Digoxin (Page 6 of 8)

8.7 Hepatic Impairment

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

8.8 Malabsorption

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

10 OVERDOSAGE

10.1 Signs and Symptoms in Adults and Children

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

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

Digoxin toxicity is related to serum concentration. As digoxin serum levels increase above

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

Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g., nausea, vomiting, anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in approximately half of the patients in most literature reports. Neurologic manifestations (e.g., dizziness, various CNS disturbances), fatigue, and malaise are very common. Visual manifestations may also occur with aberration in color vision (predominance of yellow green) the most frequent. Neurological and visual symptoms may persist after other signs of toxicity have resolved. In chronic toxicity, non-specific extra-cardiac symptoms, such as malaise and weakness, may predominate.

Children:In pediatric patients, signs and symptoms of toxicity can occur during or shortly after the dose of digoxin. Frequent non-cardiac effects are similar to those observed in adults although nausea and vomiting are not seen frequently in infants and small pediatric patients. Other reported manifestations of overdose are weight loss in older age groups, failure to thrive in infants, abdominal pain caused by mesenteric artery ischemia, drowsiness, and behavioral disturbances including psychotic episodes. Arrhythmias and combinations of arrhythmias that occur in adult patients can also occur in pediatric patients although sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in pediatric patients. Pediatric patients are more likely to develop A-V conduction disturbances, or sinus bradycardia. Any arrhythmia in a child treated with digoxin should be considered related to digoxin until otherwise ruled out. In pediatric patients aged 1 to 3 years without heart disease, clinical observations suggest that an overdose of digoxin of

6 to 10 mg would result in death of half of the patients. In the same population, a dose above 10 mg resulted in death if no Digoxin Immune Fab were administered.

10.2 Treatment

Chronic Overdose

If there is suspicion of toxicity, discontinue Digoxin Tablets and place the patient on a cardiac monitor. Correct factors such as electrolyte abnormalities, thyroid dysfunction, and concomitant medications [see Dosage and Administration (2.5)]. Correct hypokalemia by administering potassium so that serum potassium is maintained between 4.0 and 5.5 mmol/L. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and serum potassium concentration is low, potassium may be administered by the intravenous route. Monitor electrocardiogram for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. Avoid potassium salts in patients with bradycardia or heart block. Symptomatic arrhythmias may be treated with Digoxin Immune Fab.

Acute Overdose

Patients who have intentionally or accidently ingested massive doses of digoxin should receive activated charcoal orally or by nasogastric tube regardless of the time since ingestion since digoxin recirculates to the intestine by enterohepatic circulation. In addition to cardiac monitoring, temporarily discontinue Digoxin Tablets until the adverse reaction resolves. Correct factors that may be contributing to the adverse reactions [see Warnings and Precautions (5)]. In particular, correct hypokalemia and hypomagnesemia. Digoxin is not effectively removed from the body by dialysis because of its large extravascular volume of distribution. Life threatening arrhythmias (ventricular tachycardia, ventricular fibrillation, high degree A-V block, bradyarrhythma, sinus arrest) or hyperkalemia requires administration of Digoxin Immune Fab. Digoxin Immune Fab has been shown to be 80 to 90% effective in reversing signs and symptoms of digoxin toxicity. Bradycardia and heart block caused by digoxin are parasympathetically mediated and respond to atropine. A temporary cardiac pacemaker may also be used. Ventricular arrhythmias may respond to lidocaine or phenytoin. When a large amount of digoxin has been ingested, especially in patients with impaired renal function, hyperkalemia may be present due to release of potassium from skeletal muscle. In this case, treatment with Digoxin Immune Fab is indicated; an initial treatment with glucose and insulin may be needed if the hyperkalemia is life threatening. Once the adverse reaction has resolved, therapy with Digoxin Tablets may be reinstituted following a careful reassessment of dose.

11 DESCRIPTION

Digoxin is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves of Digitalis lanata. The term “digitalis” is used to designate the whole group of glycosides. The glycosides are composed of 2 portions: a sugar and a cardenolide (hence “glycosides”).

Digoxin is described chemically as (3β,5β,12β)-3-[(O -2,6-dideoxy-β-D-ribo -hexopyranosyl(1→4)-O -2,6-dideoxy-β-D-ribo- hexopyranosyl-(1→4)-2,6-dideoxy-β-D -ribo hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. Its molecular formula is C41 H64 O14 , its molecular weight is 780.95, and its structural formula is:

Structural Formula
(click image for full-size original)

Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine.

Digoxin Tablets, USP are supplied as 125 mcg (0.125 mg) or 250 mcg (0.25 mg) tablets for oral administration. Each tablet contains the labeled amount of Digoxin, USP and the following inactive ingredients:

125 mcg (0.125 mg): anhydrous lactose, colloidal silicon dioxide, corn starch, D&C yellow #10 aluminum lake, FD&C yellow #6 aluminum lake, lactose monohydrate, magnesium stearate and starch 1500.

250 mcg (0.25 mg): anhydrous lactose, colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate and starch 1500.

12 CLINICAL PHARMACOLOGY

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