Digoxin

1 INDICATIONS AND USAGE In adults, digoxin is indicated for the treatment of mild to moderate heart failure and for the control of resting ventricular rate in patients with chronic atrial fibrillation. (1) In pediatric patients with heart failure, digoxin increases myocardial contractility. 1.1 Heart Failure Digoxin Oral Solution, USP 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 increases myocardial contractility in pediatric patients with heart failure. 1.3 Atrial Fibrillation in Adults Digoxin Oral Solution, USP 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.

2 DOSAGE 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 < 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 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. [see ] Drug Interactions (7.4) . 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 admi…

5 WARNINGS 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 t…

4 CONTRAINDICATIONS Allergy to digoxin is rare. Digoxin is contraindicated in patients with a known hypersensitivity to digoxin or other forms of digitalis. Digitalis glycosides, such as digoxin, are contraindicated in ventricular fibrillation. Known hypersensitivity to digoxin or other forms of digitalis. (4) Ventricular fibrillation. (4)

7 DRUG INTERACTIONS PGP Inducers/Inhibitors: Drugs that induce or inhibit PGP have the potential to alter digoxin pharmacokinetics. (7.1) There are numerous drug interactions associated with digoxin. The potential for drug-drug interactions must be considered prior to and during drug therapy. See full prescribing information for a complete listing of pharmacokinetic (7.2) (12.3) and pharmacodynamic interactions (7.3). 7.1 P-Glycoprotein (PGP) Inducers/Inhibitors Digoxin is a substrate for 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 on Serum Digoxin Levels in Adults Digoxin concentrations increased > 50% Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring. Captopril 58% 39% Nitrendipine 57% 15% Propafenone 35-85% NA Quinidine 100% NA Ranolazine 87% 88% Ritonavir NA 86% Verapamil 50-75% NA Digoxin concentrations increased < 50% Carvedilol 16% 14% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring. Diltiazem 20% NA Nifedipine 45% NA Rabeprazole 29% 19% Telmisartan 20% NA Digoxin concentrations increased, but magnitude is unclear Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. Digoxin concentrations decreased Acarbose, Activated Charcoal, Albuterol, Antacids, Anti-cancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St. John’s Wort, Sucralfate, Sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary. No significant Digoxin concentrations changes Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. No additional actions are required. NA – Not available/reported 7.3 Pharmacodynamic Drug Interactions Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. Moricizine Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction. 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. 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 Epinepherine Can increase the risk of cardiac arrhythmias. Norepinephrine Dopamine 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 arrhyth…

8.1 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 pregnant women or can affect reproductive capacity. Digoxin should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers Digoxin levels in human milk are lower than those in maternal serum. The estimated exposure that a nursing infant would be expected to receive via breastfeeding would 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.

6 ADVERSE REACTIONS The frequency and severity of adverse reactions to digoxin when taken orally depend on the dose and the patient's underlying disease or concomitant therapies The overall incidence of adverse reactions has been reported as 5 to 20%, with 15 to 20% of them being considered serious (1 to 4% of patients receiving digoxin). Evidence suggests that the incidence of toxicity has decreased since the introduction of the serum digoxin assay and improved standardization of digoxin tablets. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. 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. [see and ] Warnings and Precautions (5) Drug Interactions (7) . The overall incidence of adverse reactions with digoxin has been reported as 5 to 20%, with 15 to 20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events. (6) To report SUSPECTED ADVERSE REACTIONS, contact Roxane Laboratories, Inc. at (614) 962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Cardiac In adults, high doses of digoxin may produce a variety of electrocardiographic changes and 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 multifocal ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation. Prophylactic use of a cardiac pacemaker may be considered if the risk of heart block is considered unacceptable. In pediatric patients, the use of digoxin may produce arrhythmias. The most common are conduction disturbances or supraventricular tachycarrhythmias, 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 arrhythmias or alteration in cardiac conduction that develops in a child taking digoxin should initially be assumed to be a consequence of digoxin intoxication. 6.2 Gastrointestinal Anorexia, nausea, vomiting and diarrhea may be early symptoms of digoxin toxicity. However, uncontrolled heart failure may also produce such symptoms. The use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines. 6.3 CNS and Special Senses Digoxin can produce visual disturbances (blurred vision, green-yellow color disturbances, halo effect), headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination). 6.4 Other Gynecomastia has been reported following the prolonged use of digoxin. Thrombocytopenia, maculopapular rash and other skin reactions have been observed.