digoxin (Rx)

1-10%

Dizziness (4.9%)

Mental disturbances (4.1%)

Diarrhea (3.2%)

Headache (3.2%)

Nausea (3.2%)

Vomiting (1.6%)

Maculopapular rash (1.6%)

<1%

Anorexia

Cardiac dysrhythmia

Arrhythmia in children (consider a toxicity)

Frequency Not Defined

Visual disturbance (blurred or yellow vision)

Heart block (1°/2°/3°)

Asystole

Tachycardia

Contraindications

Hypersensitivity

Ventricular fibrillation

Cautions

Use caution in chronic constrictive pericarditis, electrical cardioversion, severe bradycardia, severe heart failure, severe pulmonary disease, sick sinus syndrome, ventricular tachycardia, ventricular premature contractions, Wolff-Parkinson-White syndrome, electrolyte imbalance, hypothyroidism or hyperthyroidism, hypoxia, idiopathic hypertrophic subaortic stenosis, renal disease, concomitant diuretics

Not recommended in patients with acute myocardial infarction

Avoid in patients with myocarditis

Risk of advanced or complete heart block in patients with sinus node disease and AV block

Very narrow margin between effective therapeutic and toxic dosages: Therapeutic range, 0.5-2 ng/mL (target 0.5-1 ng/mL); toxic range, >2.5 ng/mL

Generally avoid if left ventricular systolic function preserved, although may be used for ventricular rate control in subgroup with chronic atrial fibrillation

Less effective in presence of hypokalemia or hypocalcemia; avoid hypercalcemia or hypomagnesemia, which may predispose to serious arrhythmias

Heart failure patients with preserved ventricular function, including acute cor pulmonale, amyloid heart disease, and constrictive pericarditis may be susceptible to digoxin toxicity

May cause false-positive ST-T changes during exercise testing

Do not switch between different PO forms or between brand and generic forms of digoxin; bioavailability varies

Serum levels drawn within 6-8 hours of dose will be falsely high because of prolonged distribution phase

Increased risk of estrogen-like effects in geriatric patients

Beriberi heart disease may not respond adequately if underlying thiamine deficiency not corrected

Atrial arrhythmias are difficult to treat if associated with hypermetabolic (hyperthyroidism) or hyperdynamic (hypoxia) states; treat underlying condition before initiating therapy

Avoid extravasation; ensure proper needle or catheter placement prior to and during administration

Monitor for proarrhythmic effects, especially with digoxin toxicity

Use caution in patients with acute myocardial infarction; may increase myocardial oxygen demand; during acute coronary syndrome, digoxin administered IV may be used to slow a rapid ventricular response and improve left ventricular function in the acute treatment of atrial fibrillation associated with severe LV function and heart failure or hemodynamic instability

Monitor serum concentration closely when used for rate control in patients with atrial fibrillation; serum concentration that is not properly controlled are associated with increased risk of mortality

Consider use of digoxin only in heart failure with reduced ejection fraction when symptoms remain despite guideline-directed medical therapy; withdrawal of digoxin in clinically stable patients with heart failure may lead to recurrence of heart failure symptoms

In hypertrophic cardiomyopathy, outflow obstruction may worsen due to positive inotropic effects of digoxin; avoid use unless used to control ventricular response with atrial fibrillation; in the absence of atrial fibrillation, digoxin is potentially harmful in the treatment of dyspnea in patients with hypertrophic cardiomyopathy

Avoid rapid IV administration in digitalized patients; may produce serious arrhythmias

Not necessary to routinely reduce or hold digoxin therapy prior to elective electrical cardioversion for atrial fibrillation; however, exclusion of digoxin toxicity is necessary prior to cardioversion; whithold digoxin and delay cardioversion until toxicity subsides if signs of digoxin excess exist

Pregnancy

Experience with digoxin in pregnant women over several decades, based on published retrospective clinical studies and case reports, has not led to the identification of a drug associated risk of major birth defects, miscarriage or adverse maternal and fetal outcomes

Untreated underlying maternal conditions (eg, heart failure, atrial fibrillation) during pregnancy pose a risk to the mother and fetus

Clinical considerations

• Pregnant women with heart failure are at increased risk for preterm birth; clinical classification of heart disease may worsen with pregnancy and lead to maternal or fetal death
• Pregnant women with atrial fibrillation are at an increased risk of delivering a low birth weight infant; atrial fibrillation may worsen with pregnancy and can lead to maternal or fetal death

Fetal/neonatal adverse reactions

• Digoxin has been shown to cross the placenta and is found in amniotic fluid
• Monitor neonates for signs and symptoms of digoxin toxicity, including vomiting, and cardiac arrhythmias

Dose adjustments during pregnancy and the postpartum period

• Digoxin requirements may increase during pregnancy and decrease in the postpartum period
• Monitor serum digoxin levels during pregnancy and the postpartum period

Labor or delivery

• Risk of arrhythmias may increase during labor and delivery
• Monitor patients continuously during labor and delivery

Lactation

The digoxin dose received through breastfeeding is up to 4% of the neonatal maintenance dosage, which is unlikely to be clinically relevant

There are no data on the effects of digoxin on the breastfed infant or the effects on milk production

Data

• Based on data from 2 lactation studies in a total of 13 breastfed infants, digoxin concentrations in breast milk ranged between 0.4-1 ng/mL following 0.25 mg/day dose in lactating women
• The amount of digoxin ingested daily by breastfed infants is ~0.03- 0.16 mcg/kg/day
• This translates to a relative infant dose of digoxin between 1-7% of the maternal weight-adjusted dose and about 0.2-4% of the neonatal maintenance dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Digoxin inhibits Na-K ATPase, which in turn causes increased availability of intracellular calcium in the myocardium and conduction system. Inotropy and automaticity are subsequently increased while conduction velocity is reduced. Therapy indirectly causes parasympathetic stimulation of autonomic nervous system, with consequent effects on the sino-atrial (SA) and atrioventricular (AV) nodes.

Digoxin reduces catecholamine reuptake at nerve terminals, rendering blood vessels more sensitive to endogenous or exogenous catecholamines. Increases baroreceptor sensitization, with consequent increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increment in mean arterial pressure. At higher concentration, increases sympathetic outflow from the central nervous system (CNS) to both cardiac and peripheral sympathetic nerves. It also allows progressive efflux of intracellular potassium, with consequent increase in serum potassium levels.

Absorption

Bioavailability: 60-80 % (tablet); 70-85% (elixir)

Onset: 0.5-2 hr (PO) for initial effect and 2-6 hr for maximal effect; 5-30 min (IV) for initial effect and 1.5-4 hr for maximal effect

Duration: 3-4 days

Peak serum time: 1-3 hr (PO)

Distribution

Protein bound: 20-25%

Vd: 6-7 L/kg

Metabolism

Metabolized by liver

Metabolites: Digoxigenin bisdigitoxoside, digoxigenin monodigitoxoside (active)

Elimination

Half-life: 1-3 days

Excretion: Urine (57-80%), feces (9-13%; includes bile)

IV Compatibilities

Solution: D5/½NS with potassium chloride 20 mEq, D5W, LR, ½NS, NS

Additive: Bretylium, cimetidine, floxacillin, furosemide, lidocaine, ranitidine, verapamil

Syringe: Heparin, milrinone

Y-site: Bivalirudin, ciprofloxacin, cisatracurium, dexmedetomidine, diltiazem, famotidine, fenoldopam, gatifloxacin, heparin with hydrocortisone, Hextend, inamrinone, linezolid, meperidine, meropenem, midazolam, milrinone, morphine sulfate, potassium chloride, remifentanil, tacrolimus, vitamins B and C

IV Incompatibilities

Additive: Dobutamine

Syringe: Doxapram

Y-site: Amphotericin B cholesteryl sulfate, amiodarone, fluconazole, foscarnet, insulin (beef, pork, and Humulin R[?]), propofol

IV Preparation

Dilute with 4-fold or greater volume of SWI, D5W, or NS

IV Administration

Administer slowly by direct IV injection over minimum of 5 minutes (longer if given undiluted)

Do not administer if precipitate present

Drug is severe skin irritant when given IV/IM and may cause severe local skin reaction with possible sloughing

Storage

Store at controlled room temperature

Protect from light