DIGOXIN: 7,708 Adverse Event Reports & Safety Profile

LANOXIN (digoxin) is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves of Digitalis lanata . The term “digitalis” is used to designate the whole group of glycosides. The glycosides are composed of 2 portions: a sugar and a cardenolide (hence “glycosides”). Digoxin is described chemically as (3β,5β,12β)-3-[( O -2,6-dideoxy-β- D-ribo -hexopyranosyl-(1→4)- O -2,6-dideoxy-β- D-ribo -hexopyranosyl-(1→4)-2,6-dideoxy-β- D-ribo -hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. Its molecular formula is C 41 H 64 O 14 , its molecular weight is 780.95, and its structural formula is: Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine.

Lanoxin

Injection and Injection Pediatric are sterile solutions of digoxin for intravenous or intramuscular injection. The vehicle contains 42.5% (W/V) propylene glycol and 10% alcohol (V/V). The injection is buffered to a pH of 6.8-7.2 with 0.17% dibasic sodium phosphate and 0.08% anhydrous citric acid.

Each

2-mL single-dose ampule or vial of LANOXIN Injection contains 500 mcg digoxin (250 mcg/mL). Dilution is not required.

Each

1-mL single-dose ampule or vial of LANOXIN Injection Pediatric contains 100 mcg digoxin (100 mcg/mL). Dilution is not required.

Digoxin Chemical

Structure

AND USAGE Digoxin is a cardiac glycoside indicated in adults for the treatment of mild to moderate heart failure and for the control of resting ventricular rate in patients with chronic atrial fibrillation. ( 1.1 , 1.3 ) In pediatric patients with heart failure, digoxin is indicated to increase myocardial contractility. ( 1.2 )

1.1 Heart Failure in Adults Digoxin Oral Solution is indicated for the treatment of mild to moderate heart failure. Digoxin increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by increased exercise capacity and decreased heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, digoxin should be used with a diuretic and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these three drugs cannot be specified.

1.2 Heart Failure in Pediatric Patients Digoxin is indicated to increase myocardial contractility in pediatric patients with heart failure.

1.3 Atrial Fibrillation in Adults Digoxin Oral Solution is indicated for the control of resting ventricular response rate in patients with chronic atrial fibrillation. Digoxin should not be used for the treatment of multifocal atrial tachycardia.

AND ADMINISTRATION Toxic levels of digoxin are only slightly higher than therapeutic levels. The pharmacokinetics of digoxin are complex and dose determination should take into account patient-specific factors (age, lean body weight, renal function, etc.). ( 2.4 , 2.5 ) Patients should be monitored for toxicity and therapeutic effect and doses should be adjusted, accordingly. ( 2.2 )

2.1 General Dosing Considerations The dose of digoxin should be based on clinical assessment but individual patient factors should be taken into consideration. Those factors are:

• Lean body weight
• Renal function
• Patient age
• Concurrent disease [see Warnings and Precautions (5) ]
• Concomitant medication [see Drug Interactions (7) ] Because the pharmacokinetics of digoxin are complex, and because toxic levels of digoxin are only slightly higher than therapeutic levels, digoxin dosing can be difficult. The recommended approach is to:
• estimate the patient’s daily maintenance dose
• adjust the estimate to account for patient-specific factors
• choose a dosing regimen
• decide whether to initiate therapy with a loading dose
• monitor the patient for toxicity and for therapeutic effect
• adjust the dose Dose titration may be accomplished by either of two general approaches that differ in dosage and frequency of administration, but reach the same total amount of digoxin accumulated in the body.
• If rapid titration is considered medically appropriate, administer a loading dose based upon projected peak digoxin body stores. Maintenance dose can be calculated as a percentage of the loading dose.
• More gradual titration may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to accumulate slowly. Steady-state serum digoxin concentrations will be achieved in approximately five half-lives of the drug for the individual patient. Depending upon the patient’s renal function, this will take between 1 and 3 weeks.

2.2 Serum Digoxin Concentrations In general, the dose of digoxin used should be determined on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in assigning certain probabilities to the likelihood of digoxin intoxication. Studies have shown diminished efficacy at serum levels &lt; 0.5 ng/mL, while levels above 2 ng/mL are associated with increased toxicity without increased benefit. The inotropic effects of digoxin tend to appear at lower concentrations than the electrophysiological effects. Based on retrospective analysis, adverse events may be higher in the upper therapeutic range. Perform sampling of serum concentrations just before the next scheduled dose of the drug. If this is not possible, sample at least 6 hours or later after the last dose, regardless of the route of administration or the formulation used. On a once-daily dosing schedule, the concentration of digoxin will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient’s renal function. On a twice-daily dosing schedule, there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose. The serum concentration of digoxin should always be interpreted in the overall clinical context, and an isolated measurement should not be used alone as the basis for increasing or decreasing the dose of the drug. When decision-making is to be guided by serum digoxin levels, the clinician must consider the possibility of reported concentrations that have been falsely elevated by endogenous digoxin-like immunoreactive substances <span class="opacity-50 text-xs">[see Drug Interactions (7.4) ]</span> . If the assay being used is sensitive to these substances, it may be prudent to obtain a baseline measurement before digoxin therapy is started, and correct later values by the reported baseline level.

2.3 Loading Dose Loading doses for each age group are given in Table 1 below. In pediatric patients, if a loading dose is needed, it can be administered with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 4- to 8-hour intervals, with careful assessment of clinical response before each additional dose. If the patient’s clinical response necessitates a change from the calculated loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given as the loading dose <span class="opacity-50 text-xs">[see Table 1 and 2 ]</span>.

Table

1: Estimate the Loading Dose Age Oral Loading Dose, mcg/kg Premature 20 to 30 Full-Term 25 to 35 1 to 24 months 35 to 60 2 to 5 years 30 to 45 5 to 10 years 20 to 35 Over 10 years 10 to 15 More gradual attainment of digoxin levels can also be accomplished by beginning an appropriate maintenance dose. The range of percentages provided in Table 2 (2.4 Estimate of Daily Maintenance Dose) can be used in calculating this dose for patients with normal renal function. Steady state will be attained after approximately 5 days in subjects with normal renal function.

2.4 Estimate of Daily Maintenance Dose The recommended daily maintenance doses for each age group are given in Table 2 below. These recommendations assume the presence of normal renal function.

Table

2: Estimate of the Daily Maintenance Dose Age Daily Oral Maintenance Dose, mcg/kg/day Dose Regimen, mcg/kg/dose Premature 4.7 to 7.8 2.3 to

3.9 Twice Daily Full-Term 7.5 to 11.3 3.8 to

5.6 Twice Daily 1 to 24 months 11.3 to 18.8 5.6 to

9.4 Twice Daily 2 to 5 years 9.4 to 13.1 4.7 to

6.6 Twice Daily 5 to 10 years 5.6 to 11.3 2.8 to

5.6 Twice Daily Over 10 years 3.0 to 4.5 3.0 to

4.5 Once Daily Dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, dosage selection must be based upon clinical assessment and ultimately therapeutic drug level monitoring of the patient. Divided daily dosing is recommended for pediatric patients under age 10. In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be made as shown in Tables 1 and 2. Renal clearance is further reduced in the premature infant. Beyond the immediate newborn period, pediatric patients generally require proportionally larger doses than adults on the basis of body weight or body surface area. Pediatric patients over 10 years of age require adult dosages in proportion to their body weight. Some researchers have suggested that infants and young pediatric patients tolerate slightly higher serum concentrations than do adults. For pediatric patients with known or suspected renal dysfunction, lower starting doses should be considered combined with frequent monitoring of digoxin levels. NOTE: The calibrated oral syringe supplied with the 60 mL bottle of digoxin oral solution is not appropriate to measure doses below 0.1 mL. Doses less than 0.1 mL require appropriate methods or measuring devices designed to administer an accurate amount to the patient.

2.5 Adjustment of Dose The body’s handling of digoxin can be affected by many different patient-specific factors. Some of the possible effects are small, so anticipatory dose adjustment might not be required, but others should be considered before initial dosing <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) and Drug Interactions (7) ]</span> . Both adults and pediatric patients with abnormal renal function need to have the dose of digoxin proportionally reduced. Recommended maintenance doses based upon lean body weight and renal function are listed in Table 3 . Developmental changes in pediatric renal function were factored into Table 3. However, age-related and other changes in adult renal function were not. The volume of distribution of digoxin is proportional to lean body weight and doses listed in Table 3 assume average body composition. The dose of digoxin must be reduced in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema.

Table

3: Usual Maintenance Dose The doses are rounded to whole numbers. Twice daily dosing is recommended for pediatric patients under 10 years of age. Once daily dosing is recommended for pediatric patients above 10 years of age and adults. Requirements (mcg) of Digoxin Based upon Age, Lean Body Weight and Renal Function Corrected Ccr (mL/min per 70 kg) Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m 2 body surface area. For adults , if only serum creatinine concentrations (Scr) are available, a Ccr (corrected to 70 kg body weight) may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. Note: This equation cannot be used for estimating creatinine clearance in infants or pediatric patients. For pediatric patients , the modified Schwartz equation may be used as listed below. The formula was based on height in cm and Scr in mg/dL where k is a constant. Ccr is corrected to 1.73 m 2 body surface area. During the first year of life, the value of k is 0.33 for pre-term babies and 0.45 for term infants. The k is 0.55 for pediatric patients and adolescent girls and 0.7 for adolescent boys. GFR (mL/min/1.73 m 2 ) = (k x Height)/Scr. Dose to be Given Twice Daily < 10 Years of Age Dose to be Given Once Daily > 10 Years of Age and Adults Number of Days Before Steady State Achieved Lean Body Weight Lean Body Weight kg lb 5 11 10 22 20 44 30 66 40 88 50 110 60 132 40 88 50 110 60 132 70 154 80 176 90 198 100 220 10 10 20 40 60 80 100 120 80 100 120 140 160 180 200 19 20 11 23 45 68 90 113 135 90 113 135 158 180 203 225 16 30 13 25 50 75 100 125 150 100 125 150 175 200 225 250 14 40 14 28 55 83 110 138 165 110 138 165 193 220 248 275 13 50 15 30 60 90 120 150 180 120 150 180 210 240 270 300 12 60 16 33 65 98 130 163 195 130 163 195 228 260 293 325 11 70 18 35 70 105 140 175 210 140 175 210 245 280 315 350 10 80 19 38 75 113 150 188 225 150 188 225 263 300 338 375 9 90 20 40 80 120 160 200 240 160 200 240 280 320 360 400 8 100 21 43 85 128 170 213 255 170 213 255 298 340 383 425 7 Determination of the target dose in milliliters of Digoxin Oral Solution based on body weight is shown in Table 4 . Provided is the volume required per dose, NOT per day.

Table

4: Dose a in Milliliters Target Dose in mcg/kg Volume to be Given in mL b 2 3 4 5 6 8 10 12 14 16 18 20 30 Weight in kg 2 0.08 b 0.12 b 0.16 b 0.2 0.2 0.3 0.4 0.5 0.6 0.6 0.7 0.8 1.2 3 0.12 b 0.18 b 0.2 0.3 0.4 0.5 0.6 0.7 0.8 1.0 1.1 1.2 1.8 4 0.16 b 0.2 0.3 0.4 0.5 0.6 0.8 1.0 1.1 1.3 1.4 1.6 2.4 5 0.2 0.3 0.4 0.5 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 3.0 6 0.2 0.4 0.5 0.6 0.7 1.0 1.2 1.4 1.7 1.9 2.2 2.4 3.6 7 0.3 0.4 0.6 0.7 0.8 1.1 1.4 1.7 2.0 2.2 2.5 2.8 4.2 8 0.3 0.5 0.6 0.8 1.0 1.3 1.6 1.9 2.2 2.6 2.9 3.2 4.8 9 0.4 0.5 0.7 0.9 1.1 1.4 1.8 2.2 2.5 2.9 3.2 3.6 5.4 10 0.4 0.6 0.8 1.0 1.2 1.6 2.0 2.4 2.8 3.2 3.6 4.0 6.0 11 0.4 0.7 0.9 1.1 1.3 1.8 2.2 2.6 3.1 3.5 4.0 4.4 6.6 12 0.5 0.7 1.0 1.2 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8 7.2 13 0.5 0.8 1.0 1.3 1.6 2.1 2.6 3.1 3.6 4.2 4.7 5.2 7.8 14 0.6 0.8 1.1 1.4 1.7 2.2 2.8 3.4 3.9 4.5 5.0 5.6 8.4 15 0.6 0.9 1.2 1.5 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 9.0 20 0.8 1.2 1.6 2.0 2.4 3.2 4.0 4.8 5.6 6.4 7.2 8.0 12.0 30 1.2 1.8 2.4 3.0 3.6 4.8 6.0 7.2 8.4 9.6 10.8 12.0 18.0 40 1.6 2.4 3.2 4.0 4.8 6.4 8.0 9.6 11.2 12.8 14.4 16.0 24.0 50 2.0 3.0 4.0 5.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 30.0 60 2.4 3.6 4.8 6.0 7.2 9.6 12.0 14.4 16.8 19.2 21.6 24.0 36.0 70 2.8 4.2 5.6 7.0 8.4 11.2 14.0 16.8 19.6 22.4 25.2 28.0 42.0 80 3.2 4.8 6.4 8.0 9.6 12.8 16.0 19.2 22.4 25.6 28.8 32.0 48.0 90 3.6 5.4 7.2 9.0 10.8 14.4 18.0 21.6 25.2 28.8 32.4 36.0 54.0 100 4.0 6.0 8.0 10.0 12.0 16.0 20.0 24.0 28.0 32.0 36.0 40.0 60.0 a Recommended dosing regimen for pediatric patients under 10 years of age is twice daily. Recommended dosing regimen for pediatric patients over 10 years of age and adults is once daily. b Use calibrated oral syringe for measurement. In the case of required volume less than 0.1 mL, a separate device is recommended for adequate measurement. On the left side of the chart, locate the patient’s weight in kilograms. At the top of the chart, identify which dose in mcg/kg will be used for this patient. The block on the chart at which the two rows (weight and target dose) intersect is the milliliter amount that should be given to the patient. The monitoring described in Section 2.2 may suggest increases or decreases in digoxin doses. Additional monitoring, and in some cases anticipatory dose adjustment, may be indicated around the time of various changes to the patient including:

• normal development through childhood;
• concomitant drug use should be considered when adjusting the estimated digoxin dose [see Drug Interactions (7) ] ;
• new co-administration of an antibiotic, especially if the patient had required high doses of digoxin in order to achieve modest serum concentrations, raising the suspicion that a substantial fraction of administered digoxin was being destroyed by colonic bacteria; and
• changes in renal function [see Table 3: Usual Maintenance Dose Requirements (mcg) of Digoxin above] . right arrow down arrow

Digoxin is contraindicated in patients with:

• Ventricular fibrillation [see Warnings and Precautions (5.1)]
• Known hypersensitivity to digoxin (reactions seen include unexplained rash, swelling of the mouth, lips or throat or a difficulty in breathing). A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin.
• Ventricular fibrillation. ( Error! Hyperlink reference not valid. )
• Known hypersensitivity to digoxin or other forms of digitalis. ( 4 )

ADVERSE REACTIONS In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when digoxin is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions. Because some patients may be particularly susceptible to side effects with digoxin, the dosage of the drug should always be selected carefully and adjusted as the clinical condition of the patient warrants. In the past, when high doses of digoxin were used and little attention was paid to clinical status or concurrent medications, adverse reactions to digoxin were more frequent and severe. Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. However, available evidence suggests that the incidence and severity of digoxin toxicity has decreased substantially in recent years. In recent controlled clinical trials, in patients with predominantly mild to moderate heart failure, the incidence of adverse experiences was comparable in patients taking digoxin and in those taking placebo. In a large mortality trial, the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking digoxin compared to 0.9% in patients taking placebo. In this trial, the most common manifestations of digoxin toxicity included gastrointestinal and cardiac disturbances; CNS manifestations were less common. Adults: Cardiac: Therapeutic doses of digoxin may cause heart block in patients with pre-existing sinoatrial or AV conduction disorders; heart block can be avoided by adjusting the dose of digoxin. Prophylactic use of a cardiac pacemaker may be considered if the risk of heart block is considered unacceptable. High doses of digoxin may produce a variety of rhythm disturbances, such as first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation. Digoxin produces PR prolongation and ST segment depression which should not by themselves be considered digoxin toxicity. Cardiac toxicity can also occur at therapeutic doses in patients who have conditions which may alter their sensitivity to digoxin (see WARNINGS and PRECAUTIONS). Gastrointestinal: Digoxin may cause anorexia, nausea, vomiting, and diarrhea. Rarely, the use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines. CNS: Digoxin can produce visual disturbances (blurred or yellow vision), headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination). Other: Gynecomastia has been occasionally observed following the prolonged use of digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed.

Table

4 summarizes the incidence of those adverse experiences listed above for patients treated with digoxin tablets or placebo from two randomized, double-blind, placebo-controlled withdrawal trials. Patients in these trials were also receiving diuretics with or without angiotensin-converting enzyme inhibitors. These patients had been stable on digoxin, and were randomized to digoxin or placebo. The results shown in Table 4 reflect the experience in patients following dosage titration with the use of serum digoxin concentrations and careful follow-up. These adverse experiences are consistent with results from a large, placebo-controlled mortality trial (DIG trial) wherein over half the patients were not receiving digoxin prior to enrollment.

Table

4: Adverse Experiences in Two Parallel, Double-Blind, Placebo-Controlled Withdrawal Trials (Number of Patients Reporting)

Adverse Experience Digoxin

Patients (n = 123)

Placebo

Patients (n = 125)

Cardiac Palpitation

Ventricular extrasystole Tachycardia Heart arrest 1 1 2 1 4 1 1 1 Gastrointestinal Anorexia Nausea Vomiting Diarrhea Abdominal pain 1 4 2 4 0 4 2 1 1 6 CNS Headache Dizziness Mental disturbances 4 6 5 4 5 1 Other Rash Death 2 4 1 3 Infants and Children: The side effects of digoxin in infants and children differ from those seen in adults in several respects. Although digoxin may produce anorexia, nausea, vomiting, diarrhea, and CNS disturbances in young patients, these are rarely the initial symptoms of overdosage. Rather, the earliest and most frequent manifestation of excessive dosing with digoxin in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmia or alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise.

AND PRECAUTIONS

• Accessory AV Pathway: Increased risk of rapid ventricular response leading to ventricular fibrillation. ( 5.1 )
• Sinus Node Disease and AV Block: Digoxin use can exacerbate the condition and may cause advanced or complete heart block. ( 5.2 )
• Misidentification of Digoxin Toxicity: Signs and symptoms of digoxin toxicity may be mistaken for worsening symptoms of congestive heart failure. ( 5.3 )
• Preserved Left Ventricular Systolic Function: Patients with heart failure with preserved left ventricular ejection fraction may be more susceptible to digoxin toxicity. ( 5.4 )
• Impaired Renal Function: Renal impairment results in increased digoxin exposure and requires dosage adjustments. ( 5.5 )
• Electrolyte Disorders: Toxicity is increased by hypokalemia, hypomagnesemia, and hypercalcemia. ( 5.6 )
• Hypermetabolic States: In patients with atrial arrhythmias associated with hypermetabolic states, control of resting ventricular rate is particularly resistant to digoxin treatment. ( 5.8 )
• The use of digoxin may result in potentially detrimental increases in coronary vascular resistance. ( 5.9 )
• Avoid digoxin in patients with myocarditis. ( 5.10 )

5.1 Use in Patients with Accessory AV Pathway (Wolff-Parkinson-White Syndrome) Patients with Wolff-Parkinson-White syndrome who develop atrial fibrillation are at high risk of ventricular fibrillation. Treatment of these patients with digoxin leads to greater slowing of conduction in the atrioventricular node than in accessory pathways, and the risks of rapid ventricular response leading to ventricular fibrillation are thereby increased.

5.2 Use in Patients with Sinus Node Disease and AV Block Because digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. Digoxin may cause severe sinus bradycardia or sinoatrial block particularly in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. In such patients consideration should be given to the insertion of a pacemaker before treatment with digoxin.

5.3 Misidentification of Digoxin Toxicity Some signs and symptoms (anorexia, nausea, vomiting, and certain arrhythmias) can equally result from digoxin toxicity as from congestive heart failure. Misidentification of their etiology might lead the clinician to continue or increase digoxin dosing, when dosing should actually be suspended. When the etiology of these signs and symptoms is not obvious, measurement of serum digoxin levels may be helpful.

5.4 Use in Patients with Preserved Left Ventricular Systolic Function Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may not benefit from digoxin treatment and may be particularly susceptible to adverse reactions when they are treated with digoxin. In patients with hypertrophic cardiomyopathy (formerly called idiopathic hypertrophic subaortic stenosis), the positive inotropic effect of digoxin leads to an increased subvalvular outflow gradient and therefore, may compromise cardiac output. Digoxin is rarely beneficial in patients with this condition. Chronic constrictive pericarditis is not generally associated with any inotropic defect, so heart failure of this etiology is unlikely to respond to treatment with digoxin. By slowing the resting heart rate, digoxin may actually decrease cardiac output in these patients. Digoxin as an inotropic agent is of limited value in patients with restrictive cardiomyopathies, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation. In addition, patients with amyloid heart disease may be more susceptible to toxicity from digoxin at therapeutic levels because of an increased binding of digoxin to extracellular amyloid fibrils.

5.5 Use in Patients with Impaired Renal Function Digoxin is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of digoxin <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Because of the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function.

5.6 Use in Patients with Electrolyte Disorders In patients with hypokalemia or hypomagnesemia, toxicity may occur at concentrations within therapeutic range because potassium or magnesium depletion sensitizes the myocardium to digoxin. Therefore, it is desirable to maintain normal serum potassium and magnesium concentrations in patients being treated with digoxin. Serum potassium levels should be carefully monitored when digoxin is given to patients at high risk of hypokalemia ( e.g. , those receiving diuretics, corticosteroids, or other drugs that commonly lead to potassium loss; those with gastrointestinal losses through diarrhea, vomiting, or nasogastric suction; or those with potassium-losing endocrinopathies or nephropathies). Digoxin toxicity is also more likely in the presence of hypomagnesemia. Hypomagnesemia is common in most of the same conditions in which hypokalemia appears. Most notably, it is commonly seen in alcoholics and in patients with diabetes mellitus or hypercalcemia. Because digoxin’s therapeutic and toxic effects are all largely mediated by intracellular calcium distribution, they are affected by abnormalities in serum calcium levels. Hypercalcemia increases the risk of digoxin toxicity, while digoxin may be therapeutically ineffective in the presence of hypocalcemia.

5.7 Use During Electrical Cardioversion Reduction of digoxin dosage may be desirable prior to electrical cardioversion to avoid induction of ventricular arrhythmias, but the physician must consider the consequences of a rapid increase in ventricular response to atrial fibrillation if digoxin is withheld 1 to 2 days prior to cardioversion. If there is a suspicion that digitalis toxicity exists, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the energy level selected should be minimal at first and carefully increased in an attempt to avoid precipitating ventricular arrhythmias.

5.8 Use in Thyroid Disorders and Hypermetabolic States Hypothyroidism may reduce the requirements for digoxin. Heart failure and atrial arrhythmias resulting from hypermetabolic or hyperdynamic states ( e.g. , hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states ( e.g. , hyperthyroidism) are particularly resistant to digoxin treatment. Large doses of digoxin are not recommended as the only treatment of these arrhythmias and care must be taken to avoid toxicity if large doses of digoxin are required. In hypothyroidism, the digoxin requirements are reduced. Digoxin responses are normal in patients with compensated thyroid disease.

5.9 Use in Patients with Acute Myocardial Infarction In patients with acute myocardial infarction, particularly if they have ongoing ischemia, the use of inotropic drugs, such as digoxin, may result in undesirable increases in myocardial oxygen demand and ischemia. Moreover, the use of digoxin may result in potentially detrimental increases in coronary vascular resistance mediated through alpha adrenergic receptor stimulation.

5.10 Use in Patients with Myocarditis Digoxin can precipitate vasoconstriction and may promote production of pro-inflammatory cytokines. Therefore, avoid digoxin in patients with myocarditis.

5.11 ECG Changes During Exercise The use of therapeutic doses of digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing that may be indistinguishable from those of ischemia. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity. Digoxin does not significantly decrease heart rate during exercise.

5.12 Laboratory Tests Patients receiving digoxin should have their serum electrolytes and renal function (serum creatinine concentrations) assessed periodically; the frequency of assessments will depend on the clinical setting. Assays of serum digoxin levels are described elsewhere <span class="opacity-50 text-xs">[see Drug Interactions (7.4) ]</span> , as is their use in patient monitoring <span class="opacity-50 text-xs">[see Dosage and Administration (2.2)]</span> .

PRECAUTIONS Use in Patients with Impaired Renal Function: Digoxin is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of digoxin (see DOSAGE AND ADMINISTRATION). Because of the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function. Use in Patients with Electrolyte Disorders: In patients with hypokalemia or hypomagnesemia, toxicity may occur despite serum digoxin concentrations below 2.0 ng/mL, because potassium or magnesium depletion sensitizes the myocardium to digoxin. Therefore, it is desirable to maintain normal serum potassium and magnesium concentrations in patients being treated with digoxin. Deficiencies of these electrolytes may result from malnutrition, diarrhea, or prolonged vomiting, as well as the use of the following drugs or procedures: diuretics, amphotericin B, corticosteroids, antacids, dialysis, and mechanical suction of gastrointestinal secretions. Hypercalcemia from any cause predisposes the patient to digitalis toxicity. Calcium, particularly when administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. On the other hand, hypocalcemia can nullify the effects of digoxin in humans; thus, digoxin may be ineffective until serum calcium is restored to normal. These interactions are related to the fact that digoxin affects contractility and excitability of the heart in a manner similar to that of calcium. Use in Thyroid Disorders and Hypermetabolic States: Hypothyroidism may reduce the requirements for digoxin. Heart failure and/or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states are particularly resistant to digoxin treatment. Care must be taken to avoid toxicity if digoxin is used. Use in Patients with Acute Myocardial Infarction: Digoxin should be used with caution in patients with acute myocardial infarction. The use of inotropic drugs in some patients in this setting may result in undesirable increases in myocardial oxygen demand and ischemia.

Use During Electrical

Cardioversion: It may be desirable to reduce the dose of digoxin for 1 to 2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequences of increasing the ventricular response if digoxin is withdrawn. If digitalis toxicity is suspected, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular arrhythmias.

Laboratory Test Monitoring

Patients receiving digoxin should have their serum electrolytes and renal function (serum creatinine concentrations) assessed periodically; the frequency of assessments will depend on the clinical setting. For discussion of serum digoxin concentrations, see DOSAGE AND ADMINISTRATION section.

Drug Interactions

Potassium-depleting diuretics are a major contributing factor to digitalis toxicity. Calcium, particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. Quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, and spironolactone raise the serum digoxin concentration due to a reduction in clearance and/or in volume of distribution of the drug, with the implication that digitalis intoxication may result. Erythromycin and clarithromycin (and possibly other macrolide antibiotics ) and tetracycline may increase digoxin absorption in patients who inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis intoxication may result (see CLINICAL PHARMACOLOGY: Absorption). Propantheline and diphenoxylate, by decreasing gut motility, may increase digoxin absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer drugs, and metoclopramide may interfere with intestinal digoxin absorption, resulting in unexpectedly low serum concentrations. Rifampin may decrease serum digoxin concentration, especially in patients with renal dysfunction, by increasing the non-renal clearance of digoxin. There have been inconsistent reports regarding the effects of other drugs [e.g., quinine, penicillamine ] on serum digoxin concentration. Thyroid administration to a digitalized, hypothyroid patient may increase the dose requirement of digoxin. Concomitant use of digoxin and sympathomimetics increases the risk of cardiac arrhythmias. Succinylcholine may cause a sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmias in digitalized patients. Although beta-adrenergic blockers or calcium channel blockers and digoxin may be useful in combination to control atrial fibrillation, their additive effects on AV node conduction can result in advanced or complete heart block. Due to the considerable variability of these interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently. Furthermore, caution should be exercised when combining digoxin with any drug that may cause a significant deterioration in renal function, since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin.

Drug/Laboratory

Test Interactions The use of therapeutic doses of digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity. Carcinogenesis, Mutagenesis, Impairment of Fertility There have been no long-term studies performed in animals to evaluate carcinogenic potential, nor have studies been conducted to assess the mutagenic potential of digoxin or its potential to affect fertility.

Pregnancy Teratogenic Effects Pregnancy

Category C. Animal reproduction studies have not been conducted with digoxin. It is also not known whether digoxin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Digoxin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Studies have shown that digoxin concentrations in the mother’s serum and milk are similar. However, the estimated exposure of a nursing infant to digoxin via breast feeding will be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when digoxin is administered to a nursing woman.

Pediatric Use

Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants 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. Digitalis glycosides can cause poisoning in children due to accidental ingestion.

Geriatric Use

The majority of clinical experience gained with digoxin has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).

INTERACTIONS Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin. Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information.

Pgp

Inducers/Inhibitors: Drugs that induce or inhibit PGP have the potential to alter digoxin pharmacokinetics. ( 7.1 ) The potential for drug-drug interactions must be considered prior to and during drug therapy. See full prescribing information. ( 7.2 , 7.3 , 12.3 ) 7.1 P-Glycoprotein (PGP)

Inducers/Inhibitors

Digoxin is a substrate of P-glycoprotein, at the level of intestinal absorption, renal tubular section and biliary-intestinal secretion. Therefore, drugs that induce/inhibit P-glycoprotein have the potential to alter digoxin pharmacokinetics.

7.2 Pharmacokinetic Drug Interactions Digoxin concentrations increased greater than 50% Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.

Captopril

58% 39% Clarithromycin NA 70% Dronedarone NA 150% Gentamicin 129% to 212% NA Erythromycin 100% NA Itraconazole 80% NA Lapatinib NA 180% Propafenone NA 60% to 270% Quinidine 100% NA Ranolazine 50% NA Ritonavir NA 86% Telaprevir 50% 85% Tetracycline 100% NA Verapamil 50% to 75% NA Digoxin concentrations increased less than 50% Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.

Carvedilol

16% 14% Conivaptan 33% 43% Diltiazem 20% NA Indomethacin 40% NA Mirabegron 29% 27% Nefazodone 27% 15% Nifedipine 45% NA Propantheline 24% 24% Quinine NA 33% Rabeprazole 29% 19% Saquinavir 27% 49% Spironolactone 25% NA Telmisartan 20% to 49% NA Ticagrelor 31% 28% Tolvaptan 30% 20% Trimethoprim 22% to 28% NA Digoxin concentrations increased, but magnitude is unclear Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. Digoxin concentrations decreased Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary. NA – Not available/reported

7.3 Potentially Significant Pharmacodynamic Drug Interactions Because of considerable variability of pharmacodynamic interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently. Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.

Antiarrhythmics Dofetilide

Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.

Sotalol

Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.

Dronedarone

Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.

Parathyroid Hormone Analog Teriparatide

Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.

Sympathomimetics Epinephrine Norepinephrine Dopamine

Can increase the risk of cardiac arrhythmias.

Neuromuscular Blocking Agents Succinylcholine

May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.

Supplements

Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. Hyperpolarization-activated cyclic nucleotide-gated channel blocker Ivabradine Can Increase the risk of bradycardia.

7.4 Drug/Laboratory Test Interactions Endogenous substances of unknown composition (digoxin-like immunoreactive substances [DLIS]) can interfere with standard radioimmunoassays for digoxin. The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced. Some assays are more subject to these failings than others. Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference. DLIS are present in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason. The measured levels of DLIS (as digoxin equivalents) are usually low (0.2 ng/mL to 0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic. In some assays, spironolactone, canrenone, and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL. Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha or Dashen can cause similar interference. Spironolactone and DLIS are much more extensively protein-bound than digoxin. As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS. It should be noted that ultrafiltration does not solve all interference problems with alternative medicines. The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in terms of specificity and limit of quantization.

7.1 P-Glycoprotein (PGP)

Inducers/Inhibitors

Digoxin is a substrate of P-glycoprotein, at the level of intestinal absorption, renal tubular section and biliary-intestinal secretion. Therefore, drugs that induce/inhibit P-glycoprotein have the potential to alter digoxin pharmacokinetics.