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  • CLASSES

    Plain Cardiac Glycosides

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and IV cardiac glycoside; inotrope used for CHF; increases LVEF, improves symptoms, and reduces hospitalizations in CHF, but overall mortality is unchanged; slows ventricular rate in AFIB.

    COMMON BRAND NAMES

    Digitek, Lanoxin, Lanoxin Pediatric

    HOW SUPPLIED

    Digitek/Digoxin/Lanoxin Oral Tab: 0.0625mg, 0.125mg, 0.1875mg, 0.25mg
    Digoxin/Lanoxin Oral Sol: 0.05mg, 1mL
    Digoxin/Lanoxin/Lanoxin Pediatric Intramuscular Inj Sol: 0.1mg, 0.25mg, 1mL, 2mL, 500mcg
    Digoxin/Lanoxin/Lanoxin Pediatric Intravenous Inj Sol: 0.1mg, 0.25mg, 1mL, 2mL, 500mcg

    DOSAGE & INDICATIONS

    For ventricular rate control in patients with chronic atrial fibrillation and/or atrial flutter†; or for the treatment of narrow-complex paroxysmal supraventricular tachycardia (PSVT)† or for paroxysmal supraventricular tachycardia (PSVT) prophylaxis† in patients without a delta wave on ECG during sinus rhythm; or for the treatment of congestive heart failure.
    NOTE: In patients with undetectable serum digoxin concentrations, the total loading dose should be based on lean body weight and clinical response, and divided into several doses administered at 4- to 8-hour intervals. Higher doses (i.e., concentrations) may be required for treating arrhythmias than for treating heart failure. Patients with moderate-severe renal insufficiency should receive smaller loading doses than patients with normal renal function due to a reduced volume of distribution.
    NOTE: Maintenance doses should be based on lean body weight, clinical response, and renal function. Higher doses (i.e., concentrations) may be required for treating arrhythmias than for treating heart failure. Lower doses should be considered for geriatric patients, patients with impaired renal function, and in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema. In 1 small study of men with NYHA class II or III heart failure who were in normal sinus rhythm, left ventricular function improved significantly on a dose of 0.125 mg/day that produced mean serum concentrations of 0.8 ng/mL but doses of 0.25 mg/day and corresponding higher concentrations of 1.5 ng/mL did not produce further improvement over the lower dosage. In another small study of men with NYHA class II or III heart failure who were in normal sinus rhythm, left ventricular ejection fraction improved significantly when digoxin was increased from a mean dose of 0.2 mg/day (mean trough 0.67 ng/mL) to a mean dose of 0.39 mg/day (mean trough 1.22 ng/mL); however, no significant changes were observed in heart failure score or exercise tolerance.
    For the transplacental treatment of fetal supraventricular tachyarrhythmias†.
    Intravenous dosage
    Adults - Pregnant Females

    A loading dose of 1.2 to 1.5 mg/day IV divided every 8 hours followed by an oral maintenance dose is recommended by the American Heart Association as first or second line therapy for supraventricular tachycardia (SVT) with hydrops or ventricular dysfunction, SVT 200 beats per minute or more without hydrops or ventricular dysfunction, or atrial flutter.

    Oral dosage
    Adults - Pregnant Females

    An IV loading dose followed by maintenance doses of 0.375 to 0.75 mg/day PO divided every 8 to 12 hours is recommended by the American Heart Association as first or second line therapy for supraventricular tachycardia (SVT) with hydrops or ventricular dysfunction, SVT 200 beats per minute or more without hydrops or ventricular dysfunction, or atrial flutter. Alternatively, a loading dose of 1.5 to 2 mg PO given in divided doses over 2 days followed by maintenance doses of 0.375 to 1 mg/day has been used in a retrospective, multicenter study. Twenty-four women pregnant with fetuses diagnosed with fetal atrial flutter (AF) or supraventricular tachycardia (SVT) (30 to 32 weeks mean gestational age at diagnosis) were treated with digoxin first-line; target maternal serum concentrations were 2 to 2.5 ng/mL. Other first-line agents used included sotalol and flecainide. Digoxin and flecainide were associated with a higher conversion of SVT to normal sinus rhythm compared to sotalol; however, sotalol was associated with higher rates of prenatal AF termination. In patients with incessant SVT or AF that persisted to 5 days, median ventricular rates declined more with digoxin and flecainide compared to sotalol.

    Loading Dose - Intravenous or Intramuscular Dosage
    Adults, Adolescents, and Children older than 10 years

    8 to 12 mcg/kg/total loading dose IV or IM divided into 3 doses, with the first dose equaling one-half the total. Administer the remaining half in 2 equally divided doses at 6- to 8-hour intervals with careful assessment of patient response before each dose. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Children 5 to 10 years

    15 to 30 mcg/kg/total loading dose IV or IM divided into 3 doses, with the first dose equaling one-half the total. Administer the remaining half in 2 equally divided doses at 6- to 8-hour intervals with careful assessment of patient response before each dose. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Children 2 to 4 years

    25 to 35 mcg/kg/total loading dose IV or IM divided into 3 doses, with the first dose equaling one-half the total. Administer the remaining half in 2 equally divided doses at 6- to 8-hour intervals with careful assessment of patient response before each dose. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Infants and Children younger than 2 years

    30 to 50 mcg/kg/total loading dose IV or IM divided into 3 doses, with the first dose equaling one-half the total. Administer the remaining half in 2 equally divided doses at 6- to 8-hour intervals with careful assessment of patient response before each dose. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Term Neonates

    20 to 30 mcg/kg/total loading dose IV or IM divided into 3 doses, with the first dose equaling one-half the total. Administer the remaining half in 2 equally divided doses at 6- to 8-hour intervals with careful assessment of patient response before each dose. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Premature Neonates

    15 to 25 mcg/kg/total loading dose IV or IM divided into 3 doses, with the first dose equaling one-half the total. Administer the remaining half in 2 equally divided doses at 6- to 8-hour intervals with careful assessment of patient response before each dose. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Loading Dose- Oral dosage (tablets)
    Adults, Adolescents, and Children older than 10 years

    Total dose of 10 to 15 mcg/kg PO given in 3 divided doses. Administer one-half (50%) the total loading dose initially, then one-fourth (25%) the loading dose every 6 to 8 hours for 2 doses (e.g., 500 mcg PO initially, followed by 250 mcg PO every 6 to 8 hours for 2 doses). Carefully assess patient response before each dose.

    Children 5 to 10 years

    Total dose of 20 to 45 mcg/kg PO given in 3 divided doses. Administer one-half (50%) the total loading dose initially, then one-fourth (25%) the loading dose every 6 to 8 hours for 2 doses. Carefully assess patient response before each dose.

    Loading Dose- Oral dosage (liquid)
    Adults, Adolescents, and Children older than 10 years

    Total dose of 10 to 15 mcg/kg PO divided into 3 or more doses, with the first dose equaling approximately one-half the total. Administer subsequent fractions of the total dose at 4 to 8 hour intervals with careful assessment of patient response before each dose.

    Children 5 to 10 years

    Total dose of 20 to 35 mcg/kg PO divided into 3 or more doses, with the first dose equaling approximately one-half the total. Administer subsequent fractions of the total dose at 4 to 8 hour intervals with careful assessment of patient response before each dose.

    Children 2 to 4 years

    Total dose of 30 to 45 mcg/kg PO divided into 3 or more doses, with the first dose equaling approximately one-half the total. Administer subsequent fractions of the total dose at 4 to 8 hour intervals with careful assessment of patient response before each dose.

    Infants and Children younger than 2 years

    Total dose of 35 to 60 mcg/kg PO divided into 3 or more doses, with the first dose equaling approximately one-half the total. Administer subsequent fractions of the total dose at 4 to 8 hour intervals with careful assessment of patient response before each dose.

    Full-term Neonate

    Total dose of 25 to 35 mcg/kg PO divided into 3 or more doses, with the first dose equaling approximately one-half the total. Administer subsequent fractions of the total dose at 4 to 8 hour intervals with careful assessment of patient response before each dose.

    Premature Neonate

    Total dose of 20 to 30 mcg/kg PO divided into 3 or more doses, with the first dose equaling approximately one-half the total. Administer subsequent fractions of the total dose at 4 to 8 hour intervals with careful assessment of patient response before each dose.

    Maintenance Dose -Intravenous or Intramuscular Dosage
    Adults, Adolescents, and Children older than 10 years

    2.4 to 3.6 mcg/kg/day IV or IM given once daily is the recommended starting maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute per 70 kg or mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Children 5 to 10 years

    4.6 to 9 mcg/kg/day IV or IM divided into 2 daily doses is the recommended starting maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Children 2 to 4 years

    7.6 to 10.6 mcg/kg/day IV or IM divided into 2 daily doses is the recommended starting maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Infants and Children younger than 2 years

    9 to 15 mcg/kg/day IV or IM divided into 2 daily doses is the recommended starting maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Term Neonates

    6 to 9 mcg/kg/day IV or IM divided into 2 daily doses is the recommended starting maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Preterm Neonates

    3.8 to 6.2 mcg/kg/day IV or IM divided into 2 daily doses is the recommended starting maintenance dose. Adjust dosage based on clinical response. IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.

    Maintenance Dose - Oral dosage (tablets)
    Adults, Adolescents, and Children older than 10 years

    3.4 to 5.1 mcg/kg/day PO given once daily is the recommended starting maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute per 70 kg or mL/minute/1.73 m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements. Monitor serum digoxin concentrations and adjust dosage accordingly. Doses are rounded to the nearest whole/half tablet. Use special care in geriatric adults. According to the Beers Criteria, digoxin is considered a potentially inappropriate medication (PIM) in geriatric adults and should be avoided as first-line therapy for atrial fibrillation or heart failure; if use is necessary, the drug should not be prescribed in daily doses greater than 0.125 mg.

    Children 5 to 10 years

    6.4 to 12.9 mcg/kg/day PO in 2 divided doses is the recommended starting maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements. Monitor serum digoxin concentrations and adjust dosage accordingly. Doses are rounded to the nearest whole/half tablet.

    Maintenance Dose - Oral dosage (liquid)
    Adults, Adolescents, and Children older than 10 years

    3 to 4.5 mcg/kg/day PO given once daily is the estimated maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute per 70 kg or mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements. Use special care in geriatric adults. According to the Beers Criteria, digoxin is considered a potentially inappropriate medication (PIM) in geriatric adults and should be avoided as first-line therapy for atrial fibrillation or heart failure; if use is necessary, the drug should not be prescribed in daily doses greater than 0.125 mg.

    Children 5 to 10 years

    5.6 to 11.3 mcg/kg/day PO in 2 divided doses is the estimated maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements.

    Children 2 to 4 years

    9.4 to 13.1 mcg/kg/day PO in 2 divided doses is the estimated maintenance dose. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements.

    Infants and Children younger than 2 years

    11.3 to 18.8 mcg/kg/day PO in 2 divided doses is the estimated maintenance dosage. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements.

    Term Neonates

    7.5 to 11.3 mcg/kg/day PO in 2 divided doses is the estimated maintenance dosage range. Usual daily maintenance dose requirements for the treatment of congestive heart failure are based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). See renal impairment dosing for usual maintenance dose requirements.

    Preterm Neonates

    4.7 to 7.8 mcg/kg/day PO in 2 divided doses is the estimated maintenance dosage range.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Digoxin has a narrow therapeutic index. In all populations, the dosage is individualized based on patient weight, renal function, clinical goals, patient response, and when needed, serum digoxin concentrations.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No specific dosage adjustments are recommended for patients with hepatic impairment. However, patients with combined renal and hepatic impairment may have reduced digoxin clearance and potential for drug accumulation; monitor serum digoxin concentrations and therapeutic response closely in such patients.

    Renal Impairment

    Dosage in patients with renal impairment is based on CrCl and lean body weight.
    Patients with renal impairment have a lower volume of distribution than patients with normal renal function; therefore, both loading and maintenance doses should be reduced.
    Usual daily maintenance dose requirements for the treatment of congestive heart failure in adult and pediatric patients based on corrected CrCl (mL/minute per 70 kg or mL/minute/1.73m2) and lean body weight (LBW) are listed below. Higher doses may be required for treating arrhythmias than for treating heart failure.
     
    Intravenous dosage: Adults, Adolescents, and Children older than 10 years
    CrCl 100 mL/minute/1.73m2 or more:
    LBW 40 to 49 kg: 136 mcg IV once daily.
    LBW 50 to 59 kg: 170 mcg IV once daily.
    LBW 60 to 69 kg: 204 mcg IV once daily.
    LBW 70 to 79 kg: 238 mcg IV once daily.
    LBW 80 to 89 kg: 272 mcg IV once daily.
    LBW 90 to 99 kg: 306 mcg IV once daily.
    LBW 100 kg or more: 340 mcg IV once daily.
     
    CrCl 90 to 99 mL/minute/1.73m2:
    LBW 40 to 49 kg: 128 mcg IV once daily.
    LBW 50 to 59 kg: 160 mcg IV once daily.
    LBW 60 to 69 kg: 192 mcg IV once daily.
    LBW 70 to 79 kg: 224 mcg IV once daily.
    LBW 80 to 89 kg: 256 mcg IV once daily.
    LBW 90 to 99 kg: 288 mcg IV once daily.
    LBW 100 kg or more: 320 mcg IV once daily.
     
    CrCl 80 to 89 mL/minute/1.73m2:
    LBW 40 to 49 kg: 120 mcg IV once daily.
    LBW 50 to 59 kg: 150 mcg IV once daily.
    LBW 60 to 69 kg: 180 mcg IV once daily.
    LBW 70 to 79 kg: 210 mcg IV once daily.
    LBW 80 to 89 kg: 240 mcg IV once daily.
    LBW 90 to 99 kg: 270 mcg IV once daily.
    LBW 100 kg or more: 300 mcg IV once daily.
     
    CrCl 70 to 79 mL/minute/1.73m2:
    LBW 40 to 49 kg: 112 mcg IV once daily.
    LBW 50 to 59 kg: 140 mcg IV once daily.
    LBW 60 to 69 kg: 168 mcg IV once daily.
    LBW 70 to 79 kg: 196 mcg IV once daily.
    LBW 80 to 89 kg: 224 mcg IV once daily.
    LBW 90 to 99 kg: 252 mcg IV once daily.
    LBW 100 kg or more: 280 mcg IV once daily.
     
    CrCl 60 to 69 mL/minute/1.73m2:
    LBW 40 to 49 kg: 104 mcg IV once daily.
    LBW 50 to 59 kg: 130 mcg IV once daily.
    LBW 60 to 69 kg: 156 mcg IV once daily.
    LBW 70 to 79 kg: 182 mcg IV once daily.
    LBW 80 to 89 kg: 208 mcg IV once daily.
    LBW 90 to 99 kg: 234 mcg IV once daily.
    LBW 100 kg or more: 260 mcg IV once daily.
     
    CrCl 50 to 59 mL/minute/1.73m2:
    LBW 40 to 49 kg: 96 mcg IV once daily.
    LBW 50 to 59 kg: 120 mcg IV once daily.
    LBW 60 to 69 kg: 144 mcg IV once daily.
    LBW 70 to 79 kg: 168 mcg IV once daily.
    LBW 80 to 89 kg: 192 mcg IV once daily.
    LBW 90 to 99 kg: 216 mcg IV once daily.
    LBW 100 kg or more: 240 mcg IV once daily.
     
    CrCl 40 to 49 mL/minute/1.73m2:
    LBW 40 to 49 kg: 88 mcg IV once daily.
    LBW 50 to 59 kg: 110 mcg IV once daily.
    LBW 60 to 69 kg: 132 mcg IV once daily.
    LBW 70 to 79 kg: 154 mcg IV once daily.
    LBW 80 to 89 kg: 176 mcg IV once daily.
    LBW 90 to 99 kg: 198 mcg IV once daily.
    LBW 100 kg or more: 220 mcg IV once daily.
     
    CrCl 30 to 39 mL/minute/1.73m2:
    LBW 40 to 49 kg: 80 mcg IV once daily.
    LBW 50 to 59 kg: 100 mcg IV once daily.
    LBW 60 to 69 kg: 120 mcg IV once daily.
    LBW 70 to 79 kg: 140 mcg IV once daily.
    LBW 80 to 89 kg: 160 mcg IV once daily.
    LBW 90 to 99 kg: 180 mcg IV once daily.
    LBW 100 kg or more: 200 mcg IV once daily.
     
    CrCl 20 to 29 mL/minute/1.73m2:
    LBW 40 to 49 kg: 72 mcg IV once daily.
    LBW 50 to 59 kg: 90 mcg IV once daily.
    LBW 60 to 69 kg: 108 mcg IV once daily.
    LBW 70 to 79 kg: 126 mcg IV once daily.
    LBW 80 to 89 kg: 144 mcg IV once daily.
    LBW 90 to 99 kg: 162 mcg IV once daily.
    LBW 100 kg or more: 180 mcg IV once daily.
     
    CrCl 10 to 19 mL/minute/1.73m2:
    LBW 40 to 49 kg: 64 mcg IV once daily.
    LBW 50 to 59 kg: 80 mcg IV once daily.
    LBW 60 to 69 kg: 96 mcg IV once daily.
    LBW 70 to 79 kg: 112 mcg IV once daily.
    LBW 80 to 89 kg: 128 mcg IV once daily.
    LBW 90 to 99 kg: 144 mcg IV once daily.
    LBW 100 kg or more: 160 mcg IV once daily.
     
    Intravenous dosage: Infants and Children 10 years and younger
    CrCl 100 mL/minute/1.73m2 or more:
    LBW 5 to 9 kg: 17 mcg IV twice daily.
    LBW 10 to 19 kg: 34 mcg IV twice daily.
    LBW 20 to 29 kg: 68 mcg IV twice daily.
    LBW 30 to 39 kg: 102 mcg IV twice daily.
    LBW 40 to 49 kg: 136 mcg IV twice daily.
    LBW 50 to 59 kg: 170 mcg IV twice daily.
    LBW 60 to 69 kg: 204 mcg IV twice daily.
     
    CrCl 90 to 99 mL/minute/1.73m2:
    LBW 5 to 9 kg: 16 mcg IV twice daily.
    LBW 10 to 19 kg: 32 mcg IV twice daily.
    LBW 20 to 29 kg: 64 mcg IV twice daily.
    LBW 30 to 39 kg: 96 mcg IV twice daily.
    LBW 40 to 49 kg: 128 mcg IV twice daily.
    LBW 50 to 59 kg: 160 mcg IV twice daily.
    LBW 60 to 69 kg: 192 mcg IV twice daily.
     
    CrCl 80 to 89 mL/minute/1.73m2:
    LBW 5 to 9 kg: 15 mcg IV twice daily.
    LBW 10 to 19 kg: 30 mcg IV twice daily.
    LBW 20 to 29 kg: 60 mcg IV twice daily.
    LBW 30 to 39 kg: 90 mcg IV twice daily.
    LBW 40 to 49 kg: 120 mcg IV twice daily.
    LBW 50 to 59 kg: 150 mcg IV twice daily.
    LBW 60 to 69 kg: 180 mcg IV twice daily.
     
    CrCl 70 to 79 mL/minute/1.73m2:
    LBW 5 to 9 kg: 14 mcg IV twice daily.
    LBW 10 to 19 kg: 28 mcg IV twice daily.
    LBW 20 to 29 kg: 56 mcg IV twice daily.
    LBW 30 to 39 kg: 84 mcg IV twice daily.
    LBW 40 to 49 kg: 112 mcg IV twice daily.
    LBW 50 to 59 kg: 140 mcg IV twice daily.
    LBW 60 to 69 kg: 168 mcg IV twice daily.
     
    CrCl 60 to 69 mL/minute/1.73m2:
    LBW 5 to 9 kg: 13 mcg IV twice daily.
    LBW 10 to 19 kg: 26 mcg IV twice daily.
    LBW 20 to 29 kg: 52 mcg IV twice daily.
    LBW 30 to 39 kg: 78 mcg IV twice daily.
    LBW 40 to 49 kg: 104 mcg IV twice daily.
    LBW 50 to 59 kg: 130 mcg IV twice daily.
    LBW 60 to 69 kg: 156 mcg IV twice daily.
     
    CrCl 50 to 59 mL/minute/1.73m2:
    LBW 5 to 9 kg: 12 mcg IV twice daily.
    LBW 10 to 19 kg: 24 mcg IV twice daily.
    LBW 20 to 29 kg: 48 mcg IV twice daily.
    LBW 30 to 39 kg: 72 mcg IV twice daily.
    LBW 40 to 49 kg: 96 mcg IV twice daily.
    LBW 50 to 59 kg: 120 mcg IV twice daily.
    LBW 60 to 69 kg: 144 mcg IV twice daily.
     
    CrCl 40 to 49 mL/minute/1.73m2:
    LBW 5 to 9 kg: 11 mcg IV twice daily.
    LBW 10 to 19 kg: 22 mcg IV twice daily.
    LBW 20 to 29 kg: 44 mcg IV twice daily.
    LBW 30 to 39 kg: 66 mcg IV twice daily.
    LBW 40 to 49 kg: 88 mcg IV twice daily.
    LBW 50 to 59 kg: 110 mcg IV twice daily.
    LBW 60 to 69 kg: 132 mcg IV twice daily.
     
    CrCl 30 to 39 mL/minute/1.73m2:
    LBW 5 to 9 kg: 10 mcg IV twice daily.
    LBW 10 to 19 kg: 20 mcg IV twice daily.
    LBW 20 to 29 kg: 40 mcg IV twice daily.
    LBW 30 to 39 kg: 60 mcg IV twice daily.
    LBW 40 to 49 kg: 80 mcg IV twice daily.
    LBW 50 to 59 kg: 100 mcg IV twice daily.
    LBW 60 to 69 kg: 120 mcg IV twice daily.
     
    CrCl 20 to 29 mL/minute/1.73m2:
    LBW 5 to 9 kg: 9 mcg IV twice daily.
    LBW 10 to 19 kg: 18 mcg IV twice daily.
    LBW 20 to 29 kg: 36 mcg IV twice daily.
    LBW 30 to 39 kg: 54 mcg IV twice daily.
    LBW 40 to 49 kg: 72 mcg IV twice daily.
    LBW 50 to 59 kg: 90 mcg IV twice daily.
    LBW 60 to 69 kg: 108 mcg IV twice daily.
     
    CrCl 10 to 19 mL/minute/1.73m2:
    LBW 5 to 9 kg: 8 mcg IV twice daily.
    LBW 10 to 19 kg: 16 mcg IV twice daily.
    LBW 20 to 29 kg: 32 mcg IV twice daily.
    LBW 30 to 39 kg: 48 mcg IV twice daily.
    LBW 40 to 49 kg: 64 mcg IV twice daily.
    LBW 50 to 59 kg: 80 mcg IV twice daily.
    LBW 60 to 69 kg: 96 mcg IV twice daily.
     
    Oral dosage (tablets): Adults, Adolescents, and Children older than 10 years
    CrCl 100 mL/minute/1.73m2 or more:
    LBW 40 to 49 kg: 187.5 mcg PO once daily.
    LBW 50 to 59 kg: 250 mcg PO once daily.
    LBW 60 to 79 kg: 312.5 mcg PO once daily.
    LBW 80 to 89 kg: 375 mcg PO once daily.
    LBW 90 to 99 kg: 437.5 mcg PO once daily.
    LBW 100 kg or more: 500 mcg PO once daily.
     
    CrCl 90 to 99 mL/minute/1.73m2:
    LBW 40 to 49 kg: 187.5 mcg PO once daily.
    LBW 50 to 69 kg: 250 mcg PO once daily.
    LBW 70 to 79 kg: 312.5 mcg PO once daily.
    LBW 80 to 89 kg: 375 mcg PO once daily.
    LBW 90 kg or more: 437.5 mcg PO once daily.
     
    CrCl 80 to 89 mL/minute/1.73m2:
    LBW 40 to 59 kg: 187.5 mcg PO once daily.
    LBW 60 to 69 kg: 250 mcg PO once daily.
    LBW 70 to 89 kg: 312.5 mcg PO once daily.
    LBW 90 to 99 kg: 375 mcg PO once daily.
    LBW 100 kg or more: 437.5 mcg PO once daily.
     
    CrCl 70 to 79 mL/minute/1.73m2:
    LBW 40 to 59 kg: 187.5 mcg PO once daily.
    LBW 60 to 79 kg: 250 mcg PO once daily.
    LBW 80 to 89 kg: 312.5 mcg PO once daily.
    LBW 90 kg or more: 375 mcg PO once daily.
     
    CrCl 60 to 69 mL/minute/1.73m2:
    LBW 40 to 49 kg: 125 mcg PO once daily.
    LBW 50 to 59 kg: 187.5 mcg PO once daily.
    LBW 60 to 79 kg: 250 mcg PO once daily.
    LBW 80 to 99 kg: 312.5 mcg PO once daily.
    LBW 100 kg or more: 375 mcg PO once daily.
     
    CrCl 40 to 59 mL/minute/1.73m2:
    LBW 40 to 49 kg: 125 mcg PO once daily.
    LBW 50 to 69 kg: 187.5 mcg PO once daily.
    LBW 70 to 89 kg: 250 mcg PO once daily.
    LBW 90 kg or more: 312.5 mcg PO once daily.
     
    CrCl 30 to 39 mL/minute/1.73m2:
    LBW 40 to 59 kg: 125 mcg PO once daily.
    LBW 60 to 79 kg: 187.5 mcg PO once daily.
    LBW 80 to 99 kg: 250 mcg PO once daily.
    LBW 100 kg or more: 312.5 mcg PO once daily.
     
    CrCl 20 to 29 mL/minute/1.73m2:
    LBW 40 to 69 kg: 125 mcg PO once daily.
    LBW 70 to 89 kg: 187.5 mcg PO once daily.
    LBW 90 kg or more: 250 mcg PO once daily.
     
    CrCl less than 20 mL/minute/1.73m2:
    LBW 40 to 49 kg: 62.5 mcg PO once daily.
    LBW 50 to 69 kg: 125 mcg PO once daily.
    LBW 70 to 99 kg: 187.5 mcg PO once daily.
    LBW 100 kg or more: 250 mcg PO once daily.
     
    Oral dosage (tablets): Children 10 years and younger
    NOTE: Doses are rounded to the nearest whole/half tablet
    CrCl 100 mL/minute/1.73m2 or more:
    LBW 20 to 29 kg: 62.5 mcg PO twice daily.
    LBW 30 to 39 kg: 125 mcg PO twice daily.
    LBW 40 to 49 kg: 187.5 mcg PO twice daily.
    LBW 50 to 59 kg: 250 mcg PO twice daily.
    LBW 60 to 69 kg: 312.5 mcg PO twice daily.
     
    CrCl 90 to 99 mL/minute/1.73m2:
    LBW 20 to 29 kg: 62.5 mcg PO twice daily.
    LBW 30 to 39 kg: 125 mcg PO twice daily.
    LBW 40 to 49 kg: 187.5 mcg PO twice daily.
    LBW 50 to 69 kg: 250 mcg PO twice daily.
     
    CrCl 80 to 89 mL/minute/1.73m2:
    LBW 20 to 29 kg: 62.5 mcg PO twice daily.
    LBW 30 to 39 kg: 125 mcg PO twice daily.
    LBW 40 to 59 kg: 187.5 mcg PO twice daily.
    LBW 60 to 69 kg: 250 mcg PO twice daily.
     
    CrCl 70 to 79 mL/minute/1.73m2:
    LBW 20 to 29 kg: 62.5 mcg PO twice daily.
    LBW 30 to 39 kg: 125 mcg PO twice daily.
    LBW 40 to 59 kg: 187.5 mcg PO twice daily.
    LBW 60 to 69 kg: 250 mcg PO twice daily.
     
    CrCl 60 to 69 mL/minute/1.73m2:
    LBW 20 to 29 kg: 62.5 mcg PO twice daily.
    LBW 30 to 49 kg: 125 mcg PO twice daily.
    LBW 50 to 59 kg: 187.5 mcg PO twice daily.
    LBW 60 to 69 kg: 250 mcg PO twice daily.
     
    CrCl 50 to 59 mL/minute/1.73m2:
    LBW 20 to 29 kg: 62.5 mcg PO twice daily.
    LBW 30 to 49 kg: 125 mcg PO twice daily.
    LBW 50 to 69 kg: 187.5 mcg PO twice daily.
     
    CrCl 40 to 49 mL/minute/1.73m2:
    LBW 20 to 39 kg: 62.5 mcg PO twice daily.
    LBW 40 to 49 kg: 125 mcg PO twice daily.
    LBW 50 to 69 kg: 187.5 mcg PO twice daily.
     
    CrCl 30 to 39 mL/minute/1.73m2:
    LBW 20 to 39 kg: 62.5 mcg PO twice daily.
    LBW 40 to 59 kg: 125 mcg PO twice daily.
    LBW 60 to 69 kg: 187.5 mcg PO twice daily.
     
    CrCl 20 to 29 mL/minute/1.73m2:
    LBW 20 to 39 kg: 62.5 mcg PO twice daily.
    LBW 40 to 69 kg: 125 mcg PO twice daily.
     
    CrCl less than 20 mL/minute/1.73m2:
    LBW 30 to 49 kg: 62.5 mcg PO twice daily.
    LBW 50 to 69 kg: 125 mcg PO twice daily.
     
    Oral dosage (liquid): Adults, Adolescents, and Children older than 10 years
    CrCl 100 mL/minute/1.73m2 or more:
    LBW 40 to 49 kg: 170 mcg PO once daily.
    LBW 50 to 59 kg: 213 mcg PO once daily.
    LBW 60 to 69 kg: 255 mcg PO once daily.
    LBW 70 to 79 kg: 298 mcg PO once daily.
    LBW 80 to 89 kg: 340 mcg PO once daily.
    LBW 90 to 99 kg: 383 mcg PO once daily.
    LBW 100 kg or more: 425 mcg PO once daily.
     
    CrCl 90 to 99 mL/minute/1.73m2:
    LBW 40 to 49 kg: 160 mcg PO once daily.
    LBW 50 to 59 kg: 200 mcg PO once daily.
    LBW 60 to 69 kg: 240 mcg PO once daily.
    LBW 70 to 79 kg: 280 mcg PO once daily.
    LBW 80 to 89 kg: 320 mcg PO once daily.
    LBW 90 to 99 kg: 360 mcg PO once daily.
    LBW 100 kg or more: 400 mcg PO once daily.
     
    CrCl 80 to 89 mL/minute/1.73m2:
    LBW 40 to 49 kg: 150 mcg PO once daily.
    LBW 50 to 59 kg: 188 mcg PO once daily.
    LBW 60 to 69 kg: 225 mcg PO once daily.
    LBW 70 to 79 kg: 263 mcg PO once daily.
    LBW 80 to 89 kg: 300 mcg PO once daily.
    LBW 90 to 99 kg: 338 mcg PO once daily.
    LBW 100 kg or more: 375 mcg PO once daily.
     
    CrCl 70 to 79 mL/minute/1.73m2:
    LBW 40 to 49 kg: 140 mcg PO once daily.
    LBW 50 to 59 kg: 175 mcg PO once daily.
    LBW 60 to 69 kg: 210 mcg PO once daily.
    LBW 70 to 79 kg: 245 mcg PO once daily.
    LBW 80 to 89 kg: 280 mcg PO once daily.
    LBW 90 to 99 kg: 315 mcg PO once daily.
    LBW 100 kg or more: 350 mcg PO once daily.
     
    CrCl 60 to 69 mL/minute/1.73m2:
    LBW 40 to 49 kg: 130 mcg PO once daily.
    LBW 50 to 59 kg: 163 mcg PO once daily.
    LBW 60 to 69 kg: 195 mcg PO once daily.
    LBW 70 to 79 kg: 228 mcg PO once daily.
    LBW 80 to 89 kg: 260 mcg PO once daily.
    LBW 90 to 99 kg: 293 mcg PO once daily.
    LBW 100 kg or more: 325 mcg PO once daily.
     
    CrCl 50 to 59 mL/minute/1.73m2:
    LBW 40 to 49 kg: 120 mcg PO once daily.
    LBW 50 to 59 kg: 150 mcg PO once daily.
    LBW 60 to 69 kg: 180 mcg PO once daily.
    LBW 70 to 79 kg: 210 mcg PO once daily.
    LBW 80 to 89 kg: 240 mcg PO once daily.
    LBW 90 to 99 kg: 270 mcg PO once daily.
    LBW 100 kg or more: 300 mcg PO once daily.
     
    CrCl 40 to 49 mL/minute/1.73m2:
    LBW 40 to 49 kg: 110 mcg PO once daily
    LBW 50 to 59 kg: 138 mcg PO once daily.
    LBW 60 to 69 kg: 165 mcg PO once daily.
    LBW 70 to 79 kg: 193 mcg PO once daily.
    LBW 80 to 89 kg: 220 mcg PO once daily.
    LBW 90 to 99 kg: 248 mcg PO once daily.
    LBW 100 kg or more: 275 mcg PO once daily.
     
    CrCl 30 to 39 mL/minute/1.73m2:
    LBW 40 to 49 kg: 100 mcg PO once daily.
    LBW 50 to 59 kg: 125 mcg PO once daily.
    LBW 60 to 69 kg: 150 mcg PO once daily.
    LBW 70 to 79 kg: 175 mcg PO once daily.
    LBW 80 to 89 kg: 200 mcg PO once daily.
    LBW 90 to 99 kg: 225 mcg PO once daily.
    LBW 100 kg or more: 250 mcg PO once daily.
     
    CrCl 20 to 29 mL/minute/1.73m2:
    LBW 40 to 49 kg: 90 mcg PO once daily.
    LBW 50 to 59 kg: 113 mcg PO once daily.
    LBW 60 to 69 kg: 135 mcg PO once daily.
    LBW 70 to 79 kg: 158 mcg PO once daily.
    LBW 80 to 89 kg: 180 mcg PO once daily.
    LBW 90 to 99 kg: 203 mcg PO once daily.
    LBW 100 kg or more: 225 mcg PO once daily.
     
    CrCl less than 20 mL/minute/1.73m2:
    LBW 40 to 49 kg: 80 mcg PO once daily.
    LBW 50 to 59 kg: 100 mcg PO once daily.
    LBW 60 to 69 kg: 120 mcg PO once daily.
    LBW 70 to 79 kg: 140 mcg PO once daily.
    LBW 80 to 89 kg: 160 mcg PO once daily.
    LBW 90 to 99 kg: 180 mcg PO once daily.
    LBW 100 kg or more: 200 mcg PO once daily.
     
    Oral dosage (liquid): Infants and Children 10 years and younger
    CrCl 100 mL/minute/1.73m2 or more:
    LBW 5 to 9 kg: 21 mcg PO twice daily.
    LBW 10 to 19 kg: 43 mcg PO twice daily.
    LBW 20 to 29 kg: 85 mcg PO twice daily.
    LBW 30 to 39 kg: 128 mcg PO twice daily.
    LBW 40 to 49 kg: 170 mcg PO twice daily.
    LBW 50 to 59 kg: 213 mcg PO twice daily.
    LBW 60 to 69 kg: 255 mcg PO twice daily.
     
    CrCl 90 to 99 mL/minute/1.73m2:
    LBW 5 to 9 kg: 20 mcg PO twice daily.
    LBW 10 to 19 kg: 40 mcg PO twice daily.
    LBW 20 to 29 kg: 80 mcg PO twice daily.
    LBW 30 to 39 kg: 120 mcg PO twice daily.
    LBW 40 to 49 kg: 160 mcg PO twice daily.
    LBW 50 to 59 kg: 200 mcg PO twice daily.
    LBW 60 to 69 kg: 240 mcg PO twice daily.
     
    CrCl 80 to 89 mL/minute/1.73m2:
    LBW 5 to 9 kg: 19 mcg PO twice daily.
    LBW 10 to 19 kg: 38 mcg PO twice daily.
    LBW 20 to 29 kg: 75 mcg PO twice daily.
    LBW 30 to 39 kg: 113 mcg PO twice daily.
    LBW 40 to 49 kg: 150 mcg PO twice daily.
    LBW 50 to 59 kg: 188 mcg PO twice daily.
    LBW 60 to 69 kg: 225 mcg PO twice daily.
     
    CrCl 70 to 79 mL/minute/1.73m2:
    LBW 5 to 9 kg: 18 mcg PO twice daily.
    LBW 10 to 19 kg: 35 mcg PO twice daily.
    LBW 20 to 29 kg: 70 mcg PO twice daily.
    LBW 30 to 39 kg: 105 mcg PO twice daily.
    LBW 40 to 49 kg: 140 mcg PO twice daily.
    LBW 50 to 59 kg: 175 mcg PO twice daily.
    LBW 60 to 69 kg: 210 mcg PO twice daily.
     
    CrCl 60 to 69 mL/minute/1.73m2:
    LBW 5 to 9 kg: 16 mcg PO twice daily.
    LBW 10 to 19 kg: 33 mcg PO twice daily.
    LBW 20 to 29 kg: 65 mcg PO twice daily.
    LBW 30 to 39 kg: 98 mcg PO twice daily.
    LBW 40 to 49 kg: 130 mcg PO twice daily.
    LBW 50 to 59 kg: 163 mcg PO twice daily.
    LBW 60 to 69 kg: 195 mcg PO twice daily.
     
    CrCl 50 to 59 mL/minute/1.73m2:
    LBW 5 to 9 kg: 15 mcg PO twice daily.
    LBW 10 to 19 kg: 30 mcg PO twice daily.
    LBW 20 to 29 kg: 60 mcg PO twice daily.
    LBW 30 to 39 kg: 90 mcg PO twice daily.
    LBW 40 to 49 kg: 120 mcg PO twice daily.
    LBW 50 to 59 kg: 150 mcg PO twice daily.
    LBW 60 to 69 kg: 180 mcg PO twice daily.
     
    CrCl 40 to 49 mL/minute/1.73m2:
    LBW 5 to 9 kg: 14 mcg PO twice daily.
    LBW 10 to 19 kg: 28 mcg PO twice daily.
    LBW 20 to 29 kg: 55 mcg PO twice daily.
    LBW 30 to 39 kg: 83 mcg PO twice daily.
    LBW 40 to 49 kg: 110 mcg PO twice daily.
    LBW 50 to 59 kg: 138 mcg PO twice daily.
    LBW 60 to 69 kg: 165 mcg PO twice daily.
     
    CrCl 30 to 39 mL/minute/1.73m2:
    LBW 5 to 9 kg: 13 mcg PO twice daily.
    LBW 10 to 19 kg: 25 mcg PO twice daily.
    LBW 20 to 29 kg: 50 mcg PO twice daily.
    LBW 30 to 39 kg: 75 mcg PO twice daily.
    LBW 40 to 49 kg: 100 mcg PO twice daily.
    LBW 50 to 59 kg: 125 mcg PO twice daily.
    LBW 60 to 69 kg: 150 mcg PO twice daily.
     
    CrCl 20 to 29 mL/minute/1.73m2:
    LBW 5 to 9 kg: 11 mcg PO twice daily.
    LBW 10 to 19 kg: 23 mcg PO twice daily.
    LBW 20 to 29 kg: 45 mcg PO twice daily.
    LBW 30 to 39 kg: 68 mcg PO twice daily.
    LBW 40 to 49 kg: 90 mcg PO twice daily.
    LBW 50 to 59 kg: 113 mcg PO twice daily.
    LBW 60 to 69 kg: 135 mcg PO twice daily.
     
    CrCl less than 20 mL/minute/1.73m2:
    LBW 5 to 9 kg: 10 mcg PO twice daily.
    LBW 10 to 19 kg: 20 mcg PO twice daily.
    LBW 20 to 29 kg: 40 mcg PO twice daily.
    LBW 30 to 39 kg: 60 mcg PO twice daily.
    LBW 40 to 49 kg: 80 mcg PO twice daily.
    LBW 50 to 59 kg: 100 mcg PO twice daily.
    LBW 60 to 69 kg: 120 mcg PO twice daily.

    ADMINISTRATION

    Oral Administration

    All dosage forms: May be administered without regard to meals.

    Oral Solid Formulations

    Tablets: May be crushed and administered with food or fluids.

    Oral Liquid Formulations

    Pediatric elixir: Administer using a calibrated measuring device.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Administer intramuscularly (IM) or intravenously (IV). The IV route is preferred due to more rapid therapeutic effect and less pain.
    Oral therapy should replace parenteral therapy as soon as possible.

    Intravenous Administration

    May be given undiluted or each 1 mL may be diluted in 4 mL of sterile water for injection, 0.9% Sodium Chloride for injection, or 5% Dextrose for injection. Diluent volumes less than 4 mL will cause precipitation. Use diluted solutions immediately.
    Inject over at least 5 minutes. Rapid injection may cause systemic and coronary arteriolar constriction.
    If tuberculin syringes are used to measure very small doses, do not flush the syringe with the parenteral solution after its contents are expelled into an indwelling vascular catheter to avoid over administration of digoxin.

    Intramuscular Administration

    IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes cannot be used.
    In adults, do not administer more than 500 mcg at any one IM injection site. In pediatric patients, do not administer more than 200 mcg at any one injection site.
    If IM administration must be used, inject deep into the muscle. Aspirate prior to injection to avoid injection into a blood vessel. Massage area after administration.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Digitek :
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    - Store in a dry place
    Lanoxicaps:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Lanoxin:
    - Do not freeze
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Lanoxin Pediatric:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Acute myocardial infarction, Adams-Stokes syndrome, AV block, bradycardia, cardiomyopathy, cor pulmonale, hyperthyroidism, hypothyroidism, hypoxemia, myocarditis, myxedema, pulmonary disease, sick sinus syndrome

    Digoxin can exacerbate bradycardia or SA block, and should be used with caution in patients with sick sinus syndrome. In patients with sinus node disease or significant AV block, consideration should be given to the insertion of a pacemaker before treatment with digoxin. Digoxin is not recommended in patients with acute myocardial infarction; use of digoxin in these patients may result in undesirable increases in myocardial oxygen demand and ischemia. Digoxin should be avoided in patients with myocarditis, because it can precipitate vasoconstriction and may promote production of pro-inflammatory cytokines. Digoxin should be used with great caution in patients with severe bradycardia or significant AV block (including second degree or intermittent complete heart block), particularly in unstable patients (e.g., acute myocardial infarction or acute myocarditis) or patients with Adams-Stokes syndrome, because complete heart block can result. Digoxin should also be used with caution in patients with severe pulmonary disease, acute cor pulmonale, hypoxemia, hypothyroidism or myxedema, severe heart failure, amyloid cardiomyopathy, restrictive cardiomyopathy, or an otherwise damaged myocardium because the myocardium is more sensitive to the effects of digoxin, increasing the risk of digitalis-induced arrhythmias. Digoxin should not be used in patients with left ventricular failure associated with predominant diastolic dysfunction, since increased cytosolic calcium levels could worsen diastolic dysfunction and digoxin is less effective for this type of heart failure. Digoxin can lower heart rate and paradoxically worsen low cardiac output states of patients with valvular stenosis, chronic pericarditis, or chronic cor pulmonale. Patients with hyperthyroidism may be less sensitive to digoxin and may require higher doses.

    Carotid sinus hypersensitivity, ventricular arrhythmias, ventricular fibrillation, ventricular tachycardia, Wolff-Parkinson-White syndrome

    Digoxin use is relatively contraindicated in patients with ventricular arrhythmias including premature ventricular contractions or ventricular tachycardia because the drug can exacerbate these arrhythmias. Digoxin is absolutely contraindicated in patients with ventricular fibrillation; carotid sinus massage has been reported to cause ventricular fibrillation in patients receiving digoxin. Digoxin is relatively contraindicated in patients with carotid sinus hypersensitivity because the drug increases vagal tone. The use of digoxin in patients with Wolff-Parkinson-White syndrome can cause fatal ventricular arrhythmias, especially when this condition is associated with atrial fibrillation.

    Renal disease, renal failure, renal impairment

    Patients with renal disease, such as acute glomerulonephritis, associated with heart failure should use digoxin with caution. Use of a lower daily dose is recommended with appropriate ECG monitoring based on clinical goals and patient conditions. Digoxin should be used with caution in patients with renal impairment including renal failure because 50% of digoxin is eliminated unchanged via the kidneys. Renal impairment reduces the excretion of the drug and can cause toxicity. Dosages should be decreased, and it should be kept in mind that the time required to reach steady-state concentrations can be prolonged in patients with renal failure.

    Geriatric

    Geriatric patients and debilitated patients require careful dosage titration because they can be more sensitive to the effects of digoxin and can experience toxic reactions at dosages that are usually well tolerated in other patients. Toxicity may occur even if serum digoxin levels appear to be within the accepted therapeutic range. According to the Beers Criteria, digoxin is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided as a first-line agent for atrial fibrillation, because more effective alternatives exist and digoxin may be associated with increased mortality. In addition, the Beers expert panel considers digoxin to have questionable effects on the risk of hospitalization in patients with heart failure, and digoxin may be associated with increased mortality in older adults with heart failure. Therefore, the Panel recommends avoiding digoxin as a first-line therapy for heart failure. Higher dosages of digoxin are not associated with additional benefit and may increase the risk of toxicity in patients with heart failure. If digoxin must be used for atrial fibrillation or heart failure, the Panel recommends avoiding dosages higher than 0.125 mg/day. Because decreased renal clearance of digoxin may lead to an increased risk of toxic effects, further dose reductions may be necessary in patients with Stage 4 or 5 chronic kidney disease. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, digoxin is indicated only for the treatment of heart failure, atrial fibrillation or flutter, and paroxysmal supraventricular tachycardia. Daily doses of digoxin in older adults should generally not exceed 0.125 mg/day except when used to control atrial arrhythmias and ventricular rate. Digoxin should be used cautiously in patients with impaired kidney function, kidney failure, or fluid/electrolyte imbalances. Renal function should be closely monitored, as well as digoxin levels, safety, and tolerability. Adverse consequences may develop with therapeutic serum concentrations, particularly in older adults. There are many potential drug interactions that may result in digoxin toxicity or elevated concentrations of other medications. Significant bradycardia is possible, especially during use with other medications affecting cardiac conduction. Digoxin has anticholinergic properties which may be problematic in the elderly. Toxicity may manifest as fatigue, nausea/vomiting, anorexia, delirium, and cardiac arrhythmias. The OBRA guidelines also caution that antiarrhythmic agents can have serious adverse effects (e.g., impairment of mental function, appetite, behavior, heart function, or falls) in older individuals.

    Hepatic disease

    Digoxin should be used with caution in patients with hepatic disease. No specific dosage adjustments are recommended for patients with hepatic impairment. However, patients with combined renal and hepatic impairment may have reduced digoxin clearance and potential for drug accumulation; monitor serum digoxin concentrations and therapeutic response closely in such patients. The risk of digoxin accumulation in patients with hepatic disease is much less than with digitoxin, which is extensively metabolized.

    Constrictive pericarditis, idiopathic hypertrophic subaortic stenosis

    Patients with chronic constrictive pericarditis can respond unfavorably to digoxin therapy because the drug slows the heart rate, which further reduces cardiac output. Digoxin is relatively contraindicated in patients with idiopathic hypertrophic subaortic stenosis because the drug can increase the obstruction to left ventricular outflow.

    Electrolyte imbalance, hypercalcemia, hyperkalemia, hypocalcemia, hypokalemia, hypomagnesemia

    Digoxin should be used with caution in patients with electrolyte imbalance. Conditions such as hypokalemia, hypomagnesemia, hypercalcemia, chronic pulmonary disease, and acute hypoxemia can increase cardiac sensitivity to digoxin, resulting in toxicity and potential for proarrhythmias. Patients with hypercalcemia or severe hyperkalemia can have an increased risk of digitalis-induced arrhythmias, particularly heart block. Digoxin may not be effective in patients with hypocalcemia; administration of calcium may be necessary.

    Hypertension

    IV administration of digoxin can transiently increase blood pressure and should be used cautiously in patients with hypertension.

    Infants, neonates, premature neonates

    Neonates and young infants display considerable variability in their tolerance and response to digoxin. Premature neonates are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity and renal function.

    Pregnancy

    Digoxin is classified in FDA pregnancy risk category C, although digoxin is considered by many cardiologists to be one of the safest antiarrhythmics for use during pregnancy. Digoxin readily passes to the fetal circulation; however, this drug has been used safely and effectively off-label for decades to treat both maternal and fetal arrhythmias. No teratogenic effect has been reported in humans. The typical dosage in pregnancy is similar to that given a non-pregnant woman. There may be difficulty, particularly in the third trimester, in interpreting serum digoxin levels as a result of an increase in an endogenous digoxin-like substance that may interfere with the digoxin assays. Thus, digoxin levels may give the impression of supratherapeutic dosing; clinicians should interpret the results in accordance with the clinical status of the mother and fetus before making dosage adjustments based on levels alone. As with most drugs, the use of digoxin during pregnancy should be avoided unless the potential benefit of digoxin therapy to the fetus or mother outweighs the potential risk to the fetus.

    Breast-feeding

    Although digoxin is transferred to breast milk to some degree, digoxin therapy during lactation appears to be safe. The American Academy of Pediatrics generally considers the use of digoxin to be compatible with breast-feeding.

    Diarrhea, malabsorption syndrome

    The absorption of digoxin may be reduced in patients with malabsorption syndrome (e.g., chronic diarrhea, short bowel syndrome, celiac sprue, jejunoileal bypass).

    Intramuscular administration

    Intramuscular administration of digoxin causes considerable pain at the injection site and is generally not recommended. If IM administration must be used, inject deeply into a large muscle mass, and massage area after administration.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 3.3-3.3
    cardiac arrest / Early / 0.8-0.8
    bradycardia / Rapid / Incidence not known
    atrial fibrillation / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    atrial tachycardia / Early / Incidence not known
    AV block / Early / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    bowel necrosis / Delayed / Incidence not known
    bowel ischemia / Delayed / Incidence not known

    Moderate

    sinus tachycardia / Rapid / 1.6-1.6
    palpitations / Early / 0.8-0.8
    premature ventricular contractions (PVCs) / Early / 0.8-0.8
    ST-T wave changes / Rapid / Incidence not known
    hypokalemia / Delayed / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    PR prolongation / Rapid / Incidence not known
    confusion / Early / Incidence not known
    delirium / Early / Incidence not known
    hallucinations / Early / Incidence not known
    depression / Delayed / Incidence not known
    xanthopsia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    dizziness / Early / 4.9-4.9
    nausea / Early / 3.3-3.3
    diarrhea / Early / 3.3-3.3
    anxiety / Delayed / 3.3-3.3
    headache / Early / 3.3-3.3
    vomiting / Early / 1.6-1.6
    rash (unspecified) / Early / 1.6-1.6
    anorexia / Delayed / 0.8-0.8
    premature atrial contractions (PACs) / Early / Incidence not known
    weakness / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Moderate) Acarbose, an alpha-glucosidase inhibitor, has been found to decrease the mean bioavailability (AUC) of digoxin by 16% (90% confidence interval: range 8-23%), decrease the mean Cmax of digoxin by 26% (90% confidence interval: range 16-34%), and decrease the mean trough concentration of digoxin by 9% (90% confidence limit: 19% decrease to 2% increase). Miglitol, also an alpha-glucosidase inhibitor, may impair the oral absorption of digoxin and lead to subtherapeutic serum digoxin concentrations in some patients. In healthy volunteers, coadministration of miglitol 50 mg or 100 mg with digoxin reduced the average plasma concentrations of digoxin by 19% and 28%, respectively. However, in diabetic patients under treatment with digoxin, plasma digoxin concentrations were not altered when coadministered with miglitol. The mechanism of the interaction is not well understood. The manufacturer of digoxin recommends measuring digoxin concentrations prior to initiating acarbose or miglitol. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary. Some experts have recommended that these agents be administered 6 hours after an oral digoxin dose to ensure time for adequate digoxin absorption.
    Acebutolol: (Moderate) Because the pharmacologic effects of acebutolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Acetaminophen; Butalbital: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Acetaminophen; Tramadol: (Moderate) An increased incidence of digoxin toxicity has been reported in some patients during post-marketing reports with the concurrent use of tramadol and digoxin.
    Adefovir: (Moderate) Adefovir is eliminated renally by a combination of glomerular filtration and active tubular secretion; coadministration of adefovir dipivoxil with drugs that reduce renal function or compete for active tubular secretion, such as digoxin, may decrease adefovir elimination by competing for common renal tubular transport systems; therefore increasing serum concentrations of either adefovir and/or digoxin may occur. Coadministration of these drugs has not been studied, but caution is warranted.
    Adenosine: (Major) Adenosine has been safely administered with digoxin, but should be used with caution and monitoring. Because of the potential for additive or synergistic depressant effects on SA and AV nodes, however, adenosine should be used with caution in the presence of agents that slow cardiac conduction, especially digoxin. Digoxin and less frequently digoxin with verapamil may be rarely associated with ventricular fibrillation when combined with adenosine. Appropriate resuscitative measures should be available during combined therapy.
    Albiglutide: (Minor) Coadministration of albiglutide with digoxin results in an increased Cmax and AUC of digoxin by approximately 11% and 9%, respectively. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If digoxin and albiglutide are co-prescribed, it may be prudent to initially monitor the patient for altered digoxin effect.
    Albuterol: (Moderate) Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol or levalbuterol and digoxin on a chronic basis is unclear. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of albuterol or levalbuterol. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Albuterol; Ipratropium: (Moderate) Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol or levalbuterol and digoxin on a chronic basis is unclear. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of albuterol or levalbuterol. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Aldesleukin, IL-2: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients.
    Alemtuzumab: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Aliskiren; Valsartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Alkylating agents: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Alogliptin; Pioglitazone: (Moderate) Concentrations of digoxin may be increased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of digoxin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with digoxin 0.2 mg twice daily (loading dose) then 0.25 mg daily (maintenance dose, 7 days) resulted in a 15% and 17% increase in digoxin AUC and Cmax, respectively. Carefully monitor serum digoxin concentrations; observe patients carefully for signs of digoxin toxicity.
    Alpha-glucosidase Inhibitors: (Moderate) Acarbose, an alpha-glucosidase inhibitor, has been found to decrease the mean bioavailability (AUC) of digoxin by 16% (90% confidence interval: range 8-23%), decrease the mean Cmax of digoxin by 26% (90% confidence interval: range 16-34%), and decrease the mean trough concentration of digoxin by 9% (90% confidence limit: 19% decrease to 2% increase). Miglitol, also an alpha-glucosidase inhibitor, may impair the oral absorption of digoxin and lead to subtherapeutic serum digoxin concentrations in some patients. In healthy volunteers, coadministration of miglitol 50 mg or 100 mg with digoxin reduced the average plasma concentrations of digoxin by 19% and 28%, respectively. However, in diabetic patients under treatment with digoxin, plasma digoxin concentrations were not altered when coadministered with miglitol. The mechanism of the interaction is not well understood. The manufacturer of digoxin recommends measuring digoxin concentrations prior to initiating acarbose or miglitol. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary. Some experts have recommended that these agents be administered 6 hours after an oral digoxin dose to ensure time for adequate digoxin absorption.
    Alprazolam: (Moderate) Digoxin toxicity may occur in patients receiving alprazolam and digoxin. This interaction may be the result of increased plasma protein binding of digoxin and/or an effect of the benzodiazepine at the renal tubules that results in decreased digoxin elimination. Patients receiving alprazolam or diazepam and digoxin concurrently should be monitored for increased serum digoxin levels.
    Altretamine: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Aluminum Hydroxide: (Moderate) Concurrent administration of liquid antacid formulations of aluminum hydroxide can decrease absorption of digoxin and other cardiac glycosides and reduce their plasma concentration. Steady state concentrations of digoxin are not lowered following administration of tablet formulations of aluminum hydroxide. Doses of liquid aluminum hydroxide and cardiac glycosides should be spaced 1 to 2 hours apart. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of an antacid. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Concurrent administration of liquid antacid formulations of aluminum hydroxide can decrease absorption of digoxin and other cardiac glycosides and reduce their plasma concentration. Steady state concentrations of digoxin are not lowered following administration of tablet formulations of aluminum hydroxide. Doses of liquid aluminum hydroxide and cardiac glycosides should be spaced 1 to 2 hours apart. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of an antacid. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Concurrent administration of liquid antacid formulations of aluminum hydroxide can decrease absorption of digoxin and other cardiac glycosides and reduce their plasma concentration. Steady state concentrations of digoxin are not lowered following administration of tablet formulations of aluminum hydroxide. Doses of liquid aluminum hydroxide and cardiac glycosides should be spaced 1 to 2 hours apart. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of an antacid. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary. (Moderate) Concurrent administration of liquid formulations of magnesium hydroxide can decrease absorption of cardiac glycosides and reduce their plasma concentration. Steady state concentrations of digoxin are not lowered following administration of tablet formulations of magnesium hydroxide. Doses of liquid magnesium hydroxide and cardiac glycosides should be spaced 1 to 2 hours apart.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Concurrent administration of liquid antacid formulations of aluminum hydroxide can decrease absorption of digoxin and other cardiac glycosides and reduce their plasma concentration. Steady state concentrations of digoxin are not lowered following administration of tablet formulations of aluminum hydroxide. Doses of liquid aluminum hydroxide and cardiac glycosides should be spaced 1 to 2 hours apart. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of an antacid. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary. (Moderate) Concurrent administration of liquid formulations of magnesium hydroxide can decrease absorption of cardiac glycosides and reduce their plasma concentration. Steady state concentrations of digoxin are not lowered following administration of tablet formulations of magnesium hydroxide. Doses of liquid magnesium hydroxide and cardiac glycosides should be spaced 1 to 2 hours apart.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Concurrent administration of liquid antacid formulations of aluminum hydroxide can decrease absorption of digoxin and other cardiac glycosides and reduce their plasma concentration. Steady state concentrations of digoxin are not lowered following administration of tablet formulations of aluminum hydroxide. Doses of liquid aluminum hydroxide and cardiac glycosides should be spaced 1 to 2 hours apart. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of an antacid. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Amiloride: (Moderate) Amiloride can alter the response to digoxin therapy if administered concomitantly. Typically, digoxin concentrations are slightly elevated by amiloride, and a reduced responsiveness to the positive inotropic effects of digoxin therapy has been noted in patients receiving both agents simultaneously. Patients receiving these two drugs concurrently should be monitored for altered responses to digoxin therapy.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Amiloride can alter the response to digoxin therapy if administered concomitantly. Typically, digoxin concentrations are slightly elevated by amiloride, and a reduced responsiveness to the positive inotropic effects of digoxin therapy has been noted in patients receiving both agents simultaneously. Patients receiving these two drugs concurrently should be monitored for altered responses to digoxin therapy.
    Amiodarone: (Major) Amiodarone increases orally administered digoxin serum concentration by 70% when given concomitantly. When amiodarone is coadministered with intravenous (IV) digoxin, the serum concentration of digoxin is increased by 17%. Measure serum digoxin concentrations before initiating amiodarone. According to the manufacturer of amiodarone, the digoxin dose should be reduced by 50% upon initiation of amiodarone. The manufacturer of digoxin recommends measuring the serum digoxin concentration before initiating amiodarone and reducing the serum digoxin concentration by reducing the oral dose by approximately 30 to 50%, decreasing the IV digoxin dose by 15 to 30%, or modifying the dosing frequency and continue monitoring. The mechanism of the increase in digoxin serum concentration is thought to result from inhibition of gastrointestinal P-glycoprotein (increased oral bioavailability) and/or a decrease in digoxin renal or nonrenal clearance. Because of the depressant effects of digoxin on the sinus and AV node, concurrent use can potentiate amiodarone's electrophysiologic and hemodynamic effects resulting in bradycardia, sinus arrest, and AV block. Furthermore, amiodarone may induce changes in thyroid function and alter sensitivity to cardiac glycosides, and thyroid function should be monitored closely in patients receiving both drugs simultaneously. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Close monitoring of serum digoxin concentrations and heart rate is essential to avoid enhanced toxicity.
    Amlodipine; Atorvastatin: (Major) Measure serum digoxin concentrations before initiating atorvastatin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Coadministration of digoxin and atorvastatin increases the serum concentration and AUC of digoxin by 22% and 15%, respectively. Digoxin and atorvastatin are both substrates for P-glycoprotein (P-gp).
    Amlodipine; Benazepril: (Moderate) Coadministration of digoxin and captopril increases the serum concentration and AUC of digoxin by 58% and 39%, respectively. However, captopril and digoxin are administered together in patients with congestive heart failure. Measure serum digoxin concentrations before initiating captopril. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. In addition, caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Amlodipine; Olmesartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Amlodipine; Telmisartan: (Major) When telmisartan is coadministered with digoxin, median increases in digoxin peak concentration (49%) and in trough concentration (20%) are observed. Measure serum digoxin concentrations before initiating telmisartan. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Amlodipine; Valsartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Amobarbital: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Amoxicillin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Clarithromycin has been reported to increase the digoxin AUC by 70% when digoxin is administered orally. No significant changes in digoxin exposure were reported when digoxin was administered intravenously (IV). Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). While this may occur, only 5% of a digoxin dose is subject to metabolism by gut flora and this mechanism does not account for the large increases in digoxin levels that occur with the coadministration of clarithromycin. A more important factor is clarithromycin inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Digoxin is a P-gp substrate. Inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. Measure serum digoxin concentrations before initiating clarithromycin. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. No dosage adjustment is required when digoxin is administered IV. (Moderate) Lansoprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Becuase, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement. (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin has been reported to increase the digoxin AUC by 70% when digoxin is administered orally. No significant changes in digoxin exposure were reported when digoxin was administered intravenously (IV). Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). While this may occur, only 5% of a digoxin dose is subject to metabolism by gut flora and this mechanism does not account for the large increases in digoxin levels that occur with the coadministration of clarithromycin. A more important factor is clarithromycin inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Digoxin is a P-gp substrate. Inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. Measure serum digoxin concentrations before initiating clarithromycin. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. No dosage adjustment is required when digoxin is administered IV. (Moderate) Omeprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Omeprazole increases the AUC of digoxin by about 10%. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Because, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement. (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Amoxicillin; Clavulanic Acid: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Amphotericin B-induced hypokalemia can potentiate the cardiac toxicity of cardiac glycosides (e.g., digoxin). If used concomitantly, closely monitor serum electrolytes and cardiac function.
    Amphotericin B lipid complex (ABLC): (Moderate) Amphotericin B-induced hypokalemia can potentiate the cardiac toxicity of cardiac glycosides (e.g., digoxin). If used concomitantly, closely monitor serum electrolytes and cardiac function.
    Amphotericin B liposomal (LAmB): (Moderate) Amphotericin B-induced hypokalemia can potentiate the cardiac toxicity of cardiac glycosides (e.g., digoxin). If used concomitantly, closely monitor serum electrolytes and cardiac function.
    Amphotericin B: (Moderate) Amphotericin B-induced hypokalemia can potentiate the cardiac toxicity of cardiac glycosides (e.g., digoxin). If used concomitantly, closely monitor serum electrolytes and cardiac function.
    Ampicillin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Ampicillin; Sulbactam: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Anthracyclines: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Antimetabolites: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Antithyroid agents: (Minor) Serum concentrations of digoxin can increase as hyperthyroidism is corrected. In patients receiving antithyroid therapy, the dosage of digoxin may need to be reduced as the patient becomes euthyroid.
    Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. It is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with cardiac glycosides.
    Arsenic Trioxide: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Aspirin, ASA; Omeprazole: (Moderate) Omeprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Omeprazole increases the AUC of digoxin by about 10%. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Because, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Atazanavir: (Moderate) Atazanavir can prolong the PR interval and pharmacodynamic interactions between atazanavir and drugs that also prolong the PR interval, such as digoxin, cannot be ruled out; caution is advised when these drugs are used together; monitor the patient for appropriate clinical responses.
    Atazanavir; Cobicistat: (Moderate) Atazanavir can prolong the PR interval and pharmacodynamic interactions between atazanavir and drugs that also prolong the PR interval, such as digoxin, cannot be ruled out; caution is advised when these drugs are used together; monitor the patient for appropriate clinical responses. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of digoxin with cobicistat. Digoxin is a substrate for P-gp; cobicistat is an inhibitor of this drug transporter. Concurrent use may result in elevated digoxin plasma concentration.
    Atenolol: (Moderate) Because the pharmacologic effects of atenolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Atenolol; Chlorthalidone: (Moderate) Because the pharmacologic effects of atenolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Atorvastatin: (Major) Measure serum digoxin concentrations before initiating atorvastatin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Coadministration of digoxin and atorvastatin increases the serum concentration and AUC of digoxin by 22% and 15%, respectively. Digoxin and atorvastatin are both substrates for P-glycoprotein (P-gp).
    Atorvastatin; Ezetimibe: (Major) Measure serum digoxin concentrations before initiating atorvastatin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Coadministration of digoxin and atorvastatin increases the serum concentration and AUC of digoxin by 22% and 15%, respectively. Digoxin and atorvastatin are both substrates for P-glycoprotein (P-gp).
    Atropine: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Atropine; Difenoxin: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Atropine; Diphenoxylate: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Atropine; Edrophonium: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known. (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Azilsartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Azilsartan; Chlorthalidone: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Azithromycin: (Moderate) Elevated digoxin concentrations have been observed when certain macrolide antibiotics, including azithromycin, have been coadministered with digoxin. Monitor patients who take both azithromycin and digoxin for possible digoxin toxicity and reduce digoxin dose as necessary. Digoxin is a substrate for the drug efflux pump P-glycoprotein (P-gp); azithromycin is a substrate and inhibitor of P-gp. Inhibition of P-gp in the intestinal cell wall may lead to increased oral absorption and decreased renal and non-renal clearance of digoxin.
    Bacillus Calmette-Guerin Vaccine, BCG: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Barbiturates: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Benazepril: (Moderate) Coadministration of digoxin and captopril increases the serum concentration and AUC of digoxin by 58% and 39%, respectively. However, captopril and digoxin are administered together in patients with congestive heart failure. Measure serum digoxin concentrations before initiating captopril. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. In addition, caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of digoxin and captopril increases the serum concentration and AUC of digoxin by 58% and 39%, respectively. However, captopril and digoxin are administered together in patients with congestive heart failure. Measure serum digoxin concentrations before initiating captopril. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. In addition, caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Bendroflumethiazide; Nadolol: (Moderate) Because the pharmacologic effects of nadolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Benztropine: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Bepridil: (Moderate) Depression of AV node conduction could be additive if cardiac glycosides, like digoxin, are used with bepridil. Bepridil has Class I antiarrhythmic properties that are additive to the effects of digitalis glycosides on cardiac conduction. In addition, the potential exists for increases in serum digoxin levels, and digoxin concentrations should be monitored carefully. Monitor heart rate and for clinical symptoms of undesirable additive effects.
    Betaxolol: (Moderate) Because the pharmacologic effects of betaxolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Bevacizumab: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Bexarotene: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Measure serum digoxin concentrations before initiating tetracyclines. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency, and continue monitoring. In approximately 10% of patients, a small portion of a digoxin dose is metabolized in the gut by intestinal Eubacterium lentum, an anaerobic bacillus, to inactive digoxin reduction products (DRPs). DRPs have little cardiac activity due to poor cardiac receptor binding and rapid excretion. Certain antibiotics can reduce the activity of intestinal bacteria, which, in turn, may enhance digoxin bioavailability via decreased DRP formation and increased enterohepatic recycling of digoxin in some patients. The addition of tetracycline to digoxin therapy has been reported to increase the serum digoxin concentration by 100%. Digoxin toxicity has been reported in patients previously stabilized on digoxin who receive antibiotics that affect E. lentum, such as tetracyclines. Other antibiotics that have activity against E. lentum may produce similar effects on digoxin metabolism.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Measure serum digoxin concentrations before initiating tetracyclines. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency, and continue monitoring. In approximately 10% of patients, a small portion of a digoxin dose is metabolized in the gut by intestinal Eubacterium lentum, an anaerobic bacillus, to inactive digoxin reduction products (DRPs). DRPs have little cardiac activity due to poor cardiac receptor binding and rapid excretion. Certain antibiotics can reduce the activity of intestinal bacteria, which, in turn, may enhance digoxin bioavailability via decreased DRP formation and increased enterohepatic recycling of digoxin in some patients. The addition of tetracycline to digoxin therapy has been reported to increase the serum digoxin concentration by 100%. Digoxin toxicity has been reported in patients previously stabilized on digoxin who receive antibiotics that affect E. lentum, such as tetracyclines. Other antibiotics that have activity against E. lentum may produce similar effects on digoxin metabolism.
    Bisoprolol: (Moderate) Because the pharmacologic effects of bisoprolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Because the pharmacologic effects of bisoprolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Bleomycin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as digoxin. In addition, Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients.
    Boceprevir: (Moderate) Monitoring of digoxin serum concentrations is advised when administering digoxin with boceprevir due to an increased potential for digoxin-related adverse events. Digoxin is a substrate for P-glycoprotein (P-gp). Boceprevir is a substrate and inhibitor of P-gp. The lowest dose of digoxin should be initially prescribed with titrations of digoxin based on serum concentrations. If digoxin dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment.
    Bortezomib: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Brimonidine: (Minor) Alpha-agonists as a class, may reduce heart rate and blood pressure. Although ophthalmic brimonidine administration generally does not have clinically significant effects on pulse and blood pressure, it should be used with caution with cardiac glycosides.
    Brimonidine; Brinzolamide: (Minor) Alpha-agonists as a class, may reduce heart rate and blood pressure. Although ophthalmic brimonidine administration generally does not have clinically significant effects on pulse and blood pressure, it should be used with caution with cardiac glycosides.
    Brimonidine; Timolol: (Moderate) Because the pharmacologic effects of timolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients. (Minor) Alpha-agonists as a class, may reduce heart rate and blood pressure. Although ophthalmic brimonidine administration generally does not have clinically significant effects on pulse and blood pressure, it should be used with caution with cardiac glycosides.
    Bupropion: (Moderate) Plasma digoxin concentrations and the patient's clinical response to digoxin therapy should be monitored during concurrent use with bupropion, due to the potential for decreased systemic exposure to digoxin. When a single oral dose of 0.5 mg of digoxin was administered 24 hours after a single 150 mg oral dose of extended-release bupropion in healthy volunteers, the digoxin exposure was decreased.
    Bupropion; Naltrexone: (Moderate) Plasma digoxin concentrations and the patient's clinical response to digoxin therapy should be monitored during concurrent use with bupropion, due to the potential for decreased systemic exposure to digoxin. When a single oral dose of 0.5 mg of digoxin was administered 24 hours after a single 150 mg oral dose of extended-release bupropion in healthy volunteers, the digoxin exposure was decreased.
    Buspirone: (Minor) Buspirone can displace digoxin from plasma proteins, but the clinical significance of this effect has yet to be determined.
    Butabarbital: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Cabozantinib: (Moderate) Monitor serum digoxin concentrations and watch for an increase in digoxin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of digoxin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and digoxin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Calcifediol: (Moderate) Monitor serum calcium and patients for signs of digitalis toxicity in patients receiving calcifediol and digoxin concurrently. Monitor more frequently when initiating or adjusting the dose of calcifediol. Hypercalemia of any cause, including calcifediol therapy, increases the risk of digitalis toxicity.
    Calcitriol: (Moderate) Calcitriol should be administered with caution to patients receiving digoxin. Vitamin D analogs may cause hypercalemia which increases the risk of digitalis toxicity. In patients receiving calcitriol and digoxin concurrently, monitor serum calcium frequently and monitor the patient for signs of digitalis toxicity. More frequent monitoring is necessary when initiating or adjusting the dose of calcitriol.
    Calcium Carbonate: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin. (Moderate) Concurrent administration of liquid formulations of magnesium hydroxide can decrease absorption of cardiac glycosides and reduce their plasma concentration. Steady state concentrations of digoxin are not lowered following administration of tablet formulations of magnesium hydroxide. Doses of liquid magnesium hydroxide and cardiac glycosides should be spaced 1 to 2 hours apart.
    Calcium Carbonate; Risedronate: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Calcium Salts: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Calcium: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Calcium; Vitamin D: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Canagliflozin: (Major) When digoxin was coadministered with canagliflozin 300 mg, there was an increase in the AUC and Cmax of digoxin (20% and 36%, respectively). Patients taking canagliflozin concomitantly with digoxin should have their digoxin levels monitored appropriately.
    Canagliflozin; Metformin: (Major) When digoxin was coadministered with canagliflozin 300 mg, there was an increase in the AUC and Cmax of digoxin (20% and 36%, respectively). Patients taking canagliflozin concomitantly with digoxin should have their digoxin levels monitored appropriately.
    Candesartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Captopril: (Major) Coadministration of digoxin and captopril increases the serum concentration and AUC of digoxin by 58% and 39%, respectively. However, captopril and digoxin are administered together in patients with congestive heart failure. Measure serum digoxin concentrations before initiating captopril. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. In addition, caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Coadministration of digoxin and captopril increases the serum concentration and AUC of digoxin by 58% and 39%, respectively. However, captopril and digoxin are administered together in patients with congestive heart failure. Measure serum digoxin concentrations before initiating captopril. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. In addition, caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Carbenicillin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Carbonic anhydrase inhibitors: (Moderate) Carbonic anhydrase inhibitors can result in hypokalemia. Patients receiving these drugs concurrently with cardiac glycosides are at an increased risk for digitalis toxicity if hypokalemia develops during treatment. Ventricular irritability may occur. Monitor for hypokalemia and supplement with potassium if needed.
    Carmustine, BCNU: (Moderate) Use carmustine and digoxin together with caution; concomitant use may result in decreased digoxin tablet absorption and reduced digoxin effectiveness. Monitor digoxin levels prior to starting carmustine and during concomitant therapy. If necessary, increase the digoxin dose by 20% to 40%; continue to monitor digoxin levels. The digoxin AUC value was reduced approximately 50% in cancer patients who received digoxin (Lanoxin tablets) with high dose chemotherapy in a pharmacokinetic study (n = 6). Patients received a digoxin 0.25-mg dose within 3 days of starting chemotherapy (baseline) and another digoxin 0.25-mg dose within 5 days of completing high-dose chemotherapy which included carmustine 350 mg/m2 IV daily for 3 days with or without melphalan.
    Carteolol: (Moderate) Because the pharmacologic effects of carteolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Carvedilol: (Major) Coadministration of orally administered digoxin and carvedilol increases the serum concentration and AUC of digoxin by 16% and 14%, respectively. No significant changes in digoxin exposure were reported when digoxin was administered intravenously (IV). Digoxin and carvedilol are both substrates for P-glycoprotein (P-gp). Measure serum digoxin concentrations before initiating carvedilol. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring. No dosage adjustment is required when digoxin is administered IV. In addition, coadministration of digoxin with beta-blockers may produce additive effects on AV node conduction resulting in bradycardia and advanced or complete heart block. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Celecoxib: (Moderate) Coadministration of digoxin and indomethacin increases the serum concentration of digoxin by 40%. Measure serum digoxin concentrations before initiating indomethacin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, concomitant use of other nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, with digoxin may result in increased serum concentrations of digoxin. Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium or ibuprofen. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Ceritinib: (Major) Avoid coadministration of ceritinib with digoxin due to the risk of additive bradycardia. If unavoidable, monitor heart rate and blood pressure regularly. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary.
    Charcoal: (Moderate) Decreased serum digoxin concentrations have been reported in patients who received digoxin and activated charcoal. Measure serum digoxin concentrations before initiating charcoal. Continue monitoring during concomitant treatment and increase the digoxin dose by 20% to 40% as necessary and clinically indicated. Patients who ingest dietary supplements containing activated charcoal should be aware that the effectiveness of digoxin may be decreased, and it is advisable to have the patient check with their health care professional before regularly taking such supplements.
    Chlorambucil: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Chlordiazepoxide; Clidinium: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Chloroquine: (Moderate) Digoxin serum concentrations have been reported to increase when hydroxychloroquine was added. Although this interaction has not been reported with chloroquine in published literature, chloroquine may similarly increase the plasma concentration of digoxin. For patients on a stable digoxin regimen and initiating chloroquine, no initial dose adjustment of either drug has been advised; however, serum digoxin concentrations should be monitored and used for digoxin dose titration as clinically necessary
    Chlorthalidone; Clonidine: (Moderate) Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate such as cardiac glycosides.
    Cholestyramine: (Moderate) Cholestyramine has been shown to significantly interfere with the absorption of digoxin. The administration of cholestyramine twice daily (8 hours before and after digoxin administration) or the use of digoxin solution may minimize this interaction. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of cholestyramine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary. Parenteral digoxin does not seem to interact with cholestyramine.
    Cholinesterase inhibitors: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as digoxin. In one study involving multiple doses of galantamine at 24 mg/day with digoxin at a dose of 0.375 mg/day, there was no effect on the pharmacokinetics of digoxin, except one healthy subject was hospitalized due to second and third degree heart block and bradycardia.
    Chromium: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Cladribine: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Clarithromycin: (Major) Clarithromycin has been reported to increase the digoxin AUC by 70% when digoxin is administered orally. No significant changes in digoxin exposure were reported when digoxin was administered intravenously (IV). Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). While this may occur, only 5% of a digoxin dose is subject to metabolism by gut flora and this mechanism does not account for the large increases in digoxin levels that occur with the coadministration of clarithromycin. A more important factor is clarithromycin inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Digoxin is a P-gp substrate. Inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. Measure serum digoxin concentrations before initiating clarithromycin. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. No dosage adjustment is required when digoxin is administered IV.
    Clofarabine: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Clonidine: (Moderate) Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate such as cardiac glycosides.
    Clozapine: (Moderate) Because clozapine is highly protein bound, other highly protein bound medications such as digoxin can displace clozapine from its binding sites, predominantly alpha1-acid glycoprotein. Clozapine, in turn, can increase the serum concentrations of digoxin.
    Cobicistat: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of digoxin with cobicistat. Digoxin is a substrate for P-gp; cobicistat is an inhibitor of this drug transporter. Concurrent use may result in elevated digoxin plasma concentration.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of digoxin with cobicistat. Digoxin is a substrate for P-gp; cobicistat is an inhibitor of this drug transporter. Concurrent use may result in elevated digoxin plasma concentration.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of digoxin with cobicistat. Digoxin is a substrate for P-gp; cobicistat is an inhibitor of this drug transporter. Concurrent use may result in elevated digoxin plasma concentration.
    Cod Liver Oil: (Moderate) Cod liver oil should be administered with caution to patients with cardiac disease or those receiving cardiac glycosides, as the vitamin D may cause hypercalcemia which may affect the actions of the cardiac glycoside and/or lead to cardiac arrhythmias.
    Colchicine: (Major) According to the manufacturer of Colcrys, both digoxin and colchicine are substrates of P-glycoprotein (Pgp) and rhabdomyolysis has been reported in patients on concurrent therapy. If such agents are co-administered, advise patients to report signs and symptoms of myotoxicity including muscle tenderness, pain, or weakness; monitoring creatine phosphokinase may not predict the development of severe myopathy.
    Colesevelam: (Moderate) Oral drugs with a narrow therapeutic range, with the potential for loss of efficacy with reduced absorption, include antiarrhythmics. The manufacturer recommends that when administering other drugs with a narrow therapeutic index, consideration should be given to separating the administration of the drug with colesevelam. Although not specifically studied, it may be prudent to administer antiarrhythmics at least 4 hours before colesevelam. Additionally, drug response and/or serum concentrations should also be monitored.
    Colestipol: (Moderate) Although colestipol and cholestyramine have been reported to reduce the bioavailability of digitoxin, their effects on digoxin absorption are hypothesized to be less since digoxin undergoes less enterohepatic recycling than digitoxin. However, cholestyramine has been shown to significantly interfere with the absorption of digoxin. Colestipol is also expected to decrease the absorption of digoxin, and has been shown to produce a clinically significant decrease in the serum half-life of digoxin. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of colestipol or cholestyramine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary.
    Collagenase: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Conivaptan: (Moderate) Coadministration of digoxin with oral conivaptan results in a reduction in clearance of digoxin. If digoxin is administered with conivaptan, the clinician should be alert to the possibility of increases in digoxin plasma concentrations. In addition, electrolyte disturbances like hypokalemia and hypomagnesemia may occur with administration of conivaptan. Drug-induced hypokalemia increases the potential for proarrhythmic effects during treatment with digoxin.
    Corticosteroids: (Moderate) Hypokalemia, hypomagnesemia, or hypercalcemia increase digoxin's effect. Corticosteroids can precipitate digoxin toxicity via their effect on electrolyte balance. It is recommended that serum potassium, magnesium, and calcium be monitored regularly in patients receiving digoxin.
    Crizotinib: (Moderate) Monitor digoxin serum concentrations and watch for an increase in digoxin-related adverse reactions if coadministration with crizotinib is necessary. Digoxin is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Cyanocobalamin, Vitamin B12: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Cyclosporine: (Major) Severe digitalis toxicity has been seen within days of starting cyclosporine in patients previously taking digoxin. Monitor serum digoxin concentrations if digoxin is used concomitantly with cyclosporine; a digoxin dosage reduction may be needed. Reduced clearance of digoxin has been observed when it is given concurrently with cyclosporine. Reduced clearance may be due to cyclosporine inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Inhibition of the P-gp-mediated renal tubular secretion of digoxin is the postulated mechanism for decreased renal clearance. A decrease in the apparent volume of distribution of digoxin has been reported after cyclosporine administration.
    Daclatasvir: (Major) Coadministration of daclatasvir with digoxin may increase digoxin exposure leading to increased or prolonged therapeutic effects and adverse events. If digoxin is initiated in a patients already receiving daclatasvir, start digoxin at the lowest appropriate dose followed by gradual and caution dose adjustments. If daclatasvir is started in a patients already receiving digoxin, obtain digoxin serum concentrations before giving daclatasvir and decrease the digoxin dose by 30% to 50%. Alternatively, the digoxin dose may be reduced by prolonging the dosing interval. Digoxin is a substrate for P-glycoprotein (P-gp); daclatasvir is a P-gp inhibitor.
    Dactinomycin, Actinomycin D: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Dapagliflozin; Saxagliptin: (Moderate) The AUC and Cmax of digoxin may be increased in the presence of saxagliptin. Dosage adjustment of digoxin is not recommended, but patients receiving these 2 drugs at the same time should be monitored closely.
    Darifenacin: (Moderate) Oral formulations of digoxin can produce higher serum concentrations when administered concurrently with antimuscarinics because of decreased GI motility induced by the antimuscarinic agent. Darifenacin coadministered with digoxin resulted in a 16 percent increase in digoxin exposure. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Darunavir: (Major) The lowest dose of digoxin should initially be prescribed when given with darunavir/ritonavir, as increased serum concentrations of digoxin may occur. Monitor serum digoxin concentrations for dosage titration.
    Darunavir; Cobicistat: (Major) The lowest dose of digoxin should initially be prescribed when given with darunavir/ritonavir, as increased serum concentrations of digoxin may occur. Monitor serum digoxin concentrations for dosage titration. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of digoxin with cobicistat. Digoxin is a substrate for P-gp; cobicistat is an inhibitor of this drug transporter. Concurrent use may result in elevated digoxin plasma concentration.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with digoxin is expected to increase digoxin serum concentrations. Digoxin's product labeling recommends a digoxin dosage reduction of 30 to 50%. Measure digoxin serum concentration before initiating dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, and then as clinically appropriate during coadministration to ensure appropriate digoxin dosage titration. Monitor for therapeutic and adverse effects. Digoxin is a P-glycoprotein (P-gp) substrate, and ritonavir and paritaprevir are a P-gp inhibitors. (Major) In a pharmacokinetic study of 11 healthy men, increases in digoxin AUC (86%), volume of distribution, and half-life were seen, while renal and non-renal clearance decreased, when coadministered with ritonavir. It appears that this interaction is mediated by ritonavir's inhibition or P-glycoprotein-mediated renal tubular secretion of digoxin. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including digoxin) has not been evaluated. Measure serum digoxin concentrations before initiating ritonavir or lopinavir; ritonavir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
    Dasatinib: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Daunorubicin Liposomal: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. Digoxin can reduce the uptake of doxorubicin into cardiac tissue and thus temper the cardiomyopathy caused by doxorubicin. Digoxin can be used to treat congestive heart failure due to doxorubicin cardiomyopathy and may offer improvement to some patients, although angiotensin-converting enzyme inhibitors may be of greater benefit. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy. It is not known if digoxin has similar effects on doxorubicin liposomal.
    Daunorubicin Liposomal; Cytarabine Liposomal: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. Digoxin can reduce the uptake of doxorubicin into cardiac tissue and thus temper the cardiomyopathy caused by doxorubicin. Digoxin can be used to treat congestive heart failure due to doxorubicin cardiomyopathy and may offer improvement to some patients, although angiotensin-converting enzyme inhibitors may be of greater benefit. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy. It is not known if digoxin has similar effects on doxorubicin liposomal.
    Demeclocycline: (Major) Measure serum digoxin concentrations before initiating tetracyclines. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency, and continue monitoring. In approximately 10% of patients, a small portion of a digoxin dose is metabolized in the gut by intestinal Eubacterium lentum, an anaerobic bacillus, to inactive digoxin reduction products (DRPs). DRPs have little cardiac activity due to poor cardiac receptor binding and rapid excretion. Certain antibiotics can reduce the activity of intestinal bacteria, which, in turn, may enhance digoxin bioavailability via decreased DRP formation and increased enterohepatic recycling of digoxin in some patients. The addition of a tetracycline to digoxin therapy has been reported to increase the serum digoxin concentration by 100%. Digoxin toxicity has been reported in patients previously stabilized on digoxin who receive antibiotics that affect E. lentum, such as tetracyclines. Other antibiotics that have activity against E. lentum may produce similar effects on digoxin metabolism.
    Denileukin Diftitox: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Dexlansoprazole: (Moderate) Dexlansoprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Becuase, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Dexmedetomidine: (Moderate) Dexmedetomidine has been associated with hypotension and bradycardia, and should be administered cautiously in combination with cardiac glycosides, such as digoxin, or other negative chronotropic agents.
    Dextromethorphan; Quinidine: (Major) Coadministration of quinidine and oral digoxin has resulted in a 100% increase in digoxin serum concentrations. When quinidine is coadministered with intravenous (IV) digoxin, the digoxin AUC is increased by 54 to 83%. Digoxin is a substrate for P-glycoprotein (P-gp). Quinidine inhibits P-gp, an energy-dependent cellular drug efflux pump. The inhibition of P-gp in the intestinal cell wall may lead to increased oral absorption of digoxin. It also has been shown that quinidine inhibits the secretion of digoxin by P-gp transporters in the kidney leading to decreased renal tubular elimination of digoxin and increased serum concentrations. Measure serum digoxin concentrations before initiating quinidine. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
    Diazepam: (Moderate) Coadministration of diazepam and digoxin has been reported to increase the half-life of digoxin due to reduced urinary excretion of digoxin. Consider measuring serum digoxin concentrations before initiating diazepam. Continue monitoring during concomitant treatment and decrease the digoxin dose as necessary.
    Diclofenac: (Moderate) Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Diclofenac; Misoprostol: (Moderate) Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Dicloxacillin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Dicyclomine: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Digoxin Immune Fab: (Minor) Digoxin immune Fab can reverse desirable as well as toxic actions of cardiac glycosides.
    Diltiazem: (Major) Coadministration of digoxin and diltiazem increases the serum concentration of digoxin by 20%. It is believed that diltiazem decreases renal and nonrenal clearance of digoxin. In addition, digoxin is a substrate for P-glycoprotein (P-gp) and diltiazem is both a substrate and an inhibitor of P-gp. Measure serum digoxin concentrations before initiating diltiazem. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Despite the potential for interactions, digoxin sometimes is intentionally used in combination with diltiazem to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Dimenhydrinate: (Moderate) Patients receiving oral digoxin therapy should be monitored for increased digoxin effects when receiving drugs with substantial anticholinergic activity. Dimenhydrinate can theoretically increase the absorption of digoxin by decreasing gastrointestinal motility. Anticholinergics, because of their ability to cause tachycardia, can also antagonize the beneficial actions of digoxin in atrial fibrillation/flutter.
    Diphenhydramine; Ibuprofen: (Moderate) Coadministration of digoxin and indomethacin increases the serum concentration of digoxin by 40%. Measure serum digoxin concentrations before initiating indomethacin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, concomitant use of other nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, with digoxin may result in increased serum concentrations of digoxin. Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium or ibuprofen. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Diphenhydramine; Naproxen: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Dofetilide: (Major) Dofetilide does not affect the pharmacokinetics of digoxin; however, the concomitant administration of digoxin with dofetilide is associated with a higher occurrence of torsade de pointes.
    Dolasetron: (Major) Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Therefore, drugs known to prolong the PR interval, such as digoxin, should be avoided in patients taking dolasetron.
    Donepezil; Memantine: (Moderate) Digoxin is eliminated by renal tubular secretion and may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or digoxin is recommended to assess for needed dosage adjustments. In selected individuals, digoxin serum concentration monitoring may be appropriate
    Dorzolamide; Timolol: (Moderate) Because the pharmacologic effects of timolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Doxercalciferol: (Moderate) Doxercalciferol should be administered with caution to patients receiving digoxin. Vitamin D analogs may cause hypercalemia which increases the risk of digitalis toxicity. In patients receiving doxercalciferol and digoxin concurrently, monitor serum calcium frequently and monitor the patient for signs of digitalis toxicity. More frequent monitoring is necessary when initiating or adjusting the dose of doxercalciferol.
    Doxorubicin Liposomal: (Minor) Digoxin can reduce the uptake of doxorubicin into cardiac tissue and thus temper the cardiomyopathy caused by doxorubicin; although the affect on liposomal doxorubicin formulations is not known. Digoxin can be used to treat congestive heart failure due to doxorubicin cardiomyopathy and may offer improvement to some patients, although angiotensin-converting enzyme inhibitors may be of greater benefit. Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; no significant change was seen with digoxin capsules, and the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. Digoxin capsules may be utilized to avoid this interaction in patients receiving antineoplastic agents and digoxin tablets. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Doxycycline: (Major) Measure serum digoxin concentrations before initiating tetracyclines. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency, and continue monitoring. In approximately 10% of patients, a small portion of a digoxin dose is metabolized in the gut by intestinal Eubacterium lentum, an anaerobic bacillus, to inactive digoxin reduction products (DRPs). DRPs have little cardiac activity due to poor cardiac receptor binding and rapid excretion. Certain antibiotics can reduce the activity of intestinal bacteria, which, in turn, may enhance digoxin bioavailability via decreased DRP formation and increased enterohepatic recycling of digoxin in some patients. The addition of tetracycline to digoxin therapy has been reported to increase the serum digoxin concentration by 100%. Digoxin toxicity has been reported in patients previously stabilized on digoxin who receive antibiotics that affect E. lentum, such as tetracyclines. Other antibiotics that have activity against E. lentum may produce similar effects on digoxin metabolism.
    Dronabinol, THC: (Major) Use caution if coadministration of dronabinol with digoxin is necessary, and monitor for an increase in digoxin levels and digoxin-related adverse effects. Dronabinol is highly bound to plasma proteins, and may displace and increase the free fraction of other concomitantly administered protein-bound drugs; caution is recommended with other drugs with a narrow therapeutic index.
    Dronedarone: (Major) Dronedarone is an inhibitor of P-glycoprotein (P-gp). Digoxin is a substrate for P-gp. In clinical trials, the coadministration of dronedarone and digoxin resulted in an increase in the exposure of digoxin by 2.5-fold, with a subsequent increase in gastrointestinal adverse effects. Furthermore, digoxin can potentiate the electrophysiologic effects of dronedarone (e.g., decreased AV node conduction). In clinical trials, sudden death was more common in patients receiving combined therapy with dronedarone and digoxin than in patients on either therapy alone. It is unclear if combination therapy contributed to this increase or if this was related to the presence of advanced heart disease. According to the manufacturer of dronedarone, concurrent administration of dronedarone and digoxin should be avoided. However, if coadministration is unavoidable, a 50% reduction in the digoxin dose is recommended. The manufacturer of digoxin recommends measuring serum digoxin concentrations before initiating dronedarone and reducing digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency; continue monitoring.
    Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to digoxin. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as digoxin. Monitor digoxin concentrations if dupilumab is initiated or discontinued in a patient taking digoxin; digoxin dose adjustments may be needed.
    Edetate Calcium Disodium, Calcium EDTA: (Major) The pharmacodynamic actions of edetate disodium oppose those of the cardiac glycosides.
    Edetate Disodium, Disodium EDTA: (Major) The pharmacodynamic actions of edetate disodium oppose those of the cardiac glycosides.
    Eliglustat: (Major) Coadministration of digoxin and eliglustat may result in increased digoxin concentrations, which may result in digoxin toxicity. Measure serum digoxin concentrations before initiating eliglustat, reduce the digoxin dose by 30%, and continue to monitor as clinically indicated. Eliglustat is a P-glycoprotein (P-gp) inhibitor, and digoxin is a P-gp substrate. During clinical trials, Cmax and AUC of digoxin increased by 1.7- and 1.5-fold, respectively, after multiple doses of eliglustat 127 mg PO twice daily in extensive and intermediate metabolizers or 84 mg PO twice daily in poor metabolizers. Of note, the only FDA-approved dose of eliglustat is 84 mg.
    Enalapril, Enalaprilat: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Enalapril; Felodipine: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. (Moderate) Felodipine reduces the clearance of digoxin and may lead to digoxin toxicity. Although some reports show no effect on digoxin, it is prudent to monitor plasma levels of digoxin when felodipine is administered to patients receiving digoxin. Transient increases in serum digoxin concentrations have been reported with concomitant administration of felodipine. This effect is believed to be due to decreased renal and nonrenal clearance of digoxin induced by felodipine. When given concomitantly with extended-release felodipine tablets in one study, the pharmacokinetics of digoxin in patients with heart failure were not significantly altered. Adding digoxin to felodipine may have clinical significance in patients with serum digoxin concentrations which are at the high end of the therapeutic range.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Entecavir: (Moderate) Both entecavir and digoxin are secreted by active tubular secretion. In theory, coadministration of entecavir with digoxin may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Epoprostenol: (Moderate) Increased serum digoxin concentrations have been reported in patients who received digoxin and epoprostenol. Measure serum digoxin concentrations before initiating epoprostenol. Monitor patients who take both epoprostenol and digoxin for possible digoxin toxicity and reduce digoxin dose as necessary.
    Eprosartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Erythromycin: (Major) The addition of erythromycin to digoxin therapy may lead to a significant increase (43-116%) in serum digoxin concentration. Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). While this may occur, only 5% of a digoxin dose is subject to metabolism by gut flora and this mechanism does not account for the large increases in digoxin levels that occur with the coadministration of erythromycin. A more important factor is erythromycin inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Digoxin is a P-gp substrate. Inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. Measure serum digoxin concentrations before initiating erythromycin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
    Erythromycin; Sulfisoxazole: (Major) The addition of erythromycin to digoxin therapy may lead to a significant increase (43-116%) in serum digoxin concentration. Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). While this may occur, only 5% of a digoxin dose is subject to metabolism by gut flora and this mechanism does not account for the large increases in digoxin levels that occur with the coadministration of erythromycin. A more important factor is erythromycin inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Digoxin is a P-gp substrate. Inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. Measure serum digoxin concentrations before initiating erythromycin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
    Esmolol: (Moderate) A potentially clinically significant interaction between esmolol and digoxin may exist due to their additive effects on the AV node. The efficacy of esmolol in controlling ventricular response and in conversion to sinus rhythm may be improved with preoperative digitalization or with subsequent concomitant therapy for new-onset atrial fibrillation or flutter. The concomitant administration of esmolol and digoxin resulted in a 10-20% increase in serum digoxin concentrations. The clinical significance of this interaction is not known; however, the manufacturer warns that esmolol should be titrated cautiously in patients receiving digoxin.
    Esomeprazole: (Moderate) Increased serum digoxin concentrations have been reported in patients who received digoxin and esomeprazole. Esomeprazole inhibits gastric acid secretion and increases the pH of the stomach. Changes in intragastric pH can potentially alter the bioavailability of other drugs with pH-dependent absorption, such as digoxin. Gastric acid pump-inhibitors may increase digoxin bioavailability; however, the magnitude of the interaction is small. Measure serum digoxin concentrations before initiating esomeprazole. Monitor patients for possible digoxin toxicity and reduce digoxin dose as necessary. In addition, proton pump inhibitors have been associated with hypomagnesemia. Because, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Esomeprazole; Naproxen: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary. (Moderate) Increased serum digoxin concentrations have been reported in patients who received digoxin and esomeprazole. Esomeprazole inhibits gastric acid secretion and increases the pH of the stomach. Changes in intragastric pH can potentially alter the bioavailability of other drugs with pH-dependent absorption, such as digoxin. Gastric acid pump-inhibitors may increase digoxin bioavailability; however, the magnitude of the interaction is small. Measure serum digoxin concentrations before initiating esomeprazole. Monitor patients for possible digoxin toxicity and reduce digoxin dose as necessary. In addition, proton pump inhibitors have been associated with hypomagnesemia. Because, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Estramustine: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Etodolac: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium or ibuprofen. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Etravirine: (Moderate) Etravirine is a P-glycoprotein (PGP) inhibitor and digoxin is a substrate for PGP transport. Digoxin Cmax may increase by 19% and the AUC may increase by 18%. For patients starting both etravirine and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating etravirine, no initial dose adjustment of either drug is necessary; however, serum digoxin concentrations should be monitored and used for digoxin dose titration.
    Exenatide: (Moderate) Repeat doses of exenatide (10 mcg SQ twice daily) decreased the Cmax of digoxin (0.25 mg PO daily) by 17% and delayed Tmax by roughly 2.5 hours. Overall steady state AUC of digoxin was not altered. The mechanism of the interaction is not known (although it may be due to delayed gastric emptying), nor is the clinical significance of this potential interaction. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of exenatide. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary.
    Ezetimibe; Simvastatin: (Moderate) Simvastatin causes a slight elevation of serum digoxin levels. Simvastatin should be used cautiously in patients receiving digoxin.
    Famotidine; Ibuprofen: (Moderate) Coadministration of digoxin and indomethacin increases the serum concentration of digoxin by 40%. Measure serum digoxin concentrations before initiating indomethacin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, concomitant use of other nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, with digoxin may result in increased serum concentrations of digoxin. Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium or ibuprofen. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Felodipine: (Moderate) Felodipine reduces the clearance of digoxin and may lead to digoxin toxicity. Although some reports show no effect on digoxin, it is prudent to monitor plasma levels of digoxin when felodipine is administered to patients receiving digoxin. Transient increases in serum digoxin concentrations have been reported with concomitant administration of felodipine. This effect is believed to be due to decreased renal and nonrenal clearance of digoxin induced by felodipine. When given concomitantly with extended-release felodipine tablets in one study, the pharmacokinetics of digoxin in patients with heart failure were not significantly altered. Adding digoxin to felodipine may have clinical significance in patients with serum digoxin concentrations which are at the high end of the therapeutic range.
    Fenoprofen: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Ferric Citrate: (Moderate) According to the manufacturer of ferric citrate, it is not necessary to separate the timing of administration of ferric citrate from digoxin. However, because a reduction in the bioavailability of digoxin would have a clinically significant effect on its safety or efficacy, it may be prudent to monitor the clinical response and serum concentration of digoxin during concurrent use of ferric citrate.
    Fingolimod: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as digoxin. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
    Flavoxate: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Flaxseed: (Moderate) Flaxseed fiber can impair the absorption of oral drugs when administered concomitantly. However, no drug interaction studies have been performed to assess the degree to which the absorption of oral drugs may be altered. Based on interactions of other plant seed fiber (e.g., psyllium) used as a bulk-forming laxative, flaxseed fiber may adsorb cardiac glycosides. Administration of prescribed oral agents should be separated from the administration of flaxseed fiber by at least 2 hours.
    Flecainide: (Moderate) Concurrent use of flecainide in patients receiving cardiac glycosides, such as digoxin, can decrease the volume of distribution for digoxin, thereby resulting in small increases in digoxin plasma levels concentrations. In a study of 15 healthy subjects, flecainide increased the pre-dose and 6 hour post-dose digoxin serum concentrations on average by 24% and 13%, respectively, with considerable variation. The risk of toxicity occurring from concomitant administration of flecainide with cardiac glycosides is generally not clinically significant except in patients with AV nodal dysfunction, high plasma digoxin levels, or high plasma flecainide levels. Close monitoring of serum digoxin concentrations is recommended when coadministered with flecainide.
    Flibanserin: (Major) The concomitant use of flibanserin, a P-glycoprotein (P-gp) inhibitor, and digoxin, a P-gp substrate, can increase digoxin concentrations, which may lead to digoxin toxicity. Increased monitoring of digoxin concentrations is recommended during concurrent use. In a controlled cross-over study in 24 healthy men and women, flibanserin 100 mg was administered once daily over 5 days followed by a single dose of 0.5 mg digoxin. Flibanserin increased the digoxin AUC by 2.0-fold and Cmax by 1.5-fold, compared to digoxin alone. Patients should be instructed to contact their healthcare provider if they experience symptoms of digoxin toxicity such as changes in color vision (more yellow color), blurred vision, eyes sensitive to light, light flashes, or halos around bright lights, changes in behavior, chest pain or palpitations, bradycardia, or loss of appetite.
    Flurbiprofen: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Fluvastatin: (Moderate) Due to data that indicate high doses of fluvastatin, 80mg/day, increase digoxin serum concentrations, the manufacturer recommends closer monitoring of patients stabilized on digoxin if fluvastatin is added.
    Fosamprenavir: (Moderate) Caution is advised when administering digoxin with fosamprenavir, as concurrent use may result in reduced digoxin plasma concentrations. Digoxin is a substrate for the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is a P-gp inducer.
    Fosinopril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. In addition, fosinopril may cause a false low measurement of serum digoxin levels with the Digi-Tab RIA Kit for Digoxin. Other kits, such as the Coat-A-Count RIA Kit, may be used.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. In addition, fosinopril may cause a false low measurement of serum digoxin levels with the Digi-Tab RIA Kit for Digoxin. Other kits, such as the Coat-A-Count RIA Kit, may be used.
    Fosphenytoin: (Moderate) Hepatic enzyme-inducing drugs, such as phenytoin and fosphenytoin, can accelerate the metabolism of cardiac glycosides, including digoxin. Decreasing cardiac glycoside serum concentrations could result. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of phenytoin. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary.
    Gallium Ga 68 Dotatate: (Moderate) Mannitol-induced diuresis increases the excretion of potassium and can lead to hypokalemia. Administration of mannitol to patients receiving cardiac glycosides can increase the risk of developing cardiac toxicity secondary to mannitol-induced hypokalemia. Serum potassium concentrations should be monitored.
    Gefitinib: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Gentamicin: (Major) The coadministration of gentamicin and digoxin resulted in a 129-212% increase in the serum concentration of digoxin. Measure serum digoxin concentrations before initiating gentamicin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
    Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of certain gingerol constituents of ginger; but it is unclear if whole ginger root exhibits these effects clinically in humans. It is theoretically possible that excessive doses of ginger could affect the action of inotropes; however, no clinical data are available.
    Ginseng, Panax ginseng: (Major) A case of an elevated digoxin serum concentration was reported in a 74 year old man who was taking Siberian ginseng concomitantly. The serum digoxin concentration returned to an acceptable level after ginseng was discontinued. Although Panax ginseng has not been reported to alter digoxin serum concentrations, the possibility of an interaction should be considered.
    Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with digoxin may increase the serum concentrations of digoxin. Measure serum digoxin concentrations prior to initiating glecaprevir; reduce digoxin concentrations by decreasing digoxin dose by approximately 50% or by modifying the dosing frequency; continue monitoring during therapy. Digoxin is a substrate of P-glycoprotein (P-gp); glecaprevir is an inhibitor of P-gp. In drug interaction studies, coadministration of digoxin with glecaprevir; pibrentasvir resulted in a 48% increase in the AUC of digoxin. (Major) Coadministration of pibrentasvir with digoxin may increase the serum concentrations of digoxin. Measure serum digoxin concentrations prior to initiating pibrentasvir; reduce digoxin concentrations by decreasing digoxin dose by approximately 50% or by modifying the dosing frequency; continue monitoring during therapy. Digoxin is a substrate of P-glycoprotein (P-gp); pibrentasvir is an inhibitor of P-gp. In drug interaction studies, coadministration of digoxin with glecaprevir; pibrentasvir resulted in a 48% increase in the AUC of digoxin.
    Glimepiride; Pioglitazone: (Moderate) Concentrations of digoxin may be increased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of digoxin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with digoxin 0.2 mg twice daily (loading dose) then 0.25 mg daily (maintenance dose, 7 days) resulted in a 15% and 17% increase in digoxin AUC and Cmax, respectively. Carefully monitor serum digoxin concentrations; observe patients carefully for signs of digoxin toxicity.
    Glycopyrrolate: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Glycopyrrolate; Formoterol: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Hawthorn, Crataegus laevigata: (Moderate) Hawthorn, Crataegus laevigata (also known as C. oxycantha) may potentiate the effects of the cardiac glycosides (i.e., digoxin) through a pharmacodynamic interaction. Clinically, hawthorn is reported to be commonly used in conjunction with digoxin in European communities in patients with heart failure (usually NYHA class 2 or milder). The pharmacokinetic effect of hawthorn on digoxin has been evaluated. In a small cross-over study in 8 volunteers, researchers evaluated digoxin 0.25 mg/day PO alone and digoxin 0.25 mg/day PO administered with Crataegus commercial extract WS1442 (Schwabe Pharmaceuticals, dose 450 mg PO twice daily ). Following 3 weeks of concomitant therapy, hawthorn did not significantly alter any pharmacokinetic parameters of digoxin. The authors suggested that both hawthorn and digoxin, in the doses and dosage form studied, may be coadministered safely. However, it is prudent to recommend close clinical observation if digoxin is administered concurrently with hawthorn, due to the potential enhanced effects, and the wide variability in the potency and purity of herbal products. Patients should be advised to only use hawthorn with digoxin after discussion with their prescriber. Monitor the patients heart rate and blood pressure, and for symptoms of digoxin toxicity.
    Heparin: (Minor) Digitalis (e.g., cardiac glycosides like digoxin or digitoxin) may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Hetastarch; Dextrose; Electrolytes: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Homatropine; Hydrocodone: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Because the pharmacologic effects of metoprolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Use with caution due to additive pharmacodynamic effects on cardiac conduction, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Dosages may need adjustment in some patients.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Major) Coadministration of digoxin and spironolactone increases the serum concentration of digoxin by 25%. Digoxin is a substrate for P-glycoprotein (P-gp); spironolactone is a potent inhibitor of P-gp. There also can be a reduction in renal clearance and attenuation of the positive inotropic effects of digoxin. Measure serum digoxin concentrations before initiating spironolactone. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Monitoring for this event is complicated by the fact that spironolactone also can cross-react with some digoxin assays.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Major) When telmisartan is coadministered with digoxin, median increases in digoxin peak concentration (49%) and in trough concentration (20%) are observed. Measure serum digoxin concentrations before initiating telmisartan. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Hydrocodone; Ibuprofen: (Moderate) Coadministration of digoxin and indomethacin increases the serum concentration of digoxin by 40%. Measure serum digoxin concentrations before initiating indomethacin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, concomitant use of other nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, with digoxin may result in increased serum concentrations of digoxin. Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium or ibuprofen. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Hydroxychloroquine: (Moderate) Digoxin serum concentrations have been reported to increase when hydroxychloroquine was added. Hydroxychloroquine may inhibit P-glycoprotein (P-gp). Digoxin is a substrate for P-gp transport. For patients on a stable digoxin regimen and initiating hydroxychloroquine, no initial dose adjustment of either drug has been advised; however, serum digoxin concentrations should be monitored and used for digoxin dose titration as clinically necessary.
    Hyoscyamine: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Ibritumomab Tiuxetan: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy. (Minor) Monitor the use of potassium phosphates closely in patients with cardiac arrhythmias (e.g., atrial fibrillation, atrial flutter, digitalis toxicity (except due to documented hypokalemia), and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia), including patients receiving digoxin or other antiarrhythmic therapy. Both hypokalemia and hyperkalemia increase the risk of digoxin toxicity. Although hyperkalemia can impair AV conduction, potassium-containing phosphorous salts can be coadministered with digoxin because these patients are often receiving potassium-depleting diuretics. Nevertheless, potassium-based phosphorus salts should be used cautiously in patients receiving cardiac glycosides.
    Ibrutinib: (Moderate) Use ibrutinib and digoxin together with caution; plasma concentrations of digoxin may increase resulting in increased toxicity. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; digoxin is a P-gp substrate with a narrow therapeutic index. In addition, some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients.
    Ibuprofen: (Moderate) Coadministration of digoxin and indomethacin increases the serum concentration of digoxin by 40%. Measure serum digoxin concentrations before initiating indomethacin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, concomitant use of other nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, with digoxin may result in increased serum concentrations of digoxin. Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium or ibuprofen. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Ibuprofen; Oxycodone: (Moderate) Coadministration of digoxin and indomethacin increases the serum concentration of digoxin by 40%. Measure serum digoxin concentrations before initiating indomethacin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, concomitant use of other nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, with digoxin may result in increased serum concentrations of digoxin. Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium or ibuprofen. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Ibuprofen; Pseudoephedrine: (Moderate) Coadministration of digoxin and indomethacin increases the serum concentration of digoxin by 40%. Measure serum digoxin concentrations before initiating indomethacin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, concomitant use of other nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, with digoxin may result in increased serum concentrations of digoxin. Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium or ibuprofen. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Ifosfamide: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Imatinib: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Indacaterol; Glycopyrrolate: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Indapamide: (Moderate) Indapamide may induce hypokalemia, increasing the potential for proarrhythmic effects (e.g., torsade de pointes) of cardiac glycosides. Potassium levels should be within the normal range prior and during administration of these agents.
    Indomethacin: (Major) Coadministration of digoxin and indomethacin increases the serum concentration of digoxin by 40%. Measure serum digoxin concentrations before initiating indomethacin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, concomitant use of other nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, with digoxin may result in increased serum concentrations of digoxin. Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium or ibuprofen. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Insulin Degludec; Liraglutide: (Minor) A single dose of digoxin 1 mg administered 7 hours after a dose of liraglutide 1.8 mg at steady state resulted in a reduction of the digoxin AUC by 16% and Cmax by 31%. The median Tmax for digoxin was delayed from 1 hour to 1.5 hours. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If digoxin and liraglutide are co-prescribed, it may be prudent to initially monitor the patient for altered digoxin effect.
    Insulin Glargine; Lixisenatide: (Moderate) Concomitant administration of lixisenatide 20 mcg and digoxin 0.25 mg (at steady state) delayed digoxin Tmax by approximately 1.5 hours and reduced Cmax by 26%. No clinically relevant effects on AUC were observed. The mechanism of this potential interaction has not been described (although it may be due to delayed gastric emptying) and the potential for clinical significance is unknown. Dosage adjustments of digoxin may be necessary.
    Interferon Alfa-2a: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Interferon Alfa-2b: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Interferon Alfa-2b; Ribavirin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Irbesartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Iron Salts: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Isavuconazonium: (Moderate) Use caution and closely monitor digoxin serum concentrations when using digoxin and isavuconazonium concurrently. Coadministration results in increased digoxin exposure, and serum concentrations should guide digoxin dose titration. Isavuconazole, the active moiety of isavuconazonium, is an inhibitor of the drug transporter P-glycoprotein (P-gp); digoxin is a substrate for this transporter.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) It appears that rifampin decreases serum concentrations of digoxin by inducing intestinal P-glycoprotein and decreasing the oral bioavailability of digoxin by 30.1%. The Cmax and AUC of digoxin were decreased by 43% and 58%, respectively. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of rifampin. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Isoniazid, INH; Rifampin: (Moderate) It appears that rifampin decreases serum concentrations of digoxin by inducing intestinal P-glycoprotein and decreasing the oral bioavailability of digoxin by 30.1%. The Cmax and AUC of digoxin were decreased by 43% and 58%, respectively. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of rifampin. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Itraconazole: (Major) Measure serum digoxin concentrations before initiating itraconazole. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. Concomitant use of digoxin with itraconazole has resulted in an 80% increase in digoxin serum concentrations. Itraconazole is an inhibitor of P-glycoprotein (P-gp); digoxin is a substrate for P-gp.
    Ivabradine: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like digoxin. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Ivacaftor: (Moderate) Coadministration of ivacaftor with digoxin may increase digoxin exposure leading to increased or prolonged therapeutic effects and adverse events. Digoxin is a substrate for P-glycoprotein (P-gp). Ivacaftor is an inhibitor of P-glycoprotein (P-gp). Use caution when administering ivacaftor and digoxin concurrently.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Digoxin is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in digoxin concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    Ketoconazole: (Moderate) Concomitant use of digoxin with ketoconazole has resulted in increased digoxin serum concentrations. Ketoconazole inhibits p-glycoprotein, an enzyme which metabolizes digoxin. Plasma concentrations of digoxin should be monitored closely if ketoconazole is added.
    Ketoprofen: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Ketorolac: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Labetalol: (Moderate) Use with caution due to additive pharmacodynamic effects on cardiac conduction, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Dosages may need adjustment in some patients.
    Lacosamide: (Moderate) Lacosamide causes PR interval prolongation in some patients. Caution is advised during coadministration of lacosamide with other drugs that cause PR prolongation, such as digoxin, since further PR prolongation is possible. If concurrent use is necessary, an ECG is recommended prior to initiation of lacosamide and after the drug is titrated to the maintenence dose. Patients receiving intravenous lacosamide should be closely monitored due to the potential for profound bradycardia and AV block during coadministration.
    Lansoprazole: (Moderate) Lansoprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Becuase, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Lansoprazole; Naproxen: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary. (Moderate) Lansoprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Becuase, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Lapatinib: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoing of digoxin therapeutic concentrations is advised when administering digoxin with ledipasvir. Digoxin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase digoxin plasma concentrations.
    Lenalidomide: (Moderate) Concomitant use of lenalidomide and digoxin may result in increased digoxin levels and exposure; use these drugs together with caution. Monitor digoxin levels periodically and as clinically indicated in patients who require both lenalidomide and digoxin. The Cmax and AUC values of digoxin were increased by 14% in patients who received digoxin following multiple oral doses of lenalidomide 10 mg/day.
    Levalbuterol: (Moderate) Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol or levalbuterol and digoxin on a chronic basis is unclear. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of albuterol or levalbuterol. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Levomilnacipran: (Major) Postural hypotension and tachycardia may occur during concurrent use of intravenous digoxin and milnacipran, a racemic mixture containing levomilnacipran. Because the manufacturer of milnacipran recommends against use of milnacipran and intravenous digoxin, use of levomilnacipran with intravenous digoxin should be approached with extreme caution.
    Liraglutide: (Minor) A single dose of digoxin 1 mg administered 7 hours after a dose of liraglutide 1.8 mg at steady state resulted in a reduction of the digoxin AUC by 16% and Cmax by 31%. The median Tmax for digoxin was delayed from 1 hour to 1.5 hours. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If digoxin and liraglutide are co-prescribed, it may be prudent to initially monitor the patient for altered digoxin effect.
    Lisinopril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Lixisenatide: (Moderate) Concomitant administration of lixisenatide 20 mcg and digoxin 0.25 mg (at steady state) delayed digoxin Tmax by approximately 1.5 hours and reduced Cmax by 26%. No clinically relevant effects on AUC were observed. The mechanism of this potential interaction has not been described (although it may be due to delayed gastric emptying) and the potential for clinical significance is unknown. Dosage adjustments of digoxin may be necessary.
    Lomitapide: (Moderate) Concomitant use of lomitapide and digoxin may result in increased serum concentrations of digoxin. According to the manufacturer of lomitapide, dose reduction of digoxin should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and digoxin is a P-gp substrate.
    Lomustine, CCNU: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Loop diuretics: (Moderate) Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as loop diuretics, increasing the risk of proarrhythmic effects of cardiac glycosides. Potassium levels should be monitored and normalized prior to and during concurrent diuretic administration and these agents.
    Lopinavir; Ritonavir: (Major) In a pharmacokinetic study of 11 healthy men, increases in digoxin AUC (86%), volume of distribution, and half-life were seen, while renal and non-renal clearance decreased, when coadministered with ritonavir. It appears that this interaction is mediated by ritonavir's inhibition or P-glycoprotein-mediated renal tubular secretion of digoxin. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including digoxin) has not been evaluated. Measure serum digoxin concentrations before initiating ritonavir or lopinavir; ritonavir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. (Major) In a pharmacokinetic study of 11 healthy men, increases in digoxin AUC (86%), volume of distribution, and half-life were seen, while renal and non-renal clearance decreased, when coadministered with ritonavir. It appears that this interaction is mediated by ritonavir's inhibition or P-glycoprotein-mediated renal tubular secretion of digoxin. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including digoxin) has not been evaluated. Measure serum digoxin concentrations before initiating ritonavir or lopinavir; ritonavir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
    Losartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Lumacaftor; Ivacaftor: (Moderate) Coadministration of ivacaftor with digoxin may increase digoxin exposure leading to increased or prolonged therapeutic effects and adverse events. Digoxin is a substrate for P-glycoprotein (P-gp). Ivacaftor is an inhibitor of P-glycoprotein (P-gp). Use caution when administering ivacaftor and digoxin concurrently.
    Lumacaftor; Ivacaftor: (Moderate) Concomitant use of digoxin and lumacaftor; ivacaftor may alter digoxin exposure. Monitor digoxin serum concentrations closely and titrate the dosage to achieve the desired therapeutic effect. Digoxin is a substrate for the P-glycoprotein (P-gp) efflux transporter. In vitro studies suggest lumacaftor; ivacaftor has the potential to both inhibit and induce P-gp.
    Lurasidone: (Minor) Dosage adjustment of digoxin is not required during concurrent use of lurasidone. Co-administration of lurasidone and digoxin increased the Cmax and AUC of digoxin by about 9% and 13%, respectively, compared to digoxin alone. However, monitor the patient for any increase in digoxin related side effects or toxicity.
    Magnesium Citrate: (Major) Concurrent use of digoxin or other cardiac glycosides with oral magnesium citrate may inhibit absorption and possibly decrease plasma concentrations of the glycoside. Because cardiac conduction changes and heart block may occur if electrolyte imbalances occur, saline laxatives such as magnesium citrate must be administered with caution to patients receiving cardiac glycoside therapy as electrolyte disturbances, particularly hypokalemia, are possible with their use. The patient's electrolytes and renal function should be closely monitored.
    Magnesium Hydroxide: (Moderate) Concurrent administration of liquid formulations of magnesium hydroxide can decrease absorption of cardiac glycosides and reduce their plasma concentration. Steady state concentrations of digoxin are not lowered following administration of tablet formulations of magnesium hydroxide. Doses of liquid magnesium hydroxide and cardiac glycosides should be spaced 1 to 2 hours apart.
    Magnesium Salts: (Major) Concurrent use of cardiac glycosides with oral magnesium salts may inhibit absorption and possibly decrease plasma concentrations of the glycoside.
    Mannitol: (Moderate) Mannitol-induced diuresis increases the excretion of potassium and can lead to hypokalemia. Administration of mannitol to patients receiving cardiac glycosides can increase the risk of developing cardiac toxicity secondary to mannitol-induced hypokalemia. Serum potassium concentrations should be monitored.
    Meclizine: (Moderate) Patients receiving oral digoxin therapy should be monitored for increased digoxin effects when receiving drugs with substantial anticholinergic activity. Meclizine can theoretically increase the absorption of digoxin by decreasing gastrointestinal motility. Anticholinergics, because of their ability to cause tachycardia, can also antagonize the beneficial actions of digoxin in atrial fibrillation/flutter.
    Meclofenamate Sodium: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Mefenamic Acid: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Meloxicam: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Melphalan: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Memantine: (Moderate) Digoxin is eliminated by renal tubular secretion and may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or digoxin is recommended to assess for needed dosage adjustments. In selected individuals, digoxin serum concentration monitoring may be appropriate
    Mepenzolate: (Moderate) Oral formulations of digoxin can produce higher serum concentrations when administered concurrently with antimuscarinics, such as mepenzolate, because of decreased GI motility induced by the antimuscarinic agent. This interaction has mostly occurred in the literature with slowly-dissolving, large-particle formulations of digoxin tablets; the manufacture of oral digoxin products today, utilizing liquid formulations and/or smaller particle sizes, theoretically reduces the potential for absorption interactions. However, there is wide variability expected in individual responses to many digoxin-drug interactions. Other pharmacodynamic and pharmacokinetic systemic interactions are possible between digoxin and select antimuscarinic agents. Anticholinergics, because of their ability to cause tachycardia, can also antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Mephobarbital: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Mesalamine, 5-ASA: (Moderate) The prodrug of mesalamine, sulfasalazine, has been shown to decrease the oral absorption of digoxin by 20%. It is unknown whether mesalamine causes a similar interaction.
    Metformin; Pioglitazone: (Moderate) Concentrations of digoxin may be increased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of digoxin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with digoxin 0.2 mg twice daily (loading dose) then 0.25 mg daily (maintenance dose, 7 days) resulted in a 15% and 17% increase in digoxin AUC and Cmax, respectively. Carefully monitor serum digoxin concentrations; observe patients carefully for signs of digoxin toxicity.
    Metformin; Saxagliptin: (Moderate) The AUC and Cmax of digoxin may be increased in the presence of saxagliptin. Dosage adjustment of digoxin is not recommended, but patients receiving these 2 drugs at the same time should be monitored closely.
    Metformin; Sitagliptin: (Moderate) There was an 11% increase in the AUC and an 18% increase in the plasma Cmax of digoxin when digoxin 0.25 mg/day PO is administered with sitagliptin 100 mg PO once daily for 10 days. Dosage adjustment of digoxin is not recommended, but patients receiving these 2 drugs at the same time should be monitored closely.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Methimazole: (Minor) Serum concentrations of digoxin can increase as hyperthyroidism is corrected. In patients receiving antithyroid therapy, the dosage of digoxin may need to be reduced as the patient becomes euthyroid.
    Methohexital: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Methotrexate: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Methoxsalen: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Methscopolamine: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Metoclopramide: (Moderate) Digoxin absorption and bioavailability may be diminished in some patients on metoclopramide due to the increased rate of transit from the stomach, where digoxin is normally absorbed. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of metoclopramide. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Metoprolol: (Moderate) Because the pharmacologic effects of metoprolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Miglitol: (Moderate) Acarbose, an alpha-glucosidase inhibitor, has been found to decrease the mean bioavailability (AUC) of digoxin by 16% (90% confidence interval: range 8-23%), decrease the mean Cmax of digoxin by 26% (90% confidence interval: range 16-34%), and decrease the mean trough concentration of digoxin by 9% (90% confidence limit: 19% decrease to 2% increase). Miglitol, also an alpha-glucosidase inhibitor, may impair the oral absorption of digoxin and lead to subtherapeutic serum digoxin concentrations in some patients. In healthy volunteers, coadministration of miglitol 50 mg or 100 mg with digoxin reduced the average plasma concentrations of digoxin by 19% and 28%, respectively. However, in diabetic patients under treatment with digoxin, plasma digoxin concentrations were not altered when coadministered with miglitol. The mechanism of the interaction is not well understood. The manufacturer of digoxin recommends measuring digoxin concentrations prior to initiating acarbose or miglitol. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary. Some experts have recommended that these agents be administered 6 hours after an oral digoxin dose to ensure time for adequate digoxin absorption.
    Milnacipran: (Major) Postural hypotension and tachycardia have occurred during concurrent use of intravenous digoxin and milnacipran. Use of this combination is not recommended. Per the product labeling, there was no pharmacokinetic interaction between milnacipran and orally administered digoxin in healthy subjects. The possibility of a pharmacodynamic interaction should not be excluded.
    Minocycline: (Major) Measure serum digoxin concentrations before initiating tetracyclines. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency, and continue monitoring. In approximately 10% of patients, a small portion of a digoxin dose is metabolized in the gut by intestinal Eubacterium lentum, an anaerobic bacillus, to inactive digoxin reduction products (DRPs). DRPs have little cardiac activity due to poor cardiac receptor binding and rapid excretion. Certain antibiotics can reduce the activity of intestinal bacteria, which, in turn, may enhance digoxin bioavailability via decreased DRP formation and increased enterohepatic recycling of digoxin in some patients. The addition of tetracycline to digoxin therapy has been reported to increase the serum digoxin concentration by 100%. Digoxin toxicity has been reported in patients previously stabilized on digoxin who receive antibiotics that affect E. lentum, such as tetracyclines. Other antibiotics that have activity against E. lentum may produce similar effects on digoxin metabolism. Additionally, injectable minocycline contains magnesium sulfate heptahydrate. Magnesium salts, such as magnesium sulfate, can antagonize the electrophysiologic effects of cardiac glycosides such as digoxin.
    Mirabegron: (Major) When given in combination, mirabegron increased the mean digoxin Cmax by 29% and the AUC by 27%. Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
    Mitomycin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Mitoxantrone: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Moexipril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Moricizine: (Moderate) Both moricizine and cardiac glycosides depress AV nodal conduction, resulting in PR prolongation.Moricizine should be used cautiously, if at all, in patients receiving cardiac glycosides.
    Nabumetone: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Nadolol: (Moderate) Because the pharmacologic effects of nadolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Nafcillin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Naproxen: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Naproxen; Pseudoephedrine: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Naproxen; Sumatriptan: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Nebivolol: (Moderate) Administer nebivolol and digoxin together cautiously. Nebivolol and digoxin slow atrioventricular conduction and decrease heart rate. Concomitant use of nebivolol and digoxin or other drugs that significantly depress AV nodal conduction can increase the risk of bradycardia and AV block. No significant changes in the pharmacokinetics of digoxin or nebivolol were seen with the concomitant administration of digoxin 0.25 mg once daily and nebivolol 10 mg once daily for 10 days in 14 healthy volunteers. No significant changes in the extent of in vitro binding of nebivolol to human plasma proteins was observed in the presence of a high digoxin concentration, and, similarly, at therapeutic digoxin concentrations, nebivolol did not significantly change the binding of digoxin to human plasma proteins.
    Nebivolol; Valsartan: (Moderate) Administer nebivolol and digoxin together cautiously. Nebivolol and digoxin slow atrioventricular conduction and decrease heart rate. Concomitant use of nebivolol and digoxin or other drugs that significantly depress AV nodal conduction can increase the risk of bradycardia and AV block. No significant changes in the pharmacokinetics of digoxin or nebivolol were seen with the concomitant administration of digoxin 0.25 mg once daily and nebivolol 10 mg once daily for 10 days in 14 healthy volunteers. No significant changes in the extent of in vitro binding of nebivolol to human plasma proteins was observed in the presence of a high digoxin concentration, and, similarly, at therapeutic digoxin concentrations, nebivolol did not significantly change the binding of digoxin to human plasma proteins. (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Nefazodone: (Major) Coadministration of digoxin and nefazodone increases the serum concentration and AUC of digoxin by 27% and 15%, respectively. Measure serum digoxin concentrations before initiating nefazodone. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
    Nelarabine: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Neomycin: (Moderate) Large doses of neomycin have been reported to reduce the absorption of digoxin leading to reduced steady-state digoxin concentrations of 28%. It is thought that the decrease in digoxin absorption is due to alterations in the properties of the gut wall. Therefore, separating the time of administration between these drugs and digoxin will probably not reduce the potential interaction. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of neomycin. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Neratinib: (Moderate) Monitor digoxin levels and watch for digoxin-related toxicities if coadministration with neratinib is necessary. Digoxin is a P-glycoprotein (P-gp) substrate. Coadministration with neratinib increased the mean Cmax and AUC of digoxin by 54% and 32%, respectively.
    Nesiritide, BNP: (Major) Nesiritide may have additive inoptropic effects with cardiac glycosides.
    Niacin; Simvastatin: (Moderate) Simvastatin causes a slight elevation of serum digoxin levels. Simvastatin should be used cautiously in patients receiving digoxin.
    Nicardipine: (Minor) Some calcium-channel blockers cause serum digoxin concentrations to rise. Although this reaction has not been reported with nicardipine, patients should be monitored closely for this possibility if nicardipine is added to digoxin therapy.
    Nifedipine: (Major) Coadministration of digoxin and nifedipine increases the serum concentration of digoxin by 45%. This is believed to be due to decreased renal and nonrenal clearance of digoxin by nifedipine. In addition, digoxin is a substrate for P-glycoprotein (P-gp) and nifedipine is a mild inhibitor of P-gp. Measure serum digoxin concentrations before initiating nifedipine. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
    Nilotinib: (Major) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein. Digoxin is a P-glycoprotein substrate. Increased concentrations of digoxin are likely if it is coadministered with nilotinib; exercise caution.
    Nisoldipine: (Moderate) The manufacturer of Sular reports that there are no significant interactions between nisoldipine core-coat and warfarin or digoxin. However, in a study of chronic coadministration of immediate release nisoldipine and digoxin in 10 patients with heart failure, nisoldipine was shown to elevate trough digoxin plasma concentrations by about 15%. A structurally related dihydropyridine, nifedipine, has been reported to increase digoxin levels up to 45%. In individual patients, significant elevation of digoxin plasma levels could occur with nisoldipine coadministration; monitoring of digoxin levels is advised.
    Olmesartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Olsalazine: (Moderate) Mesalamine, the metabolite of olsalazine, can decrease the GI absorption of digoxin.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with digoxin is expected to increase digoxin serum concentrations. Digoxin's product labeling recommends a digoxin dosage reduction of 30 to 50%. Measure digoxin serum concentration before initiating dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, and then as clinically appropriate during coadministration to ensure appropriate digoxin dosage titration. Monitor for therapeutic and adverse effects. Digoxin is a P-glycoprotein (P-gp) substrate, and ritonavir and paritaprevir are a P-gp inhibitors. (Major) In a pharmacokinetic study of 11 healthy men, increases in digoxin AUC (86%), volume of distribution, and half-life were seen, while renal and non-renal clearance decreased, when coadministered with ritonavir. It appears that this interaction is mediated by ritonavir's inhibition or P-glycoprotein-mediated renal tubular secretion of digoxin. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including digoxin) has not been evaluated. Measure serum digoxin concentrations before initiating ritonavir or lopinavir; ritonavir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
    Omeprazole: (Moderate) Omeprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Omeprazole increases the AUC of digoxin by about 10%. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Because, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Omeprazole; Sodium Bicarbonate: (Moderate) Omeprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Omeprazole increases the AUC of digoxin by about 10%. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Because, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Oxacillin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Oxaprozin: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Oxybutynin: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Oxymetazoline: (Major) Caution is advised when taking cardiac glycosides with alpha adrenergic agonists, such as oxymetazoline. Alpha adrenergic agonist can enhance ectopic pacemaker activity; thus, concurrent use with cardiac glycosides may result in arrhythmias.
    Pancuronium: (Moderate) Pancuronium increases the risk of developing arrhythmias and should be used with caution in patients receiving cardiac glycosides.
    Pantoprazole: (Moderate) Pantoprazole has not been shown to slightly increase digoxin bioavailability, although other proton pump inhibitors (PPIs) have slightly increased digoxin levels due to the long lasting effect of the PPIs on gastric acid secretion, which affects the absorption of some drugs. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Becuase, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Pantothenic Acid, Vitamin B5: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Parathyroid Hormone: (Moderate) Caution is warranted in patients receiving concomitant parathyroid hormonone and digoxin therapy. Parathyroid hormone (PTH) therapy causes transient increases in serum calcium concentrations. Since the inotropic effects of digoxin are affected by serum calcium concentrations, hypercalcemia may predispose patients to digoxin toxicity. Monitor the patient's serium calcium and digoxin concentrations and for signs and symptoms of digitalis toxicity. Adjustment of digoxin and/or parathyroid hormone may be nececessary.
    Paricalcitol: (Moderate) Paricalcitol should be administered with caution to patients receiving digoxin. Vitamin D analogs may cause hypercalemia which increases the risk of digitalis toxicity. In patients receiving paricalcitol and digoxin concurrently, monitor serum calcium frequently and monitor the patient for signs of digitalis toxicity. More frequent monitoring is necessary when initiating or adjusting the dose of paricalcitol.
    Paromomycin: (Moderate) In approximately 10% of patients, a small portion of oral digoxin is metabolized by GI flora. Administration of a nonabsorbable aminoglycoside antibiotic such as paromomycin can depress colonic bacteria and increase the oral bioavailability of digoxin in these patients. Large doses of neomycin have been reported to reduce the absorption of digoxin leading to reduced steady-state digoxin concentrations of 28%. Since paromomycin is structurally related to neomycin, it is possible that paromomycin could also reduce digoxin bioavailability. It is thought that the decrease in digoxin absorption is due to alterations in the properties of the gut wall. Therefore, separating the time of administration between these drugs and digoxin will probably not reduce the potential interaction. Since it is impossible to predict which patients will be affected in this manner, digoxin serum concentrations should be monitored closely if oral paromomycin is added.
    Paroxetine: (Minor) Paroxetine may slightly decrease mean digoxin area under the curve values. Until more clinical data are known, patients should be monitored for loss of digoxin clinical effect if paroxetine is added.
    Pegaspargase: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Penbutolol: (Moderate) Because the pharmacologic effects of penbutolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Penicillamine: (Moderate) Decreased serum digoxin concentrations have been reported in patients who received digoxin and penicillamine. Measure serum digoxin concentrations before initiating penicillamine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Penicillin G Benzathine: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Penicillin G Benzathine; Penicillin G Procaine: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Penicillin G Procaine: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Penicillin G: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Penicillin V: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Penicillins: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Pentobarbital: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Perindopril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Perindopril; Amlodipine: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Phenobarbital: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Phentermine; Topiramate: (Moderate) Serum digoxin AUC was decreased by 12% when coadministered with topiramate. Although the clinical relevance has not been determined, the clinician should be aware that serum digoxin concentrations may be affected when digoxin and topiramate are used concomitantly.
    Phenytoin: (Moderate) Hepatic enzyme-inducing drugs, such as phenytoin and fosphenytoin, can accelerate the metabolism of digoxin. Decreasing digoxin serum concentrations could result. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of phenytoin. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary.
    Phosphorus Salts: (Minor) Monitor the use of potassium phosphates closely in patients with cardiac arrhythmias (e.g., atrial fibrillation, atrial flutter, digitalis toxicity (except due to documented hypokalemia), and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia), including patients receiving digoxin or other antiarrhythmic therapy. Both hypokalemia and hyperkalemia increase the risk of digoxin toxicity. Although hyperkalemia can impair AV conduction, potassium-containing phosphorous salts can be coadministered with digoxin because these patients are often receiving potassium-depleting diuretics. Nevertheless, potassium-based phosphorus salts should be used cautiously in patients receiving cardiac glycosides.
    Pindolol: (Moderate) Because the pharmacologic effects of pindolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Pioglitazone: (Moderate) Concentrations of digoxin may be increased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of digoxin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with digoxin 0.2 mg twice daily (loading dose) then 0.25 mg daily (maintenance dose, 7 days) resulted in a 15% and 17% increase in digoxin AUC and Cmax, respectively. Carefully monitor serum digoxin concentrations; observe patients carefully for signs of digoxin toxicity.
    Piperacillin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Piperacillin; Tazobactam: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Piroxicam: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Polycarbophil: (Major) Since electrolyte disorders modify the actions of cardiac glycosides (e.g., digoxin and digitoxin), drugs that can affect electrolyte balance can potentially affect the response to digoxin. Hypercalcemia increases digoxin's effect, and each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg). It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Ponatinib: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and digoxin, a P-gp substrate, may increase the exposure of digoxin. Monitor serum digoxin concentrations if these agents are used together.
    Porfimer: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Posaconazole: (Moderate) Posaconazole and digoxin should be used together with caution due to the potential for digoxin-related adverse events. If used in combination, carefully monitor digoxin plasma concentrations during and at discontinuation of posaconazole therapy. Both posaconazole and digoxin are substrates of the drug efflux protein, P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. Increased plasma concentrations of digoxin have been reported during coadministration with posaconazole.
    Potassium Phosphate; Sodium Phosphate: (Minor) Monitor the use of potassium phosphates closely in patients with cardiac arrhythmias (e.g., atrial fibrillation, atrial flutter, digitalis toxicity (except due to documented hypokalemia), and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia), including patients receiving digoxin or other antiarrhythmic therapy. Both hypokalemia and hyperkalemia increase the risk of digoxin toxicity. Although hyperkalemia can impair AV conduction, potassium-containing phosphorous salts can be coadministered with digoxin because these patients are often receiving potassium-depleting diuretics. Nevertheless, potassium-based phosphorus salts should be used cautiously in patients receiving cardiac glycosides.
    Potassium: (Minor) Potassium levels should be monitored closely in patients receiving digoxin and potassium supplementation. Both hypokalemia and hyperkalemia increase the risk of digoxin toxicity. Some patients at increased risk are patients with renal impairment, patients on diuretics, and patients who are on potassium-sparing medications concurrently. Monitor renal function, potassium concentrations, and digoxin concentrations and clinical response during concurrent treatment.
    Primidone: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Propafenone: (Major) Propafenone reduces the clearance of digoxin and may lead to digoxin toxicity. Increases in digoxin serum concentrations may occur in over 80% of patients when propafenone is added to the regimen. Concomitant use of propafenone and digoxin has been reported to increase the steady-state AUC of orally administered digoxin by 60 to 270%, and decrease digoxin clearance by 31 to 67%. When propafenone is coadministered with intravenous (IV) digoxin, the serum concentration of digoxin is increased by 28%. Although the exact mechanism for this interaction has not been established, several mechanisms have been proposed including reduced distribution volume and nonrenal clearance of digoxin, as well as potential inhibition of P-glycoprotein renal tubular transport of digoxin. Measure serum digoxin concentrations before initiating propafenone. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50%, decreasing the IV digoxin dose by 15 to 30%, or by modifying the dosing frequency and continue monitoring.
    Propantheline: (Major) Coadministration of digoxin and propantheline increases both the serum concentration and AUC of digoxin by 24%. Measure serum digoxin concentrations before initiating propantheline. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Anticholinergics, because of their ability to cause tachycardia, can also antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Propranolol: (Moderate) Use with caution due to additive pharmacodynamic effects on cardiac conduction, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Dosages may need adjustment in some patients.
    Propylthiouracil, PTU: (Minor) Serum concentrations of digoxin can increase as hyperthyroidism is corrected. In patients receiving antithyroid therapy, the dosage of digoxin may need to be reduced as the patient becomes euthyroid.
    Psyllium: (Moderate) Psyllium can interfere with the absorption of certain oral drugs if administered together. Psyllium can adsorb cardiac glycosides. Per the manufacturer, administration of other oral drugs should be separated from the administration of psyllium by at least 2 hours.
    Pyridoxine, Vitamin B6: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Pyrimidine analogs: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Quinapril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Quinidine: (Major) Coadministration of quinidine and oral digoxin has resulted in a 100% increase in digoxin serum concentrations. When quinidine is coadministered with intravenous (IV) digoxin, the digoxin AUC is increased by 54 to 83%. Digoxin is a substrate for P-glycoprotein (P-gp). Quinidine inhibits P-gp, an energy-dependent cellular drug efflux pump. The inhibition of P-gp in the intestinal cell wall may lead to increased oral absorption of digoxin. It also has been shown that quinidine inhibits the secretion of digoxin by P-gp transporters in the kidney leading to decreased renal tubular elimination of digoxin and increased serum concentrations. Measure serum digoxin concentrations before initiating quinidine. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
    Quinine: (Major) Coadministration of digoxin and quinine increases the AUC of digoxin by 33%. Both digoxin and quinine are substrates for P-glycoprotein (P-gp). Measure serum digoxin concentrations before initiating quinine. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Lower doses of quinine may have no effect on digitalis clearance.
    Rabeprazole: (Moderate) Rabeprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. When rabeprazole was co-administered with digoxin, the AUC and Cmax for digoxin increased 19% and 29%, respectively. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Becuase, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Ramipril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Ranolazine: (Major) In vitro studies suggest that ranolazine is a P-glycoprotein inhibitor. Ranolazine increases digoxin concentrations by 1.5-fold in healthy volunteers receiving ranolazine (1000 mg PO twice daily) and digoxin (0.125 mg PO once daily). Measure serum digoxin concentrations before initiating ranolazine. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. In contrast, digoxin does not increase the plasma concentrations of ranolazine. No dose adjustment of ranolazine is required for patients treated with digoxin.
    Regadenoson: (Major) Because of the potential for additive or synergistic depressant effects on SA and AV nodes, regadenoson should be used with caution in the presence of agents that slow cardiac conduction, especially digoxin.
    Reserpine: (Moderate) Concomitant administration of reserpine and cardiac glycosides can increase the risk of developing arrhythmias, especially when large doses of reserpine are used.
    Rifampin: (Moderate) It appears that rifampin decreases serum concentrations of digoxin by inducing intestinal P-glycoprotein and decreasing the oral bioavailability of digoxin by 30.1%. The Cmax and AUC of digoxin were decreased by 43% and 58%, respectively. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of rifampin. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Rifapentine: (Moderate) Rifamycins induce hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by either of these enzymes, including cardiac glycosides, may require dosage adjustments when administered concurrently with rifamycins.
    Ritonavir: (Major) In a pharmacokinetic study of 11 healthy men, increases in digoxin AUC (86%), volume of distribution, and half-life were seen, while renal and non-renal clearance decreased, when coadministered with ritonavir. It appears that this interaction is mediated by ritonavir's inhibition or P-glycoprotein-mediated renal tubular secretion of digoxin. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including digoxin) has not been evaluated. Measure serum digoxin concentrations before initiating ritonavir or lopinavir; ritonavir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
    Rolapitant: (Moderate) Avoid the concurrent use of digoxin and rolapitant if possible; if coadministration is necessary, monitor digoxin levels and watch for digoxin-related adverse effects. Digoxin is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Rufinamide: (Moderate) Shortening of the QT interval has occurred during treatment with rufinamide. Therefore, caution is advisable during co-administration with other drugs associated with QT-shortening including digoxin.
    Sacubitril; Valsartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and digoxin as coadministration may result in increased systemic exposure of digoxin. Digoxin is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of digoxin.
    Saquinavir: (Major) The concurrent use of saquinavir boosted with ritonavir and digoxin should be used very cautiously due to the potential for increased serum digoxin concentrations and possible cardiac arrhythmias. The increase in serum concentrations may be greater in females, as compared to males. Additionally, saquinavir boosted with ritonavir causes dose-dependent PR prolongation; if possible, avoid use with other drugs that may prolong the PR interval, such as digoxin. If concomitant therapy cannot be avoided, measure serum digoxin concentrations before initiating saquinavir boosted with ritonavir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
    Saxagliptin: (Moderate) The AUC and Cmax of digoxin may be increased in the presence of saxagliptin. Dosage adjustment of digoxin is not recommended, but patients receiving these 2 drugs at the same time should be monitored closely.
    Scopolamine: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Secobarbital: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Sevelamer: (Moderate) Studies of concomitant sevelamer and digoxin have not demonstrated an interaction. However, sevelamer may interfere with the absorption of many drugs; this is especially important with narrow therapeutic index drugs such as digoxin. Administer digoxin at least 1 hour before or 3 hours after sevelamer doses and monitor digoxin drug concentrations to minimize the potential for a drug interaction.
    Simeprevir: (Moderate) Coadministration of digoxin with simeprevir, a P-glycoprotein (P-gp) inhibitor, results in increased digoxin plasma concentrations. If these drugs are administered together, routine monitoring of digoxin plasma concentrations is recommended.
    Simvastatin: (Moderate) Simvastatin causes a slight elevation of serum digoxin levels. Simvastatin should be used cautiously in patients receiving digoxin.
    Simvastatin; Sitagliptin: (Moderate) Simvastatin causes a slight elevation of serum digoxin levels. Simvastatin should be used cautiously in patients receiving digoxin. (Moderate) There was an 11% increase in the AUC and an 18% increase in the plasma Cmax of digoxin when digoxin 0.25 mg/day PO is administered with sitagliptin 100 mg PO once daily for 10 days. Dosage adjustment of digoxin is not recommended, but patients receiving these 2 drugs at the same time should be monitored closely.
    Sitagliptin: (Moderate) There was an 11% increase in the AUC and an 18% increase in the plasma Cmax of digoxin when digoxin 0.25 mg/day PO is administered with sitagliptin 100 mg PO once daily for 10 days. Dosage adjustment of digoxin is not recommended, but patients receiving these 2 drugs at the same time should be monitored closely.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Digoxin may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, digoxin should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution. In addition, the manufacturer cautions the use of sodium picosulfate; magnesium oxide; anhydrous citric acid solution in patients receiving drugs where hypokalemia is a particular risk, such as digoxin.
    Sodium Polystyrene Sulfonate: (Moderate) Since electrolyte disorders modify the actions of digoxin, drugs that can affect electrolyte balance, such as sodium polystyrene sulfonate, potentially can increase the effect and potentiate the toxicity of digoxin.
    Sofosbuvir; Velpatasvir: (Moderate) Therapeutic serum concentration monitoring of digoxin is recommended when coadministered with velpatasvir due to the potential for increased digoxin serum concentrations. A digoxin dose modification may be necessary. A single-dose pharmacokinetic study showed increases in the Cmax (188%) and AUC (134%) of digoxin when administered with velpatasvir compared to no coadministration. Digoxin is a P-glycoprotein (P-gp) substrate and velpatasvir inhibits P-gp.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Increased digoxin serum concentrations may occur when digoxin is coadministered with voxilaprevir. Monitor digoxin serum concentrations and adjust digoxin dose as necessary. Digoxin is a P-glycoprotein (P-gp) substrate and voxilaprevir inhibits P-gp. (Moderate) Therapeutic serum concentration monitoring of digoxin is recommended when coadministered with velpatasvir due to the potential for increased digoxin serum concentrations. A digoxin dose modification may be necessary. A single-dose pharmacokinetic study showed increases in the Cmax (188%) and AUC (134%) of digoxin when administered with velpatasvir compared to no coadministration. Digoxin is a P-glycoprotein (P-gp) substrate and velpatasvir inhibits P-gp.
    Sorafenib: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Sotalol: (Moderate) Sotalol and digoxin should be used together cautiously. Digoxin and sotalol slow AV conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. In addition, digoxin used concomitantly with sotalol can increase the possibility of proarrhythmia. Proarrhythmic events were more common in sotalol-treated patients also receiving digoxin; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia. Single and multiple doses of sotalol do not appear to interfere substantially with digoxin serum concentrations.
    Spironolactone: (Major) Coadministration of digoxin and spironolactone increases the serum concentration of digoxin by 25%. Digoxin is a substrate for P-glycoprotein (P-gp); spironolactone is a potent inhibitor of P-gp. There also can be a reduction in renal clearance and attenuation of the positive inotropic effects of digoxin. Measure serum digoxin concentrations before initiating spironolactone. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Monitoring for this event is complicated by the fact that spironolactone also can cross-react with some digoxin assays.
    St. John's Wort, Hypericum perforatum: (Moderate) An interaction between St. John's wort, Hypericum perforatum and digoxin has been noted. After the achievement of steady state digoxin levels, 25 healthy volunteers received digoxin (0.25 mg/day) either with placebo or with St. John's wort extract (900 mg/day) for another 10 days. After 10 days of co-treatment with hypericum extract LI160, the patients' digoxin AUCs decreased by 25%. Digoxin trough concentrations and Cmax decreased by 33% and 26%, respectively. The effect of St. John's wort on digoxin concentrations became increasingly pronounced until the tenth day of co-medication. The authors have postulated that St. John's wort induces the P-glycoprotein intestinal drug transporter, which extrudes digoxin back into the GI tract and results in decreased systemic bioavailability. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of St. John's wort, Hypericum perforatum. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary. Conversely, the discontinuation of St. John's wort could lead to increased digoxin bioavailability and potential toxicity in a patient previously stabilized on digoxin.
    Succinylcholine: (Major) Concomitant use of digoxin with succinylcholine can cause arrhythmias because succinylcholine causes extrusion of potassium from the muscle cells.
    Sucralfate: (Moderate) Sucralfate, because it contains aluminum in its structure and due to its mechanism of action, can bind with digoxin in the GI tract, reducing its bioavailability. Sucralfate should be given 2 hours before or after the oral administration of digoxin. In addition, the manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of sucralfate. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Because both trimethoprim and digoxin undergo tubular secretion, trimethoprim can interfere with the renal tubular secretion of digoxin when administered concomitantly. The renal clearance of digoxin decreased significantly in elderly subjects receiving trimethoprim for 14 days, resulting in a 22% increase in digoxin concentrations. Similar changes were not noted in a single-dose study of young healthy volunteers. Patients receiving digoxin, especially the elderly, should be monitored carefully for digoxin toxicity if trimethoprim is added.
    Sulfasalazine: (Moderate) Sulfasalazine has been reported to reduce the absorption of digoxin by 20%. It is thought that the decrease in digoxin absorption is due to alterations in the properties of the gut wall. Therefore, separating the time of administration between sulfasalazine and digoxin will probably not reduce the potential interaction.The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of sulfasalazine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Sulindac: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Sunitinib: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Suvorexant: (Major) Digoxin concentrations should be monitored during use with suvorexant. In one evaluation, concomitant administration of digoxin and suvorexant slightly increased digoxin levels presumably due to inhibition of intestinal P-glycoprotein (P-gp) by suvorexant.
    Sympathomimetics: (Major) Concomitant use of cardiac glycosides with sympathomimetics can cause arrhythmias because sympathomimetics enhance ectopic pacemaker activity. Caution is warranted during co-administration of digoxin and sympathomimetics.
    Taxanes: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Teduglutide: (Moderate) Teduglutide may increase absorption of digoxin because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of digoxin is recommended.
    Tegaserod: (Minor) When digoxin is combined with tegaserod, a reduction in digoxin peak plasma concentration occurs. Digoxin dose adjustments are unlikely to be required when combined with tegaserod. Until further clinical use is gained with tegaserod, use caution and consider monitoring digoxin levels more frequently if combined with tegaserod.
    Telaprevir: (Moderate) Monitoring of digoxin serum concentrations is advised when administering digoxin with telaprevir due to an increased potential for digoxin-related adverse events. The lowest dose of digoxin should be initially prescribed with titrations of digoxin based on serum concentrations. If digoxin dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment.
    Telithromycin: (Moderate) Concomitant administration of telithromycin and digoxin increased digoxin peak and trough plasma levels by 73% and 21%, respectively, in healthy volunteers. However, trough levels ranged from 0.74 to 2.17 ng/ml. There were no significant ECG changes and no signs of digoxin toxicity. Monitoring of digoxin adverse effects or serum levels should be considered during administration with telithromycin.
    Telmisartan: (Major) When telmisartan is coadministered with digoxin, median increases in digoxin peak concentration (49%) and in trough concentration (20%) are observed. Measure serum digoxin concentrations before initiating telmisartan. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. In addition, caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with digoxin is necessary, and monitor digoxin levels and for an increase in digoxin-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and digoxin is a P-gp substrate with a narrow therapeutic range. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to digoxin is likely to increase.
    Teriparatide: (Minor) Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Because teriparatide increases serum calcium it should be used with caution in patients taking digoxin. Administering a single dose of teriparatide to patients with steady state digoxin levels did not alter the effect of digoxin on the systolic time interval.
    Tetracycline: (Major) Measure serum digoxin concentrations before initiating tetracyclines. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency, and continue monitoring. In approximately 10% of patients, a small portion of a digoxin dose is metabolized in the gut by intestinal Eubacterium lentum, an anaerobic bacillus, to inactive digoxin reduction products (DRPs). DRPs have little cardiac activity due to poor cardiac receptor binding and rapid excretion. Certain antibiotics can reduce the activity of intestinal bacteria, which, in turn, may enhance digoxin bioavailability via decreased DRP formation and increased enterohepatic recycling of digoxin in some patients. The addition of tetracycline to digoxin therapy has been reported to increase the serum digoxin concentration by 100%. Digoxin toxicity has been reported in patients previously stabilized on digoxin who receive antibiotics that affect E. lentum, such as tetracyclines. Other antibiotics that have activity against E. lentum may produce similar effects on digoxin metabolism.
    Thalidomide: (Moderate) Thalidomide and digoxin should be used cautiously due to the potential for additive bradycardia. The pharmacokinetic parameters of thalidomide and digoxin were not affected when a single dose of digoxin 0.5 mg was administered in 16 healthy men who were receiving thalidomide 200 mg/day (at steady state levels).
    Thiazide diuretics: (Moderate) Thiazide diuretics can cause hypokalemia, hypomagnesemia, or hypercalcemia which may increase digoxin's pharmacologic effect. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. It is also recommended that serum potassium, magnesium, and calcium be monitored regularly in patients receiving digoxin.
    Thiopental: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
    Thyroid hormones: (Minor) Thyroid disease is known to alter the response to digoxin. Digoxin toxicity is more likely to occur in patients with hypothyroidism, while the response to digoxin is diminished in patients with hyperthyroidism. These reactions should be kept in mind when therapy with thyroid hormones is begun or interrupted. When hypothyroid patients are administered thyroid hormone, the dose requirement of digoxin may be increased.
    Ticagrelor: (Moderate) Monitor digoxin concentrations when used concomitantly with ticagrelor. Ticagrelor is a P-gp inhibitor and digoxin is metabolized by P-gp.
    Ticarcillin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Ticarcillin; Clavulanic Acid: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Ticlopidine: (Minor) Ticlopidine has been shown to slightly decrease digoxin plasma levels. The magnitude of this pharmacokinetic interaction may not be clinically significant.
    Timolol: (Moderate) Because the pharmacologic effects of timolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Tolmetin: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with digoxin may result in increased serum concentrations of digoxin. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Tolterodine: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Tolvaptan: (Major) Coadministration of digoxin and tolvaptan increases the serum concentration of digoxin by 30%. Digoxin is a substrate for P-glycoprotein (P-gp); tolvaptan is a substrate and inhibitor of P-gp. Measure serum digoxin concentrations before initiating tolvaptan. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
    Topiramate: (Moderate) Serum digoxin AUC was decreased by 12% when coadministered with topiramate. Although the clinical relevance has not been determined, the clinician should be aware that serum digoxin concentrations may be affected when digoxin and topiramate are used concomitantly.
    Tositumomab: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Tramadol: (Moderate) An increased incidence of digoxin toxicity has been reported in some patients during post-marketing reports with the concurrent use of tramadol and digoxin.
    Trandolapril: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Trandolapril; Verapamil: (Major) Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively; serum concentrations of orally administered digoxin can increase by 50 to 75% during the first week of combination therapy, possibly resulting in digitalis toxicity. When verapamil is coadministered with intravenous (IV) digoxin, the digoxin AUC is increased by 24%. Measure serum digoxin concentrations before initiating verapamil. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50%, decreasing the IV digoxin dose by 15 to 30%, or by modifying the dosing frequency and continue monitoring. In addition to serum concentration information, the manufacturer of verapamil recommends adjusting the digoxin dosage according to clinical response, since digoxin serum concentrations may not accurately reflect response. Digoxin is a substrate for P-glycoprotein (P-gp). Verapamil inhibits P-gp, an energy-dependent cellular drug efflux pump. The inhibition of P-gp in the intestinal cell wall may lead to increased oral absorption of digoxin. It also has been shown that verapamil inhibits the secretion of digoxin by P-gp transporters in the kidney leading to decreased renal tubular elimination of digoxin and increased serum concentrations. Both drugs slow conduction through the AV node, and for this reason, these drugs are sometimes used together for ventricular control in patients with atrial fibrillation or flutter. In clinical trials in patients with atrial fibrillation or atrial flutter on both verapamil and digoxin, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. Additionally, the effect of verapamil on the pharmacokinetics of digoxin is magnified in patients with hepatic cirrhosis. (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin-converting enzyme inhibitors (ACE inhibitors). A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Trastuzumab: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Trazodone: (Moderate) Increased serum digoxin levels have been reported in patients taking trazodone and digoxin concomitantly. The clinical significance of this interaction is not known.
    Tretinoin, ATRA: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Trihexyphenidyl: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Trimethoprim: (Major) Because both trimethoprim and digoxin undergo tubular secretion, trimethoprim can interfere with the renal tubular secretion of digoxin when administered concomitantly. The renal clearance of digoxin decreased significantly in elderly subjects receiving trimethoprim for 14 days, resulting in a 22% increase in digoxin concentrations. Similar changes were not noted in a single-dose study of young healthy volunteers. Patients receiving digoxin, especially the elderly, should be monitored carefully for digoxin toxicity if trimethoprim is added.
    Trospium: (Moderate) Oral formulations of digoxin can produce higher serum concentrations when administered concurrently with antimuscarinics (e.g., propantheline) because of decreased GI motility induced by the antimuscarinic agent. This interaction has mostly occurred in the literature with slowly-dissolving, large-particle formulations of digoxin tablets; the manufacture of oral digoxin products today, utilizing liquid formulations and/or smaller particle sizes, theoretically reduces the potential for absorption interactions. However, there is wide variability expected in individual responses to many digoxin-drug interactions. Other pharmacodynamic and pharmacokinetic systemic interactions are possible between digoxin and select antimuscarinic agents. Both trospium (a selective antimuscarinic) and digoxin are eliminated by active renal tubular secretion; coadministration has the potential to increase serum concentrations of trospium or digoxin due to competition for the drug elimination pathway. Darifenacin (30 mg daily) coadministered with digoxin (0.25 mg daily) resulted in a 16% increase in digoxin exposure. Anticholinergics, because of their ability to cause tachycardia, can also antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Ulipristal: (Minor) In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as digoxin may increase the digoxin concentrations; use caution. With single doses of ulipristal for emergency contraception it is not clear this interaction will have clinical consequence. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Uridine Triacetate: (Moderate) Coadministration of uridine triacetate and digoxin may increase digoxin serum concentrations; monitor digoxin serum concentrations and therapeutic/adverse effects if these drugs are administered together. Both digoxin and uridine triacetate are substrates for P-glycoprotein (P-gp). Due to the potential for high local gut concentrations of the drug after dosing, the interaction of uridine triacetate with digoxin and other orally administered P-gp substrate drugs cannot be ruled out.
    Valbenazine: (Major) Digoxin concentrations should be monitored during concurrent use of valbenazine. During co-administration of valbenazine and digoxin, the Cmax of digoxin increased nearly 2-fold and the AUC increased over 1-fold due to inhibition of intestinal P-glycoprotein (P-gp) by valbenazine. An increase in digoxin exposure may result in digoxin toxicity (e.g., cardiac arrhythmias, nausea and vomiting, and visual disturbances), A dosage adjustment of digoxin may be necessary.
    Valsartan: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Vandetanib: (Moderate) Use caution and monitor closely if coadministration of vandetanib with digoxin is necessary, due to a possible increase in digoxin-related adverse reactions including arrhythmias, confusion, vision changes, and nausea. Digoxin is a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin by 29% and 23%, respectively.
    Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and digoxin; increased digoxin exposure has been reported. If coadministration is unavoidable, consider a digoxin dose reduction and monitor patients carefully for signs and symptoms of digoxin toxicity (e.g., arrhythmias, heart block). Vemurafenib is a substrate and inhibitor P-glycoprotein (P-gp) and digoxin is a sensitive P-gp substrate with a narrow therapeutic index. The digoxin AUC and Cmax values were increased by 1.8-fold (90% CI, 1.6 to 2) and 1.5-fold (90% CI, 1.3 to 1.7), respectively, in 26 cancer patients who received vemurafenib 960 mg PO twice daily for 22 days and a single 0.25 mg-dose of digoxin.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and digoxin as digoxin levels may be increased. If concomitant use of these drugs is required, administer digoxin at least 6 hours before venetoclax. Monitor patients for signs and symptoms of digoxin toxicity. Venetoclax is an inhibitor of P-glycoprotein (P-gp) and digoxin is a P-gp substrate with a narrow therapeutic index; these agents may interact in the gastrointestinal tract.
    Verapamil: (Major) Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively; serum concentrations of orally administered digoxin can increase by 50 to 75% during the first week of combination therapy, possibly resulting in digitalis toxicity. When verapamil is coadministered with intravenous (IV) digoxin, the digoxin AUC is increased by 24%. Measure serum digoxin concentrations before initiating verapamil. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50%, decreasing the IV digoxin dose by 15 to 30%, or by modifying the dosing frequency and continue monitoring. In addition to serum concentration information, the manufacturer of verapamil recommends adjusting the digoxin dosage according to clinical response, since digoxin serum concentrations may not accurately reflect response. Digoxin is a substrate for P-glycoprotein (P-gp). Verapamil inhibits P-gp, an energy-dependent cellular drug efflux pump. The inhibition of P-gp in the intestinal cell wall may lead to increased oral absorption of digoxin. It also has been shown that verapamil inhibits the secretion of digoxin by P-gp transporters in the kidney leading to decreased renal tubular elimination of digoxin and increased serum concentrations. Both drugs slow conduction through the AV node, and for this reason, these drugs are sometimes used together for ventricular control in patients with atrial fibrillation or flutter. In clinical trials in patients with atrial fibrillation or atrial flutter on both verapamil and digoxin, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. Additionally, the effect of verapamil on the pharmacokinetics of digoxin is magnified in patients with hepatic cirrhosis.
    Vilazodone: (Moderate) Concomitant use of digoxin, a P-gp substrate, and vilazodone may increase digoxin concentrations. Because digoxin is a narrow therapeutic index drug, serum digoxin concentrations should be measured before initiating vilazodone, with periodic monitoring throughout concurrent treatment. Adjust the digoxin dose as necessary.
    Vinca alkaloids: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Vorinostat: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Zinc Salts: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and digoxin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Digoxin is classified in FDA pregnancy risk category C, although digoxin is considered by many cardiologists to be one of the safest antiarrhythmics for use during pregnancy. Digoxin readily passes to the fetal circulation; however, this drug has been used safely and effectively off-label for decades to treat both maternal and fetal arrhythmias. No teratogenic effect has been reported in humans. The typical dosage in pregnancy is similar to that given a non-pregnant woman. There may be difficulty, particularly in the third trimester, in interpreting serum digoxin levels as a result of an increase in an endogenous digoxin-like substance that may interfere with the digoxin assays. Thus, digoxin levels may give the impression of supratherapeutic dosing; clinicians should interpret the results in accordance with the clinical status of the mother and fetus before making dosage adjustments based on levels alone. As with most drugs, the use of digoxin during pregnancy should be avoided unless the potential benefit of digoxin therapy to the fetus or mother outweighs the potential risk to the fetus.

    Although digoxin is transferred to breast milk to some degree, digoxin therapy during lactation appears to be safe. The American Academy of Pediatrics generally considers the use of digoxin to be compatible with breast-feeding.

    MECHANISM OF ACTION

    Digoxin inhibits the Na-K-ATPase membrane pump. Na-K-ATPase regulates intracellular sodium and potassium. Inhibition of this enzyme leads to an increase in intracellular sodium concentration (i.e., decreased outward transport) and ultimately to an increase in intracellular calcium as sodium-calcium exchange is stimulated by high intracellular sodium concentrations. It is believed that increased intracellular concentrations of calcium allow for greater activation of contractile proteins (e.g., actin, myosin). While the contractile proteins and the troponin-tropomysin system are directly involved in muscular contraction, it is not clear how digoxin augments their action. Digoxin does not directly affect these proteins or the cellular mechanisms that provide energy for contraction, nor does it affect contraction in skeletal muscle. Digoxin also increases sympathetic tone, however, this does not account for the positive inotropic effect which persists even in the presence of beta-adrenergic blockade.
     
    Digoxin directly increases the force and velocity of myocardial contraction in both healthy and failing hearts. In the failing heart, an increased force of contraction raises cardiac output, resulting in greater systolic emptying and a smaller diastolic heart size. End-diastolic pressures decrease, leading to a reduction in pulmonary and systemic venous pressures. In patients with normal hearts, however, cardiac output remains unchanged. Digoxin also possesses direct vasoconstrictive properties and reflex CNS-mediated peripheral vasoconstriction. Although this increases vascular resistance, in patients with failing hearts, increased myocardial contractility predominates and total peripheral resistance drops. In patients with congestive heart failure, an increased cardiac output will decrease sympathetic tone, thereby reducing the heart rate and causing diuresis in edematous patients and improving coronary blood flow.
     
    In addition to its inotropic effects, digoxin also possesses significant actions on the electrical activity of the heart. It increases the slope of phase 4 depolarization, shortens the action potential duration, and decreases the maximal diastolic potential. The increase in vagal activity mediated by cardiac glycosides decreases conduction velocity through the atrioventricular (AV) node, prolonging its effective refractory period. In atrial flutter or fibrillation, digoxin decreases the number of atrial depolarizations that reach the ventricle, thereby slowing ventricular rate. Sympathetic stimulation, however, easily overrides the beneficial inhibitory effects of digoxin on AV nodal conduction. Thus, verapamil and diltiazem are gradually replacing digoxin as the agent to control ventricular rate in atrial tachyarrhythmias. While digoxin is somewhat effective in controlling ventricular rate in atrial fibrillation, it appears to be no better than placebo for converting recent-onset atrial fibrillation to normal sinus rhythm.

    PHARMACOKINETICS

    Digoxin is administered orally, intravenously, or intramuscularly. It distributes throughout the body tissues, with the highest concentrations found in the heart, kidneys, intestine, liver, stomach, and skeletal muscle. Small amounts can be found in the brain. The presence of congestive heart failure slows the rate at which steady-state distribution is achieved. Only 20—30% of the drug is plasma protein-bound. Digoxin crosses the placenta, and maternal and fetal plasma concentrations of the drug are equal.
     
    A small amount of digoxin is metabolized in the liver to inactive metabolites. Thirty to fifty percent of a dose is excreted unchanged in the urine. The elimination half-life in adults is normally 30—40 hours, but heart failure or renal impairment can prolong digoxin elimination.
     
    Affected cytochrome P450 isoenzymes: none

    Oral Route

    In general, digoxin is rapidly absorbed from the GI tract following an oral dose. In approximately 10% of patients, significant amounts of orally ingested digoxin are metabolized in the gut by intestinal bacteria. Bioavailability from capsules is essentially complete but is approximately 75—85% from oral elixir and 70—80% from tablets. Onset of therapeutic effects generally occurs within 30 minutes to 2 hours after oral administration. The peak effect generally occurs between 2—6 hours after oral administration of a dose.

    Intravenous Route

    Onset of therapeutic effects generally occurs within 5—30 minutes following IV administration.