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)

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.

LANOXIN increases myocardial contractility in pediatric patients with heart failure.

LANOXIN is indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation.

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)

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 orinitiated 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)].

Discard unused portion of LANOXIN Injection and LANOXIN Injection Pediatric.

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

The maintenance dose is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology ( 12.3)] .

The recommended startingmaintenance 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 3provides 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 2body 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 pediatricpatients, 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 2body 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

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 startingmaintenance 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	3-4.5
1-24 Months	4.5-7.5
2-5 Years	3.8-5.3
5-10 Years	2.3-4.5

Table 5provides 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 ^aBased 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

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.

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

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)

• 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 LANOXIN in patients with myocarditis. ( 5.6)

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.

LANOXIN may cause severe sinus bradycardia or sinoatrial block particularly in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. Consider insertion of a pacemaker before treatment with digoxin.

Signs and symptoms of digoxin toxicity include anorexia, nausea, vomiting, visual changes and cardiac arrhythmias [first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation]. Toxicity is usually associated with digoxin levels greater than 2 ng/mL although symptoms may also occur at lower levels. Low body weight, advanced age or impaired renal function, hypokalemia, hypercalcemia, or hypomagnesemia may predispose to digoxin toxicity. Obtain serum digoxin levels in patients with signs or symptoms of digoxin therapy and interrupt or adjust dose if necessary [see Adverse Reactions ( 6) and Overdosage ( 10)]. Assess serum electrolytes and renal function periodically.

The earliest and most frequent manifestation of digoxin toxicity in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmias or alteration in cardiac conduction that develops in a child taking digoxin should initially be assumed to be a consequence of digoxin intoxication.

Given that adult patients with heart failure have some symptoms in common with digoxin toxicity, it may be difficult to distinguish digoxin toxicity from heart failure. Misidentification of their etiology might lead the clinician to continue or increase LANOXIN dosing, when dosing should actually be suspended. When the etiology of these signs and symptoms is not clear, measure serum digoxin levels.

It may be desirable to reduce the dose of or discontinue LANOXIN for 1-2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequences of increasing the ventricular response if digoxin is decreased or withdrawn. If digitalis toxicity is suspected, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular arrhythmias.

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

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

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

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

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.

Hypothyroidism may reduce the requirements for digoxin.

Heart failure and/or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states are particularly resistant to digoxin treatment. Patients with beri beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly.

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 1-877-411-2510 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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.