Lanoxin

1 INDICATIONS & USAGE Digoxin is a cardiac glycoside indicated for: Treatment of mild to moderate heart failure in adults. ( 1.1 ) Increasing myocardial contractility in pediatric patients with heart failure. ( 1.2 ) Control of resting ventricular rate in patients with chronic atrial fibrillation in adults. ( 1.3 ) 1.1 Heart Failure in Adults Digoxin is indicated for the treatment of mild to moderate heart failure in adults. Digoxin increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by improved exercise capacity and decreased heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, digoxin should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor. 1.2 Heart Failure in Pediatric Patients Digoxin increases myocardial contractility in pediatric patients with heart failure. 1.3 Atrial Fibrillation in Adults Digoxin is indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation.

2 DOSAGE & ADMINISTRATION Digoxin dose is based on patient-specific factors (age, lean body weight, renal function, etc.). See full prescribing information. Monitor for toxicity and therapeutic effect. 2.1 Important Dosing and Administration Information In selecting a digoxin dosing regimen, it is important to consider factors that affect digoxin blood levels (e.g., body weight, age, renal function, concomitant drugs) since toxic levels of digoxin are only slightly higher than therapeutic levels. Dosing can be either initiated with a loading dose followed by maintenance dosing if rapid titration is desired or initiated with maintenance dosing without a loading dose. Consider interruption or reduction in digoxin dose prior to electrical cardioversion [see Warnings and Precautions (5.4) ] . Use digoxin solution to obtain the appropriate dose in infants, young pediatric patients, or patients with very low body weight. 2.2 Loading Dosing Regimen in Adults and Pediatric Patients For adults and pediatric patients if a loading dosage is to be given, administer half the total loading dose initially, then ¼ the loading dose every 6-8 hours twice, with careful assessment of clinical response and toxicity before each dose. The recommended loading dose is displayed in Table 1. Table 1. Recommended Digoxin Oral Loading Dose Age Total Oral Loading Dose (mcg/kg) Administer half the total loading dose initially, then ¼ the loading dose every 6 to 8 hours twice 5 to 10 years 20-45 Adults and pediatric patients over 10 years 10-15 mcg = microgram 2.3 Maintenance Dosing in Adults and Pediatric Patients Over 10 Years Old The maintenance dose is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology (12.3) ] . The recommended starting maintenance dose in adults and pediatric patients over 10 years old with normal renal function is given in Table 2. Doses may be increased every 2 weeks according to clinical response, serum drug levels, and…

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action All of digoxin’s actions are mediated through its effects on Na-K ATPase. This enzyme, the “sodium pump,” is responsible for maintaining the intracellular milieu throughout the body by moving sodium ions out of and potassium ions into cells. By inhibiting Na-K ATPase, digoxin causes increased availability of intracellular calcium in the myocardium and conduction system, with consequent increased inotropy, increased automaticity, and reduced conduction velocity indirectly causes parasympathetic stimulation of the autonomic nervous system, with consequent effects on the sino-atrial (SA) and atrioventricular (AV) nodes 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 increases (at higher concentrations) sympathetic outflow from the central nervous system (CNS) to both cardiac and peripheral sympathetic nerves allows (at higher concentrations) progressive efflux of intracellular potassium, with consequent increase in serum potassium levels. The cardiologic consequences of these direct and indirect effects are an increase in the force and velocity of myocardial systolic contraction (positive inotropic action), a slowing of the heart rate (negative chronotropic effect), decreased conduction velocity through the AV node, and a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect). 12.2 Pharmacodynamics The times to onset of pharmacologic effect and to peak effect of preparations of digoxin are shown in Table 7. Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of Digoxin Product Time to Onset of Effect a Time to Peak Effect a Digoxin Tablets 0.5-2 hours…

6 ADVERSE REACTIONS The following adverse reactions are included in more detail in the Warnings and Precautions section of the label: Cardiac arrhythmias [see Warnings and Precautions (5.1 , 5.2 )] Digoxin Toxicity [see Warnings and Precautions (5.3) ] The overall incidence of adverse reactions with digoxin has been reported as 5-20%, with 15-20% 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Oliva Therapeutics at 1-877-200-6088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 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, is maintained within the therapeutic serum concentration range, and when there is careful attention to concurrent medications and conditions. In the DIG trial (a trial investigating the effect of digoxin on mortality and morbidity in patients with heart failure), the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking digoxin tablets compared to 0.9% in patients taking placebo [see Clinical Studies (14.1) ] . The overall incidence of adverse reactions with digoxin has been reported as 5-20%, with 15-20% 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.…

4 CONTRAINDICATIONS 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. ( 4 ) Known hypersensitivity to digoxin or other forms of digitalis. ( 4 )

5 WARNINGS AND PRECAUTIONS Risk of rapid ventricular response leading to ventricular fibrillation in patients with AV accessory pathway. ( 5.1 ) Risk of advanced or complete heart block in patients with sinus node disease and AV block. ( 5.2 ) Digoxin toxicity: Indicated by nausea, vomiting, visual disturbances, and cardiac arrhythmias. Advanced age, low body weight, impaired renal function and electrolyte abnormalities predispose to toxicity. ( 5.3 ) Risk of ventricular arrhythmias during electrical cardioversion. ( 5.4 ) Not recommended in patients with acute myocardial infarction. ( 5.5 ) Avoid digoxin in patients with myocarditis. ( 5.6 ) 5.1 Ventricular Fibrillation 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 Sinus Bradycardia and Sino-atrial Block 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. Consider insertion of a pacemaker before treatment with digoxin. 5.3 Digoxin Toxicity Signs and symptoms of digoxin toxicity include anorexia, nausea, vomiting, visual changes and cardiac arrhythmias [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]. Toxicity is usually associated with digoxin levels greater than 2 ng/ml although…

7 DRUG 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 30-50% or by modifying the dosing frequency and continue monitoring. Captopril 58% 39% Clarithromycin NA 70% Dronedarone NA 150% Gentamicin 129-212% NA Erythromycin 100% NA Itraconazole 80% NA Lapatinib NA 180% Propafenone NA 60-270% Quinidine 100% NA Ranolazine 50% NA Ritonavir NA 86% Telaprevir 50% 85% Tetracycline 100% NA Verapamil 50-75% NA Digoxin concentrations increased less than 50% Atorvastatin 22% 15% Carvedilol 16% 14% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Conivaptan 33% 43% Diltiazem 20% NA Indomethacin 40% NA…