Digoxin is indicated for the treatment of mild to moderate heart failure in adults. Digoxin 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, digoxin should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor.

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

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 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 Digoxin Injection should be injected into a single site.  For pediatric patients, see the full prescribing information for pediatric digoxin injection (not available from Hikma Pharmaceutical) 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.

Consider interruption or reduction in digoxin dose prior to electrical cardioversion [see Warnings and Precautions (5.4)].

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1. Recommended Digoxin Injection Loading Dose</span> </caption> <col width="49%"/> <col width="51%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top"> mcg = microgram</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Age</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Total IV Loading Dose (mcg/kg) </span> <br/> <span class="Bold">     </span>Administer half the total loading dose initially,     <br/>then ¼ the loading dose every 6-8 hours twice</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Adults and pediatric patients over 10 years old</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 8-12</p> </td> </tr> </tbody> </table></div>

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

The recommended starting maintenance dose in adults and pediatric patients over 10 years old with normal renal function is given in Table 2. Doses may be increased every 2 weeks according to clinical response, serum drug levels, and toxicity.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2. Recommended Starting Digoxin Injection Maintenance Dosage in Adults and Pediatric Patients Over 10 Years Old</span> </caption> <col width="50%"/> <col width="50%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top"> mcg = microgram</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Age</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">     Total Intravenous Maintenance Dose,     </span> <br/> <span class="Bold">mcg/kg/day</span> <br/> <span class="Bold">(given once daily)</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Adults and pediatric patients over 10 years old</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 2.4-3.6</p> </td> </tr> </tbody> </table></div>

Table 3 provides the recommended (once daily) maintenance dose for adults and pediatric patients over 10 years old 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.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3. Recommended Maintenance Dose (in micrograms given once daily) of Digoxin Injection in Pediatric Patients Over 10 Years Old and Adults by Lean Body Weight and by Renal Function</span> </caption> <col width="16%"/> <col width="8%"/> <col width="8%"/> <col width="8%"/> <col width="8%"/> <col width="8%"/> <col width="8%"/> <col width="8%"/> <col width="9%"/> <col width="19%"/> <tfoot> <tr class="First"> <td align="left" colspan="10" valign="top"> <span class="Sup">a</span>  <span class="Italics">For adults</span>, creatinine clearance was corrected to 70-kg body weight or 1.73 m<span class="Sup">2 </span>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. </td> </tr> <tr> <td align="left" colspan="10" valign="top"><span class="Italics">For pediatric </span>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<span class="Sup">2</span> 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.</td> </tr> <tr> <td align="left" colspan="10" valign="top">GFR (mL/min/1.73 m<span class="Sup">2</span>) = (k x Height)/Scr</td> </tr> <tr> <td align="left" colspan="10" valign="top"><span class="Sup">b</span>  If no loading dose administered</td> </tr> <tr class="Last"> <td align="left" colspan="10" valign="top"><span class="Sup">c</span>  The doses listed assume average body composition.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="bottom"> <p class="First"> <span class="Bold">     Corrected     </span> <br/> <span class="Bold">Creatinine Clearance<span class="Sup">a</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="8" valign="top"> <p class="First"> <span class="Bold">Lean Body Weight<span class="Sup">c</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="bottom"> <p class="First"> <span class="Bold">     Number of Days </span> <br/> <span class="Bold">Before Steady</span> <br/> <span class="Bold">State Achieved<span class="Sup">b</span></span> </p> </td> </tr> <tr> <td align="center" class="Lrule" valign="top"> <p class="First"> <span class="Bold">  kg  </span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">   40   </span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">   50   </span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">   60   </span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">   70   </span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">   80   </span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">   90   </span> </p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> <span class="Bold">   100   </span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="bottom"> <p class="First"> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First">     </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> </p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First"> </p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 10 mL/min</p> </td><td align="center" class="Lrule" valign="top"> <p class="First"> </p> </td><td align="center" valign="top"> <p class="First"> 64</p> </td><td align="center" valign="top"> <p class="First"> 80</p> </td><td align="center" valign="top"> <p class="First"> 96</p> </td><td align="center" valign="top"> <p class="First"> 112</p> </td><td align="center" valign="top"> <p class="First"> 128</p> </td><td align="center" valign="top"> <p class="First"> 144</p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> 160</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 19</p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 20 mL/min</p> </td><td align="center" class="Lrule" valign="top"> <p class="First"> </p> </td><td align="center" valign="top"> <p class="First"> 72</p> </td><td align="center" valign="top"> <p class="First"> 90</p> </td><td align="center" valign="top"> <p class="First"> 108</p> </td><td align="center" valign="top"> <p class="First"> 126</p> </td><td align="center" valign="top"> <p class="First"> 144</p> </td><td align="center" valign="top"> <p class="First"> 162</p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> 180</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 16</p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 30 mL/min</p> </td><td align="center" class="Lrule" valign="top"> <p class="First"> </p> </td><td align="center" valign="top"> <p class="First"> 80</p> </td><td align="center" valign="top"> <p class="First"> 100</p> </td><td align="center" valign="top"> <p class="First"> 120</p> </td><td align="center" valign="top"> <p class="First"> 140</p> </td><td align="center" valign="top"> <p class="First"> 160</p> </td><td align="center" valign="top"> <p class="First"> 180</p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> 200</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 40 mL/min</p> </td><td align="center" class="Lrule" valign="top"> <p class="First"> </p> </td><td align="center" valign="top"> <p class="First"> 88</p> </td><td align="center" valign="top"> <p class="First"> 110</p> </td><td align="center" valign="top"> <p class="First"> 132</p> </td><td align="center" valign="top"> <p class="First"> 154</p> </td><td align="center" valign="top"> <p class="First"> 176</p> </td><td align="center" valign="top"> <p class="First"> 198</p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> 220</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 13</p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 50 mL/min</p> </td><td align="center" class="Lrule" valign="top"> <p class="First"> </p> </td><td align="center" valign="top"> <p class="First"> 96</p> </td><td align="center" valign="top"> <p class="First"> 120</p> </td><td align="center" valign="top"> <p class="First"> 144</p> </td><td align="center" valign="top"> <p class="First"> 168</p> </td><td align="center" valign="top"> <p class="First"> 192</p> </td><td align="center" valign="top"> <p class="First"> 216</p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> 240</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 12</p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 60 mL/min</p> </td><td align="center" class="Lrule" valign="top"> <p class="First"> </p> </td><td align="center" valign="top"> <p class="First"> 104</p> </td><td align="center" valign="top"> <p class="First"> 130</p> </td><td align="center" valign="top"> <p class="First"> 156</p> </td><td align="center" valign="top"> <p class="First"> 182</p> </td><td align="center" valign="top"> <p class="First"> 208</p> </td><td align="center" valign="top"> <p class="First"> 234</p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> 260</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 11</p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 70 mL/min</p> </td><td align="center" class="Lrule" valign="top"> <p class="First"> </p> </td><td align="center" valign="top"> <p class="First"> 112</p> </td><td align="center" valign="top"> <p class="First"> 140</p> </td><td align="center" valign="top"> <p class="First"> 168</p> </td><td align="center" valign="top"> <p class="First"> 196</p> </td><td align="center" valign="top"> <p class="First"> 224</p> </td><td align="center" valign="top"> <p class="First"> 252</p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> 280</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 10</p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 80 mL/min</p> </td><td align="center" class="Lrule" valign="top"> <p class="First"> </p> </td><td align="center" valign="top"> <p class="First"> 120</p> </td><td align="center" valign="top"> <p class="First"> 150</p> </td><td align="center" valign="top"> <p class="First"> 180</p> </td><td align="center" valign="top"> <p class="First"> 210</p> </td><td align="center" valign="top"> <p class="First"> 240</p> </td><td align="center" valign="top"> <p class="First"> 270</p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> 300</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 9</p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 90 mL/min</p> </td><td align="center" class="Lrule" valign="top"> <p class="First"> </p> </td><td align="center" valign="top"> <p class="First"> 128</p> </td><td align="center" valign="top"> <p class="First"> 160</p> </td><td align="center" valign="top"> <p class="First"> 192</p> </td><td align="center" valign="top"> <p class="First"> 224</p> </td><td align="center" valign="top"> <p class="First"> 256</p> </td><td align="center" valign="top"> <p class="First"> 288</p> </td><td align="center" class="Rrule" valign="top"> <p class="First"> 320</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 8</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 100 mL/min</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First"> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> 136</p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> 170</p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> 204</p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> 238</p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> 272</p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> 306</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 340</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 7</p> </td> </tr> </tbody> </table></div>

Monitor for signs and symptoms of digoxin toxicity and clinical response.  Adjust dose based on toxicity, efficacy, and blood levels.

Serum digoxin levels less than 0.5 ng/mL have been associated with diminished efficacy, while levels above 2 ng/mL have been associated with increased toxicity without increased benefit.

Interpret the serum digoxin concentration in the overall clinical context, and do not use an isolated measurement of serum digoxin concentration as the basis for increasing or decreasing the digoxin 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.

When switching from intravenous to oral digoxin formulations, make allowances for differences in bioavailability when calculating maintenance dosages (see Table 4).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4. Comparison of the Systemic Availability and Equivalent Doses of Oral and Intravenous Digoxin</span> </caption> <col width="29%"/> <col width="28%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Absolute      Bioavailability     </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Equivalent Doses (mcg)</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> Digoxin Tablets</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 60-80%</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First">    62.5   </p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First">    125   </p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First">    250   </p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First">    500   </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Digoxin Intravenous Injection     </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 100%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 50</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 100</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 200</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 400</p> </td> </tr> </tbody> </table></div>

Digoxin Injection: Ampuls of 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25 mg] per 1 mL).

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Digoxin is contraindicated in patients with:

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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.

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 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 digoxin 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 digoxin 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.

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

Digoxin 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 digoxin.  Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin. Patients with amyloid heart disease may be more susceptible to digoxin toxicity at therapeutic levels because of an increased binding of digoxin to extracellular amyloid fibrils.

Digoxin 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.

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

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. 

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).

<div class="scrollingtable"><table width="100%"> <col width="19%"/> <col width="20%"/> <col width="20%"/> <col width="41%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First"> Digoxin concentrations increased greater than 50% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">      Digoxin Serum     <br/> Concentration<br/> Increase</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">      Digoxin AUC     <br/> Increase</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Recommendations</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Quinidine</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> NA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">  54-83%</p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">Measure serum digoxin concentrations before     <br/> initiating concomitant drugs. Reduce digoxin<br/> concentrations by decreasing dose by<br/> approximately 30-50% or by modifying the<br/> dosing frequency and continue monitoring.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Ritonavir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> NA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 86%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First"> Digoxin concentrations increased less than 50%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Amiodarone</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 17%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 40%</p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="6" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Propafenone</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 28%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 29%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Quinine </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> NA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 34-38%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Spironolactone     </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> NA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 44%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Verapamil</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> NA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 24%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Mirabegron</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 29%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27% </p> </td> </tr> </tbody> </table></div>

Because of considerable variability of pharmacodynamic interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently.

<div class="scrollingtable"><table width="100%"> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Drugs that Affect Renal          <br/>Function</p> </td><td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">A decline in GFR or tubular secretion, as from ACE inhibitors,          <br/>angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs<br/>[NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Antiarrthymics</p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Dofetilide</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Sotalol</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> 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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Dronedarone</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Parathyroid Hormone<br/>Analog</p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Teriparatide</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Thyroid supplement</p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Thyroid</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Sympathomimetics</p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Epinephrine Norepinephrine Dopamine</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Can increase the risk of cardiac arrhythmias.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Neuromuscular Blocking<br/>Agents</p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Succinylcholine</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Supplements</p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Calcium</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Beta-adrenergic blockers<br/>and calcium channel<br/>blockers</p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First"> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Ivabradine </p> </td><td class="Botrule Lrule Toprule" colspan="2" valign="top"> <p class="First">Can increase the risk of bradycardia. </p> </td> </tr> </tbody> </table></div>

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.

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. Confidential 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 Digoxin 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)].

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 mcg/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.

The safety and effectiveness of digoxin in the control of ventricular rate in children with atrial fibrillation have not been established.

The safety and effectiveness of digoxin 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.

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)].

The clearance of digoxin can be primarily correlated with the renal function as indicated by creatinine clearance. Table 3 provides 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.

Plasma digoxin concentrations in patients with acute hepatitis generally fall within the range of profiles in a group of healthy subjects.

The absorption of digoxin is reduced in some malabsorption conditions such as chronic diarrhea.

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.

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.

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”).

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Digoxin has the chemical name: 3β-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopy‑ranosyl-(1→4)-2,6-dideoxy-β-D-ribo-hexopyranosyl)oxy]-12β,14-dihydroxy-5β-card-20(22)-enolide, and the following structural formula:

{ "type": "p", "children": [], "text": "Digoxin has the chemical name: 3β-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopy‑ranosyl-(1→4)-2,6-dideoxy-β-D-ribo-hexopyranosyl)oxy]-12β,14-dihydroxy-5β-card-20(22)-enolide, and the following structural formula:" }

C41H64O14                                                    MW 780.94

{ "type": "p", "children": [], "text": "C41H64O14                                                    MW 780.94" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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." }

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

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).

The times to onset of pharmacologic effect and to peak effect of preparations of digoxin are shown in Table 5.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of Digoxin</span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top"><span class="Sup">a</span>  Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes.<br/> <span class="Sup">b</span>  Depending upon rate of infusion.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Product</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">     Time to Onset of Effect<span class="Sup">a</span>     </span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">     Time to Peak Effect<span class="Sup">a</span>     </span> </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> Digoxin Tablets</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 0.5-2 hours</p> </td><td align="center" class="Lrule Rrule" valign="top"> <p class="First"> 2-6 hours</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Digoxin Injection/IV     </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 5-30 minutes<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 1-4 hours</p> </td> </tr> </tbody> </table></div>

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 digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing.  These electrophysiologic effects are not indicative of toxicity.  Digoxin does not significantly reduce heart rate during exercise.

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 digoxin are shown in Table 4 [see Dosage and Administration (2.5)].

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.

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.

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%).

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.

Digoxin Injection, USP is available as:

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500 mcg/2 mL (250 mcg/mL) ampuls packaged:

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Overbagged with 5 x 2 mL ampuls in each bag, NDC 55154-5106-5

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WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children.

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Store at 20˚ to 25˚C (68˚ to 77˚F), excursions permitted to 15˚ to 30˚C (59˚ to 86˚F) [see USP Controlled Room Temperature]. Protect from light.

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Manufactured by:

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HIKMA FARMACÊUTICA (PORTUGAL), S.A.

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Estrada do Rio da Mό, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGAL

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Distributed by:

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Hikma Pharmaceuticals USA Inc.

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Berkeley Heights, NJ 07922

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Distributed By:

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Cardinal Health

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Dublin, OH 43017

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L26960450424

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Revised January 2025

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462-636-06

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PIN299-WES/7

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NDC 55154-5106-5

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DIGOXIN INJECTION, USP

{ "type": "p", "children": [], "text": "\nDIGOXIN INJECTION, USP\n" }

500 mcg per 2 mL

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0.5 mg/2 mL (250 mcg/mL)

{ "type": "p", "children": [], "text": "\n0.5 mg/2 mL (250 mcg/mL)\n" }

5 x 2 mL AMPULS

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Digoxin Oral Solution, USP is indicated for the treatment of mild to moderate heart failure. Digoxin increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by increased exercise capacity and decreased heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, digoxin should be used with a diuretic and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these three drugs cannot be specified.

Digoxin increases myocardial contractility in pediatric patients with heart failure.

Digoxin Oral Solution, USP is indicated for the control of resting ventricular response rate in patients with chronic atrial fibrillation. Digoxin should not be used for the treatment of multifocal atrial tachycardia.

The dose of digoxin should be based on clinical assessment but individual patient factors should be taken into consideration. Those factors are:

Because the pharmacokinetics of digoxin are complex, and because toxic levels of digoxin are only slightly higher than therapeutic levels, digoxin dosing can be difficult. The recommended approach is to

Dose titration may be accomplished by either of two general approaches that differ in dosage and frequency of administration, but reach the same total amount of digoxin accumulated in the body.

In general, the dose of digoxin used should be determined on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in assigning certain probabilities to the likelihood of digoxin intoxication.

Studies have shown diminished efficacy at serum levels < 0.5 ng/mL, while levels above 2 ng/mL are associated with increased toxicity without increased benefit. The inotropic effects of digoxin tend to appear at lower concentrations than the electrophysiological effects. Based on retrospective analysis, adverse events may be higher in the upper therapeutic range.

Perform sampling of serum concentrations just before the next scheduled dose of the drug. If this is not possible, sample at least 6 hours or later after the last dose, regardless of the route of administration or the formulation used. On a once-daily dosing schedule, the concentration of digoxin will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient’s renal function. On a twice-daily dosing schedule, there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose. The serum concentration of digoxin should always be interpreted in the overall clinical context, and an isolated measurement should not be used alone as the basis for increasing or decreasing the dose of the drug.

When decision-making is to be guided by serum digoxin levels, the clinician must consider the possibility of reported concentrations that have been falsely elevated by endogenous digoxin-like immunoreactive substances If the assay being used is sensitive to these substances, it may be prudent to obtain a baseline measurement before digoxin therapy is started, and correct later values by the reported baseline level. [see ] Drug Interactions (7.4). 

Loading doses for each age group are given in Table 1 below.

In pediatric patients, if a loading dose is needed, it can be administered with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 4- to 8-hour intervals, with careful assessment of clinical response before each additional dose. If the patient’s clinical response necessitates a change from the calculated loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given as the loading dose [see and ]. Table 12

<div class="scrollingtable"><table border="single" width="432"> <caption> <span>Table 1: Estimate the Loading Dose</span> </caption> <col width="29.2%"/> <col width="70.8%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Age</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">Oral Loading Dose, mcg/kg</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">Premature</td><td align="center" class="Botrule Rrule" valign="middle">20 - 30</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">Full-Term</td><td align="center" class="Botrule Rrule" valign="middle">25 - 35</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">1 to 24 months</td><td align="center" class="Botrule Rrule" valign="middle">35 - 60</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">2 to 5 years</td><td align="center" class="Botrule Rrule" valign="middle">30 - 45</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">5 to 10 years</td><td align="center" class="Botrule Rrule" valign="middle">20 - 35</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="middle">Over 10 years</td><td align="center" class="Botrule Rrule" valign="middle">10 - 15</td> </tr> </tbody> </table></div>

 More gradual attainment of digoxin levels can also be accomplished by beginning an appropriate maintenance dose. The range of percentages provided in Table 2 (2.4 Estimate of Daily Maintenance Dose) can be used in calculating this dose for patients with normal renal function. Steady state will be attained after approximately 5 days in subjects with normal renal function.

The recommended daily maintenance doses for each age group are given in Table 2 below. These recommendations assume the presence of normal renal function.

<div class="scrollingtable"><table border="single" width="432"> <caption> <span>Table 2: Estimate of the Daily Maintenance Dose</span> </caption> <col width="18.8%"/> <col width="33.3%"/> <col width="47.9%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Age</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">Daily Oral Maintenance Dose, mcg/kg/day</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Dose Regimen, mcg/kg/dose</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">Premature</td><td align="center" class="Botrule Rrule" valign="middle">4.7 – 7.8</td><td align="center" class="Botrule Rrule" valign="top">2.3 – 3.9 Twice daily</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">Full-Term</td><td align="center" class="Botrule Rrule" valign="middle">7.5 – 11.3</td><td align="center" class="Botrule Rrule" valign="top">3.8 – 5.6 Twice daily</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">1 to 24 months</td><td align="center" class="Botrule Rrule" valign="middle">11.3 – 18.8</td><td align="center" class="Botrule Rrule" valign="top">5.6 – 9.4 Twice daily</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">2 to 5 years</td><td align="center" class="Botrule Rrule" valign="middle">9.4 – 13.1</td><td align="center" class="Botrule Rrule" valign="top">4.7 – 6.6 Twice daily</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">5 to 10 years</td><td align="center" class="Botrule Rrule" valign="middle">5.6 – 11.3</td><td align="center" class="Botrule Rrule" valign="top">2.8 – 5.6 Twice daily</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="middle">Over 10 years</td><td align="center" class="Rrule" valign="middle">3.0 – 4.5</td><td align="center" class="Botrule Rrule" valign="middle">3.0 – 4.5 Once daily</td> </tr> </tbody> </table></div>

Dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, dosage selection must be based upon clinical assessment and ultimately therapeutic drug level monitoring of the patient.

Divided daily dosing is recommended for pediatric patients under age 10. In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be made as shown in Tables 1 and 2. Renal clearance is further reduced in the premature infant. Beyond the immediate newborn period, pediatric patients generally require proportionally larger doses than adults on the basis of body weight or body surface area. Pediatric patients over 10 years of age require adult dosages in proportion to their body weight. Some researchers have suggested that infants and young pediatric patients tolerate slightly higher serum concentrations than do adults. For pediatric patients with known or suspected renal dysfunction, lower starting doses should be considered combined with frequent monitoring of digoxin levels.

The calibrated dropper supplied with the 60 mL bottle of digoxin oral solution is not appropriate to measure doses below 0.2 mL. Doses less than 0.2 mL require appropriate methods or measuring devices designed to administer an accurate amount to the patient, such as a graduated syringe. NOTE:

The body’s handling of digoxin can be affected by many different patient-specific factors. Some of the possible effects are small, so anticipatory dose adjustment might not be required, but others should be considered before initial dosing . [see and Clinical Pharmacology (12.2)] Drug Interactions (7)

Both adults and pediatric patients with abnormal renal function need to have the dose of digoxin proportionally reduced. Recommended maintenance doses based upon lean body weight and renal function are listed in . Developmental changes in pediatric renal function were factored into Table 3. However, age-related and other changes in adult renal function were not. Table 3

The volume of distribution of digoxin is proportional to lean body weight and doses listed in Table 3 assume average body composition. The dose of digoxin must be reduced in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema. 

<div class="scrollingtable"><table border="single" width="549"> <caption> <span>Table 3: Usual Maintenance Dose Requirements (mcg) of Digoxin Based upon Age, Lean Body Weight and Renal Function</span> </caption> <col width="9.8%"/> <col width="3.6%"/> <col width="4.6%"/> <col width="4.6%"/> <col width="4.9%"/> <col width="5.6%"/> <col width="5.6%"/> <col width="5.6%"/> <col width="5.6%"/> <col width="5.6%"/> <col width="5.6%"/> <col width="5.6%"/> <col width="6.6%"/> <col width="5.6%"/> <col width="5.6%"/> <col width="5.6%"/> <col width="9.5%"/> <tfoot> <tr> <td align="left" colspan="17"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m body surface area. , if only serum creatinine concentrations (Scr) are available, a Ccr (corrected to 70 kg body weight) may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. 2Foradults</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>The doses are rounded to whole numbers.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>Twice daily dosing is recommended for pediatric patients under 10 years of age. Once daily dosing is recommended for pediatric patients above 10 years of age and adults.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="5" valign="top"> <p class="First"> <span class="Bold">Corrected Ccr</span> </p> <span class="Bold">(mL/min per 70 kg) <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span></td><td align="left" class="Botrule" valign="top"> </td><td align="center" class="Botrule Rrule" colspan="7" valign="middle">Dose to be given <a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a><span class="Bold">Twice Daily <a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a></span></td><td align="center" class="Rrule" colspan="7" valign="middle">Dose to be given <span class="Bold">Once Daily</span></td><td align="center" class="Botrule Rrule" rowspan="5" valign="top"> <p class="First">Number of Days Before Steady State Achieve</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top"> </td><td align="center" class="Botrule Rrule" colspan="7" valign="middle"><span class="Bold">&lt; 10 years of age</span></td><td align="center" class="Botrule Rrule" colspan="7" valign="middle"><span class="Bold">&gt; 10 years of age and adults</span></td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top"></td><td align="center" class="Botrule Rrule" colspan="7" valign="top">Lean Body Weight</td><td align="center" class="Botrule Rrule" colspan="7" valign="top">Lean Body Weight</td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top"><span class="Bold">kg</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">5</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">10</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">20</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">30</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">40</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">50</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">60</span></td><td align="center" class="Botrule" valign="top"><span class="Bold">40</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">50</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">60</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">70</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">80</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">90</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">100</span></td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top">lb</td><td align="center" class="Botrule" valign="top">11</td><td align="center" class="Botrule" valign="top">22</td><td align="center" class="Botrule" valign="top">44</td><td align="center" class="Botrule" valign="top">66</td><td align="center" class="Botrule" valign="top">88</td><td align="center" class="Botrule" valign="top">110</td><td align="center" class="Botrule Rrule" valign="top">132</td><td align="center" class="Botrule" valign="top">88</td><td align="center" class="Botrule Rrule" valign="top">110</td><td align="center" class="Botrule Rrule" valign="top">132</td><td align="center" class="Botrule Rrule" valign="top">154</td><td align="center" class="Botrule Rrule" valign="top">176</td><td align="center" class="Botrule Rrule" valign="top">198</td><td align="center" class="Botrule Rrule" valign="top">220</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">10</td><td align="center" class="Botrule" valign="middle"></td><td align="center" valign="middle">10</td><td align="center" valign="middle">20</td><td align="center" valign="middle">40</td><td align="center" valign="middle">60</td><td align="center" valign="middle">80</td><td align="center" valign="middle">100</td><td align="center" class="Rrule" valign="middle">120</td><td align="center" valign="middle">80</td><td align="center" class="Botrule Rrule" valign="middle">100</td><td align="center" class="Botrule Rrule" valign="middle">120</td><td align="center" class="Botrule Rrule" valign="middle">140</td><td align="center" class="Botrule Rrule" valign="middle">160</td><td align="center" class="Botrule Rrule" valign="middle">180</td><td align="center" class="Botrule Rrule" valign="middle">200</td><td align="center" class="Botrule Rrule" valign="middle">19</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">20</td><td align="center" class="Botrule" valign="middle"></td><td align="center" valign="middle">11</td><td align="center" valign="middle">23</td><td align="center" valign="middle">45</td><td align="center" valign="middle">68</td><td align="center" valign="middle">90</td><td align="center" valign="middle">113</td><td align="center" class="Rrule" valign="middle">135</td><td align="center" valign="middle">90</td><td align="center" class="Botrule Rrule" valign="middle">113</td><td align="center" class="Botrule Rrule" valign="middle">135</td><td align="center" class="Botrule Rrule" valign="middle">158</td><td align="center" class="Botrule Rrule" valign="middle">180</td><td align="center" class="Botrule Rrule" valign="middle">203</td><td align="center" class="Botrule Rrule" valign="middle">225</td><td align="center" class="Botrule Rrule" valign="middle">16</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">30</td><td align="center" class="Botrule" valign="middle"></td><td align="center" valign="middle">13</td><td align="center" valign="middle">25</td><td align="center" valign="middle">50</td><td align="center" valign="middle">75</td><td align="center" valign="middle">100</td><td align="center" valign="middle">125</td><td align="center" class="Rrule" valign="middle">150</td><td align="center" valign="middle">100</td><td align="center" class="Botrule Rrule" valign="middle">125</td><td align="center" class="Botrule Rrule" valign="middle">150</td><td align="center" class="Botrule Rrule" valign="middle">175</td><td align="center" class="Botrule Rrule" valign="middle">200</td><td align="center" class="Botrule Rrule" valign="middle">225</td><td align="center" class="Botrule Rrule" valign="middle">250</td><td align="center" class="Botrule Rrule" valign="middle">14</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">40</td><td align="center" class="Botrule" valign="middle"></td><td align="center" valign="middle">14</td><td align="center" valign="middle">28</td><td align="center" valign="middle">55</td><td align="center" valign="middle">83</td><td align="center" valign="middle">110</td><td align="center" valign="middle">138</td><td align="center" class="Rrule" valign="middle">165</td><td align="center" valign="middle">110</td><td align="center" class="Botrule Rrule" valign="middle">138</td><td align="center" class="Botrule Rrule" valign="middle">165</td><td align="center" class="Botrule Rrule" valign="middle">193</td><td align="center" class="Botrule Rrule" valign="middle">220</td><td align="center" class="Botrule Rrule" valign="middle">248</td><td align="center" class="Botrule Rrule" valign="middle">275</td><td align="center" class="Botrule Rrule" valign="middle">13</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">50</td><td align="center" class="Botrule" valign="middle"></td><td align="center" valign="middle">15</td><td align="center" valign="middle">30</td><td align="center" valign="middle">60</td><td align="center" valign="middle">90</td><td align="center" valign="middle">120</td><td align="center" valign="middle">150</td><td align="center" class="Rrule" valign="middle">180</td><td align="center" valign="middle">120</td><td align="center" class="Botrule Rrule" valign="middle">150</td><td align="center" class="Botrule Rrule" valign="middle">180</td><td align="center" class="Botrule Rrule" valign="middle">210</td><td align="center" class="Botrule Rrule" valign="middle">240</td><td align="center" class="Botrule Rrule" valign="middle">270</td><td align="center" class="Botrule Rrule" valign="middle">300</td><td align="center" class="Botrule Rrule" valign="middle">12</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">60</td><td align="center" class="Botrule" valign="middle"></td><td align="center" valign="middle">16</td><td align="center" valign="middle">33</td><td align="center" valign="middle">65</td><td align="center" valign="middle">98</td><td align="center" valign="middle">130</td><td align="center" valign="middle">163</td><td align="center" class="Rrule" valign="middle">195</td><td align="center" valign="middle">130</td><td align="center" class="Botrule Rrule" valign="middle">163</td><td align="center" class="Botrule Rrule" valign="middle">195</td><td align="center" class="Botrule Rrule" valign="middle">228</td><td align="center" class="Botrule Rrule" valign="middle">260</td><td align="center" class="Botrule Rrule" valign="middle">293</td><td align="center" class="Botrule Rrule" valign="middle">325</td><td align="center" class="Botrule Rrule" valign="middle">11</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">70</td><td align="center" class="Botrule" valign="middle"></td><td align="center" valign="middle">18</td><td align="center" valign="middle">35</td><td align="center" valign="middle">70</td><td align="center" valign="middle">105</td><td align="center" valign="middle">140</td><td align="center" valign="middle">175</td><td align="center" class="Rrule" valign="middle">210</td><td align="center" valign="middle">140</td><td align="center" class="Botrule Rrule" valign="middle">175</td><td align="center" class="Botrule Rrule" valign="middle">210</td><td align="center" class="Botrule Rrule" valign="middle">245</td><td align="center" class="Botrule Rrule" valign="middle">280</td><td align="center" class="Botrule Rrule" valign="middle">315</td><td align="center" class="Botrule Rrule" valign="middle">350</td><td align="center" class="Botrule Rrule" valign="middle">10</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">80</td><td align="center" class="Botrule" valign="middle"></td><td align="center" valign="middle">19</td><td align="center" valign="middle">38</td><td align="center" valign="middle">75</td><td align="center" valign="middle">113</td><td align="center" valign="middle">150</td><td align="center" valign="middle">188</td><td align="center" class="Rrule" valign="middle">225</td><td align="center" valign="middle">150</td><td align="center" class="Botrule Rrule" valign="middle">188</td><td align="center" class="Botrule Rrule" valign="middle">225</td><td align="center" class="Botrule Rrule" valign="middle">263</td><td align="center" class="Botrule Rrule" valign="middle">300</td><td align="center" class="Botrule Rrule" valign="middle">338</td><td align="center" class="Botrule Rrule" valign="middle">375</td><td align="center" class="Botrule Rrule" valign="middle">9</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">90</td><td align="center" class="Botrule" valign="middle"></td><td align="center" valign="middle">20</td><td align="center" valign="middle">40</td><td align="center" valign="middle">80</td><td align="center" valign="middle">120</td><td align="center" valign="middle">160</td><td align="center" valign="middle">200</td><td align="center" class="Rrule" valign="middle">240</td><td align="center" valign="middle">160</td><td align="center" class="Botrule Rrule" valign="middle">200</td><td align="center" class="Botrule Rrule" valign="middle">240</td><td align="center" class="Botrule Rrule" valign="middle">280</td><td align="center" class="Botrule Rrule" valign="middle">320</td><td align="center" class="Botrule Rrule" valign="middle">360</td><td align="center" class="Botrule Rrule" valign="middle">400</td><td align="center" class="Botrule Rrule" valign="middle">8</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle">100</td><td align="center" class="Botrule" valign="middle"></td><td align="center" class="Botrule" valign="middle">21</td><td align="center" class="Botrule" valign="middle">43</td><td align="center" class="Botrule" valign="middle">85</td><td align="center" class="Botrule" valign="middle">128</td><td align="center" class="Botrule" valign="middle">170</td><td align="center" class="Botrule" valign="middle">213</td><td align="center" class="Rrule" valign="middle">255</td><td align="center" class="Botrule" valign="middle">170</td><td align="center" class="Rrule" valign="middle">213</td><td align="center" class="Rrule" valign="middle">255</td><td align="center" class="Rrule" valign="middle">298</td><td align="center" class="Rrule" valign="middle">340</td><td align="center" class="Rrule" valign="middle">383</td><td align="center" class="Rrule" valign="middle">425</td><td align="center" class="Botrule Rrule" valign="middle">7</td> </tr> </tbody> </table></div>

Determination of the target dose in milliliters of Digoxin Oral Solution based on body weight is shown in . Provided is the volume required per dose, NOT per day.  Table 4

<div class="scrollingtable"><table border="single" width="539"> <caption> <span>Table 4: Dose in Milliliters</span> </caption> <col width="8.4%"/> <col width="5.9%"/> <col width="7.2%"/> <col width="6.6%"/> <col width="7.2%"/> <col width="6.1%"/> <col width="6.1%"/> <col width="7.5%"/> <col width="5.6%"/> <col width="7.7%"/> <col width="6.6%"/> <col width="6.6%"/> <col width="6.6%"/> <col width="6.0%"/> <col width="5.7%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" colspan="2" rowspan="2" valign="top"> <p class="First"> </p> <img alt="right arrow" src="/dailymed/image.cfm?name=32fdd8c0-1ea6-4976-9f2f-6a0dd4130ac6-01.jpg&amp;setid=dcf907d9-0f0e-4ecc-a555-7e6dcc08c166"/><span class="Bold">Target Dose in mcg/kg</span></td><td align="left" class="Botrule Rrule" colspan="13" valign="top">  <span class="Bold">Volume to be given in mL</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">2</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">3</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">4</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">5</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">6</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">8</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">10</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">12</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">14</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">16</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">18</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">20</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">30</span></td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" rowspan="23" valign="top">  <p class="First"> <img alt="down arrow" src="/dailymed/image.cfm?name=32fdd8c0-1ea6-4976-9f2f-6a0dd4130ac6-02.jpg&amp;setid=dcf907d9-0f0e-4ecc-a555-7e6dcc08c166"/><span class="Bold">Weight in kg</span> </p> <p> </p> <p> </p> <p> </p> <p> </p> <p> </p> <p> </p> <p> </p> <p> </p> <p> </p> <p> </p> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">2</span></td><td align="center" class="Botrule Rrule" valign="middle">0.08 <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="middle">0.12 <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="middle">0.16 <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="middle">0.2</td><td align="center" class="Botrule Rrule" valign="middle">0.2</td><td align="center" class="Botrule Rrule" valign="middle">0.3</td><td align="center" class="Botrule Rrule" valign="middle">0.4</td><td align="center" class="Botrule Rrule" valign="middle">0.5</td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.7</td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.2</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">3</span></td><td align="center" class="Botrule Rrule" valign="middle">0.12 <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="middle">0.18 <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="middle">0.2</td><td align="center" class="Botrule Rrule" valign="middle">0.3</td><td align="center" class="Botrule Rrule" valign="middle">0.4</td><td align="center" class="Botrule Rrule" valign="middle">0.5</td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.7</td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.0</td><td align="center" class="Botrule Rrule" valign="middle">1.1</td><td align="center" class="Botrule Rrule" valign="middle">1.2</td><td align="center" class="Botrule Rrule" valign="middle">1.8</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">4</span></td><td align="center" class="Botrule Rrule" valign="middle">0.16 <span class="Sup">b</span></td><td align="center" class="Botrule Rrule" valign="middle">0.2</td><td align="center" class="Botrule Rrule" valign="middle">0.3</td><td align="center" class="Botrule Rrule" valign="middle">0.4</td><td align="center" class="Botrule Rrule" valign="middle">0.5</td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.0</td><td align="center" class="Botrule Rrule" valign="middle">1.1</td><td align="center" class="Botrule Rrule" valign="middle">1.3</td><td align="center" class="Botrule Rrule" valign="middle">1.4</td><td align="center" class="Botrule Rrule" valign="middle">1.6</td><td align="center" class="Botrule Rrule" valign="middle">2.4</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">5</span></td><td align="center" class="Botrule Rrule" valign="middle">0.2</td><td align="center" class="Botrule Rrule" valign="middle">0.3</td><td align="center" class="Botrule Rrule" valign="middle">0.4</td><td align="center" class="Botrule Rrule" valign="middle">0.5</td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.0</td><td align="center" class="Botrule Rrule" valign="middle">1.2</td><td align="center" class="Botrule Rrule" valign="middle">1.4</td><td align="center" class="Botrule Rrule" valign="middle">1.6</td><td align="center" class="Botrule Rrule" valign="middle">1.8</td><td align="center" class="Botrule Rrule" valign="middle">2.0</td><td align="center" class="Botrule Rrule" valign="middle">3.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">6</span></td><td align="center" class="Botrule Rrule" valign="middle">0.2</td><td align="center" class="Botrule Rrule" valign="middle">0.4</td><td align="center" class="Botrule Rrule" valign="middle">0.5</td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.7</td><td align="center" class="Botrule Rrule" valign="middle">1.0</td><td align="center" class="Botrule Rrule" valign="middle">1.2</td><td align="center" class="Botrule Rrule" valign="middle">1.4</td><td align="center" class="Botrule Rrule" valign="middle">1.7</td><td align="center" class="Botrule Rrule" valign="middle">1.9</td><td align="center" class="Botrule Rrule" valign="middle">2.2</td><td align="center" class="Botrule Rrule" valign="middle">2.4</td><td align="center" class="Botrule Rrule" valign="middle">3.6</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">7</span></td><td align="center" class="Botrule Rrule" valign="middle">0.3</td><td align="center" class="Botrule Rrule" valign="middle">0.4</td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.7</td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.1</td><td align="center" class="Botrule Rrule" valign="middle">1.4</td><td align="center" class="Botrule Rrule" valign="middle">1.7</td><td align="center" class="Botrule Rrule" valign="middle">2.0</td><td align="center" class="Botrule Rrule" valign="middle">2.2</td><td align="center" class="Botrule Rrule" valign="middle">2.5</td><td align="center" class="Botrule Rrule" valign="middle">2.8</td><td align="center" class="Botrule Rrule" valign="middle">4.2</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">8</span></td><td align="center" class="Botrule Rrule" valign="middle">0.3</td><td align="center" class="Botrule Rrule" valign="middle">0.5</td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.0</td><td align="center" class="Botrule Rrule" valign="middle">1.3</td><td align="center" class="Botrule Rrule" valign="middle">1.6</td><td align="center" class="Botrule Rrule" valign="middle">1.9</td><td align="center" class="Botrule Rrule" valign="middle">2.2</td><td align="center" class="Botrule Rrule" valign="middle">2.6</td><td align="center" class="Botrule Rrule" valign="middle">2.9</td><td align="center" class="Botrule Rrule" valign="middle">3.2</td><td align="center" class="Botrule Rrule" valign="middle">4.8</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">9</span></td><td align="center" class="Botrule Rrule" valign="middle">0.4</td><td align="center" class="Botrule Rrule" valign="middle">0.5</td><td align="center" class="Botrule Rrule" valign="middle">0.7</td><td align="center" class="Botrule Rrule" valign="middle">0.9</td><td align="center" class="Botrule Rrule" valign="middle">1.1</td><td align="center" class="Botrule Rrule" valign="middle">1.4</td><td align="center" class="Botrule Rrule" valign="middle">1.8</td><td align="center" class="Botrule Rrule" valign="middle">2.2</td><td align="center" class="Botrule Rrule" valign="middle">2.5</td><td align="center" class="Botrule Rrule" valign="middle">2.9</td><td align="center" class="Botrule Rrule" valign="middle">3.2</td><td align="center" class="Botrule Rrule" valign="middle">3.6</td><td align="center" class="Botrule Rrule" valign="middle">5.4</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">10</span></td><td align="center" class="Botrule Rrule" valign="middle">0.4</td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.0</td><td align="center" class="Botrule Rrule" valign="middle">1.2</td><td align="center" class="Botrule Rrule" valign="middle">1.6</td><td align="center" class="Botrule Rrule" valign="middle">2.0</td><td align="center" class="Botrule Rrule" valign="middle">2.4</td><td align="center" class="Botrule Rrule" valign="middle">2.8</td><td align="center" class="Botrule Rrule" valign="middle">3.2</td><td align="center" class="Botrule Rrule" valign="middle">3.6</td><td align="center" class="Botrule Rrule" valign="middle">4.0</td><td align="center" class="Botrule Rrule" valign="middle">6.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">11</span></td><td align="center" class="Botrule Rrule" valign="middle">0.4</td><td align="center" class="Botrule Rrule" valign="middle">0.7</td><td align="center" class="Botrule Rrule" valign="middle">0.9</td><td align="center" class="Botrule Rrule" valign="middle">1.1</td><td align="center" class="Botrule Rrule" valign="middle">1.3</td><td align="center" class="Botrule Rrule" valign="middle">1.8</td><td align="center" class="Botrule Rrule" valign="middle">2.2</td><td align="center" class="Botrule Rrule" valign="middle">2.6</td><td align="center" class="Botrule Rrule" valign="middle">3.1</td><td align="center" class="Botrule Rrule" valign="middle">3.5</td><td align="center" class="Botrule Rrule" valign="middle">4.0</td><td align="center" class="Botrule Rrule" valign="middle">4.4</td><td align="center" class="Botrule Rrule" valign="middle">6.6</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">12</span></td><td align="center" class="Botrule Rrule" valign="middle">0.5</td><td align="center" class="Botrule Rrule" valign="middle">0.7</td><td align="center" class="Botrule Rrule" valign="middle">1.0</td><td align="center" class="Botrule Rrule" valign="middle">1.2</td><td align="center" class="Botrule Rrule" valign="middle">1.4</td><td align="center" class="Botrule Rrule" valign="middle">1.9</td><td align="center" class="Botrule Rrule" valign="middle">2.4</td><td align="center" class="Botrule Rrule" valign="middle">2.9</td><td align="center" class="Botrule Rrule" valign="middle">3.4</td><td align="center" class="Botrule Rrule" valign="middle">3.8</td><td align="center" class="Botrule Rrule" valign="middle">4.3</td><td align="center" class="Botrule Rrule" valign="middle">4.8</td><td align="center" class="Botrule Rrule" valign="middle">7.2</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">13</span></td><td align="center" class="Botrule Rrule" valign="middle">0.5</td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.0</td><td align="center" class="Botrule Rrule" valign="middle">1.3</td><td align="center" class="Botrule Rrule" valign="middle">1.6</td><td align="center" class="Botrule Rrule" valign="middle">2.1</td><td align="center" class="Botrule Rrule" valign="middle">2.6</td><td align="center" class="Botrule Rrule" valign="middle">3.1</td><td align="center" class="Botrule Rrule" valign="middle">3.6</td><td align="center" class="Botrule Rrule" valign="middle">4.2</td><td align="center" class="Botrule Rrule" valign="middle">4.7</td><td align="center" class="Botrule Rrule" valign="middle">5.2</td><td align="center" class="Botrule Rrule" valign="middle">7.8</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">14</span></td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.1</td><td align="center" class="Botrule Rrule" valign="middle">1.4</td><td align="center" class="Botrule Rrule" valign="middle">1.7</td><td align="center" class="Botrule Rrule" valign="middle">2.2</td><td align="center" class="Botrule Rrule" valign="middle">2.8</td><td align="center" class="Botrule Rrule" valign="middle">3.4</td><td align="center" class="Botrule Rrule" valign="middle">3.9</td><td align="center" class="Botrule Rrule" valign="middle">4.5</td><td align="center" class="Botrule Rrule" valign="middle">5.0</td><td align="center" class="Botrule Rrule" valign="middle">5.6</td><td align="center" class="Botrule Rrule" valign="middle">8.4</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">15</span></td><td align="center" class="Botrule Rrule" valign="middle">0.6</td><td align="center" class="Botrule Rrule" valign="middle">0.9</td><td align="center" class="Botrule Rrule" valign="middle">1.2</td><td align="center" class="Botrule Rrule" valign="middle">1.5</td><td align="center" class="Botrule Rrule" valign="middle">1.8</td><td align="center" class="Botrule Rrule" valign="middle">2.4</td><td align="center" class="Botrule Rrule" valign="middle">3.0</td><td align="center" class="Botrule Rrule" valign="middle">3.6</td><td align="center" class="Botrule Rrule" valign="middle">4.2</td><td align="center" class="Botrule Rrule" valign="middle">4.8</td><td align="center" class="Botrule Rrule" valign="middle">5.4</td><td align="center" class="Botrule Rrule" valign="middle">6.0</td><td align="center" class="Botrule Rrule" valign="middle">9.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">20</span></td><td align="center" class="Botrule Rrule" valign="middle">0.8</td><td align="center" class="Botrule Rrule" valign="middle">1.2</td><td align="center" class="Botrule Rrule" valign="middle">1.6</td><td align="center" class="Botrule Rrule" valign="middle">2.0</td><td align="center" class="Botrule Rrule" valign="middle">2.4</td><td align="center" class="Botrule Rrule" valign="middle">3.2</td><td align="center" class="Botrule Rrule" valign="middle">4.0</td><td align="center" class="Botrule Rrule" valign="middle">4.8</td><td align="center" class="Botrule Rrule" valign="middle">5.6</td><td align="center" class="Botrule Rrule" valign="middle">6.4</td><td align="center" class="Botrule Rrule" valign="middle">7.2</td><td align="center" class="Botrule Rrule" valign="middle">8.0</td><td align="center" class="Botrule Rrule" valign="middle">12.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">30</span></td><td align="center" class="Botrule Rrule" valign="middle">1.2</td><td align="center" class="Botrule Rrule" valign="middle">1.8</td><td align="center" class="Botrule Rrule" valign="middle">2.4</td><td align="center" class="Botrule Rrule" valign="middle">3.0</td><td align="center" class="Botrule Rrule" valign="middle">3.6</td><td align="center" class="Botrule Rrule" valign="middle">4.8</td><td align="center" class="Botrule Rrule" valign="middle">6.0</td><td align="center" class="Botrule Rrule" valign="middle">7.2</td><td align="center" class="Botrule Rrule" valign="middle">8.4</td><td align="center" class="Botrule Rrule" valign="middle">9.6</td><td align="center" class="Botrule Rrule" valign="middle">10.8</td><td align="center" class="Botrule Rrule" valign="middle">12.0</td><td align="center" class="Botrule Rrule" valign="middle">18.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">40</span></td><td align="center" class="Botrule Rrule" valign="middle">1.6</td><td align="center" class="Botrule Rrule" valign="middle">2.4</td><td align="center" class="Botrule Rrule" valign="middle">3.2</td><td align="center" class="Botrule Rrule" valign="middle">4.0</td><td align="center" class="Botrule Rrule" valign="middle">4.8</td><td align="center" class="Botrule Rrule" valign="middle">6.4</td><td align="center" class="Botrule Rrule" valign="middle">8.0</td><td align="center" class="Botrule Rrule" valign="middle">9.6</td><td align="center" class="Botrule Rrule" valign="middle">11.2</td><td align="center" class="Botrule Rrule" valign="middle">12.8</td><td align="center" class="Botrule Rrule" valign="middle">14.4</td><td align="center" class="Botrule Rrule" valign="middle">16.0</td><td align="center" class="Botrule Rrule" valign="middle">24.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">50</span></td><td align="center" class="Botrule Rrule" valign="middle">2.0</td><td align="center" class="Botrule Rrule" valign="middle">3.0</td><td align="center" class="Botrule Rrule" valign="middle">4.0</td><td align="center" class="Botrule Rrule" valign="middle">5.0</td><td align="center" class="Botrule Rrule" valign="middle">6.0</td><td align="center" class="Botrule Rrule" valign="middle">8.0</td><td align="center" class="Botrule Rrule" valign="middle">10.0</td><td align="center" class="Botrule Rrule" valign="middle">12.0</td><td align="center" class="Botrule Rrule" valign="middle">14.0</td><td align="center" class="Botrule Rrule" valign="middle">16.0</td><td align="center" class="Botrule Rrule" valign="middle">18</td><td align="center" class="Botrule Rrule" valign="middle">20.0</td><td align="center" class="Botrule Rrule" valign="middle">30.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">60</span></td><td align="center" class="Botrule Rrule" valign="middle">2.4</td><td align="center" class="Botrule Rrule" valign="middle">3.6</td><td align="center" class="Botrule Rrule" valign="middle">4.8</td><td align="center" class="Botrule Rrule" valign="middle">6.0</td><td align="center" class="Botrule Rrule" valign="middle">7.2</td><td align="center" class="Botrule Rrule" valign="middle">9.6</td><td align="center" class="Botrule Rrule" valign="middle">12.0</td><td align="center" class="Botrule Rrule" valign="middle">14.4</td><td align="center" class="Botrule Rrule" valign="middle">16.8</td><td align="center" class="Botrule Rrule" valign="middle">19.2</td><td align="center" class="Botrule Rrule" valign="middle">21.6</td><td align="center" class="Botrule Rrule" valign="middle">24.0</td><td align="center" class="Botrule Rrule" valign="middle">36.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">70</span></td><td align="center" class="Botrule Rrule" valign="middle">2.8</td><td align="center" class="Botrule Rrule" valign="middle">4.2</td><td align="center" class="Botrule Rrule" valign="middle">5.6</td><td align="center" class="Botrule Rrule" valign="middle">7.0</td><td align="center" class="Botrule Rrule" valign="middle">8.4</td><td align="center" class="Botrule Rrule" valign="middle">11.2</td><td align="center" class="Botrule Rrule" valign="middle">14.0</td><td align="center" class="Botrule Rrule" valign="middle">16.8</td><td align="center" class="Botrule Rrule" valign="middle">19.6</td><td align="center" class="Botrule Rrule" valign="middle">22.4</td><td align="center" class="Botrule Rrule" valign="middle">25.2</td><td align="center" class="Botrule Rrule" valign="middle">28.0</td><td align="center" class="Botrule Rrule" valign="middle">42.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">80</span></td><td align="center" class="Botrule Rrule" valign="middle">3.2</td><td align="center" class="Botrule Rrule" valign="middle">4.8</td><td align="center" class="Botrule Rrule" valign="middle">6.4</td><td align="center" class="Botrule Rrule" valign="middle">8.0</td><td align="center" class="Botrule Rrule" valign="middle">9.6</td><td align="center" class="Botrule Rrule" valign="middle">12.8</td><td align="center" class="Botrule Rrule" valign="middle">16.0</td><td align="center" class="Botrule Rrule" valign="middle">19.2</td><td align="center" class="Botrule Rrule" valign="middle">22.4</td><td align="center" class="Botrule Rrule" valign="middle">25.6</td><td align="center" class="Botrule Rrule" valign="middle">28.8</td><td align="center" class="Botrule Rrule" valign="middle">32.0</td><td align="center" class="Botrule Rrule" valign="middle">48.0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">90</span></td><td align="center" class="Botrule Rrule" valign="middle">3.6</td><td align="center" class="Botrule Rrule" valign="middle">5.4</td><td align="center" class="Botrule Rrule" valign="middle">7.2</td><td align="center" class="Botrule Rrule" valign="middle">9.0</td><td align="center" class="Botrule Rrule" valign="middle">10.8</td><td align="center" class="Botrule Rrule" valign="middle">14.4</td><td align="center" class="Botrule Rrule" valign="middle">18.0</td><td align="center" class="Botrule Rrule" valign="middle">21.6</td><td align="center" class="Botrule Rrule" valign="middle">25.2</td><td align="center" class="Botrule Rrule" valign="middle">28.8</td><td align="center" class="Botrule Rrule" valign="middle">32.4</td><td align="center" class="Botrule Rrule" valign="middle">36.0</td><td align="center" class="Botrule Rrule" valign="middle">54.0</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">100</span></td><td align="center" class="Rrule" valign="middle">4.0</td><td align="center" class="Rrule" valign="middle">6.0</td><td align="center" class="Rrule" valign="middle">8.0</td><td align="center" class="Rrule" valign="middle">10.0</td><td align="center" class="Rrule" valign="middle">12.0</td><td align="center" class="Rrule" valign="middle">16.0</td><td align="center" class="Rrule" valign="middle">20.0</td><td align="center" class="Rrule" valign="middle">24.0</td><td align="center" class="Rrule" valign="middle">28.0</td><td align="center" class="Rrule" valign="middle">32.0</td><td align="center" class="Rrule" valign="middle">36.0</td><td align="center" class="Rrule" valign="middle">40.0</td><td align="center" class="Botrule Rrule" valign="middle">60.0</td> </tr> </tbody> </table></div>

Recommended dosing regimen for pediatric patients under 10 years of age is twice daily. Recommended dosing regimen for pediatric patients over 10 years of age and adults is once daily. a

Use calibrated dropper for measurement. In the case of required volume less than 0.2 mL, a separate device such as a graduated syringe is recommended for adequate measurement. b

On the left side of the chart, locate the patient’s weight in kilograms. At the top of the chart, identify which dose in mcg/kg will be used for this patient. The block on the chart at which the two rows (weight and target dose) intersect is the milliliter amount that should be given to the patient.

The monitoring described in Section 2.2 may suggest increases or decreases in digoxin doses. Additional monitoring, and in some cases anticipatory dose adjustment, may be indicated around the time of various changes to the patient including:

Each 1 mL of clear, colorless Digoxin Oral Solution contains 0.05 mg (50 mcg).

{ "type": "p", "children": [], "text": "Each 1 mL of clear, colorless Digoxin Oral Solution contains 0.05 mg (50 mcg)." }

The Digoxin Oral Solution bottles are to be used with the graduated droppers provided in the carton. Starting at 0.2 mL, this 1 mL dropper is marked in divisions of 0.1 mL, corresponding to 5 mcg or 0.005 mg of digoxin.

{ "type": "p", "children": [], "text": "The Digoxin Oral Solution bottles are to be used with the graduated droppers provided in the carton. Starting at 0.2 mL, this 1 mL dropper is marked in divisions of 0.1 mL, corresponding to 5 mcg or 0.005 mg of digoxin." }

The calibrated dropper supplied with the 60 mL bottle of Digoxin Oral Solution is not appropriate to measure doses below 0.2 mL. Doses less than 0.2 mL require appropriate methods or measuring devices designed to administer an accurate amount to the patient, such as a graduated syringe. NOTE:

{ "type": "p", "children": [], "text": "The calibrated dropper supplied with the 60 mL bottle of Digoxin Oral Solution is not appropriate to measure doses below 0.2 mL. Doses less than 0.2 mL require appropriate methods or measuring devices designed to administer an accurate amount to the patient, such as a graduated syringe.\n \n NOTE:\n" }

Allergy to digoxin is rare. Digoxin is contraindicated in patients with a known hypersensitivity to digoxin or other forms of digitalis. Digitalis glycosides, such as digoxin, are contraindicated in ventricular fibrillation.

{ "type": "p", "children": [], "text": "Allergy to digoxin is rare. Digoxin is contraindicated in patients with a known hypersensitivity to digoxin or other forms of digitalis. Digitalis glycosides, such as digoxin, are contraindicated in ventricular fibrillation." }

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.

Because digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. Digoxin 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. In such patients consideration should be given to the insertion of a pacemaker before treatment with digoxin.

Some signs and symptoms (anorexia, nausea, vomiting, and certain arrhythmias) can equally result from digoxin toxicity as from congestive heart failure. Misidentification of their etiology might lead the clinician to continue or increase digoxin dosing, when dosing should actually be suspended. When the etiology of these signs and symptoms is not obvious, measurement of serum digoxin levels may be helpful.

Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may not benefit from digoxin treatment and may be particularly susceptible to adverse reactions when they are treated with digoxin.

In patients with hypertrophic cardiomyopathy (formerly called idiopathic hypertrophic subaortic stenosis), the positive inotropic effect of digoxin leads to an increased subvalvular outflow gradient and therefore, may compromise cardiac output. Digoxin is rarely beneficial in patients with this condition.

Chronic constrictive pericarditis is not generally associated with any inotropic defect, so heart failure of this etiology is unlikely to respond to treatment with digoxin. By slowing the resting heart rate, digoxin may actually decrease cardiac output in these patients.

Digoxin as an inotropic agent is of limited value in patients with restrictive cardiomyopathies, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation. In addition, patients with amyloid heart disease may be more susceptible to toxicity from digoxin at therapeutic levels because of an increased binding of digoxin to extracellular amyloid fibrils.

Digoxin is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of digoxin . 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. [see Dosage and Administration (2.4)

In patients with hypokalemia or hypomagnesemia, toxicity may occur at concentrations within therapeutic range because potassium or magnesium depletion sensitizes the myocardium to digoxin. Therefore, it is desirable to maintain normal serum potassium and magnesium concentrations in patients being treated with digoxin. Serum potassium levels should be carefully monitored when digoxin is given to patients at high risk of hypokalemia ( , those receiving diuretics, corticosteroids, or other drugs that commonly lead to potassium loss; those with gastrointestinal losses through diarrhea, vomiting, or nasogastric suction; or those with potassium-losing endocrinopathies or nephropathies). Digoxin toxicity is also more likely in the presence of hypomagnesemia. Hypomagnesemia is common in most of the same conditions in which hypokalemia appears. Most notably, it is commonly seen in alcoholics and in patients with diabetes mellitus or hypercalcemia. e.g.

Because digoxin’s therapeutic and toxic effects are all largely mediated by intracellular calcium distribution, they are affected by abnormalities in serum calcium levels. Hypercalcemia increases the risk of digoxin toxicity, while digoxin may be therapeutically ineffective in the presence of hypocalcemia.

Reduction of digoxin dosage may be desirable prior to electrical cardioversion to avoid induction of ventricular arrhythmias, but the physician must consider the consequences of a rapid increase in ventricular response to atrial fibrillation if digoxin is withheld 1 to 2 days prior to cardioversion. If there is a suspicion that digitalis toxicity exists, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the energy level selected should be minimal at first and carefully increased in an attempt to avoid precipitating ventricular arrhythmias.

Hypothyrodism may reduce the requirements for digoxin. Heart failure and 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 ( , hyperthyroidism) are particularly resistant to digoxin treatment. Large doses of digoxin are not recommended as the only treatment of these arrhythmias and care must be taken to avoid toxicity if large doses of digoxin are required. In hypothyroidism, the digoxin requirements are reduced. Digoxin responses are normal in patients with compensated thyroid disease. e.g.

In patients with acute myocardial infarction, particularly if they have ongoing ischemia, the use of inotropic drugs, such as digoxin, may result in undesirable increases in myocardial oxygen demand and ischemia. Moreover, the use of digoxin may result in potentially detrimental increases in coronary vascular resistance mediated through alpha adrenergic receptor stimulation.

5.10 Use in Patients with Myocarditis

Digoxin can precipitate vasoconstriction and may promote production of pro-inflammatory cytokines. Therefore, avoid digoxin in patients with myocarditis.

5.11 ECG Changes During Exercise

The use of therapeutic doses of digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing that may be indistinguishable from those of ischemia. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity. Digoxin does not significantly decrease heart rate during exercise.

5.12 Laboratory Tests

Patients receiving digoxin should have their serum electrolytes and renal function (serum creatinine concentrations) assessed periodically; the frequency of assessments will depend on the clinical setting.

Assays of serum digoxin levels are described elsewhere , as is their use in patient monitoring . [see ] Drug Interactions (7.4)[see Dosage and Administration (2.2)]

In adults, high doses of digoxin may produce a variety of electrocardiographic changes and rhythm disturbances, such as first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multifocal ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation. Prophylactic use of a cardiac pacemaker may be considered if the risk of heart block is considered unacceptable.

In pediatric patients, the use of digoxin may produce arrhythmias. The most common are conduction disturbances or supraventricular tachycarrhythmias, 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.

Anorexia, nausea, vomiting and diarrhea may be early symptoms of digoxin toxicity. However, uncontrolled heart failure may also produce such symptoms. The use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines.

Digoxin can produce visual disturbances (blurred vision, green-yellow color disturbances, halo effect), headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination).

Gynecomastia has been reported following the prolonged use of digoxin. Thrombocytopenia, maculopapular rash and other skin reactions have been observed.

Digoxin is a substrate for 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.

<div class="scrollingtable"><table border="single" width="455"> <col width="16.2%"/> <col width="19.3%"/> <col width="20.4%"/> <col width="44.2%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">Digoxin concentrations increased &gt; 50%</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top">Digoxin Serum Concentration Increase</td><td align="center" class="Botrule Rrule" valign="top">Digoxin AUC Increase</td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Recommendations</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Amiodarone</td><td align="center" class="Botrule Rrule" valign="top">70%</td><td align="center" class="Botrule Rrule" valign="top">NA</td><td align="left" class="Botrule Rrule" rowspan="8" valign="top">Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Captopril</td><td align="center" class="Botrule Rrule" valign="top">58%</td><td align="center" class="Botrule Rrule" valign="top">39%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Nitrendipine</td><td align="center" class="Botrule Rrule" valign="top">57%</td><td align="center" class="Botrule Rrule" valign="top">15%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Propafenone</td><td align="center" class="Botrule Rrule" valign="top">35-85%</td><td align="center" class="Botrule Rrule" valign="top">NA</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Quinidine</td><td align="center" class="Botrule Rrule" valign="top">100%</td><td align="center" class="Botrule Rrule" valign="top">NA</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ranolazine</td><td align="center" class="Botrule Rrule" valign="top">87%</td><td align="center" class="Botrule Rrule" valign="top">88%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ritonavir</td><td align="center" class="Botrule Rrule" valign="top">NA</td><td align="center" class="Botrule Rrule" valign="top">86%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Verapamil</td><td align="center" class="Botrule Rrule" valign="top">50-75%</td><td align="center" class="Botrule Rrule" valign="top">NA</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">Digoxin concentrations increased &lt; 50%</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Carvedilol</td><td align="center" class="Botrule Rrule" valign="top">16%</td><td align="center" class="Botrule Rrule" valign="top">14%</td><td align="left" class="Botrule Rrule" rowspan="5" valign="top">Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Diltiazem</td><td align="center" class="Botrule Rrule" valign="top">20%</td><td align="center" class="Botrule Rrule" valign="top">NA</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Nifedipine</td><td align="center" class="Botrule Rrule" valign="top">45%</td><td align="center" class="Botrule Rrule" valign="top">NA</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Rabeprazole</td><td align="center" class="Botrule Rrule" valign="top">29%</td><td align="center" class="Botrule Rrule" valign="top">19%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Telmisartan</td><td align="center" class="Botrule Rrule" valign="top">20%</td><td align="center" class="Botrule Rrule" valign="top">NA</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">Digoxin concentrations increased, but magnitude is unclear</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top">Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline</td><td align="left" class="Botrule Rrule" valign="top">Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">Digoxin concentrations decreased</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First">Acarbose, Activated Charcoal, Albuterol, Antacids, Anti-cancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St. John’s Wort, Sucralfate, Sulfasalazine</p> </td><td align="left" class="Botrule Rrule" valign="top">Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">No significant Digoxin concentrations changes</span></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top">Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.</td><td align="left" class="Botrule Rrule" valign="top">No additional actions are required.</td> </tr> </tbody> </table></div>

NA – Not available/reported

<div class="scrollingtable"><table border="single" width="443"> <col width="29.1%"/> <col width="21.0%"/> <col width="49.9%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="top"><span class="Bold">Antiarrhythmics</span></td><td align="left" class="Botrule" valign="top">Dofetilide</td><td align="left" class="Botrule Rrule" valign="top">Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.</td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top">Moricizine</td><td align="left" class="Botrule Rrule" valign="top">Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.</td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top">Sotalol</td><td align="left" class="Botrule Rrule" valign="middle">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.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Parathyroid Hormone Analog</span></td><td align="left" class="Botrule" valign="top">Teriparatide</td><td align="left" class="Botrule Rrule" valign="top">Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Thyroid Supplement</span></td><td align="left" class="Botrule" valign="top">Thyroid</td><td align="left" class="Botrule Rrule" valign="top">Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="3" valign="top"><span class="Bold">Sympathomimetics</span></td><td align="left" valign="middle">Epinepherine</td><td align="left" class="Botrule Rrule" rowspan="3" valign="top">Can increase the risk of cardiac arrhythmias.</td> </tr> <tr> <td align="left" class="Rrule" valign="middle">Norepinephrine</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">Dopamine</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Neuromuscular Blocking Agents</span></td><td align="left" class="Botrule" valign="top">Succinylcholine</td><td align="left" class="Botrule Rrule" valign="middle">May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Supplements</span></td><td align="left" class="Botrule" valign="top">Calcium</td><td align="left" class="Botrule Rrule" valign="middle">If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Beta-adrenergic blockers and calcium channel blockers</span></td><td align="left" class="Botrule Rrule" colspan="2" valign="top"> <p class="First">Additive effects on AV node conduction can result in complete heart block.</p> </td> </tr> </tbody> </table></div>

Endogenous substances of unknown composition (digoxin-like immunoreactive substances, DLIS) can interfere with standard radioimmunoassays for digoxin. The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced. Some assays are more subject to these failings than others. Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference. DLIS are present in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason. The measured levels of DLIS (as digoxin equivalents) are usually low (0.2 to 0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic.

In some assays, spironolactone, canrenone and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL. Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha or Dashen, can cause similar interference.

Spironolactone and DLIS are much more extensively protein-bound than digoxin. As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS. It should be noted that ultrafiltration does not solve all interference problems with alternative medicines. The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in term of specificity and limit of quantization.

Teratogenic Effects (Pregnancy Category C)

Animal reproduction studies have not been conducted with digoxin. It is also not known whether digoxin can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Digoxin should be given to a pregnant woman only if clearly needed.

There is not enough data from clinical trials to determine the safety and efficacy of digoxin during labor and delivery.

Digoxin levels in human milk are lower than those in maternal serum. The estimated exposure that a nursing infant would be expected to receive via breastfeeding would be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when digoxin is administered to a nursing woman.

Digoxin increases myocardial contractility in pediatric patients with congestive heart failure. There are no clinical efficacy studies demonstrating benefit in pediatric patients with heart failure. There are no controlled randomized studies of digoxin in pediatric patients with atrial tachyarrhythmias . [see ] Clinical Studies (14.2)

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 (2.4).

No clinically significant gender differences in digoxin pharmacokinetics have been reported.

The clearance of digoxin can be primarily correlated with renal function as indicated by creatinine clearance. Table 3 provides the usual daily maintenance dose requirements of solution based on creatinine clearance (per 70 kg or per 1.73 m ) ]. 2[see Dosage and Administration (2.4)

For pediatric patients with known or suspected renal dysfunction, lower starting doses should be considered combined with frequent monitoring of digoxin levels.

Plasma digoxin concentrations in patients with acute hepatitis generally fall within the range of profiles in a group of healthy subjects.

In hyperthyroidism, lower serum digoxin concentrations have been reported because of decreased absorption. Hypothyroid patients may require smaller doses of digoxin.

Race differences in digoxin pharmacokinetics have not been formally studied, but are not expected.

Race differences in digoxin pharmacokinetics have not been formally studied, but are not expected.

In adults, the signs and symptoms of toxicity are similar to those described in but may be more frequent and severe. The most common signs and symptoms of digoxin toxicity are nausea, vomiting, anorexia, and fatigue that occur in 30 to 70% of patients who are overdosed. Extremely high serum concentrations produce hyperkalemia especially in patients with impaired renal function. Almost every type of cardiac arrhythmia has been associated with digoxin overdose and multiple rhythm disturbances in the same patient are common. Peak cardiac effects occur 3 to 6 hours following ingestion and may persist for 24 hours or longer. Arrhythmias that are considered more characteristic of digoxin toxicity are new-onset Mobitz type 1 A-V block, accelerated junctional rhythms, non-paroxysmal atrial tachycardia with A-V block, and bi-directional ventricular tachycardia. Cardiac arrest from asystole or ventricular fibrillation is usually fatal. Adverse Reactions (6)

Digoxin toxicity is related to serum concentration. As serum levels increase above 1.2 ng/mL, there is a potential for increase in adverse events. The effect on adverse events is enhanced by lower potassium levels. In adults with heart disease, clinical observations suggest that an overdose of digoxin of 10 to 15 mg results in death of half of patients. A dose above 25 mg ingested by an adult without heart disease appeared to be uniformly fatal if no Digoxin Immune Fab (DIGIBIND®, DIGIFAB®) was administered.

In pediatric patients, signs and symptoms of toxicity can occur during or shortly after the dose of digoxin. Frequent non-cardiac effects are similar to those observed in adults although nausea and vomiting are not seen frequently in infants and small pediatric patients. Other reported manifestations of overdose are weight loss in older age groups, failure to thrive in infants, abdominal pain caused by mesenteric artery ischemia, drowsiness, and behavioral disturbances including psychotic episodes. Arrhythmias and combinations of arrhythmias that occur in adult patients can also occur in pediatric patients although sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in pediatric patients. Pediatric patients are more likely to develop A-V conduction disturbances, or sinus bradycardia. Any arrhythmia in a child treated with digoxin should be considered related to digoxin until otherwise ruled out. In pediatric patients aged 1 to 3 years without heart disease, clinical observations suggest that an overdose of digoxin of 6 to 10 mg would result in death of half of the patients. In the same population, a dose above 10 mg resulted in death if no Digoxin Immune Fab (DIGIBIND®, DIGIFAB®) was administered.

Chronic Overdose

If there is suspicion of toxicity, digoxin should be discontinued and the patient placed on a cardiac monitor. Contributing factors such as electrolyte abnormalities, thyroid dysfunction, and concomitant medications should be corrected Hypokalemia should be corrected 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 cautiously by the intravenous route. The electrocardiogram should be monitored for any evidence of potassium toxicity (e.g. peaking of T waves) and to observe the effect on the arrhythmia. Potassium salts should be avoided in patients with bradycardia or heart block. Symptomatic arrhythmias may be treated with Digoxin Immune Fab (DIGIBIND®, DIGIFAB®). [see . ] Dosage and Administration (2.5)

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, digoxin should be temporarily discontinued until the adverse reaction resolves. Factors that may be contributing to the adverse reactions should also be corrected . In particular, hypokalemia and hypomagnesemia should be corrected. 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 (DIGIBIND , DIGIFAB ). 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 (DIGIBIND , DIGIFAB ) 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. [see] Warnings and Precautions (5)®®®®

Digoxin is one of the cardiac glycosides, a closely-related group of plant-derived drugs with shared pharmacological effects. The term "digitalis" is used to designate the whole group. Digoxin is extracted from the leaves of the common foxglove, . Like each of the other cardiac glycosides, digoxin consists of a polycyclic core and a sugar side chain. Digoxin’s chemical name is 3β-[ -2,6-dideoxy-β-D- -hexopyranosyl-(1→4)- -2, 6-dideoxy-β-D- -hexopyranosyl-(1→4)-2, 6-dideoxy-β-D- -hexopyranosyl)oxy]-12β, 14-dihydroxy-5β-card-20(22)-enolide; its structural formula is: Digitalis lanata0ribo0riboribo

{ "type": "p", "children": [], "text": "Digoxin is one of the cardiac glycosides, a closely-related group of plant-derived drugs with shared pharmacological effects. The term \"digitalis\" is used to designate the whole group. Digoxin is extracted from the leaves of the common foxglove, . Like each of the other cardiac glycosides, digoxin consists of a polycyclic core and a sugar side chain. Digoxin’s chemical name is 3β-[ -2,6-dideoxy-β-D- -hexopyranosyl-(1→4)- -2, 6-dideoxy-β-D- -hexopyranosyl-(1→4)-2, 6-dideoxy-β-D- -hexopyranosyl)oxy]-12β, 14-dihydroxy-5β-card-20(22)-enolide; its structural formula is:\n \n Digitalis lanata0ribo0riboribo\n" }

Its molecular formula is C H O , and its molecular weight is 780.95. Digoxin is practically insoluble in water and in ether, slightly soluble in 50% ethanol and in chloroform, and freely soluble in pyridine. Digoxin powder consists of odorless white crystals. 416414

{ "type": "p", "children": [], "text": "Its molecular formula is C H O , and its molecular weight is 780.95. Digoxin is practically insoluble in water and in ether, slightly soluble in 50% ethanol and in chloroform, and freely soluble in pyridine. Digoxin powder consists of odorless white crystals.\n \n 416414\n" }

Digoxin Oral Solution, USP is formulated for oral administration, and each mL contains 50 mcg (0.05 mg digoxin). The lime-flavored solution contains the following inactive ingredients: alcohol 10% (by volume at 60°F), glycerin, lime (imitation), methylparaben 0.1%, propylparaben 0.02%, purified water, sodium citrate, and sorbitol solution.

{ "type": "p", "children": [], "text": "Digoxin Oral Solution, USP is formulated for oral administration, and each mL contains 50 mcg (0.05 mg digoxin). The lime-flavored solution contains the following inactive ingredients: alcohol 10% (by volume at 60°F), glycerin, lime (imitation), methylparaben 0.1%, propylparaben 0.02%, purified water, sodium citrate, and sorbitol solution." }

All of digoxin’s actions are mediated through its effects on NaK–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 NaK–ATPase, digoxin

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), and 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).

Short- and long-term treatment with digoxin slows heart rate, increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions.

Absorption

Following oral administration, peak serum concentrations of digoxin occur at 30 to 90 minutes. In pediatric patients and in adult volunteers, absolute bioavailability of digoxin from the solution formulation is 70 to 85%, similar to that seen (in adults) with standard tablets (60 to 80%). When the solution is taken after meals, the peak serum concentrations increase by 20% and the total amount of digoxin absorbed increases by 43%, but the rate of digoxin absorption is unchanged. When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Digoxin absorption may also be affected by various concomitant therapy modulating gastric pH and P-glycoprotein . [see ] Drug Interactions (7)

Comparisons of the systemic availability and equivalent doses for preparations of digoxin are shown in . Table 5

<div class="scrollingtable"><table width="431.000"> <caption> <span>Table 5: Comparisons of the Systemic Availability and Equivalent Doses for Preparations of Digoxin</span> </caption> <col width="16.7%"/> <col width="19.0%"/> <col width="14.2%"/> <col width="16.7%"/> <col width="16.7%"/> <col width="16.7%"/> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>For example, 125 mcg tablets equivalent to 125 mcg solution equivalent to 100 mcg capsules equivalent to 100 mcg injection/IV.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top">Product <br/> </td><td align="center" class="Botrule Rrule" valign="top">Absolute Bioavailability <br/> </td><td align="center" class="Botrule Rrule" colspan="4" valign="top">Equivalent Doses (mcg) Among Dosage Forms <br/> <a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Tablets</td><td align="center" class="Botrule Rrule" valign="top">60-80%</td><td align="center" class="Botrule Rrule" valign="top">62.5</td><td align="center" class="Botrule Rrule" valign="top">125</td><td align="center" class="Botrule Rrule" valign="top">250</td><td align="center" class="Botrule Rrule" valign="top">500</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Solution</td><td align="center" class="Botrule Rrule" valign="top">70-85%</td><td align="center" class="Botrule Rrule" valign="top">62.5</td><td align="center" class="Botrule Rrule" valign="top">125</td><td align="center" class="Botrule Rrule" valign="top">250</td><td align="center" class="Botrule Rrule" valign="top">500</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Capsules</td><td align="center" class="Botrule Rrule" valign="top">90-100%</td><td align="center" class="Botrule Rrule" valign="top">50</td><td align="center" class="Botrule Rrule" valign="top">100</td><td align="center" class="Botrule Rrule" valign="top">200</td><td align="center" class="Botrule Rrule" valign="top">400</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection/IV</td><td align="center" class="Rrule" valign="top">100%</td><td align="center" class="Rrule" valign="top">50</td><td align="center" class="Rrule" valign="top">100</td><td align="center" class="Rrule" valign="top">200</td><td align="center" class="Botrule Rrule" valign="top">400</td> </tr> </tbody> </table></div>

In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggested that one in ten patients treated with digoxin will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of digoxin in such patients. The magnitude of rise in serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as two-fold in some cases.

Distribution

Following drug administration, a 6- to 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. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its sites 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 (2.2)

Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. 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 with lean (i.e., ideal) body weight, not total body weight.

Metabolism

Sixteen percent of digoxin is metabolized. The end metabolites include 3-β-digoxigenin, 3-keto-digoxigenin, and their glucuronide and sulfate conjugates. The metabolism of digoxin is not dependent on the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system.

Excretion

Elimination of digoxin is predominantly renal, although in adult volunteers about a quarter of serum digoxin is eliminated through the intestine, excreted in bile or secreted directly into the lumen by P-glycoprotein. Elimination of digoxin follows first order kinetics.

Following intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to glomerular filtration rate.

The serum half-life of digoxin in pediatric patients is reported to be 18 to 36 hours, and in adults it is typically 36 to 48 hours. The half-life in anuric patients is prolonged to 3.5 to 5 days.

Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or cardiopulmonary bypass because most of the drug is bound to tissue.

Drug-drug Interactions

Based on literature reports no significant changes in digoxin exposure were reported when digoxin was co-administered with the following drugs: alfuzosin, aliskiren, amlodipine, aprepitant, argatroban, aspirin, atorvastatin, benazepril, bisoprolol, black cohosh, bosentan, candesartan, citalopram, clopidogrel, colesevelam, dipyridamole, disopyramide, donepezil, doxazosin, dutasteride, echinacea, enalapril, eprosartan, ertapenem, escitalopram, esmolol, ezetimibe, famciclovir, felodipine, finasteride, flecainide, fluvastatin, fondaparinux, galantamine, gemifloxacin, grapefruit juice, irbesartan, isradipine, ketorolac, levetiracetam, levofloxacin, lisinopril, losartan, lovastatin, meloxicam, mexilitine, midazolam, milk thistle, moexipril, montelukast, moxifloxacin, mycophenolate, nateglinide, nesiritide, nicardipine, nisoldipine, olmesartan, orlistat, pantoprazole, paroxetine, perindopril, pioglitazone, pravastatin, prazosin, procainamide, quinapril, raloxifene, ramipril, repaglinide, rivastigmine, rofecoxib, ropinirole, rosiglitazone, rosuvastatin, sertraline, sevelamer, simvastatin, sirolimus, solifenacin, tamsulosin, tegaserod, terbinafine, tiagabine, ticlopidine, tigecycline, topiramate, torsemide, tramadol, trandolapril, triamterene, trospium, trovafloxacin, valacyclovir, valsartan, varenicline, voriconazole, zaleplon, and zolpidem.

There have been no long-term studies performed in animals to evaluate carcinogenic potential, nor have studies been conducted to assess the mutagenic potential of digoxin or its potential to affect fertility.

Two small12-week, double-blind, randomized trials compared digoxin to placebo in adult patients with chronic congestive heart failure, New York Heart Association Class II or III. The enrolled patients had all been receiving digoxin before the trials, but this was withdrawn before randomization. They continued to receive diuretics and (in the larger trial) ACE inhibitors. The trials enrolled 178 and 88 patients, respectively. In each of these trials, randomization to digoxin was associated with better preservation of exercise capacity and with reduced need of failure-related hospitalization, emergency care, and concomitant heart-failure therapy. NYHA class and patients' global assessments were also improved, although this effect achieved statistical significance only in the larger of the two studies.

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 ≤0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving a concomitant ACE inhibitor (94%) and diuretics (82%). As in the smaller trials described above, patients who had been receiving open-label digoxin were withdrawn from this treatment before randomization. Randomization to digoxin was again associated with a significant reduction in the incidence of hospitalization, whether scored as number of hospitalizations for heart failure (relative risk 75%), risk of having at least one such hospitalization during the trial (RR 72%), or number of hospitalizations for any cause (RR 94%). On the other hand, randomization to digoxin had no apparent effect on mortality (RR 99%, with confidence limits of 91 to 107%).

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.

No controlled randomized study of digoxin in pediatric patients with atrial tachyarrhythmias has been done.

There are no reports of controlled trials of digoxin for conversion of atrial flutter, rate control during atrial flutter, or reduction of the frequency of recurrence of atrial flutter in adults.

There are no reports of controlled trials of digoxin for conversion of supraventricular tachycardia (SVT), rate control during SVT, or reduction of the frequency of recurrence of SVT in adults.

Patients receiving digoxin should be given the following instructions by the physician.

{ "type": "p", "children": [], "text": "Patients receiving digoxin should be given the following instructions by the physician." }

{ "type": "ul", "children": [ "Advise patients that digoxin is a cardiac glycoside used to treat heart failure and heart arrhythmias. Digoxin helps the heart beat more efficiently in adults and pediatric patients and decreases the heart rate at rest during abnormal rhythms in adults.", "Instruct patients to take this medication as directed by their physician. The dose of digoxin should not be adjusted without consulting with a physician or other healthcare professional.", "Advise patients that many drugs can interact with digoxin. Patients should be instructed to inform their doctor and pharmacist if they are taking any over the counter medications, including herbal medication, or are started on a new prescription.", "The patient should be made aware that blood tests will be necessary to ensure that their digoxin dose is appropriate for them.", "Advise patients to contact their doctor or a health care professional if they experience nausea, vomiting, persistent diarrhea, confusion, weakness, or visual disturbances (including blurred vision, green-yellow color disturbances, halo effect) as these could be signs that the dose of digoxin may be too high.", "Advise parents or caregivers that the symptoms of having too high digoxin 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.", "Suggest to the patient to monitor and record their heart rate and blood pressure daily.", "Instruct patients to use the calibrated dropper to measure their digoxin dose and to avoid less precise measuring tools, such as teaspoons. For doses less than 0.2 mL, another measuring syringe should be provided to the patient for accurate dosing, since the provided calibrated dropper is not appropriate to measure doses less than 0.2 mL.", "Instruct women of childbearing potential who become or are planning to become pregnant to consult a physician prior to initiation or continuing therapy with digoxin." ], "text": "" }

Roxane Laboratories, Inc.

{ "type": "p", "children": [], "text": "Roxane Laboratories, Inc." }

Columbus, Ohio 43216

{ "type": "p", "children": [], "text": "Columbus, Ohio 43216" }

10001143/06Revised November 2011

{ "type": "p", "children": [], "text": "\n10001143/06Revised November 2011\n" }

© RLI, 2011

{ "type": "p", "children": [], "text": "© RLI, 2011" }

Digoxin is indicated for the treatment of mild to moderate heart failure in adults. Digoxin 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, Digoxin should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor.

Digoxin increases myocardial contractility in pediatric patients with heart failure.

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

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 slightly higher than therapeutic levels. Dosing can be either initiated with a loading dose followed by maintenance dosing if rapid titration is desired or initiated with maintenance dosing without a loading dose.

Consider interruption or reduction in Digoxin dose prior to electrical cardioversion [see Warnings and Precautions (5.4)].

Use digoxin solution to obtain the appropriate dose in infants, young pediatric patients, or patients with very low body weight.

For adults and pediatric patients if a loading dosage is to be given, administer half the total loading dose initially, then ¼ the loading dose every 6-8 hours twice, with careful assessment of clinical response and toxicity before each dose. The recommended loading dose is displayed in Table 1.

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <caption> <span>Table 1. Recommended Digoxin Oral Loading Dose</span> </caption> <col width="41%"/> <col width="59%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Age</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Total Oral Loading Dose (mcg/kg)</span> </p> <p>Administer half the total loading dose initially,</p> <p>then ¼ the loading dose every 6 to 8 hours twice</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">5 to 10 years</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">20 - 45</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Adults and pediatric patients over 10 years</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">10 - 15</p> </td> </tr> </tbody> </table></div>

mcg = microgram

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

The recommended starting maintenance dose in adults and pediatric patients over 10 years old with normal renal function is given in Table 2. Doses may be increased every 2 weeks according to clinical response, serum drug levels, and toxicity.

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <caption> <span>Table 2. Recommended Starting Digoxin Maintenance Dosage in Adults and Pediatric Patients Over 10 Years Old</span> </caption> <colgroup> <col width="41%"/> <col width="59%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Age</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Total</span> </p> <p> <span class="Bold">Oral Maintenance Dose, mcg/kg/day</span> </p> <p> <span class="Bold">(given once daily)</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Adults and pediatric patients over 10 years</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3.4 - 5.1</p> </td> </tr> </tbody> </table></div>

mcg = microgram

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 Digoxin in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema.

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <caption> <span>Table 3. Recommended Maintenance Dose (in micrograms given once daily) of Digoxin in Pediatric Patients Over 10 Years Old and Adults by Lean Body Weight and by Renal Function <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> </caption> <colgroup> <col width="13%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <col width="18%"/> </colgroup> <tfoot> <tr> <td align="left" colspan="10"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Doses are rounded to the nearest dose possible using whole Digoxin tablets. Recommended doses approximately 30 percent lower than the calculated dose are designated with an*. Monitor digoxin levels in patients receiving these initial doses and increase dose if needed.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>For adults, creatinine clearance was corrected to 70-kg body weight or 1.73 m2 body surface area. If only serum creatinine concentrations (Scr) are available, a corrected Ccr may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. For pediatric patients, the modified Schwartz equation may be used. The formula is based on height in cm and Scr in mg/dL where k is a constant. Ccr is corrected to 1.73 m2 body surface area. During the first year of life, the value of k is 0.33 for pre-term babies and 0.45 for term infants. The k is 0.55 for pediatric patients and adolescent girls and 0.7 for adolescent boys. GFR (mL/min/1.73 m2) = (k x Height)/Scr </dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>The doses listed assume average body composition.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">§</a> </dt> <dd>If no loading dose administered.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Corrected Creatinine Clearance</span><a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="8" valign="middle"> <p class="First"> <span class="Bold">Lean Body Weight</span><a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a> </p> </td><td class="Botrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Number of Days Before Steady State Achieved</span><a class="Sup" href="#footnote-4" name="footnote-reference-4">§</a> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">kg</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">40</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">50</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">60</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">70</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">80</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">90</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">100</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">10 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5*</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">19</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">20 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">30 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">40 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">50 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">60 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">375</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">70 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">375</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">375</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">80 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">375</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">437.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">90 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">375</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">437.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">437.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">8</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">100 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">375</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">437.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">500</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">7</p> </td> </tr> </tbody> </table></div>

The starting maintenance dose for heart failure in pediatric patients less than 10 years old is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology (12.3)] . The recommended starting maintenance dose for pediatric patients between 5 years and 10 years old is given in Table 4. These recommendations assume the presence of normal renal function

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <caption> <span>Table 4. Recommended Starting Digoxin Oral Maintenance Dosage in Pediatric Patients between 5 and 10 Years Old</span> </caption> <colgroup> <col width="41%"/> <col width="59%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Age</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Oral Maintenance Dose, mcg/kg/dose</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">5 years to 10 years</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3.2-6.4 <span class="Bold">Twice daily</span> </p> </td> </tr> </tbody> </table></div>

Table 5 provides average daily maintenance dose requirements for pediatric patients between 5 and 10 years old (to be given twice daily) with heart failure based on age, lean body weight, and renal function.

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <caption> <span>Table 5. Recommended Maintenance Dose (in micrograms given TWICE daily) of Digoxin in Pediatric Patients between 5 and 10 Years of Agea Based upon Lean Body Weight and Renal Function <a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a><a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a></span> </caption> <colgroup> <col width="15%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="24%"/> </colgroup> <tfoot> <tr> <td align="left" colspan="8"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Recommended are doses to be given twice daily.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>The doses are rounded to the nearest dose possible using whole Digoxin tablets. Recommended doses approximately 30 percent lower than the calculated dose are designated with an*. Monitor digoxin levels in patients receiving these initial doses and increase dose if needed.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>The modified Schwartz equation may be used to estimate creatinine clearance. See footnote b under Table 3.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">§</a> </dt> <dd>If no loading dose administered.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Corrected Creatinine Clearance</span><a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="6" valign="middle"> <p class="First"> <span class="Bold">Lean Body Weight</span> </p> </td><td class="Botrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Number of days before SteadyState Achieved</span><a class="Sup" href="#footnote-8" name="footnote-reference-8">§</a> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">kg</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">20</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">30</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">40</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">50</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">60</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">10 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">-</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5*</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">19</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">20 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">30 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5*</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">40 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5*</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">50 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">60 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">70 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">80 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5*</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">90 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5*</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">8</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">100 mL/min</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5*</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">187.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">312.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">7</p> </td> </tr> </tbody> </table></div>

Monitor for signs and symptoms of digoxin toxicity and clinical response. Adjust dose based on toxicity, efficacy, and blood levels.

Serum digoxin levels less than 0.5 ng/mL have been associated with diminished efficacy, while levels above 2 ng/mL have been associated with increased toxicity without increased benefit.

Interpret the serum digoxin concentration in the overall clinical context, and do not use an isolated measurement of serum digoxin concentration as the basis for increasing or decreasing the Digoxin 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.

When switching from intravenous to oral digoxin formulations, make allowances for differences in bioavailability when calculating maintenance dosages (see Table 6).

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <caption> <span>Table 6. Comparison of the Systemic Availability and Equivalent Doses of Oral and Intravenous Digoxin</span> </caption> <col width="41%"/> <col width="22%"/> <col width="10%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Absolute Bioavailability</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">Equivalent Doses (mcg)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Digoxin Tablets</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">60-80%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">62.5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">500</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Digoxin Intravenous Injection</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">100%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">50</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">100</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">200</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">400</p> </td> </tr> </tbody> </table></div>

Unscored Tablets: 62.5 mcg are peach colored, circular, biconvex, beveled, uncoated tablets debossed with “N” on one side and “200” on the other side.

{ "type": "p", "children": [], "text": "Unscored Tablets: 62.5 mcg are peach colored, circular, biconvex, beveled, uncoated tablets debossed with “N” on one side and “200” on the other side." }

Scored Tablets: 125 mcg are yellow, circular, beveled, uncoated tablets scored between “N” and “201” on one side and plain on other side.

{ "type": "p", "children": [], "text": "Scored Tablets: 125 mcg are yellow, circular, beveled, uncoated tablets scored between “N” and “201” on one side and plain on other side." }

Scored Tablets: 250 mcg are white to off-white, circular, beveled, uncoated tablets scored between “N” and “202” on one side and plain on other side.

{ "type": "p", "children": [], "text": "Scored Tablets: 250 mcg are white to off-white, circular, beveled, uncoated tablets scored between “N” and “202” on one side and plain on other side." }

Digoxin is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Digoxin is contraindicated in patients with:" }

{ "type": "ul", "children": [ "Ventricular fibrillation\n \n [seeWarnings and Precautions (5.1)]\n", "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." ], "text": "" }

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.

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

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

Digoxin 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 Digoxin. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin. Patients with amyloid heart disease may be more susceptible to digoxin toxicity at therapeutic levels because of an increased binding of digoxin to extracellular amyloid fibrils.

Digoxin 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.

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 Digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when Digoxin 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 Digoxin compared to 0.9% in patients taking placebo [seeClinical 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.

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.

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="19%"/> <col width="24%"/> <col width="19%"/> <col width="39%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">Digoxin concentrations increased greater than 50%</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Digoxin Serum Concentration</span> </p> <p> <span class="Bold">Increase</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Digoxin AUC Increase</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Recommendations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Amiodarone</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">70%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td><td class="Botrule Rrule" rowspan="15" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Captopril</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">58%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">39%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clarithromycin</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">70%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Dronedarone</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">150%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Gentamicin</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">129-212%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Erythromycin</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">100%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Itraconazole</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">80%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Lapatinib</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">180%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Propafenone</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">60-270%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Quinidine</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">100%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ranolazine</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">50%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ritonavir</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">86%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Telaprevir</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">50%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">85%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Tetracycline</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">100%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Verapamil</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">50-75%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">Digoxin concentrations increased less than 50%</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Atorvastatin</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">22%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">15%</p> </td><td class="Botrule Rrule" rowspan="17" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Carvedilol</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">16%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">14%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Conivaptan</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">33%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">43%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Diltiazem</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">20%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Indomethacin</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">40%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Mirabegron</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">29%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">27%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Nefazodone</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">27%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">15%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Nifedipine</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">45%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Propantheline</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">24%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">24%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Quinine</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">33%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Rabeprazole</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">29%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">19%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Saquinavir</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">27%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">49%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Spironolactone</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">25%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Telmisartan</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">20-49%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ticagrelor</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">31%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">28%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Tolvaptan</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">30%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">20%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Trimethoprim</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">22-28%</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">Digoxin concentrations increased, but magnitude is unclear</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="middle"> <p class="First">Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole</p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">Digoxin concentrations decreased</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="3" valign="middle"> <p class="First">Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine</p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.</p> </td> </tr> </tbody> </table></div>

NA – Not available/reported

Because of considerable variability of pharmacodynamic interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently.

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="27%"/> <col width="23%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Drugs that Affect Renal Function</p> </td><td class="Botrule Rrule Toprule" colspan="2" valign="middle"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Antiarrhythmics</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Dofetilide</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Concomitant administration with digoxin was associated with a higher rate of torsades de pointes</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"> <p class="First">Sotalol</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"> <p class="First">Dronedarone</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Parathyroid Hormone Analog</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Teriparatide</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Thyroid supplement</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Thyroid</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Sympathomimetics</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Epinephrine</p> <p>Norepinephrine</p> <p>Dopamine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Can increase the risk of cardiac arrhythmias</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Neuromuscular Blocking Agents</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Succinylcholine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Supplements</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Calcium</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Beta-adrenergic blockers and calcium channel blockers</p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"> <p class="First">Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperpolarization-activated cyclic nucleotide-gated channel blocker</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Ivabradine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Can increase the risk of bradycardia</p> </td> </tr> </tbody> </table></div>

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.

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 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 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, cardiac arrhythmias [see Warnings and Precautions (5.3)].

Dose adjustments during pregnancy and the postpartum period Digoxin requirements may increase during pregnancy and decrease in the postpartum period. Monitor serum digoxin levels during pregnancy and postpartum period [see Dosage and Administration (2.5)].

Labor or Delivery Risk of arrhythmias may increase during labor and delivery. Monitor patients continuously during labor and delivery [see Warnings and Precautions (5.1and 5.2)].

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 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 relative infant dose of digoxin between 1 to 7% of maternal weight- adjusted dose and about 0.2 to 4% of the neonatal maintenance dose.

The safety and effectiveness of Digoxin in the control of ventricular rate in children with atrial fibrillation have not been established.

The safety and effectiveness of Digoxin 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.

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 [seeDosage and Administration (2.1)].

The clearance of digoxin can be primarily correlated with the renal function as indicated by creatinine clearance. Tables 3 and 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.

Plasma digoxin concentrations in patients with acute hepatitis generally fall within the range of profiles in a group of healthy subjects.

The absorption of digoxin is reduced in some malabsorption conditions such as chronic diarrhea.

The signs and symptoms of toxicity are generally similar to those described in the Adverse Reactions (6.1) but may be more frequent and can be more severe. Signs and symptoms of digoxin toxicity become more frequent with levels above 2 ng/mL. However, in deciding whether a patient’s symptoms are due to digoxin, the clinical state together with serum electrolyte levels and thyroid function are important factors [see Dosage and Administration (2)] .

Adults: The most common signs and symptoms of digoxin toxicity are nausea, vomiting, anorexia, and fatigue that occur in 30-70% 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, non-specific extra-cardiac symptoms, such as malaise and weakness, may predominate.

Children: In pediatric patients, signs and symptoms of toxicity can occur during or shortly after the dose of digoxin. Frequent non-cardiac effects are similar to those observed in adults although nausea and vomiting are not seen frequently in infants and small pediatric patients. Other reported manifestations of overdose are weight loss in older age groups, failure to thrive in infants, abdominal pain caused by mesenteric artery ischemia, drowsiness, and behavioral disturbances including psychotic episodes.

Arrhythmias and combinations of arrhythmias that occur in adult patients can also occur in pediatric patients although sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in pediatric patients. Pediatric patients are more likely to develop A-V conduction disturbances, or sinus bradycardia. Any arrhythmia in a child treated with digoxin should be considered related to digoxin until otherwise ruled out. In pediatric patients aged 1-3 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.

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 (2.5)]. Correct hypokalemia by administering potassium so that serum potassium is maintained between 4.0 and 5.5 mmol/L. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and serum potassium concentration is low, potassium may be administered by the intravenous route. Monitor electrocardiogram for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. Avoid potassium salts in patients with bradycardia or heart block. Symptomatic arrhythmias may be treated with Digoxin Immune Fab.

Acute Overdose Patients who have intentionally or accidently ingested massive doses of digoxin should receive activated charcoal orally or by nasogastric tube regardless of the time since ingestion since digoxin recirculates to the intestine by enterohepatic circulation. In addition to cardiac monitoring, temporarily discontinue Digoxin 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.

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”).

{ "type": "p", "children": [], "text": "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 \n 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”).\n " }

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 C41H64O14, its molecular weight is 780.95, and its structural formula is:

{ "type": "p", "children": [], "text": "Digoxin is described chemically as (3β,5β,12β)-3-[( \n O-2,6-dideoxy-β- \n D-ribo-hexopyranosyl-(1→4)- \n O- 2,6-dideoxy-β- \n D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β- \n D- \n ribo-hexopyranosyl)oxy]-12,14- dihydroxy-card-20(22)-enolide. Its molecular formula is C41H64O14, its molecular weight is 780.95, and its structural formula is:\n " }

Digoxin exists as white or almost white powder or colorless crystals. The drug is practically insoluble in water; soluble in mixture of methanol & methylene chloride and slightly soluble in ethyl alcohol.

{ "type": "p", "children": [], "text": "Digoxin exists as white or almost white powder or colorless crystals. The drug is practically insoluble in water; soluble in mixture of methanol & methylene chloride and slightly soluble in ethyl alcohol." }

Digoxin is supplied as 62.5 mcg (unscored), 125 mcg (scored), and 250 mcg (scored) tablets for oral administration. Each tablet contains the labeled amount of digoxin USP and the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, lactose anhydrous, magnesium stearate. Additionally, the 62.5 mcg tablets contain FD&C Yellow No. 6 and 125 mcg tablets contain yellow iron oxide.

{ "type": "p", "children": [], "text": "Digoxin is supplied as 62.5 mcg (unscored), 125 mcg (scored), and 250 mcg (scored) tablets for oral administration. Each tablet contains the labeled amount of digoxin USP and the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, lactose anhydrous, magnesium stearate. Additionally, the 62.5 mcg tablets contain FD&C Yellow No. 6 and 125 mcg tablets contain yellow iron oxide." }

Meets USP Dissolution Test 2.

{ "type": "p", "children": [], "text": "\nMeets USP Dissolution Test 2.\n" }

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

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).

The times to onset of pharmacologic effect and to peak effect of preparations of Digoxin are shown in Table 7.

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <caption> <span>Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of Digoxin</span> </caption> <colgroup> <col width="30%"/> <col width="36%"/> <col width="34%"/> </colgroup> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes.</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">†</a> </dt> <dd>Depending upon rate of infusion.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Product</span> </p> </td><td class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Time to Onset of Effect</span><a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a> </p> </td><td class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Time to Peak Effect</span><a class="Sup" href="#footnote-9">*</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Digoxin Tablets</p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">0.5-2 hours</p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">2-6 hours</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Digoxin Injection/IV</p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">5-30 minutes <a class="Sup" href="#footnote-10" name="footnote-reference-10">†</a> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">1-4 hours</p> </td> </tr> </tbody> </table></div>

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 Digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects are not indicative of toxicity. Digoxin does not significantly reduce heart rate during exercise.

Note: The following data are from studies performed in adults, unless otherwise stated.

Absorption: Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hours. Absorption of digoxin from Digoxin Tablets has been demonstrated to be 60-80% complete compared to an identical intravenous dose of digoxin (absolute bioavailability). When Digoxin Tablets are taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Comparisons of the systemic availability and equivalent doses for oral preparations of Digoxin are shown in Dosage and Administration (2.6).

Digoxin is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin.

In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggest that 1 in 10 patients treated with digoxin tablets, colonic bacteria will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of digoxin in such patients. Although inactivation of these bacteria by antibiotics is rapid, the serum digoxin concentration will rise at a rate consistent with the elimination half-life of digoxin. Serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as doubled in some cases [see Drug Interactions (7.2)] .

Patients with malabsorption syndromes (e.g., short bowel syndrome, celiac sprue, jejunoileal bypass) may have a reduced ability to absorb orally administered digoxin.

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.

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.

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%).

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.

Digoxin Tablets have "N" on one side and are supplied as follows:

{ "type": "p", "children": [], "text": "\nDigoxin Tablets have \"N\" on one side and are supplied as follows:\n" }

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <colgroup> <col width="8%"/> <col width="11%"/> <col width="22%"/> <col width="13%"/> <col width="45%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Mcg</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Scored</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Color</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Imprint</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Unit dose packages of Ñ00 (10x10)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">125</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">Yes</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">Yellow</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">201</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NDC 60687-858-01</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">250</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">Yes</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">White to off-white</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">202</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NDC 60687-869-01</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" cellspacing=\"0pt\" width=\"100%\">\n<colgroup>\n<col width=\"8%\"/>\n<col width=\"11%\"/>\n<col width=\"22%\"/>\n<col width=\"13%\"/>\n<col width=\"45%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Mcg</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Scored</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Color</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Imprint</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Unit dose packages of Ñ00 (10x10)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">125</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">\n<p class=\"First\">Yes</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">\n<p class=\"First\">Yellow</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">\n<p class=\"First\">201</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">\n<p class=\"First\">NDC 60687-858-01</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">250</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">\n<p class=\"First\">Yes</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">\n<p class=\"First\">White to off-white</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">\n<p class=\"First\">202</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"middle\">\n<p class=\"First\">NDC 60687-869-01</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature] in a dry place and protect from light.

{ "type": "p", "children": [], "text": "\nStore at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature] in a dry place and protect from light.\n" }

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

{ "type": "p", "children": [], "text": "\nFOR YOUR PROTECTION: Do not use if blister is torn or broken.\n " }

Keep this and all medication out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep this and all medication out of the reach of children.\n" }

{ "type": "ul", "children": [ "Advise patients that many drugs can interact with Digoxin. Instruct patients to inform their doctor and pharmacist if they are taking any over the counter medications, including herbal medication, or are started on a new prescription.", "Advise patients to contact their doctor or a health care professional if they experience nausea, vomiting, persistent diarrhea, confusion, weakness, or visual disturbances (including blurred vision, green-yellow color disturbances, halo effect) as these could be signs that the dose of Digoxin may be too high.", "Advise parents or caregivers that the symptoms of having too high Digoxin 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." ], "text": "" }

PACKAGING INFORMATION American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Novitium Pharma LLC as follows: (125 mcg / 100 UD) NDC 60687‐858‐01 packaged from NDC 70954‐201 (250 mcg / 100 UD) NDC 60687‐869‐01 packaged from NDC 70954‐202

{ "type": "p", "children": [], "text": "\nPACKAGING INFORMATION \n \nAmerican Health Packaging unit dose blisters (see How Supplied section) contain drug product from Novitium Pharma LLC as follows: \n (125 mcg / 100 UD) NDC 60687‐858‐01 packaged from NDC 70954‐201 \n (250 mcg / 100 UD) NDC 60687‐869‐01 packaged from NDC 70954‐202\n\n " }

Distributed by: American Health Packaging Columbus, OH 43217

{ "type": "p", "children": [], "text": "Distributed by:\n \n \n American Health Packaging \n \nColumbus, OH 43217\n\n " }

8485801/0824

{ "type": "p", "children": [], "text": "\n8485801/0824\n" }

NDC 60687- 858-01

{ "type": "p", "children": [], "text": "NDC 60687-\n 858-01\n " }

Digoxin Tablets, USP

{ "type": "p", "children": [], "text": "\nDigoxin \n\nTablets, USP\n " }

125 mcg

{ "type": "p", "children": [], "text": "\n125 mcg\n" }

100 Tablets (10 x 10)                 Rx Only

{ "type": "p", "children": [], "text": "\n100 Tablets (10 x 10)                 Rx Only\n" }

Each scored tablet contains 125 mcg.

{ "type": "p", "children": [], "text": "\nEach scored tablet contains 125 mcg.\n" }

Usual Dosage: See full prescribing information.

{ "type": "p", "children": [], "text": "\nUsual Dosage: See full prescribing information.\n " }

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] in a dry place and protect from light.

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F); excursions permitted between\n \n15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]\n \nin a dry place and protect from light.\n " }

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

{ "type": "p", "children": [], "text": "\nFOR YOUR PROTECTION: Do not use if blister is torn or broken.\n " }

The drug product contained in this package is from NDC # 70954-201, Novitium Pharma LLC.

{ "type": "p", "children": [], "text": "The drug product contained in this package is from\n \nNDC # 70954-201, Novitium Pharma LLC.\n " }

Distributed by: American Health Packaging, Columbus, Ohio 43217

{ "type": "p", "children": [], "text": "Distributed by: American Health Packaging, Columbus, Ohio 43217" }

785801 0485801/0824

{ "type": "p", "children": [], "text": "785801\n \n0485801/0824\n " }

Digoxin Tablet, USP

{ "type": "p", "children": [], "text": "Digoxin Tablet, USP" }

125 mcg

{ "type": "p", "children": [], "text": "\n125 mcg\n" }

NDC 60687- 869-01

{ "type": "p", "children": [], "text": "NDC 60687-\n 869-01\n " }

Digoxin Tablets, USP

{ "type": "p", "children": [], "text": "\nDigoxin \n\nTablets, USP\n " }

250 mcg

{ "type": "p", "children": [], "text": "\n250 mcg\n" }

100 Tablets (10 x 10)                 Rx Only

{ "type": "p", "children": [], "text": "\n100 Tablets (10 x 10)                 Rx Only\n" }

Each scored tablet contains 250 mcg.

{ "type": "p", "children": [], "text": "\nEach scored tablet contains 250 mcg.\n" }

Usual Dosage: See full prescribing information.

{ "type": "p", "children": [], "text": "\nUsual Dosage: See full prescribing information.\n " }

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] in a dry place and protect from light.

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F); excursions permitted between\n \n15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]\n \nin a dry place and protect from light.\n " }

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

{ "type": "p", "children": [], "text": "\nFOR YOUR PROTECTION: Do not use if blister is torn or broken.\n " }

The drug product contained in this package is from NDC # 70954-202, Novitium Pharma LLC.

{ "type": "p", "children": [], "text": "The drug product contained in this package is from\n \nNDC # 70954-202, Novitium Pharma LLC.\n " }

Distributed by: American Health Packaging, Columbus, Ohio 43217

{ "type": "p", "children": [], "text": "Distributed by: American Health Packaging, Columbus, Ohio 43217" }

786901 0486901/0824

{ "type": "p", "children": [], "text": "786901\n \n0486901/0824\n " }

Digoxin Tablet, USP

{ "type": "p", "children": [], "text": "Digoxin Tablet, USP" }

250 mcg

{ "type": "p", "children": [], "text": "\n250 mcg\n" }