DIGITEK (Page 4 of 9)

5.5 Risk of Ischemia in Patients With Acute Myocardial Infarction

Digoxin is not recommended in patients with acute myocardial infarction because digoxin may increase myocardial oxygen demand and lead to ischemia.

5.6 Vasoconstriction in Patients With Myocarditis

Digoxin can precipitate vasoconstriction and may promote production of pro-inflammatory cytokines; therefore, avoid use in patients with myocarditis.

5.7 Decreased Cardiac Output in Patients With Preserved Left Ventricular Systolic Function

Patients with heart failure associated with preserved left ventricular ejection fraction may experience decreased cardiac output with use of digoxin. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin. Patients with amyloid heart disease may be more susceptible to digoxin toxicity at therapeutic levels because of an increased binding of digoxin to extracellular amyloid fibrils.

Digoxin should generally be avoided in these patients, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation.

5.8 Reduced Efficacy in Patients With Hypocalcemia

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.

5.9 Altered Response 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. Patients with beri beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly.

6 ADVERSE REACTIONS

The following adverse reactions are included in more detail in the Warnings and Precautions section of the label:

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 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.

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

NA = Not available/reported

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 and sulfasalazine

Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

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