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| Product NDC Code | 70515-260 | ||||
|---|---|---|---|---|---|
| Drug Name | Lanoxin |
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| Type | Brand | ||||
| Pharm Class | Cardiac Glycoside [EPC], Cardiac Glycosides [CS] |
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| Active Ingredients |
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| Route | INTRAMUSCULAR, INTRAVENOUS | ||||
| Dosage Form | INJECTION, SOLUTION | ||||
| RxCUI drug identifier | 104208, 204504, 208135, 208137 |
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| Application Number | NDA009330 | ||||
| Labeler Name | Covis Pharma US, Inc | ||||
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| Check if available Online | Get Medication Prices online with Discount |
Overdosage of LANOXIN
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE 10.1 Signs and Symptoms in Adults and Children 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. 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 1-3 years without heart disease, clinical observations suggest that an overdose of digoxin of 6-10 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 LANOXIN 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 LANOXIN 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 LANOXIN may be reinstituted following a careful reassessment of dose.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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 Covis Pharma at 1-866-488-4423 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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.
LANOXIN Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.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 ) 7.1 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 Serum Concentration Increase Digoxin AUC Increase 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 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. 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 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. 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 (0.2-0.4 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 Danshen 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.
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 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). 12.2 Pharmacodynamics The times to onset of pharmacologic effect and to peak effect of preparations of LANOXIN are shown in Table 7 . Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of LANOXIN a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion. Product Time to Onset of Effect a Time to Peak Effect a LANOXIN Tablets 0.5-2 hours 2-6 hours LANOXIN Injection/IV 5-30 minutes b 1-4 hours Hemodynamic Effects: Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance in patients with heart failure. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions. ECG Changes: The use of therapeutic doses of LANOXIN may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. LANOXIN may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects are not indicative of toxicity. LANOXIN does not significantly reduce heart rate during exercise. 12.3 Pharmacokinetics Note: The following data are from studies performed in adults, unless otherwise stated. Comparisons of the systemic availability and equivalent doses for oral preparations of LANOXIN are shown in Table 6 [see Dosage and Administration ( 2.6 )] . Distribution: Following drug administration, a 6-8 hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak height and slope of the early portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects [see Dosage and Administration ( 2.1 )] . Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution (approximately 475-500 L). Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight. Metabolism: Only a small percentage (13%) of a dose of digoxin is metabolized in healthy volunteers. The urinary metabolites, which include dihydrodigoxin, digoxigenin bisdigitoxoside, and their glucuronide and sulfate conjugates are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system. Excretion: Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50-70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to creatinine clearance and is largely independent of urine flow. In healthy volunteers with normal renal function, digoxin has a half-life of 1.5-2 days. The half-life in anuric patients is prolonged to 3.5-5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues. Special Populations: Geriatrics: Because of age-related declines in renal function, elderly patients would be expected to eliminate digoxin more slowly than younger subjects. Elderly patients may also exhibit a lower volume of distribution of digoxin due to age-related loss of lean muscle mass. Thus, the dosage of digoxin should be carefully selected and monitored in elderly patients [see Use in Specific Populations ( 8.5 )] . Gender: In a study of 184 patients, the clearance of digoxin was 12% lower in female than in male patients. This difference is not likely to be clinically important. Hepatic Impairment: Because only a small percentage (approximately 13%) of a dose of digoxin undergoes metabolism, hepatic impairment would not be expected to significantly alter the pharmacokinetics of digoxin. In a small study, plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects. No dosage adjustments are recommended for patients with hepatic impairment; however, serum digoxin concentrations should be used, as appropriate, to help guide dosing in these patients. Renal Impairment: Since the clearance of digoxin correlates with creatinine clearance, patients with renal impairment generally demonstrate prolonged digoxin elimination half-lives and greater exposures to digoxin. Therefore, titrate carefully in these patients based on clinical response and based on monitoring of serum digoxin concentrations, as appropriate. Race: The impact of race differences on digoxin pharmacokinetics has not been formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected.
| a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion. | ||
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.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).
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics The times to onset of pharmacologic effect and to peak effect of preparations of LANOXIN are shown in Table 7 . Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of LANOXIN a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion. Product Time to Onset of Effect a Time to Peak Effect a LANOXIN Tablets 0.5-2 hours 2-6 hours LANOXIN Injection/IV 5-30 minutes b 1-4 hours Hemodynamic Effects: Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance in patients with heart failure. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions. ECG Changes: The use of therapeutic doses of LANOXIN may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. LANOXIN may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects are not indicative of toxicity. LANOXIN does not significantly reduce heart rate during exercise.
| a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion. | ||
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Note: The following data are from studies performed in adults, unless otherwise stated. Comparisons of the systemic availability and equivalent doses for oral preparations of LANOXIN are shown in Table 6 [see Dosage and Administration ( 2.6 )] . Distribution: Following drug administration, a 6-8 hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak height and slope of the early portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects [see Dosage and Administration ( 2.1 )] . Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution (approximately 475-500 L). Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight. Metabolism: Only a small percentage (13%) of a dose of digoxin is metabolized in healthy volunteers. The urinary metabolites, which include dihydrodigoxin, digoxigenin bisdigitoxoside, and their glucuronide and sulfate conjugates are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system. Excretion: Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50-70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to creatinine clearance and is largely independent of urine flow. In healthy volunteers with normal renal function, digoxin has a half-life of 1.5-2 days. The half-life in anuric patients is prolonged to 3.5-5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues. Special Populations: Geriatrics: Because of age-related declines in renal function, elderly patients would be expected to eliminate digoxin more slowly than younger subjects. Elderly patients may also exhibit a lower volume of distribution of digoxin due to age-related loss of lean muscle mass. Thus, the dosage of digoxin should be carefully selected and monitored in elderly patients [see Use in Specific Populations ( 8.5 )] . Gender: In a study of 184 patients, the clearance of digoxin was 12% lower in female than in male patients. This difference is not likely to be clinically important. Hepatic Impairment: Because only a small percentage (approximately 13%) of a dose of digoxin undergoes metabolism, hepatic impairment would not be expected to significantly alter the pharmacokinetics of digoxin. In a small study, plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects. No dosage adjustments are recommended for patients with hepatic impairment; however, serum digoxin concentrations should be used, as appropriate, to help guide dosing in these patients. Renal Impairment: Since the clearance of digoxin correlates with creatinine clearance, patients with renal impairment generally demonstrate prolonged digoxin elimination half-lives and greater exposures to digoxin. Therefore, titrate carefully in these patients based on clinical response and based on monitoring of serum digoxin concentrations, as appropriate. Race: The impact of race differences on digoxin pharmacokinetics has not been formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS LANOXIN is contraindicated in patients with: • Ventricular fibrillation [see Warnings and Precautions ( 5.1 )] • Known hypersensitivity to digoxin (reactions seen include unexplained rash, swelling of the mouth, lips or throat or a difficulty in breathing). A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin. • Ventricular fibrillation. ( 4 ) • Known hypersensitivity to digoxin or other forms of digitalis. ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION LANOXIN (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. LANOXIN Injection and Injection Pediatric are sterile solutions of digoxin for intravenous or intramuscular injection. The vehicle contains 42.5% (W/V) propylene glycol and 10% alcohol (V/V). The injection is buffered to a pH of 6.8-7.2 with 0.17% dibasic sodium phosphate and 0.08% anhydrous citric acid. Each 2-mL ampule or vial of LANOXIN Injection contains 500 mcg (0.5 mg) digoxin (250 mcg [0.25 mg] per mL). Dilution is not required. Each 1-mL ampule or vial of LANOXIN Injection Pediatric contains 100 mcg (0.1 mg) digoxin. Dilution is not required. Digoxin Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION LANOXIN 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. ( 2 ) 2.1 Important Dosing and Administration Information In selecting a LANOXIN 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. Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orally. 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 LANOXIN Injection should be injected into a single site. For pediatric patients, no more than 200 mcg of LANOXIN Injection Pediatric should be injected into a single site. Administer the dose over a period of 5 minutes or longer and avoid bolus administration to prevent systemic and coronary vasoconstriction. Mixing of LANOXIN Injection and Injection Pediatric with other drugs in the same container or simultaneous administration in the same intravenous line is not recommended. LANOXIN Injection and Injection Pediatric 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. Consider interruption or reduction in LANOXIN dose prior to electrical cardioversion [see Warnings and Precautions ( 5.4 )]. 2.2 Loading Dosing Regimen in Adults and Pediatric Patients Table 1. Recommended LANOXIN Injection Loading Dose mcg = microgram Age Total IV Loading Dose (mcg/kg) Administer half the total loading dose initially, then ¼ the loading dose every 6-8 hours twice Premature 15-25 Full-Term 20-30 1-24 Months 30-50 2-5 Years 25-35 5-10 Years 15-30 Adults and pediatric patients over 10 years 8-12 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 doses in adults and pediatric patients over 10 years old with normal renal function are given in Table 2 . Doses may be increased every 2 weeks according to clinical response, serum drug levels, and toxicity. Table 2. Recommended Starting LANOXIN Injection Maintenance Dosage in Adults and Pediatric Patients Over 10 Years Old mcg = microgram Age Total Intravenous Maintenance Dose, mcg/kg/day (given once daily) Adults and pediatric patients over 10 years 2.4-3.6 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) x % Daily Loss/100 (% Daily Loss = 14 + Creatinine clearance/5) Reduce the dose of LANOXIN 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 LANOXIN Injection in Pediatric Patients Over 10 Years Old and Adults by Lean Body Weight and by Renal Function a For adults , creatinine clearance was corrected to 70-kg body weight or 1.73 m 2 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 m 2 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 m 2 ) = (k x Height)/Scr b If no loading dose administered c The doses listed assume average body composition. Corrected Creatinine Clearance a Lean Body Weight c Number of Days Before Steady State Achieved b kg 40 50 60 70 80 90 100 10 mL/min 64 80 96 112 128 144 160 19 20 mL/min 72 90 108 126 144 162 180 16 30 mL/min 80 100 120 140 160 180 200 14 40 mL/min 88 110 132 154 176 198 220 13 50 mL/min 96 120 144 168 192 216 240 12 60 mL/min 104 130 156 182 208 234 260 11 70 mL/min 112 140 168 196 224 252 280 10 80 mL/min 120 150 180 210 240 270 300 9 90 mL/min 128 160 192 224 256 288 320 8 100 mL/min 136 170 204 238 272 306 340 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 doses for pediatric patients are given in Table 4 . These recommendations assume the presence of normal renal function. Table 4. Recommended Starting LANOXIN Injection Maintenance Dosage in Pediatric Patients Less Than 10 Years Old mcg = microgram Age Dose Regimen, mcg/kg/dose (given TWICE daily) Premature 1.9-3.1 Full-Term 3.0-4.5 1-24 Months 4.5-7.5 2-5 Years 3.8-5.3 5-10 Years 2.3-4.5 Table 5 provides average daily maintenance dose requirements for pediatric patients less than 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 LANOXIN Injection in Pediatric Patients Less Than 10 Years of Age a Based upon Lean Body Weight and Renal Function a a Recommended are doses to be given twice daily. b The modified Schwartz equation may be used to estimate creatinine clearance. See footnote a under Table 3 . c If no loading dose administered. Corrected Creatinine Clearance b Lean Body Weight Number of Days Before Steady State Achieved c kg 5 10 20 30 40 50 60 10 mL/min 8 16 32 48 64 80 96 19 20 mL/min 9 18 36 54 72 90 108 16 30 mL/min 10 20 40 60 80 100 120 14 40 mL/min 11 22 44 66 88 110 132 13 50 mL/min 12 24 48 72 96 120 144 12 60 mL/min 13 26 52 78 104 130 156 11 70 mL/min 14 28 56 84 112 140 168 10 80 mL/min 15 30 60 90 120 150 180 9 90 mL/min 16 32 64 96 128 160 192 8 100 mL/min 17 34 68 102 136 170 204 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 LANOXIN 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 LANOXIN and correct post-treatment values by the reported baseline level. Obtain serum digoxin concentrations just before the next scheduled LANOXIN 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. 2.6 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 LANOXIN Absolute Bioavailability Equivalent Doses (mcg) LANOXIN Tablets 60-80% 62.5 125 250 500 LANOXIN Intravenous Injection 100% 50 100 200 400
| mcg = microgram | |
| mcg = microgram | |
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| mcg = microgram | |
| a Recommended are doses to be given twice daily. b The modified Schwartz equation may be used to estimate creatinine clearance. See footnote a under | |||||||||||
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS LANOXIN Injection: Ampules of 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per 1 mL). LANOXIN Injection: Vials of 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per 1 mL). LANOXIN Injection Pediatric: Ampules of 100 mcg (0.1 mg) in 1 mL. LANOXIN Injection Pediatric: Vials of 100 mcg (0.1 mg) in 1 mL. LANOXIN ® Injection: Ampules containing 500 mcg (0.5 mg) in 2 mL. ( 3 ) LANOXIN ® Injection: Vials containing 500 mcg (0.5 mg) in 2 mL. ( 3 ) LANOXIN ® Injection Pediatric: Ampules of 100 mcg (0.1 mg) in 1 mL. ( 3 ) LANOXIN ® Injection Pediatric: Vials of 100 mcg (0.1 mg) in 1 mL. ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE LANOXIN is 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 adults with chronic atrial fibrillation. ( 1.3 ) 1.1 Heart Failure in Adults LANOXIN is indicated for the treatment of mild to moderate heart failure in adults. LANOXIN increases left ventricular ejection fraction and 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, LANOXIN should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor. 1.2 Heart Failure in Pediatric Patients LANOXIN increases myocardial contractility in pediatric patients with heart failure. 1.3 Atrial Fibrillation in Adults LANOXIN is indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation.
Spl product data elements
Usually a list of ingredients in a drug product.LANOXIN digoxin DIGOXIN DIGOXIN PROPYLENE GLYCOL ALCOHOL SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM ANHYDROUS CITRIC ACID LANOXIN digoxin DIGOXIN DIGOXIN PROPYLENE GLYCOL ALCOHOL SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM ANHYDROUS CITRIC ACID LANOXIN digoxin DIGOXIN DIGOXIN PROPYLENE GLYCOL ALCOHOL SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM ANHYDROUS CITRIC ACID LANOXIN digoxin DIGOXIN DIGOXIN PROPYLENE GLYCOL ALCOHOL SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM ANHYDROUS CITRIC ACID
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin, nor have studies been conducted to assess its potential to affect fertility.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin, nor have studies been conducted to assess its potential to affect fertility.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - Adult Carton Label - Ampule Adult Carton Label - Ampule C O V I S 10 ampuls 2 mL each NDC 70515-260-10 LANOXIN ® (digoxin) Injection 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL) A sterile solution for intravenous or intramuscular injection. Dilution not required. In a vehicle of 42.5% (W/V) propylene glycol and 10% alcohol (V/V). Dibasic sodium phosphate 0.17%, citric acid anhydrous 0.08%. See prescribing information for dosage information. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] and protect from light. Rx only Manufactured for Covis Pharma Zug, 6300 Switzerland Made in Germany ©2017, Covis Pharma Principal Display Panel - Adult Carton Label - Ampule
PRINCIPAL DISPLAY PANEL - Adult Carton Label - Vial Adult Carton Label - Vial C O V I S NDC 70515-261-10 10 vials 2 mL each LANOXIN ® (digoxin) Injection 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL). Rx only NDC 70515-261-10 LANOXIN ® (digoxin) Injection 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL) A sterile solution for intravenous or intramuscular injection. Dilution not required. In a vehicle of 42.5% (W/V) propylene glycol and 10% alcohol (V/V). Dibasic sodium phosphate 0.17%, citric acid anhydrous 0.08%. See prescribing information for dosage information. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] and protect from light. GTIN S/N EXP MMM YYYY LOT Manufactured for Covis Pharma Zug, 6300 Switzerland Made in Germany ©2019, Covis Pharma Principal Display Panel - Adult Carton Label - Vial
PRINCIPAL DISPLAY PANEL - Pediatric Carton Label - Ampule Pediatric Carton Label - Ampule NDC 70515-262-10 10 ampuls 1 mL each LANOXIN ® (digoxin) Injection Pediatric 100 mcg (0.1 mg) in 1 mL A sterile solution for intravenous or intramuscular injection. Dilution not required. In a vehicle of 42.5% (W/V) propylene glycol and 10% alcohol (V/V). Sodium phosphate 0.17%. Citric acid anhydrous 0.08%. See prescribing information for dosage information. Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature] and protect from light. Rx only C O V I S Principal Display Panel - Pediatric Carton Label - Ampule
PRINCIPAL DISPLAY PANEL - Pediatric Carton Label - Vial Pediatric Carton label - Vial NDC 70515-263-10 10 vials 1 mL each Rx only LANOXIN ® (digoxin) Injection Pediatric 100 mcg (0.1 mg) in 1 mL C O V I S NDC 70515-263-10 10 vials 1 mL each LANOXIN ® (digoxin) Injection Pediatric 100 mcg (0.1 mg) in 1 mL A sterile solution for intravenous or intramuscular injection. Dilution not required. In a vehicle of 42.5% (W/V) propylene glycol and 10% alcohol (V/V). Sodium phosphate 0.17%. Citric acid anhydrous 0.08%. See prescribing information for dosage information. Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature] and protect from light. GTIN S/N EXP MMM YYYY LOT Manufactured for Covis Pharma Zug, 6300 Switzerland Made in Germany ©2019, Covis Pharma Principal Display Panel - Pediatric Carton Label - Vial
LANOXIN: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION • 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 LANOXIN may be too high. • Advise parents or caregivers that the symptoms of having too high LANOXIN 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. LANOXIN is registered trademark of GlaxoSmithKline. Manufactured for Covis Pharma Zug, 6300 Switzerland 2020, Covis Pharma. All rights reserved. Covis Logo
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 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 LANOXIN Tablets. Both trials demonstrated better preservation of exercise capacity in patients randomized to LANOXIN. Continued treatment with LANOXIN 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 LANOXIN 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.
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.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 )] .
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use The safety and effectiveness of LANOXIN in the control of ventricular rate in children with atrial fibrillation have not been established. The safety and effectiveness of LANOXIN 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
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary Experience with digoxin in pregnant women over several decades, based on published retrospective clinical studies and case reports, has not led to the identification of a drug associated risk of major birth defects, miscarriage or adverse maternal and fetal outcomes. Untreated underlying maternal conditions, such as heart failure and atrial fibrillation, during pregnancy pose a risk to the mother and fetus (see Clinical Consideration) . Animal reproduction studies have not been conducted with digoxin. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnant women with heart failure are at increased risk for preterm birth. Clinical classification of heart disease may worsen with pregnancy and lead to maternal or fetal death. Pregnant women with atrial fibrillation are at an increased risk of delivering a low birth weight infant. Atrial fibrillation may worsen with pregnancy and can lead to maternal or fetal death. Fetal/neonatal adverse reactions Digoxin has been shown to cross the placenta and is found in amniotic fluid. Monitor neonates for signs and symptoms of digoxin toxicity, including vomiting, and cardiac arrhythmias [see Warnings and Precautions (5.3)] . Dose adjustments during pregnancy and the postpartum period LANOXIN requirements may increase during pregnancy and decrease in the postpartum period. Monitor serum digoxin levels during pregnancy and the postpartum period [see Dosage and Administration (2.5)] . Labor or Delivery Risk of arrhythmias may increase during the labor and delivery. Monitor patients continuously during labor and delivery [see Warnings and Precautions (5.1 and 5.2)] .
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS • Pediatric patients: Newborn infants display variability in tolerance to LANOXIN. ( 8.4 ) • Geriatric patients: Consider renal function in dosage selection, and carefully monitor for side effects. ( 8.5 ) • Renal impairment: LANOXIN is excreted by the kidneys. Consider renal function during dosage selection. ( 8.6 ) 8.1 Pregnancy Risk Summary Experience with digoxin in pregnant women over several decades, based on published retrospective clinical studies and case reports, has not led to the identification of a drug associated risk of major birth defects, miscarriage or adverse maternal and fetal outcomes. Untreated underlying maternal conditions, such as heart failure and atrial fibrillation, during pregnancy pose a risk to the mother and fetus (see Clinical Consideration) . Animal reproduction studies have not been conducted with digoxin. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnant women with heart failure are at increased risk for preterm birth. Clinical classification of heart disease may worsen with pregnancy and lead to maternal or fetal death. Pregnant women with atrial fibrillation are at an increased risk of delivering a low birth weight infant. Atrial fibrillation may worsen with pregnancy and can lead to maternal or fetal death. Fetal/neonatal adverse reactions Digoxin has been shown to cross the placenta and is found in amniotic fluid. Monitor neonates for signs and symptoms of digoxin toxicity, including vomiting, and cardiac arrhythmias [see Warnings and Precautions (5.3)] . Dose adjustments during pregnancy and the postpartum period LANOXIN requirements may increase during pregnancy and decrease in the postpartum period. Monitor serum digoxin levels during pregnancy and the postpartum period [see Dosage and Administration (2.5)] . Labor or Delivery Risk of arrhythmias may increase during the labor and delivery. Monitor patients continuously during labor and delivery [see Warnings and Precautions (5.1 and 5.2)] . 8.2 Lactation Risk Summary The digoxin dose received through breastfeeding is up to 4% of the neonatal maintenance dosage, which is unlikely to be clinically relevant. There are no data on the effects of digoxin on the breastfed infant or the effects on milk production. Data Based on data from two lactation studies in a total of 13 breastfed infants, the digoxin concentrations in breast milk were between 0.4 – 1.0 ng/mL following 0.25 mg once daily dose of digoxin in the lactating mother. Thus, the amount of digoxin ingested daily by the infants is estimated to be between 0.03 to 0.16 µg/kg/day. This translates to a relative infant dose of digoxin between 1 to 7% of the maternal weight-adjusted dose and about 0.2 to 4% of the neonatal maintenance dose. 8.4 Pediatric Use The safety and effectiveness of LANOXIN in the control of ventricular rate in children with atrial fibrillation have not been established. The safety and effectiveness of LANOXIN 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. 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 )] . 8.6 Renal Impairment The clearance of digoxin can be primarily correlated with the renal function as indicated by creatinine clearance. Table 3 and Table 5 provide the usual daily maintenance dose requirements for digoxin based on creatinine clearance [see Dosage and Administration ( 2.3 )] . Digoxin is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of digoxin [see Dosage and Administration ( 2.3 )] . Because of the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function. 8.7 Hepatic Impairment Plasma digoxin concentrations in patients with acute hepatitis generally fall within the range of profiles in a group of healthy subjects. 8.8 Malabsorption The absorption of digoxin is reduced in some malabsorption conditions such as chronic diarrhea.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING LANOXIN (digoxin) Injection, 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL); box of 10 ampules (NDC 70515 260 10) LANOXIN (digoxin) Injection, 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per mL); box of 10 vials (NDC 70515 261 10) LANOXIN (digoxin) Injection Pediatric, 100 mcg (0.1 mg) in 1 mL; box of 10 ampules (NDC 70515 262 10) LANOXIN (digoxin) Injection Pediatric, 100 mcg (0.1 mg) in 1 mL; box of 10 vials (NDC 70515 263 10) Store at 25 °C (77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature] and protect from light.
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API