Digibind (Digoxin Immune Fab)

DIGIBIND®

Glaxo Wellcome

Digoxin Immune Fab (Ovine)

Specific Antibody for Digoxin

Action And Clinical Pharmacology: Digoxin immune Fab (ovine) is a sterile lyophilized powder of antigen binding fragments (Fab) derived from specific antidigoxin antibodies raised in sheep. It binds molecules of digoxin, making them unavailable for binding at their site of action on cells in the body. The Fab fragment-digoxin complex accumulates in the blood, from which it is excreted by the kidney. The net effect is to shift the equilibrium away from binding of digoxin to its receptors in the body, thereby, reversing its effects.

After i.v. injection of digoxin immune Fab (ovine) in the baboon, digoxin-specific Fab fragments are excreted in the urine with a biological half-life of about 9 to 13 hours. In humans with normal renal function the half-life appears to be 15 to 20 hours. Experimental studies in animals indicate that these antibody fragments have a large volume of distribution in the extracellular space, unlike whole antibody which distributes in a space only about twice that of the plasma volume. Ordinarily, following administration of digoxin immune Fab (ovine), improvement in signs and symptoms of digitalis intoxication begins within one-half hour or less.

The affinity of digoxin for digoxin immune Fab (ovine) is in the range of 10to 101M1 which is greater than the affinity of digoxin for (sodium, potassium) ATPase, the presumed receptor for its toxic effects. The affinity of digoxin immune Fab (ovine) for digitoxin is about 10 times less than for digoxin (10to 10M1).

Indications And Clinical Uses: For treatment of potentially life-threatening digoxin intoxication. Although designed specifically to treat life-threatening digoxin toxicity, it has also been used successfully to treat life-threatening toxicity due to digitoxin. Since human experience is limited and the consequences of repeated exposures are unknown, this product is not indicated for milder cases of digitalis toxicity.

Manifestations of life-threatening toxicity 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 not responsive to atropine.

Ingestion of more than 10 mg of digoxin in previously healthy adults or 4 mg of digoxin in previously healthy children, or ingestion causing steady-state serum concentrations greater than 10 ng/mL, often results in cardiac arrest. Digitalis-induced progressive elevation of the serum potassium concentration also suggests imminent cardiac arrest. If the potassium concentration exceeds 5 mEq/L in the setting of severe digitalis intoxication, digoxin immune Fab (ovine) therapy is indicated.

Contra-Indications: There are no known contraindications to the use of digoxin immune Fab (ovine).

Manufacturers’ Warnings In Clinical States: Suicidal ingestion often involves more than one drug; thus, toxicity from other drugs should not be overlooked.

One should consider the possibility of anaphylactic, hypersensitivity or febrile reactions to digoxin immune Fab (ovine). If an anaphylactoid reaction occurs, the drug infusion should be discontinued and appropriate therapy initiated using aminophylline, oxygen, volume expansion, diphenhydramine, corticosteroids and airway management as indicated. The need for epinephrine should be balanced against its potential risk in the setting of digitalis toxicity.

Since the Fab fragment of the antibody lacks the antigenic determinants of the Fc fragment, it should pose less of an immunogenic threat to patients than does an intact immunoglobulin molecule. Patients with known allergies would be particularly at risk, as would individuals who have previously received antibodies or Fab fragments raised in sheep.

Papain is used to cleave the whole antibody into Fab and Fc fragments, and traces of papain or inactivated papain residues may be present in digoxin immune Fab (ovine). Patients with allergies to papain, chymopapain, or other papaya extracts also may be particularly at risk.

Skin testing for allergy was performed during the clinical investigation of digoxin immune Fab (ovine). Only one patient developed erythema at the site of skin testing, with no accompanying wheal reaction; this individual had no adverse reaction to systemic treatment with digoxin immune Fab (ovine). Since allergy testing can delay urgently needed therapy, it is not routinely required before treatment of life-threatening digitalis toxicity with digoxin immune Fab (ovine).

Skin Testing: Skin testing may be appropriate for high risk individuals, especially patients with known allergies or those previously treated with digoxin immune Fab (ovine). The intradermal skin test can be performed by:

1. Diluting 0.1 mL of reconstituted Digibind (9.5 mg/mL) in 9.9 mL sterile isotonic saline (1:100 dilution, 95 µg/mL).

2. Injecting 0.1 mL of the 1:100 dilution (9.5 µg) intradermally and observing for an urticarial wheal surrounded by a zone of erythema. The test should be read at 20 minutes.

The scratch test procedure is performed by placing 1 drop of a 1:100 dilution of digoxin immune Fab (ovine) on the skin and then making a 1/4 inch scratch through the drop with a sterile needle. The scratch site is inspected at 20 minutes for an urticarial wheal surrounded by erythema. If skin testing causes a systemic reaction, a tourniquet should be applied above the site of testing and measures to treat anaphylaxis should be instituted. Further administration should be avoided unless its use is absolutely essential, in which case the patient should be pretreated with corticosteroids and diphenhydramine. The physician should be prepared to treat anaphylaxis.

Precautions: General: Standard therapy for digitalis intoxication includes withdrawal of the drug and correction of factors that may contribute to toxicity, such as electrolyte disturbances, hypoxia, acid-base disturbances and agents such as catecholamines. Also, treatment of arrhythmias may include judicious potassium supplements, lidocaine, phenytoin, procainamide and/or propranolol; treatment of sinus bradycardia or atrioventricular block may involve atropine or pacemaker insertion.

Massive digitalis intoxication can cause hyperkalemia; administration of potassium supplements in the setting of massive intoxication may be hazardous (see Laboratory Tests). After treatment with digoxin immune Fab (ovine), the serum potassium concentration may drop rapidly and must be monitored frequently, especially over the first several hours after digoxin immune Fab (ovine) is given (see Laboratory Tests).

The elimination half-life in the setting of renal failure has not been clearly defined. Patients with renal dysfunction have been successfully treated with digoxin immune Fab (ovine). There is no evidence to suggest the time-course of therapeutic effect is any different in these patients than in patients with normal renal function, but excretion of the Fab fragment-digoxin complex from the body is probably delayed. In patients who are functionally anephric, one would anticipate failure to clear the Fab fragment-digoxin complex from the blood by glomerular filtration and renal excretion. Whether failure to eliminate the Fab fragment-digoxin complex in severe renal failure can lead to reintoxication following release of newly unbound digoxin into the blood is uncertain. Such patients should be monitored for a prolonged period for possible recurrence of digitalis toxicity.

Patients with intrinsically poor cardiac function may deteriorate from withdrawal of the inotropic action of digoxin. Studies in animals have shown that the reversal of inotropic effect is relatively gradual, occurring over hours. When needed, additional support can be provided by use of i.v. inotropes, such as dopamine or dobutamine, or vasodilators. One must be careful in using catecholamines not to aggravate digitalis toxic rhythm disturbances. Clearly, other types of digitalis glycosides should not be used in this setting. Redigitalization should be postponed, if possible, until the Fab fragments have been eliminated from the body, which may require several days. Patients with impaired renal function may require a week or longer.

Laboratory Tests: Digoxin immune Fab (ovine) will interfere with digitalis immunoassay measurements. Thus, the standard serum digoxin concentration measurement can be clinically misleading until the Fab fragment is eliminated from the body.

Serum digoxin or digitoxin concentration should be obtained before digoxin immune Fab (ovine) administration, if at all possible. These measurements may be difficult to interpret if drawn soon after the last digitalis dose, since at least 6 to 8 hours are required for equilibration of digoxin between serum and tissue. Patients should be closely monitored, including temperature, blood pressure, electrocardiogram and potassium concentration, during and after administration of digoxin immune Fab (ovine). The total serum digoxin concentration may rise precipitously following administration of digoxin immune Fab (ovine), but this will be almost entirely bound to the Fab fragment and therefore, not able to react with receptors in the body.

Potassium concentrations should be followed carefully. Severe digitalis intoxication can cause life-threatening elevation in serum potassium concentration by shifting potassium from inside to outside the cell. The elevation in serum potassium concentration can lead to increased renal excretion of potassium. Thus, these patients may have hyperkalemia with total body deficit of potassium. When the effect of digitalis is reversed by digoxin immune Fab (ovine), potassium shifts back inside the cell, with a resulting decline in serum potassium concentration. Hypokalemia may thus develop rapidly. For these reasons, serum potassium concentration should be monitored repeatedly, especially over the first several hours after digoxin immune Fab (ovine) is given, and cautiously treated when necessary.

Carcinogenesis, Mutagenesis, Impairment of Fertility: There have been no long-term studies performed in animals to evaluate carcinogenic potential.

Pregnancy: Animal reproduction studies have not been conducted with digoxin immune Fab (ovine). It is also not known whether digoxin immune Fab (ovine) can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. It should be given to a pregnant woman only if clearly needed.

Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when digoxin immune Fab (ovine) is administered to a nursing woman.

Children: Digoxin immune Fab (ovine) has been successfully used in infants with no apparent adverse sequelae. As in all other circumstances, use of this drug in infants should be based on careful consideration of the benefits of the drug balanced against the potential risks involved.

Adverse Reactions: Allergic reactions to digoxin immune Fab (ovine) have been reported rarely. Patients with a history of allergy, especially to antibiotics, appear to be at particular risk (see Warnings). In a few instances, low cardiac output states and congestive heart failure could have been exacerbated by withdrawal of the inotropic effects of digitalis. Hypokalemia may occur from reactivation of (sodium, potassium) ATPase (see Precautions, Laboratory Tests). Patients with atrial fibrillation may develop a rapid ventricular response from withdrawal of the effects of digitalis on the atrioventricular node.

Dosage And Administration: General Guidelines: The dosage of digoxin immune Fab (ovine) varies according to the amount of digoxin (digitoxin) to be neutralized. The average dose used during clinical testing was 10 vials.

Dosage for Acute Ingestion of Unknown Amount: Twenty (20) vials (760 mg) is adequate to treat most life-threatening ingestions in both adults and children. However, in children it is important to monitor for volume overload. The physician may consider administering 10 vials, observing the patient’s response, and following with an additional 10 vials if indicated.

Dosage for Toxicity During Chronic Therapy: For adults, 6 vials (228 mg) usually is adequate to reverse most cases of toxicity. This dose can be used in patients who are in acute distress or for whom a serum digoxin or digitoxin concentration is not available. In infants and small children (£20 kg) a single vial usually should suffice.

Methods for calculating the dose of digoxin immune Fab (ovine) required to neutralize the known or estimated amount of digoxin or digitoxin in the body are given below (see Dosage Calculation section).

When determining the dose for digoxin immune Fab (ovine), the following guidelines should be considered:

Erroneous calculations may result from inaccurate estimates of the amount of digitalis ingested or absorbed, or from nonsteady-state serum digitalis concentrations. Inaccurate serum digitalis concentration measurements are a possible source of error. Most serum digoxin assay kits are designed to measure values less than 5 ng/mL. Dilution of samples is required to obtain accurate measures above 5 ng/mL.

Dosage calculations are based on a steady-state volume of distribution of approximately 5 L/kg for digoxin (0.5 L/kg for digitoxin) to convert serum digitalis concentration 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.

If toxicity has not adequately reversed after several hours or appears to recur, readministration of digoxin immune Fab (ovine) at a dose guided by clinical judgment may be required.

Failure to respond to digoxin immune Fab (ovine) 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 (ovine), the diagnosis of digitalis toxicity should be questioned.

Dosage Calculation: Acute Ingestion of Known Amount: Each vial of Digibind contains 38 mg of purified digoxin-specific Fab fragments which will bind approximately 0.5 mg of digoxin (or digitoxin). Thus, one can calculate the total number of vials required by dividing the total digitalis body load in mg by 0.5 mg/vial (see Formula 1).

For toxicity from an acute ingestion, total body load in mg will be approximately equal to the amount ingested in mg multiplied by 0.80 (to account for incomplete absorption) for digoxin tablets. For digitoxin, the total body load will be approximately equal to the amount ingested in mg.

Administration: Digoxin immune Fab (ovine) is administered by the i.v. route over 30 minutes. It is recommended that it be infused through a 0.22 micron membrane filter to ensure no undissolved particulate matter is administered. If cardiac arrest is imminent, it can be given as a bolus injection.

Reconstituted Solutions: The contents in each vial should be dissolved with 4 mL of Sterile Water for Injection, by gentle mixing, to give clear, colorless, approximately isosmotic solution with a protein concentration of 9.5 mg/mL. Reconstituted product should be used promptly. If it is not used immediately, it may be stored under refrigeration at 2 to 8°C for up to 4 hours. The reconstituted product may be diluted with sterile isotonic saline to a convenient volume. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Availability And Storage: Each vial of sterile, lyophilized powder for injection contains: digoxin-specific Fab fragments 38 mg, sorbitol 75 mg as a stabilizer and sodium chloride 28 mg. Preservative-free. Each vial will bind approximately 0.5 mg digoxin (or digitoxin). Refrigerate at 2 to 8°C. Unreconstituted vials can be stored at up to 30°C for a total of 30 days.

DIGIBIND® Glaxo Wellcome Digoxin Immune Fab (Ovine) Specific Antibody for Digoxin

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