DIGIFAB

General Administration Information
For storage information, see the specific product information within the How Supplied section.
-If possible, determine the serum digoxin or digitoxin concentration before administration of digoxin immune Fab. This measurement establishes the level of serum digoxin or digitoxin at the time of diagnosis of digitalis intoxication. At least 6-8 hours are required for digoxin equilibration between tissue and serum. Consider the time for equilibration in the interpretation of serum digoxin concentrations.
-Following administration of digoxin immune Fab, standard serum digoxin concentration measurements may be clinically misleading until the Fab fragments are eliminated from the body. Measure free (unbound) serum digitalis concentration to determine an accurate concentration.

Route-Specific Administration

Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Digoxin immune Fab is administered by intravenous infusion or bolus injection.
-Closely monitor the patient's temperature, blood pressure, electrocardiogram, and serum potassium concentration before and after digoxin immune Fab administration.
-If digoxin immune Fab that is reconstituted is not used immediately, it may be stored under refrigeration at 2-8 degrees C (36-46 degrees F) for up to 4 hours. Digoxin immune Fab has no preservatives.

Reconstitution/Dilution
-Reconstitute by adding 4 ml of sterile water for injection to the vial and gently mixing. The resulting solution should be clear, colorless, approximately isosmotic, and contain 10 mg/ml of digoxin immune Fab. The reconstituted product may be diluted with normal saline to a convenient volume.
-For patients receiving relatively small doses, the appropriate dose of the reconstituted solution may be withdrawn using a tuberculin syringe and then injected IV or diluted in NS injection and infused or injected IV.
-For patients receiving doses < 3 mg, dilute the reconstituted solution with 36 ml of NS injection to give a solution containing 1 mg/ml of digoxin immune Fab.

Infusion
-Infuse IV slowly over at least 30 minutes. If infusion rate-related reactions occur, stop the infusion and restart at a slower rate. If cardiac arrest is imminent, bolus administration is acceptable. An increased incidence of infusion-related reactions may be expected with bolus injection.

As digoxin immune Fab is an ovine (i.e., sheep) product, allergic reactions including anaphylaxis are possible. Carefully monitor for signs and symptoms of an acute allergic reaction such as urticaria, pruritus, erythema, angioedema, bronchospasm with wheezing or cough, stridor, laryngeal edema, hypotension, rash (unspecified), and tachycardia. Infusion-related reactions that may be related to administration rate may occur. For example, 1 of 8 adult patients who received DigiFab had moderate orthostatic hypotension that became mild in severity before resolving. If digoxin immune Fab is given by bolus injection because of imminent cardiac arrest, an increased incidence of infusion-related reactions may occur. Stop the infusion if infusion rate-related reactions or if infusion-related anaphylactoid reactions occur such as hypotension, wheezing, or urticaria. Balance the need for epinephrine with the potential risk of its administration in the setting of digitalis toxicity. If appropriate, the infusion can be re-started at a slower rate. Patients with known allergies to sheep protein are particularly at risk for an anaphylactic reaction, as are individuals who have previously received intact ovine antibodies or ovine Fab. Do not administer DigiFab to patients with a known history of hypersensitivity to papaya or papain unless the benefits outweigh the risks and appropriate management for anaphylactic reactions is readily available.

The most common adverse reactions related to DigiFab administration in adults are worsening congestive heart failure (13%) and worsening atrial fibrillation (7%). Due to the high efficiency of digoxin immune Fab in removing digoxin, precipitation of heart failure may occur due to the loss of the positive inotropic effects of digoxin. Also, the loss of effects of digoxin on the atrioventricular node may lead to a rapid ventricular response in patients with atrial fibrillation.

Hypokalemia (13%) was a common adverse reaction related to DigiFab administration in adults. Acute digoxin overdose causes hyperkalemia and a compensatory hyperkaliuresis. Reversal of digoxin effects on sodium-potassium ATPase by digoxin immune Fab can lead to hypokalemia. Serum potassium should be monitored closely before, during, and after therapy with digoxin immune Fab.

Antibody formation is possible, as exposure to digoxin-specific ovine immune Fab may cause sensitization to ovine serum protein. Hypothetically, the presence of human antibodies against ovine Fab could lead to diminution of the drug's efficacy. However, no clinical reports exist of human anti-ovine immunoglobulin antibodies causing a reduction in binding of ovine digoxin immune Fab or neutralization response to ovine digoxin immune Fab. Digoxin immune Fab should only be administered in specific conditions.

An injection site reaction may occur during the intravenous infusion of digoxin immune Fab. One of 8 adult patients who received DigiFab had phlebitis of the infusion vein.

Digoxin immune Fab is a foreign (sheep-derived) protein. Digoxin immune Fab should be used cautiously in patients with known ovine protein hypersensitivity. Digoxin immune Fab is prepared by isolating the immunoglobulin fraction of the ovine serum, digesting it with papain, and isolating the digoxin-specific Fab fragments by affinity chromatography. Patients with papain hypersensitivity or allergies to chymopapain, other papaya extracts, or the pineapple extract bromelain may have an allergic response to the product. Do not administer digoxin immune Fab to a patient with a known history of hypersensitivity to papaya or papain unless the benefits outweigh the risks and appropriate management for anaphylactic reactions is readily available. Patients with a history of an allergy to antibiotics, latex, or dust mites may also be at risk for an allergic reaction to digoxin immune Fab. Some dust mite allergens and some latex allergens share antigenic structures with papain.

Digoxin immune Fab should be used with caution in patients with renal impairment or renal failure. Elimination of digoxin immune Fab-digoxin complexes may be delayed in patients with reduced renal function. The risk of digoxin release from the Fab fragment-digoxin complex is potentially increased when excretion of the complex is slowed. Free digoxin could cause toxicity to recur. For example, a functionally anephric patient had recurrence of atrioventricular block due to digoxin 10 days after reversal by digoxin immune Fab. However, in a study, toxicity recurrence was only associated with an inadequate initial dose. No dose reduction or escalation is needed for patients with impaired kidney function. In patients functionally anephric, digoxin immune Fab is not excreted and may be eliminated by the reticuloendothelial system. It is not clear if detoxification or reintoxification will occur; therefore, prolonged monitoring for digoxin toxicity is recommended. Also, do not begin treatment with digoxin until all Fab fragments have been eliminated by the body, which may take a week or longer in patients with impaired renal function. Monitoring of free (unbound) digoxin concentrations after the administration may be appropriate in renal failure patients.

Do not administer digoxin in the setting of digoxin toxicity, and correct any electrolyte imbalance, acid/base imbalance, and hypoxia. Patients with digoxin toxicity and hypokalemia may need potassium supplementation. Acute digoxin overdose causes hyperkalemia and a compensatory hyperkaluresis. Reversal of digoxin effects on sodium-potassium ATPase by digoxin immune Fab can lead to hypokalemia. Closely monitor serum potassium concentrations before, during, and after therapy with digoxin immune Fab.

Description: Digoxin immune Fab is a protein that consists of antibody fragments, which are used as an antidote for digitalis toxicity. The antibody fragments are obtained by immunizing sheep with a digoxin derivative (DigiFab), isolating immunoglobulins from the sheep serum, digesting the immunoglobulins with papain, and obtaining the specific antibody fragments through affinity chromatography. The antibody fragments (Fab) represent the antigen-binding section of an immunoglobulin (IgG). The Fab fragments are smaller, exhibit less antigenicity, have greater distribution, and are eliminated faster than the larger IgG parent. Digoxin immune Fab will bind both digoxin and digitoxin molecules, although the binding affinity for the antidote is greater for digoxin than for digitoxin. Digibind was approved by the FDA in 1986 but is no longer marketed in the U.S.; DigiFab was approved by the FDA in August of 2001.

For the treatment of life-threatening or potentially life-threatening digoxin toxicity, digitoxin toxicity, digoxin overdose, or digitoxin overdose including known suicidal or accidental consumption of fatal doses of digoxin (i.e., 4 mg or more or 0.1 mg/kg or more in children, or ingestion resulting in serum concentrations greater than 10 ng/mL; chronic ingestions resulting in steady-state digoxin concentrations greater than 4 ng/mL in children; and manifestations of digoxin toxicity due to overdose (e.g., life-threatening cardiac glycoside-induced arrhythmias, progressive bradycardia, second or third degree heart block unresponsive to atropine, serum potassium greater than 6 mEq/L in children):
-for acute ingestion of an unknown amount of digoxin or digitoxin (e.g., either the serum concentration or the amount ingested is not known):
Intravenous dosage:
Children and Adolescents: Administer 800 mg (20 vials) IV; this dose should be adequate to treat most life-threatening overdoses. May administer as a single dose or alternatively, may give 400 mg (10 vials) with careful monitoring of the patient's response, followed by an additional 400 mg (10 vials) if necessary. In patients less than 20 kg, monitor closely for volume overload. In general, a large dose has a faster onset, but may also enhance the possibility of a febrile reaction. Failure to respond to digoxin immune Fab should alert the clinician to the possibility that the problem may not be caused by digitalis toxicity.
-for toxicity during chronic therapy for patients in acute distress or for whom serum digoxin or digitoxin concentrations are not available:
Intravenous dosage:
Infants and Children weighing less than 20 kg: 40 mg (1 vial) IV should be sufficient to reverse most cases of toxicity. Failure to respond to digoxin immune Fab should alert the clinician to the possibility that the problem may not be caused by digitalis toxicity.
Children and Adolescents weighing 20 kg or more: 240 mg (6 vials) IV should be sufficient to reverse most cases of toxicity. Failure to respond to digoxin immune Fab should alert the clinician to the possibility that the problem may not be caused by digitalis toxicity.
-dosage calculation based on known amount of acutely-ingested digoxin tablets:
NOTE: If toxicity has not adequately reversed after several hours or appears to recur, another dose of digoxin immune Fab may be necessary. Measurement of serum drug concentrations may also be necessary. Failure to respond to digoxin immune Fab should alert the clinician to the possibility that the problem may not be caused by digitalis toxicity.
Intravenous dosage:
Infants, Children, and Adolescents: Intravenous dose in vials = (amount of cardiac glycoside administered [mg] x 0.8)/0.5 mg digitalis bound per vial (40 mg of digoxin immune Fab binds approximately 0.5 mg of digoxin). Because infants and children have smaller doses, the dosage may be converted to mg instead of number of vials using the following equation: intravenous dose (in mg) = dose (in number of vials) x 40 mg/vial.
-dosage calculation based on steady-state serum DIGOXIN concentrations:
NOTE: If toxicity has not adequately reversed after several hours or appears to recur, another dose of digoxin immune Fab may be necessary. Measurement of serum drug concentrations may also be necessary. Failure to respond to digoxin immune Fab should alert the clinician to the possibility that the problem may not be caused by digitalis toxicity.
Intravenous dosage:
Infants, Children, and Adolescents with a serum digoxin concentration of 1 ng/mL: Intravenous dose in vials = (serum digoxin concentration in ng/mL x body weight in kg)/100. Because infants and small children have smaller doses, the dosage may be converted to mg instead of number of vials using the following equation: Dose in mg = intravenous dose (in number of vials) x 40 mg/vial. Alternatively, the estimated dose (mg) needed based on a steady-state serum digoxin concentration of 1 ng/mL and patient weight (kg) is as follows: 1 to less than 3 kg give 0.4 mg; 3 to less than 5 kg give 1 mg; 5 to less than 10 kg give 2 mg; 10 to less than 20 kg give 4 mg; and 20 kg or more give 8 mg.
Infants, Children, and Adolescents with a serum digoxin concentration of 2 ng/mL: Intravenous dose in vials = (serum digoxin concentration in ng/mL x body weight in kg)/100. Because infants and small children have smaller doses, the dosage may be converted to mg instead of number of vials using the following equation: Dose in mg = intravenous dose (in number of vials) x 40 mg/vial. Alternatively, the estimated dose (mg) needed based on a steady-state serum digoxin concentration of 2 ng/mL and patient weight (kg) is as follows: 1 to less than 3 kg give 1 mg; 3 to less than 5 kg give 2.5 mg; 5 to less than 10 kg give 4 mg; 10 to less than 20 kg give 8 mg; and 20 kg or more give 16 mg.
Infants, Children, and Adolescents with a serum digoxin concentration of 4 ng/mL: Intravenous dose in vials = (serum digoxin concentration in ng/mL x body weight in kg)/100. Because infants and small children have smaller doses, the dosage may be converted to mg instead of number of vials using the following equation: Dose in mg = intravenous dose (in number of vials) x 40 mg/vial. Alternatively, the estimated dose (mg) needed based on a steady-state serum digoxin concentration of 4 ng/mL and patient weight (kg) is as follows: 1 to less than 3 kg give 1.5 mg; 3 to less than 5 kg give 5 mg; 5 to less than 10 kg give 8 mg; 10 to less than 20 kg give 16 mg; and 20 kg or more give 32 mg.
Infants, Children, and Adolescents with a serum digoxin concentration of 8 ng/mL: Intravenous dose in vials = (serum digoxin concentration in ng/mL x body weight in kg)/100. Because infants and small children have smaller doses, the dosage may be converted to mg instead of number of vials using the following equation: Dose in mg = intravenous dose (in number of vials) x 40 mg/vial. Alternatively, the estimated dose (mg) needed based on a steady-state serum digoxin concentration of 8 ng/mL and patient weight (kg) is as follows: 1 to less than 3 kg give 3 mg; 3 to less than 5 kg give 10 mg; 5 to less than 10 kg give 16 mg; 10 to less than 20 kg give 32 mg; and 20 kg or more give 64 mg.
Infants, Children, and Adolescents with a serum digoxin concentration of 12 ng/mL: Intravenous dose in vials = (serum digoxin concentration in ng/mL x body weight in kg)/100. Because infants and small children have smaller doses, the dosage may be converted to mg instead of number of vials using the following equation: Dose in mg = intravenous dose (in number of vials) x 40 mg/vial. Alternatively, the estimated dose (mg) needed based on a steady-state serum digoxin concentration of 12 ng/mL and patient weight (kg) is as follows: 1 to less than 3 kg give 5 mg; 3 to less than 5 kg give 14 mg; 5 to less than 10 kg give 24 mg; 10 to less than 20 kg give 48 mg; and 20 kg or more give 96 mg.
Infants, Children, and Adolescents with a serum digoxin concentration of 16 ng/mL: Intravenous dose in vials = (serum digoxin concentration in ng/mL x body weight in kg)/100. Because infants and small children have smaller doses, the dosage may be converted to mg instead of number of vials using the following equation: Dose in mg = intravenous dose (in number of vials) x 40 mg/vial. Alternatively, the estimated dose (mg) needed based on a steady-state serum digoxin concentration of 16 ng/mL and patient weight (kg) is as follows: 1 to less than 3 kg give 6.5 mg; 3 to less than 5 kg give 19 mg; 5 to less than 10 kg give 32 mg; 10 to less than 20 kg give 64 mg; and 20 kg or more give 128 mg.
Infants, Children, and Adolescents with a serum digoxin concentration of 20 ng/mL: Intravenous dose in vials = (serum digoxin concentration in ng/mL x body weight in kg)/100. Because infants and small children have smaller doses, the dosage may be converted to mg instead of number of vials using the following equation: Dose in mg = intravenous dose (in number of vials) x 40 mg/vial. Alternatively, the estimated dose (mg) needed based on a steady-state serum digoxin concentration of 20 ng/mL and patient weight (kg) is as follows: 1 to less than 3 kg give 8 mg; 3 to less than 5 kg give 24 mg; 5 to less than 10 kg give 40 mg; 10 to less than 20 kg give 80 mg; and 20 kg or more give 160 mg.
-dosage calculation based on known amount of acutely-ingested digitoxin tablets or intravenous digoxin or digitoxin:
NOTE: If toxicity has not adequately reversed after several hours or appears to recur, another dose of digoxin immune Fab may be necessary. Measurement of serum drug concentrations may also be necessary. Failure to respond to digoxin immune Fab should alert the clinician to the possibility that the problem may not be caused by digitalis toxicity.
Intravenous dosage:
Infants, Children, and Adolescents: Intravenous dose in vials = amount of cardiac glycoside ingested (mg)/0.5 mg digitalis bound per vial. Because infants and children have smaller doses, the dosage may be converted to mg instead of vials using the following equation: intravenous dose (in mg) = dose (in number of vials) x 40 mg/vial.
-dosage calculation based on steady-state serum DIGITOXIN concentrations:
NOTE: If toxicity has not adequately reversed after several hours or appears to recur, another dose of digoxin immune Fab may be necessary. Measurement of serum drug concentrations may also be necessary. Failure to respond to digoxin immune Fab should alert the clinician to the possibility that the problem may not be caused by digitalis toxicity.
Intravenous dosage:
Infants, Children, and Adolescents: Intravenous dose in vials = (serum digitoxin concentration in ng/mL x body weight in kg)/1,000. Equation provides a dosage in an amount equimolar to the amount of digitoxin present. Because infants and children have smaller doses, the dosage may be converted to mg instead of vials using the following equation: intravenous dose (in mg) = dose (in number of vials) x 40 mg/vial.

Therapeutic Drug Monitoring:
-Measure serum digoxin concentrations prior to administration of Digoxin Immune Fab, if possible.
-The total serum digoxin concentration may rise precipitously following administration of Digoxin immune Fab; however, this will be almost entirely bound to the Fab fragment. Digoxin bound to Fab fragments is not able to react with receptors in the body and therefore cannot result in toxicity. Standard serum digoxin concentration measurements may be clinically misleading until the Fab fragments are eliminated from the body. This may take several days or a week or more in patients with markedly impaired renal function.
-The serum concentration of digoxin obtained prior to administration of Digoxin Immune Fab will establish the level of serum digoxin at the time of diagnosis of digitalis intoxication. Absorption of the last dose may continue from the intestine, because at least 6-8 hours are required for equilibration of digoxin between serum and tissue. Therefore, serum measurements may be difficult to interpret if samples are drawn soon after the last digitalis dose.
-Closely monitor temperature, blood pressure, electrocardiogram, and potassium concentration, during and after administration of Digoxin Immune Fab.
-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 necessary. If a patient is in need of readministration of Digoxin immune Fab due to recurrent toxicity, or to a new toxic episode that occurs soon after the first episode, measurement of free (unbound) serum digitalis concentrations should be considered since Fab may still be present in the body.

Maximum Dosage Limits:
The amount of digoxin immune Fab needed depends on patient-specific factors such as age, amount of digoxin ingested, and patient response.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Elimination of digoxin immune Fab-digoxin complexes may be delayed in patients with renal impairment. It is not clear if deintoxification or reintoxification will occur, therefore prolonged monitoring for digoxin toxicity is recommended.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Digoxin immune Fab is an immunoglobulin fragment with a specific and high affinity for both digoxin and digitoxin molecules. The affinity between the antidote and the cardiac glycoside is greater than the affinity between the cardiac glycoside and tissue binding sites (e.g., Na-K-ATPase). Molecules of digoxin or digitoxin are removed from tissue binding sites and are sequestered in the extracellular fluid, shifting equilibrium away from binding of the drug to its tissue receptors. Signs and symptoms of digoxin toxicity are reversed, often within minutes. In some patients, beneficial clinical actions of digitalis are also reversed. One 40 mg vial of DigiFab will bind approximately 0.5 mg of digoxin or digitoxin. Digoxin immune Fab effectively treats digitoxin toxicity, as the antidote binds both digitoxin and digoxin (10% of digitoxin is metabolized to digoxin).

Pharmacokinetics: Digoxin immune Fab is administered intravenously. Digoxin immune Fab distributes beyond the extracellular space with a volume of distribution of 0.3 L/kg. Minutes after Fab is administered, total (i.e., bound and free) digoxin serum concentrations increase by 10- to 30-fold, and free digoxin decreases from roughly 80% to 0-5%. It is unknown if the antibody fragment or the glycoside-antibody complex penetrates CSF. Elimination is via the kidney. Free digoxin and the digoxin-Fab complex may be eliminated independently. In patients with normal renal function, the elimination half-life of DigiFab is 15 hours.

Administration of digoxin immune Fab led to a reduction in the serum free digoxin concentration to below the limit of assay quantitation for several hours. The cumulative urinary excretion of digoxin was comparable and exceeded 40% of the administered dose by 24 hours in patients with normal renal function.

Affected cytochrome P450 isoenzymes: none


-Special Populations
Hepatic Impairment
No pharmacokinetic data are available in patients with hepatic impairment.

Renal Impairment
In patients with renal impairment, the elimination half-life appears to be increased up to 10-fold, but the volume of distribution is unaffected. The elimination half-life for the digoxin-Fab complex averages 118 hours in patients with various degrees of renal dysfunction. In patients with renal failure, clearance is probably dependent on the reticuloendothelial system. As compared to data from patients with normal renal function, the time course of therapeutic effect in patients with renal failure appears to be the same, although the excretion of the Fab fragment-digoxin complex is probably delayed.