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Pronunciation

(di JOKS in)

Index Terms

  • Digitalis
  • Lanoxicaps

Dosage Forms

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 (1 mL [DSC], 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 fd&c yellow #6 (sunset yellow)]

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

Lanoxin: 125 mcg [DSC] [contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Lanoxin: 187.5 mcg, 250 mcg [DSC]

Lanoxin: 250 mcg [scored]

Generic: 125 mcg, 250 mcg

Brand Names: U.S.

  • Digitek
  • Digox
  • Lanoxin
  • Lanoxin Pediatric

Pharmacologic Category

  • Antiarrhythmic Agent, Miscellaneous
  • Cardiac Glycoside

Pharmacology

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.

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

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

Excretion

Urine (50% to 70% as unchanged drug)

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)

Time to Peak

Serum: Oral: 1 to 3 hours

Duration of Action

Adults: 3 to 4 days

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

Parent drug: 38 hours; Metabolites: Digoxigenin: 4 hours; Monodigitoxoside: 3 to 12 hours

Protein Binding

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

Special Populations: Renal Function Impairment

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

Use: Labeled Indications

Atrial fibrillation: Control of ventricular response rate in adults with chronic atrial fibrillation.

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

Note: In treatment of atrial fibrillation (AF), use is not considered first-line in patients with AF; digoxin may be considered for rate control in patients with heart failure with reduced ejection fraction (HFrEF) without pre-excitation or in sedentary patients (AHA/ACC/HRS [January, 2014]). In the treatment of heart failure, digoxin should be considered for use only in HF with reduced ejection fraction (HFrEF) when symptoms remain despite guideline-directed medical therapy or as initial therapy in patients with severe symptoms yet to respond to guideline-directed medical therapy (ACCF/AHA [Yancy, 2013]).

Use: Unlabeled

Fetal tachycardia with or without hydrops; to slow ventricular rate in supraventricular tachyarrhythmias such as supraventricular tachycardia (SVT) excluding atrioventricular reciprocating tachycardia (AVRT)

Contraindications

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

Dosing: Adult

Note: When changing from oral (tablets or liquid) or IM to IV therapy, dosage should be reduced by 20% to 25%.

Atrial fibrillation (rate control) (off-label dose):

Total digitalizing dose (TDD): IV: 8 to 12 mcg/kg; administer half of TDD over 5 minutes with the remaining portion as 25% fractions at 4 to 8 hour intervals (ACLS [Neumar, 2010]) or may administer 0.25 mg with repeat dosing to a maximum of 1.5 mg over 24 hours followed by an oral maintenance regimen (AHA/ACC/HRS [January, 2014]).

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

Heart failure: Daily maintenance dose (Note: Loading dose not recommended): Oral: 0.125 to 0.25 mg once daily; higher daily doses (eg, 0.375 to 0.5 mg daily) 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]). Note: IV digoxin may be used to control ventricular response in patients with atrial fibrillation and heart failure with reduced ejection fraction (HFrEF) who do not have an accessory pathway or pre-excitation syndrome (AHA/ACC/HRS [January, 2014]). The addition of a beta-blocker to digoxin is usually more effective in controlling ventricular response, particularly during exercise (ACCF/AHA [Yancy, 2013]).

Supraventricular tachyarrhythmias (rate control):

Initial: Total digitalizing dose:

Oral: 0.75 to 1.5 mg

IV, IM: 0.5 to 1 mg (Note: IM not preferred due to severe injection site pain.)

Give 1/2 (one-half) of the total digitalizing dose (TDD) as the initial dose, then give 1/4 (one-quarter) of the TDD in each of 2 subsequent doses at 6- to 8-hour intervals. Obtain ECG 6 hours after each dose to assess potential toxicity.

Daily maintenance dose:

Oral: 0.125 to 0.5 mg once daily

IV, IM: 0.1 to 0.4 mg once daily (Note: IM not preferred due to severe injection site pain.)

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 2015]).

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 2015]).

Dosing: Pediatric

Atrial dysrhythmias (rate control), HF: When changing from oral (tablets or liquid) or IM to IV therapy, dosage should be reduced by 20% to 25%. See table.

Dosage Recommendations for Digoxin1

Age

Total Digitalizing Dose2,3

(mcg/kg)

Daily Maintenance Dose3,4

(mcg/kg)

Oral

IV or IM5

Oral

IV or IM5

1Heart failure: A lower serum digoxin concentration may be adequate to treat heart failure (compared to cardiac arrhythmias); consider doses at the lower end of the recommended range for treatment of heart failure; a digitalizing dose (loading dose) may not be necessary when treating heart failure (Ross, 2001).

2Do not give full total digitalizing dose (TDD) at once. Give one-half of the total digitalizing dose (TDD) in the initial dose, then give one-quarter of the TDD in each of two subsequent doses at 6- to 8-hour intervals. Obtain ECG 6 hours after each dose to assess potential toxicity.

3Based on lean body weight and normal renal function for age. Decrease dose in patients with decreased renal function; digitalizing dose often not recommended in infants and children.

4Divided every 12 hours in infants and children <10 years of age. Given once daily to children >10 years of age and adults.

5IM not preferred due to severe injection site pain. If IM route is necessary, administer as deep injection followed by massage of injection site.

Preterm infant

20-30

15-25

5-7.5

4-6

Full-term infant

25-35

20-30

6-10

5-8

1 mo - 2 y

35-60

30-50

10-15

7.5-12

2-5 y

30-40

25-35

7.5-10

6-9

5-10 y

20-35

15-30

5-10

4-8

>10 y

10-15

8-12

2.5-5

2-3

Table has been converted to the following text.

Dosage Recommendations for Digoxin1

Preterm infant:

• Total digitalizing dose2,3:

– Oral: 20-30 mcg/kg

– IV or IM5: 15-25 mcg/kg

• Daily maintenance dose2,4:

– Oral: 5-7.5 mcg/kg

– IV or IM5: 4-6 mcg/kg

Full-term infant:

• Total digitalizing dose2,3:

– Oral: 25-35 mcg/kg

– IV or IM5: 20-30 mcg/kg

• Daily maintenance dose2,4:

– Oral: 6-10 mcg/kg

– IV or IM5: 5-8 mcg/kg

1 month to 2 years:

• Total digitalizing dose2,3:

– Oral: 35-60 mcg/kg

– IV or IM5: 30-50 mcg/kg

• Daily maintenance dose2,4:

– Oral: 10-15 mcg/kg

– IV or IM5: 7.5-12 mcg/kg

2-5 years:

• Total digitalizing dose2,3:

– Oral: 30-40 mcg/kg

– IV or IM5: 25-35 mcg/kg

• Daily maintenance dose2,4:

– Oral: 7.5-10 mcg/kg

– IV or IM5: 6-9 mcg/kg

5-10 years:

• Total digitalizing dose2,3:

– Oral: 20-35 mcg/kg

– IV or IM5: 15-30 mcg/kg

• Daily maintenance dose2,4:

– Oral: 5-10 mcg/kg

– IV or IM5: 4-8 mcg/kg

>10 years:

• Total digitalizing dose2,3:

– Oral: 10-15 mcg/kg

– IV or IM5: 8-12 mcg/kg

• Daily maintenance dose2,4:

– Oral: 2.5-5 mcg/kg

– IV or IM5: 2-3 mcg/kg

1Heart failure: A lower serum digoxin concentration may be adequate to treat heart failure (compared to cardiac arrhythmias); consider doses at the lower end of the recommended range for treatment of heart failure; a digitalizing dose (loading dose) may not be necessary when treating heart failure (Ross, 2001).

2Based on lean body weight and normal renal function for age. Decrease dose in patients with decreased renal function; digitalizing dose often not recommended in infants and children.

3Do not give full total digitalizing dose (TDD) at once. Give one-half of the total digitalizing dose (TDD) in the initial dose, then give one-quarter of the TDD in each of two subsequent doses at 6- to 8-hour intervals. Obtain ECG 6 hours after each dose to assess potential toxicity.

4Divided every 12 hours in infants and children <10 years of age. Give once daily to children >10 years of age and adults.

5IM not preferred due to severe injection site pain. If IM route is necessary, administer as deep injection followed by massage of injection site.

Dosing: Renal Impairment

Adults: Oral, IV:

Loading dose: There are no dosage adjustments provided in the manufacturer’s labeling, however, 50% to 70% of a digoxin dose is excreted unchanged in the urine. The following adjustments have been recommended:

ESRD: If loading dose necessary, reduce dose by 50% (Aronoff, 2007)

Acute renal failure: Based on expert opinion, if patient in acute renal failure requires ventricular rate control (eg, in atrial fibrillation), consider alternative therapy. If loading digoxin becomes necessary, patient volume of distribution may be increased and reduction in loading dose may not be necessary; however, maintenance dosing will require adjustment as long as renal failure persists.

Maintenance dose:

Manufacturer’s labeling: Dosage reductions and close monitoring recommended; see product labeling for specific dosage recommendations based on CrCl.

Alternate dosing (Golightly, 2014):

GFR >50 mL/minute: No dosage adjustment necessary.

GFR 10 to 50 mL/minute: 0.0625 mg every 24 to 36 hours (25% to 75% of the usual dose every 24 to 36 hours).

GFR <10 mL/minute: 0.0625 mg every 48 hours (10% to 25% of the usual dose every 48 hours).

Hemodialysis: Nondialyzable (due to extensive binding to skeletal muscle and myocardium): 0.0625 mg every 48 hours (10% to 25% of the usual dose every 48 hours). No supplemental dose necessary (Mooradian, 1988).

CAPD: 0.0625 mg every 48 hours (10% to 25% of the usual dose every 48 hours).

Continuous renal replacement therapy (CRRT): 0.0625 mg every 48 hours (10% to 25% of the usual dose every 48 hours).

Heart failure: Initial maintenance dose (Bauman, 2006; Jusko, 1974; Koup, 1975): Note: The following suggested dosing recommendations are intended to achieve a target digoxin concentration of 0.7 ng/mL. Renal function estimated using Cockcroft-Gault formula.

CrCl >120 mL/minute: 0.25 mg once daily

CrCl 80 to 120 mL/minute: Alternate between doses of 0.25 mg and 0.125 mg once daily

CrCl 30 to 80 mL/minute: 0.125 mg once daily

CrCl <30 mL/minute: 0.125 mg every 48 hours

Note: A contemporary digoxin dosing nomogram using creatinine clearance and ideal body weight or height has been published for determining the initial maintenance dose in patients with heart failure to achieve a target digoxin concentration of 0.7 ng/mL (Bauman, 2006).

Pediatric: Oral, IV:

Loading dose: There are no dosage adjustments provided in the manufacturer’s labeling; however, 50% to 70% of a digoxin dose is excreted unchanged in the urine.

Maintenance dose: Dosage reductions and close monitoring recommended; see product labeling for specific dosage recommendations based on CrCl.

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Reconstitution

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.

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.

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.

Dietary Considerations

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

Compatibility

Stable in D51/2NS with KCl 20 mEq, D5NS, D5W, D10W, LR, 1/2NS, and NS. May be diluted fourfold in D5W, NS, or SWFI for direct injection (or may be administered undiluted).

Y-site administration: Incompatible with amiodarone, amphotericin B cholesteryl sulfate complex, fluconazole, foscarnet, pantoprazole, telavancin.

Compatibility in syringe: Incompatible with doxapram, pantoprazole.

Storage

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.

Drug Interactions

5-ASA Derivatives: May decrease the serum concentration of Cardiac Glycosides. Monitor therapy

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

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

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

Aminoquinolines (Antimalarial): May increase the serum concentration of Cardiac Glycosides. 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. Consider therapy modification

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

Antineoplastic Agents (Anthracycline, Systemic): Cardiac Glycosides may diminish the cardiotoxic effect of Antineoplastic Agents (Anthracycline, Systemic). Antineoplastic Agents (Anthracycline, Systemic) 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. Monitor therapy

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

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

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

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

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

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

Boceprevir: May increase the serum concentration of Digoxin. Management: In patients initiating digoxin during boceprevir treatment, initiate at the lowest possible digoxin dose, monitor serum digoxin concentrations, and titrate carefully due to a possible risk of elevated digoxin concentrations. Consider therapy modification

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

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

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

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

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

Carvedilol: Digoxin may enhance the bradycardic effect of Carvedilol. Carvedilol may increase the serum concentration of Digoxin. 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. Avoid combination

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

Colchicine: Digoxin may increase the serum concentration of Colchicine. Monitor therapy

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

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

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

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. Consider therapy modification

Edrophonium: May enhance the AV-blocking effect of Cardiac Glycosides. 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. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

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

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

Midodrine: Cardiac Glycosides may enhance the bradycardic effect of Midodrine. 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. 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. 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. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

Protease Inhibitors: May increase the serum concentration of Digoxin. Increased serum concentrations of digoxin may increase risk of AV nodal blockade. 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). Consider therapy modification

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

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

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

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

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

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

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

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

St John's Wort: May decrease the serum concentration of Digoxin. 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 or at least 6 hours after sucralfate. Consider therapy modification

Telaprevir: May increase the serum concentration of Digoxin. Management: Use the lowest possible digoxin dose when starting therapy in a patient who is being treated with telaprevir, and monitor clinical response and serum concentrations closely for further dosing adjustments. Consider therapy modification

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

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

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

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

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

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

Velpatasvir: May increase the serum concentration of Digoxin. 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. Consider therapy modification

Venetoclax: May increase the serum concentration of Digoxin. Management: Administer digoxin at least 6 hours before venetoclax when concomitant therapy is required. Consider therapy modification

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

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

Test Interactions

Spironolactone may interfere with digoxin radioimmunoassay.

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

Ocular: Visual disturbances (blurred or yellow vision)

Respiratory: Laryngeal edema

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

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 (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) (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]).

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)

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Digoxin crosses the placenta and serum concentrations are similar in the mother and fetus at delivery. Digoxin is recommended in the treatment of fetal tachycardia determined to be SVT. In pregnant women, use of digoxin is recommended as a first-line agent for chronic treatment of highly symptomatic SVT; the lowest effective dose is recommended (Page [ACC/AHA/HRS 2015]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache. Have patient report immediately to prescriber severe dizziness, syncope, considerable nausea, significant diarrhea, sudden vision changes, weight loss, lack of appetite, intolerable asthenia, melena, illogical thinking, bradycardia, tachycardia, arrhythmia, hallucinations, mood changes, severe dyspepsia, or injection site irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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