart/serum concentration is 70:1. Pharmacologic effects are delayed and do not correlate well with serum concentrations during distribution phase.

Hyperthyroidism: Increased Vd

Hyperkalemia, hyponatremia: Decreased digoxin distribution to heart and muscle

Hypokalemia: Increased digoxin distribution to heart and muscles

Concomitant quinidine therapy: Decreased Vd

Chronic renal failure: 4 to 6 L/kg

Decreased sodium/potassium ATPase activity - decreased tissue binding

Neonates, full-term: 7.5 to 10 L/kg

Children: 16 L/kg

Adults: 7 L/kg, decreased with renal disease

Protein binding: ~25%; in uremic patients, digoxin is displaced from plasma protein binding sites

Metabolism: Via sequential sugar hydrolysis in the stomach or by reduction of lactone ring by intestinal bacteria (in ~10% of population, gut bacteria may metabolize up to 40% of digoxin dose); once absorbed, only ~16% is metabolized to 3-beta-digoxigenin, 3-keto-digoxigenin, and glucuronide and sulfate conjugates; metabolites may contribute to therapeutic and toxic effects of digoxin; metabolism is reduced with decompensated HF

Bioavailability: Oral (formulation dependent): Elixir: 70% to 85%; Tablet: 60% to 80%

Half-life elimination (age, renal and cardiac function dependent):

Neonates: Premature: 61 to 170 hours; Full-term: 35 to 45 hours

Infants: 18 to 25 hours

Children: 18 to 36 hours

Adults: 36 to 48 hours

Adults, anephric: 3.5 to 5 days

Half-life elimination: Parent drug: 38 hours; Metabolites: Digoxigenin: 4 hours; Monodigitoxoside: 3 to 12 hours

Time to peak, serum: Oral: 1 to 3 hours

Excretion: Urine (50% to 70% as unchanged drug)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Clearance correlates with CrCl. Half-life is 3.5 to 5 days in anuric patients.

Local Anesthetic/Vasoconstrictor Precautions

Use vasoconstrictor with caution due to risk of cardiac arrhythmias with digoxin

Effects on Dental Treatment

Sensitive gag reflex may cause difficulty in taking a dental impression.

Effects on Bleeding

No information available to require special precautions

Related Information

• Antiarrhythmic Drugs
• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Management of Drug Extravasations
• Narrow Therapeutic Index Drugs
• Relative Infant Dose

Index Terms

Digitalis; Lanoxicaps

FDA Approval Date

October 24, 1975

References

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Brand Names: International

Agoxin (BD); Cadef Elixir Pediatric (KR); Cardcor (BR, LI); Cardiacin (TW); Cardicaps (EG); Cardigo (LK); Cardiogoxin (AR); Cardioxin (PH); Cardixin (EG); Cardoxin (IL); Centoxin (BD); Digosin (JP, KR); Digox (PH); Digoxicor (LV); Digoxil (PY); Digoxin (PL); Digoxin NI (ID); Digoxin ”Dak” (DK); Digoxin-Actavis (HK); Digoxin-Sandoz (BF, BJ, CH, CI, ET, GH, GM, GN, ID, JP, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM); Digoxin-Zori (IL); Digoxina (CO, ES, GT, HN, NI, PE); Digoxine Nativelle (LU); Digoxine Navtivelle (FR); Dilacor (BG); Dilanacin (CY, IQ, SD); Dixcool (LK); Eudigox (IT); Fargoxin (ID); Grekin (LI); Grexin (TH); Ke Li (CN); Lanacordin (ES); Lanibos (KW, SA); Lanicor (AR, AT, BB, BF, BJ, BM, BS, BZ, CI, CY, CZ, DE, EC, ET, GH, GM, GN, GR, GY, HR, IQ, IR, JM, KE, LI, LR, LU, LY, MA, ML, MR, MU, MW, NE, NG, OM, SC, SD, SL, SN, SR, SY, TN, TT, TZ, UG, VE, YE, ZM); Lanikor (RU); Lanioxin (IS); Lanitop (SA); Lanoxin (AE, AR, AU, BB, BD, BE, BF, BH, BJ, BM, BS, BZ, CI, CR, CY, DO, EG, ET, GB, GH, GM, GN, GR, GT, GY, HK, HN, IE, IL, IN, IQ, IR, IT, JM, JO, JP, KE, KR, KW, LB, LI, LR, LU, LY, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NI, NL, NO, NZ, OM, PA, PH, PK, PT, PY, QA, RU, SA, SC, SD, SE, SG, SL, SN, SR, SV, SY, TH, TN, TR, TT, TW, TZ, UG, UY, YE, ZM, ZW); Lanoxin PG (BH, NZ, QA); Lenoxin (DE); Mapluxin (MX); Myoxin (BD); Purgoxin (ZA); Sigmaxin (AU); Toloxin (TH); Valvulan (CR, DO, GT, HN, NI, PA, SV); Vidaxil (MX)

Last Updated 7/25/20