AHFS Class:

• Antitoxins and Immune Globulins 80:04

Generic Name(s):

• Digoxin Immune Fab (Ovine)

Digoxin immune Fab (ovine) is a monovalent preparation containing ovine immunoglobulin Fab fragments capable of binding digoxin.1,2,3,4,5,6,7,20

Digoxin Toxicity

Digoxin immune Fab (ovine) is used for treatment of life-threatening or potentially life-threatening digoxin toxicity or overdosage,1,82,83,84,85,87,120,127 and is designated an orphan drug by FDA for the treatment of potentially life-threatening cardiac glycoside intoxication refractory to conventional management.62

Digoxin immune Fab (ovine) also has been used for the treatment of life-threatening overdosage or toxicity of digitoxin†1,1,82 or lanatoside C†49 (cardiac glycosides not commercially available in the US).

Digoxin immune Fab (ovine) may be indicated in acute digoxin ingestions (e.g., known suicidal or accidental consumption) of 10 mg or more of digoxin in previously healthy adults or 4 mg (or more than 0.1 mg/kg) of digoxin in previously healthy children.1 The immune Fab also is indicated in acute ingestions resulting in steady-state serum digoxin concentrations of 10 ng/mL or greater or chronic ingestions resulting in steady-state serum digoxin concentrations exceeding 6 ng/mL in adults or 4 ng/mL in children.1 In addition, digoxin immune Fab (ovine) is indicated when there are manifestations of life-threatening digoxin toxicity, including severe ventricular arrhythmias, progressive bradycardia (e.g., second- or third-degree heart block not responsive to atropine), or serum potassium concentrations exceeding 5.5 mEq/L in adults or 6 mEq/L in children with rapidly progressive signs and symptoms of digoxin toxicity.1

Advanced cardiac glycoside toxicity may manifest as almost any type of cardiac arrhythmia, including progressive bradyarrhythmias such as severe sinus bradycardia and second- or third-degree AV block unresponsive to atropine, supraventricular arrhythmias, and ventricular arrhythmias such as ventricular tachycardia and fibrillation.1,4,22,23,24 In addition, progressive elevation of the serum potassium concentration may occur in severe intoxication, especially acute intoxication, presumably secondary to inhibition of the Na⁺-K⁺-ATPase pump.1,36,45,46,47,48 Results from clinical studies indicate that progressive hyperkalemia correlates with poor prognosis in patients treated by conventional supportive and symptomatic measures that do not include therapy with digoxin immune Fab (ovine).6,40,45,46,47,68 Minimum toxic or lethal doses of digoxin are not well established.56 Acute ingestion of more than 10 mg of digoxin in previously healthy adults or 4 mg in previously healthy children often results in cardiac arrest.68,74

Conventional management of cardiac glycoside toxicity includes immediate discontinuance of the glycoside, efforts to inhibit further GI absorption and/or enterohepatic circulation of the glycoside, and correction of factors that may contribute to toxicity (e.g., fluid and electrolyte disturbances, acid-base imbalances, hypoxia).22,23,24,48 IV sympathomimetic drugs should be used with extreme caution since they may potentially exacerbate or precipitate cardiac glycoside-induced ventricular arrhythmias.1,22,48 Treatment of cardiac arrhythmias in chronic cardiac glycoside intoxication may include cautious use of potassium supplements, if there is evidence of potassium depletion.1,22,48 However, administration of potassium supplements in acute cardiac glycoside intoxication requires extreme caution since potentially life-threatening hyperkalemia may develop rapidly in advanced toxicity.1,22,48,56,69 In cases of severe toxicity, cardiac arrhythmias and hyperkalemia are often refractory to conventional treatment.3,23,24,30,38 Unlike usual supportive and symptomatic therapies, digoxin immune Fab (ovine) is a specific antidote for digoxin toxicity.4,17,20,30,49,51,127 Therefore, the immune Fab is considered a recommended treatment for acute and chronic digoxin toxicity.82,127

In patients with life-threatening toxicity resistant to usual supportive and symptomatic treatment, response to digoxin immune Fab (ovine) usually is evident within 30 minutes following administration,6,68 with complete resolution of toxicity subsequently occurring in most patients.2,3,6,20,30,33,35,37,38,63,73 Failure of digoxin immune Fab (ovine) treatment has occurred rarely and has been attributed to inadequate dosage,3,6 extensive cerebral and/or myocardial morbidity prior to administering digoxin immune Fab (ovine),3,6,20,33 other concurrent pathologic conditions,20 or toxicity complicated by concurrent overdosage with other drugs.6

In patients responding to digoxin immune Fab (ovine), serum potassium concentrations return to within normal limits,2,3,5,6,17,34,37,39,68,72 usually within 2-6 hours,6,34,37,39,68,72 and cardiac arrhythmias (e.g., AV junctional tachycardia, ventricular tachycardia or fibrillation, heart block) are controlled,1,2,3,5,6,17,20,30,32,33,34,35,36,37,38 usually within about 3 hours (range: 0.5-13 hours).1,20,68,69,73 Improved hemodynamics occur in most patients as toxicity resolves,3 although digoxin immune Fab (ovine) potentially may decrease the therapeutic effects (e.g., positive inotropic effect) of cardiac glycosides in some patients being treated with the drugs.3,63 Extracardiac effects (e.g., nausea, vomiting, drowsiness) also resolve in intoxicated patients receiving digoxin immune Fab (ovine).3,6,30,31,35,36,37,38

For further information regarding clinical manifestations, risk factors, and treatment of cardiac glycoside toxicity, see Acute Toxicity and Chronic Toxicity in Digoxin 24:04.08.

Poisonings Involving Cardiotoxic Plants and Other Substances

Digoxin immune Fab (ovine) has been used with some success for the treatment of poisonings involving ingestion of certain cardiotoxic plants, including common or pink oleander† ( Nerium oleander ),79,87,92 yellow oleander† ( Thevetia peruviana ),87,89,90,95,125 Indian hemp† ( Apocynum cannabinum ),87 and foxglove† ( Digitalis purpurea ),122,126 and has reversed or improved cardiotoxicity in some individuals.79,87,89,90,95,122 Additional study is needed to evaluate use of digoxin immune Fab (ovine) in cardiotoxic plant poisonings.92,95

In a few patients, digoxin immune Fab (ovine) reversed or improved cardiotoxicity associated with ingestion of toad venom†.94,123 Toad venom contains several cardioactive steroids (bufadienolides), including bufalin, cinobufagin, cinobufotalin, and resibufogenin,87,94,123 and has been identified in illicit street drugs marketed as aphrodisiacs.87,94,123,124

Preeclampsia and Eclampsia

Digoxin immune Fab (ovine) has been used with some success in a limited number of women for the management of severe preeclampsia† or eclampsia†,109,110,111,112,115,116,121 and is designated an orphan drug by FDA for the treatment of severe preeclampsia and eclampsia.62

Severe preeclampsia and eclampsia are major causes of maternal and fetal morbidity and mortality.109,110,111,112,113,115,116,118,121 Although the precise etiology of preeclampsia is unknown and may involve multiple factors, there is some evidence that increased concentrations of endogenous cardiotonic steroids, including endogenous digitalis-like factors (EDLFs), in maternal and/or cord blood may contribute to its pathogenesis, particularly the elevated blood pressure that occurs in women with preeclampsia.109,111,112,114,115,116,117,118,119,121 Based on results of in vitro and animal studies,109,110,111,112,114,115,117,118,119 antepartum use of digoxin immune Fab (ovine) in women with severe preeclampsia has been investigated;109,110,111,113,121 however, additional study is needed.109,110,113,116

Reconstitution and Administration

Digoxin immune Fab (ovine) usually is administered by IV infusion.1,2,3,6,20

If cardiac arrest is imminent, the manufacturer states that digoxin immune Fab (ovine) may be given by rapid IV injection;1 however, rapid IV injection may be associated with an increased risk of infusion reactions or other adverse effects (e.g., allergic reactions)1,6,69 and is not generally recommended.69

Reconstitution and Dilution

Each vial labeled as containing 40 mg of digoxin immune Fab (ovine) is reconstituted by adding 4 mL of sterile water for injection and gently mixing to provide a solution containing approximately 10 mg/mL.1 The reconstituted solution should be visually inspected for particulate matter and discoloration;1 the solution should not be used if it appears cloudy, turbid, or contains particulates.1

For IV infusion, the reconstituted solution of digoxin immune Fab (ovine) may be diluted with 0.9% sodium chloride injection to an appropriate volume.1

For infants or small children weighing less than 20 kg receiving a small digoxin immune Fab (ovine) dose (less than 1 mL), the manufacturer states that the 40-mg vial of the drug should be reconstituted as directed for adults and the dose may administered undiluted by IV injection using a tuberculin syringe.1 Alternatively, when a very small dose (3 mg or less) is required, the reconstituted solution may be diluted with 36 mL of 0.9% sodium chloride injection to provide a solution containing 1 mg/mL.1

Rate of Administration

The appropriate dose of digoxin immune Fab (ovine) usually is infused IV over at least 30 minutes.1,3,6,20 Although slower IV infusion rates have been used (e.g., over 1-5 hours),2,20,32,49,73,82 these slower rates do not appear to offer any advantage over the recommended rate and may delay the response to digoxin immune Fab (ovine).49,69

If cardiac arrest is imminent, the manufacturer states that digoxin immune Fab (ovine) may be administered by rapid IV injection.1,6

Although some clinicians have suggested that an administration regimen that includes an initial IV loading dose followed by a constant IV infusion for several hours69,73 may optimize the binding of digoxin immune Fab (ovine) to the cardiac glycoside by minimizing the amount of unbound Fab lost via rapid excretion and allowing for the cardiac glycoside to move extracellularly where it can be bound,73 such regimens have not been adequately evaluated and are not recommended.73

Dosage

Digoxin immune Fab (ovine) is commercially available in the US as DigiFab^® (40-mg single-use vials).1 Although a different preparation of digoxin immune Fab (ovine) also was previously available (Digibind^®) and product-specific dosage recommendations were required,44 this other preparation of digoxin immune Fab (ovine) is no longer commercially available in the US.

Digoxin immune Fab (ovine) usually is given as a single dose.1 If toxicity is not adequately reversed within several hours after administration of the dose or if toxicity recurs, an additional dose of digoxin immune Fab (ovine) may be necessary and clinical judgment should be used to guide dose selection.1,120

The contents of one vial of DigiFab^® neutralizes approximately 0.5 mg of digoxin.1 For treatment of life-threatening or potentially life-threatening digoxin toxicity, the dose of digoxin immune Fab (ovine) varies according to the amount of digoxin to be neutralized.1,2,3,6,20,120

When the amount of digoxin ingested is unknown and cannot be estimated and when serum digoxin concentrations are unavailable, general dosing guidelines can be used and may be adequate to treat most life-threatening digoxin overdosages.1 (See General Dosing for Digoxin Toxicity under Dosage and Administration: Dosage.)

If the amount of digoxin ingested is known, the dose of digoxin immune Fab (ovine) required to neutralize the cardiac glycoside can be calculated using an estimate of the total body load (TBL) of digoxin, which takes into consideration the amount (mg of digoxin) and bioavailability of the digoxin preparation ingested.1 Alternatively, the dose of digoxin immune Fab (ovine) can be calculated based on steady-state serum digoxin concentrations.1 (See Calculated Dose for Digoxin Toxicity under Dosage and Administration: Dosage.)

If there is no response to an adequate dose of digoxin immune fab (ovine), the possibility that the clinical problem is not caused by digitalis intoxication should be considered and the diagnosis should be re-evaluated.1

General Dosing for Digoxin Toxicity

For treatment of digoxin toxicity following acute ingestion of digoxin when the ingested amount is unknown and cannot be estimated and when serum digoxin concentrations are unavailable, the manufacturer states that a digoxin immune Fab (ovine) dose of 800 mg (twenty 40-mg vials) can be used and should be adequate to treat most life-threatening ingestions in adults and children;1 however, small children weighing less than 20 kg should be monitored for fluid overload when this large dose is used.1 The manufacturer states that a digoxin immune Fab (ovine) dose of 400 mg (ten 40-mg vials) should be administered initially and then an additional dose of 400 mg may be administered if clinically indicated to help avoid febrile reactions.1

For treatment of digoxin toxicity in adults and children weighing 20 kg or more receiving chronic digoxin therapy when serum digoxin concentrations are unavailable, the manufacturer states that a digoxin immune Fab (ovine) dose of 240 mg (six 40-mg vials) generally is sufficient.1 For treatment of digoxin toxicity in infants and small children weighing less than 20 kg receiving chronic digoxin therapy when serum digoxin concentrations are unavailable, the manufacturer states that a single dose of 40 mg of digoxin immune Fab (ovine) usually is sufficient.1

Calculated Dose for Digoxin Toxicity

When a calculated dose of digoxin immune Fab (ovine) is used, clinicians should consider that an inaccurate estimate of the amount of digoxin ingested or absorbed may occur if serum digoxin concentrations were not measured at steady state or were outside measurable limits of the assay used (digoxin assay kits are designed to measure serum concentrations less than 5 ng/mL; dilution of the serum sample is required to accurately measure digoxin concentrations exceeding 5 ng/mL).1

Clinicians also should consider that an average steady-state volume of distribution of digoxin (5 L/kg) is used to convert serum digoxin concentrations to TBL of digoxin, but the volume of distribution of the drug may vary widely among individuals.1 Therefore, many patients may require a higher dose of digoxin immune Fab (ovine) for complete neutralization and doses should be rounded up to the nearest whole vial.1

If the dose of digoxin immune Fab (ovine) estimated based on the acute ingested dose of digoxin differs substantially from the dose calculated using the serum digoxin concentration, the manufacturer states that it may be preferable to use the higher dose.1

Toxicity Following Acute Ingestion of Known Amount of Digoxin

When toxicity occurs following an acute ingestion of a known amount of digoxin, the dose of digoxin immune Fab (ovine) for adults and children may be calculated based on this known amount and the estimated TBL of digoxin, taking into consideration the bioavailability of the preparation ingested.1 Digoxin tablets are 80% absorbed; digoxin liquid-filled capsules are 100% absorbed.1

If digoxin was ingested as tablets, the TBL of digoxin is approximately equal to the dose (in mg) multiplied by 0.8.1

TBL (in mg) = mg of digoxin (as tablets) ingested × 0.8

If digoxin was ingested as liquid-filled capsules1 or was administered IV,68 the TBL of digoxin is approximately equal to the dose (in mg) ingested or administered IV (i.e., the dose ingested or administered IV should not be multiplied by 0.8).1

TBL (in mg) = mg of digoxin (as liquid-filled capsules) ingested

The dose of digoxin immune Fab (ovine) for adults and children expressed as number of vials is then calculated by dividing the TBL (in mg) by 0.5 since each vial of digoxin immune Fab (ovine) binds approximately 0.5 mg of digoxin.1

Dose (in number of vials) = TBL (in mg) / 0.5 (mg of digoxin bound per vial)1

Alternatively, if a single large digoxin dose was ingested (as 0.25-mg tablets or 0.2-mg liquid-filled capsules) and the approximate number of tablets or capsules ingested is known, the manufacturer states that the approximate dose of digoxin immune Fab (ovine) (in number of vials) for adults and children can be estimated using Table 1.1

The dose for infants and small children weighing less than 20 kg should be calculated as mg of digoxin immune Fab (ovine) (see Table 3). 1

Toxicity During Chronic Digoxin Therapy When Serum Digoxin Concentrations Are Known

For treatment of digoxin toxicity during chronic digoxin therapy in adults and children when steady-state serum digoxin concentrations are available, the dose of digoxin immune Fab (ovine) (in number of vials) is calculated by multiplying the serum digoxin concentration (in ng/mL) by the patient's weight (kg) and dividing by 100.1

Dose of digoxin immune Fab (ovine) (in number of vials) = [Conc of digoxin (in ng/mL) × body weight (in kg)]/100

Dose of digoxin immune Fab (ovine) (in mg) is then calculated by multiplying the dosage (in number of vials) by 40 mg/vial.1

Dose of digoxin immune Fab (ovine) (in mg) = [Conc of digoxin (in ng/mL) × body weight (in kg) × 40 mg/vial]/100

Alternatively, the manufacturer states that the dose of digoxin immune Fab (ovine) for adults can be estimated based on the patient's weight and steady-state serum digoxin concentrations (see Table 2).1

The manufacturer states that the dose of digoxin immune Fab (ovine) for infants and small children weighing less than 20 kg should be calculated as mg, but can be estimated based on the patient's weight and steady-state serum digoxin concentrations (see Table 3).1

Digoxin immune Fab (ovine) generally is well tolerated following IV administration.2,3,6,20

Adverse effects reported in more than 7% of patients receiving digoxin immune Fab (ovine) (DigiFab^®) in clinical studies include worsening of heart failure, hypokalemia, and worsening of atrial fibrillation.1

Cardiovascular Effects

Although a causal relationship was not established,6 use of digoxin immune Fab (ovine) has been associated with a worsening of low cardiac output states and heart failure in several patients, possibly by decreasing the effective inotropic concentrations of digoxin in these patients.1,3,6,7,26,30 Impaired ventricular function has occurred within several hours to 1 day after administration of digoxin immune Fab (ovine), but it is difficult to assess whether this effect was causally related to the immune Fab since other factors (e.g., changes in fluid status, concurrent treatment with vasodilators and diuretics, underlying cardiac disease) may have contributed to low cardiac output in these patients.3,6 Studies in animals suggest that reversal of inotropy by digoxin immune Fab (ovine) occurs relatively slowly compared with reversal of cardiac arrhythmias.26 Use of inotropic agents (e.g., dopamine or dobutamine) or vasodilators may be considered in patients who develop decreased cardiac output during digoxin immune Fab (ovine) therapy;1 however, sympathomimetic drugs should be used cautiously in these patients since the drugs may exacerbate or precipitate cardiac glycoside-induced ventricular arrhythmias.1,24,28 Blood pressure decreased within 15 minutes after IV infusion of digoxin immune Fab (ovine) in one patient, but this effect could not be directly attributed to the immune Fab.20

Patients with preexisting atrial fibrillation may develop a rapid ventricular rate following administration of digoxin immune Fab (ovine) secondary to reversal of the effects of cardiac glycosides on the AV node.2,6 In one patient, the ventricular rate increased from a pretreatment level of 90 beats per minute (bpm) to about 120 bpm during infusion of digoxin immune Fab (ovine); the rate continued to increase to a maximum of about 160 bpm about 3 hours after completion of the infusion.6

Hypokalemia and Hyperkalemia

Hypokalemia may occur, sometimes developing rapidly, in patients receiving digoxin immune Fab (ovine).1,2,34,39,120 In one patient, serum potassium concentrations decreased from a pretreatment concentration of about 9 mEq/L to 3.4 mEq/L at 7 hours after administration of digoxin immune Fab (ovine); the patient subsequently received a total of 120 mEq of potassium orally over the next 6 hours to maintain serum potassium concentrations of about 4 mEq/L.2 Hypokalemia may result from reversal by digoxin immune Fab (ovine) of cardiac glycoside-induced inhibition of Na⁺-K⁺-ATPase activity and a subsequent intracellular shift of potassium.1,6,8,29,33

Serum potassium concentrations should be monitored frequently in patients treated with digoxin immune Fab (ovine), especially during the first several hours following administration of the immune Fab.1,2,37,120 If hypokalemia is treated, it should be done cautiously1,2,37 since hyperkalemia can develop rapidly in advanced intoxication.1,22,23,24,50,56 (See Cautions: Precautions and Contraindications.)

Sensitivity Reactions and Antibody Formation

Allergic reactions (including urticarial rash, facial swelling and redness) have been reported rarely in patients receiving digoxin immune Fab (ovine); individuals with a history of allergy, especially to antibiotics, appear to be particularly at risk.79

The possibility of hypersensitivity reactions occurring, including anaphylaxis, should be considered in patients treated with digoxin immune Fab (ovine).1 Negative skin and/or conjunctival tests have been reported in almost all patients who underwent sensitivity testing prior to administration of digoxin immune Fab (ovine).2,3,6,14,20 Slight erythema at the site of skin testing has been reported in at least one patient; however, subsequent IV administration of digoxin immune Fab (ovine) was well tolerated without systemic reaction.6 Fever developed in several patients who received digoxin immune Fab (ovine), but did not appear to be drug or endotoxin induced; evidence of infection was present.6

Human Anti-ovine Fab Antibodies

Digoxin immune Fab (ovine) is derived from ovine immunoglobulin and patients may develop ovine Fab-specific antibodies after receiving the drug.1 Patients previously treated with digoxin immune Fab (ovine) are considered at risk of sensitization to ovine serum protein and, if retreated, theoretically a decreased drug efficacy secondary to the presence of human antibodies against ovine Fab could occur.1 To date, human anti-ovine immunoglobulin antibodies have not been reported in association with reduced binding of ovine digoxin immune Fab or a neutralization response to the drug.1

Because digoxin immune Fab (ovine) lacks the antigenic Fc fragment, digoxin immune Fab (ovine) should be less immunogenic than the intact immunoglobulin molecule,2,3,4,5,6,17,20,25,51 and there is animal evidence to support this;20,25 however, additional clinical experience is necessary to more fully determine the immunogenic risk of digoxin immune Fab (ovine),5,6,20,51,63 particularly in patients with known allergies and patients previously exposed to the Fab5,6,51 or other ovine-derived preparations.51,68,69

Precautions and Contraindications

The manufacturer states that there are no known contraindications to the use of digoxin immune Fab (ovine).1

Precautions Related to Sensitivity Reactions and Antibody Formation

Although the risk, if any, of using digoxin immune Fab (ovine) in patients previously exposed to the drug is not known,5,6,51 individuals who have an allergy to sheep protein or those who have previously received intact ovine antibodies or ovine Fab are at increased risk of a hypersensitivity reaction to digoxin immune Fab (ovine).1

Papain is used during the manufacturing process to cleave the whole antibody into the immune Fab fragments, and traces of papain or inactivated papain residues may be present in digoxin immune Fab (ovine).1 Therefore, patients with a history of allergy to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may be at risk of a hypersensitivity reaction to digoxin immune Fab (ovine).1 The manufacturer states that digoxin immune Fab (ovine) should not be used in patients with a history of hypersensitivity to papaya or papain unless benefits of the drug outweigh the risks.1

Patients should be carefully monitored for manifestations of an acute allergic reaction (e.g., urticaria, pruritus, erythema, angioedema, bronchospasm with wheezing or cough, stridor, laryngeal edema, hypotension, tachycardia).1 If an anaphylactic reaction occurs during administration of digoxin immune Fab (ovine), infusion of the immune Fab should be discontinued immediately and appropriate treatment administered.1 Appropriate equipment for maintenance of an adequate airway and other supportive measures and agents (e.g., tourniquet, corticosteroids, diphenhydramine, oxygen) for the treatment of anaphylaxis or other severe systemic reaction should be immediately and readily available whenever digoxin immune Fab (ovine) is administered.1 If administration of epinephrine is considered, the potential risk associated with use of the drug in a patient with digitalis toxicity should be considered.1

Patients should be advised to contact their clinician immediately if they experience any signs and symptoms of delayed allergic reactions or serum sickness (e.g., rash, pruritus, urticaria) after treatment with digoxin immune Fab (ovine) and hospital discharge.1

Precautions Related to Suicidal Digoxin Ingestion

In patients with known or suspected suicidal ingestion of digoxin, clinicians should consider that suicidal ingestion often involves more than a single drug and should be alert to possible toxic manifestations secondary to drugs other than the cardiac glycoside, especially in cases where manifestations of digitalis toxicity are not relieved by administration of digoxin immune Fab (ovine).1

Laboratory Monitoring

Prior to initiation of digoxin immune Fab (ovine) therapy, serum digoxin concentrations should be obtained whenever possible.1,2,5,6 Serum digoxin concentrations obtained after initiation of digoxin immune Fab (ovine) therapy may be difficult to interpret and clinically misleading.1,6,52 (See Laboratory Test Interferences: Serum Cardiac Glycoside Assays.) Patients should be monitored closely during and after administration of digoxin immune Fab (ovine), including periodic determinations of body temperature, blood pressure, and ECG monitoring.1

Serum potassium concentrations should be monitored carefully during and after administration of digoxin immune Fab (ovine).1 Advanced cardiac glycoside toxicity can cause life-threatening hyperkalemia by shifting potassium extracellularly and/or by inhibiting potassium movement into cells.1,6,29,45,46,47 Increased renal excretion of potassium may result, and thus some patients may appear hyperkalemic while having a total body deficit of potassium.1 When the effect on Na⁺-K⁺-ATPase activity is reversed by digoxin immune Fab (ovine), potassium shifts back into the cells, resulting in a decline in serum potassium concentrations and, potentially, hypokalemia.1,6,29,45 Therefore, monitoring of serum potassium concentrations is particularly important during the first several hours after administration of digoxin immune Fab (ovine), since hypokalemia may develop, sometimes rapidly.1,2,34,39 Although potassium supplementation may occasionally be necessary,1,2 potassium salts should be administered cautiously since hyperkalemia may develop rapidly in advanced intoxication.1,22,23,24,50,56

Renal Impairment

Renal elimination of the Fab fragment-digoxin complex is prolonged in patients with renal impairment and the elimination half-life of digoxin immune Fab (ovine) has not been clearly defined in such patients.1,6,101,104 (See Pharmacokinetics: Elimination.)

The manufacturer makes no recommendations for dosage adjustments of digoxin immune Fab (ovine) in patients with renal impairment.1 However, patients with renal impairment, especially those who are functionally anephric, should be monitored for a prolonged period of time for possible recurrence of cardiac glycoside toxicity.1,97,101,104 Monitoring of free (unbound) digoxin concentrations after digoxin immune Fab (ovine) administration may be considered to detect occurrence of reintoxication in patients with renal failure.1

Redigitalization should not be attempted until elimination of digoxin immune Fab (ovine) is complete.1 This may require several days in patients with normal renal function and a week or longer in patients with renal insufficiency.1

Pediatric Precautions

Although safety data are limited,1 digoxin immune Fab (ovine) has been used successfully in some infants and children without unusual adverse effects.3,6,20,23,31,33,35,36,38 The estimated dose of digoxin immune Fab (ovine) recommended for pediatric patients is based on dose calculations for adults.1

Geriatric Precautions

In one clinical study evaluating digoxin immune Fab (ovine) for treatment of digoxin toxicity, approximately 53% of patients were 65 years of age or older;1 the oldest patient was 86 years of age.1 No overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience has not revealed any evidence of age-related differences.1 (See Renal Impairment under Cautions: Precautions and Contraindications.)

Mutagenicity and Carcinogenicity

Studies to evaluate the carcinogenic and mutagenic potentials of digoxin immune Fab (ovine) have not been performed to date.1,68

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed with digoxin immune Fab (ovine) and it is not known whether the immune Fab can cause fetal harm when administered to pregnant women or can affect reproductive capacity.1 Digoxin immune Fab (ovine) should be used during pregnancy only when clearly needed.1

Lactation

Since it is not known whether digoxin immune Fab (ovine) is distributed into milk, the immune Fab should be used with caution in nursing women and should only be used in such women when clearly needed.1

Cardiac Glycosides

Patients generally will not benefit therapeutically from cardiac glycosides (e.g., digoxin) during digoxin immune Fab (ovine) therapy.5,7,17,49 Redigitalization is theoretically possible only if the molar amount of cardiac glycoside administered is greater than the molar amount of digoxin immune Fab (ovine) present in the body.5,7 The manufacturer recommends that redigitalization be postponed until the Fab fragments have been eliminated from the body, which may take several days in patients with normal renal function and a week or longer in those with renal impairment.1

Laboratory Test Interferences

Serum Cardiac Glycoside Assays

Specimens for determination of serum digoxin concentration should be obtained prior to administration of digoxin immune Fab (ovine) whenever possible.1,2,5,6 However, these serum concentrations may be difficult to interpret if drawn shortly after the last dose of glycoside since equilibration between serum and tissue may not have occurred.1,20,53,55,61,65 Usually, at least 6-8 hours are necessary for digoxin to equilibrate between serum and tissue; any serum specimens drawn prior to this time may give glycoside concentrations greater than those present after equilibration.1,53,55,61,65,68,69,77

Following IV administration of digoxin immune Fab, there is a rapid rise in total serum digoxin concentration, consisting almost completely of the Fab-bound, pharmacologically inactive form of the glycoside.1,2,4,6,20 Total serum glycoside concentrations after IV infusion of digoxin immune Fab (ovine) generally exceed pretreatment concentrations by 10- to 20-fold.4,6,14,20 In addition, depending on the assay used, digoxin immune Fab (ovine) may interfere with immunoassays used to measure serum glycoside concentrations.1,2,6,52,75,76,106,107 Results of serum glycoside determinations can be falsely increased or decreased, depending on the separation method used during the radioimmunoassay procedure, until Fab fragments are eliminated from the body (several days in patients with intact renal function, but a week or longer in patients with renal impairment).1,6,52,75,76 Accurate determinations of total serum glycoside concentration can be made by using specialized techniques in which the binding activity of digoxin immune Fab (ovine) is destroyed via heating and centrifugation of the sample;2,6 however, this value does not represent free, active glycoside.6 Free digoxin concentrations can be determined using equilibrium dialysis techniques;2,6 however, these procedures are not routinely available in most clinical settings.69

Acute Toxicity

Limited information is available on the acute toxicity of digoxin immune Fab (ovine).6,49 Patients receiving large doses of digoxin immune Fab (ovine) theoretically may be at increased risk of developing an acute allergic or febrile reaction or delayed serum sickness.1,6,7,40,49,51 In addition, administration of large doses may prolong the time period before which redigitalization and accurate interpretation of serum glycoside concentrations can be performed.1,6

Pharmacology

Digoxin immune Fab (ovine) contains specific antigen-binding fragments that bind to free (unbound) digoxin intravascularly and in extracellular fluid,1,2,5,6,11,12,17,20,29,51,63,70,71 thereby preventing and reversing the pharmacologic and toxic effects of the glycoside.1,2,3,4,5,6,7,8,12,17,20,26,27,28,29,30,31,32,33,34,35,36,37,38,39,49,51,55,66,70,71 Cardiac glycoside-specific antibodies block and reverse glycoside-induced inhibition of sodium-potassium-activated adenosine triphosphatase (Na⁺-K⁺-ATPase), the enzyme presumed to mediate at least partially the pharmacologic and toxic effects of cardiac glycosides;1,66 a similar action is likely for glycoside-specific antibody fragments, including digoxin immune Fab (ovine).3 The affinity of digoxin immune Fab (ovine) for digoxin is greater than the affinity of digoxin for Na⁺-K⁺-ATPase.1,9 Since the interaction of cardiac glycosides with their receptors appears to be a reversible process, a concentration gradient may be established as extracellular free digoxin concentrations decrease secondary to digoxin immune Fab (ovine) binding, resulting in a progressive efflux of cellular (membrane-bound or intracellular) digoxin from its presumed site of action and subsequent inactivation via binding to the immune Fab.2,6,11,17,20,21,23,29,71

The ability of digoxin immune Fab (ovine) to reverse experimentally induced digoxin toxicity, including biochemical and cardiac effects, is well documented both in vitro and in animals.1,2,3,5,6,20,22,24,26,27,30,31,32,33,34,35,36,37,38,39,65,70 Digoxin-specific antibodies have reversed both toxic electrophysiologic and inotropic effects induced by digoxin in vitro,8,28 and have successfully reversed digoxin-induced inhibition of the active influx of monovalent cations such as potassium into cells.8,12,29 Data from animal studies indicate that electrophysiologic toxicity of digoxin is reversed more rapidly than the inotropic effects of the drug.26

Digoxin immune Fab (ovine) has reversed toxicity induced by digitoxin (no longer commercially available in the US) in animals15 and in humans.1,3,13,14,15,16,18,19,20 Although the affinity of digoxin immune Fab (ovine) for digitoxin is somewhat less than for digoxin (10⁸-10⁹ M^-1 for digitoxin versus 10⁹-10¹⁰ M^-1 for digoxin), digoxin immune Fab's affinity for digitoxin is still greater than digitoxin's affinity for Na⁺-K⁺-ATPase.68,69 Some evidence in animals and humans suggests that digoxin immune Fab (ovine) is also capable of binding to other digoxin derivatives (e.g., β-methyldigoxin and β-acetyldigoxin),31,32 to some of the cardioactive metabolites of digoxin,7 and possibly to some other cardiac glycosides (e.g., lanatoside C).49

Digoxin immune Fab (ovine) may bind to oleander glycosides.67,68,69

In vitro studies indicate that digoxin immune Fab (ovine) may cross-react with and bind to endogenous cardiotonic steroids, including endogenous digitalis-like factors (EDLFs), identified in maternal and/or cord blood from women with preeclampsia.115,118

Pharmacokinetics

Absorption

Peak serum concentrations of Fab fragments reportedly occur at the completion of IV infusion of digoxin immune Fab (ovine).2,25 In a patient who received 1.1 g of digoxin immune Fab (ovine) IV over 2 hours, serum Fab fragment concentrations were 50 mcg/mL 1 hour after initiating the infusion and achieved a peak of 90 mcg/mL at the completion of the infusion.2 Serum concentrations of the fragments declined rapidly to about 13 mcg/mL at 16 hours and then more slowly to about 4 mcg/mL at about 50 hours after initiating the infusion.2

The pharmacokinetics of antibody-hapten association between digoxin and Fab fragments have not been fully elucidated, but it appears that the association reaction between Fab fragments and molecules of these glycosides occurs rapidly.5,6,20,22,42,43,71,73 In patients with toxic serum concentrations of digoxin, serum concentrations of free (unbound) glycoside decline to undetectable levels within several minutes following completion of a 15- to 30-minute IV infusion of digoxin immune Fab,6 and remain low for about 8-12 hours after completing the infusion.6,20,68 The decline in free serum glycoside concentration appears to correlate clinically with reversal of toxicity.1,2,3,6,7,21,23,45 Total serum digoxin concentrations increase rapidly after IV infusion of digoxin immune Fab, generally exceeding pretreatment serum concentrations of these glycosides by 10- to 20-fold;4,6,20 almost all of the glycoside in serum is bound to Fab (and thus is inactive) during the first 12 hours after administration of digoxin immune Fab (ovine).6,20,68 In an adult who ingested an estimated 22.5 mg of digoxin and had a total serum digoxin concentration of 17.6 ng/mL, just prior to IV infusion (approximately 12 hours after ingestion) over 2 hours of a 1.1-g dose of digoxin immune Fab, free serum digoxin concentrations were undetectable at 1-9 hours in this patient and increased to 1.5, 2, 1.5, and 1.5 ng/mL at 12, 16, 36, and 56 hours, respectively, after initiating the Fab infusion.2 Total serum digoxin concentrations increased from 17.6 ng/mL to about 220 ng/mL 1-12 hours after initiating Fab infusion and then decreased to about 35 ng/mL 56 hours after initiating the infusion.2

Improvement in the signs and symptoms of cardiac glycoside toxicity generally is apparent within 30 minutes after completing a 15- to 30-minute IV infusion of digoxin immune Fab,1,3,6,37 but the onset of response is variable and probably depends on the rate of IV infusion, the dose of digoxin immune Fab (ovine) administered relative to the body load of the cardiac glycoside, and possibly other factors.6,68,69,73 Response may be apparent within minutes of initiating the infusion in some patients;6,20,30,37 rapid responses have been empirically evident in infants and young children.6,20,68,69 Data from animal studies suggest that reversal of toxic electrophysiologic effects may occur more rapidly than reversal of inotropy.26,28 In a group of patients with ventricular fibrillation or other severe arrhythmia(s), rhythm stabilized within a mean of 3.2 hours (range: 0.5-13 hours) after an initial dose of digoxin immune Fab (ovine).20 Reversal of cardiac glycoside toxicity,6,17,68,69,72,73 including hyperkalemia,6,34,37,39,68,72 often is complete within 2-6 hours after administration of the immune Fab.6

Distribution

Distribution of digoxin immune Fab (ovine) into human body tissues and fluids has not been fully characterized.68,69 The volume of distribution of digoxin immune Fab (ovine) following IV administration is 0.3-0.4 L/kg in healthy adults and is similar in patients with renal impairment.1 Following IV administration, digoxin immune Fab (ovine) appears to distribute rapidly throughout the extracellular space, into both plasma and interstitial fluid.2,7,17,20,21,27 There is some evidence that some intracellular distribution of digoxin immune Fab (ovine) may occur in spite of its large molecular mass,25,73 but additional study is necessary.68 In animals, digoxin immune Fab (ovine) is distributed more extensively and rapidly than digoxin immune globulin (IgG).25,27

Digoxin immune Fab (ovine) binds rapidly with free digoxin in serum and other extracellular fluids.5,7,12,17,20

It is not known whether digoxin immune Fab (ovine) is distributed into milk.1

Elimination

Plasma digoxin immune Fab (ovine) concentrations appear to decline in a biphasic manner.2,25,27 Digoxin immune Fab (ovine) is eliminated by renal excretion and the reticuloendothelial system.1 In patients with normal renal function, the plasma elimination half-life of the immune Fab ranges from 14-20 hours.1,2,6,73 In animals, digoxin immune Fab (ovine) has been shown to be more rapidly eliminated than digoxin immune globulin.21,25,27,71 The terminal elimination half-life of digoxin immune Fab (ovine) has been reported to be 25-137 hours in some patients with renal impairment;97,101 half-life may be increased as much as tenfold in such patients.1

Digoxin immune Fab (ovine) is eliminated renally1,7,20,21,73 via glomerular filtration, principally as the cardiac glycoside-Fab fragment complex in intoxicated patients.1,7,20 In one digoxin-overdosed patient who received 1.1 g of digoxin immune Fab IV over 2 hours, urinary concentrations of Fab peaked at 42.5 mcg/mL, decreasing to less than 2 mcg/mL in urine collected 30-52 hours after initiating the infusion.2 Total urinary digoxin concentration, probably as digoxin bound to Fab, peaked at 960 ng/mL during the initial 24 hours after infusion, while free digoxin concentrations were undetectable for at least 6 hours after initiating the infusion; urinary digoxin was exclusively present as free drug by 30 hours after Fab infusion.2 The contribution, if any, of renal tubular secretion to the elimination of drug bound to Fab fragments has not been elucidated.21

Although only limited information is available, hemodialysis and peritoneal dialysis appear to have no effect or only a very minimal effect on removal of digoxin immune Fab (ovine).101,104,105

Chemistry and Stability

Chemistry

Digoxin immune Fab (ovine) is an antigen-binding agent used as an antidote in the treatment of digoxin toxicity.1,2,3,4,5,6,7,20 The drug is a sterile preparation of monovalent, digoxin-specific antigen binding fragments (Fab) derived from antidigoxin antibodies.1,2,3,4,5,7,8,9,10,20,51 The antidigoxin antibodies are obtained from the serum of healthy sheep that have been immunized with a conjugate of digoxin (the hapten) and albumin human (a protein carrier).1,2,3,4,8,9,10,20,68 The antidigoxin antibodies are then cleaved by papain to form an Fc fragment (crystallizable fragment that contains most of the antigenic and complement-binding determinants) and 2 identical monovalent Fab fragments.1,2,4,5,6,8,20,51,64 Following enzymatic cleavage, digoxin-specific Fab is isolated and purified via affinity chromatography,1,2,3,6,8 yielding fragments with a molecular mass of approximately 46,000 daltons.1,3,6

The average intrinsic affinity constants of digoxin immune Fab (ovine) for digoxin is reportedly 10⁹-10¹⁰ M^-1.1,3,8,9

Digoxin immune Fab (ovine) commercially available in the US (DigiFab^®) occurs as a sterile lyophilized powder.1 Digoxin immune Fab (ovine) is freely soluble in water and in 0.9% sodium chloride injection.68,81 The immune Fab contains mannitol and sodium acetate as a buffering agent.1 Following reconstitution as directed with sterile water for injection, digoxin immune Fab (ovine) solutions containing 10 mg of the immune Fab per mL are clear to slightly opalescent or pale yellow and have a pH of 4.5-5.5.81

Stability

Digoxin immune Fab (ovine) powder for injection should be refrigerated at 2-8°C and should not be frozen.1 Solutions of the immune Fab contain no preservatives and should be used immediately after reconstitution; if reconstituted solutions are not used immediately, they may be refrigerated at 2-8°C for up to 4 hours.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. BTG International. Digifab^® (digoxin immune Fab [ovine]) prescribing information. West Conshohocken, PA; 2017 Jun.

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