DRUG INTERACTIONS
7 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 or inhibit P-glycoprotein in intestine or kidney have the potential to alter digoxin pharmacokinetics.
7.2 Pharmacokinetic Drug Interactions Digoxin concentrations increased greater than 50% NA – Not available/reported 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 to 50% or by modifying the dosing frequency and continue monitoring.
Captopril 58% 39% Clarithromycin NA 70% Dronedarone NA 150% Gentamicin 129 to 212% NA Erythromycin 100% NA Itraconazole 80% NA Lapatinib NA 180% Nitrendipine 57% 15% Propafenone NA 60 to 270% Quinidine 100% NA Ranolazine 50% NA Ritonavir NA 86% Telaprevir 50% 85% Tetracycline 100% NA Verapamil 50 to 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 to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol 16% 14% Conivaptan 33% 43% Diltiazem 20% NA Indomethacin 40% NA Nefazodone 27% 15% Nifedipine 45% NA Propantheline 24% 24% Quinine NA 33% Raberprazole 29% 19% Saquinavir 27% 49% Spironolactone 25% NA Telmisartan 20 to 49% NA Teicagrelor 31% 28% Tolvaptan 30% NA Trimethoprim 22 to 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 to 40% as necessary.
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 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 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 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 Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias 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 arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker Ivabradine Can increase the risk of bradycardia 7.4 Drug/Laboratory Test Interactions Endogenous substances of unknown composition (digoxin-like immunoreactive substances [DLIS]) can interfere with standard radioimmunoassays for digoxin.
The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced.
Some assays are more subject to these failings than others.
Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference.
DLIS are present in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason.
The measured levels of DLIS (as digoxin equivalents) are usually low (0.2 to 0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic.
In some assays, spironolactone, canrenone, and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL.
Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha or Dashen can cause similar interference.
Spironolactone and DLIS are much more extensively protein-bound than digoxin.
As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS.
It should be noted that ultrafiltration does not solve all interference problems with alternative medicines.
The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in terms of specificity and limit of quantization.
OVERDOSAGE
10 10.1 Signs and Symptoms in Adults and Children The signs and symptoms of toxicity are generally similar to those described in the Adverse Reactions (6.1) but may be more frequent and can be more severe.
Signs and symptoms of digoxin toxicity become more frequent with levels above 2 ng/mL.
However, in deciding whether a patient’s symptoms are due to digoxin, the clinical state together with serum electrolyte levels and thyroid function are important factors [see Dosage and Administration (2) ].
Adults: The most common signs and symptoms of digoxin toxicity are nausea, vomiting, anorexia, and fatigue that occur in 30 to 70% of patients who are overdosed.
Extremely high serum concentrations produce hyperkalemia especially in patients with impaired renal function.
Almost every type of cardiac arrhythmia has been associated with digoxin overdose and multiple rhythm disturbances in the same patient are common.
Peak cardiac effects occur 3 to 6 hours following ingestion and may persist for 24 hours or longer.
Arrhythmias that are considered more characteristic of digoxin toxicity are new-onset Mobitz type 1 A-V block, accelerated junctional rhythms, non-paroxysmal atrial tachycardia with A-V block, and bi-directional ventricular tachycardia.
Cardiac arrest from asystole or ventricular fibrillation is usually fatal.
Digoxin toxicity is related to serum concentration.
As digoxin serum levels increase above 1.2 ng/mL, there is a potential for increase in adverse reactions.
Furthermore, lower potassium levels increase the risk for adverse reactions.
In adults with heart disease, clinical observations suggest that an overdose of digoxin of 10 to 15 mg results in death of half of patients.
A dose above 25 mg ingested by an adult without heart disease appeared to be uniformly fatal if no Digoxin Immune Fab (DIGIBIND ® , DIGIFAB ® ) was administered.
Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g., nausea, vomiting, anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in approximately half of the patients in most literature reports.
Neurologic manifestations (e.g., dizziness, various CNS disturbances), fatigue, and malaise are very common.
Visual manifestations may also occur with aberration in color vision (predominance of yellow green) the most frequent.
Neurological and visual symptoms may persist after other signs of toxicity have resolved.
In chronic toxicity, non-specific extra-cardiac symptoms, such as malaise and weakness, may predominate.
Children: In pediatric patients, signs and symptoms of toxicity can occur during or shortly after the dose of digoxin.
Frequent non-cardiac effects are similar to those observed in adults although nausea and vomiting are not seen frequently in infants and small pediatric patients.
Other reported manifestations of overdose are weight loss in older age groups, failure to thrive in infants, abdominal pain caused by mesenteric artery ischemia, drowsiness, and behavioral disturbances including psychotic episodes.
Arrhythmias and combinations of arrhythmias that occur in adult patients can also occur in pediatric patients although sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in pediatric patients.
Pediatric patients are more likely to develop A-V conduction disturbances, or sinus bradycardia.
Any arrhythmia in a child treated with digoxin should be considered related to digoxin until otherwise ruled out.
In pediatric patients aged 1 to 3 years without heart disease, clinical observations suggest that an overdose of digoxin of 6 to 10 mg would result in death of half of the patients.
In the same population, a dose above 10 mg resulted in death if no Digoxin Immune Fab were administered.
10.2 Treatment Chronic Overdose If there is suspicion of toxicity, discontinue digoxin tablets and place the patient on a cardiac monitor.
Correct factors such as electrolyte abnormalities, thyroid dysfunction, and concomitant medications [see Dosage and Administration (2.5) ].
Correct hypokalemia by administering potassium so that serum potassium is maintained between 4.0 and 5.5 mmol/L.
Potassium is usually administered orally, but when correction of the arrhythmia is urgent and serum potassium concentration is low, potassium may be administered by the intravenous route.
Monitor electrocardiogram for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia.
Avoid potassium salts in patients with bradycardia or heart block.
Symptomatic arrhythmias may be treated with Digoxin Immune Fab.
Acute Overdose Patients who have intentionally or accidently ingested massive doses of digoxin should receive activated charcoal orally or by nasogastric tube regardless of the time since ingestion since digoxin recirculates to the intestine by enterohepatic circulation.
In addition to cardiac monitoring, temporarily discontinue digoxin tablets until the adverse reaction resolves.
Correct factors that may be contributing to the adverse reactions [see Warnings and Precautions (5) ].
In particular, correct hypokalemia and hypomagnesemia.
Digoxin is not effectively removed from the body by dialysis because of its large extravascular volume of distribution.
Life-threatening arrhythmias (ventricular tachycardia, ventricular fibrillation, high degree A-V block, bradyarrhythmia, sinus arrest) or hyperkalemia requires administration of Digoxin Immune Fab.
Digoxin Immune Fab has been shown to be 80 to 90% effective in reversing signs and symptoms of digoxin toxicity.
Bradycardia and heart block caused by digoxin are parasympathetically mediated and respond to atropine.
A temporary cardiac pacemaker may also be used.
Ventricular arrhythmias may respond to lidocaine or phenytoin.
When a large amount of digoxin has been ingested, especially in patients with impaired renal function, hyperkalemia may be present due to release of potassium from skeletal muscle.
In this case, treatment with Digoxin Immune Fab is indicated; an initial treatment with glucose and insulin may be needed if the hyperkalemia is life-threatening.
Once the adverse reaction has resolved, therapy with digoxin tablets may be reinstituted following a careful reassessment of dose.
DESCRIPTION
11 Digoxin is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium.
These drugs are found in a number of plants.
Digoxin is extracted from the leaves of Digitalis lanata .
The term “digitalis” is used to designate the whole group of glycosides.
The glycosides are composed of 2 portions: a sugar and a cardenolide (hence “glycosides”).
Digoxin is described chemically as (3β,5β,12β)-3-[( O -2,6-dideoxy-β- D-ribo -hexopyranosyl-(1→4)- O -2,6-dideoxy-β- D-ribo- hexopyranosyl-(1→4)-2,6-dideoxy-β- D – ribo -hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide.
Its molecular formula is C 41 H 64 O 14 , its molecular weight is 780.95, and its structural formula is: Digoxin exists as odorless white crystals that melt with decomposition above 230°C.
The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine.
Digoxin tablets, USP are supplied as 125 mcg (0.125 mg) and 250 mcg (0.25 mg) tablets for oral administration.
Each tablet contains the labeled amount of digoxin USP and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and corn starch.
The 125 mcg (0.125 mg) tablets contain FD&C Yellow No.
5 (tartrazine).
Chemical Structure
CLINICAL STUDIES
14 14.1 Chronic Heart Failure Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) adult patients with NYHA Class II or III heart failure previously treated with oral digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with digoxin tablets.
Both trials demonstrated better preservation of exercise capacity in patients randomized to digoxin tablets.
Continued treatment with digoxin tablets reduced the risk of developing worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy.
DIG Trial of Digoxin Tablets in Patients with Heart Failure The Digitalis Investigation Group (DIG) main trial was a 37-week, multicenter, randomized, double-blind mortality study comparing digoxin to placebo in 6800 adult patients with heart failure and left ventricular ejection fraction less than or equal to 0.45.
At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving a concomitant ACE inhibitor (94%) and diuretics (82%).
As in the smaller trials described above, patients who had been receiving open-label digoxin were withdrawn from this treatment before randomization.
Randomization to digoxin was again associated with a significant reduction in the incidence of hospitalization, whether scored as number of hospitalizations for heart failure (relative risk 75%), risk of having at least one such hospitalization during the trial (RR 72%), or number of hospitalizations for any cause (RR 94%).
On the other hand, randomization to digoxin had no apparent effect on mortality (RR 99%, with confidence limits of 91 to 107%).
14.2 Chronic Atrial Fibrillation Digoxin has also been studied as a means of controlling the ventricular response to chronic atrial fibrillation in adults.
Digoxin reduced the resting heart rate, but not the heart rate during exercise.
In 3 different randomized, double-blind trials that included a total of 315 adult patients, digoxin was compared to placebo for the conversion of recent-onset atrial fibrillation to sinus rhythm.
Conversion was equally likely, and equally rapid, in the digoxin and placebo groups.
In a randomized 120-patient trial comparing digoxin, sotalol, and amiodarone, patients randomized to digoxin had the lowest incidence of conversion to sinus rhythm, and the least satisfactory rate control when conversion did not occur.
In at least one study, digoxin was studied as a means of delaying reversion to atrial fibrillation in adult patients with frequent recurrence of this arrhythmia.
This was a randomized, double-blind, 43-patient crossover study.
Digoxin increased the mean time between symptomatic recurrent episodes by 54%, but had no effect on the frequency of fibrillatory episodes seen during continuous electrocardiographic monitoring.
HOW SUPPLIED
16 /STORAGE AND HANDLING Digoxin tablets USP, 125 mcg (0.125 mg) are light yellow, round, flat-faced beveled edge tablets debossed with “981” on top of bisect on one side and plain on the other side.
Unit dose packages of 100 (10 × 10) NDC 68084-366-01 Digoxin tablets USP, 250 mcg (0.25 mg) are off-white to light tan, round, convex tablets debossed with “982” on top of bisect on one side and plain on the other side.
Unit dose packages of 100 (10 × 10) NDC 68084-680-01 Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].
Keep out of reach of children.
FOR YOUR PROTECTION: Do not use if blister is torn or broken.
GERIATRIC USE
8.5 Geriatric Use The majority of clinical experience gained with digoxin has been in the elderly population.
This experience has not identified differences in response or adverse effects between the elderly and younger patients.
However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be useful to monitor renal function [see Dosage and Administration (2.1) ].
MECHANISM OF ACTION
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).
INDICATIONS AND USAGE
1 Digoxin tablets, USP are 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 tablets, USP are indicated for the treatment of mild to moderate heart failure in adults.
Digoxin tablets, USP increase left ventricular ejection fraction and improve 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 tablets, USP should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor.
1.2 Heart Failure in Pediatric Patients Digoxin tablets, USP increase myocardial contractility in pediatric patients with heart failure.
1.3 Atrial Fibrillation in Adults Digoxin tablets, USP are indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of digoxin tablets in the control of ventricular rate in children with atrial fibrillation have not been established.
The safety and effectiveness of digoxin tablets in the treatment of heart failure in children have not been established in adequate and well-controlled studies.
However, in published literature of children with heart failure of various etiologies (e.g., ventricular septal defects, anthracycline toxicity, patent ductus arteriosus), treatment with digoxin has been associated with improvements in hemodynamic parameters and in clinical signs and symptoms.
Newborn infants display considerable variability in their tolerance to digoxin.
Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity.
PREGNANCY
8.1 Pregnancy Pregnancy Category C.
Digoxin tablets should be given to a pregnant woman only if clearly needed.
It is also not known whether digoxin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.
Animal reproduction studies have not been conducted with digoxin.
NUSRING MOTHERS
8.3 Nursing Mothers Studies have shown that digoxin distributes into breast milk and that the milk-to-serum concentration ratio is approximately 0.6 to 0.9.
However, the estimated exposure of a nursing infant to digoxin via breastfeeding is far below the usual infant maintenance dose.
Therefore, this amount should have no pharmacologic effect upon the infant.
WARNING AND CAUTIONS
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 tablets 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 tablets 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 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 tablets dosing, when dosing should actually be suspended.
When the etiology of these signs and symptoms is not clear, measure serum digoxin levels.
5.4 Risk of Ventricular Arrhythmias During Electrical Cardioversion It may be desirable to reduce the dose of or discontinue digoxin tablets 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 not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular arrhythmias.
5.5 Risk of Ischemia in Patients With Acute Myocardial Infarction Digoxin tablets are 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 tablets 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 tablets.
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 tablets 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients that digoxin is used to treat heart failure and heart arrhythmias.
Instruct patients to take this medication as directed.
Advise patients that many drugs can interact with digoxin tablets.
Instruct patients to inform their doctor and pharmacist if they are taking any over the counter medications, including herbal medication, or are started on a new prescription.
Advise patient that blood tests will be necessary to ensure that their digoxin tablets dose is appropriate for them.
Advise patients to contact their doctor or a health care professional if they experience nausea, vomiting, persistent diarrhea, confusion, weakness, or visual disturbances (including blurred vision, green-yellow color disturbances, halo effect) as these could be signs that the dose of digoxin tablets may be too high.
Advise parents or caregivers that the symptoms of having too high digoxin tablets doses may be difficult to recognize in infants and pediatric patients.
Symptoms such as weight loss, failure to thrive in infants, abdominal pain, and behavioral disturbances may be indications of digoxin toxicity.
Instruct the patient to monitor and record their heart rate and blood pressure daily.
Instruct women of childbearing potential who become or are planning to become pregnant to consult a physician prior to initiation or continuing therapy with digoxin tablets.
DIGIBIND ® is a registered trademark of GlaxoSmithKline.
DIGIFAB ® is a registered trademark of Prostherics Inc.
DOSAGE AND ADMINISTRATION
2 Digoxin tablets, USP 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 ) 2.1 Important Dosing and Administration Information In selecting a digoxin tablets 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 tablets 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 to 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 Tablets Oral Loading Dose mcg = microgram 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 to 45 Adults and pediatric patients over 10 years 10 to 15 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 toxicity.
Table 2.
Recommended Starting Digoxin Tablets Maintenance Dosage in Adults and Pediatric Patients Over 10 Years Old mcg = microgram Age Total Oral Maintenance Dose, mcg/kg/day (given once daily) Adults and pediatric patients over 10 years 3.4 to 5.1 Table 3 provides the recommended (once daily) maintenance dose for adults and pediatric patients over 10 years old (to be given once daily) according to lean body weight and renal function.
The doses are based on studies in adult patients with heart failure.
Alternatively, the maintenance dose may be estimated by the following formula (peak body stores lost each day through elimination): Total Maintenance Dose = Loading Dose (i.e., Peak Body Stores) × % Daily Loss/100 (% Daily Loss = 14 + Creatinine clearance/5) Reduce the dose of digoxin tablets in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema.
Table 3.
Recommended Maintenance Dose (in micrograms given once daily) of Digoxin Tablets in Pediatric Patients Over 10 Years Old and Adults by Lean Body Weight and by Renal Function Doses are rounded to the nearest dose possible using whole and/or half digoxin tablets.
Recommended doses approximately 30 percent lower than the calculated dose are designated with an *.
Monitor digoxin levels in patients receiving these initial doses and increase dose if needed.
Corrected Creatinine Clearance For adults, creatinine clearance was corrected to 70-kg body weight or 1.73 m2 body surface area.
If only serum creatinine concentrations (Scr) are available, a corrected Ccr may be estimated in men as (140 – Age)/Scr.
For women, this result should be multiplied by 0.85.
For pediatric patients, the modified Schwartz equation may be used.
The formula is based on height in cm and Scr in mg/dL where k is a constant.
Ccr is corrected to 1.73 m2 body surface area.
During the first year of life, the value of k is 0.33 for pre-term babies and 0.45 for term infants.
The k is 0.55 for pediatric patients and adolescent girls and 0.7 for adolescent boys.
GFR (mL/min/1.73 m2) = (k × Height)/Scr Lean Body Weight The doses listed assume average body composition.
Number of Days Before Steady State Achieved If no loading dose administered.
kg 40 50 60 70 80 90 100 10 mL/min 62.5* 125 125 187.5 187.5 187.5 250 19 20 mL/min 125 125 125 187.5 187.5 250 250 16 30 mL/min 125 125 187.5 187.5 250 250 312.5 14 40 mL/min 125 187.5 187.5 250 250 312.5 312.5 13 50 mL/min 125 187.5 187.5 250 250 312.5 312.5 12 60 mL/min 125 187.5 250 250 312.5 312.5 375 11 70 mL/min 187.5 187.5 250 250 312.5 375 375 10 80 mL/min 187.5 187.5 250 312.5 312.5 375 437.5 9 90 mL/min 187.5 250 250 312.5 375 437.5 437.5 8 100 mL/min 187.5 250 312.5 312.5 375 437.5 500 7 2.4 Maintenance Dosing in Pediatric Patients Less Than 10 Years Old The starting maintenance dose for heart failure in pediatric patients less than 10 years old is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology (12.3) ].
The recommended starting maintenance dose for pediatric patients between 5 years and 10 years old is given in Table 4.
These recommendations assume the presence of normal renal function.
Table 4.
Recommended Starting Digoxin Tablets Oral Maintenance Dosage in Pediatric Patients between 5 and 10 Years Old Age Oral Maintenance Dose, mcg/kg/dose 5 years to 10 years 3.2 to 6.4 Twice daily Table 5 provides average daily maintenance dose requirements for pediatric patients between 5 and 10 years old (to be given twice daily) with heart failure based on age, lean body weight, and renal function.
Table 5.
Recommended Maintenance Dose (in micrograms given TWICE daily) of Digoxin Tablets in Pediatric Patients between 5 and 10 Years of Age Recommended are doses to be given twice daily.
Based upon Lean Body Weight and Renal Function , The doses are rounded to the nearest dose possible using whole and/or half digoxin tablets.
Recommended doses approximately 30 percent lower than the calculated dose are designated with an *.
Monitor digoxin levels in patients receiving these initial doses and increase dose if needed.
Corrected Creatinine Clearance The modified Schwartz equation may be used to estimate creatinine clearance.
See footnote b under Table 3.
Lean Body Weight Number of Days Before Steady State Achieved If no loading dose administered.
kg 20 30 40 50 60 10 mL/min – 62.5 62.5* 125 125 19 20 mL/min 62.5 62.5 125 125 125 16 30 mL/min 62.5 62.5* 125 125 187.5 14 40 mL/min 62.5 62.5* 125 187.5 187.5 13 50 mL/min 62.5 125 125 187.5 187.5 12 60 mL/min 62.5 125 125 187.5 250 11 70 mL/min 62.5 125 187.5 187.5 250 10 80 mL/min 62.5* 125 187.5 187.5 250 9 90 mL/min 62.5* 125 187.5 250 250 8 100 mL/min 62.5* 125 187.5 250 312.5 7 2.5 Monitoring to Assess Safety, Efficacy, and Therapeutic Blood Levels Monitor for signs and symptoms of digoxin toxicity and clinical response.
Adjust dose based on toxicity, efficacy, and blood levels.
Serum digoxin levels less than 0.5 ng/mL have been associated with diminished efficacy, while levels above 2 ng/mL have been associated with increased toxicity without increased benefit.
Interpret the serum digoxin concentration in the overall clinical context, and do not use an isolated measurement of serum digoxin concentration as the basis for increasing or decreasing the digoxin tablets dose.
Serum digoxin concentrations may be falsely elevated by endogenous digoxin-like substances [see Drug Interactions (7.4) ].
If the assay is sensitive to these substances, consider obtaining a baseline digoxin level before starting digoxin tablets and correct post-treatment values by the reported baseline level.
Obtain serum digoxin concentrations just before the next scheduled digoxin tablets dose or at least 6 hours after the last dose.
The digoxin concentration is likely to be 10 to 25% lower when sampled right before the next dose (24 hours after dosing) compared to sampling 8 hours after dosing (using once-daily dosing).
However, there will be only minor differences in digoxin concentrations using twice daily dosing whether sampling is done at 8 or 12 hours after a dose.
2.6 Switching from Intravenous Digoxin to Oral Digoxin When switching from intravenous to oral digoxin formulations, make allowances for differences in bioavailability when calculating maintenance dosages (see Table 6).
Table 6.
Comparison of the Systemic Availability and Equivalent Doses of Oral and Intravenous Digoxin Tablets Absolute Bioavailability Equivalent Doses (mcg) Digoxin Tablets 60 to 80% 62.5 125 250 500 Digoxin Intravenous Injection 100% 50 100 200 400