digoxin 500 MCG per 2 ML Injection
Generic Name: DIGOXIN
Brand Name: Digoxin
- Substance Name(s):
- DIGOXIN
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).
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.
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 (0.2-0.4 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.
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OVERDOSAGE
10.1 Signs and Symptoms in Adults The signs and symptoms of toxicity are generally similar to those previously described [see 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 30-70% 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 3-6 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 increases the risk for adverse reactions.
In adults with heart disease, clinical observations suggest that an overdose of digoxin of 10-15 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, nonspecific extra-cardiac symptoms, such as malaise and weakness, may predominate.
10.2 Treatment Chronic Overdose If there is suspicion of toxicity, discontinue digoxin and place the patient on a cardiac monitor.
Correct factors such as electrolyte abnormalities, thyroid dysfunction, and concomitant medications [see Dosage and Administration ( 2.4 ].
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 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, bradyarrhythma, sinus arrest) or hyperkalemia requires administration of Digoxin Immune Fab.
Digoxin Immune Fab has been shown to be 80-90% 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 may be reinstituted following a careful reassessment of dose.
DESCRIPTION
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 two portions: a sugar and a cardenolide (hence “glycosides”).
Digoxin has the chemical name: 3β-[(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]-12β,14-dihydroxy-5β-card-20(22)-enolide, and the following structural formula: 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 Injection is a sterile solution for slow intravenous or deep intramuscular injection.
Each mL contains digoxin 250 mcg (0.25 mg), alcohol 0.1 mL, propylene glycol 0.4 mL, dibasic sodium phosphate, anhydrous 3 mg and citric acid, anhydrous 0.8 mg in Water for Injection.
pH 6.7-7.3; citric acid and/or sodium phosphate added, if necessary, for pH adjustment.
Dilution is not required.
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CLINICAL STUDIES
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.
Continued treatment with digoxin 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 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 91-107%).
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
/STORAGE AND HANDLING Digoxin Injection, USP is available as: 500 mcg/2 mL (250 mcg/mL) ampuls packaged in 25s (NDC 0641-1410-35) Store at 20˚-25˚C (68˚-77˚F), excursions permitted to 15˚-30˚C (59˚-86˚F) [see USP Controlled Room Temperature].
Protect from light.
DOSAGE FORMS AND STRENGTHS
Digoxin Injection: Ampuls of 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25] per 1 mL).
Digoxin Injection: Ampuls containing 500 mcg (0.5 mg) in 2 mL.
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INDICATIONS AND USAGE
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use digoxin safely and effectively.
See full prescribing information for digoxin.
Digoxin Injection, for intravenous or intramuscular use Initial U.S.
Approval: 1954 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 imporves heart failure symptoms, as evidenced by 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 Atrial Fibrillation in Adults Digoxin is indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation.
Digoxin is a cardiac glycoside indicated for: Treatment of mild to moderate heart failure in adults.
(1.1) Control of resting ventricular rate in adults with chronic artial fibrillation.
(1.2)
WARNING AND CAUTIONS
WARNINGS AND PRECAUTIONS 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 sino-atrial 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 pacemake 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 usuallyassociated 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, 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 product any arrhythmia.
The most common are conduction disturbances or supraventricular tacharrhythmias, 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 sympotoms 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 itiology 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 for 1-2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequenc3es 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 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 pulmonate.
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 ore susceptible to digoxin toxicity 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, hyposia, or arteriovenous shunt) are best treated by addressing the underlying condition.
Atrial arrhythmias associated with hypermetabollic 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.
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)
DOSAGE AND ADMINISTRATION
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 slightlyhigher 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.
Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orallly.
Intramuscular injection can lead to severe pain at the injection site, thus intravenous administration is preferred.
If the drug must be administered by the intramuscular route, it should be injected deep into the muscle followed by massage.
For adults, no more than 500 mcg of Digoxin Injection should be injected into a single site.
For pediatric patients, see the full prescribing information for pediatric digoxin injection (not available from West-Ward) for specific recommendations.
Administer the dose over a period of 5 minutes or longer and avoid bolus administration to prevent systemic and coronary vasoconstriction.
Mixing of Digoxin Injection with other drugs in the same container or simultaneous administration in the same intravenous line is not recommended.
Digoxin Injection can be administered undiluted or diluted with a 4-fold or greater volume of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection.
The use of less than a 4 fold-volume of diluent could lead to precipitation of the digoxin.
Immediate use of the diluted product is recommended.
If tuberculin syringes are used to measure very small doses do not flush with the parenteral solution after its contents are expelled into an indwelling vascular catheter to avoid over administration of digoxin.
Consider interruption or reduction in digoxin dose prior to electriclal cardioversion [see Warnings and Precautions (5.4)].
2.2 Loading Dosing Regimen in Adult Patients 2.3 Maintenance Dosing in Adult Patients The maintenance dose is based on lead body weight, renal function, age, and concomitant products [ see Clinical Pharmacology (12.3)].
The recommended starting maintenance dose in adult patients 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 3 provides the recommended (once daily) maintenance dose for adult patients 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) x % Daily Loss/100 (%Daily Loss = 14 + Creatinine clearance/5) Reduce the dose of digoxin in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema.
2.4 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 vessels.
Serum digoxin levels less than 0.5 ng/nL 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 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 and correct post-treatment values by the reported baseline level.
Obtain serum digoxin concentrations just before the next scheduled digoxin dose or at least 6 hours after the last dose.
The digoxin concentration is likely to be 10-25% 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.
2.5 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 4).
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) Intravenous administration is preferable to intramuscular.
Avoid bolus administration.
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