Digoxin .125 mg Tablet, 100-count

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)

5.1Ventricular 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.

5.2Sinus 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.

5.3Digoxin 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 symptoms may also occur at lower levels.

Low body weight, advanced age or impaired renal function, hypokalemia, hypercalcemia, or hypomagnesemia may predispose to digoxin toxicity. Obtain serum digoxin levels in patients with signs or symptoms of digoxin therapy and interrupt or adjust dose if necessary [see Adverse Reactions (6) and Overdosage (10) ]. Assess serum electrolytes and renal function periodically.

The earliest and most frequent manifestation of digoxin toxicity 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 arrhythmias or alteration in cardiac conduction that develops in a child taking digoxin should initially be assumed to be a consequence of digoxin intoxication.

Given that adult patients with heart failure have some symptoms in common with digoxin toxicity, it may be difficult to distinguish digoxin toxicity from 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 clear, measure serum digoxin levels.

5.4Risk of Ventricular Arrhythmias During Electrical Cardioversion It may be desirable to reduce the dose of or discontinue 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 decreased or withdrawn. If digitalis toxicity is suspected, elective cardioversion should be delayed. If it is no…

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 Novitium Pharma LLC at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 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.

Gastrointestinal: In addition to nausea and vomiting, the use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines. CNS: Digoxin can cause 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.

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 )

7.1P-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.

7.2Pharmacokinetic 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% 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. 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 20-49% NA Ticagrelor 31% 28% Tolvaptan 30% 20% Trimethoprim 22-28% 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, sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs.

Continue monitoring and increase digoxin dose by approximately 20-40% as necessary. NA – Not available/reported

7.3Potentially 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 receiv…