Digoxin Immune Fab (Ovine Systemic)


VA CLASSIFICATION
Primary: AD900

Commonly used brand name(s): Digibind.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidote, to digitalis glycoside toxicity—

Indications

Accepted

Toxicity, digitalis glycoside (treatment)—Digoxin immune Fab (ovine) is indicated for treatment of potentially life-threatening digoxin or digitoxin overdose (i.e., with severe arrhythmias or hyperkalemia). {01} {02} {06} {07} {08} {09} {11} {12} {17} {20} {22} {25}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Produced by a process involving immunization of sheep with digoxin that has been coupled as a hapten to human serum albumin, to stimulate production of digoxin-specific antibodies. After papain digestion of the antibody, digoxin-specific antigen binding (Fab) fragments (molecular weight 46,200 {16} {22} daltons) are isolated and purified by affinity chromatography {01} {06} {08} {10} {11} {15} {17}.
Molecular weight—
    46,200 {16} {22}

Mechanism of action/Effect:

Preferentially binds molecules of digoxin or digitoxin, and the complex is then excreted by the kidneys. As free serum digoxin is removed, tissue-bound digoxin is also released into the serum to maintain the equilibrium and is bound and removed by digoxin immune Fab. The net result is a reduction in serum and tissue digoxin {01} {06} {15}.

Half-life:

15 to 20 hours {01} {07} {15}.

Onset of action:

Reduction of free active serum digoxin or digitoxin—Less than 1 minute {06} {07} {14} {15} {16} {18}.

Improvement in signs and symptoms of digitalis toxicity—15 to 30 minutes after administration {01} {02} {05} {07} {10} {11} {15} {18} (reversal of inotropic effect is usually slower than reversal of arrhythmias and hyperkalemia and may take several hours {01} {11}).

Elimination:
    Renal {01} {06} {07} {10} {11}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to sheep or any product of ovine origin may be sensitive to digoxin immune Fab (ovine) also {01}.

Carcinogenicity

Studies have not been done in either animals or humans. {01} {20} {22}

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans. {01}

Studies have not been done in animals.

FDA Pregnancy Category C. {22}

Breast-feeding

It is not known whether digoxin immune Fab (ovine) passes into breast milk. {22} Problems in humans have not been documented. {01}

Pediatrics

Studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of digoxin immune Fab (ovine) in children. {22} {24}


Geriatrics


No information is available on the relationship of age to the effects of digoxin immune Fab (ovine) in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving this medication.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Digitalis concentration determinations by immunoassay    (may be interfered with {01} {07} {11} {13} {15} {22})

With physiology/laboratory test values
Digoxin or digitoxin concentrations, serum    (free active concentrations rapidly fall to undetectable levels {06} {07} {14} {15} {16} {18})

    (total serum concentrations rise suddenly after administration of Fab antibody but are almost totally bound to the Fab fragment and are inactive {01} {06} {10} {14} {15} {16} {18}; these concentrations decline to undetectable levels several days later as Fab-digoxin complexes are excreted {10} {14} {15} {16} {18})


Potassium concentrations, serum    (may decrease rapidly from high concentrations associated with digitalis toxicity {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Allergy, history of    (risk of allergic reaction to Fab antibody may be increased {19})


Renal function impairment    (elimination of Fab-digoxin complexes may be delayed since the complex is eliminated renally {01} {19}. In patients who are functionally anephric, glomerular filtration and renal excretion would not be expected to occur; instead, the complex may be eliminated by the reticuloendothelial system; because it is not clear whether reintoxication would result, prolonged monitoring for digitalis toxicity is recommended in these patients {21})


» Sensitivity to digoxin immune Fab (ovine){01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Body temperature and
Electrocardiogram (ECG)    (monitoring recommended during treatment {01} {22})


» Digoxin or digitoxin concentrations, serum    (recommended prior to administration of Fab antibody to aid in dosage calculation {01} {22}, but not useful for at least {19} 5 to 7 days after Fab antibody treatment is begun because of interference by the antibody with the test {11} {13} {15})


» Potassium concentrations, serum    (recommended at frequent intervals during treatment; hypokalemia should be treated promptly {01} {22})




Side/Adverse Effects
Allergic or febrile reactions to digoxin immune Fab (ovine) have been reported rarely. Patients previously treated with the product or allergic to ovine proteins appear to be especially at risk {01} {02} {03} {21}.

Side/adverse effects are related more to withdrawal of digitalis effects than to a direct effect of the antibody fragment {01} {11}. Low cardiac output, including congestive heart failure, may be exacerbated as a result of withdrawal of the inotropic effects of digitalis {01} {07} {11} {15} {17}. Ventricular rate may increase as a result of withdrawal of digitalis being used for atrial fibrillation {07} {11}. Hypokalemia may occur as elevated serum potassium concentrations fall rapidly.



General Dosing Information
It is recommended that equipment and medications necessary for cardiopulmonary resuscitation be immediately available during administration of digoxin immune Fab (ovine). If necessary, in patients who respond poorly to withdrawal of digoxin's inotropic effect, other intravenous inotropes such as dopamine or dobutamine or cardiac load–reducing agents may be used. Caution is necessary in use of catecholamines because of the risk of aggravation of digitalis toxicity–associated arrhythmias. {01}
Skin-testing for allergy to digoxin immune Fab (ovine) may be performed prior to administration in high-risk patients (i.e., those previously treated with the Fab antibody or with known allergy, especially to sheep proteins). One of two methods may be used {01} {22}:

   • Intradermal test: Dilute 0.1 mL of the reconstituted solution (containing 9.5 mg of the Fab antibody per mL) in 9.9 mL of 0.9% sodium chloride injection to produce 10 mL of a solution containing 95 mcg (0.095 mg) per mL; then inject 0.1 mL (9.5 mcg or 0.0095 mg) intradermally. {22} After 20 minutes, inspect the injection site for presence of an urticarial wheal surrounded by a zone of erythema. {22}
   • Scratch test: Dilute 0.1 mL of the reconstituted solution (containing 9.5 mg of the Fab antibody per mL) in 9.9 mL of 0.9% sodium chloride injection to produce 10 mL of a solution containing 95 mcg (0.095 mg) per mL; {22} then place 1 drop of the solution on the skin and make a 1/4-inch scratch through the drop with a sterile needle. After 20 minutes, inspect the site for presence of an urticarial wheal surrounded by a zone of erythema. {22}If a positive skin test occurs, use of digoxin immune Fab (ovine) should be avoided unless absolutely necessary.If a systemic reaction occurs, measures to treat anaphylaxis should be used.
After reconstitution, digoxin immune Fab (ovine) is administered by intravenous infusion, through a 0.22-micron membrane filter, over 30 minutes {01} {07} {14} {15} {17} {22}. However, it may be given by rapid direct intravenous injection if cardiac arrest is imminent {01} {07} {22}.

Redigitalization of the patient, if necessary, should be delayed until elimination of Fab fragments from the body is complete, usually after several days but may be up to a week or longer in patients with renal function impairment {01}.


Parenteral Dosage Forms

DIGOXIN IMMUNE FAB(OVINE)FOR INJECTION

Usual adult and adolescent dose
Antidote, to digitalis glycoside toxicity
Intravenous, in an amount equimolar to the amount of digoxin or digitoxin in the patient"s body (total body load [TBL]) {01} {15} {17}. A dose of 38 mg of digoxin immune Fab (ovine) binds approximately 0.5 mg of digoxin or digitoxin {16} {22}.
Dosage may be calculated using one of the following formulas:


1) Based on dose of digoxin or digitoxin ingested:


For digoxin tablets, oral solution, or intramuscular injection—
Dose (mg) = (Dose ingested [mg] × 0.8)/0.5 × 38



For digitoxin tablets, digoxin capsules, or intravenous injection of digoxin or digitoxin—
Dose (mg) = [Dose ingested (mg)/0.5] × 38

Approximate dose of digoxin immune Fab (ovine) when amount of digoxin ingested is known.


Number of digoxin tablets or capsules ingested *
Dose of digoxin immune Fab (ovine)
mg
Number of 38-mg vials
25
380
10
50
760
20
75
1140
30
100
1520
40
150
2280
60
200
3040
80
*  0.25-mg tablets with 80% bioavailability, or 0.2-mg capsules.




2) Based on steady-state serum digoxin or digitoxin concentration (SDC) :


For digoxin—
Dose (mg) = (SDC [nanograms/mL] × body weight [kg])/100 × 38



For digitoxin—
Dose (mg) = (SDC [nanograms/mL] × body weight [kg])/1000 × 38

Table 2. Approximate adult and adolescent dose (number of 38-mg vials) of digoxin immune Fab (ovine) when serum digoxin concentration (SDC) is known.


SDC
(ng/mL)
Patient weight (kg)
40
60
70
80
100
1
0.5
0.5
1
1
1
2
1
1
2
2
2
4
2
3
3
3
4
8
3
5
6
7
8
12
5
7
9
10
12
16
7
10
11
13
16
20
8
12
14
16
20




Note: Dosage of digoxin immune Fab (ovine) is approximate, since total body digitalis load can be difficult to estimate. After the initial dose, need for and amount of additional dosing should be determined using clinical judgment. {01}
If neither an estimated ingestion amount of digitalis nor the SDC is available, 760 mg of digoxin immune Fab (ovine) may be administered, which will be adequate to treat most life-threatening ingestions {22}.


Usual pediatric dose
See Usual adult and adolescent dose (including Note).

Note: In small children, monitoring for volume overload is important. {01}
For infants, who can have much smaller dosage requirements, it is recommended that digoxin immune Fab (ovine) be reconstituted as directed and administered with a tuberculin syringe. For very small doses, a reconstituted 38-mg vial can be diluted with 34 mL of 0.9% sodium chloride injection to produce a solution containing 1 mg per mL. {22}
For approximate dose when amount of digoxin ingested is known, see Usual adult and adolescent doseTable 1.


Table 3. Approximate pediatric dose (mg) of digoxin immune Fab (ovine) when serum digoxin concentration (SDC) is known.


SDC
(ng/mL)
Patient weight (kg)
1
3
5
10
20
1
0.4
1
2
4
8
2
1
2
4
8
15
4
1.5
5
8
15
30
8
3
9
15
30
61
12
5
14
23
46
91
16
6
18
30
61
122
20
8
23
38
76
152

Size(s) usually available:
U.S.—


38 mg (Rx) [Digibind (preservative-free)]

Canada—


38 mg (Rx) [Digibind (preservative-free)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Unreconstituted vials may be stored at up to 30 °C (86 °F) for up to 30 days. {16} {22}

Preparation of dosage form:
Digoxin immune Fab (ovine) for injection is reconstituted for intravenous administration by dissolving 38 mg in 4 mL of sterile water for injection and mixing gently, to produce a solution containing 9.5 mg per mL. The resulting solution may be further diluted with 0.9% sodium chloride injection to a convenient volume for administration by intravenous infusion. {01}

Stability:
Reconstituted solution should be used immediately, but may be stored for up to 4 hours between 2 and 8 °C (36 and 46 °F). {01}



Revised: 08/17/1995



References
  1. Digibind package insert (Burroughs Wellcome—US), Rec 4/86.
  1. Proudfoot AT. A star treatment for digoxin overdose? Br Med J 1986 Sep 13; 293: 642-3.
  1. Smolarz A, Roesch E, Lenz E, Neubert H, Abshagen P. Digoxin specific antibody (Fab) fragments in 34 cases of severe digitalis intoxication. J Toxicol Clin Toxicol 1985; 23: 327-40.
  1. Hess T, Riesen W, Scholtysik G, Stucki P. Digitoxin intoxication with severe thrombocytopenia: reversal by digoxin-specific antibodies. Eur J Clin Invest 1983; 13: 159-63.
  1. Spiegel A, Marchlinski FE. Time course for reversal of digoxin toxicity with digoxin-specific antibody fragments. Am Heart J 1985; 109: 1397-9.
  1. Cole PL, Smith TW. Use of digoxin-specific Fab fragments in the treatment of digitalis intoxication. Drug Intell Clin Pharm 1986 Apr; 20: 267-70.
  1. Digoxin antibody fragments for digitalis toxicity. Med Lett Drugs Ther 1986 Sep 12; 28: 87-8.
  1. Smith TW. New advances in the assessment and treatment of digitalis toxicity. J Clin Pharmacol 1985 Oct; 25: 522-8.
  1. Stolshek BS, Osterhout SK, Dunham G. The role of digoxin-specific antibodies in the treatment of digitalis poisoning. Med Toxicol 1988; 3: 167-71.
  1. Leikin J, Vogel S, Graff J, et al. Use of Fab fragments of digoxin-specific antibodies in the therapy of massive digoxin poisoning. Ann Emerg Med 1985 Feb; 14: 175-8.
  1. Butler VP, Smith TW. Immunologic treatment of digitalis toxicity: a tale of two prophecies [editorial]. Ann Intern Med 1986 Oct; 105: 613-4.
  1. Nicholls DP, Murtagh JG, Holt DW. Use of amiodarone and digoxin specific Fab antibodies in digoxin overdosage. Br Heart J 1985 Apr; 53: 462-4.
  1. Gibb I, Parnham A. A star treatment for digoxin overdose? [letter] Br Med J 1986 Nov 1; 293: 1171-2.
  1. Rossi R, Leititis JU, Hagel KJ, Smolarz A, Brandis M. Severe digoxin intoxication in a child treated by infusion of digoxin-specific Fab-antibody-fragments. Eur J Pediatr 1984 Jun; 142: 138.
  1. Wenger TL, Butler VP, Haber E, Smith TW. Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments. J Am Coll Cardiol 1985; 5(Suppl A): 118A-123A.
  1. Digibind package insert (Burroughs Wellcome—Canada), Rev 12/94, Rec 4/95.
  1. Smith TW, Butler VP, Haber E, et al. Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases. N Engl J Med 1982; 307(22): 1357-62.
  1. Zucker AR, Lacina SJ, DasGupta DS, et al. Fab fragments of digoxin-specific antibodies used to reverse ventricular fibrillation induced by digoxin ingestion in a child. Pediatrics 1982; 70(3): 468-71.
  1. Manufacturer comment, 3/5/87.
  1. Digibind package insert (Burroughs Wellcome—US), Rev 8/90, Rec 6/92.
  1. Digibind product information. In: PDR Physicians' desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 769.
  1. Digibind package insert (Burroughs Wellcome—US), Rev 5/94, Rec 1/95.
  1. Antman EM, Wenger TL, Butler VP, Haber E, Smith TW. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Circulation 1990; 81: 1744-52.
  1. Woolf AD, Wenger T, Smith TW, Lovejoy FH. The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. N Engl J Med 1992; 326: 1739-44.
  1. Hickey AR, Wenger TL, Carpenter V, et al. Digoxin immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational study. J Am Coll Cardiol 1991; 17: 590-8.
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