Before the advent of digoxin immune fab (DIF), supportive interventions were the mainstay for treating cardiac glycoside toxicity. In 1976, Smith et al. reported the first use of these antibody fragments and were made commercially available by 1986.[1] Due to its high effectiveness, they are now the mainstay for treating severe life-threatening digoxin toxicity or overdose.[2] However, recommendations do not include non-life-threatening cardiac glycoside intoxications.

Current FDA Approved Indications :

• Chronic ingestion of digoxin leading to a steady-state concentration of >4 ng/mL in children or >6 ng/mL in adults. 

• Acute ingestion of a fatal digoxin dose - this includes accidental or suicidal consumption of >10 mg in a healthy adult or >4 mg (>0.1 mg/kg) in a healthy child.   

• Ingestion resulting in a steady serum concentration of 10 ng/mL or more acutely.

• Digoxin overdose resulting in life-threatening instances such as : 
  • Symptomatic and hemodynamically significant bradycardia
  • Asystole
  • Atropine non-responsive second or third-degree Atrioventricular heart block
  • Ventricular tachycardia
  • Ventricular fibrillation
  • Signs and symptoms of end-organ dysfunction
  • Serum potassium >5.5 mEq/L in adults.[3]
  • Serum potassium >6 mEq/L in children [3]      

• FDA labeled orphan drug, also beneficial for Pre-eclampsia and eclampsia.[4][5]

Non-FDA Approved Indications:

Several studies have yielded a comfortable degree of cross-reactivity between digoxin and other plant-derived cardiac glycosides.[6] This cross-reactivity forms the basis for administering digoxin immune fab in patients with poisoning from plants such as Acokanthera oblongifolia, Adonis microcarpa (pheasants eye), Asclepias physocarpa (balloon cotton bush), Bryophyllum tubiflorum (mother of millions), Calotropis procera (kings crown), Carissa laxiflora, Cerbera manghas (sea-mango), Cryptostegia grandiflora (rubber-vine), Nerium oleander, Thevetia peruviana (yellow oleander), Indian hemp and Cerbera odollam (pong-pong seeds).[6][7] Furthermore, they bind and inhibit the ability of toad venom to block sodium-potassium ATPases.[8] Therefore, in addition to supportive care and gastric decontamination, digoxin immune Fab can also be administered to reverse cardiotoxicity from toad venom.[8]

As per recent analysis in the United States, digoxin toxicity presents in 10-18% of nursing home individuals.[9] It also presents in 1.1% of outpatient and 0.4% of all hospitalized patients, respectively.[9] The past decade has seen an overall reduction in the use of digoxin as a treatment modality.[10][11] Research has shown a similar decline in the number of toxicity cases.[11] Primarily, DIF is an antidote for severe life-threatening. Therefore, to grasp its reversal effect, it is essential to appreciate digoxin's pharmacological mechanism and its toxicity. Digoxin, a potent cardiac glycoside, is indicated for the treatment of heart failure and atrial fibrillation. It shows affinity to bind and block the potassium ion subunit of the sodium/potassium ATPase pump in cardiac myocytes.[11] The pump functions to maintain a low concentration of sodium inside the myocyte normally. This blocking results in an increased concentration of sodium inside the myocyte cell. This increment of sodium hampers the ion exchange mechanism of other transporters located in the myocyte cell membrane. One such transporter, the sodium-calcium exchanger (NCX), helps maintain low intracellular calcium levels in exchange for pumping sodium inside. However, when administering digoxin, the elevated sodium concentration inside the myocyte decreases this exchange resulting in elevated calcium levels within the myocyte. The extra available calcium is actively reabsorbed and stored by the sarcoplasmic endoplasmic reticulum ATPase (SERCA). The resultant increase in overall calcium availability for cross-bridge formation between actin and myosin filaments ultimately leads to increased cardiac contractility (positive inotropic effect). Digoxin is also known to increase vagal tone in SA and AV nodes.[11] The overall effect is to increase refractoriness and decrease conduction velocity in specialized conductive cardiac tissue. During toxicity, the Na/K ATPase is inhibited to a greater degree resulting in increased automaticity and inotropy. Furthermore, there is decreased dromotropy due to excessive inhibition of the AV node as a result of increased vagal tone.

Digoxin immune fab (DIF) are mixed anti-digoxin immunoglobulin fragments obtained from healthy sheep immunized with digoxin dicarboxymethoxylamine (DDMA). DDMA contains a cyclo-Penta-per-hydro-phenanthrene: lactone ring coupled to keyhole hemocyanin. This ring is an essential component of the final product. After isolation of immunoglobulins from the ovine serum, these isolates undergo digestion by papain and a process of affinity chromatography, yielding digoxin specific IgG Fab fragments.[12]

DIF has an affinity for digoxin that ranges from 10^9 to 10^10 M-1. Its affinity is higher than the affinity of digoxin for the sodium pump receptor. This receptor is presumed responsible for its therapeutic and toxic effects. When administered to the intoxicated patient, DIF binds to digoxin molecules and reduces free digoxin levels. The reduction results in an equilibrium shift away from receptor binding and thereby decreases cardio-toxic effects. The kidney and the reticuloendothelial system eventually clear fab-digoxin complexes.[9]

Clinical studies have also indicated the clinical utility of digoxin immune fab in pre-eclampsia. Pre-eclampsia is an exaggerated inflammatory condition compounded by altered endothelial function.[5] It constitutes widespread activation of platelets and WBC followed by elevated levels of IL-γ, IL-6, and tumor necrosis factor-α (TNF-α).[5] Digoxin immune fab can also downregulate TNF-α induced endothelial surface adhesion molecules (ICAM, VCAM, and E-selectin).[5] Furthermore, DIF also reduces TNF-α mediated downregulation of Na/K pumps.[5] Maternal serum in pre-eclamptic females also contains elevated endogenous digoxin-like factors (EDLFs) such as cardenolide, ouabain, bufadienolide, and marinobufagenin.[4][5] These factors have also demonstrated the capacity to inhibit the mesenteric artery and erythrocyte Na/K ATPase activity.[5] Maternal hypertension in pre-eclampsia occurs when reduced Na/K pump activity contributes to the accumulation of intracellular calcium and thus systemic vasoconstriction. Therefore, digoxin immune fab can improve fetoplacental circulation and eclamptic/pre-eclamptic symptoms by restoring cellular Na/K ATPase activity.[5] It may also provide protective effects against TNF-α mediated endothelial cell dysfunction to offset the exaggerated inflammatory state.[5] 

Digoxin immune fab comes as a lyophilized powder for solution. Each vial is for single use only and contains 40 mg of digoxin immune Fab protein. It must be mixed with 4mL of sterile water (reconstitution/dilution) to produce a solution containing 10 mg/mL of DIF protein. If the solution is not used immediately, it can be refrigerated (2 to 8 degrees Celcius) for no more than 4 hours after its dilution. The diluted digoxin immune fab is added to 0.9% NaCl for use as an intravenous injection. The administration of the infusion should be for at least over thirty minutes. If infusion rate-related reactions occur, then infusion should be stopped and readministered at a slower rate. Bolus injections should be a consideration for patients with imminent cardiac arrest. Patients with chronic toxicity, with no immediate life-threatening presentations, initially receive an infusion of half the original dose, which prevents the unmasking of underlying co-morbid that required digoxin administration.

Pharmacokinetics of Digoxin Immune Fab

Multiple types of formulations are readily available for therapy. Using randomized control studies, researchers compared the pharmacokinetic properties of various anti-digoxin antibodies. Consistent across all, an equal decrease in serum-free digoxin levels were noted.[13] Measurement of total free digoxin levels before and after fab administration were also similar. These results indicate an equimolar binding affinity to digoxin.[13] Furthermore, digoxin excreted in urine was also similar, with greater than 40% of the dose excreted by 24 hours.[13] These findings indicate similar pharmacokinetic profiles.[13] Therapeutically, data has also indicated similar response rates in patients.[14][15] Digoxin immune fab has a larger volume of distribution (Vd) when compared to IgG. It spreads across the extracellular space with a volume of distribution (Vd) of 0.3 L/kg. In patients with normal renal function, it has a half-life of 12 to 20 hours. Upon fab administration, there is a 10- to 30-fold increase in the bound and free serum digoxin concentration within minutes. Digoxin-fab complexes are eliminated from the blood by renal excretion. This decreases free digoxin levels from 80% to from 0 to 5%. Urinary digoxin levels go undetectable within 5 to 7 days. Its renal clearance is estimated to be at 960 ng/mL (1.229 mmol/L). Hemodialysis and peritoneal dialysis do not help facilitate their excretion.

Dosage Considerations

As a rule of thumb, each vial is known to bind 0.5 mg of digoxin. The dose of digoxin immune fab needs to be adjusted depending on the amount of digoxin that requires neutralization. It is important to note that there is not much of a correlation between digoxin concentration and symptoms.[11] Once administered, levels of serum digoxin concentrations are unreliable, and only unbound digoxin levels are helpful in clinical estimation. The following guidelines m considered while calculating a required dosage:

• If the patient does not respond to treatment, the diagnosis of digoxin toxicity may be inaccurate and may indicate other clinical problems.

• The volume of distribution (Vd) varies in a given population. The dosage calculation takes into account the volume of distribution for digoxin (5 L/Kg).

• Digoxin assay kits only measure concentrations <5 ng/mL. This can lead to inaccurate estimation of the amount of digitalis ingested.

• More accurate assessments of digoxin (>5 ng/mL) are achievable via sample dilution.

• Re-administration due to retoxification requires measurement of unbound serum digoxin concentration.

• If the administered dose does not result in toxicity reversal, additional dose administration should be guided by clinical judgment.

Dosage Calculation Formulas :

• Formula 1: Dose (no. of vials)= total digoxin body load(mg) / 0.5 mg of digoxin bound per vial.[14]

• Formula 2: Dose= (serum digoxin concentration in ng/mL) x (weight in Kg)/100.[14]

• Formula 3: Dose (in mg)= (40 mg/vial) x ( (serum digoxin concentration in ng/mL) x (weight in Kg)/100).[14]

• Formula 4: Dose (no. of vials)= (serum digitoxin concentration in ng/mL) x (weight in kg)/1000.[14]

The number of vials required must be rounded off to the nearest whole number.

 Dosage and Treatment Based On Clinical Scenarios:

• For ingestion of known amount of digoxin: Following an acute overdose, if the amount of ingested digoxin is known and not the concentration, the number of vials needed can be calculated based on total body digoxin load (TBL). First, calculate the total body load by multiplying the dose of digoxin ingested (in mg) by 0.8 (bioavailability of digoxin). Next, using formula 1, calculate the number of vials required by dividing the total body load of digoxin by the amount of digoxin neutralized or bound per vial (0.5 mg per vial). 

• Known steady-state digoxin concentration: In such scenarios, the calculation is based on formula 2. The product of the patients' drug concentration and weight in kilograms is divided by 100. This formula is known to provide a quick estimate for the amount of antidote needed for treatment.

• Serum digoxin level and ingested amount both unknown: This situation should have treatment with empirically with ten vials of fab fragments. Ther ten vials can be repeated in the event of an inadequate clinical response is achieved. Small children can be treated empirically with five vials of fab fragments; the clinician can further add depending on the type of clinical response obtained. When treating small children (<20 Kg), volume overload should also merit consideration.

• Cardiac glycoside poisoning other than digoxin/digitoxin: In other cardiac glycoside poisonings, it is crucial to understand that the quantitative serum levels can not be correlated and therefore be used to calculate the dosage. Such cases need to be treated empirically with ten vials initially and added further depending on the clinical response achieved in 30 minutes.

• Cardiac arrest: Via rapid intravenous injections first administer ten vials. Monitor and repeat in 15 minutes PRN.

• Chronic intoxication due to therapy in adults (weight>20kg): Adults in acute distress or with unknown serum digoxin levels, 240 mg (6 vials) should correct toxicity. The dose can also be calculated using formula 2 (see above). 

• Chronic intoxication in children (weight<20kg): For small children weighing less than 20 kilograms, administration of a single vial (40mg IV) should suffice. The dosage in such cases can be calculated using formula 3. For infants or children, who require lower dosing, reconstitute the vial similarly and administer an undiluted solution. Very small doses can be achieved by further diluting the reconstituted vial with 36 mL of isotonic saline. 

The frequency of many adverse events remains undefined. Adverse effects can be categorized depending on severity. The following adverse effects have been documented with the use of digoxin immune fab:

Severe Adverse Effects:

• Rare allergic reactions in patients with a past medical history of asthma or other allergies.[16] Such events are rapid and include angioedema and anaphylactoid reactions

• Withdrawal of digoxins' negative dromotropic effect on the atrioventricular node worsens atrial fibrillation (7%). It can lead to re-development of rapid ventricular response (ventricular tachycardia), leading to a risk of compromising cardiac output compromised cardiac output.

• The worsening of underlying heart failure (13%), pulmonary edema, bilateral pleural effusion, and renal failure - this is due to the withdrawal of the inotropic effect of digoxin.

Moderate Adverse Effects:

• Hypokalemia (13%): Reversal of digoxin by digoxin immune fab leads to reactivation of sodium/potassium pumps. Therefore, a shift in potassium from extracellular space to the intracellular compartment can result in life-threatening hypokalemia. Furthermore, hypokalemia can present as confusion, increased thirst, and muscle weakness. It is also a common side effect of therapy.

• Moderate postural hypotension

• Phlebitis of the infusion vein

• Wheezing

• Hypotension

• Serum sickness

• Fever with the use of greater than ten vials

• Reports exist of the formation of antibodies to immune fab products in patients with prior fab treatment; this carries a risk of reduced efficacy of the drug.  

Mild Adverse Effects:

• Pruritis

• Rash

• Utricaria

• Injection site reaction such as erythema

(Note: Specific contraindications as yet remain undetermined)

Pregnancy and Lactation:

Fab products have been designated pregnancy category C by the FDA. This rating indicates that it should be used with caution and only if the benefit justifies the risks imposed on the fetus. It is not known if fab products can cause harm to the fetus or affect future reproductive ability. Due to a lack of human and animal studies, no clear data on their safety exists. Therefore, digoxin immune fab should only be administered in pregnancy only if needed.

Nursing Mothers:

Although not a contraindication, its excretion into milk is unknown. Many studies have revealed that drugs are actively secretable into milk. Caution is necessary when administering a nursing mother digoxin immune fab. However, the risk appears to be small because the immune fab fragments in ingested milk would undergo digestion in the infant's stomach. However, risk in infants cannot be ruled out.

Ovine Protein Hypersensitivity:

Digoxin immune fab is a sheep derived protein. The immunoglobulin fractions are isolated from the serum of immunized sheep. In certain individuals, animal antibodies facilitate the formation of immune complexes. The adverse events include anaphylaxis, delayed allergic reactions, and a possible febrile response. Prior exposure/therapy with ovine fab is another potential risk factor for the development of acute allergic reactions related to Fab product administration. The Fab product is devoid of the antigenic determining Fc portion. This feature makes it less immunogenic and, therefore, less capable of mounting a fatal immune response. Due to its monovalence, it is also unlikely to form extended antigen-antibody immune complexes.

Hypersensitivity to Papaya Extracts and Bromelain:

Clinicians should not administer digoxin immune fab to patients with allergies to papain, chymopapain, and bromelain. Papain targets the isolated immunoglobulin fractions and cleaves them into Fab and Fc fragments. Trace amounts of activated or inactivated papain may still be present in the final product. Other allergens such as dust mite and latex have a certain homology to antigenic structures in papain. Such cases may also carry a risk of being allergic to papain.[17] Administring the drug should only be considered if the benefits outweigh the risks, and treatment modalities of anaphylactic reactions are within an arm's reach.