What are the drug-drug interactions with Digoxin?

Digoxin Drug-Drug Interactions

Digoxin has a narrow therapeutic window and is vulnerable to numerous clinically significant drug interactions, primarily through P-glycoprotein (P-gp) inhibition/induction, renal impairment, and electrolyte disturbances, requiring careful monitoring when combined with interacting medications. 1, 2, 3

P-Glycoprotein-Mediated Interactions

Digoxin is a well-established P-glycoprotein substrate, making it highly susceptible to interactions with P-gp modulators 1, 2:

P-gp Inhibitors (Increase Digoxin Levels)

Strong P-gp inhibitors are contraindicated or require significant caution:

• Quinidine and systemic ketoconazole are contraindicated due to marked increases in digoxin exposure and bleeding risk 1
• Amiodarone increases digoxin AUC and Cmax by approximately 50-60%, with effects persisting for weeks after discontinuation due to amiodarone's long half-life 1
• Verapamil increases digoxin levels by 60-180% depending on formulation and timing; immediate-release formulations given 1 hour before digoxin cause the largest increases (180% Cmax, 150% AUC), while effects are negligible if verapamil is taken 2 hours after digoxin 1
• Clarithromycin increases digoxin AUC and Cmax by approximately 19% and 15% 1
• Erythromycin, itraconazole, cyclosporine, propafenone, and flecainide all increase digoxin levels 2, 3
• Dronedarone significantly increases digoxin exposure 2

P-gp Inducers (Decrease Digoxin Levels)

Strong P-gp inducers may decrease digoxin efficacy:

• Rifampicin and St. John's wort significantly decrease digoxin Cmax and AUC, potentially reducing therapeutic efficacy 1

Hepatitis C Direct-Acting Antivirals

Sofosbuvir/ledipasvir and sofosbuvir/velpatasvir require caution with digoxin:

• Ledipasvir inhibits P-gp and BCRP, potentially increasing intestinal absorption of digoxin; careful monitoring is warranted 1
• Velpatasvir similarly inhibits P-gp and BCRP; caution is advised due to digoxin's narrow therapeutic window 1
• These combinations are color-coded as "amber" (potential interaction requiring dose adjustment or monitoring) in hepatology guidelines 1

Anticoagulant Interactions

Dabigatran and digoxin have minimal pharmacokinetic interaction:

• After 4 days of combined therapy, there was little effect on the pharmacokinetics of either drug in healthy volunteers 1
• However, both are P-gp substrates, so caution remains warranted when combined with P-gp inhibitors 1

Statin Interactions

Atorvastatin at high doses modestly increases digoxin levels:

• Atorvastatin 80 mg increases digoxin levels by approximately 20% 4
• This interaction is generally considered clinically manageable with monitoring 4

Drugs Causing Renal Impairment

Nephrotoxic drugs dramatically increase digoxin toxicity risk:

• NSAIDs, ACE inhibitors, angiotensin II receptor antagonists, and cyclosporine can cause renal impairment, reducing digoxin clearance (50-70% excreted unchanged renally) 4, 3
• Digoxin elimination half-life is 36-48 hours, making accumulation likely with renal dysfunction 4

Electrolyte-Altering Medications

Hypokalemia and hypomagnesemia potentiate digoxin toxicity even at therapeutic serum levels:

• Diuretics causing hypokalemia are particularly dangerous; 23.8% of digoxin-toxic patients had hypokalemia, with all having digoxin levels below 3 ng/mL and within therapeutic range 5
• Co-trimoxazole with renin-angiotensin system inhibitors can cause unrecognized hyperkalemia and sudden death 1
• Hypercalcemia-inducing drugs also potentiate cardiac adverse effects 3

Drugs Affecting Cardiac Conduction

Bradyarrhythmias are common with combined use:

• Beta-blockers, verapamil, diltiazem combined with digoxin require cautious use due to additive effects on sinus and AV nodal function 1, 6
• Amiodarone or beta-blockers used with digoxin necessitate careful monitoring for significant sinus or AV block 6
• Digoxin should not be administered to patients with significant sinus or AV block unless treated with a permanent pacemaker 6

Drugs Reducing Digoxin Absorption

Several agents decrease digoxin bioavailability:

• Sucralfate, acarbose, cytotoxic agents (paclitaxel, gemcitabine), and enzyme inducers reduce digoxin plasma concentrations through decreased gastrointestinal absorption or increased elimination 3, 1

Proarrhythmic Combinations

QT-prolonging drugs combined with digoxin increase arrhythmia risk:

• Quinolones, azithromycin, erythromycin, clarithromycin increase risk of polymorphic VT and cardiac death, especially in women 1
• Many non-cardiac medications inhibit potassium channels and increase TdP risk in susceptible patients 1

Clinical Management Algorithm

When prescribing medications with digoxin:

1. Verify baseline renal function and electrolytes (potassium, magnesium, calcium) before initiating any interacting drug 2
2. Check baseline digoxin level if patient is already on therapy; target therapeutic range is 0.5-1.0 ng/mL for heart failure 2
3. Reduce digoxin dose to 0.125 mg daily in patients over 70 years, those with impaired renal function, or low lean body mass 2, 6
4. Monitor for early warning signs of toxicity: bradycardia, gastrointestinal disorders (nausea, vomiting), and neuropsychological symptoms 3
5. Avoid loading doses in chronic heart failure; they are unnecessary 6
6. When adding amiodarone, reduce digoxin dose due to persistent interaction 1, 6

Common Pitfalls

• Relying solely on digoxin levels: Toxicity can occur at therapeutic levels when hypokalemia or hypomagnesemia coexist 5, 3
• Ignoring timing with verapamil: Administering verapamil 2 hours after digoxin minimizes interaction 1
• Overlooking diuretic-induced hypokalemia: This is the most common preventable cause of digoxin toxicity 5
• Forgetting amiodarone's long half-life: Interaction persists for weeks after stopping amiodarone 1