LANOXIN (Page 4 of 8)

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:

Cardiac arrhythmias [see Warnings and Precautions (5.1, 5.2)]
Digoxin Toxicity [see Warnings and Precautions (5.3)]

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 LANOXIN are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when LANOXIN 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 LANOXIN 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

Pharmacokinetic interactions have been observed and reported primarily when digoxin is co-administered by oral route. There are very few studies that have evaluated the drug interaction when digoxin is administered via IV route. The magnitude of digoxin exposure change through IV route is generally lower than that through oral route. Table below provides available interaction data using digoxin IV formulation (NA means not available).

Digoxin concentrations increased greater than 50%

Digoxin SerumConcentrationIncrease

Digoxin AUCIncrease

Recommendations

Quinidine

NA

54-83%

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.

Ritonavir

NA

86%

Digoxin concentrations increased less than 50%

Amiodarone

17%

40%

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.

Propafenone

28%

29%

Quinine

NA

34-38%

Spironolactone

NA

44%

Verapamil

NA

24%

Mirabegron

29%

27%

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 RenalFunction

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.

Antiarrthymics

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 HormoneAnalog

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 BlockingAgents

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 blockersand calcium channelblockers

Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

Ivabradine

Can increase the risk of bradycardia.

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