Toxicology Details - MICROMEDEX®

2016/9/24
Toxicology details - MICROMEDEX
CARDIAC GLYCOSIDES
POISINDEX
OVERVIEW
LIFE SUPPORT
A) This overview assumes that basic life support measures have been instituted.
CLINICAL EFFECTS
0.2.1) SUMMARY OF EXPOSURE
A) USES: Cardiac glycosides are medications derived from naturally occurring toxins; digitalis is
the most widely used, digitoxin is used outside the US. Plants and animals that contain cardiac
glycosides are covered in separate managements. Cardiac glycosides are used for congestive
heart failure and for ventricular rate control in atrial fibrillation.
B) PHARMACOLOGY: Cardiac glycosides inhibit the sodium-potassium ATPase pump. The
increase in intracellular sodium leads to increased activity of the sodium-calcium exchanger,
which elevates intracellular calcium and improves cardiac contractility. Cardiac glycosides also
increase cardiac vagal tone which decreases cardiac sympathetic activity.
C) TOXICOLOGY: The effects in overdose are an extension of the therapeutic effects. Increased
intracellular calcium leads to early afterdepolarization, cardiac irritability, and dysrhythmias.
Increased vagal and decreased sympathetic tones lead to bradycardia and heart block. Inhibition
of the sodium-potassium ATPase pump causes hyperkalemia.
D) EPIDEMIOLOGY: Cardiac glycoside toxicity is uncommon, but severe toxicity and deaths may
occur. Most cases are due to exposure to pharmaceuticals, but occasionally patients will develop
symptoms after ingestion of plant or animal products containing cardiac glycosides.
E) WITH THERAPEUTIC USE
1) Headache, fatigue, stupor, gynecomastia, skin rash, and thrombocytopenia have been
associated with chronic use.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Toxicity from cardiac glycosides can be acute (from a single
overdose due to accidental ingestion by a child or due to a self-harm attempt by an adult) or
chronic toxicity (due to increased dosing or decreased drug clearance). The manifestations and
treatment are slightly different. The most common symptoms following acute ingestion are
nausea, vomiting, abdominal pain, lethargy, and bradycardia. With chronic toxicity, patients often
present with bradycardia, malaise, nausea, anorexia, delirium, and vision changes.
2) SEVERE TOXICITY: Patients with acute poisoning may develop severe bradycardia, heart
block, vomiting, and shock. Hyperkalemia is a marker of severe acute toxicity and serum
potassium is the best predictor of cardiac glycoside toxicity after acute overdose. Severe chronic
toxicity causes ventricular dysrhythmias and varying degrees of heart block, but hyperkalemia is
uncommon.
0.2.20) REPRODUCTIVE
A) Digoxin has been classified as FDA pregnancy category C. There are no adequate and wellcontrolled studies of digoxin in pregnant women. Animal studies have not been conducted.
Congenital anomalies and perinatal problems have not been linked with cardiac glycoside use
during pregnancy. Digoxin can be used in pregnancy, but may require dosage adjustments due to
increased plasma volume, decreased protein binding, and increased renal excretion in the
pregnant patient. Digoxin has been used in pregnant women without apparent harm to the
mother or fetus. The fetus is able to metabolize digoxin and excretes it in the bile. Low birth
weight has been observed in infants of mothers receiving digitalis glycosides, presumably due to
decreased gestational age and not due to intrauterine growth retardation. In addition, adverse
effects to the fetus have been found when the mother develops digitalis toxicity. As it is unknown
whether digoxin causes fetal harm when administered during pregnancy, it is recommended that
the drug be administered in pregnant women only if clearly necessary.
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0.2.21) CARCINOGENICITY
A) Digoxin has been associated with chronic lymphocytic leukemia, but data are lacking to assess
the potential carcinogenic activity of digoxin.
LABORATORY/MONITORING
A) Monitor serial serum digoxin concentrations and serum electrolytes every hour, until patient is
improved and digoxin concentrations are clearly declining towards therapeutic. False positive
digoxin concentrations have been reported in patients with pregnancy, liver disease, and
hypothermia.
B) Monitor renal function.
C) For acute cardiac glycoside exposure, serum potassium (hyperkalemia) is the best marker of
toxicity. Serum potassium should be monitored every 60 minutes following any potentially
significant acute exposure to a cardiac glycoside. Serum potassium is NOT predictive of toxicity for
chronic cardiac glycoside toxicity.
D) Institute continuous cardiac monitoring and obtain serial ECG's.
TREATMENT OVERVIEW
0.4.2) ORAL/PARENTERAL EXPOSURE
A) MANAGEMENT OF MILD TO MODERATE TOXICITY
1) Patients who do not develop significant cardiac toxicity require only supportive care and
monitoring. Patients with mild bradycardia and nonspecific symptoms from chronic poisoning
should be monitored and rehydrated, but do not require specific therapy.
B) MANAGEMENT OF SEVERE TOXICITY
1) Following acute ingestion, patients with hyperkalemia (greater than 5 mEq/L), symptomatic
bradycardia, ventricular ectopy, or dysrhythmias should be treated with digoxin immune Fab.
Digoxin immune Fab is also indicated for patients with chronic toxicity with ventricular ectopy or
symptomatic bradycardia. If digoxin immune Fab is not available, patients can be treated with
atropine or cardiac pacing for bradycardia and antidysrhythmics (lidocaine or amiodarone) for
ventricular ectopy or dysrhythmias. Other treatments have been suggested. Phenytoin (100 mg
to 300 mg IV bolus) and magnesium sulfate (2 g) have both been anecdotally reported to
produce resolution of dysrhythmias from cardiac glycoside poisoning. Finally, cardiac pacing (at a
rate that exceeds cardiac ectopy) can be used for patients who do not respond to medical
management.
C) DECONTAMINATION
1) PREHOSPITAL: Emesis is not recommended for cardiac glycoside ingestion. Activated
charcoal should be given to patients who can protect their airway and are not actively vomiting.
2) HOSPITAL: Cardiac glycosides are well adsorbed by charcoal; administration of charcoal
should be considered in all cases that present within 1 to 2 hours of ingestion.
D) AIRWAY MANAGEMENT
1) Airway protection is mandatory in patients with altered mental status.
E) ANTIDOTE
1) The antidote for cardiac glycoside poisoning is digoxin immune Fab (digoxin immune antibody
fragment) which rapidly reverses the effect of cardiac glycosides.
2) INDICATIONS: Indications for digoxin immune Fab include manifestations of severe toxicity
(ventricular dysrhythmias, progressive bradyarrhythmias, 2nd or 3rd degree heart block),
refractory hypotension, hyperkalemia (greater than 5 mEq/L in acute overdose), significant risk
of cardiac arrest (ingestion greater than 10 mg in an adult or greater than 4 mg in a child, serum
digoxin concentration greater 10 ng/mL post-distribution [generally 6 hours after ingestion]), or
lack of response to conventional therapy. The appropriate dose can be calculated from either the
ingested dose or the steady state serum digoxin concentration.
3) BY INGESTED DOSE: The digoxin immune Fab dose (in vials) equals the ingested dose of
capsules (in mg) divided by 0.5 mg per vial OR the ingested dose of tablets (in mg) multiplied by
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capsules (in mg) divided by 0.5 mg per vial OR the ingested dose of tablets (in mg) multiplied by
0.8 (for 80% bioavailability) and divided by 0.5 mg per vial.
4) BY STEADY STATE CONCENTRATION: The digoxin immune Fab dose (in vials) equals the
steady state serum digoxin concentration (in ng/mL) multiplied by the patient weight (in kg)
divided by 100. Administer 10 to 20 vials for critically ill patients or patients in cardiac arrest.
5) ADVERSE EFFECTS: Allergic reactions are rare, but can happen, especially in patients with a
history of asthma and/or allergy to antibiotics. Hypokalemia, worsening of heart failure, and loss
of ventricular rate control can also occur.
F) ENHANCED ELIMINATION
1) Hemodialysis does not increase the clearance of digoxin. Multiple dose charcoal enhances
digoxin clearance and may be considered in a patient who can protect their airway if digoxin
immune Fab is not available.
G) PATIENT DISPOSITION
1) OBSERVATION CRITERIA: Patients who have only GI symptoms and a clearly decreasing
serum digoxin concentration can be discharged after a minimum of 8 hours of observation.
2) ADMISSION CRITERIA: Admit all patients, who develop dysrhythmias, heart block, severe
vomiting, or who require digoxin immune Fab treatment, to an ICU setting. Admit patients to a
monitored setting if they have digoxin concentrations that are not clearly declining during 8 hours
of observation.
H) PITFALLS
1) Digoxin has a slow redistribution phase, so high serum concentrations are expected for
several hours following doses. A single high digoxin concentration in an otherwise asymptomatic
patient is not an indication for treatment. Severe toxicity from cardiac glycosides is very difficult
to treat if digoxin immune Fab is not available. Serum digoxin concentrations will rise after
digoxin immune Fab treatment if the assay used does not distinguish free from bound digoxin.
I) PHARMACOKINETICS
1) Digoxin is concentrated in tissues and therefore has a large volume of distribution. Time to
onset of action is about 0.5 to 2 hours after oral dosing and peaks at 2 to 6 hours, and is
excreted unchanged by the kidney. The elimination half-life is about 30 to 45 hours for a
therapeutic level in a patient with normal renal function. Digitoxin is extensively metabolized by
the liver, primarily excreted in bile, and has an elimination half-life of about 4 to 7 days.
J) TOXICOKINETICS
1) Digoxin half-life may be prolonged in overdose (72 to 94 hours).
K) DIFFERENTIAL DIAGNOSIS
1) The differential diagnosis should include other causes of bradycardia, heart block, altered
mental status, and hypotension, including calcium channel antagonists, beta-blockers, clonidine,
and medical causes such as acute myocardial infarction or hypoxia.
RANGE OF TOXICITY
A) ADULTS: Healthy adults may develop symptoms after acute ingestions of more than 2 to 3 mg,
but rarely develop life-threatening toxicity with acute ingestions of less than 5 mg. Ingestions
causing cardiac arrest in healthy adults are generally 10 mg digoxin or more.
B) PEDIATRIC: A healthy child can probably tolerate an acute ingestion of 2 mg digoxin without
severe toxicity. Toxic effects are likely with ingestions of more than 0.1 mg/kg, and acute
ingestions of 4 mg digoxin or more in young children may be fatal.
C) THERAPEUTIC DOSE: Varies with formulation. ADULTS: (intravenous and/or oral capsule) For
rapid digitalization, give a digoxin loading dose of 0.4 to 0.6 mg orally or IV; for gradual
digitalization, give digoxin maintenance doses of 0.05 to 0.350 mg orally once daily. (Tablet) 0.5 to
0.75 mg orally as a loading dose for rapid digitalization, then 0.125 to 0.5 mg orally once daily.
(Solution) maintenance dose of 3 mcg/kg orally daily. CHILDREN: (intravenous and/or oral
capsule) For rapid digitalization, give orally or IV in divided doses (premature) 15 to 25 mcg/kg;
(full-term) 20 to 30 mcg/kg; (1 to 24 months) 30 to 50 mcg/kg; (2 to 5 years) 25 to 35 mcg/kg; (5
to 10 years) 15 to 30 mcg/kg; (over 10 years) 8 to 12 mcg/kg; for daily maintenance doses for
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gradual digitalization, give 20% to 30% of IV digitalizing dose for premature infants or 25% to
35% of oral or IV digitalizing dose for all other pediatric patients. (Solution) older than 2 years,
maintenance dose of 10 mcg/kg/day orally. (Tablet) 2 to 5 years of age, 10 to 15 mcg/kg/day in
divided doses; 5 to 10 years of age, 7 to 10 mcg/kg/day in divided doses; over 10 years of age, 3
to 5 mcg/kg/day in divided doses.
SUBSTANCES INCLUDED/SYNONYMS
THERAPEUTIC/TOXIC CLASS
A) Cardiac glycosides are medications derived from naturally occurring toxins; digitalis is the most
widely used, digitoxin is used outside the US. Cardiac glycosides are used for congestive heart
failure and for ventricular rate control in atrial fibrillation. Plants and animals that contain cardiac
glycosides are covered in separate managements.
SPECIFIC SUBSTANCES
A) CARDIAC GLYCOSIDES
1) Cardioactive Steroids (synonym)
2) Carditoxin (synonym)
3) Deslanoside (synonym)
4) Digitalis Glycoside (synonym)
5) Digitalis leaf (synonym)
6) Digitoxin (synonym)
7) Digoxin (synonym)
8) Lanatoside C (synonym)
9) Lanoxin (synonym)
10) Ouabain (synonym)
11) CAS 20830-75-5 (Digoxin) (synonym)
12) CAS 71-63-6 (Digitoxin) (synonym)
13) CAS 36-06-6 (Ouabain) (synonym)
14) CAS 630-60-4 (Ouabain) (synonym)
AVAILABLE FORMS/SOURCES
A) FORMS
1) DIGOXIN: 0.05 mg, 0.1 mg, and 0.2 mg capsules; 0.125 mg and 0.25 mg tablets; 0.05 mg/mL
pediatric elixir; 0.25 mg/mL injection; 0.1 mg/mL pediatric injection (USP-DI, 2001).
2) DIGITOXIN: 0.1 mg tablets (available in Canada) (USP-DI, 2001).
3) DESLANOSIDE: 0.2 mg/mL injection (no longer available in the United States)
B) SOURCES
1) Cardiac glycosides are contained in digitalis leaf, foxglove (Digitalis purpurea), Lilly of the
Valley (Convallaria majalis), oleander (Nerium oleander), Digitalis lanata, Strophantus
kombe/gratis, hispidus seeds, squill (Urginea maritima/indica bulbs), Dogbane (Apocynum
cannabinum), Adonis vernalis, and Thevetia peruviana.
2) Acetyldigitoxin is a crystalline glycoside derived from Digitalis lanata and is the natural
occurring cardiac glycoside defined as the alpha acetyl ester of digitoxin.
C) USES
1) These drugs are indicated for the treatment of mild to moderate heart failure and for control of
ventricular response rate in patients with chronic atrial fibrillation. Digoxin increases left
ventricular ejection fraction resulting in improvement of heart failure symptoms. Digoxin is often
used in conjunction with a diuretic and an angiotensin-converting enzyme inhibitor for the
treatment of heart failure (Prod Info LANOXICAPS(R) oral capsules, 2005).
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treatment of heart failure (Prod Info LANOXICAPS(R) oral capsules, 2005).
CLINICAL EFFECTS
SUMMARY OF EXPOSURE
A) USES: Cardiac glycosides are medications derived from naturally occurring toxins; digitalis is
the most widely used, digitoxin is used outside the US. Plants and animals that contain cardiac
glycosides are covered in separate managements. Cardiac glycosides are used for congestive
heart failure and for ventricular rate control in atrial fibrillation.
B) PHARMACOLOGY: Cardiac glycosides inhibit the sodium-potassium ATPase pump. The increase
in intracellular sodium leads to increased activity of the sodium-calcium exchanger, which elevates
intracellular calcium and improves cardiac contractility. Cardiac glycosides also increase cardiac
vagal tone which decreases cardiac sympathetic activity.
C) TOXICOLOGY: The effects in overdose are an extension of the therapeutic effects. Increased
intracellular calcium leads to early afterdepolarization, cardiac irritability, and dysrhythmias.
Increased vagal and decreased sympathetic tones lead to bradycardia and heart block. Inhibition
of the sodium-potassium ATPase pump causes hyperkalemia.
D) EPIDEMIOLOGY: Cardiac glycoside toxicity is uncommon, but severe toxicity and deaths may
occur. Most cases are due to exposure to pharmaceuticals, but occasionally patients will develop
symptoms after ingestion of plant or animal products containing cardiac glycosides.
E) WITH THERAPEUTIC USE
1) Headache, fatigue, stupor, gynecomastia, skin rash, and thrombocytopenia have been
associated with chronic use.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Toxicity from cardiac glycosides can be acute (from a single
overdose due to accidental ingestion by a child or due to a self-harm attempt by an adult) or
chronic toxicity (due to increased dosing or decreased drug clearance). The manifestations and
treatment are slightly different. The most common symptoms following acute ingestion are
nausea, vomiting, abdominal pain, lethargy, and bradycardia. With chronic toxicity, patients often
present with bradycardia, malaise, nausea, anorexia, delirium, and vision changes.
2) SEVERE TOXICITY: Patients with acute poisoning may develop severe bradycardia, heart
block, vomiting, and shock. Hyperkalemia is a marker of severe acute toxicity and serum
potassium is the best predictor of cardiac glycoside toxicity after acute overdose. Severe chronic
toxicity causes ventricular dysrhythmias and varying degrees of heart block, but hyperkalemia is
uncommon.
HEENT
3.4.2) HEAD
A) WITH THERAPEUTIC USE
1) CASE REPORT: A 62-year-old man on chronic digoxin therapy (0.25 mg/day) developed taste
disturbances. An electric gustometer and measurement with a filter paper disk indicated a
diminished sense of sweet, bitter, and salt tastes. At the same time, the patient also
experienced decreased visual acuity and a decreased sense of smell. Laboratory studies showed
that his serum digoxin level peaked at 6 ng/mL (normal 1.9 ng/mL). Digoxin therapy was
discontinued and all of the patient's sensory disturbances resolved following normalization of his
serum digoxin level (Ishimaru & Yokogawa, 2006).
3.4.3) EYES
A) VISUAL DISTURBANCES: Photophobia, amblyopia, aberrations of color vision (predominance
of yellow-green), decreased visual acuity, miosis, and scotoma may occur, but generally are seen
only in chronic digitalis toxicity.
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1) Cones are 50-fold more sensitive than rods. Inhibition of light response by photoreceptors is
concentration-dependent and reversible (Madreperla et al, 1994).
a) CASE REPORT: Piltz et al (1993) report the case of an 88-year-old woman presenting to the
emergency department with decreased visual acuity and an increased serum digoxin level (Piltz
et al, 1993). Electroretinographic (ERG) studies suggested a cone deficit implicating a retinal
dysfunction.
b) CASE REPORT: A 62-year-old man on chronic digoxin therapy (0.25 mg/day) developed
photophobia with decreased visual acuity, as well as taste and olfactory disturbances.
Laboratory studies showed that his serum digoxin level peaked at 6 ng/mL (normal 1.9 ng/mL).
Digoxin therapy was discontinued and all of the patient's sensory disturbances resolved
following normalization of his serum digoxin level (Ishimaru & Yokogawa, 2006).
c) CASE REPORT: Diplopia and blurred and yellow vision were reported in a 30-year-old woman
following intentional ingestion of 70 0.25-mg digoxin tablets (total dose 17.5 mg). Serum digoxin
level was 12.63 ng/mL (normal range 0.8 to 2 ng/mL) (Juneja et al, 2012).
B) CORNEAL EDEMA: Topical application of digitoxin (0.02 mg/10 mL) and digoxin (25 mg/100
mL resulted in corneal edema. The effects appeared to be reversible upon discontinuation of the
medication (Grant & Schuman, 1993).
C) CONE DYSFUNCTION: Electroretinography revealed cone dysfunction in dogs poisoned with
digitalis (Maehara et al, 2005).
D) PHOTOPSIA: A 72-year-old woman, who was taking 0.125 mg of digoxin daily, developed a
sudden onset of binocular photopsia. A review of her history revealed that she had diarrhea and
appetite loss for 10 days. Laboratory analysis showed a serum creatinine level of 1.8 mg/dL, a
serum potassium level of 5.7 mEq/L, and a serum digoxin level of 1.70 ng/mL . The photopsia
resolved following discontinuation of digoxin therapy and administration of fluids (Oishi et al,
2006).
3.4.5) NOSE
A) WITH THERAPEUTIC USE
1) CASE REPORT: A 62-year-old man on chronic digoxin therapy (0.25 mg/day) developed a
decreased sense of smell, along with decreased visual acuity and taste disturbances. Laboratory
studies showed that his serum digoxin level peaked at 6 ng/mL (normal 1.9 ng/mL). Digoxin
therapy was discontinued and all of the patient's sensory abnormalities resolved following
normalization of his serum digoxin level (Ishimaru & Yokogawa, 2006).
CARDIOVASCULAR
3.5.2) CLINICAL EFFECTS
A) CONDUCTION DISORDER OF THE HEART
1) WITH THERAPEUTIC USE
a) Exercise-induced ventricular tachycardia and a widened QRS complex were reported in a
patient 2 weeks after therapy with digoxin (0.25 mg/day) had been instituted. The dysrhythmia
produced no symptoms and terminated spontaneously after 25 seconds (Gosselink et al, 1993).
b) CASE REPORT: A 6-month-old infant, experiencing persistent tachycardia (140 to 230 bpm)
and an increase in serum creatinine levels (from 67 mcmol/L to 99 mcmol/L) after cardiac
surgery, received 3 doses of intravenous digoxin (0.16 mg, 0.08 mg, and 0.08 mg). Despite
digoxin administration, there was no improvement in the patient's tachycardia and the serum
creatinine level increased to 134 mcmol/L with complete anuria. Serum digoxin concentration,
obtained 24 hours after initiation of digoxin therapy, was 8.1 nmol/L. The patient's serum
potassium level was elevated, peaking at 7.8 mmol/L, and she developed an AV junctional
tachycardia (300 bpm). Digibind(R) was initiated intravenously at a bolus dose of 14.2 mg and,
1 minute later, the AV junctional tachycardia converted to regular sinus rhythm at a rate of 140
bpm and, 20 minutes later, the patient's potassium level normalized to 4.5 mmol/L (Husby et al,
2003). The authors speculated that the toxic digoxin levels may have been due to a too rapid
administration of the 0.08 mg follow-up doses in a patient with renal impairment.
c) CASE REPORT: An 86-year-old woman, taking 0.25 mg of digoxin daily for chronic atrial
fibrillation, developed cardiac arrest. She was successfully resuscitated following electrical
cardioversion. An ECG revealed alternating QRS complexes with a regularity of tachycardia
characteristic of bidirectional ventricular tachycardia. Laboratory studies showed a serum
creatinine level of 10 mg/L, a creatinine clearance of 45 mL/min, and a serum digoxin level of 13
ng/mL (normal is less than 2). A review of her medication history revealed that in addition to 6/69
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ng/mL (normal is less than 2). A review of her medication history revealed that in addition to
digoxin, the patient was also taking perindopril, fosinopril, isosorbide dinitrate, and
acetylsalicylic acid. It is believed that a combination of dehydration and several nephrotoxic
medications, leading to decreased renal function, may have resulted in digoxin toxicity. The
patient recovered with supportive care (Grimard et al, 2005).
d) CASE REPORT: A 79-year-old woman, with a history of congestive heart failure and
persistent atrial fibrillation, developed bidirectional tachycardia followed by ventricular fibrillation
approximately 20 days after initiating therapy with IV digoxin 0.125 mg daily and approximately
14 days after receiving hemodialysis for acute renal failure. Her serum digoxin and potassium
concentrations were 2.4 ng/mL and 2.7 mEq/L, respectively. The patient recovered following
successful defibrillation (Kaneko et al, 2011).
2) WITH POISONING/EXPOSURE
a) SUMMARY: The hallmark of digitalis poisoning is increased automaticity coupled with
concomitant conduction delay. Every known type of dysrhythmia has been associated with
digitalis intoxication, including bradycardia, all degrees of heart block, PAT with block, bundle
branch block, nodal tachycardia with A-V dissociation, atrial and ventricular ectopy, and
ventricular tachycardia and fibrillation; any or all may occur in the same patient (Rodensky &
Wasserman, 1961; Bhatia & Smith, 1987; Soffer, 1961; Lyon & DeGraff, 1967; Gould et al, 1986;
Nordt et al, 1998; Caspi et al, 1997; Fenton et al, 1996; Ma et al, 2001; Guijarro-Morales et al,
2002).
1) Although no single dysrhythmia is always present, commonly appearing aberrations include
frequent premature ventricular contractions, bradydysrhythmias, paroxysmal atrial tachycardia
with high degree atrioventricular block, and junctional tachycardia. Bidirectional ventricular
tachycardia is rare but pathognomonic (Ma et al, 2001).
2) In a case of an intentional overdose (probably 5 to 10 mg), an unusual ECG pattern was
seen in a 46-year-old woman with no cardiac symptoms. Initial ECG revealed slow ventricular
repolarization (33 beats/minute) characterized by apparent QT-interval prolongation and a QTinterval dispersion. Prominent and prolonged U-waves were also seen (Lanzarini et al, 2002).
3) PEDIATRIC EXPOSURE: The most common presenting symptoms in a pediatric patient are
gastrointestinal complaints, sinus bradycardia, or first-degree AV block (Morini et al, 2003;
Gittelman et al, 1999).
b) Torsades de Pointes may also occur with digitalis toxicity (Bhatia & Smith, 1987).
c) Atrial and ventricular ectopy appear to be more common in patients with underlying heart
disease (Hickey et al, 1991).
1) CASE REPORT: Digitoxin toxicity was reported in a 79-year-old man who had been taking
digitoxin for 2 years and who also was taking therapy for atrial fibrillation. The patient
experienced ventricular ectopy which correlated well with his serum digitoxin concentration and
was apparently precipitated by adrenergic drive during exertion (Lehmann et al, 2000).
d) In 1 study involving 29 pediatric patients with severe digitalis poisoning, atrioventricular block
was the most common sign of toxicity, occurring in 76% of the patients (Woolf et al, 1992).
e) Chan et al (1995) describe an unusual bidirectional ventricular tachycardia associated with
digoxin toxicity in a 55-year-old man with new onset renal insufficiency. Resolution of the
tachycardia occurred following Digibind (Chan et al, 1995).
f) CASE REPORT: A 22-month-old boy presented to the emergency department the day
following ingestion of an unknown quantity of digoxin tablets. ECG revealed a Mobitz 1, seconddegree heart block with a PR interval of 0.20 seconds. A digoxin level of 11.9 ng/mL was
reported (Gittelman et al, 1999).
g) CASE REPORT: A 30-year-old woman developed persistent vomiting, diplopia, blurred and
yellow vision, and intermittent episodes of bradycardia with hypotension after ingesting 70 0.25mg digoxin tablets (total dose 17.5 mg). An initial serum digoxin level was 12.63 ng/mL (normal
range, 0.8 to 2 ng/mL). An ECG revealed prolonged and varying PR interval with atrial ectopics,
subsequently converting to complete heart block. Because of continued bradycardic episodes,
transcutaneous pacing was applied and a temporary pacemaker was inserted. Due to a high
serum digoxin level and unavailability of digoxin Fab fragments, resin hemoperfusion was
performed over a 4-hour period. Within 4 hours, the patient's vision improved and her nausea
and vomiting resolved. Over the next 24 to 36 hours, her cardiac status improved with resolution
of her heart block and a decrease in her digoxin level to 2.56 ng/mL. The patient was discharged
4 days after admission following normalization of her serum digoxin level and complete
resolution of symptoms (Juneja et al, 2012).
h) CASE REPORT: A 26-year-old pregnant woman, at 21 weeks gestation, presented to the
emergency department with burning pain, abdominal cramps, and lightheadedness
approximately 2 hours after being injected intraperitoneally into the stomach with 1 mg digoxin.
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approximately 2 hours after being injected intraperitoneally into the stomach with 1 mg digoxin.
An ECG revealed sinus tachycardia, with a heart rate of 140. An initial digoxin level, obtained 2
hours post-injection, was 8.1 mg/dL and her potassium level was 3.4 mEq/L. Digibind was not
administered and, 7 hours post-injection, her digoxin level decreased to 2.5 mg/dL. Following
continued observation and resolution of symptoms, she was discharged 24 hours later. The
outcome of the fetus was unknown (Mellesmoen & Gummin, 2015).
B) CARDIAC ARREST
a) Hypotension and cardiac arrest may occur. Peak cardiac effects generally occur 3 to 6 hours
following digoxin overdosage and may persist for the ensuing 24 hours or longer (Caspi et al,
1997; Williams & Erickson, 1998).
b) CASE REPORT: Cardiac arrest was reported approximately 4 hours following an overdose of
10 mg digoxin in a 79-year-old man. Catecholamines were given during percutaneous
cardiopulmonary bypass to maintain mean arterial pressure and the patient was placed on a
respirator. Twelve days after the overdose the patient died from septic shock (Behringer et al,
1998).
c) CASE REPORT: Two weeks after undergoing an open-heart surgery, a 12-week-old girl with
known cardiac disease (a double outlet right ventricle with a subaortic ventricular septal defect
and a single coronary artery) presented in asystolic cardiac arrest secondary to an acute on
chronic digoxin poisoning (125 mcg twice daily instead of 25 mcg twice daily; 750 mcg over a 3day period instead of 150 mcg). Her digoxin level was 12.6 ng/mL. Following a successful
resuscitation and the use of Digoxin-specific antibody fragments, she converted to normal sinus
rhythm. She was discharged 6 days after the admission with full neurological recovery (Eyal et
al, 2005).
C) VASCULAR DISORDER
a) NON-OCCLUSIVE MESENTERIC INFARCTION and refractory shock resulting in death have
been reported following digoxin toxicity. A 79-year-old woman, with a serum digoxin level of 4.9
ng/mL, was hospitalized. On the fourth hospital day she developed abdominal pain, acidosis,
refractory hypotension and absent bowel sounds; she died within a few hours. Autopsy showed
massive small bowel infarction and histologic examination showed ischemic necrosis of the
small bowel with no thrombosis in the superior mesenteric artery, left atrium or ventricle. The
authors suggest that onset of non-occlusive mesenteric infarction may be delayed after cardiac
glycoside toxicity and results from potent vasoconstrictor effects on the splanchnic arteries and
arterioles (Guglielminotti et al, 2000).
b) CASE REPORT: An 84-year-old woman presented with signs and symptoms of digitalis
intoxication (abdominal pain, nausea, vomiting, and confusion). Past medical history included
hypertension and mild congestive heart failure. The patient was currently taking digitoxin at 0.07
mg/day. Abdominal examination revealed faint bowel sounds without signs of abdominal
tenderness, distention, or rigidity. Laboratory analysis showed a decreased potassium level of
2.9 mmol/L and an elevated digitoxin plasma level of 32.3 ng/mL (normal range 13 to 25
ng/mL). Discontinuation of digitoxin therapy resulted in normalization of the potassium level, but
the patient complained of worsening abdominal pain. An abdominal roentgenography and
sonography showed signs of a paralytic ileus. The patient died approximately 48 hours later due
to cardiovascular failure.
1) An autopsy revealed a diffusely dilated, intensely congested large and small intestine. The
wall of the intestine was edematous and hemorrhagic. Histopathological examination showed
pronounced edema of the submucosa and several areas of necrotic ulcerations and intramural
bleeding, all of which was consistent with generalized non-occlusive gangrenous mesenteric
ischemia (Weil et al, 2004).
c) CASE REPORT: A 76-year-old woman, on digitalis therapy, presented to the emergency
department with a 3-day history of nausea and mild abdominal pain. Initial serum digoxin
concentration was elevated at 6.04 ng/mL (normal range 0.8 to 2 ng/mL), indicating digitalis
overdose. Three days after hospital admission, the patient developed sudden onset
hematochezia with severe abdominal pain. A colonoscopy revealed hyperemia of the entire colon
with generalized edema, and an abdominal CT scan demonstrated diffuse thickening of the
descending colonic wall, all of which was consistent with a diagnosis of acute mesenteric
ischemia. A mesenteric angiography revealed that, although the main branches of the superior
mesenteric artery (SMA) and the inferior mesenteric artery (IMA) were intact, distal narrowings
of the segmental and subsegmental branches were noted, with diminished intestinal mural
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perfusion, indicating non-occlusive mesenteric ischemia believed to be secondary to digitalis

intoxication. Papaverine hydrochloride infusion was then initiated as treatment, but
approximately 30 minutes later, the patient developed severe hypotension and the infusion was
discontinued. The patient's condition deteriorated with the development of sepsis, hyperthermia,
and leukocytosis. Despite aggressive supportive measures, including intravenous fluid
replacement and antibiotic therapy, the patient was unresponsive and subsequently died
(Kayahan et al, 2008).
3.5.3) ANIMAL EFFECTS
A) ANIMAL STUDIES
1) DYSRHYTHMIA
a) DOGS: In a canine model of acute digoxin toxicity, Meggs et al (1998) found that cardiac
dysrhythmias (bradycardia in 2 dogs and multifocal PVS's in 1 dog) developed prior to
hyperkalemia in all dogs, suggesting that hyperkalemia is separate from cardiac toxicity in the
setting of acute digoxin poisoning (Meggs et al, 1998). Hyperkalemia and hypotension (which
developed in 1 dog) resolved following Digibind(R) dosing.
RESPIRATORY
A) ACUTE LUNG INJURY
a) CASE REPORT: Severe adult respiratory distress syndrome developed within 6 days in a 79year-old man following an ingestion of 100 tablets of digoxin 0.1 mg. The patient was unable to
be weaned from the respirator and died 12 days after the ingestion from septic shock (Behringer
et al, 1998).
NEUROLOGIC
A) CENTRAL NERVOUS SYSTEM DEFICIT
a) Lethargy, drowsiness, weakness, paresthesias, and headache may occur with digoxin toxicity
(Morini et al, 2003; Song et al, 2001; Ekins & Watanabe, 1978; Smith & Willerson, 1971).
b) Extreme weakness and decreased muscle strength are commonly seen following cardiac
glycoside intoxications (Cooke, 1993).
c) CASE REPORT: A misdiagnosis of depression was made in a 77-year-old woman about one
month after the initiation of digitalis therapy (digoxin 0.5 mg/day). When therapy for depression
was ineffective, the patient was transferred to another hospital where serum digoxin
concentrations revealed a toxic level of digoxin (3.2 ng/mL). The patient improved over the next
several days after stopping digoxin (Song et al, 2001).
B) CHOREOATHETOSIS
a) One case of digoxin-induced chorea has been reported (Wedzicha et al, 1984).
C) PSYCHOTIC DISORDER
a) CASE REPORT: An 84-year-old woman previously controlled on 0.625 mg digoxin developed
visual hallucinations without other symptoms of digitalis intoxication 2 days following the
addition of a diuretic to her drug therapy (Closson, 1983).
a) Hallucinations, nightmares, paranoia, agitation, confusion, and delirium have been reported;
these effects are common and usually resolve as the serum digitalis level declines (Song et al,
2001; Eisendrath & Sweeney, 1987; Rabinovitz et al, 1987; Carney et al, 1985; Closson, 1983).
b) Often, CNS signs will be the only presentation of digitalis toxicity, before cardiac or
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gastrointestinal symptoms (Cooke, 1993).
c) CASE REPORT: Psychosis was also noted in a 68-year-old woman with a serum digoxin level
of 1.7 ng/mL (2.18 nmol/mL) (Carney et al, 1985).
d) CASE REPORT: Paranoid ideas with associated auditory hallucinations were reported with an
elevated serum digoxin level of 5 ng/mL (6.4 nmol/mL), which resolved as the serum level
returned to normal (Carney et al, 1985).
GASTROINTESTINAL
A) VOMITING
a) Nausea, vomiting and abdominal pain are early manifestations of acute and chronic toxicity
(Juneja et al, 2012; Ekins & Watanabe, 1978; Gittelman et al, 1999). Persistent vomiting may
occur with resultant dehydration.
B) VASCULAR INSUFFICIENCY OF INTESTINE
a) PEDIATRIC: A 2-month-old infant presented with a 12-hour history of drowsiness, vomiting,
and mottled skin. Past medical history of the patient included cystic fibrosis and congenital heart
disease characterized by ventricular septal defect, patent foramen ovale, and patent ductus
arteriosus. Daily medications, prior to hospital admission, included pancreatic enzyme
supplements, antibiotics, and digoxin (0.01 mg/kg/day). It was determined that the patient had
been receiving digoxin at 0.1 mg/kg/day (a 10-fold dose) for approximately one week prior to
admission. Digoxin intoxication was confirmed by a serum digoxin level of 4.5 ng/mL. Physical
examination showed tachypnea, tachycardia, and a distended and tympanic abdomen with no
bowel sounds. Administration of Digoxin-specific FAB antibody fragments resolved the patient's
tachycardia, however she became lethargic and dehydrated with worsening respiratory distress,
requiring mechanical ventilation.
1) An abdominal x-ray revealed signs suggesting necrotizing enterocolitis. A repeat abdominal
x-ray suggested bowel perforation, however a laparotomy showed generalized small bowel
ischemia and mild, bloodstained peritoneal fluid with no evidence of perforation. The patient's
clinical condition continued to worsen over the next week and the patient developed partial
wound dehiscence and evisceration with extensive bowel necrosis. A second exploratory
operation revealed that the large bowel was healthy, but only 30 cm of small bowel appeared
viable. On postoperative day 1 of the second surgery, the patient developed severe bradycardia,
respiratory acidosis, and oliguria. Despite aggressive supportive measures, the patient died
approximately 11 days after admission of hemorrhagic bowel necrosis, secondary to nonocclusive mesenteric ischemia (based on histologic evidence) (Morini et al, 2003).
FLUID-ELECTROLYTE
A) HYPERKALEMIA
a) Hyperkalemia may be profound (Smith & Willerson, 1971; Citrin et al, 1972; Hastreiter et al,
1984; Antman & Smith, 1985) and life threatening, and has been reported in some cases to be
refractory to conventional therapy (Rees & Nelson, 1997; Fenton et al, 1996), but responsive to
digoxin-specific antibodies (Fab) (Husby et al, 2003).
b) PROGNOSIS: The degree of hyperkalemia has been correlated with mortality in acute
digitoxin overdose, with potassium greater than 5.5 mEq/dL signaling 100% mortality in the era
predating digoxin immune Fab (Bismuth et al, 1973). Elevated potassium level (above 5.0
milliequivalents/Liter) is an indication for digoxin immune Fab.
c) CASE SERIES: A review of cases from a single poison control center from 2002 to 2014 was
conducted, identifying 358 cases of digoxin exposure. Of these 358 cases, 210 were treated at a
healthcare facility, where 42 patients were identified as hyperkalemic following digoxin
http://www.micromedexsolutions.com/micromedex2/librarian/CS/0E4411/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/2251
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healthcare facility, where 42 patients were identified as hyperkalemic following digoxin

exposure. Sixteen of the 42 patients were not treated with digoxin specific Fab fragments, with
1 death recorded. The median digoxin levels in the survivors and in the 1 death were 3.1 ng/mL
and 4 ng/mL, respectively, with median potassium levels of 6 and 6.3 mEq/L, respectively. Of
the 26 hyperkalemic patients who received treatment with Fab fragments, 2 deaths occurred.
The median digoxin levels in the survivors and in each of the 2 fatalities were 4.3, 6, and 3.1
ng/mL, respectively, with potassium levels of 6.1, 6.1, and 6.3 mEq/L, respectively. Based on
these results, the outcome appeared to be similar regardless of therapy; however, limitations to
this study include lower serum digoxin levels in the patients not treated with Fab fragments,
indicating less severe digoxin toxicity, and the possibility of pseudohyperkalemia (Emswiler et al,
2015).
B) HYPOKALEMIA
a) Hypokalemia due to concurrent diuretic administration can result in digitalis toxicity (Weil et
al, 2004) even with therapeutic plasma levels (Gomez-Arnau et al, 1982). Hypokalemia may also
occur in chronic digitalis intoxication in the absence of diuretic use.
C) HYPOMAGNESEMIA
a) Hypomagnesemia may have a similar effect to hypokalemia on digitalis toxicity (Beller et al,
1974).
3.12.3) ANIMAL EFFECTS
A) ANIMAL STUDIES
1) HYPERKALEMIA
a) DOGS: In a canine model of acute digoxin toxicity, Meggs et al (1998) found that cardiac
dysrhythmias developed prior to hyperkalemia, suggesting that hyperkalemia is separate from
cardiac toxicity in the setting of acute digoxin poisoning. Hyperkalemia resolved following
Digibind(R) dosing (Meggs et al, 1998).
HEMATOLOGIC
A) THROMBOCYTOPENIC DISORDER
a) Digitoxin-induced severe thrombocytopenia (5,000/mm(3)) was reported in a patient with
congestive heart failure associated with Sjogren's Syndrome. The platelet count recovered
quickly following discontinuation of digitoxin, transfusion of platelet-rich plasma, and
prednisolone and potassium treatment (Haro et al, 2000).
a) Digitoxin-induced severe thrombocytopenia (26,000/mm(3)), which was rapidly (within 16 h)
reversed by digoxin specific antibodies has been reported (Hess et al, 1983).
PSYCHIATRIC
A) HALLUCINATIONS
a) Hallucinations, nightmares, paranoia, agitation, confusion, and delirium have been reported;
these effects are common and usually resolve as the serum digitalis level declines (Song et al,
2001; Eisendrath & Sweeney, 1987; Rabinovitz et al, 1987; Carney et al, 1985; Closson, 1983).
gastrointestinal symptoms (Cooke, 1993).
c) CASE REPORT: Psychosis was also noted in a 68-year-old woman with a serum digoxin level
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d) CASE REPORT: Paranoid ideas with associated auditory hallucinations were reported with an
elevated serum digoxin level of 5 ng/mL (6.4 nmol/mL), which resolved as the serum level
returned to normal (Carney et al, 1985).
REPRODUCTIVE
3.20.1) SUMMARY
A) Digoxin has been classified as FDA pregnancy category C. There are no adequate and wellcontrolled studies of digoxin in pregnant women. Animal studies have not been conducted.
Congenital anomalies and perinatal problems have not been linked with cardiac glycoside use
during pregnancy. Digoxin can be used in pregnancy, but may require dosage adjustments due to
pregnant patient. Digoxin has been used in pregnant women without apparent harm to the
mother or fetus. The fetus is able to metabolize digoxin and excretes it in the bile. Low birth
weight has been observed in infants of mothers receiving digitalis glycosides, presumably due to
decreased gestational age and not due to intrauterine growth retardation. In addition, adverse
effects to the fetus have been found when the mother develops digitalis toxicity. As it is unknown
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY
1) Digoxin is FDA pregnancy category C (Prod Info LANOXIN(R) intravenous injection,
intramuscular injection, 2013).
B) DIGOXIN
1) There are no adequate and well-controlled studies of digoxin in pregnant women. Animal
studies have not been conducted (Prod Info LANOXIN(R) intravenous injection, intramuscular
injection, 2013). Digoxin can be used in pregnancy, but may require dosage adjustments due to
pregnant patient (Shotan et al, 1998). Digoxin has been used in pregnant women without
apparent harm to the mother or fetus. The fetus is able to metabolize digoxin and excretes it in
the bile. Low birth weight has been observed in infants of mothers receiving digitalis glycosides,
presumably due to decreased gestational age and not due to intrauterine growth retardation
(Witter et al, 1981; Weaver & Pearson, 1973; Rogers et al, 1972; Norris, 1961). In addition,
adverse effects to the fetus have been found when the mother develops digitalis toxicity.
Miscarriage was attributed to digitalis overdose in 1 case (Potondi, 1967). In another case,
maternal digitalis toxicity was associated with ECG changes in the newborn and subsequent
death, presumably due to intrauterine anoxia (Sherman & Locke, 1960). As it is unknown
the drug be administered in pregnant women only if clearly necessary (Prod Info LANOXIN(R)
intravenous injection, intramuscular injection, 2013).
C) LACK OF EFFECT
1) There are no adequate and well-controlled studies of digoxin in pregnant women. Animal
studies have not been conducted (Prod Info LANOXIN(R) intravenous injection, intramuscular
injection, 2013). Congenital anomalies and perinatal problems have not been linked with cardiac
glycoside use during pregnancy (Schardein, 1985).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK
1) Two women receiving 0.25 mg digoxin during pregnancy continued therapy while
breastfeeding. Starting on day 14, milk samples were collected after each feeding for a 24-hour
period. Although detected in the milk samples, digoxin could not be detected in the plasma of
either infant. Four to six hours after dosage, milk concentrations peaked at 0.96 and 0.61 ng/ml.
Even at maternal toxicity levels, digoxin intake by infants would be less than 5% of the
recommended dose. Digoxin was considered to be safe during breastfeeding (Loughnan, 1978).
2) Digoxin is excreted into breast milk and studies have shown that the milk-to-serum
concentration ratio is approximately 0.6 to 0.9. However, the estimated exposure to digoxin in a
nursing infant is far below the usual maintenance dose for an infant (Prod Info LANOXIN(R)
intravenous injection, intramuscular injection, 2013). Therefore, this amount appears too low to
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intravenous injection, intramuscular injection, 2013). Therefore, this amount appears too low to
be pharmacologically significant to the breastfeeding infant (Reinhardt et al, 1982; Berlin, 1981).
3.20.5) FERTILITY
A) LACK OF INFORMATION
1) No studies assessing the potential for digoxin to affect fertility have been conducted (Prod
Info LANOXIN(R) intravenous injection, intramuscular injection, 2013).
CARCINOGENICITY
3.21.1) IARC CATEGORY
A) IARC Carcinogenicity Ratings for CAS20830-75-5 (International Agency for Research on
Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group
on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation
of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic
Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans,
2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC,
2004):
1) Not Listed
B) IARC Carcinogenicity Ratings for CAS71-63-6 (International Agency for Research on Cancer
(IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the
Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of
Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic
2004):
1) Not Listed
C) IARC Carcinogenicity Ratings for CAS630-60-4 (International Agency for Research on Cancer
2004):
1) Not Listed
D) IARC Carcinogenicity Ratings for CAS36-06-6 (International Agency for Research on Cancer
2004):
1) Not Listed
3.21.2) SUMMARY/HUMAN
A) Digoxin has been associated with chronic lymphocytic leukemia, but data are lacking to assess
the potential carcinogenic activity of digoxin.
3.21.3) HUMAN STUDIES
A) LEUKEMIA
1) There was an association between past treatment with digoxin and incidence of chronic
lymphocytic leukemia in Yorkshire (UK) (Cartwright et al, 1987). Digoxin is not considered a
human carcinogen at the time of this review (Prod Info LANOXIN(R) oral tablets, 2011; Prod Info
LANOXIN(R) IV, IM injection, 2011).
B) UTERINE CANCER
1) In a population-based study of postmenopausal Danish women aged 20 years and older,
current use of digoxin was associated with a higher incidence of uterine cancer compared with
nonusers. Registries identified 104,648 women with digoxin exposure with 249,652 person years
(PY) of follow up for current exposure and 143,186 PY of follow up for prior exposure. During the
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(PY) of follow up for current exposure and 143,186 PY of follow up for prior exposure. During the
study, uterine cancer, ovarian cancer, and cervical cancer were diagnosed in 8124, 7124, and
5001 women, respectively. Age-adjusted analysis revealed a higher incidence of uterine cancer in
women with current digoxin use (n=350) compared with nonexposed women (risk ratio (RR),
1.48; 95% CI, 1.32 to 1.65). The incidence of uterine cancer increased significantly in women
with a digoxin treatment duration of 36 months or longer compared with those using digoxin for
13 to 35 months (incidence rate ratio, 37 vs 71; p=0.0008); among all women using digoxin for
at least 36 months (n=123), the overall RR for uterine cancer was 1.57 (1.31 to 1.89). The
overall RR was not increased for ovarian or cervical cancers among digoxin users compared with
nonusers. The incidence of uterine, ovarian, and cervical cancers were also not increased in
other angina drug users compared with nonusers. For former digoxin users (starting 6 months
after last digoxin prescription) there was a nonsignificant increase in uterine cancer (RR, 1.20;
95% CI, 0.99 to 1.45), while ovarian and cervical cancer incidence rates did not increase (Biggar
et al, 2012)
GENOTOXICITY
A) There was no evidence of genotoxicity with digoxin in the in vitro Ames test and mouse
lymphoma studies (Prod Info LANOXIN(R) oral tablets, 2011; Prod Info LANOXIN(R) IV, IM
injection, 2011).
OTHER
A) AT RISK - FINDING
a) AGE FACTOR: Pahor et al (1993) have demonstrated through a prospective multivariate
logistic regression analysis that patients aged 65 to 79 had a similar risk of digoxin toxicity as
those aged less than 65 years (Pahor et al, 1993). Patients greater than 80 years of age appear
to have an increased risk of digoxin toxicity. Miura et al (2000) reported that patients greater
than 71 years of age had a rate of clinical evidence of digoxin toxicity of 26.5% in spite of their
serum digoxin concentrations remaining in the normal therapeutic range (Miura et al, 2000).
b) VARIOUS FACTORS: In a prospective study, Abad-Santos et al (2000) reported a univariate
analysis of 41 toxic patients which showed intoxicated patients to generally be older, mostly
women, and have compromised renal function and higher digoxin serum levels (Abad-Santos et
al, 2000). In a multivariate analysis, the only independent factor related to digitalis toxicity was
digoxin serum level. For certain digoxin levels, a different risk of toxicity was reported for each
clinical manifestation. Patients demonstrating signs of automaticity in the ECG had an increased
likelihood of being digitalis toxic than patients with GI symptoms, atrioventricular block, or
bradycardia.
B) DRUG INTERACTION
a) SUMMARY: Drug interactions resulting in digoxin toxicity may result from inhibition of renal
tubular secretion of digoxin. Koren et al (1998) have theorized that since digoxin is actively
secreted by the renal tubular cell via the p-glycoprotein drug efflux pump, that many commonly
interacting drugs do so by inhibition of renal tubular secretion of digoxin (Koren et al, 1998).
b) Potassium-wasting diuretics may potentiate the actions of cardiac glycosides and result in
digitalis toxicity.
c) Common drugs that may reduce the elimination of cardiac glycosides and result in digitalis
intoxication include: amiodarone, propafenone, quinidine, and verapamil (Aronson, 1993).
d) MACROLIDE ANTIBIOTICS: Clarithromycin, erythromycin and telithromycin have induced
digoxin toxicity (Laberge & Martineau, 1997; Nordt et al, 1997; Nordt et al, 1998; Trivedi et al,
1998; Nawarskas et al, 1997; Gooderham et al, 1999).
1) This may be due to decreased renal elimination of digoxin secondary to inhibition of the Pglycoprotein transporter in the renal proximal tubular cells (Juurlink & Ito, 1999; Nenciu et al,
2006). Alternatively, it may be attributable to the ability of these drugs to inhibit the growth of
Eubacterium lentum which can lead to an increase in digoxin bioavailability and blood
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Eubacterium lentum which can lead to an increase in digoxin bioavailability and blood
concentrations
2) Patients at risk may include those with renal insufficiency and borderline (elevated normal
range) digoxin levels (Laberge & Martineau, 1997) or the elderly (Guerriero et al, 1997).
e) AZITHROMYCIN has induced digitoxin toxicity in 2 patients, with previously normal digitoxin
serum levels, following 3 days of azithromycin therapy (Thalhammer et al, 1998). Digoxin
intoxication was reported in a young child who was concurrently receiving digoxin and
azithromycin (Eick et al, 2000). It has been hypothesized that macrolide antibiotics, including
azithromycin, may alter the presence of Eubacterium lentum, which metabolizes digoxin, in the
gut flora of the 5% to 10% of the population who carry this organism (Miner, 2001).
f) FLUOXETINE, concomitantly administered with digoxin, was associated with an elevated
serum digoxin level in one patient. Discontinuation of digoxin and fluoxetine resulted in the
decrease of the serum digoxin level to normal values (Leibovitz et al, 1998).
g) PAROXETINE: Concurrent administration of digoxin and paroxetine resulted in digitalis
toxicity (serum digoxin concentration 5.2 ng/mL; normal range 0.5-2 ng/mL) in a 68-year-old
woman. An in vitro study reported that paroxetine has a potent P-glycoprotein inhibitory activity.
In addition, several interaction studies have reported that digoxin is a substrate of Pglycoprotein. The high levels of digoxin during paroxetine administration probably resulted from
P-glycoprotein inhibition in the kidney (Yasui-Furukori & Kaneko, 2006).
h) ITRACONAZOLE has been reported to substantially increase the half-life of digoxin, thus
resulting in digoxin toxicity (Cone et al, 1996; Alderman & Allcroft, 1997) possibly by
itraconazole or a metabolite causing decreased tubular secretion of digoxin (Alderman &
Allcroft, 1997).
i) ST JOHN'S WORT (Hypericum perforatum): A time dependent kinetic interaction between St
John's wort and digoxin has been reported. After the tenth day of St John's wort added to
digoxin regimen, a significant decrease in digoxin area under the curve by 25% resulted. Digoxin
trough concentration reductions of 33% and Cmax reductions of 26% were reported (Johne et
al, 1999). The suggested mechanism of this interaction was induction of the P-glycoprotein drug
transporter.
j) TELITHROMYCIN: Concurrent administration of telithromycin for acute bronchitis in one
woman taking chronic digoxin resulted in malaise and multiple episodes of syncope. Laboratory
analysis revealed elevated digoxin plasma levels, and electrocardiography showed several
nonspecific repolarization anomalies. By inhibiting the transport of digoxin by P-glycoprotein,
telithromycin may have decreased digoxin elimination in the intestinal lumen and its renal
tubular excretion, resulting in elevated plasma levels and drug toxicity (Nenciu et al, 2006).
k) DRONEDARONE: An 82-year-old woman, started on dronedarone and metoprolol for
paroxysmal atrial fibrillation, experienced dizziness after receiving a third dose of digoxin 0.25
mg (total digoxin dose of 0.75 mg) for continued atrial fibrillation . An ECG demonstrated
junctional bradycardia and laboratory data revealed hypomagnesemia (1.8 mg/dL, normal range
of 1.93 to 2.45 mg/dL) and an elevated serum digoxin concentration (greater than 5 ng/mL).
Following cessation of all medications and administration of digoxin-specific antibody fragments,
the patient recovered uneventfully and was discharged 3 days later. It is believed that
dronedarone, as a P-glycoprotein substrate, decreased renal elimination of digoxin (another Pglycoprotein substrate), resulting in digoxin toxicity (Vallakati et al, 2013).
l) BUFALIN: Some Chinese herbal medicines contain the cardioactive compound, bufalin, which
has been shown to displace digitoxin from its serum albumin binding site in patients taking
digitoxin, resulting in elevated serum free digitoxin levels and possible toxicity. The magnitude of
displacement increases with higher bufalin serum concentrations (Datta & Dasgupta, 2000).
Digitoxin is generally strongly bound to serum albumin (95% to 97%) while digoxin, in contrast,
is only 25% bound to serum albumin.
m) LICORICE: Concurrent administration of digoxin with a Chinese herbal laxative containing
licorice resulted in the development of severe bradycardia (heart rate 30 beats/minute), digoxin
toxicity (serum concentration 2.9 ng/mL) and congestive heart failure in an 84-year-old man. It
is suggested that digitalis intolerance was enhanced via licorice-induced pseudo-aldosteronism
and may have been due to several factors, including an age-related decline in renal function and
a decrease in the volume of digitalis distribution, the presence of mitral regurgitation with atrial
fibrillation in the patient which may have heightened the susceptibility to digitalis toxicity, and
electrolyte imbalances (i.e., hypokalemia and hypomagnesemia) which may have resulted from
the combined use of other medicines, primarily diuretics (Harada et al, 2002).
n) DRUG-LABORATORY INTERFERENCE: Steimer et al (1999) reported falsely low readings in a
common assay for digoxin (AxSym MEIA) due to negative cross- reactivity from canrenone
(active metabolite of potassium canrenoate) and spironolactone (Steimer et al, 1999). A case of
digoxin toxicity resulted from elevated digoxin dosing due to dose adjustments guided by falsely
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digoxin toxicity resulted from elevated digoxin dosing due to dose adjustments guided by falsely
low laboratory readings.
LABORATORY/MONITORING
MONITORING PARAMETERS/LEVELS
4.1.1) SUMMARY
hypothermia.
significant acute exposure to a cardiac glycoside. Serum potassium is NOT predictive of toxicity
for chronic cardiac glycoside toxicity.
4.1.2) SERUM/BLOOD
A) BLOOD/SERUM CHEMISTRY
1) SERUM POTASSIUM: For acute cardiac glycoside exposure, serum potassium (hyperkalemia)
is the best marker of toxicity. Serum potassium should be monitored every 60 minutes following
any potentially significant acute exposure to a cardiac glycoside. Serum potassium is NOT
predictive of toxicity for chronic cardiac glycoside toxicity; in these patients hyper- or
hypokalemia may occur
a) HYPERKALEMIA may be profound (Smith & Willerson, 1971; Citrin et al, 1972; Hastreiter et
al, 1984; Antman & Smith, 1985) and life threatening. The degree of hyperkalemia has been
correlated with mortality in digitoxin overdose (Bismuth et al, 1973).
b) HYPOKALEMIA: Due to concurrent diuretic administration can result in digitalis toxicity even
with therapeutic plasma levels (Gomez-Arnau et al, 1982). May also occur in chronic digitalis
poisoning in the absence of diuretic use.
2) SERUM DIGOXIN: Monitor serial serum digoxin concentrations and serum electrolytes every
hour, until the patient is improved and digoxin concentrations are clearly declining towards
therapeutic. False positive digoxin concentrations have been reported in patients with pregnancy,
liver disease, and hypothermia.
3) Monitor renal function.
4) GLUCOSE: Hypoglycemia (43 mg/dL) was noted 13 hours after administration of digoxin
immune Fab in a one-week-old infant, despite intravenous dextrose administration (42
mg/kg/min) (Kaufman et al, 1990).
B) SPECIFIC AGENT
1) DIGOXIN RANGE OF LEVELS: Therapeutic range 0.5 to 2 nanograms/mL (0.64 to 2.56
nmol/L). Patients have survived with levels as high as 48 nanograms/mL (61.49 nmol/L)
(Springer et al, 1986). Deaths have been reported with levels as low as 3.5 nanograms/mL (4.48
nmol/L) (Baselt & Cravey, 1989). Toxicity from acute overdose in most patients is seen above 10
nanograms/mL (12.8 nmoL/L).
a) In overdose, the distribution phase may be prolonged, therefore, serum digoxin levels may
not be meaningful until approximately 6 hours post-ingestion (Smith et al, 1993).
2) DIGOXIN SAMPLING TIME: Digoxin toxicity may erroneously be reported in a patient if serum
digoxin concentrations are sampled prior to completion of drug distribution. Due to digoxin
pharmacokinetics, serum samples should not be drawn within 6 hours of the previous dose,
unless toxicity or overdose is strongly suspected (Williamson et al, 1998). Digoxin levels are not
meaningful following administration of Digoxin-specific FAB, depending on the assay used. False
elevations can be noted if the "free digoxin assay" is not used or if excess FAB has been
administered.
3) DIGOXIN NORMAL LEVELS AND TOXICITY: Cardiotoxicity has been reported with serum
digoxin concentrations in the therapeutic range. Patients with digoxin-induced cardiac toxicity
and therapeutic serum digoxin concentrations showed significant increases in the calcium to
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and therapeutic serum digoxin concentrations showed significant increases in the calcium to
potassium ratio and arterial pH (Sonnenblick et al, 1983).
4) DIGOXIN MORTALITY: A retrospective study examining the relationship between digoxin
serum levels and outcome 4 weeks after the level demonstrated the following mortality rates
(Ordog et al, 1987):
Digoxin level
Number Patients
Number
Deaths
4 week mortality
rate
0*
ng/mL
1000
20
2%
0-1
ng/mL
1366
26
2%
1.1-2
ng/mL
3184
159
5%
2.1-4
ng/mL
409
36
8.6%
4.1-6
ng/mL
40
7.5%
>6
ng/mL
11
50%
~ *Admitted medical patients not on digoxin who served as matched-pair controls.
5) DIGOXIN AND THE PEDIATRIC PATIENT: Pediatric patients appear to be more resistant to
the cardiotoxic effects of digoxin than adults at comparable serum levels (Pearce et al, 1980;
Lewander et al, 1986; Springer et al, 1986; Harris et al, 1981).
a) Children excrete digoxin more rapidly than older patients (Krasula et al, 1972). Koren et al
(1988) reported elevation in serum digoxin concentration in 11 of 15 profoundly sick, digitalized
infants and children long after cessation of therapy (Koren et al, 1988).
6) DIGOXIN AND EXERCISE: One study evaluating the influence of everyday exercise on steadystate digoxin concentrations found a significant difference in concentrations comparing baseline,
one hour of immobilization prior to exercise (increase 30%), one hour of exercise (decrease
26.8%), and one hour of immobilization after exercise (increase 36.6%) (Hall et al, 1989).
7) DIGOXIN STEADY STATE: Tayeb et al (1988) using calculated digoxin clearance values were
able to accurately predict serum steady state digoxin levels (r = 0.96) (Tayeb et al, 1988).
8) DIGITOXIN: Therapeutic range of DIGITOXIN or DIGITALIS LEAF is 18 to 22 nanograms/mL
(23 to 28.18 nmol/L). Toxicity in most patients is above 25 nanograms/mL (32 nmol/L).
C) LABORATORY INTERFERENCE
1) DIGOXIN IMMUNE FAB: Serum levels may rise precipitously after digoxin immune fab is
administered, as antibody-bound digoxin is also measured. Serum digoxin concentration
measurements can be clinically misleading when digoxin Fab fragments are present because the
digoxin immune Fab interferes with digitalis immunoassay measurements (Personal
Communication, 1989).
2) A number of studies have addressed this problem. Several immunoassays appear to be able
to quantitate free serum digoxin in the presence of Fab. The use of ultrafiltration (which removes
Fab and Fab-bound digoxin) with some assays allows the measurement of both total (bound and
unbound) and free digoxin (Banner, 1989; (Hansell, 1989; Ujhelyi et al, 1990) .
3) An evaluation of 28 assay methods showed 7 methods that could accurately measure free
digoxin in the presence of digoxin immune Fab. These assays were (Hansell, 1989):
1) Abbott PEG
2) Baxter Healthcare STRATUS
3) Becton Dickinson ARIA HT
4) Becton Dickinson ARIA II
5) Becton Dickinson Solid Phase
6) Leeco Diagnostics
7) Nuclear Medical Laboratories
4) In other studies, assays tested included FPIA-TDX Digoxin II-Abbott Laboratories, EMIT-Syva,
RIA-Quantitope ULTRA-FIPA (ultrafiltration with FIPA), and STRATUS-Baxter Dade. EMIT,
STRATUS, and ULTRA-FPIA were able to quantitate free total serum digoxin concentrations in
the presence of Fab. Ultra-FPIA was the most accurate and reliable assay (Ujhelyi et al, 1992;
Ujhelyi et al, 1990).
5) DLIS: Digoxin-like immunoreactive substance (DLIS) is an endogenous natriuretic
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substance(s) found in the blood of neonates, seriously ill older infants (Spiehler et al, 1985),
pregnant women (Gilson et al, 1997), and patients with a variety of disease states including
renal (Graves et al, 1983; Greenway & Nanji, 1985) Shild, 1985) and hepatic failure, heart failure,
diabetes and hypertension (Tzou et al, 1997; Martinka et al, 1998). Its role, if any, is not known.
a) DLIS cross react with several immunologic assay methods used for digoxin, leading to
elevation of levels and potential confusion in the interpretation of results (Luke & Dasgupta,
1997). Apparent levels of DLIS as high as 3.7 ng/mL (Karboski et al, 1988) and 0.3 to 1.1 ng/mL
(Tzou et al, 1997) have been reported. A microparticle enzyme immunoassay (MEIA) method
appears to have a very low cross-reactivity with DLIS compared with the fluorescence
polarization immunoassay (FPIA) (Crossey & Dasgupta, 1997).
b) Morris et al (1990) have reported the cross reactivity to DLIS demonstrated by 10
commercial assay methods. The Diagnostic Products Corporation "Coat-a-Count" RIA and the
Syva EMIT column run on a Cobas MIRA by Roche produced the least interference (Morris et al,
1990).
c) Baseline serum digoxin concentrations should be measured prior to administration of digoxin
in neonates.
d) DLISs are highly protein bound. Because of their high protein binding and the poor protein
binding of digoxin, either measuring digoxin concentrations in protein-free ultrafiltrate or
monitoring free digoxin concentrations can eliminate the positive and negative crossinterference of the DLIS (Dasgupta, 2002).
6) OTHER SUBSTANCES: Ingestion of exogenous digoxin-like immunoreactive substances,
including spironolactone and its active metabolite, canrenone, and traditional Chinese medicines
(Chan Su, Siberian Ginseng, and Dan Shen) may also cause positive and negative crossinterference with immunoassays used to measure serum digoxin concentrations (Dasgupta,
2002).
7) OLEANDER GLYCOSIDES: Glycosides found in oleander may cross-react with antibodies found
in most radioimmunoassay kits and result in digoxin being reported as present (Haynes et al,
1985; Shumaik et al, 1988).
4.1.4) OTHER
A) OTHER
1) ECG
a) Institute continuous cardiac monitoring and obtain serial ECG's.
METHODS
A) IMMUNOASSAY
1) Determination of cardiac glycosides in serum is available in most hospitals by
radioimmunoassay, which is a reliable technique (Smith et al, 1969; Williamson et al, 1998;
Lecointre et al, 2001). An EMIT(R) homogeneous enzyme immunoassay and fluorescent
polarization methodology (Abbott TDx system (R)) are also used. Clinical studies show excellent
correlation between these methods and RIA.
a) A modified EMIT 2000 digoxin assay for determining very low digoxin plasma concentrations
was developed on the Cobas Mira plus analyzer. Detection and quantification limits of 0.02 and
0.08 ng/mL, respectively, were reported. Good correlation between this modified EMIT assay and
RIA was shown (Radembino et al, 1999).
2) Plasma levels obtained soon after an overdose may not accurately reflect toxicity, as the drug
may still be in the distribution phase, which normally takes approximately 6 hours from the last
dose (Williamson et al, 1998).
3) It may take several hours to obtain laboratory results and the diagnosis should be considered
on clinical grounds.
4) DRUG-LABORATORY INTERFERENCE a) In the presence of Digoxin immune Fab, positive interference may be expected due to
competition with assay capture antibodies. Interference with most methods is concentrationdependent, following a linear relationship. Interference by these large molecules may be
minimized by ultrafiltration. McMillin et al (2002) reported the following assay methods which
had minimal interference: TDx, AxSYM, Synchron, and CEDIA methods. In the presence of Fab
products, ultrafiltration appears to be the optimal strategy for accurate determination of free
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products, ultrafiltration appears to be the optimal strategy for accurate determination of free
digoxin concentrations (McMillin et al, 2002).
b) Steimer et al (1999) reported falsely low readings in a common assay for digoxin (AxSYM
MEIA) due to negative cross-reactivity from canrenone (an active metabolite of potassium
canrenoate) and spironolactone. A case of digoxin toxicity resulted from elevated digoxin dosing
guided by falsely low laboratory readings (Steimer et al, 1999).
c) Assays that employ mouse monoclonal antibody reagents may result in falsely elevated serum
digoxin levels in patients who have human anti-mouse antibody in their serum which interferes
with the agent (Ingels et al, 1999). Interference in assays with newer reagents does not result
with this antibody.
B) OTHER
1) Serum levels may rise precipitously after digoxin immune fab is administered, as antibodybound digoxin is also measured. Serum digoxin concentration measurements can be clinically
misleading when digoxin Fab fragments are present because the Fab fragments interfere with
digitalis immunoassay measurements (Personal Communication, 1989).
2) A number of studies have addressed this problem. Several immunoassays appear to be able to
quantitate free serum digoxin in the presence of Fab. The use of ultrafiltration (which removes
Fab and Fab-bound digoxin) with some assays allows the measurement of both total (bound and
unbound) and free digoxin (Banner, 1989; (Hansell, 1989) Ujelyi, 1990; (Jortani et al, 1999).
Analysis of ultrafiltrate by immunoassay which does not have matrix bias appears to be the most
accurate method in measuring unbound digoxin in presence of antidote.
a) An evaluation of 28 assay methods showed 7 methods that could accurately measure free
digoxin in the presence of Fab fragments. These assays were (Hansell, 1989):
1) Abbott PEG
2) Baxter Healthcare STRATUS
3) Becton Dickinson ARIA HT
4) Becton Dickinson ARIA II
5) Becton Dickinson Solid Phase
6) Leeco Diagnostics
7) Nuclear Medical Laboratories
b) In other studies, assays tested included FPIA-TDX Digoxin II-Abbott Laboratories, EMIT-Syva,
RIA-Quantitope ULTRA-FIPA (ultrafiltration with FIPA), and STRATUS-Baxter Dade. EMIT,
STRATUS, and ULTRA-FPIA were able to quantitate free total serum digoxin concentrations in
the presence of Fab. Ultra-FPIA was the most accurate and reliable assay (Ujhelyi et al, 1992;
Ujhelyi et al, 1990).
c) In one case report of digoxin intoxication, 3 immunoassay techniques produced very different
values. The serum digoxin levels were 9.44 ng/mL (on admission), 6.46 ng/mL, and 2.63 ng/mL
using the enzyme multiplied immunoassay (EMIT) reagents (Cobas Mira autoanalyzer), the
fluorescence polarization immunoassay (FPIA/FLx technique [Digoxin II assay]), and the
microparticle enzyme immunoassay (MEIA/AxSYM technique [Digoxin II assay]), respectively.
The digoxin level of 5.46 ng/mL was obtained using the liquid chromatography-electrospray-mass
spectrometry (LC-ES-MS) method. The authors concluded that MEIA/AxSYM result was greatly
underestimated and these findings reinforce the doubt on the reliability of this technique for
detecting digoxin overdose (Tribut et al, 2005).
d) Banner et al (1989) compared two immunoassays for digoxin in the presence of Fab
fragments; the Abbott TDx(R) and the Dade Stratus(R) methods. Serum spiked with digoxin 0 to
50 ng/mL and Fab 0 to 3 mcg/mL was assayed by TDx with and without ultrafiltration, and by
Stratus. TDx was found to accurately quantitate total serum digoxin concentrations (i.e., both
bound and non-bound by Fab), whereas Stratus measured only non-bound drug. After
ultrafiltration, the TDx assay measured non-Fab-bound digoxin levels. Banner et al (1992)
confirmed their previous findings in a similar follow-up study (Banner et al, 1989; Banner et al,
1992).
3) The effect of digoxin Fab antibody on the measurement of total and free digitoxin by
fluorescence polarization and chemiluminescent immunoassay was reported. Interference in the
measurement of TOTAL digitoxin concentration by both laboratory tests was seen in vitro, with
falsely lowered total digitoxin levels. Monitoring of FREE digitoxin concentrations revealed no
interference in vitro and was found to be accurate when measured by either assay (Dasgupta et
al, 1999).
substance(s) found in the blood of neonates, seriously ill older infants (Spiehler et al, 1985),
pregnant women, and patients with a variety of disease states including renal (Graves et al,
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pregnant women, and patients with a variety of disease states including renal (Graves et al,
1983; Greenway & Nanji, 1985) Shild, 1985) and hepatic failure, heart failure, and hypertension.
Its role, if any is not known.
a) DLIS cross reacts with several immunologic assay methods used for digoxin, leading to
elevation of levels and potential confusion in the interpretation of results. Apparent levels of DLIS
as high as 3.7 ng/mL have been reported (Karboski et al, 1988).
b) Morris et al (1990) have reported the cross reactivity to DLIS demonstrated by 10 commercial
assay methods. The Diagnostic Products Corporation "Coat-a-Count" RIA and the Syva EMIT
column run on a Cobas MIRA by Roche produced the least interference (Morris et al, 1990).
c) Ingestion of exogenous digoxin-like immunoreactive substances, including spironolactone and
its metabolite, canrenone, and traditional Chinese medicines (Chan Su, Siberian Ginseng, and
Dan Shen) may also cause positive and negative cross-interference with immunoassays used to
measure serum digoxin concentrations (Dasgupta, 2002).
d) DLISs are highly protein bound. Because of their high protein binding and the poor protein
binding of digoxin, either measuring digoxin concentrations in protein-free ultrafiltrate or
monitoring free digoxin concentrations can eliminate the positive and negative cross-interference
of the DLIS (Dasgupta, 2002).
5) OLEANDER GLYCOSIDES: Glycosides found in oleander may cross-react with antibodies found
in most radioimmunoassay kits and result in digoxin being reported as present (Haynes et al,
1985; Shumaik et al, 1988).
a) There is no correlation of the serum level to toxicity in these cases (Osterloh, 1988).
6) The Abbott TDx analyzer used with Digoxin II reagents, may qualitatively identify other
cardiac glycosides as well, but the concentration relationship is not linear (Cheung et al, 1989).
7) POSTMORTEM LEVELS: Levels may increase and persist postmortem. In one series of 27
digitalized children, digoxin levels obtained within the first 24 hours after death were 6.5 (SD 1.1)
nmol/L higher than calculated digoxin levels at the time of death (Koren et al, 1989). This finding
may be due to redistribution from fat or muscle and/or increased DLIS secretion postmortem
(Vorpahl & Coe, 1978; Holt & Benstead, 1975) Koren, 1989; Thomas, 1979).
ABSTRACTS
CASE REPORTS
A) OTHER
1) FAB: One case of a patient in renal failure whose free serum digoxin concentration rose
fourfold 5 days after Fab administration has been reported. The authors attributed this rise to
possible Fab fragment/digoxin complex dissociation after ruling out other possible causes. They
suggest that patients with renal failure who are treated with Fab fragments should have free
serum digoxin concentration monitored (Schneider et al, 1991).
2) FAB: Kurowski et al (1992) reported that a massive overdose of digitoxin (35 mg) was
successfully treated with FAB therapy (Kurowski et al, 1992). FAB treatment was initiated 11
hours postingestion when the total serum concentration was 535 mmol/L. The patient required 2
additional infusions at 21 and 37 hours postingestion because of recurrence of toxic symptoms.
TREATMENT
LIFE SUPPORT
A) Support respiratory and cardiovascular function.
PATIENT DISPOSITION
6.3.1) DISPOSITION/ORAL EXPOSURE
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6.3.1.1) ADMISSION CRITERIA/ORAL

A) Admit all patients, who develop dysrhythmias, heart block, severe vomiting, or who require
digoxin immune Fab treatment, to an ICU setting. Admit patients to a monitored setting if they
have digoxin concentrations that are not clearly declining during 8 hours of observation.
6.3.1.2) HOME CRITERIA/ORAL
A) Healthy asymptomatic children who are not chronically taking cardiac glycosides or other
antiarrhythmic drugs may be observed at home after accidental ingestions of less than a
digitalizing dose.
6.3.1.5) OBSERVATION CRITERIA/ORAL
A) Patients who have only GI symptoms and a clearly decreasing serum digoxin concentration
can be discharged after a minimum of 8 hours of observation.
MONITORING
hypothermia.
significant acute exposure to a cardiac glycoside. Serum potassium is NOT predictive of toxicity for
chronic cardiac glycoside toxicity.
ORAL EXPOSURE
6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
A) TRIAGE/DECONTAMINATION
1) SUMMARY - All patients with a history of unintentional ingestion of more than a digitalizing
dose or intentional overdose of any amount of cardiac glycoside should be referred to a hospital
for evaluation and treatment.
B) CHILDREN
1) Children with a history of unintentional ingestion of more than a digitalizing dose of a cardiac
glycoside should be referred to a health care facility for gastric lavage, activated charcoal, and
observation for a minimum of 8 hours. Prehospital administration of activated charcoal should be
considered in these patients if it is readily available.
C) EMESIS/NOT RECOMMENDED
1) Emesis may enhance vagal stimulation and exacerbate bradycardia or heart block, and is not
recommended for cardiac glycoside ingestion.
D) ACTIVATED CHARCOAL
1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients
with a potentially toxic ingestion who are awake and able to protect their airway. Activated
charcoal is most effective when administered within one hour of ingestion. Administration in the
prehospital setting has the potential to significantly decrease the time from toxin ingestion to
activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et
al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
1) In patients who are at risk for the abrupt onset of seizures or mental status depression,
activated charcoal should not be administered in the prehospital setting, due to the risk of
aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated
charcoal improves the palatability for children and may facilitate successful administration 21/69
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charcoal improves the palatability for children and may facilitate successful administration
(Guenther Skokan et al, 2001; Dagnone et al, 2002).
2) CHARCOAL DOSE
a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose
not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in
children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1
gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no
evidence that cathartics reduce drug absorption and cathartics are known to cause adverse
effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally
hypotension (None Listed, 2004).
b) ADVERSE EFFECTS/CONTRAINDICATIONS
1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by
acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al,
2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et
al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED
CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning
gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al,
2005).
6.5.2) PREVENTION OF ABSORPTION
A) SUMMARY
1) CHILDREN
a) Children with a history of accidental ingestion of more than a digitalizing dose of a cardiac
glycoside presenting to a health care facility should receive activated charcoal. Consider gastric
lavage in recent ingestions.
2) ADULTS
a) Adults with a history of accidental ingestion or intentional overdose of any amount of a
cardiac glycoside should be referred to a hospital for evaluation and administration of activated
charcoal. Consider gastric lavage in recent ingestions.
B) MULTIPLE DOSE ACTIVATED CHARCOAL
1) While digoxin immune Fab fragments are the preferred treatment for severe or lifethreatening cardiac glycoside intoxication, multiple dose activated charcoal may be useful in
situations in which Fab fragments are not available. Multiple dose activated charcoal has been
shown to enhance elimination of digoxin and/or digitoxin in animal models (Chyka et al, 1995),
volunteers (Park et al, 1985; Reissell & Manninen, 1982; Lalonde et al, 1985), and overdose
cases (Pond et al, 1981; Blody et al, 1985) (Lake et al, 84) (Critchley & Critchley, 1997; Ibanez
et al, 1995). It has not been shown to affect outcome after overdose.
2) Multiple dose activated charcoal should be considered in patients with potentially life
threatening poisoning when digoxin immune Fab fragments are not readily available.
3) MULTIPLE DOSE ACTIVATED CHARCOAL
a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of
activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose
equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours
(Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more
frequent doses are more effective at enhancing drug elimination than larger less frequent doses
(Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established.
After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram
body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4
hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters,
including drug concentrations if available, are improving (Vale et al, 1999). The patient should
be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis
or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the
likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al,
1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely22/69
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d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to
allow MDAC therapy to be effective include: small volume of distribution, low protein binding,
prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka,
1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal
obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of
aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg,
decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999;
Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis,
charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult
respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al,
1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris &
Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al,
2001; Graff et al, 2002).
C) GASTRIC LAVAGE
1) CAUTION: Gastric lavage may enhance vagal stimulation and exacerbate bradycardia or heart
block.
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40
French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French
{diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed
soon after ingestion (generally within 60 minutes).
a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and
substances known to form bezoars or concretions.
3) PRECAUTIONS:
a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with
suction available. Patients with depressed mental status should be intubated with a cuffed
endotracheal tube prior to lavage.
4) LAVAGE FLUID:
a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38
degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body
weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is
clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluidelectrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte
imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young
children and the elderly.
5) COMPLICATIONS:
a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia,
mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale,
1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all
poisoned patients (Vale, 1997).
6) CONTRAINDICATIONS:
a) Loss of airway protective reflexes or decreased level of consciousness if patient is not
intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential),
patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
7) PRECAUTIONS
a) Cardiac arrest has been noted during gastric lavage, believed to be secondary to a vagal
response in a patient with preexisting nodal rhythm (Hobson & Zettner, 1973). Some authors
suggest pretreatment with atropine before lavage (Sharff & Bayer, 1982), but this is NOT
recommended.
b) An intravenous line should be established and atropine should be readily available for
administration if bradycardia occurs during the lavage procedure.
D) WHOLE BOWEL IRRIGATION (WBI)
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1) May be useful after large ingestions.

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene
glycol balanced electrolyte solution appears to be a safe means of gastrointestinal
decontamination. It is particularly useful when sustained release or enteric coated formulations,
substances not adsorbed by activated charcoal, or substances known to form concretions or
bezoars are involved in the overdose.
1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs
after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al,
1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in
overdose.
b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or
are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by
endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel
obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant
gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein
et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R),
Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the
head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose
not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12
years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until
rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and
electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have
not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation
may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk
for aspiration.
6.5.3) TREATMENT
A) SUPPORT
1) Digoxin and potassium concentrations should be followed; continuous ECG monitoring is also
indicated. Therapy should be guided by the occurrence of life threatening dysrhythmia, significant
cardiac compromise or severe hyperkalemia rather than by digoxin concentration alone. In the
absence of major clinical signs/symptoms, an absolute digoxin concentration of greater than 10
nanomoles/liter (6 hours after last dose) is an indication for the use of digoxin Fab fragments
(Dawson & Whyte, 2001).
2) Indications for digoxin immune Fab include manifestations of severe toxicity (ventricular
dysrhythmias, progressive bradyarrhythmias, 2nd or 3rd degree heart block not responsive to
atropine), hyperkalemia (greater than 5.0 mEq/dL in acute overdose), significant risk of cardiac
arrest, ingestion of greater than 10 mg in an adult or greater than 4 mg in a child, level greater
than 10 ng/mL post-distribution, progressive increase in potassium concentration postingestion,
and unresponsiveness to immediately available conventional therapy.
a) Bosse & Pope (1994) reported a case of a 38-year-old man who took an overdose of digoxin
and other medications on 3 separate occasions as a suicide attempt. Digibind(R) was
administered successfully on each occasion. The third overdose produced a Wenckebach AV
block with a ventricular rate of 38 beats/minute which was successfully treated with atropine
followed by 7 vials (total 266 mg) of Digibind(R). No allergic manifestations to Digibind(R)
occurred after administration for the 3 separate overdose events (Bosse & Pope, 1994).
b) CASE REPORT: A 6-month-old child developed AV junctional tachycardia (heart rate of 300
bpm) after receiving 3 doses of digoxin intravenously (0.16 mg, 0.08 mg, and 0.08 mg). One
minute after receiving Digoxin Immune FAB, given as an intravenous bolus dose of 14.2 mg, the
AV junctional tachycardia converted to a regular sinus rhythm at a heart rate of 140 bpm (Husby
et al, 2003).
3) Antiarrhythmics that may be useful include atropine, phenytoin, and lidocaine.
4) Bradycardia unresponsive to atropine or phenytoin may be treated with external or pacing.
5) If digoxin immune Fab is unavailable, hyperkalemia may be treated with insulin, dextrose, and
bicarbonate; magnesium sulfate may be effective for digoxin-induced dysrhythmias.
6) CHRONIC POISONING: When the patient is hemodynamically stable, many common
manifestations, such as first-degree heart block, bradycardia, and ventricular ectopy, can be
treated with only temporary withdrawal of the medication and close monitoring.
B) MONITORING OF PATIENT
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B) MONITORING OF PATIENT
1) Monitor serial serum digoxin concentrations and serum electrolytes every hour, until patient is
hypothermia.
2) Monitor renal function.
3) For acute cardiac glycoside exposure, serum potassium (hyperkalemia) is the best marker of
significant acute exposure to a cardiac glycoside. Serum potassium is NOT predictive of toxicity
for chronic cardiac glycoside toxicity.
4) Institute continuous cardiac monitoring and obtain serial ECG's.
C) DIGOXIN IMMUNE FAB (OVINE)
1) Digoxin immune Fab is available as DigiFab(R), which is made using keyhole-limpet
hemocyanin as the large carrier protein.
2) INDICATIONS (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution,
2012; Bayer, 1991a):
a) Manifestations of severe toxicity: ventricular dysrhythmias, progressive bradyarrhythmias,
2nd or 3rd degree heart block not responsive to atropine, refractory hypotension.
b) Hyperkalemia (greater than 5.0 mEq/L) in acute overdose.
c) Significant risk of cardiac arrest: ingestion of greater than 10 mg in an adult, greater than 4
mg in a child, level greater than 10 ng/mL post-distribution (generally 6 to 8 hours
postingestion), progressive increase in potassium concentration postingestion.
d) Unresponsiveness to immediately available conventional therapy.
e) Digoxin serum levels of greater than 10 ng/mL by 6 hours after the overdose, even in
asymptomatic patients, is considered an indication for digoxin immune FAB by some authors
(Bailey et al, 1997).
3) DOSING
a) GENERAL DOSING INFORMATION
1) Dosing varies according to the amount of digoxin ingested. In cases, of acute exposure of an
unknown amount, 20 vials (800 mg) of DigiFab(R) is adequate in both adults and children to
treat most life-threatening ingestions. In clinical testing, the average dose was 10 vials (Prod
Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
2) The six-vial dose (240 mg) is usually adequate to reverse most cases of chronic toxicity in
an adult and in children weighing at least 20 kg (Prod Info DigiFab(R) intravenous injection
lyophilized powder for solution, 2012).
3) Doses of 10 or more vials are more likely to elicit a febrile reaction (Prod Info DigiFab(R)
intravenous injection lyophilized powder for solution, 2012).
4) When determining the dose for DIGOXIN IMMUNE FAB, the following guidelines should be
considered (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012):
a) Erroneous calculations may result from inaccurate estimates of the amount of digitalis
ingested or absorbed or from non-steady state serum digitalis concentrations.
b) Inaccurate serum digitalis concentration measurements are a possible source of error. Most
serum digoxin assay kits are designed to measure values less than 5 nanograms/milliliter
(ng/mL). Dilution of samples is required to obtain accurate measures above 5 ng/mL.
c) Dosage calculations are based on a steady-state volume of distribution of approximately 5
liters per kilogram for digoxin (0.5 liters/kilogram for digitoxin) to convert serum digitalis
concentrations to the amount of digitalis in the body. The conversion is based on the principle
that body load equals drug steady-state serum concentration multiplied by volume of
distribution. These volumes are population averages and vary widely among individuals. Many
patients may require higher doses for complete neutralization. Doses should ordinarily be
rounded up to the next whole vial.
d) If toxicity has not adequately reversed after several hours or appears to recur,
readministration of DIGOXIN IMMUNE FAB at a dose guided by clinical judgment may be
required.
e) Failure to respond to DIGOXIN IMMUNE FAB raises the possibility that the clinical problem
is not caused by digitalis intoxication. If there is no response to an adequate dose of DIGOXIN
IMMUNE FAB, the diagnosis of digitalis toxicity should be reconsidered.
b) ACUTE INGESTION OF UNKNOWN AMOUNT OF DIGOXIN
1) ADULTS AND CHILDREN
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a) DOSAGE SUMMARY
1) Initial dose, 20 vials (800 mg); OR
2) Initial dose, 10 vials with close monitoring of clinical response and repeat dosing of 10 vials
as required (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012)
b) DOSING INFORMATION
1) Administer digoxin immune Fab by intravenous infusion over 30 minutes using an in-line
0.22 micron membrane filter. If cardiac arrest is imminent, give as a bolus injection (Prod Info
DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
2) Each vial of DigiFab(R) (40 mg purified digoxin-specific Fab fragments) will bind
approximately 0.5 digoxin (Prod Info DigiFab(R) intravenous injection lyophilized powder for
solution, 2012).
3) PEDIATRIC: Since infants and small children can have much smaller dosage requirements,
it is recommended that the 40-mg vial be reconstituted as directed and administered with a
tuberculin syringe. For very small doses, a reconstituted vial can be diluted with 36-mL of
sterile isotonic saline to achieve a concentration of 1 mg/mL. In children it is important to
monitor for volume overload (Prod Info DigiFab(R) intravenous injection lyophilized powder for
solution, 2012).
c) ACUTE INGESTION OF KNOWN AMOUNT OF DIGOXIN
a) Calculations Based on Estimated Amount of Digoxin Ingested (Prod Info DigiFab(R)
intravenous injection lyophilized powder for solution, 2012):
DIGIFAB(R) (milligrams of digoxin)x F*
Dose
=
--------------------------(vials)
0.5 mg of digitalis bound/vial
1) F* = bioavailability
2) F* = 0.8 for 0.25 mg tablets
3) F* = 1 for 0.2 mg Lanoxicaps
d) SINGLE INGESTION OF KNOWN AMOUNT
a) Approximate Dose of DigiFab(R) for Reversal of a Single Large Digoxin Overdose (Prod Info
DigiFab(R) intravenous injection lyophilized powder for solution, 2012):
Number of Digoxin Tablets* or Capsules** Ingested
DigiFab(R) Dose (vials)
25
10
50
20
75
30
100
40
150
60
200
80
1) * = 0.25 milligram (mg) tablets with 80% bioavailability

2) ** = 0.2 mg Lanoxicaps with 100% bioavailability
e) CHRONIC DIGOXIN INGESTION TOXICITY
1) ADULTS AND OLDER/LARGER CHILDREN
a) DOSAGE SUMMARY
1) Adults and older/larger pediatric patients in acute distress and without known serum
digoxin concentration (Prod Info DigiFab(R) intravenous injection lyophilized powder for
solution, 2012):
1) Initial dose, 6 vials (240 mg)
b) CALCULATIONS BASED ON STEADY-STATE DIGOXIN CONCENTRATIONS
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DIGIFAB(R) Serum digoxin (ng/mL) x weight (kg)

Dose
=
--------------------------(vials)
100
1) Estimated DigiFab(R) dose (in number of vials) per Steady-State serum Digoxin
Concentration (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution,
2012):
a) PATIENT WEIGHT = 40 kg
Serum Digoxin (ng/mL)
DIGIFAB(R) Dose (vials)
0.5
12
16
20
b) PATIENT WEIGHT = 60 kg
0.5
12
16
10
20
12
c) PATIENT WEIGHT = 70 kg
12
16
11
20
14
d) PATIENT WEIGHT = 80 kg
12
10
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16
13
20
16
e) PATIENT WEIGHT = 100 kg

12
12
16
16
20
20
2) INFANTS/SMALL CHILDREN
a) Infants and Small Children Dose Estimates of DIGOXIN IMMUNE FAB (in mg) from SteadyState Serum Digoxin Concentration (Prod Info DigiFab(R) intravenous injection lyophilized
powder for solution, 2012):
1) FORMULA: Dose (in mg) = (Dose [in # of vials]) (40 mg/vial)
2) PATIENT WEIGHT = 1 kg
DIGIFAB(R) Dose
0.4 mg*
1 mg*
1.5 mg*
3 mg*
12
5 mg
16
6.5 mg
20
8 mg
a) * = Dilution of reconstituted vial to 1 mg/mL may be desirable

DIGIFAB(R) Dose
1 mg*
2.5 mg*
5 mg
10 mg
12
14 mg
16
19 mg
20
24 mg

DIGIFAB(R) Dose
2 mg*
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4 mg
8 mg
16 mg
12
24 mg
16
32 mg
20
40 mg

DIGIFAB(R) Dose
4 mg
8 mg
16 mg
32 mg
12
48 mg
16
64 mg
20
80 mg
DIGIFAB(R) Dose
8 mg
16 mg
32 mg
64 mg
12
96 mg
16
128 mg
20
160 mg
3) CALCULATIONS BASED ON STEADY-STATE DIGITOXIN CONCENTRATION

DIGIFAB(R) Serum digitoxin (ng/mL) x weight (kg)
Dose
=
--------------------------(vials)
1000
4) PRECAUTIONS
a) SERUM DIGOXIN LEVELS: Free digoxin rebound peaks about 3 to 24 hours following Fab
administration in patients with normal renal function and then a slow steady decline in free
digoxin occurs at a rate dependent on Fab and renal and nonrenal routes of elimination (Ujhelyi
et al, 1993).
b) RENAL FAILURE
1) Dialysis is probably first-line therapy to restore potassium to normal levels in an anephric
patient. Digoxin and the digoxin Fab complex are believed to be poorly dialyzable due to
molecular weights in excess of 500 as well as due to extensive tissue binding of digoxin and the
large volume of distribution of digoxin (Clifton et al, 1989).
2) In an anephric patient, one might predict failure to clear the Fab/digoxin complex. The
reticuloendothelial system has been suggested as a mechanism to eliminate the complex (Prod
Info, 1991). The elimination half-life has been reported to be delayed in these patients (Colucci
et al, 1989; Erdmann et al, 1989; Nuwayhid & Johnson, 1989).
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et al, 1989; Erdmann et al, 1989; Nuwayhid & Johnson, 1989).

3) Allen et al (1991) reported that free serum digoxin levels gradually rose from 0 to 2.9 ng/mL
44 to 97 hours after Fab treatment in 4 digoxin toxic patients with renal failure (Allen et al,
1991).
4) CASE REPORT: A newborn, with acute renal failure and digoxin toxicity was treated with
FAB 6 mg intravenously. In view of severe metabolic acidosis and high potassium and creatinine
plasma concentrations, peritoneal dialysis was initiated. Laboratory analysis revealed a very low
level of free digoxin in the plasma and dialysate and low concentrations of total digoxin in the
dialysate, indicating poor elimination of the digoxin-FAB complex through peritoneal dialysis.
Plasma creatinine did not improve, but potassium concentration returned to normal, sodium
levels increased, and the acidosis was corrected (Berkovitch et al, 1994).
5) Ujhelyi et al (1993) reported that the time to peak free digoxin rebound occurred 127 +/- 40
hours in end-stage renal failure patients as compared to 55 +/- 28 hours in other patients. The
level of the maximum free digoxin rebound was similar between patients with and without endstage renal failure (1.79 +/- 0.96 compared with 1.61 +/- 1.41 nmol/mL, respectively) (Ujhelyi
et al, 1993).
a) Renal dysfunction appears to slow the elimination of total digoxin following Fab therapy and
the rebound in free digoxin may be affected by renal function. Monitoring of free digoxin
following administration of Fab is recommended in order to monitor additional Fab dosing,
confirm possible rebound toxicity, or guide the reinitiation of digoxin therapy.
6) PLASMA EXCHANGE for the removal of digoxin-specific antibody fragments in anuric renal
failure is reported. In patients with normal renal function, Fab-digoxin complexes are eliminated
via glomerular filtration. Zdunek et al (2000) concluded in a case report that optimal timing of
plasma exchange should be within the first 3 hours after FAB administration (to parallel the
peak of bound digoxin levels). Plasma exchange was found to be efficacious for removing
digoxin-Fab complexes (preventing rebound digoxin toxicity) but was not efficacious for
improving total digoxin clearance due to the large apparent volume of distribution of digoxin
(Zdunek et al, 2000).
a) In another case, Chillet et al (2002) also reported the use of plasma exchange in an anuric
renal failure patient with digoxin toxicity; a waiting period ranging between 24 and 40 hours,
corresponding to the usual return to free blood digoxin after Fab injection in renal failure, was
followed. Free serum digoxin was reported to decrease from 9.86 mcg/L at the second plasma
exchange to 1.67 mcg/L after the third plasma exchange (Chillet et al, 2002).
c) RECURRENT DIGITALIS TOXICITY: Commonly reported (Sinclair et al, 1989; Hursting et al,
1987; Hewett et al, 1989; Kurowski et al, 1992). More likely to occur in patients receiving less
than the estimated required DigiFab(R) dose. Onset generally within 3 days of initial treatment,
but may occur as late as 11 days post treatment; reported in 3% of 717 patients in one study
(Hickey et al, 1991). If free (unbound) digoxin level is not available, the decision to retreat with
Fab should be made on clinical grounds.
1) Mehta et al (2002) described a patient who presented with atrial fibrillation with a
ventricular response of 44 beats/min in the setting of chronic digoxin intoxication (acute renal
failure, serum digoxin 16 ng/dL). ECG returned to baseline after 8 vials of digoxin specific Fab
fragments. After 24 hours ECG showed atrial fibrillation with bigemini, which was felt to
represent rebound digoxin toxicity. Serum for free digoxin concentration was not obtained, the
patient continued to deteriorate hemodynamically and clinically and died (Mehta et al, 2002).
5) ADVERSE EFFECTS
a) HYPOKALEMIA: May occur precipitously after administration of digoxin immune Fab. Serum
potassium concentration should be closely monitored (Antman et al, 1990).
b) ALLERGIC REACTIONS: Rare; reported in less than 1% of patients. Skin reactions most
common; others rare (Smith, 1989; Antman et al, 1990; Hickey et al, 1991) .
1) Hickey et al (1991) reported a 0.8% incidence of allergic responses during treatment with
Fab in a total Fab treatment population of 717 patients (Hickey et al, 1991).
c) CONGESTIVE HEART FAILURE: May be precipitated in patients who require digitalis to
maintain cardiac output who are then given digoxin immune Fab (Antman et al, 1990).
d) APNEA: Occurred transiently in one neonate during Fab infusion (Antman, 1991).
e) HYPOGLYCEMIA: Reported in one neonate 13 hours post-Fab infusion (Kaufman et al, 1990).
6) EFFICACY
a) Successfully used in the management of severe acute digoxin and digitoxin poisoning in
children (Zucker et al, 1982; Murphy et al, 1982; Rossi et al, 1984; Woolf et al, 1991; Woolf et
al, 1992), in premature infants (Presti et al, 1985; Menget et al, 1989), in a neonate (Kaufman30/69
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al, 1992), in premature infants (Presti et al, 1985; Menget et al, 1989), in a neonate (Kaufman
et al, 1990), and adults (Smith et al, 1976; Leikin et al, 1985; Schaumann et al, 1986; Smolarz
et al, 1985; Spiegel & Marchlinski, 1985) Wenger, 1985; (Kurowski et al, 1992). Also effective in
treating patients with lanatoside C intoxication (Hess et al, 1979), and oleander poisoning
(Shumaik et al, 1988).
b) In a trial involving 150 patients treated with Fab fragments, 75% of patients showed an
initial response to treatment within 60 minutes, while complete reversal of digoxin toxicity was
usually evident within 4 hours of administration (Antman et al, 1990). In addition, a total of 80%
of patients responded completely to treatment and 10% improved substantially.
c) In a study involving 717 patients, 50% had a complete response to treatment with Fab
fragments, 24% a partial response and 12% had no response (Hickey et al, 1991a).
d) Digibind(R) and Digitab(R) were compared in the reversal of digoxin-induced cardiac toxicity
in the rat model. The two drugs appeared to be equally effective in the reversal of the PTQ
((PTQ = PR interval(sec) x T score)/QTc(sec)) and hyperkalemia (Dart et al, 1995).
7) PHARMACOKINETICS: Digoxin-specific Fab, which is eliminated via renal and nonrenal routes,
has a volume of distribution of approximately 0.4 L/kg and an elimination half-life of 16 to 20
hours. Elimination half-lives may be increased up to 10-fold in patients with renal dysfunction,
while volume of distribution is unaffected. Digoxin-toxic patients with preserved renal function
have systemic clearance of digoxin-specific Fab of about 0.32 mL/min/kg while renal failure
decreases Fab clearance by up to 75%. Anephric patients may have Fab in their serum for 2 to 3
weeks following its administration (Ujhelyi & Robert, 1995).
a) Pharmacokinetic demise of total digoxin after digoxin-specific Fab dosing follows that of Fab.
D) HYPERKALEMIA
1) OVERVIEW: May be life-threatening. Caused by poisoning of Na-K pump by glycoside, so that
intracellular potassium becomes extracellular; there is not increased total body potassium.
Digoxin immune Fab is first-line treatment; if unavailable, insulin, glucose, and bicarbonate may
be given (and will lower potassium level for up to 12 hours). Calcium increases cardiac effects of
glycosides, and may precipitate dysrhythmias and should be given with great caution, if at all.
Kayexalate(R) is not indicated (lowers total body potassium). Use caution with beta-2 agonist
inhalers due to prodysrhythmic effects.
2) CAUTION: Fab fragments and bicarbonate/insulin/glucose should not be used simultaneously
because severe hypokalemia may result.
3) DIGOXIN IMMUNE FAB: Indications include hyperkalemia (generally greater than 5 mEq/L) or
progressively increasing levels postingestion. First-line treatment, if available. Restores Na-K
pump function and rapidly reverses hyperkalemia. (NOTE: See above for doses).
a) CASE REPORT: A 6-month-old child developed hyperkalemia, with a peak serum potassium
concentration of 7.8 mmol/L after receiving three doses of digoxin intravenously (0.16 mg,
0.08mg, and 0.08 mg). Twenty minutes after receiving Digoxin immune FAB, the patient's serum
potassium concentration normalized (4.5 mmol/L) (Husby et al, 2003).
4) CASE SERIES: A review of cases from a single poison control center from 2002 to 2014 was
conducted, identifying 358 cases of digoxin exposure. Of these 358 cases, 210 were treated at a
healthcare facility, where 42 patients were identified as hyperkalemic following digoxin exposure.
Sixteen of the 42 patients were not treated with digoxin specific Fab fragments, with 1 death
recorded. The median digoxin levels in the survivors and in the 1 death were 3.1 ng/mL and 4
ng/mL, respectively, with median potassium levels of 6 and 6.3 mEq/L, respectively. Of the 26
hyperkalemic patients who received treatment with Fab fragments, 2 deaths occurred. The
median digoxin levels in the survivors and in each of the 2 fatalities were 4.3, 6, and 3.1 ng/mL,
respectively, with potassium levels of 6.1, 6.1, and 6.3 mEq/L, respectively. Based on these
results, the outcome appeared to be similar regardless of therapy; however, limitations to this
study include lower serum digoxin levels in the patients not treated with Fab fragments,
indicating less severe digoxin toxicity, and the possibility of pseudohyperkalemia (Emswiler et al,
2015).
5) SODIUM BICARBONATE
a) INDICATIONS: Life-threatening hyperkalemia (K greater than 6.5 mEq/L) if digoxin immune
Fab not readily available. Use with insulin/D50.
b) DOSE: ADULT: 2 ampules (44 mEq/ampule) IV. CHILD: 1 to 2 mEq/L.
c) MECHANISM: Causes intracellular shift of potassium.
6) DEXTROSE/INSULIN
a) INDICATIONS: Life-threatening hyperkalemia (K greater than 6.5 mEq/L) if digoxin immune
Fab not readily available. Use with sodium bicarbonate.
b) DOSE: ADULT: Regular insulin 5-10 units IV push, D50W 2 amps (100 mL) IV push. CHILD:31/69
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b) DOSE: ADULT: Regular insulin 5-10 units IV push, D50W 2 amps (100 mL) IV push. CHILD:
Regular insulin 0.2 units/kg IV push, D50W 1 mL/kg IV push.
7) ECG MONITORING: Indicated continuously during hyperkalemia treatment.
8) CALCIUM: The effects of cardiac glycosides on the myocardium are increased by elevated
serum calcium levels. Administration of parenteral calcium to a digitalized patient should be done
with extreme caution, to avoid the possible precipitation of cardiac dysrhythmias. If necessary,
calcium should be administered slowly and in small quantities (Hansten & Horn, 1989; Zucchero
& Hogan, 1990).
a) A retrospective review of medical records was conducted from 1989 to 2005 at a tertiary
care medical center in Boston, Massachusetts, identifying 159 patients with digoxin toxicity. Of
the 159 patients with digoxin toxicity, 23 patients were given intravenous calcium as treatment.
There were no life-threatening dysrhythmias that occurred within 4 hours following calcium
administration. Five of the 23 patients (22%) who received calcium died during their
hospitalization, with 3 of the 5 deaths (60%) attributed to digoxin toxicity and not associated
with calcium administration. In comparison, 27 of the 136 patients (20%) who did not receive
calcium died during their hospitalization, with 15 of the 27 deaths (56%) attributed to digoxin
toxicity. A multivariate controlled analysis showed a non-significant decrease in mortality in
patients who received calcium (OR 0.76; 95% CI 0.24 to 2.5) (Levine et al, 2009).
E) ATROPINE
1) INDICATIONS: Useful in the management of bradycardia, and varying degrees of heart block
due to the digitalis-induced effects of enhanced vagal tone on SA node rhythmicity and on
conduction through the AV node (Smith & Willerson, 1971; Duke, 1972).
2) DOSE
a) ATROPINE/DOSE
1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if
bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully
vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia
in adults (Neumar et al, 2010).
2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg,
giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or
intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure
breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE
DOSE: Children: 0.5 milligram; adolescent: 1 mg.
a) There is no minimum dose (de Caen et al, 2015).
b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al,
2010).
F) LIDOCAINE
1) INDICATIONS: Useful in the management of ventricular tachydysrhythmias, PVCs, and
bigeminy. Lidocaine does not improve conduction through the AV node. Digoxin immune Fab is
preferred therapy for dysrhythmias.
2) LIDOCAINE/DOSE
a) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional
bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum
dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during
cardiac arrest.
1) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per
minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase
the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al,
2010).
b) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50
micrograms/kilogram/minute (de Caen et al, 2015).
3) LIDOCAINE/MAJOR ADVERSE REACTIONS
a) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression
or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block.
Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third
degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al,
2010).
4) LIDOCAINE/MONITORING PARAMETERS
a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl
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a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl
intravenous injection solution, 2006).
G) PHENYTOIN
1) INDICATIONS: Useful as a third-line agent in the management of digitalis-induced ventricular
dysrhythmias (PVCs, ventricular tachycardia and bigeminy) and improves conduction through the
AV node (Damato et al, 1970; Helfant et al, 1967). Digoxin immune Fab is preferred therapy for
dysrhythmias.
2) DOSE
a) IMPAIRED AV CONDUCTION: Low dose phenytoin (ADULT: 25 mg/dose IV at 1 to 2 hour
intervals; CHILD: 0.5 to 1.0 mg/kg/dose IV at 1 to 2 hour intervals) appears to improve AV
conduction (Rumack et al, 1974).
b) VENTRICULAR DYSRHYTHMIAS: Larger doses needed: LOADING DOSE FOR ADULTS AND
CHILDREN: Administer 15 mg/kg up to 1.0 g IV not to exceed a rate of 0.5 mg/kg/minute.
MAINTENANCE DOSE: ADULT: Administer 2 mg/kg IV every 12 hours as needed; CHILD:
Administer 2 mg/kg every 8 hours as needed.
3) MONITOR SERUM PHENYTOIN LEVELS just prior to initiating and during maintenance therapy
to assure therapeutic levels of 10 to 20 mcg/mL (39.64 to 79.28 nanomoles/liter). Monitor ECG
carefully.
H) MAGNESIUM
1) Magnesium has been reported to reverse digoxin-induced tachydysrhythmias (Davey, 2002;
French et al, 1984; Neff et al, 1972; Reisdorff et al, 1986). It should be used extremely cautiously
if at all in the presence of renal failure or bradycardia. Digoxin immune Fab is preferred therapy
for dysrhythmias.
2) DOSE: ADULT: 20 mL of 20% solution over 20 minutes by slow infusion. Infusion should be
stopped if patient vomits, becomes hypotensive, develops worsening heart block, or loses deep
tendon reflexes. Magnesium levels in serum should be followed.
3) CASE REPORT: Kinlay & Buckley (1995) report a case of an 83-year-old woman with digoxin
toxicity, ventricular tachycardia and a minimally elevated serum magnesium who was treated
with IV magnesium sulfate. 20 mmol of IV magnesium sulfate resulted in a more stable
junctional rhythm with bigeminy (Kinlay & Buckley, 1995).
I) AMIODARONE
1) Successfully used in 2 patients with dysrhythmias resistant to lidocaine, phenytoin, and
cardioversion (Maheswaran et al, 1983; Nicholls et al, 1985).
2) LOADING DOSE: ADULT: 150 mg infused over 15 minutes.
3) MAINTENANCE DOSE: ADULT: 1 mg/min over the first 6 hours, followed by 0.5 mg/min over
the following 18 hours.
J) EMERGENCY CARDIAC PACEMAKER
1) INDICATIONS: Digoxin immune Fab fragments are the treatment of choice for dysrhythmias
secondary to cardiac glycoside toxicity. Pacemaker (external or transvenous) use should be
considered in severe bradycardia and/or slow ventricular rate due to second or high-degree AV
block that fails to respond to atropine and/or phenytoin when digoxin Fab are not available (Citrin
et al, 1973; Bismuth et al, 1977; Schwartz, 1977; Taboulet et al, 1993).
2) ACUTE OVERDOSE: Taboulet et al (1993) studied 51 patients with cardiac glycoside
overdoses who were treated with cardiac pacing and/or Fab fragments. Results showed an 8%
failure rate with Fab in the prevention of life-threatening dysrhythmias and a 23% failure with
cardiac pacing. In this study pacing was associated with a high rate of complications (14 out of
39, 5 of them fatal) including 6 cases of pacing-induced dysrhythmias, 6 pacing failures and 2
cases of sepsis (Taboulet et al, 1993)
3) CHRONIC POISONING: In a retrospective study, the safety of transvenous temporary cardiac
pacing (TCP) was evaluated in patients (n=70; 74 +/- 12 years) with unintentional digoxinrelated symptomatic bradyarrhythmias. Of those that received TCP for various arrhythmias (sinus
arrest with junctional bradyarrhythmias, atrial fibrillation with a slow ventricular rate, and highdegree AV block), no major dysrhythmias or mortality were reported. In the comparison group
(no TCP) two deaths were reported due to ventricular tachyarrhythmias (Chen et al, 2004).
a) The authors concluded that TCP is safe for individuals experiencing chronic digoxin overdose
associated with symptomatic bradycardia, but concluded that the findings may not be applicable
following an acute exposure (ie, attempted suicide). Following acute exposure, patients may be
at greater risk to develop more frequent ventricular responses, and the use of TCP in the
overdrive mode may increase the risk of ventricular tachyarrhythmias resulting in potentially
serious complications (Chen et al, 2004).
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serious complications (Chen et al, 2004).

K) CARDIOPULMONARY BYPASS OPERATION
1) Percutaneous cardiopulmonary bypass has been used for therapy resistant cardiac arrest due
to digoxin overdose. Catecholamines may be needed during bypass to maintain arterial pressure.
This method may provide hemodynamic support and sufficient tissue perfusion to allow
neutralization by digoxin immune Fab in patients with cardiac arrest due to massive cardiac
glycoside overdoses (Behringer et al, 1998).
L) DRUG THERAPY FINDING
1) Other agents such as sodium salts of EDTA, lactones, heparin, propranolol, or calcium
channel blockers are of questionable value following acute massive overdose.
M) EXPERIMENTAL THERAPY
1) HYPERINSULINEMIA-EUGLYCEMIA (HIE) THERAPY: In a rat model of acute digoxin toxicity,
HIE infusion delayed abnormalities in cardiac conduction and improved rat survival. At this time,
HIE therapy should still be considered experimental for cardiac glycoside poisoning and is not
recommended in humans until more data is available (Oubaassine et al, 2006).
ENHANCED ELIMINATION
A) CHOLESTYRAMINE
1) DIGITOXIN elimination appears to be enhanced by the serial administration of cholestyramine,
4 g orally every 6 hours (Pieroni & Fisher, 1981; Cady et al, 1979). In one patient with chronic
toxicity cholestyramine effect was delayed for 48 hours and appeared limited to the gut; serum
clearance was not increased.
2) Cholestyramine was found to have minimal effect on DIGOXIN absorption and excretion in
man (Hall et al, 1977); but was reported to decrease the serum digoxin half-life from 75.5 hours
to 19.9 hours in a 94-year-old man with chronic digoxin toxicity and renal insufficiency (Henderson
& Solomon, 1988).
B) COLESTIPOL
1) COLESTIPOL, a steroid binding resin, has been claimed to enhance the elimination of digoxin
and digitoxin (Kilgore & Lehmann) (Bazzano & Bazzano, 1972).
C) DIURESIS
1) Furosemide-induced forced diuresis has been reported to enhance excretion by some authors
(Rotmensch et al, 1978; Koren & Klein, 1988), while others have shown no effect (Semple et al,
1975; Brown et al, 1976).
D) HEMODIALYSIS
1) Hemodialysis is ineffective in removing cardiac glycosides but may assist in restoring serum
potassium to normal levels.
E) HEMOPERFUSION
1) SUMMARY: Plain, charcoal, and immobilized antidigoxin antibody hemoperfusion have all been
used in digoxin and digitoxin overdose. None of these techniques have proven utility in these
ingestions.
2) PLAIN HEMOPERFUSION
a) DIGOXIN: Not useful; removes less than 1% of total ingested dose (Warren & Fanestil,
1979).
b) DIGITOXIN: Increased clearance in one study (n=11) using Amberlite XAD 4 resin column.
Removal rate increased 8.6 times with 1 column and 14 times with 2, with corresponding
reductions in serum level of 32% and 59% (Mathiew, 1983).
3) B2-MG ADSORPTION COLUMN
a) Digoxin intoxication was successfully managed by hemoperfusion with specific columns for
B2-microglobulin-adsorption (Lixelle(TM)) in a maintenance hemodialysis patient with renal
failure. The direct hemoperfusion column was connected to the arterial end of a hemodialyzer.
Serum digoxin concentration decreased from 6.00 to 2.31 ng/mL, with marked improvement in
the patient's GI symptoms (level rebounded to 3.59 ng/mL). Six days later the same therapy was
repeated, with further improvement of digoxin serum concentration from 3.59 to 1.70 ng/mL
(Kaneko et al, 2001).
1) Tsuruoka et al (2001) also reported successful lowering of digoxin concentrations in 8
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1) Tsuruoka et al (2001) also reported successful lowering of digoxin concentrations in 8

hemodialysis patients following hemoperfusion with a column for B2-microglobulin-adsorption.
This column appears to selectively adsorb digoxin and it possesses a higher capacity for digoxin
removal than activated charcoal in vitro (Tsuruoka et al, 2001).
4) CHARCOAL HEMOPERFUSION
a) DIGOXIN: Used in a few cases (Smiley et al, 1978) (Marbury, 1979); (Gibson, 1990); (Suzuki,
1988). Pharmacokinetic data suggest the procedure is not useful (Freed, 1979).
b) DIGITOXIN: One case report of 50% removal of a 10 mg dose in 8 hours (Gilfrich, 1979).
Half-life reduced from 145 to 20 hours.
5) IMMOBILIZED ANTIDIGOXIN ANTIBODY HEMOPERFUSION
a) TECHNIQUE: Plasma flows across small columns containing antidigoxin antibodies bound to
polyacrolein microspheres in agarose microspheres.
b) RESULTS: One human trial (Savin, 1987) reported 87 mL/min plasma clearance in 10 digoxin
toxic patients. One animal study (Brizgys, 1989) reported 5% to 20% removal of total dose
without measurable effect on serum digoxin level.
c) CONCLUSION: Not recommended at present.
6) RESIN HEMOPERFUSION
a) CASE REPORT: A 30-year-old woman developed persistent vomiting, diplopia, blurred and
range 0.8 to 2 ng/mL). An ECG revealed prolonged and varying PR interval with atrial ectopics,
subsequently converting to complete heart block. Because of continued bradycardic episodes,
transcutaneous pacing was applied and a temporary pacemaker was inserted. Due to a high
serum digoxin level and unavailability of digoxin Fab fragments, resin hemoperfusion was
performed over a 4-hour period. Within 4 hours, the patient's vision improved and her nausea and
vomiting resolved. Over the next 24 to 36 hours, her cardiac status improved with resolution of
her heart block and a decrease in her digoxin level to 2.56 ng/mL. The patient was discharged 4
days after admission following normalization of her serum digoxin level and complete resolution
of symptoms (Juneja et al, 2012).
F) MULTIPLE DOSE ACTIVATED CHARCOAL
1) While digoxin immune Fab fragments are the preferred treatment for severe or life-threatening
cardiac glycoside intoxication, multiple dose activated charcoal may be useful in situations in
which Fab fragments are not available. Multiple dose activated charcoal has been shown to
enhance elimination of digoxin and/or digitoxin in animal models (Chyka et al, 1995), volunteers
(Park et al, 1985; Reissell & Manninen, 1982; Lalonde et al, 1985), and overdose cases (Pond et
al, 1981; Blody et al, 1985) (Lake et al, 84) (Critchley & Critchley, 1997; Ibanez et al, 1995). It
has not been shown to affect outcome after overdose.
2) Multiple dose activated charcoal should be considered in patients with potentially life
threatening poisoning when digoxin immune Fab fragments are not readily available.
3) MULTIPLE DOSE ACTIVATED CHARCOAL
a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of
activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose
equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours
(Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more
frequent doses are more effective at enhancing drug elimination than larger less frequent doses
(Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established.
After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram
body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4
hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters,
including drug concentrations if available, are improving (Vale et al, 1999). The patient should be
frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or
intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the
likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al,
1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to
allow MDAC therapy to be effective include: small volume of distribution, low protein binding,
prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka,
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e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal
obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of
aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg,
decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999;
Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis,
charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult
respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al,
1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris &
Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al,
2001; Graff et al, 2002).
G) PLASMA EXCHANGE
1) NOT INDICATED: Multiple plasma exchange did not significantly alter digoxin kinetics and had
a slight effect on digitoxin. The estimated fraction of the body burden removed by one exchange
was 5.5% for digitoxin and 1.2% for digoxin (Keller et al, 1985).
H) HEMOFILTRATION
1) Used to treat a patient with chronic renal failure who developed hyperkalemia and complete
heart block associated with a digoxin level of 3.2 ng/mL (4.1 nanomoles/liter). Hyperkalemia
corrected within 6 hours and heart block resolved 12 hours after continuous arteriovenous
hemofiltration (Lai et al, 1986).
I) PERITONEAL DIALYSIS
1) Peritoneal dialysis was initiated in a newborn with acute renal failure and digoxin toxicity
treated with intravenous FAB. Peritoneal dialysis was ineffective in removing the digoxin-FAB
complex but was helpful in restoring serum potassium to normal levels and correcting the acidosis
(Berkovitch et al, 1994).
2) CASE REPORT: Caspi et al (1997) reported no significant enhanced clearance of digoxin with
an intensive peritoneal dialysis schedule in a 64-year-old man with chronic renal failure and
digoxin toxicity (Caspi et al, 1997).
RANGE OF TOXICITY
SUMMARY
A) ADULTS: Healthy adults may develop symptoms after acute ingestions of more than 2 to 3 mg,
but rarely develop life-threatening toxicity with acute ingestions of less than 5 mg. Ingestions
causing cardiac arrest in healthy adults are generally 10 mg digoxin or more.
B) PEDIATRIC: A healthy child can probably tolerate an acute ingestion of 2 mg digoxin without
severe toxicity. Toxic effects are likely with ingestions of more than 0.1 mg/kg, and acute
ingestions of 4 mg digoxin or more in young children may be fatal.
C) THERAPEUTIC DOSE: Varies with formulation. ADULTS: (intravenous and/or oral capsule) For
rapid digitalization, give a digoxin loading dose of 0.4 to 0.6 mg orally or IV; for gradual
digitalization, give digoxin maintenance doses of 0.05 to 0.350 mg orally once daily. (Tablet) 0.5 to
0.75 mg orally as a loading dose for rapid digitalization, then 0.125 to 0.5 mg orally once daily.
(Solution) maintenance dose of 3 mcg/kg orally daily. CHILDREN: (intravenous and/or oral
capsule) For rapid digitalization, give orally or IV in divided doses (premature) 15 to 25 mcg/kg;
(full-term) 20 to 30 mcg/kg; (1 to 24 months) 30 to 50 mcg/kg; (2 to 5 years) 25 to 35 mcg/kg; (5
to 10 years) 15 to 30 mcg/kg; (over 10 years) 8 to 12 mcg/kg; for daily maintenance doses for
gradual digitalization, give 20% to 30% of IV digitalizing dose for premature infants or 25% to
35% of oral or IV digitalizing dose for all other pediatric patients. (Solution) older than 2 years,
maintenance dose of 10 mcg/kg/day orally. (Tablet) 2 to 5 years of age, 10 to 15 mcg/kg/day in
divided doses; 5 to 10 years of age, 7 to 10 mcg/kg/day in divided doses; over 10 years of age, 3
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to 5 mcg/kg/day in divided doses.
THERAPEUTIC DOSE
7.2.1) ADULT
A) SPECIFIC DISEASE STATE
1) HEART FAILURE
a) IV/IM: For rapid digitalization, give loading dose of 8 to 12 mcg/kg IV/IM; administer one-half
of total loading dose initially, followed by one-fourth of the total loading dose every 6 to 8 hours
for 2 doses. For maintenance dosing, the recommended dose is 2.4 to 3.6 mcg/kg IV/IM once
daily; may increase dose every 2 weeks based on clinical response, drug levels, and toxicity
(Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013).
b) ORAL TABLETS: For rapid digitalization, the total loading dose is 10 to 15 mcg/kg orally;
administer one-half of total loading dose initially, followed by one-fourth of the total loading dose
every 6 to 8 hours twice. For daily maintenance doses or for gradual digitalization, the
recommended dose 3.4 to 5.1 mcg/kg orally once daily; titrate every 2 weeks (Prod Info
LANOXIN(R) oral tablets, 2013).
c) ORAL SOLUTION: For maintenance dosing, the recommended oral dose is 3 to 4.5
mcg/kg/day (Prod Info digoxin oral solution, 2011).
d) ORAL CAPSULES: Lanoxicap(R) digoxin capsules have been discontinued by the
manufacturer. Divided daily dosing is presently recommended for patients requiring a daily dose
of 300 micrograms (mcg) or greater, for patients with a previous history of digitalis toxicity, for
patients considered likely to become toxic, and for patients in whom compliance is not a
problem. For rapid digitalization, give loading dose of 8 to 12 mcg/kg IV/IM; administer one-half
for 2 doses. For maintenance dosing, the recommended dose is 50 to 350 mcg once daily,
titrating every 2 weeks (Prod Info LANOXICAPS(R) oral capsules, 2005).
2) ATRIAL FIBRILLATION
a) The American College of Cardiology/American Heart Association/European Society of
Cardiology guidelines recommend a loading dose of 0.25 mg IV/orally every 2 hours up to 1.5 mg
MAX. The recommended maintenance dose is 0.125 to 0.375 mg orally daily OR 0.125 to 0.25
mg IV daily (guideline dosing)(Fuster et al, 2006).
b) IV/IM: For rapid digitalization, give loading dose of 8 to 12 mcg/kg IV/IM; administer one-half
for 2 doses. For maintenance dose, give 2.4 to 3.6 mcg/kg IV/IM once daily; may increase dose
every 2 weeks based on clinical response, drug levels, and toxicity (manufacturer dosing) (Prod
Info LANOXIN(R) intravenous injection, intramuscular injection, 2013).
c) ORAL TABLETS: For rapid digitalization, give total loading dose of 10 to 15 mcg/kg ORALLY;
administer one-half of total loading dose initially, followed by one-fourth of the total loading dose
every 4 to 8 hours twice. For daily maintenance doses or for gradual digitalization, give 3.4 to
5.1 mcg/kg ORALLY once daily; titrate every 2 weeks (manufacturer dosing) (Prod Info
LANOXIN(R) oral tablets, 2012).
7.2.2) PEDIATRIC
A) LOADING DOSE ("RAPID DIGITALIZATION")
1) Generally used only in urgent situations (eg, treating arrhythmias or acute congestive heart
failure). The total digitalizing dose is usually given over 16 to 24 hours as 3 divided doses every 6
to 8 hours (Hobbins et al, 1981).
2) Oral doses should be 25% greater than IV doses. A slower digitalization can be accomplished
by initiating an appropriate maintenance dose (Prod Info LANOXIN(R) intravenous injection,
intramuscular injection, 2013; Jain & Vaidyanathan, 2009; Park, 1986).
B) MAINTENANCE DOSE
1) Maintenance doses are approximately 25% of digitalizing doses. Twice-daily dosing (over
once-daily dosing) is recommended in younger children (10 years of age and younger). This
minimizes the potential risk of toxic peak concentrations and subtherapeutic trough levels (Jain &
Vaidyanathan, 2009; Bakir & Bilgic, 1994; Park, 1986). In a study in children (n=30), statistically
significant differences were noted in peak levels for once-daily dosing (2.3 +/- 0.8 nanograms
(ng)/mL) compared with twice-daily dosing (1.6 +/- 0.7 ng/mL) (Bakir & Bilgic, 1994).
C) SPECIFIC DISEASE STATE
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C) SPECIFIC DISEASE STATE

1) HEART FAILURE
a) IV/IM: For rapid digitalization, administer one-half of total loading dose initially, followed by
one-fourth of the total loading dose every 6 to 8 hours for 2 doses. Total IV/IM loading dose:
(premature) 15 to 25 mcg/kg; (full-term) 20 to 30 mcg/kg; (1 to 24 months) 30 to 50 mcg/kg;
(2 to 5 years) 25 to 35 mcg/kg; (5 to 10 years) 15 to 30 mcg/kg; (over 10 years) 8 to 12
mcg/kg (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013)
b) ORAL SOLUTION: For loading dose, first dose: give half the total loading dose; subsequent
doses: as clinically indicated, give additional fractions of the total loading dose at 4- to 8-hour
intervals; TOTAL ORAL loading dose: (premature) 20 to 30 mcg/kg; (full term) 25 to 35 mcg/kg;
(1 to 24 months) 35 to 60 mcg/kg; (2 to 5 years) 30 to 45 mcg/kg; (5 to 10 years) 20 to 35
mcg/kg; (over 10 years) 10 to 15 mcg/kg (Prod Info digoxin oral solution, 2011).
1) For maintenance dosing, recommended oral doses are (premature) 2.3 to 3.9 mcg/kg twice
daily; (full term) 3.8 to 5.6 mcg/kg twice daily; (1 to 24 months) 5.6 to 9.4 mcg/kg twice daily;
(2 to 5 years) 4.7 to 6.6 mcg/kg twice daily; (5 to 10 years) 2.8 to 5.6 mcg/kg twice daily;
(over 10 years) 3 to 4.5 mcg/kg once daily (Prod Info digoxin oral solution, 2011).
c) ORAL TABLETS:
1) 5 to 10 years: For rapid digitalization, the total loading dose is 20 to 45 mcg/kg orally;
administer one-half of total loading dose initially, followed by one-fourth of the total loading
dose every 6 to 8 hours twice. For daily maintenance doses or for gradual digitalization, give 3.2
to 6.4 mcg/kg orally twice daily (Prod Info LANOXIN(R) oral tablets, 2013).
2) 11 years and older: For rapid digitalization, the total loading dose is 10 to 15 mcg/kg orally;
administer one-half of total loading dose initially, followed by one-fourth of the total loading
dose every 6 to 8 hours twice. For daily maintenance doses or for gradual digitalization, give 3.4
to 5.1 mcg/kg orally once daily; titrate every 2 weeks (Prod Info LANOXIN(R) oral tablets,
2013)
d) ORAL CAPSULES:
1) Lanoxicap(R) digoxin capsules have been discontinued by the manufacturer. For rapid
digitalization, the recommended doses were 25 to 35 mcg/kg (ages, 2 to 5 years), 15 to 30
mcg/kg (ages, 5 to 10 years), and 8 to 12 mcg/kg (ages over 10 years). The maintenance dose
was 25% to 35% of the oral or IV digitalizing dose (Prod Info LANOXICAPS(R) oral capsules,
2005).
2) SUPRAVENTRICULAR TACHYCARDIA (SVT)
a) Higher oral maintenance doses (up to 15 mcg/kg/day) may be necessary to control the
ventricular rate in infants and children with SVT (Pfammatter & Stocker, 1998; Luedtke et al,
1997).
MINIMUM LETHAL EXPOSURE

A) ACUTE
1) Adult patients with normal hearts rarely develop life threatening toxicity with less than 5
milligrams in an acute ingestion. Fatal ingestions resulting in cardiac arrest are usually greater
than 10 milligrams in healthy adults or greater than 4 mg in a previously healthy child (Prod Info
LANOXICAPS(R) oral capsules, 2005).
2) Survival has been reported in adults following acute ingestion of 20 milligrams digoxin.
3) There is insufficient controlled data in the literature to accurately determine the minimum
toxic or lethal dose in humans.
MAXIMUM TOLERATED EXPOSURE

A) ACUTE
1) Acute single ingestions of greater than 2 to 3 milligrams are generally associated with
manifestations of toxicity. Acute ingestion of less than 2 to 3 mg in a patient on chronic (daily)
digoxin therapy may result in toxicity.
2) A child with a normal heart can probably tolerate two milligrams orally without cardiac
toxicity, but should be observed in a hospital for at least 8 hours.
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toxicity, but should be observed in a hospital for at least 8 hours.

3) A 36-year-old man survived a massive overdose of digitoxin (35 mg) following treatment with
FAB fragments. Prior to FAB therapy, the total serum concentration was 535 nanomoles/liter at
11 hours postingestion (Kurowski et al, 1992).
4) Two weeks after undergoing an open-heart surgery, a 12-week-old girl with known cardiac
disease (a double outlet right ventricle with a subaortic ventricular septal defect and a single
coronary artery) presented in asystolic cardiac arrest secondary to an acute on chronic digoxin
poisoning (125 mcg twice daily instead of 25 mcg twice daily; 750 mcg over a 3-day period
instead of 150 mcg). Her digoxin level was 12.6 ng/mL. Following a successful resuscitation and
the use of Digoxin-specific antibody fragments, she converted to normal sinus rhythm. She was
discharged 6 days after the admission with full neurological recovery (Eyal et al, 2005).
5) CASE REPORT: A 30-year-old woman developed persistent vomiting, diplopia, blurred and
range 0.8 to 2 ng/mL). An ECG revealed prolonged and varying PR interval with atrial ectopics,
subsequently converting to complete heart block. Following resin hemoperfusion, the patient
gradually recovered and was discharged on hospital day 4 (Juneja et al, 2012).
6) CASE REPORT: A 26-year-old pregnant woman, at 21 weeks gestation, presented to the
emergency department with burning pain, abdominal cramps, and lightheadedness approximately
2 hours after being injected intraperitoneally into the stomach with 1 mg digoxin. An ECG
revealed sinus tachycardia, with a heart rate of 140. An initial digoxin level, obtained 2 hours
post-injection, was 8.1 mg/dL and her potassium level was 3.4 mEq/L. Digibind was not
administered and, 7 hours post-injection, her digoxin level decreased to 2.5 mg/dL. Following
continued observation and resolution of symptoms, she was discharged 24 hours later. The
outcome of the fetus was unknown (Mellesmoen & Gummin, 2015).
SERUM/PLASMA/BLOOD CONCENTRATIONS
7.5.1) THERAPEUTIC CONCENTRATIONS
A) THERAPEUTIC CONCENTRATION LEVELS
1) GENERAL
a) Digoxin toxicity has been reported in 4 patients with normal therapeutic serum digoxin levels
(0.6-2.6 ng/mL). Gastrointestinal symptoms of major bowel disease was evident in 3 of the
patients and tiredness and bradycardia was reported in 1 patient (Mitchell, 1997).
7.5.2) TOXIC CONCENTRATIONS
A) TOXIC CONCENTRATION LEVELS
1) ADULT
a) Following an overdose of digitoxin, one patient died from ventricular fibrillation 24 hours after
admission, with a plasma digitoxin concentration of 124 nanograms/milliliter (160
millimoles/liter) shortly before death (Hansteen et al, 1981).
b) A serum digoxin concentration of 38.5 nanomoles/liter at 4 hours and 40 minutes following
an overdose of 100 digoxin tablets 0.1 milligram (total of 10 milligrams) and increasing to a peak
of 93.6 nanomoles/liter at 24 hours was reported in a 79-year-old male, who died 12 days later
of septic shock (Behringer et al, 1998).
c) An 82-year-old male with underlying heart disease (treated with digoxin during the previous 2
years) ingested a full bottle of digoxin (quantity and strength not reported). He developed fatal
cardiac arrest 4 hours later. A serum sample taken 2.5 hours after the ingestion, revealed a
serum digoxin concentration between 12.2 and 13.2 nanograms/milliliter (Rodriguez-Calvo et al,
2002).
d) CASE SERIES - In a case series of 1,433 patients with digoxin assays, 115 (8%) were
reported to have elevated levels (greater than 2.4 ng/mL). Eighty- two of these had complete
records, and 59 (72%) of these had experienced electrocardiographic or clinical features of
digoxin toxicity. A combination of impaired renal function, particularly in elder patients, and drug
interactions mainly contributed to the elevated digoxin serum levels (Marik & Fromm, 1998).
e) Retrospective analysis of data from the DIG trial indicates a beneficial effect of digoxin on
morbidity and no excess mortality in women at serum concentrations from 0.5 to 0.9 ng/mL,
whereas serum concentrations greater or equal to 1.2 ng/mL may be harmful (Adams et al,
2005).
2) PEDIATRIC
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2) PEDIATRIC
a) CASE REPORT - Two weeks after undergoing an open-heart surgery, a 12-week-old girl with
known cardiac disease (a double outlet right ventricle with a subaortic ventricular septal defect
and a single coronary artery) presented in asystolic cardiac arrest secondary to an acute on
chronic digoxin poisoning (125 mcg twice daily instead of 25 mcg twice daily; 750 mcg over a 3day period instead of 150 mcg). Her digoxin level was 12.6 ng/mL. Following a successful
resuscitation and the use of Digoxin-specific antibody fragments, she converted to normal sinus
rhythm. She was discharged 6 days after the admission with full neurological recovery (Eyal et
al, 2005).
WORKPLACE STANDARDS
A) ACGIH TLV Values for CAS20830-75-5 (American Conference of Governmental Industrial
Hygienists, 2010):
1) Not Listed
B) ACGIH TLV Values for CAS71-63-6 (American Conference of Governmental Industrial
Hygienists, 2010):
1) Not Listed
C) ACGIH TLV Values for CAS630-60-4 (American Conference of Governmental Industrial
Hygienists, 2010):
1) Not Listed
D) ACGIH TLV Values for CAS36-06-6 (American Conference of Governmental Industrial
Hygienists, 2010):
1) Not Listed
E) NIOSH REL and IDLH Values for CAS20830-75-5 (National Institute for Occupational Safety and
Health, 2007):
1) Not Listed
F) NIOSH REL and IDLH Values for CAS71-63-6 (National Institute for Occupational Safety and
Health, 2007):
1) Not Listed
G) NIOSH REL and IDLH Values for CAS630-60-4 (National Institute for Occupational Safety and
Health, 2007):
1) Not Listed
H) NIOSH REL and IDLH Values for CAS36-06-6 (National Institute for Occupational Safety and
Health, 2007):
1) Not Listed
I) Carcinogenicity Ratings for CAS20830-75-5 :
1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for
Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to
Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a;
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working 40/69
2016/9/24
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working
Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the
Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National
Toxicology Project ): Not Listed
J) Carcinogenicity Ratings for CAS71-63-6 :
K) Carcinogenicity Ratings for CAS630-60-4 :
L) Carcinogenicity Ratings for CAS36-06-6 :
M) OSHA PEL Values for CAS20830-75-5 (U.S. Occupational Safety, and Health Administration
(OSHA), 2010):
1) Not Listed
N) OSHA PEL Values for CAS71-63-6 (U.S. Occupational Safety, and Health Administration
(OSHA), 2010):
1) Not Listed
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O) OSHA PEL Values for CAS630-60-4 (U.S. Occupational Safety, and Health Administration
(OSHA), 2010):
1) Not Listed
P) OSHA PEL Values for CAS36-06-6 (U.S. Occupational Safety, and Health Administration
(OSHA), 2010):
1) Not Listed
TOXICITY INFORMATION
7.7.1) TOXICITY VALUES
A) DIGITOXIN
1) LD50- (ORAL)MOUSE:
a) 5 mg/kg (RTECS , 2001)
2) LD50- (ORAL)RAT:
a) 24 mg/kg (RTECS , 2001)
B) DIGOXIN
a) 18 mg/kg (RTECS , 2001)
2) LD50- (ORAL)RAT:
a) 28 mg/kg (RTECS , 2001)
C) OUABAIN
1) LD50- (INTRAPERITONEAL)MOUSE:
a) 11 mg/kg ((RTECS, 1998))
a) 5 mg/kg ((RTECS, 1998))
3) LD50- (SUBCUTANEOUS)MOUSE:
a) 5 mg/kg ((RTECS, 1998))
CALCULATIONS
A) BIOLOGICAL CONVERSIONS
1) SI UNIT CONVERSION
a) DIGOXIN (PLASMA)
1) To convert traditional units (nanograms/milliliter) into SI units (nanomoles/liter), multiply
traditional units by 1.281.
2) To convert SI units (nanomoles/liter) into traditional units (nanograms/milliliter), divide SI
units by 1.281.
OTHER
A) OTHER
1) SUMMARY
a) Serum concentrations of digoxin-like immunoactivity (DLIA) have been reported to be
elevated in patients with diabetes mellitus and hypertension, which may affect therapeutic
monitoring of digitalization in these patients (Martinka et al, 1998). Tzou et al (1997) also report
elevated concentrations in patients with renal and hepatic diseases and Gilson et al (1997) 42/69
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elevated concentrations in patients with renal and hepatic diseases and Gilson et al (1997)
report elevated concentrations in pregnancy. Further investigation is necessary to determine the
significance of these findings (Tzou et al, 1997; Gilson et al, 1997).
KINETICS
ABSORPTION
A) THERAPEUTIC DOSE
1) DIGOXIN - Readily and almost completely absorbed from the GI tract (Doherty, 1973), with
peak serum concentrations occurring within 1.5 to 6 hours after an oral dose (Borron et al, 1997).
a) Absolute bioavailability of various digoxin oral dosage forms is as follows (Prod Info
LANOXICAPS(R) oral capsules, 2005):
DOSE FORM
ABSOLUTE BIOAVAILABILITY
Tablets
60% - 80%
Elixir
70% - 85%
Capsules
90% - 100%
2) DIGITOXIN - Readily and completely absorbed from the GI tract.

B) OVERDOSE
1) DIGOXIN - The onset of cardiac toxicity following acute digoxin overdose is 30 minutes.
2) DIGITOXIN - For digitoxin and digitalis leaf onset of cardiac toxicity is 1 to 2 hours.
DISTRIBUTION
8.2.1) DISTRIBUTION SITES
A) TISSUE/FLUID SITES
1) DIGOXIN - Following ingestion, a 6- to 8-hour tissue distribution phase is observed, with
digoxin becoming concentrated in tissues; thus it has a large apparent volume of distribution.
Following chronic use, the steady-state post-distribution serum concentrations are in equilibrium
with tissue concentrations and correlate with pharmacologic effects (Prod Info LANOXICAPS(R)
oral capsules, 2005).
a) Digoxin crosses the blood-brain barrier and the placenta. Serum digoxin concentrations in the
newborn are similar to that of the mother at birth.
B) PEAK PLASMA LEVEL
1) DIGOXIN - Peak levels following therapeutic oral doses occurs in 2 to 3 hours. The peak of
cardiac toxicity following acute digoxin overdose is 3 to 12 hours (mean 3 to 6 hours). Steady
state levels are accurate 6 hours after ingestion. Serum concentrations do not appear to differ by
gender (Lee & Chan, 2006).
2) DIGITOXIN - For digitoxin and digitalis leaf, the peak of cardiac toxicity is 4 to 12 hours.
C) PROTEIN BINDING
1) DIGOXIN - Approximately 25% (Prod Info LANOXICAPS(R) oral capsules, 2005)
2) DIGITOXIN - Extensively bound to plasma proteins (97%).
8.2.2) DISTRIBUTION KINETICS
A) VOLUME OF DISTRIBUTION
1) DIGOXIN - The volume of distribution is proportional to lean body mass, with muscular
individuals having a larger Vd than obese individuals. Vd can decrease by as much as 50% in
patients with renal failure. Values range from 5.1 to 7.4 liters/kg (Baselt, 1982); one study
showed variability of the steady-state volume of distribution in patients in renal failure of from
195 to 489 liters/1.73m(2) (Koup et al, 1975).
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195 to 489 liters/1.73m(2) (Koup et al, 1975).

a) DIGOXIN TOXICITY - Vd decreases as the serum concentration increases. The mean Vd was
reported as 208 L in a group (n=30) of patients with serum digoxin concentration > 2.2 mcg/L,
while mean Vd was reported as 316 L in a group (n=30) of patients with normal digoxin serum
concentrations (Lecointre et al, 2001).
b) The kinetics of digoxin may be altered in profoundly sick infants and children such that serum
concentrations of digoxin may continue to rise long after cessation of therapy (Koren & Klein,
1988). The mechanism of this observation has yet to be determined.
2) DIGITOXIN - 0.6 L/kg (Prod Info, 1991).
B) DISTRIBUTION HALF LIFE
1) DIGOXIN - This phase may take 4 to 6 hours in therapeutic doses. The distribution T1/2 is
approximately 30 minutes (Borron et al, 1997). In overdose, the distribution phase may be
prolonged.
METABOLISM
8.3.2) METABOLITES
A) SPECIFIC SUBSTANCE
1) DIGOXIN - Metabolized to a very minor extent (about 16%) via hydrolysis, oxidation, and
conjugation (Prod Info LANOXICAPS(R) oral capsules, 2005). Metabolism is not dependent on
the cytochrome P450 system.
2) DIGITOXIN - After a single dose digoxin is the major serum and urine metabolite. In chronic
administration, digoxin represents less than 1% of serum metabolites (Baselt, 1982).
EXCRETION
8.4.1) KIDNEY
A) DIGOXIN - Single dose IV studies report 57% to 80% of the administered dose excreted
within 6 to 12 hours. Renal tubular secretion of digoxin appears to be the primary mechanism
(Koren et al, 1986; Borron et al, 1997). About 50% to 70% is excreted unchanged in the urine
(Prod Info LANOXICAPS(R) oral capsules, 2005).
B) DIGITOXIN - Slowly eliminated from the body 60 to 80% of a dose appearing in the urine as
metabolites, over 3 weeks.
8.4.2) FECES
A) Three to 5% of total body stores are excreted daily in the stool.
8.4.3) BILE
A) Biliary excretion with enterohepatic recycling has been reported with up to 30% of an IV dose
reaching GI tract in 24 hours (Caldwell & Cline, 1976).
ELIMINATION HALF-LIFE
8.5.1) PARENT COMPOUND
A) SPECIFIC SUBSTANCE
1) DIGOXIN - 36 to 51 hours; but may be decreased in overdose situations to as low as 15 hours
(Hobson & Zettner, 1973). Others have reported prolonged half-life in overdose up to 32 hours
(Smith & Willerson, 1971), and 135 hours in a child treated with Fab (Kearns et al, 1989).
a) DIGOXIN TOXICITY - Elimination half-life increases with toxic serum digoxin concentrations.
Elimination half-life was reported as a mean of 94 hours in a group (n=30) of patients with
digoxin serum concentrations > 2.2 mcg/L, while mean elimination half-life of 72 hours was
reported in a group (n=30) of patients with normal serum digoxin concentrations (Lecointre et
al, 2001).
2) DIGITOXIN - 4 to 6 days; a half-life of 2.9 to 6.2 days were calculated in five patients who
had ingested an overdose of digitoxin (Hansteen et al, 1981). Prolonged digitoxin half-life (mean
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had ingested an overdose of digitoxin (Hansteen et al, 1981). Prolonged digitoxin half-life (mean
+/- SD: 25 +/- 9 days) has been reported in very elderly patients in the eight and ninth decade
of life than in younger patients (half-life 6.7 +/- 1.7 days). In these elderly patients, digitoxin
may be accumulated even after a dose of 0.05 mg/day (Bohmer & Roseth, 1998).
3) DIGOXIN IMMUNE FAB - In humans, the elimination half-life is 15 to 20 hours (normal renal
function) (Smith et al, 1982).
PHARMACOLOGY/TOXICOLOGY
TOXICOLOGIC MECHANISM
A) Massive acute cardiac glycoside overdose differs significantly from chronic toxicity. In the acute
overdose the sodium-potassium pump is poisoned, producing a fall in intracellular potassium and a
rise in extracellular potassium, which may be marked. The normal membrane resting potential is
reduced, and electrical conduction is slowed, with eventual complete loss of myocardial electrical
function. Furthermore, vagal tone is increased. Clinically this results in high grade heart block, and
eventually in asystole, which may not respond to electrical pacing.
PHYSICOCHEMICAL
PHYSICAL CHARACTERISTICS
A) DIGOXIN
1) Odorless (HSDB, 2003)
2) Clear to white crystals or a white, crystalline powder (HSDB, 2003)
3) Radially arranged, four- and five-sided triclinic plates from dilute alcohol or dilute pyridine
(Budavari, 1996)
B) DIGITOXIN
1) White or pale buff microcrystalline powder or elongated leaflets(HSDB, 2003)
2) Very small elongated, rectangular plates from dilute alcohol (Budavari, 1996)
C) OUABAIN
1) Odorless, white, hygroscopic, crystalline powder as an octahydrate (HSDB, 2003)
2) Stable in air but is affected by light (Budavari, 1996)
MOLECULAR WEIGHT
1) Digoxin - 780.95 (Budavari, 1996)
2) Digitoxin - 764.92 (Budavari, 1996)
3) Ouabain - 584.66 (Budavari, 1996)
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the drug be administered in pregnant women only if clearly necessary.

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treatment of heart failure (Prod Info LANOXICAPS(R) oral capsules, 2005).

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perfusion, indicating non-occlusive mesenteric ischemia believed to be secondary to digitalis

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healthcare facility, where 42 patients were identified as hyperkalemic following digoxin

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of 1.7 ng/mL (2.18 nmol/mL) (Carney et al, 1985).

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~ *Admitted medical patients not on digoxin who served as matched-pair controls.

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5) DLIS: Digoxin-like immunoreactive substance (DLIS) is an endogenous natriuretic

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6.3.1.1) ADMISSION CRITERIA/ORAL

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1) May be useful after large ingestions.

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DigiFab(R) Dose (vials)

1) * = 0.25 milligram (mg) tablets with 80% bioavailability

Toxicology details - MICROMEDEX

DIGIFAB(R) Serum digoxin (ng/mL) x weight (kg)

DIGIFAB(R) Dose (vials)

DIGIFAB(R) Dose (vials)

DIGIFAB(R) Dose (vials)

DIGIFAB(R) Dose (vials)

Toxicology details - MICROMEDEX

e) PATIENT WEIGHT = 100 kg

DIGIFAB(R) Dose (vials)

a) * = Dilution of reconstituted vial to 1 mg/mL may be desirable

a) * = Dilution of reconstituted vial to 1 mg/mL may be desirable

Toxicology details - MICROMEDEX

a) * = Dilution of reconstituted vial to 1 mg/mL may be desirable

3) CALCULATIONS BASED ON STEADY-STATE DIGITOXIN CONCENTRATION

Toxicology details - MICROMEDEX

et al, 1989; Erdmann et al, 1989; Nuwayhid & Johnson, 1989).

Toxicology details - MICROMEDEX

Toxicology details - MICROMEDEX

Toxicology details - MICROMEDEX

Toxicology details - MICROMEDEX

serious complications (Chen et al, 2004).

Toxicology details - MICROMEDEX

1) Tsuruoka et al (2001) also reported successful lowering of digoxin concentrations in 8

Toxicology details - MICROMEDEX

1995; Ghannoum & Gosselin, 2013).