Dosing regimen for digoxin-specific antibody (Fab) fragments in patients with digoxin toxicity

INTRODUCTION — Digoxin-specific antibody (Fab) fragments are the definitive treatment for patients with severe digitalis poisoning.

Prior to the advent of digoxin-specific antibodies, treatment for cardiac glycoside toxicity was largely supportive [1]. In 1976, antibody fragments were first used successfully to treat patients [2]. These antibodies are highly effective, safe, and widely used in clinical practice [3].

The dosing of Fab fragments based upon different clinical scenarios is discussed here. The indications for treatment with Fab fragments, the diagnosis and general management of digitalis poisoning, and the clinical use of digitalis are all reviewed separately.

●(See "Digitalis (cardiac glycoside) poisoning", section on 'Antidotal therapy with antibody (Fab) fragments'.)

●(See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".)

●(See "Treatment with digoxin: Initial dosing, monitoring, and dose modification".)

●(See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.)

WHAT ARE FAB FRAGMENTS? — Fab fragments are purified preparations consisting of the Fab portion of IgG anti-digoxin antibodies derived from immunized sheep. These fragments bind free digoxin, thereby forming digoxin-immune fragment complexes. As the level of free digoxin in plasma falls, the resulting concentration gradient facilitates dissociation of digoxin from the sodium-potassium ATPase. Digoxin-immune fragment complexes are renally excreted. Because of the large size of both digoxin and the digoxin-immune complex, neither is effectively cleared by hemodialysis.

KINETICS AND ADVERSE EFFECTS OF FAB FRAGMENTS — Fab fragments are commercially available as DigiFab [4]. Each vial of DigiFab contains 40 mg of Fab fragments and binds approximately 0.5 mg of digoxin. DigiFab has an elimination half-life of approximately 15 to 20 hours. However, the half-life may be up to 10 times longer with renal impairment. The volume of distribution for DigiFab is 0.3 L/kg.

Hypersensitivity reactions are the primary adverse effects of DigiFab. Although uncommon, patients with known allergies to sheep or sensitivity to papain or other papaya extracts used to cleave the antibody are at highest risk.

Use of DigiFab may result in complete reversal of cardiac glycoside effects, precipitating an acute congestive heart failure exacerbation or loss of rate control in patients with atrial fibrillation.

CALCULATING THE DOSE — The dose of DigiFab is determined by different methods depending on the clinical scenario and information available. The indications for treatment with DigiFab are described separately. (See "Digitalis (cardiac glycoside) poisoning", section on 'Antidotal therapy with antibody (Fab) fragments'.)

Neither the digoxin level nor amount ingested is known — Treatment in cases of severe toxicity when the amount of digoxin ingested is unknown consists of empiric Fab fragment dosing. Our approach depends upon whether or not cardiac arrest appears imminent.

●Patient with relative hemodynamic stability – Most patients with digoxin poisoning are relatively stable, and arrest is not imminent. In such patients, we administer two vials of Fab fragments over 30 minutes [5,6]. If clinical response is inadequate (ie, a perfusing rhythm has not returned), then an additional one to two vials are administered.

●Patient in cardiac arrest or cardiac arrest appears imminent – The traditional empiric dosing strategy of 10 vials of Fab fragments in adults or five vials in children administered by slow intravenous (IV) push is reasonable [4]. The initial dose can be repeated if there is inadequate clinical response (although at this time, it is reasonable to reconsider the diagnosis of digoxin toxicity). When empiric dosing is required in very small children, concern for volume overload must be considered.

Amount of digoxin ingested is known but concentration is unknown — The number of Fab fragment vials to give the patient with an acute overdose, when only the amount ingested is known, is based upon the total body load (TBL):

●Step 1 – Calculate the TBL:

(The value 0.8 reflects the bioavailability of digoxin)

The number of vials should be rounded up to the nearest whole number. As an example, if the TBL is determined to be 3.125 mg, the number of vials is 3.125/0.5 = 6.25, which is rounded up to 7 vials.

Steady state digoxin concentration is known — The number of Fab fragment vials needed for treatment (ie, full reversal of digoxin effects) when the concentration is known is calculated based upon the drug concentration and the patient's weight:

The number of vials should be rounded up to the nearest whole number. As an example, if a patient has a digoxin level of 4.4 ng/mL and weighs 65 kg, the number of vials would be (4.4 x 65)/100 = 2.86, which is rounded up to 3 vials. This formula provides an accurate and quick estimate of the antidote needed for treatment and is derived from a more complex pharmacokinetic calculation [4].

Partial reversal of digoxin effects can be accomplished by providing half the calculated number of vials using the equation above. This approach is reasonable when concerned that full reversal may precipitate an acute congestive heart failure exacerbation or loss of rate control in atrial fibrillation (eg, patient with baseline reduced ejection fraction).

Note that the formula for calculating the number of Fab fragment vials needed based upon the serum concentration of digitoxin (which remains in use outside the United States) is not the same as that used for digoxin.

Cardiac glycoside poisoning other than digoxin or digitoxin — Quantitative serum levels obtained in poisonings from cardiac glycosides other than digoxin or digitoxin do not correlate with measurements of these drugs and cannot be used to calculate the Fab fragment dose. Therefore, empiric treatment is provided as if neither the amount ingested nor the concentration was known (10 vials initially). These are starting doses; higher doses may be needed if clinical response is inadequate.

HOW TO ADMINISTER THE DRUG

Basic guidelines — Fab fragments should be given over 30 minutes in all patients except those in cardiac arrest or in whom arrest is imminent. In such patients, the Fab fragments can be given as a slow intravenous (IV) push. It is important to emphasize that after Fab fragments are administered, total serum digoxin concentrations will be unreliable; only free or unbound digoxin levels will be clinically useful.

Chronic toxicity without severe signs — In individuals with chronic toxicity who do not manifest immediately life-threatening dysrhythmias (eg, atrioventricular [AV] nodal blockade present on electrocardiogram [ECG] but patient maintains normal blood pressure and clear mentation), half the recommended dose can be given initially in order to avoid unmasking the condition for which the patient is taking digoxin. Giving a full dose can elicit acute decompensated heart failure or atrial fibrillation with rapid ventricular response.

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment".)

SUMMARY AND RECOMMENDATIONS

●Mechanism of action – Digoxin-specific antibody (Fab) fragments consist of the Fab portion of IgG anti-digoxin antibodies. These fragments bind free digoxin, thereby forming digoxin-immune fragment complexes. As the level of free digoxin in plasma falls, the resulting concentration gradient facilitates dissociation of digoxin from the sodium-potassium ATPase. Fab fragment complexes are renally excreted. (See 'What are Fab fragments?' above.)

●Dosing regimens – The dosing of Fab fragments is based upon the clinical scenario, including whether the amount of digoxin ingested or the serum digoxin concentration is known. (See 'Calculating the dose' above and 'How to administer the drug' above.)

•Known steady state digoxin concentration (see 'Steady state digoxin concentration is known' above):

-Partial reversal of digoxin effects: Half the number of vials calculated from the full reversal of digoxin effects formula above

•Neither digoxin concentration nor amount ingested is known (see 'Neither the digoxin level nor amount ingested is known' above):

-In patients with relative hemodynamic stability, we administer two vials of Fab fragments, each over 30 minutes, and repeat based on clinical response.

-In patients in cardiac arrest or if cardiac arrest appears imminent, we administer, by slow intravenous (IV) push, 10 vials of Fab fragments in adults or five vials in children. The initial dose can be repeated if there is inadequate clinical response.

•Ingested digoxin amount is known but concentration unknown: Number of vials (rounded up to whole number) = Dose (in mg) ingested x 1.6 (see 'Amount of digoxin ingested is known but concentration is unknown' above)