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DIGOXIN IMMUNE FAB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Digoxin immune Fab is derived from specific antidigoxin antibodies that are produced in sheep immunized to digoxin. These antibodies are used in the treatment of life-threatening digitalis toxicity.

Specific Substances

    1) ATC: V03AB24
    2) Digoxin-specific antibody fragments
    3) Digoxin immune fab (ovine)
    4) DigiFab
    5) Digitalis antidote

Available Forms Sources

    A) FORMS
    1) Digoxin immune fab is available in vials containing 40 mg of purified lyophilized digoxin-specific Fab fragments. Supplied in a box of 1 (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012)
    B) USES
    1) Digoxin immune Fab is used in the treatment of digoxin toxicity. It is intended for use following a life-threatening digoxin overdose. Digoxin Fab fragments should not be used for mild cases of toxicity, as these patients generally do well with supportive care (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    a) INDICATIONS: The use of digoxin immune Fab is limited to severe or potentially severe toxicity which may include any of the following (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012; Clarke & Ramoska, 1988):
    1) Ingestion of large, possibly lethal amounts of digitalis (Adult > 10 mg; Child: > 4 mg)
    2) Hyperkalemia secondary to digitalis intoxication (serum K+ > 5 to 6 mEq/L)
    3) Life-threatening dysrhythmias (eg, ventricular tachycardia, ventricular fibrillation, progressive bradycardia, high degree AV nodal block) or the potential to develop malignant arrhythmias
    b) NOTE: Serum concentrations drawn shortly after ingestion (post absorption but prior to distribution of digoxin to tissues) may be quite elevated without significant associated signs and symptoms of toxicity. In the absence of dysrhythmias, digoxin Fab may not be necessary in these cases. A second level drawn 4 to 6 hours after ingestion is recommended.
    2) Digoxin immune Fab fragments have also been used to reverse toxicity associated with cardiac glycosides that are present in some plants, including, Apocynum cannabinum (Indian hemp), D. purpurea (of limited benefit), Nerium oleander (common or pink oleander) and Thevetia peruviana (yellow oleander) (Flanagan & Jones, 2004). It has also been used successfully in poisoning due to products containing toad venom (Sweetman, 2007).
    3) Preliminary in vitro and in vivo studies, have suggested that digoxin immune Fab was effective in binding Chan Su, a Chinese medicine prepared from the skin glands of Chinese toads, that is used in the treatment of cardiovascular diseases. The cardiotonic effects of Chan Su is attributed to bufadienolides which appears to have digitoxin activity (Dasgupta et al, 2001).

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: Digoxin immune Fab is derived from specific antidigoxin antibodies that are produced in sheep immunized to digoxin. These antibodies are used in the treatment of life-threatening digitalis toxicity.
    B) PHARMACOLOGY: Binds digoxin molecules and make them unavailable for binding at their site of action. Although Fab fragments have a larger volume of distribution than IgG, they do not distribute directly to digoxin receptor sites.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Worsening congestive heart failure and a rapid ventricular response in patients with atrial fibrillation may occur as a result of therapy due to the reversal of digoxin effects. Anaphylactic, hypersensitivity, or febrile reactions may occur with therapy. Hypokalemia is possible following therapy due to the reversal of digoxin effects (a shift of potassium into the cell) producing a decline in serum potassium concentration. Hypotension has occurred rarely.
    E) WITH POISONING/EXPOSURE
    1) Overdose events are anticipated to be an extension of adverse events reported with therapy.
    0.2.20) REPRODUCTIVE
    A) Digoxin immune Fab is classified as FDA pregnancy category C. At the time of this review, animal studies have not been conducted and it is not known whether it may cause fetal harm when given to a pregnant woman.

Laboratory Monitoring

    A) Monitor serial potassium levels following Fab fragments.
    B) Monitor fluid status; volume overload has been reported with therapy.
    C) Obtain a baseline ECG along with continuous cardiac monitoring. Monitor vital signs including temperature and blood pressure.
    D) Assess renal function following a significant exposure or as indicated.
    E) Serum digoxin concentration will be elevated after administration of digoxin Fab if the assay used cannot distinguish free and bound digoxin.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is primarily symptomatic and supportive. Mild to moderate congestive heart failure may occur. Atrial fibrillation with rapid ventricular response may also develop. Monitor vital signs, obtain an ECG and institute continuous cardiac monitoring. Monitor fluid status and respiratory function. If control of ventricular rate is necessary in patients with atrial fibrillation, a calcium channel blocker (eg, diltiazem) or beta blocker may be used. A short acting titratable agent such as esmolol may be preferred. Hypokalemia may occur due to a shift of potassium into the cell following reversal of digoxin effects. Monitor serial serum potassium levels; obtain hourly initially and repeat as indicated. Replace potassium as necessary. In patients with an acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Treat severe hypotension with IV fluids, dopamine, or norepinephrine.
    C) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    D) ANTIDOTE
    1) None
    E) ENHANCED ELIMINATION
    1) Hemodialysis, continuous arteriovenous hemofiltration and peritoneal dialysis are unlikely to be successful at removing digoxin-Fab complex .
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management, and digoxin immune Fab is generally only used in the hospital setting.
    2) OBSERVATION CRITERIA: All patients requiring administration of digoxin immune Fab should be monitored for several hours following administration to assess cardiac function or development of an allergic reaction.
    3) ADMISSION CRITERIA: Patients with persistent cardiac dysrhythmias should be admitted to an ICU setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) Symptoms of overdose are similar to reported adverse effects following therapy.
    H) PHARMACOKINETICS
    1) The volume of distribution is 0.46 L/kg. The Fab fragment-digoxin complex accumulates in the blood and is excreted via the kidney. The elimination half-life in patients with normal renal function is 15 to 20 hours. In patients with renal insufficiency, elimination may be delayed up to 5 to 10 days.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Doses up to 1280 mg (32 vials) in a child and 1600 mg (40 vials) in an adult have been well-tolerated with the occurrence of minimal to no symptoms related to digoxin immune Fab administration.
    B) THERAPEUTIC: ADULT and PEDIATRIC: ACUTE INGESTION: Dosing varies according to the amount of digoxin ingested. In cases of acute exposure of an unknown amount in adults and children, 20 vials (800 mg) of Digifab(R) is adequate to treat most life-threatening ingestions. In clinical testing, the average dose was 10 vials.

Clinical Effects

Summary Of Exposure

    A) USES: Digoxin immune Fab is derived from specific antidigoxin antibodies that are produced in sheep immunized to digoxin. These antibodies are used in the treatment of life-threatening digitalis toxicity.
    B) PHARMACOLOGY: Binds digoxin molecules and make them unavailable for binding at their site of action. Although Fab fragments have a larger volume of distribution than IgG, they do not distribute directly to digoxin receptor sites.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Worsening congestive heart failure and a rapid ventricular response in patients with atrial fibrillation may occur as a result of therapy due to the reversal of digoxin effects. Anaphylactic, hypersensitivity, or febrile reactions may occur with therapy. Hypokalemia is possible following therapy due to the reversal of digoxin effects (a shift of potassium into the cell) producing a decline in serum potassium concentration. Hypotension has occurred rarely.
    E) WITH POISONING/EXPOSURE
    1) Overdose events are anticipated to be an extension of adverse events reported with therapy.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) 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).
    2) No febrile reactions have been reported that were definitely attributable to Fab fragment therapy; in all febrile patients, clear evidence of an infection existed (Wenger et al, 1985a; Wenger et al, 1986).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Congestive heart failure has occurred following administration of digoxin immune Fab in several patients due to withdrawal of inotropic effects of digoxin (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012; Smith, 1991; Antman et al, 1990a; Wenger et al, 1986; Wenger et al, 1985a). Clinical evidence of impaired ventricular function appeared several hours to one day after Fab treatment in 6 of 63 patients (Wenger et al, 1985a). However, it is impossible to evaluate causality as numerous other events could have contributed (adjustments in fluid volume, diuretic therapy, vasodilator therapy, occurrence of cardiac arrest during time of Fab treatment).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) There have been infrequent reports of hypotensive episodes following the use of Fab therapy (Antman et al, 1990a).
    b) CASE REPORT: One report of hypotension over a several hour-period occurred in one patient during Fab infusion for mixed digoxin and barbiturate intoxication. It is unclear if Fab therapy was the actual cause; the hypotensive effect persisted following normalization of rhythm and conduction disturbances (Smolarz et al, 1984).
    C) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Poor cardiac function in patients may worsen, due to the withdrawal of the inotropic effects of digitalis during therapeutic use (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Worsening rate control of atrial fibrillation may occur. Patients with a history of atrial fibrillation may develop a rapid ventricular response following digoxin immune Fab therapy due to the reversal of digoxin effects (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012; Smith, 1991; Wenger et al, 1985a).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH THERAPEUTIC USE
    a) In a series of 150 patients with life-threatening digitalis toxicity, one neonate (only a few hours old) developed transient apnea during Fab therapy (Antman et al, 1990a).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea has been described infrequently following therapy, but may be attributable to the underlying effects of digitalis toxicity (Antman et al, 1990a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Slight erythema occurred at the site of testing with digoxin immune Fab in one patient; however, there was no systemic reaction to therapeutic administration (Wenger et al, 1986).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity and anaphylactic reactions may occur. Patients with a history of allergy to sheep proteins or who have previously received intact ovine antibodies or ovine Fab may be at greater risk (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    b) CASE SERIES: In an observational surveillance study, 717 adults received Digoxin Immune Fab (Ovine) following digoxin toxicity. Of those patients, 6 (0.8%; 95% CI 0.3% to 1.8%) had an allergic reaction related to digoxin-specific antibody fragments. Symptoms included urticaria, body rash, swelling of eyelids, facial flushing, pruritic rash, and chills. Four patients had a reaction on the day of therapy with three patients developing a pruritic rash. The authors noted that patients with a history of allergy or asthma were more likely to develop an allergic response (Hickey et al, 1991).
    c) CASE REPORT/LACK OF EFFECT: A 38-year-old healthy man, with a history of several suicide attempts, was admitted on three separate occasions over a 7-month period following the intentional ingestion of large amounts of digoxin and other co-ingestants. The patient was given digoxin-specific Fab antibody during each admission (range: 7 to 10 vials) and developed no signs or symptoms of allergic reaction or serum sickness syndrome (Bosse & Pope, 1994).

Reproductive

    3.20.1) SUMMARY
    A) Digoxin immune Fab is classified as FDA pregnancy category C. At the time of this review, animal studies have not been conducted and it is not known whether it may cause fetal harm when given to a pregnant woman.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) It is unknown whether digoxin immune Fab can cause fetal harm when given to a pregnant woman. Its use in pregnancy should be only when it is clearly indicated (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    B) ANIMAL STUDIES
    1) At the time of this review, no reproductive animal studies have been conducted (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Digoxin immune Fab is classified as FDA pregnancy category C (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    B) ANIMAL STUDIES
    1) At the time of this review, no reproductive animal studies have been conducted (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether digoxin immune Fab is excreted in human breast milk (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial potassium levels following Fab fragments.
    B) Monitor fluid status; volume overload has been reported with therapy.
    C) Obtain a baseline ECG along with continuous cardiac monitoring. Monitor vital signs including temperature and blood pressure.
    D) Assess renal function following a significant exposure or as indicated.
    E) Serum digoxin concentration will be elevated after administration of digoxin Fab if the assay used cannot distinguish free and bound digoxin.
    4.1.2) SERUM/BLOOD
    A) Obtain serial serum potassium levels pre- and post-antidote therapy. Check potassium concentrations every hour for the first several hours after administration (Allen & Dunham, 1990). Hyperkalemia is commonly present with digitalis toxicity, which is followed by rapid shifting in serum potassium producing hypokalemia after the administration of digoxin immune Fab.
    B) Monitor renal function; renal insufficiency can significantly prolong the half-life and elimination of Fab fragments. Elimination may be delayed up to 5 to 10 days (Allen & Dunham, 1990); normal elimination is 15 to 20 hours (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    4.1.4) OTHER
    A) OTHER
    1) DIGITALIS IMMUNOASSAY MEASUREMENT
    a) The administration of digoxin immune Fab can interfere with the standard measurement of serum digoxin concentration. Serum digoxin concentration will be elevated after administration of digoxin Fab if the assay used cannot distinguish free and bound digoxin. This is due to the presence of digitalis that is bound to the Fab fragment and, therefore, not able to react with receptors in the body (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    2) CONGESTIVE HEART FAILURE
    a) Monitor respiratory effort and function, as well as fluid status following exposure. Patients may develop rapid congestive heart failure following fab antibody fragments. Children may be at increased risk for volume overload following exposure . Obtain a chest x-ray as indicated.
    3) CARDIAC MONITORING
    a) Obtain baseline ECG; continuous cardiac monitoring for up to 24 hours to assess for arrhythmias or possible rebound digoxin toxicity (Bara, 2001).

Treatment

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis, continuous arteriovenous hemofiltration and peritoneal dialysis are unlikely to be successful at removing digoxin-Fab complex (Berkovitch et al, 1994).

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with persistent cardiac dysrhythmias should be admitted to an ICU setting.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management, and digoxin immune Fab is generally only used in the hospital setting.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) All patients requiring administration of digoxin immune Fab should be monitored for several hours following administration to assess cardiac function or development of an allergic reaction.

Monitoring

    A) Monitor serial potassium levels following Fab fragments.
    B) Monitor fluid status; volume overload has been reported with therapy.
    C) Obtain a baseline ECG along with continuous cardiac monitoring. Monitor vital signs including temperature and blood pressure.
    D) Assess renal function following a significant exposure or as indicated.
    E) Serum digoxin concentration will be elevated after administration of digoxin Fab if the assay used cannot distinguish free and bound digoxin.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not necessary because digoxin immune Fab is administered parenterally.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Doses up to 1280 mg (32 vials) in a child and 1600 mg (40 vials) in an adult have been well-tolerated with the occurrence of minimal to no symptoms related to digoxin immune Fab administration.
    B) THERAPEUTIC: ADULT and PEDIATRIC: ACUTE INGESTION: Dosing varies according to the amount of digoxin ingested. In cases of acute exposure of an unknown amount in adults and children, 20 vials (800 mg) of Digifab(R) is adequate to treat most life-threatening ingestions. In clinical testing, the average dose was 10 vials.

Therapeutic Dose

    7.2.1) ADULT
    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 adults 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 (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) 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)
    2) DOSING INFORMATION
    a) 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).
    b) 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).
    C) ACUTE INGESTION OF KNOWN AMOUNT OF DIGOXIN
    1) 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
    1) 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** IngestedDigiFab(R) Dose (vials)
    2510
    5020
    7530
    10040
    15060
    20080

    1) * = 0.25 milligram (mg) tablets with 80% bioavailability
    2) ** = 0.2 mg Lanoxicaps with 100% bioavailability
    E) CHRONIC DIGOXIN INGESTION TOXICITY
    1) DOSAGE SUMMARY
    a) Adults 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)
    2) CALCULATIONS BASED ON STEADY-STATE DIGOXIN CONCENTRATIONS
    DIGIFAB(R)  Serum digoxin (ng/mL) x weight (kg)
Dose      =    ---------------------------
(vials)                        100

    a) 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):
    1) PATIENT WEIGHT = 40 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    10.5
    21
    42
    83
    125
    167
    208

    2) PATIENT WEIGHT = 60 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    10.5
    21
    43
    85
    127
    1610
    2012

    3) PATIENT WEIGHT = 70 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    11
    22
    43
    86
    129
    1611
    2014

    4) PATIENT WEIGHT = 80 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    11
    22
    43
    87
    1210
    1613
    2016

    5) PATIENT WEIGHT = 100 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    11
    22
    44
    88
    1212
    1616
    2020

    3) STUDIES
    a) DIGOXIN IMMUNE FAB was successfully used to treat toxicity associated with digitalis glycosides. The final report of an open-label multicenter clinical trial reviewed the treatment of 150 patients with potentially life-threatening digitalis toxicity using digoxin immune Fab (ovine, Digibind(R)) (Antman et al, 1990).
    b) Seventy-five patients (50%) were receiving long-term digitalis therapy, 15 (10%) accidentally ingested overdoses of digitalis, and 59 (39%) intentionally took an overdose of digitalis in suicidal attempts. Two patients had an unspecified clinical response to Digibind(R) therapy. Of the 148 evaluable patients, 119 (80%) had complete resolution of all signs and symptoms of digitalis toxicity, 14 (10%) improved, and 15 (10%) showed no response. The median time of initial response, after termination of the Digibind(R) infusion, was 19 minutes; and 75% of the patients had some evidence of a response by 60 minutes. Only 14 patients experienced adverse effects attributed to Digibind(R). The most common adverse events were rapid development of hypokalemia and exacerbation of congestive heart failure. No allergic reactions were identified in response to Fab treatment.
    c) A summary of data is provided based on 114 patients treated in the US with digoxin-specific antibody fragments (Digibind(R)) for digoxin or digitoxin intoxication; all but a small number responded positively to this treatment (Wenger et al, 1986). Patients ranged from 1 day to 87 years of age (mean, 50 years). Second- or third-degree atrioventricular block was the primary manifestation of toxicity (50% of patients), with ventricular tachycardia, fibrillation, and hyperkalemia occurring in 54%, 32%, and 36%, respectively. Over 75% of patients had serum concentrations of digoxin exceeding 5 nanograms/mL. Doses of digoxin-specific Fab fragments ranged from 4 to 1600 milligrams (mg) (average, 384 mg). Renal function was normal in 35% of 80 evaluable subjects, with 65% having abnormal renal function (mean creatinine 2.9 mg%). Of the 114 patients treated, 101 were evaluable for clinical response. Ninety-four of 101 patients responded to digoxin-specific Fab, with 7 being non-responders. Clinical response was generally observed within one-half hour after termination of IV infusion of Fab fragments (given over 15 to 30 minutes in most patients), with complete reversal of cardiac and noncardiac manifestations of toxicity occurring in 3 to 4 hours after termination of infusion. A rapid drop in serum potassium levels was observed in many patients, with hypokalemia occurring in several patients within 1 to 5 hours after therapy.
    d) In an observational surveillance study (Hickey et al, 1991a), approximately 75% of patients with digoxin toxicity responded to digoxin immune Fab treatment. Investigators monitored the safety and efficacy of digoxin immune Fab therapy in 717 adults who received this drug for digoxin toxicity. Digoxin immune FAB therapy resulted in complete response in 50%. In 24% of the patients only a partial response was achieved and 12% had no response to digoxin immune Fab. No information was available on the other 14%.
    e) Digoxin intoxication was successfully treated with digoxin-specific antibody fragments (Fab) in a 65-year-old man with chronic renal failure, on continuous ambulatory peritoneal dialysis (CAPD). On admission to the hospital, digoxin administration was terminated and peritoneal dialysis was continued. After 2 days, his condition seriously deteriorated, and he was treated on the fifth day with Fab 80 milligrams, infused intravenously over 30 minutes. His hemodynamic parameters improved immediately, and he was discharged 4 weeks later after an uneventful recovery. Peritoneal dialysis was not effective in removing digoxin or Fab (Caspi et al, 1997).
    f) Successful treatment of severe bradycardia secondary to digoxin toxicity in 3 patients was reported using Fab fragments (Marchlinski, 1985). Digoxin serum levels were 21, 16, and 4.7 nanograms/mL, respectively. Suicidal attempts accounted for toxicity in 2 patients, with the arrhythmia occurring in the third while the patient was being treated with 0.125 mg daily of digoxin in the presence of chronic renal failure. All patients responded promptly to IV Fab fragments with restoration of normal sinus rhythm within one hour, and no toxicity was observed. Bradycardia did not reoccur in any patient.
    g) Concomitant therapy with AMIODARONE and digoxin-specific Fab fragments has also been utilized (Nicholls et al, 1985); in this report, amiodarone controlled refractory ventricular arrhythmias while Fab antibodies were effective in resolving persistent hyperkalemia. Digoxin immune Fab therapy is associated with decreases in active (unbound) digoxin serum concentrations to 0 or near 0 following administration, with a concomitant increase in total serum digoxin by 10- to 20-fold. These increases in total serum digoxin represent digoxin bound to antibody fragments and are pharmacologically inactive. Renal excretion of digoxin bound to Fab fragments has also been documented following administration of digoxin immune Fab. In most patients, an evident clinical response to Fab fragments has occurred in less than one-half hour following termination of IV infusion (generally given over 15 to 30 minutes); complete reversal of toxicity has generally occurred within 3 to 4 hours after completion of IV infusion (Wenger et al, 1986).
    7.2.2) PEDIATRIC
    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 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 children weighing at least 20 kg (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    3) 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 (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    4) In children it is important to monitor for volume overload (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    5) 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).
    6) 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).
    7) 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).
    8) 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 considered.
    B) ACUTE INGESTION OF UNKNOWN AMOUNT OF DIGOXIN
    1) 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)
    2) DOSING PREPARATION INFORMATION
    a) In children, it is important to monitor for volume overload.
    b) 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).
    c) 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).
    d) 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).
    C) ACUTE INGESTION OF KNOWN AMOUNT OF DIGOXIN
    1) 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
    1) 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** IngestedDigiFab(R) Dose (vials)
    2510
    5020
    7530
    10040
    15060
    20080

    1) * = 0.25 milligram (mg) tablets with 80% bioavailability
    2) ** = 0.2 mg Lanoxicaps with 100% bioavailability
    E) CHRONIC DIGOXIN INGESTION TOXICITY
    1) Infants and Small Children Dose Estimates of DIGOXIN IMMUNE FAB (in mg) from Steady-State Serum Digoxin Concentration (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012):
    a) FORMULA: Dose (in mg) = (Dose [in # of vials]) (40 mg/vial)
    b) PATIENT WEIGHT = 1 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose
    10.4 mg*
    21 mg*
    41.5 mg*
    83 mg*
    125 mg
    166.5 mg
    208 mg

    1) * = Dilution of reconstituted vial to 1 mg/mL may be desirable
    c) PATIENT WEIGHT = 3 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose
    11 mg*
    22.5 mg*
    45 mg
    810 mg
    1214 mg
    1619 mg
    2024 mg

    1) * = Dilution of reconstituted vial to 1 mg/mL may be desirable
    d) PATIENT WEIGHT = 5 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose
    12 mg*
    24 mg
    48 mg
    816 mg
    1224 mg
    1632 mg
    2040 mg

    1) * = Dilution of reconstituted vial to 1 mg/mL may be desirable
    e) PATIENT WEIGHT = 10 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose
    14 mg
    28 mg
    416 mg
    832 mg
    1248 mg
    1664 mg
    2080 mg

    f) PATIENT WEIGHT = 20 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose
    18 mg
    216 mg
    432 mg
    864 mg
    1296 mg
    16128 mg
    20160 mg

    2) For Older/Larger Children: Dose Estimates of DIGOXIN IMMUNE FAB (in mg) from Steady-State Serum Digoxin Concentration (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012):
    DIGIFAB(R)  Serum digoxin conc (ng/mL) x wt (kg)
Dose       = ------------------------------------
(vials)                     100

    1) conc = concentration
    2) wt = weight
    3) PATIENT WEIGHT = 40 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    10.5
    21
    42
    83
    125
    167
    208

    4) PATIENT WEIGHT = 60 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    10.5
    21
    43
    85
    127
    1610
    2012

    5) PATIENT WEIGHT = 70 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    11
    22
    43
    86
    129
    1611
    2014

    6) PATIENT WEIGHT = 80 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    11
    22
    43
    87
    1210
    1613
    2016

    7) PATIENT WEIGHT = 100 kg
    Serum Digoxin (ng/mL) DIGIFAB(R) Dose (vials)
    11
    22
    44
    88
    1212
    1616
    2020

    F) CALCULATIONS BASED ON STEADY-STATE DIGITOXIN CONCENTRATION
    DIGIFAB(R)  Serum digitoxin (ng/mL) x weight (kg)
Dose      =    ---------------------------
(vials)                        1000
    G) STUDIES
    1) Treatment of 34 patients, aged 2 to 80 years, with digoxin immune Fab fragments resulted in favorable outcomes in 32 patients (Smolarz et al, 1985). In 27 patients the ingestion was suicidal, in 3 it was accidental, and in 4 it was iatrogenic. Patients were treated if substantial serum digoxin levels and life-threatening arrhythmias were present. Digoxin levels at the time of treatment were 3.4 to 29 nanograms/mL. In 32 patients, a full recovery was made. One patient developed septic shock and anuria and died 8 days after treatment. Another patient, with preexisting heart failure, died 15 hours after treatment in cardiogenic shock.
    2) One report described successful digoxin immune Fab therapy in 27 of 29 children. The effect of digoxin-specific Fab in 29 children with intoxication to digoxin (28 patients) and digitoxin (1 patient) was studied (Woolf et al, 1992). It was reported that in 27 patients, the administration of Fab resolved the digitalis toxicity.
    3) One case demonstrated the efficacy and safety of digoxin immune Fab in a 2-year-old child. The 2-year-old girl ingested 90 to 92 (0.25 mg) tablets of digoxin and within 4 hours developed vomiting, lethargy, tachycardia, and atrioventricular block (Kearns et al, 1989a). Her total and free serum digoxin concentrations were 17.1 and 12.4 ng/mL, respectively. Within 40 minutes after gastrointestinal decontamination and the administration of 1280 milligrams of digoxin immune Fab, the electrocardiographic abnormalities were resolved; the free serum digoxin level was reduced to 0.11 ng/mL.
    4) Reversal of digoxin toxicity with digoxin immune Fab was reported in an infant (17 days old) who developed renal failure (Gelband & Sherron, 1985). The patient responded successfully to 20 mg of Fab, despite the occurrence of acute renal failure. These data suggest the efficacy and safety of Fab fragments in infants even when acute renal failure is present.

Minimum Lethal Exposure

    A) A minimum lethal dose has not been established.
    B) CASE SERIES: In an observational surveillance study of 717 adults who received digoxin immune Fab, 171 (24%) patients died; none were attributable to Fab therapy (Hickey et al, 1991).

Maximum Tolerated Exposure

    A) CASE REPORT: A 2-year-old 10.5 kg girl received 32 vials (1280 mg) of digoxin immune Fab after a massive digoxin (ingested 90-92 0.25 mg tablets; peak serum digoxin concentration 120.9 ng/mL) overdose. ECG abnormalities resolved within 40 minutes and no symptoms related to therapy developed (Kearns et al, 1989).
    B) CASE SERIES: In an observational surveillance study of 717 adults who received digoxin immune Fab, the dose administered ranged from 8 mg (less than 1 vial) to 40 vials (1600 mg) with the most commonly reported dose being approximately 80 mg (2 vials). Of those patients, only 7% (52 patients) had adverse events considered to be related to therapy. No deaths could be attributed to therapy (Hickey et al, 1991).
    C) CASE REPORT: A 38-year-old man was given Fab fragments on three different occasions following the intentional ingestion of digoxin and other co-ingestants over a 7 month period. The patient did not develop any evidence of an allergic reaction or serum sickness syndrome (Bosse & Pope, 1994).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Digoxin immune antigen-binding fragments (Fab) are specific antibodies for the reversal of the toxic effects of digitalis (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012; Wenger et al, 1985).
    B) Digoxin immune Fab (Digibind(R)) is prepared initially by immunization of sheep with digoxin that has been coupled as a hapten to human albumin to produce antibodies specific for the antigenic determinants of the digoxin molecule. This antibody is papain digested; the digoxin-specific Fab fragments are then isolated and purified by affinity chromatography. Antibody fragments have a molecular weight of approximately 46,000 daltons (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012; Cole & Smith, 1986). Each vial of digoxin immune Fab (Digifab(R)) contains 40 mg of purified lyophilized digoxin-specific Fab fragments, which will bind approximately 0.5 mg digoxin (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    C) The mechanism of action of digoxin immune Fab is to bind digoxin molecules and make them unavailable for binding at their site of action in body cells. Although Fab fragments have a larger volume of distribution than IgG, they do not distribute directly to digoxin receptor sites (Sullivan, 1986); the Fab fragment-digoxin complex accumulates in the blood and is excreted via the kidney(Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012). Reversal of toxicity occurs by several mechanisms, including binding of digoxin in extracellular fluid, creation of a concentration gradient to the central compartment, and binding recently dissociated digoxin (Sullivan, 1986; Butler, 1982; Skubitz & Smith, 1975). It appears that the Fab-digoxin complex in blood creates a gradient with the net effect being a shift of equilibrium away from binding of digoxin to its receptors in the body, and thereby reversing its effects (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012). The affinity of digoxin immune Fab for digoxin is in the range of 10(9) to 10(10) M(-1), which is greater than the affinity of digoxin for ATPase, the presumed receptor for its toxic effects (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
    D) Due to the close structural similarity of digoxin and digitoxin, digoxin immune Fab has been shown to cross-react with digitoxin and can also reverse digitoxin toxicity (Sullivan, 1986; Bismuth et al, 1982; Ochs & Smith, 1977; Smith et al, 1982).
    E) In vitro and in vivo studies in animals have demonstrated the ability of Fab fragments and digoxin-specific antibodies to reverse digoxin toxicity. Reversal of digoxin-induced inhibition of sodium and potassium transport in erythrocytes has been demonstrated during incubation with digoxin antibody and antibody fragments; digoxin-induced increases in developed tension in guinea pig atrial muscle strips has been reversed with the addition of digoxin antibody fragments, with muscle tension returning to pre-digoxin levels (Curd et al, 1971; Gardner et al, 1973; Wenger et al, 1985). Reversal of digoxin toxicity in animals that had received lethal doses of digoxin has been reported after administration of both intact antibodies and Fab fragments (Lloyd & Smith, 1978; Schmidt & Butler, 1971). Even advanced toxicity has been reversed with adequate neutralizing doses of antibody, with reversal of both inotropic and arrhythmogenic effects (Ochs et al, 1978). Reversal of inotropic effects appears to occur more slowly than arrhythmia reversal (Ochs et al, 1978). Both whole antibodies and Fab fragments were effective in reversing digoxin toxicity in dogs given a lethal IV dose of digoxin (following ventricular tachycardia development) (Lloyd & Smith, 1978); however, in the group receiving Fab fragments, return to sinus rhythm occurred more rapidly than in the group receiving whole antibody (36 minutes versus 85 minutes). This study supports the advantage of purified digoxin-specific Fab fragments over intact IgG.
    F) Digoxin immune Fab (Digifab(R)) is currently recommended for the treatment of potentially life-threatening digoxin intoxication. The preparation used successfmay also be used to treat life-threatening digitoxin overdose. Digifab(R) is not indicated for milder cases of digitalis toxicity. Manifestations of life-threatening toxicity that may indicate treatment include severe ventricular arrhythmias (such as ventricular tachycardia or ventricular fibrillation), or progressive bradyarrhythmias such as severe sinus bradycardia or second or third degree heart block unresponsive to atropine (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012). The manufacturer also states that ingestion of more than 10 mg digoxin in previously healthy adults or 4 mg digoxin in previously healthy children (or ingestion causing steady state serum levels greater than 10 nanograms/mL) may result in cardiac arrest, and a history of an ingestion of that magnitude may be an indication for treatment with digoxin Fab fragments. Digitalis-induced progressive elevation of serum potassium concentrations also suggests imminent cardiac arrest, and if potassium levels exceed 5 mEq/L in the setting of severe digitalis intoxication, digoxin immune Fab therapy is indicated (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).

References

General Bibliography

    1) Allen NM & Dunham GD: Treatment of digitalis intoxication with emphasis on the clinical use of digoxin immune Fab. DICP 1990; 24(10):991-998.
    2) Antman EM, Wenger TL, Butler VP Jr, et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: final report of a multicenter study. Circulation 1990; 81:1744-1752.
    3) Antman EM, Wenger TL, Butler VP, et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. final report of a multicenter study. Circulation 1990a; 81(6):1744-1752.
    4) Bara V: Digoxin overdose: clinical features and management. Emerg Nurse 2001; 9(3):16-21.
    5) Berkovitch M, Akilesh MR, Gerace R, et al: Acute digoxin overdose in a newborn with renal failure: use of digoxin immune Fab and peritoneal dialysis. Ther Drug Monit 1994; 16(5):531-533.
    6) Bismuth C, Baud F, Pontal PG, et al: Reversal of advanced digitoxin intoxication with Fab fragments of digoxin-specific antibodies. Vet Hum Toxicol 1982; 24:26.
    7) Bosse GM & Pope TM: Recurrent digoxin overdose and treatment with digoxin-specific Fab antibody fragments. J Emerg Med 1994; 12(2):179-185.
    8) Butler VP: Antibodies as specific antagonists of toxins, drugs and hormones. Pharmacol Rev 1982; 34:109.
    9) Caspi O, Zylber-Katz E, Gotsman O, et al: Digoxin intoxication in a patient with end-stage renal disease: Efficacy of digoxin-specific Fab antibody fragments and peritoneal dialysis. Ther Drug Monitor 1997; 19:510-515.
    10) Caspi O, Zylber-Katz E, Gotsman O, et al: Digoxin intoxication in a patient with end-stage renal disease: Efficacy of digoxin-specific Fab antibody fragments and peritoneal dialysis. Ther Drug Monitor 1997a; 19:510-515.
    11) Clarke W & Ramoska EA: Acute digoxin overdose: use of digoxin-specific antibody fragments. Am J Emerg Med 1988; 6(5):465-470.
    12) Cole PL & Smith TW: Use of digoxin-specific Fab fragments in the treatment of digitalis intoxication. Drug Intell Clin Pharm 1986; 20:267-270.
    13) Curd J, Smith TW, Jaton JC, et al: The isolation of digoxin-specific antibody and its use in reversing the effects of digoxin. Proc Natl Acad Sci USA 1971; 68:2401-2406.
    14) Dasgupta A, Lopez AE, Wells A, et al: The Fab fragment of anti-digoxin antibody (digibind) binds digitoxin-like immunoreactive components of Chinese medicine Chan Su: monitoring the effect by measuring free digitoxin. Clin Chim Acta 2001; 309(1):91-95.
    15) Flanagan RJ & Jones AL: Fab antibody fragments: some applications in clinical toxicology. Drug Saf 2004; 27(14):1115-1133.
    16) Gardner JD, Kiino DR, Swartz JJ, et al: Effects of digoxin-specific antibodies on accumulation and binding of digoxin by human erythrocytes. J Clin Invest 1973; 52:1820-1833.
    17) Gelband H & Sherron P: The role of digitoxin antibody fragments (Digibind(R)) symposium, Burroughs-Wellcome Co, San Francisco, CA, 1985.
    18) Hickey AR, Wenger TL, Carpenter VP, et al: Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study. J Am Coll Cardiol 1991; 17(3):590-598.
    19) Hickey AR, Wenger TL, Carpenter VP, et al: Digoxin immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study. J Am Coll Cardiol 1991a; 17:590-598.
    20) Kearns GL, Moss MM, Clayton BD, et al: Pharmacokinetics and efficacy of digoxin specific Fab fragments in a child following massive digoxin overdose. J Clin Pharmacol 1989; 29(10):901-908.
    21) Kearns GL, Moss MM, Clayton BD, et al: Pharmacokinetics and efficacy of digoxin specific Fab fragments in a child following massive digoxin overdose. J Clin Pharmacol 1989a; 29:901-908.
    22) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    23) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    24) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    25) Lloyd BL & Smith TW: Contrasting rates of reversal digoxin toxicity by digoxin-specific IgG and Fab fragments. Circulation 1978; 58:280-283.
    26) Marchlinski F: The role of digoxin antibody fragments (Digibind(R)) symposium, Burroughs-Wellcome Co, San Francisoco, CA, 1985.
    27) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    28) Nicholls DP, Murtagh JG, & Hot DW: Use of amiodarone and digoxin specific Fab antibodies in digoxin overdosage. Br Heart J 1985; 53:462-464.
    29) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    30) Ochs HR & Smith TW: Reversal of advanced digitoxin toxicity and modification of pharmacokinetics by specific antibodies and Fab fragments. J Clin Invest 1977; 1303-1313, 1977.
    31) Ochs HR, Vatner SF, & Smith TW: Reversal of inotropic effects of digoxin by specific antibodies and their Fab fragments in the conscious dog. J Pharmacol Exp Ther 1978; 207:64-71.
    32) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    33) Product Information: DigiFab(R) intravenous injection lyophilized powder for solution, digoxin immune fab ovine intravenous injection lyophilized powder for solution. BTG International Inc. (per manufacturer), West Conshohocken, PA, 2012.
    34) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    35) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    36) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    37) Schmidt DH & Butler VP Jr: Reversal of digoxin toxicity with specific antibodies. J Clin Invest 1971; 50:1738-1744.
    38) Skubitz EM & Smith TW: Determination of antibody-hapten association kinetics: A simplified experimental approach. J Immunol 1975; 114:1369-1374.
    39) Smith TW, Butler VP, Haber E, et al: Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. N Engl J Med 1982; 307:1357-1398.
    40) Smith TW, Haber E, Yeatman L, et al: Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976; 294:797-800.
    41) Smith TW, Lloyd BL, Spicer N, et al: Immunogenicity and kinetics of distribution and elimination of sheep digoxin-specific IgG and Fab fragments in the rabbit and baboon. Clin Exp Immunol 1979; 36:384-396.
    42) Smith TW: Review of clinical experience with digoxin immune Fab (ovine). Am J Emerg Med 1991; 9(2 Suppl 1):1-6.
    43) Smolarz A, Roesch E, Lenz E, et al: Digoxin specific antibody (Fab) fragments in 34 cases of severe digitalis intoxication. Clin Toxicol 1985; 23:327-340.
    44) Smolarz A, Roesch E, Lenz H, et al: Report on the treatment of 16 cases of glycoside poisoning with sheep antidigoxin fragments (Fab). Z Kardiol 1984; 73:113-119.
    45) Sullivan JB: Immunotherapy in the poisoned patient. Overview of present applications and future trends. Med Toxicol 1986; 1:47-60.
    46) Sweetman, S: Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic Version, Thomson Healthcare. Greenwood Village, CO. 2007.
    47) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    48) Wenger T, Butler VP, Haber E et al: Digoxin-specific antibody treatment of digitalis toxicity: update Data on File. Burroughs-Wellcome Co, 1986, 1986.
    49) Wenger T, Butler VP, Haber E et al: Digoxin-specific antibody treatment of digitalis toxicity: update Data on File. Burroughs-Wellcome Co, 1986, 1986a.
    50) Wenger TL, Butler VP Jr, Haber E, et al: Treatment of sixty-three severely digitalis toxic patients with digoxin-specific antibody fragments. J Am Coll Cardiol 1985; 5:118A-123A.
    51) Wenger TL, Butler VP Jr, Haber E, et al: Treatment of sixty-three severely digitalis toxic patients with digoxin-specific antibody fragments. J Am Coll Cardiol 1985a; 5:118A-123A.
    52) Woolf AD, Wenger T, Smith TW, et al: The use of digoxin-specific fab fragments for severe digitalis intoxication in children. N Engl J Med 1992; 326:1739-1744.