Digoxin

 

Generic name: digoxin (oral/injection) (di JOX in)

Brand name: Digitek, Digox, Lanoxin, Lanoxicaps, Cardoxin
Drug class: Group V antiarrhythmics, Inotropic agents

What is digoxin?

Digoxin is derived from the leaves of a digitalis plant. Digoxin helps make the heart beat stronger and with a more regular rhythm.

Digoxin is used to treat heart failure.

Digoxin is also used to treat atrial fibrillation, a heart rhythm disorder of the atria (the upper chambers of the heart that allow blood to flow into the heart).

Warnings

You should not use digoxin if you have ventricular fibrillation (a heart rhythm disorder of the ventricles, or lower chambers of the heart that allow blood to flow out of the heart).

Digoxin Indications:

• Atrial fibrillation or atrial flutter, rate control:

  • It is indicated for the control of ventricular response rate in adults with chronic atrial fibrillation.

• Heart failure with reduced ejection fraction:

  • It is used for the 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.

• Off Label Use of Digoxin in Adults:

  • Sustained fetal tachycardia.
  • Supraventricular tachycardia (eg, atrioventricular nodal reentrant tachycardia), rate control.

Digoxin dose in adults:

Note:

• While switching from oral to IV, dose reduction by 20% to 25% might be needed.
• In case of renal failure, periodic digoxin concentrations as appropriate for the condition being treated.
• Toxicity such as hypokalemia can occur with therapeutic concentrations in some cases.

Digoxin dose as an alternative agent in the treatment of Atrial fibrillation or atrial flutter (for rate control):

Note:

• Patients should be given digoxin when their heart rate is not adequately controlled with other agents.
• Digoxin is not effective in the case of high-adrenergic states such as exercise, alternately a beta-blocker should be used.
• In patients with preexcitation associated with an accessory pathway, digoxin use can result in ventricular arrhythmia.

• Total digitalizing dose:

  • 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 OR
    • 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 total digitalizing dose over 5 minutes and the remaining 50% as 2 doses of 25% of TDD at 4- to 8-hour intervals after the initial dose, follow either of these TDD regimens with an oral maintenance regimen.
  • Maintenance dose:
    • Oral: 0.125 to 0.25 mg once daily.

Digoxin Dose in the treatment of sustained fetal tachycardia, (maternal and transplacental administration) (off-label):

Note:

• In the case of fetal hydrops, maternal administration of digoxin may be less effective due to decreased placental transfer, hence direct fetal administration might be needed.
• In order to avoid maternal adverse events, the lowest possible dose should be given.
• Appropriateness of therapy to the mother (including maternal electrolytes, renal function, ECG) should be evaluated before starting treatment.

• Maternal dose:

  • Loading dose (may be given oral or IV):

    • IV: 1.2 to 1.5 mg given in divided doses every 8 hours over 24 hours; follow with oral maintenance regimen.
    • Oral: 1 to 2 mg given in divided doses over 24 to 48 hours (eg, 0.5 mg followed by 0.25 mg, and then 0.25 mg); follow with an oral maintenance regimen.

  • Maintenance dose:

    • Oral: 0.375 mg to 0.75 mg per day given in divided doses every 8 to 12 hours. The dose should be adjusted to maintain a target maternal blood level between 0.7 and 2 ng/mL.

Digoxin dose as alternative agent Heart failure with reduced ejection fraction:

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.

• The maintenance dose (loading dose not recommended):

  • Oral: 0.125 to 0.25 mg once daily; higher daily doses are rarely necessary.
  • Low initial dose (such as 0.125mg daily or alternate day) should be given in elderly >70 years of age, impaired renal function, low BMI, low doses.
  • A dosing nomogram is also available based on lean body weight and CrCl.

Digoxin Dose as an alternative agent in the treatment of Supraventricular tachycardia (eg, atrioventricular nodal reentrant tachycardia [AVNRT]), rate control (off-label):

Note: Some experts reserve digoxin for supraventricular tachycardia that is not terminated or controlled by other agents or maneuvers.

• 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).
  • 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).

• Maintenance dose:

  • Oral: 0.125 to 0.25 mg once daily.

 

Digoxin dose in children:

Note:

• Dose depends on individual variation, renal function, lean body weight.
• Dose reduction by 25-50% is required when changing from oral solution to IV therapy.

The treatment dose of 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.

Digoxin Digitalizing dose, initial regimen (optional):

• The total digitalizing dose should be divided (see below);
• Digitalizing dose (loading dose) may not be necessary;
• Consider use if rapid titration is desired.
• The lowest possible dose should be initiated to avoid toxicity. Dosage is based on patient response (eg, clinical response, serum drug levels).

Dosage Recommendations for Digitalizing DoseA (Optional)

Age	Total Digitalizing Dose (mcg/kg) Administer in 3 divided dosesB
	Oral Solution	Tablets	IVC
1 to 24 months	35 to 60	–	30 to 50
2 to 5 months	30 to 45	–	25 to 35
5 to 10 months	20 to 35	20 to 45	15 to 30
>10 months	10 to 15	10 to 15	8 to 12
ABased on lean body weight and normal renal function for age.
BDo not give full total digitalizing dose (TDD) at once. Give one-half of the TDD for the initial dose, then give one-quarter of the TDD for each of 2 subsequent doses at 6- to 8-hour intervals; prior to additional doses, the clinical response should be fully evaluated (eg, ECG).
CMay also be administered by IM; however, not recommended.

Maintenance Dosage Recommendations for DigoxinA,B

Age	Daily Maintenance Dose (mcg/kg/day) If ≤10 years, administer in equally divided doses twice daily If >10 years, administer once daily
	Oral Solution	Tablets	IVC,D
1 to 24 months	10 to 15	–	9 to 15
2 to 5 months	8 to 10	–	6 to 9
5 to 10 months	5 to 10	6 to 12	4 to 8
>10 months	2.5 to 5	2.5 to 5	2 to 3
ADosing reflects the clinical practice and in some cases, varies from manufacturer labeling.
BBased on lean body weight and normal renal function for age. Decrease maintenance dose in patients with decreased renal function.
CMay also be administered by IM; however, not recommended.
DDaily maintenance IV dose is typically 20% to 30% of total digitalizing IV dose in pediatric patients ≤24 months and 25% to 35% in older pediatric patients.

Digoxin dose in the treatment of Tachyarrhythmias: 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, use twice-daily dosing in infants and young children.

 

Digoxin Pregnancy Category: C (FDA), A (AU TGA)

• Digoxin can cross the placenta.
• The available guidelines indicate that digoxin use in pregnancy has been extensive.
• Although adverse pregnancy outcomes have not yet been documented, untreated maternal fibrillation and maternal heart disease may increase the likelihood of preterm births and low birth weights.
• Monitor neonates for symptoms and signs of digoxin poisoning after in utero exposure, as recommended by the manufacturer.
• Due to changes in the physiological status of a pregnant woman, digoxin’s pharmacokinetic properties may be affected.
• It is important to monitor maternal serum digoxin closely. Dose adjustments may be necessary during pregnancy and after birth.
• Pregnancy can lead to atrial fibrillation and worsening heart failure.
• Digoxin is recommended for supraventricular Tachycardia during pregnancy as a first-line treatment. It has the lowest effective dose.
• Digoxin can also be used to control the long-term rate of atrial fibrillation or maternal atrial tachycardia in the event of failure to respond to other treatments.
• Monitoring maternal arrhythmias during labor and delivery should be a priority.
• For the management in utero of fetal SVT, atrial flutter with Hydrops or ventricular dysfunction, digoxin may be administered either maternally (or directly to the foetus).
• SVT can be administered with digoxin without hydrops, ventricular dysfunction, or atrial flutter if the heart beat is >=200 BPM, or any other rare tachycardias that have an average heartbeat of >=200 BPM.

Digoxin use during breastfeeding:

• Breast milk contains digoxin.
• According to the manufacturer, the relative infant dose for digoxin is 1% to 7 percent of the weight-adjusted maternal dose and 0.2% to 4 percent of a neonatal maintenance dosage.
• Breastfeeding is allowed when the RID of medication falls below 10%
• Manufacturer used milk concentrations of 0.4-1 ng/mL to calculate the RID of digoxin. This gives an estimated daily infant dose of 0.03-1.16 mcg/kg/day.
• After 13 lactating mothers were given digoxin 0.25mg once daily, this milk concentration was achieved. After an IV bolus of 500 mg to one breastfeeding woman, higher milk concentrations were achieved (12ng/mL). However digoxin levels quickly dropped to 1ng/mL within two hours.
• The study revealed that milk concentrations decreased in tandem with maternal serum levels, regardless of whether they were administered via IV or oral route.
• Breastfed infants can have digoxin in their serum.
• Breast milk does not contain enough digoxin to make it clinically relevant.
• Digoxin is compatible with breastfeeding according to the World Health Organization.

 

Digoxin Dose adjustment in renal disease:

• 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%.
  • Acute renal failure:
    • Based on expert opinion, alternate treatment should be given in case of patients with acute renal failure requiring ventricular rate control (eg, in atrial fibrillation).
    • If loading digoxin becomes necessary, the patient volume of distribution may be increased and reduction in loading dose may not be necessary; however, in case of persistent renal failure, adjustment of maintenance dosing is necessary.

  • Maintenance dose:

    • 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.
  • 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.
• Note: The following suggested dosing recommendations are intended to achieve a target digoxin concentration of 0.7 ng/mL. Renal function estimated using the 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 lean 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.

 

Dose adjustment in liver disease:

No dosage adjustment is necessary.

 

Side effects of digoxin:

• 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
  • Mental disturbances
  • Headache
  • Apathy
  • Anxiety
  • Confusion
  • Delirium
  • Depression
  • Fever
  • Hallucinations

• Dermatologic:

  • Rash (erythematous, maculopapular [most common], papular, scarlatiniform, vesicular or bullous)
  • Pruritus
  • Urticaria
  • Angioneurotic edema

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Diarrhea
  • Abdominal pain
  • Anorexia

• Neuromuscular & skeletal:

  • Weakness

• Ophthalmic:

  • Visual disturbances (blurred or yellow vision)

• Respiratory:

  • Laryngeal edema

 

Contraindications to Digoxin:

• • • Hypersensitivity to digoxin or other forms of digitalis or any component of this formulation
    • Ventricular fibrillation

Warnings and precautions

• • Digoxin toxicities:

    • Digoxin toxicities are characterized by anorexia and nausea, vomiting, visual problems, cardiac arrhythmias, and dizziness. However, symptoms can occur at lower levels.
    • Digoxin toxicities can be caused by low body weight, poor nutrition, and electrolyte impairments such as hypokalemia or hypercalcemia.

  • Extravasation:

    • IV administration: Vesicant. Proper needle or catheter placement is required before and during administration to avoid extravasation.

  • Proarrhythmic effects

    • Digoxin toxicity can cause proarrhythmic symptoms. It is important to monitor for these effects.

  • Accessory bypass tract (eg, Wolff-Parkinson-White [WPW] syndrome):

    • It can cause increased anterograde conduction via the accessory pathway, which could lead to ventricular fibrillation in cases of atrial fibrillation.

  • Acute coronary syndrome

    • Digoxin can cause an increase in myocardial oxygen need and ischemia. It should therefore be used with caution.
    • IV digoxin can be used in acute coronary syndrome to reduce ventricular activity and improve left ventricular function. This is for the acute treatment or reversal of severe LV dysfunction, heart failure, hemodynamic instability, and severe LV function.

  • Atrial fibrillation:

    • Patients with atrial fibrillation need to be closely monitored for changes in serum concentrations. Uncontrolled serum concentrations can increase the risk of death.

  • BeriBeri Heart Disease:

    • Digoxin therapy may not be effective for patients with beriberi cardiac disease. Patients who have underlying thiamine deficiencies should be treated concurrently.

  • Electrolyte imbalance:

    • Before and during therapy, electrolyte disturbances should be treated, particularly hypokalemia and hypomagnesemia. Toxicity can occur even with therapeutic digoxin concentrations of 2ng/mL.
    • Hypocalcemia can cause digoxin toxicity, and hypercalcemia can increase the risk. Normal calcium levels should be maintained.

  • Heart failure:

    • If symptoms persist despite medical treatment, digoxin should only be considered in patients with heart failure and reduced ejection fraction.
    • Beta-blockers are preferable to digoxin in patients with atrial fibrillation and HF.
    • Digoxin withdrawal in patients with heart failure who are clinically stable may cause recurrences.
    • It is important to monitor serum levels closely as uncontrolled levels can lead to increased mortality risk.

  • Hypermetabolic states

    • Arrhythmia should not be caused by any underlying condition such as hyperthyroidism, hyperdynamic (hypoxia or arteriovenous Shunt), but rather an underlying disease.
    • Digoxin should not be used if it is toxic.

  • Hypertrophic cardiomyopathy and outflow tract obstruction

    • Digoxin’s positive inotropic effects can cause outflow obstruction to worsen, so it should not be used to treat ventricular fibrillation.
    • Patients with HCM without atrial fibrillation may experience dyspnea if they are treated with digoxin.

  • Myocarditis

    • As demonstrated in a murine model for viral myocarditis, higher doses of digoxin may cause damage.
    • Humans should not be exposed to lower doses of digoxin without close monitoring.
    • According to the manufacturer, patients suffering from myocarditis should avoid digoxin.

  • Left ventricular function preserved:

    • It can cause decreased cardiac output in patients with preserved left-ventricular systolic functions, such as restrictive or hypertrophic cardiomyopathy and constrictive pericarditis.
    • It should not be used to treat ventricular fibrillation.

  • Renal impairment

    • Patients with impaired renal function should be cautious; adjustment of dosage is necessary.

  • Sinus node disease, atrioventricular blocks:

    • Digoxin slows the rate of sinoatrial or AV conduction, which in turn leads to a prolongation of PR intervals.
    • Digoxin can cause severe sinus bradycardia and sinoatrial block in patients with pre-existing sinus disease.
    • Patients with complete heart block, even if they have a functioning artificial pacemaker, can develop it.
    • If digoxin is required for these patients, a pacemaker should be installed.

  • Thyroid disease:

    • Hypothyroidism can lead to digoxin levels that are higher due to lower digoxin clearance.
    • Patients with hyperthyroidism have lower digoxin levels due to increased renal clearance.
    • There were no significant differences in absorption between thyroid conditions and those with normal thyroid function.
    • Notice: A thyroid evaluation is necessary in the event of new-onset atrial fibrillation, or exacerbation ventricular arrhythmias.

 

Digoxin: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use
  

  Risk Factor C (Monitor therapy).
  5-Aminosalicylic Acid Derivatives	May lower the serum concentrations of Cardiac Glycosides.
  Acarbose	Could lower the serum level of Digoxin.
  Adenosine	Adenosine may be made more toxic by Digoxin.
  Aminoglycosides	Could cause a decrease in serum levels of Cardiac Glycosides. This effect was only demonstrated by oral aminoglycoside administration. Exceptions: Amikacin (Systemic); Arbekacin; Isepamicin; Plazomicin; Streptomycin; Tobramycin (Systemic).
  Aminoquinolines (Antimalarial)	May increase serum levels of Cardiac Glycosides.
  Amphotericin B	May increase the toxic/adverse effects of Cardiac Glycosides.
  Anagliptin	May increase serum Digoxin concentrations
  Anthracyclines	Cardiac Glycosides could reduce the cardiotoxic effects of Anthracyclines. Cardiac Glycosides may be lessened by Anthracyclines. 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.
  Antithyroid Drugs	May increase serum levels of Cardiac Glycosides.
  Asunaprevir	May increase serum Digoxin concentrations
  AtorvaSTATin	May increase serum Digoxin concentrations
  Barnidipine	Digoxin may have an adverse/toxic effect that can be increased.
  Benidipine	May increase serum Digoxin concentrations
  Beta-Blockers	Cardiac Glycosides may increase bradycardic effects. Levobunolol and Metipranolol are exceptions.
  Bile Acid Sequestrants	May reduce the absorption Cardiac Glycosides. Colesevelam is an exception.
  Bradycardia-Causing Agents	May increase the bradycardic effects of Bradycardia-Causing agents.
  Bretylium	May increase the bradycardic effects of Bradycardia Causing Agents. Patients receiving AV blocking drugs may experience a reduction in atrioventricular (AV), blockade due to Bretylium.
  Brimonidine (Topical)	Digoxin may increase the bradycardic effects of Digoxin.
  BuPROPion	Could lower the serum level of Digoxin.
  Calcium Channel Blockers (Nondihydropyridine)	May increase the AV-blocking effects of Cardiac Glycosides. Calcium Channel Blockers (Nondihydropyridine), may increase serum levels of Cardiac Glycosides.
  Calcium Polystyrene Sulfonate	May increase the toxic/adverse effects of Cardiac Glycosides.
  Calcium Salts	May increase the arrhythmogenic effects of Cardiac Glycosides.
  Canagliflozin	May increase serum Digoxin concentrations
  Carvedilol	Carvedilol’s bradycardic effects may be enhanced by Digoxin. Digoxin may be increased by Carvedilol.
  CloNIDine	May increase the AV-blocking effects of Cardiac Glycosides. It is possible to increase the risk of sinus node dysfunction.
  Cobicistat	May increase serum Digoxin concentrations
  Colchicine	Colchicine serum concentration may be increased by Digoxin
  Conivaptan	May increase serum Digoxin concentrations
  CycloSPORINE Systemic	May increase serum Digoxin concentrations
  Diacerein	May increase the arrhythmogenic effects of Cardiac Glycosides.
  Edrophonium	May increase the AV-blocking effects of Cardiac Glycosides.
  Elagolix	May increase serum Digoxin concentrations
  EPHEDrine (Nasal)	Cardiac Glycosides could increase the arrhythmogenic effects of EPHEDrine.
  EPHEDrine (Systemic)	May increase the arrhythmogenic effects of Cardiac Glycosides.
  Epoprostenol	May increase serum Digoxin concentrations
  Erdafitinib	Increased serum concentrations of P-glycoprotein/ABCB1 Substrates may be possible.
  Etravirine	Increase in serum Digoxin concentrations. Monitoring serum digoxin levels is important. If necessary, adjust the dose. Digoxin should not be administered to patients who are attempting to take etravirine and digoxin together.
  Flecainide	May increase serum Digoxin concentrations
  Flibanserin	May increase serum Digoxin concentrations
  Fostamatinib	May increase serum Digoxin concentrations
  Glycopyrrolate (Systemic)	May increase serum Digoxin concentrations
  Ibrutinib	May increase serum Digoxin concentrations
  Isavuconazonium sulfate	May increase serum Digoxin concentrations
  Ivabradine	Bradycardia-Causing agents may increase the bradycardic effects of Ivabradine.
  Kaolin	May lower the serum concentrations of Cardiac Glycosides.
  Lacosamide	Bradycardia-Causing Agents can increase the AV-blocking effects of Lacosamide.
  Lenalidomide	May increase serum Digoxin concentrations
  Levosulpiride	May increase the toxic/adverse effects of Cardiac Glycosides. Levosulpiride, in particular, may reduce symptoms of cardiac glycoside-related toxicities.
  Licorice	May increase the toxic/adverse effects of Cardiac Glycosides.
  Loop Diuretics	Cardiac Glycosides may have an adverse/toxic effect. The hypokalemic or hypomagnesemic effects of loop diuretics may increase cardiac glycoside toxicities.
  Lumacaftor	May lower the serum concentrations of P-glycoprotein/ABCB1 Substrates. Lumacaftor could increase serum levels of P-glycoprotein/ABCB1 Substrates.
  Antibiotics with Macrolide	May increase serum levels of Cardiac Glycosides. Fidaxomicin, Roxithromycin, and Spiramycin are exceptions.
  Metaraminol	May increase the arrhythmogenic effects of Cardiac Glycosides.
  Midodrine	May increase the bradycardic effects of Bradycardia Causing Agents.
  MiFEPRIStone	The serum Digoxin concentration may increase. Management: Monitor serum digoxin levels for at least two weeks after mifepristone is initiated. Then adjust the dose according to normal clinical practice.
  Multivitamins/Fluoride (with ADE)	May increase the arrhythmogenic effects of Cardiac Glycosides.
  Multivitamins/Minerals (with ADEK, Folate, Iron)	May increase the arrhythmogenic effects of Cardiac Glycosides.
  Multivitamins/Minerals (with AE, No Iron)	May increase the arrhythmogenic effects of Cardiac Glycosides.
  Nefazodone	May increase serum Digoxin concentrations
  Neratinib	May increase serum Digoxin concentrations
  Neuromuscular-Blocking Agents	May increase the arrhythmogenic effects of Cardiac Glycosides.
  NIFEdipine	May increase serum Digoxin concentrations
  Nonsteroidal Anti-Inflammatory Drugs	May increase serum Digoxin concentrations
  Parathyroid Hormone	Cardiac Glycosides may have an adverse/toxic effect. Parathyroid Hormone-related hypercalcemia could lead to digitalis toxicities.
  Paricalcitol	Digoxin may have an adverse/toxic effect that can be increased.
  PenicillAMINE	Could lower the serum level of Digoxin.
  P-glycoprotein/ABCB1 Inducers	The serum concentrations of Pglycoprotein/ABCB1 Substrates may be decreased. Inducers of pglycoprotein may limit the distribution to certain cells/tissues/organs in which p-glycoprotein exists in high amounts (e.g. brain, T-lymphocytes and testes). .
  P-glycoprotein/ABCB1 Inhibitors	Increases serum concentration of Pglycoprotein/ABCB1 substrates. P-glycoprotein inhibitors can also increase the distribution of pglycoprotein substrates to certain cells/tissues/organs in which p-glycoprotein exists in high amounts (e.g. brain, T-lymphocytes and testes). .
  Polyethylene Glycol 3350	Could lower the serum level of Digoxin.
  Polyethylene Glycol 4000	Could lower the serum level of Digoxin.
  Posaconazole	May increase serum Digoxin concentrations
  Potassium-Sparing Diuretics	Cardiac Glycosides may have a less therapeutic effect. Digoxin’s inotropic effects are particularly diminished. Potassium-Sparing diuretics could increase serum levels of Cardiac Glycosides. Spironolactone may have this effect.
  Propafenone	May increase serum levels of Cardiac Glycosides.
  QuiNINE	May increase serum Digoxin concentrations
  Ranolazine	May increase serum Digoxin concentrations
  Regorafenib	Digoxin may increase the bradycardic effects of Digoxin.
  Reserpine	May increase the toxic/adverse effects of Cardiac Glycosides.
  Roxithromycin	May increase serum levels of Cardiac Glycosides.
  Ruxolitinib	May increase the bradycardic effects of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labels recommend that bradycardia-causing agent be avoided to the greatest extent possible.
  Sarecycline	May increase serum Digoxin concentrations
  Simeprevir	May increase serum Digoxin concentrations
  SITagliptin	May increase serum Digoxin concentrations
  Sodium Polystyrene Sulfonate	Digoxin may have an adverse/toxic effect that can be increased.
  Spironolactone	Increases the serum level of Digoxin. Spironolactone and/or its metabolites may also cause interference with Digoxin assays. This could lead to falsely increasing or decreasing Digoxin levels.
  St John’s Wort	Could lower the serum level of Digoxin.
  Telmisartan	May increase serum levels of Cardiac Glycosides.
  Terlipressin	May increase the bradycardic effects of Bradycardia Causing Agents.
  Thiazide and Thiazide – Like Diuretics	Cardiac Glycosides may have an adverse/toxic effect. Particularly, hypokalemic or hypomagnesemic effects of thiazide Diuretics may increase cardiac glycoside toxicities.
  Ticagrelor	May increase serum Digoxin concentrations
  Tofacitinib	May increase the bradycardic effects of Bradycardia Causing Agents.
  Tolvaptan	May increase serum Digoxin concentrations
  Trimethoprim	May increase serum Digoxin concentrations
  Valbenazine	May increase serum Digoxin concentrations
  Vandetanib	May increase serum Digoxin concentrations
  Velpatasvir	May increase serum Digoxin concentrations
  Vilazodone	May increase serum Digoxin concentrations
  Vitamin D Analogs	May increase the arrhythmogenic effects of Cardiac Glycosides.
  Risk Factor D (Consider therapy modifications)
  Amiodarone	May cause an increase in serum levels of Cardiac Glycosides. Management: Lower the dosage of cardiac glycosides from 30% to 50%, or decrease the frequency of administration when concomitant amiodarone treatment is initiated. Monitor for elevated serum levels and toxic effects of cardiac Glycosides.
  Ceritinib	Bradycardia-Causing agents may increase Ceritinib’s bradycardic effects. Management: If the combination is not possible, monitor patients for signs of bradycardia and closely track blood pressure and heart beat during therapy. Separate monographs will discuss exceptions.
  Daclatasvir	May increase serum Digoxin concentrations. Management: See full interaction monograph for details.
  Dronedarone	Digoxin could increase the AV-blocking effects of Dronedarone. Digoxin could also increase the electrophysiologic effects Dronedarone’s other properties. The serum level of Digoxin may be increased by Dronedarone. When possible, avoid concurrent digoxin use. Concurrent use of digoxin should be avoided at all costs.
  Eliglustat	Increase in serum Digoxin concentrations. Treatment: Before initiating eliglustat, take digoxin serum levels from patients who are taking digoxin. Reduce digoxin doses 30% before eliglustat initiation. Continue monitoring.
  Glecaprevir und Pibrentasvir	Increase in serum Digoxin concentrations. Management: Measure serum digoxin concentrations before initiating glecaprevir/pibrentasvir. You can reduce digoxin levels by decreasing digoxin doses by 50% or changing the frequency of dosing; monitor concomitant therapy.
  Itraconazole	Increased serum concentrations of Cardiac Glycosides may be a possibility. Management: Preemptive dose adjustments for cardiac glycosides should be considered when itraconazole is commenced, changed, or discontinued.
  Milnacipran	Digoxin may have an adverse/toxic effect that can be increased. There is a higher risk of postural hypotension or tachycardia when IV digoxin is used, especially in patients with IV digoxin. Patients receiving milnacipran should not use intravenous (IV), digoxin concurrently. Milnacipran and oral digoxin should be used together. Monitor closely for signs of hypotension or tachycardia and keep your pulse rate under control.
  Mirabegron	Increased serum Digoxin concentrations may occur. Concurrent mirabegron: Use the lowest possible dose of digoxin. To help you determine the right dose of digoxin, it is important to monitor serum digoxin levels.
  Ombitasvir and Paritaprevir are the three main ingredients in Ritonavir.	Increase in serum Digoxin concentrations 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.
  QuiNIDine	Increased serum levels of Cardiac Glycosides may be a problem. Management: Reduce the dose of cardiac glycosides immediately after quinidine is initiated. Continue monitoring glycoside serum concentrations for clinical responses until quinidine reaches a steady state (5-10 Days).
  Ritonavir	May increase serum Digoxin concentrations
  Siponimod	Bradycardia-Causing Drugs can increase Siponimod’s bradycardic effects. Management: Siponimod should not be taken with bradycardia-causing drugs.
  Sucralfate	Could lower the serum level of Digoxin. Suprafate can decrease digoxin absorption. Management: Digoxin should be administered at least two hours before sucralfate or at least six hours after sucralfate.
  Vemurafenib	Increased serum Digoxin concentrations may occur. Avoid coadministration of digoxin and vemurafenib. Digoxin dose reduction is an option if concomitant use can’t be avoided.
  Venetoclax	The serum Digoxin concentration may increase. Treatment: Digoxin should be administered at least six hours before venetoclax if concomitant therapy is necessary.
  Risk Factor X (Avoid Combination)
  Benznidazole	May increase the toxic/adverse effects of products containing propylene glycol.
  MetroNIDAZOLE Systemic	May increase the toxic/adverse effects of products containing propylene glycol. It is possible to experience a disulfiram-like reaction.

 

Monitoring parameters:

• Heart rate and rhythm
• Periodic ECGs to assess desired effects and signs of toxicity
• Baseline and periodic serum creatinine.
• Periodic monitoring of electrolytes including serum potassium, magnesium, and calcium especially if on medications where these electrolyte disturbances can occur (eg, diuretics), or if the patient has a history of hypokalemia or hypomagnesemia.
• Noncardiac signs of toxicity such as  confusion, and depression.

When to draw serum digoxin concentrations:

• Due to the narrow therapeutic index, monitoring of digoxin serum concentrations is necessary.
• The therapeutic endpoint is difficult to quantify and digoxin toxicity may be life-threatening.
• Irrespective of the route of administration, digoxin serum concentrations should be drawn at least 6 to 8 hours after the last dose.

Note: Due to increased skeletal muscle uptake, serum digoxin concentration can be reduced due to exercise, a period of rest (eg, about 2 hours) after exercise may be necessary before 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 before the next dose or at a minimum of 6 to 8 hours after the last dose.

Digoxin serum concentrations should be obtained within 5 to 7 days (approximate time to steady-state) after any dosage changes. In case of a change in the maintenance dose, digoxin serum concentrations should be checked up to 7 to 14 days.

Note:

• It may take 15 to 20 days to reach a steady-state in patients with end-stage renal disease.
• Close monitoring is required in patients who are receiving electrolyte-depleting medications such as diuretics, serum potassium, magnesium, and calcium.
• 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)

 

How to administer Digoxin?

IM:

• IV route preferred.
• If IM injection is necessary, it should be given as a deep injection followed by a 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.
• Maternal doses can be given orally or IV in case of management of fetal tachycardia (maternal/transplacental administration; off-label use).

It is a vesicant; ensure proper needle or catheter placement before and during administration to avoid extravasation.

Extravasation management:

• If extravasation occurs, IV administration should be stopped immediately and disconnected, leaving cannula/needle in place.
• The extravasated solution should be gently aspirated without flushing the line.
• The needle/cannula should be removed and the extremity should be elevated.

 

Digoxin Mechanism of action:

Heart failure:

• Digoxin inhibits the sodium/potassiumATPase pump of myocardial cells, resulting in a temporary increase in intracellular sodium. This in turn promotes calcium uptake via the sodium-calcium interchange pump, leading to greater contractility. You can increase your baroreflex sensitivity.

Supraventricular arrhythmias:

• This results in a longer effective refractory time and decreased conduction speed by direct suppression of the AV node positive inotropic effect. It also enhances vagal tone and decreases the ventricular rate for fast atrial arrhythmias.
• Higher serum digoxin levels may increase sensitivity and tolerance in atrial fibrillation.

The 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, the median time to ventricular rate control in one study was 6 hours (range: 3 to 15 hours).

Duration:

• Adults: 3 to 4 days.

Absorption:

• By passive non-saturable diffusion in the upper small intestine;
• food may delay, but does not affect the 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 the distribution phase.
• Hyperthyroidism: Increased Volume of distribution
• Hyperkalemia, hyponatremia: Decreased digoxin distribution to heart and muscle
• Hypokalemia: Increased digoxin distribution to heart and muscles

Protein binding:

• About 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 the 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;
• The metabolites may contribute to therapeutic and toxic effects of digoxin;
• Drug 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)

 

International Brand Names of Digoxin:

• Digitek
• Digox
• Lanoxin
• Lanoxin Pediatric
• APO-Digoxin
• PMS-Digoxin
• Toloxin
• Agoxin
• Cadef Elixir Pediatric
• Cardcor
• Cardiacin
• Cardicaps
• Cardigo
• Cardiogoxin
• Cardioxin
• Cardixin
• Cardoxin
• Centoxin
• Digosin
• Digox
• Digoxicor
• Digoxil
• Digoxin
• Digoxin NI
• Digoxin ”Dak”
• Digoxin-Actavis
• Digoxin-Sandoz
• Digoxin-Zori
• Digoxina
• Digoxine Nativelle
• Digoxine Navtivelle
• Dilacor
• Dilanacin
• Dixcool
• Eudigox
• Fargoxin
• Grekin
• Grexin
• Ke Li
• Lanacordin
• Lanibos
• Lanicor
• Lanikor
• Lanioxin
• Lanitop
• Lanoxin
• Lanoxin PG
• Lenoxin
• Mapluxin
• Myoxin
• Purgoxin
• Sigmaxin
• Toloxin
• Valvulan
• Vidaxil

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