Status: approved; marketed

Organizations involved:

Wellcome Foundation, Ltd. – Manuf.; R&D; Tech.

GlaxoSmithKline Inc. – USA mark.

GlaxoSmithKline plc – Intl. mark.; Parent co.

Cross ref: See the entries for Antivenin Products (#747) and; Digoxin Immune Fab (Ovine) from Protherics, Inc. (#914)

Description: Digibind is a lyophilized (freeze-dried) formulation of digoxin-binding ovine (sheep) immune globulin (antibody) Fab fragments enzymatically derived from pooled immune globulin containing antibodies from digoxin-immunized sheep. The Fab antibody fragments have a molecular weight of about 46.2 kDa.

Digibind, like DigiFab (see entry below), is used for treatment (as an antidote) for digitalis (and digoxin) overdosage (poisoning). The Fab fragments in Digibind bind digitalis/digoxin molecules, making them unavailable for binding at their site of action on cells in the body. The complexes accumulate in the blood and are excreted by the kidneys. The net effect is to shift the equilibrium away from binding of digoxin to its receptors in the body, reversing the drug’s toxic effects.

Each vial contains 38 mg of digoxin-specific ovine Fab fragments sufficient to bind 0.5 mg of digoxin (or digitoxin). Dosage (number of vials) can be determined by dividing the total digitalis body load (dosage in mg) by 0.5 mg/vial. The product is stored at 2-8˚C (refrigerated). The dating period is three years from date of manufacture, defined as the date of the last potency assay, providing the assay is performed within 90 days of sterile filtration.

Biological.: See the DigiFab entry (#914) below for background about digitalis/digoxin poisoning.

Nomenclature: Digoxin Immune Globulin, ovine Fab/GSK [BIO]; Digibind [TR]; Digoxin Immune Fab (Ovine) [FDA]; ovine digoxin-specific antibody Fab fragments [SY]; NDC 0173-0230-44 [NDC]

Companies.: Digibind is manufactured by The Wellcome Foundation Ltd., GlaxoSmithKline Ltd. (Dartford, Kent, U.K.), FDA biologics est. no. 0129. [Note, FDA still uses Wellcome Foundation Ltd, Wellcome Research Labs. as the manufacturer/establishment name, not reflecting the merger of Wellcome and Glaxo, nor the more recent merger of Glaxo Wellcome with SmithKline Beecham to form GlaxoSmithKline]. Digibind is marketed in the U.S. by GlaxoSmithKline Inc., and internationally by Glaxo SmithKline plc affiliates.

Manufacture: Sheep are immunized with a digoxin-albumin conjugate (digoxin conjugated to human serum albumin as a hapten to boost immune responses to the digoxin moiety). Blood is collected and centrifuged. The immune globulin (antibodies) from the sheep plasma is digested with papain. This enzyme derived from papaya cleaves whole immune globulin antibodies into Fab and Fc (antigenic constant or framework region) fragments. Digoxin-specific Fab fragments are purified by affinity chromatography, sterile filtered, filled, and lyophilized (freeze-dried). The original 1986 FDA Summary Basis of Approval (SBA) does not include mention of heat or other viral inactivation steps.

The final product is tested for total protein by biuret reaction (36-44 mg); pH (6.0-8.0); digoxin binding activity by RIA (480-720 µg digoxin bound/vial); anti-HSA (human serum albumin) activity by passive hemagglutination inhibition (NMT 5 µg bound/mg); state of aggregation by HPLC (NMT 10% protein above monomer); moisture by gravimetric method (NMT 1.5%); identity followed by anti-digoxin specific serological tests (positively identified); dissolution (NMT 2 min.); sorbitol by oxidation or chromatography (67.5-82.5 mg); sodium chloride (7.02-8.95 mg/ml); and sterility, general safety and pyrogenicity (according to 21 CFR 600).

FDA class: Biologic PLA

CBER class: Blood And Blood Derivatives

Approvals: Date = 19860422, PLA ref. no. 84-394/ELA ref. no. 84-393; orphan designation (expired 4/22/1993)

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:

Digoxin Immune Fab (Ovine) is indicated for the treatment of potentially life threatening digitalis intoxication. Although designed specifically to treat life-threatening digoxin overdose, it has also been used successfully to treat life-threatening digitoxin overdose. 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 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.

Trials: The pivotal open-label trial enrolled 63 patients with life-threatening digitalis poisoning. Serum digoxin levels in the patients ranged from 2.4 to >100 ng/ml with an average concentration of 14.1 ng/mL. The administered dose averaged 520 mg (range 4-1,600). Dosage was calculated to be equimolar with the estimated total body load of digoxin or digitoxin in the patient. Among 56 patients, 53 recovered within a mean time of four hours after administration of Digibind. Digibind reversed hyperkalemia in all patients with elevated serum potassium concentrations. Approval was also supported by several non-U.S. studies using Digoxin Immune Fab (Ovine) from other commercial sources (but not DigiFab, which came much later). These other products demonstrated responses and safety profiles similar to Digibind.

Medical: Prior to use, the contents of each Digibind vial is dissolved in 4 mL of Sterile Water for Injection, to yield a protein content of 9.5 mg/mL. The recommended dose is equimolar to the estimated amount of digoxin or digitoxin in the body. Digibind is usually administered by intravenous injection over 30 minutes, generally using a 0.22 µm membrane filter to ensure no undissolved particular matter is administered. If cardiac arrest is imminent, it can be given as a bolus injection.

Market: Protherics, which markets a competing product, DigiFab, reports that DigiBind holds one-third of the worldwide market (for digoxin/digitalis immune globulin products), with the total digitalis/digoxin poisoning market about $30 million. This indicates that the current market for DigiBind is on the order of $10 million/year.

The 2007 Average Wholesale Price (AWP) is $727.91/vial (no change from 2004) (Red Book, 2007).