Digoxin Immune Fab (Ovine)

• Monovalent, digoxin-specific antigen binding fragments (Fab) derived from antidigoxin antibodies1 2 3 4 5 7 8 9 10 20 51 80 obtained from serum of immunized sheep (ovine).1 2 3 4 8 9 10 20 68 80

• Binds to free (unbound) digoxin intravascularly and in extracellular fluid;1 2 5 6 11 12 17 20 29 51 63 70 71 prevents and reverses pharmacologic and toxic effects of digoxin, including biochemical and cardiac effects.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 80

• Reverses toxicity induced by digitoxin (no longer commercially available in US). 1 3 13 14 15 16 18 19 20 80

• Binds to other digoxin derivatives (e.g., β-methyldigoxin, β-acetyldigoxin),31 32 some of the cardioactive metabolites of digoxin,7 and possibly some other cardiac glycosides (e.g., lanatoside C).49

• 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

DIGIBIND, Digoxin Immune Fab (Ovine), is indicated for treatment of potentially life-threatening digoxin intoxication. 3 Although designed specifically to treat life-threatening digoxin overdose, it has also been used successfully to treat life-threatening digitoxin overdose. 3 Since human experience is limited and the consequences of repeated exposures are unknown, DIGIBIND 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, therapy with DIGIBIND is indicated.

There are no known contraindications to the use of DIGIBIND.

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 DIGIBIND, the serum potassium concentration may drop rapidly 2 and must be monitored frequently, especially over the first several hours after DIGIBIND 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 DIGIBIND. 4 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 intravenous 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:   DIGIBIND will interfere with digitalis immunoassay measurements. 6 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 administration of DIGIBIND 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 DIGIBIND. The total serum digoxin concentration may rise precipitously following administration of DIGIBIND, 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 a total body deficit of potassium. When the effect of digitalis is reversed by DIGIBIND, potassium shifts back inside the cell, with a resulting decline in serum potassium concentration. 4 Hypokalemia may thus develop rapidly. For these reasons, serum potassium concentration should be monitored repeatedly, especially over the first several hours after DIGIBIND 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:   Pregnancy Category C. Animal reproduction studies have not been conducted with DIGIBIND. It is also not known whether DIGIBIND can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DIGIBIND should be given to a pregnant woman only if clearly needed.

Nursing Mothers:   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 DIGIBIND is administered to a nursing woman.

Pediatric Use:   DIGIBIND 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 risk involved.

Geriatric Use:   Of the 150 subjects in an open-label study of DIGIBIND, 42% were 65 and over, while 21% were 75 and over. In a post-marketing surveillance study that enrolled 717 adults, 84% were 60 and over, and 60% were 70 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

The kidney excretes the Fab fragment-digoxin complex, and the risk of digoxin release with recurrence of toxicity is potentially increased when excretion of the complex is slowed by renal failure. However, recurrence of toxicity was reported for only 2.8% of patients in the surveillance study and the only factor associated with recurrence of toxicity was inadequacy of initial dose--not renal function. Calculation of dose is the same for patients of all ages and for patients with normal and impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function and to observe for possible recurrence of toxicity.

General Guidelines:   The dosage of DIGIBIND varies according to the amount of digoxin (or 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) of DIGIBIND is adequate to treat most life-threatening ingestions in both adults and children. However, in children it is important to monitor for volume overload. In general, a large dose of DIGIBIND has a faster onset of effect but may enhance the possibility of a febrile reaction. The physician may consider administering 10 vials, observing the patient's response, and following with an additional 10 vials if clinically indicated.

Dosage for Toxicity During Chronic Therapy:   For adults, six 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 DIGIBIND 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 DIGIBIND, 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 DIGIBIND at a dose guided by clinical judgment may be required.
• Failure to respond to DIGIBIND raises the possibility that the clinical problem is not caused by digitalis intoxication. If there is no response to an adequate dose of DIGIBIND, 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 milligrams will be approximately equal to the amount ingested in milligrams for digoxin capsules and digitoxin, or the amount ingested in milligrams multiplied by 0.80 (to account for incomplete absorption) for digoxin tablets.

Table 1 gives dosage estimates in number of vials for adults and children who have ingested a single large dose of digoxin and for whom the approximate number of tablets or capsules is known. The dose of DIGIBIND (in number of vials) represented in Table 1 can be approximated using the following formula:

Calculations Based on Steady-State Serum Digoxin Concentrations: Table 2 gives dosage estimates in number of vials for adult patients for whom a steady-state serum digoxin concentration is known. The dose of DIGIBIND (in number of vials) represented in Table 2 can be approximated using the following formula:

Table 3 gives dosage estimates in milligrams for infants and small children based on the steady-state serum digoxin concentration. The dose of DIGIBIND represented in Table 3 can be estimated by multiplying the dose (in number of vials) calculated from Formula 2 by the amount of DIGIBIND contained in a vial (38 mg/vial) (see Formula 3). Since infants and small children can have much smaller dosage requirements, it is recommended that the 38-mg vial be reconstituted as directed and administered with a tuberculin syringe. For very small doses, a reconstituted vial can be diluted with 34 mL of sterile isotonic saline to achieve a concentration of 1 mg/mL.

Formula 3

Dose (in mg) = (Dose [in # of vials]) (38 mg/vial)

Calculation Based on Steady-State Digitoxin Concentration:   The dose of DIGIBIND for digitoxin toxicity can be approximated using the following formula:

If the dose based on ingested amount differs substantially from that calculated from the serum digoxin or digitoxin concentration, it may be preferable to use the higher dose.

ADMINISTRATION:   The contents in each vial to be used should be dissolved with 4 mL of Sterile Water for Injection, by gentle mixing, to give a 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 (36° to 46°F) 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.

DIGIBIND, Digoxin Immune Fab (Ovine), is administered by the intravenous 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.

1. Smith TW, Lloyd BL, Spicer N, Haber E. 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.
2. Smith TW, Haber E, Yeatman L, Butler VP Jr. Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med. 1976; 294:797-800.
3. Smith TW, Butler VP Jr, Haber E, Fozzard H, Marcus FI, Bremner WF, Schulman IC, Phillips A. Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: Experience in 26 cases. N Engl J Med. 1982; 307:1357-1362.
4. Wenger TL, Butler VP Jr, Haber E, Smith TW. Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments. J Am Coll Cardiol. 1985; 5:118A-123A.
5. Spiegel A, Marchlinski FE. Time course for reversal of digoxin toxicity with digoxin-specific antibody fragments. Am Heart J. 1985; 109:1397-1399.
6. Gibb I, Adams PC, Parnham AJ, Jennings K. Plasma digoxin: Assay anomalies in Fab-treated patients. Br J Clin Pharmacol. 1983; 16:445-447.

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