Digibind

Allergic reactions to DIGIBIND (digoxin immune fab) 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 re-activation of (sodium, potassium) ATPase (see Laboratory Tests). Patients with atrial fibrillation may develop a rapid ventricular response from withdrawal of the effects of digitalis on the atrioventricular node.4

Follow your doctor's instructions about any restrictions on food, beverages, or activity after you are treated with digoxin immune FAB.

After intravenous 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.1 In humans with normal renal function, the half-life appears to be 15 to 20 hours.2 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 the plasma volume.1 Ordinarily, following administration of Digibind, improvement in signs and symptoms of digitalis intoxication begins within one-half hour or less.2,3,4,5

The affinity of Digibind for digoxin is in the range of 109 to 1011 M-1, which is greater than the affinity of digoxin for (sodium, potassium) ATPase, the presumed receptor for its toxic effects. The affinity of Digibind for digitoxin is about 108 to 109 M-1.

Digibind 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.

There are no known contraindications to the use of Digibind.

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. 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 Digibind. 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 Digibind. 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 Digibind. Since allergy testing can delay urgently needed therapy, it is not routinely required before treatment of life-threatening digitalis toxicity with Digibind.

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 mcg/mL).
2. Injecting 0.1 mL of the 1:100 dilution (9.5 mcg) 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 one drop of a 1:100 dilution of Digibind on the skin and then making a ¼-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 of Digibind 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.

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:

* 0.25 mg tablets with 80% bioavailability or 0.2 mg LANOXICAPS® Capsules with 100% bioavailability.

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:

V = vials

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)

*Dilution of reconstituted vial to 1 mg/mL may be desirable.

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.

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.

Refrigerate at 2° to 8°C (36° to 46°F). Unreconstituted vials can be stored at up to 30°C (86°F) for a total of 30 days.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.