Digoxin Immune Fab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

DigiFab: 40 mg (1 ea)

Pharmacology

Mechanism of Action

Digoxin immune antigen-binding fragments (Fab) are specific antibodies for the treatment of digitalis intoxication in carefully selected patients; binds with molecules of digoxin and is then excreted by the kidneys and removed from the body.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 0.3 L/kg

Excretion

Urine (concentrations declining within 5 to 7 days)

Onset of Action

IV: Digitalis toxicity: Improvement may be seen within 20 to 90 minutes (Betten, 2006)

Half-Life Elimination

15 to 20 hours; may be increased up to 10-fold in patient with renal impairment

Use: Labeled Indications

Digoxin toxicity: Treatment of life-threatening or potentially life-threatening digoxin intoxication, including:

- Acute digoxin ingestion (≥10 mg in adults; 4 mg [>0.1 mg/kg] in children); resulting in serum concentration ≥10 ng/mL). Note: Serum digoxin concentrations do not reflect myocardial digoxin concentrations until distribution occurs (~4 to 6 hours). Therefore, an initially elevated concentration (in the absence of overt toxicity) may not indicate the use of digoxin immune fab. However, an initial serum concentration in excess of 10 ng/mL may be predictive of toxicity (Hack 2019).

- Chronic ingestion leading to steady state digoxin concentrations >6 ng/mL in adults or >4 ng/mL in children.

- Manifestations of life-threatening digoxin toxicity due to overdose (severe ventricular arrhythmias, progressive bradycardia, second- or third-degree heart block not responsive to atropine, serum potassium concentration >5.5 mEq/L in adults or >6 mEq/L in children).

Use: Off Label

Cardiac glycoside toxicityc

Digoxin immune fab has been used anecdotally in the treatment of toxicity from botanicals that contain cardioactive glycosides (eg, Thevetia peruviana, Nerium oleander) Flanagan 2004.

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosage and Administration

Dosing: Adult

Each vial of digoxin immune Fab 40 mg will bind ~0.5 mg of digoxin.

Digoxin toxicity: Note: Estimation of the dose is based on the body burden of digoxin. This may be calculated if the amount ingested is known or the postdistribution serum drug level is known (round the dose up to the nearest whole vial). If the amount ingested is unknown, general dosing guidelines should be used.

Acute ingestion of unknown amount: IV: Initial: 10 vials; if needed, administer a second dose of 10 vials (20 vials total is adequate to treat most life-threatening ingestions).

Acute ingestion of known amount: IV:

Based on number of tablets or capsules ingested:

Step 1: Calculate total body load (mg)

Digoxin capsules: Note: This assumes 100% bioavailability of digoxin.

Total body load (mg) = Amount (mg) digoxin capsules ingested

Digoxin tablets: Note: This assumes 80% bioavailability of digoxin.

Total body load (mg) = 0.8 x (amount [mg] digoxin tablets ingested)

Step 2: Calculate number of vials needed

Digoxin Immune Fab Dose (vials) = Total body load (mg) / (0.5)

Alternatively, the following table gives an estimation of the number of vials needed based on the number of digoxin tablets or capsules ingested.

Table has been converted to the following text.

Number of digoxin tablets or capsules ingested¹: 25

Dose of digoxin immune fab: 10 vials

Number of digoxin tablets or capsules ingested¹: 50

Dose of digoxin immune fab: 20 vials

Number of digoxin tablets or capsules ingested¹: 75

Dose of digoxin immune fab: 30 vials

Number of digoxin tablets or capsules ingested¹: 100

Dose of digoxin immune fab: 40 vials

Number of digoxin tablets or capsules ingested¹: 150

Dose of digoxin immune fab: 60 vials

Number of digoxin tablets or capsules ingested¹: 200

Dose of digoxin immune fab: 80 vials

¹250 mcg tablets with 80% bioavailability or 200 mcg capsules with 100% bioavailability.

Based on steady-state serum digoxin concentration: Adults: Note: If the calculated dose based on the digoxin concentration is different from the estimated dose based on the known ingested amount (if available), use the higher dose.

Digoxin Immune Fab Dose (vials) = (serum digoxin concentration [ng/mL] x weight [kg]) / 100

Alternatively, the following table gives an estimation of the number of vials needed based on the steady-state serum digoxin concentration.

Table has been converted to the following text.

Adult Dose Estimates of Digoxin Immune Fab (in # of Vials) From Steady-State Serum Digoxin Concentration

Patient Weight (kg): Serum Digoxin Concentration (ng/mL): Digoxin immune Fab (in # of Vials)

40 kg

1 ng/mL: 0.5 vial

2 ng/mL: 1 vial

4 ng/mL: 2 vials

8 ng/mL: 3 vials

12 ng/mL: 5 vials

16 ng/mL: 7 vials

20 ng/mL: 8 vials

60 kg

1 ng/mL: 0.5 vial

2 ng/mL: 1 vial

4 ng/mL: 3 vials

8 ng/mL: 5 vials

12 ng/mL: 7 vials

16 ng/mL: 10 vials

20 ng/mL: 12 vials

70 kg

1 ng/mL: 1 vial

2 ng/mL: 2 vials

4 ng/mL: 3 vials

8 ng/mL: 6 vials

12 ng/mL: 9 vials

16 ng/mL: 11 vials

20 ng/mL: 14 vials

80 kg

1 ng/mL: 1 vial

2 ng/mL: 2 vials

4 ng/mL: 3 vials

8 ng/mL: 7 vials

12 ng/mL: 10 vials

16 ng/mL: 13 vials

20 ng/mL: 16 vials

100 kg

1 ng/mL: 1 vial

2 ng/mL: 2 vials

4 ng/mL: 4 vials

8 ng/mL: 8 vials

12 ng/mL: 12 vials

16 ng/mL: 16 vials

20 ng/mL: 20 vials

Chronic toxicity (serum digoxin concentration unavailable): IV: Adults: 6 vials is adequate to reverse most cases of toxicity. Patients who receive digoxin therapeutically often require lower doses than those with acute overdosage because their total body burden of digoxin is generally low comparatively (Smith 2019). One study showed that 1 to 2 vials may be adequate in some patients (Chan 2016).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Digoxin toxicity: Infants, Children, and Adolescents: Note: Estimation of the dose is based on the body burden of digitalis. This may be calculated if the amount ingested is known or the post-distribution serum drug concentration is known (round the dose up to the nearest whole vial). If the amount ingested is unknown, general dosing guidelines should be used.

Acute ingestion of unknown amount: IV: Initial: 10 vials; if needed, may administer a second dose of 10 vials (to avoid a febrile reaction); a total dose of 20 vials is adequate to treat most life-threatening ingestions. In small children (<20 kg), it is important to monitor for fluid overload.

Acute ingestion of known amount: IV:

Step 1: Calculate total body load (mg): If parenteral overdose of digoxin or from ingestion or oral capsules, total body load of digoxin is equal to the dose administered. If oral digoxin ingestion/overdose from elixir or tablets, the total body load should be calculated based on the following equation:

Total body load (mg) = 0.8 x [amount (mg) digoxin tablets or elixir ingested]

Step 2: Calculate number of vials needed: Each vial of digoxin immune Fab 40 mg will bind ~0.5 mg of digoxin.

Digoxin Immune Fab Dose (vials) = Total digoxin body load (mg) / 0.5 mg/vial

Based on steady-state serum digoxin concentration: IV: Dose may be determined by estimation with the following tables or calculated based on the following equations for either mg dose or number of vials needed (use precaution to ensure appropriate equation):

Note: Infants and Children ≤20 kg may require smaller doses; calculate the dose in milligrams (mg)

Digoxin Immune Fab Dose (mg) = [(serum digoxin concentration [ng/mL] x weight [kg]) / 100] x 40 mg/vial

Digoxin Immune Fab Dose (vials) = (serum digoxin concentration [ng/mL] x weight [kg]) / 100

The following tables give an estimation of the amount of Digoxin Immune Fab needed based on the steady-state serum digoxin concentration.

Table has been converted to the following text.

Infants and Children <20 kg: Dose Estimates of Digoxin Immune Fab From Serum Digoxin Concentration:

Patient weight 3 kg and serum digoxin concentration:

1 ng/mL: 1 mg^A

2 ng/mL: 2.5 mg^A

4 ng/mL: 5 mg

8 ng/mL: 10 mg

12 ng/mL: 14 mg

16 ng/mL: 19 mg

20 ng/mL: 24 mg

Patient weight 5 kg and serum digoxin concentration:

1 ng/mL: 2 mg^A

2 ng/mL: 4 mg

4 ng/mL: 8 mg

8 ng/mL: 16 mg

12 ng/mL: 24 mg

16 ng/mL: 32 mg

20 ng/mL: 40 mg

Patient weight 10 kg and serum digoxin concentration:

1 ng/mL: 4 mg

2 ng/mL: 8 mg

4 ng/mL: 16 mg

8 ng/mL: 32 mg

12 ng/mL: 48 mg

16 ng/mL: 64 mg

20 ng/mL: 80 mg

Patient weight 20 kg and serum digoxin concentration:

1 ng/mL: 8 mg

2 ng/mL: 16 mg

4 ng/mL: 32 mg

8 ng/mL: 64 mg

12 ng/mL: 96 mg

16 ng/mL: 128 mg

20 ng/mL: 160 mg

^ADilution of reconstituted vial to 1 mg/mL may be desirable.

Table has been converted to the following text.

Children and Adolescents ≥40 kg: Dose Estimate of Digoxin Immune Fab (in Vials) From Serum Digoxin Concentration

Patient weight 40 kg and serum digoxin concentration:

1 ng/mL: 0.5 vial

2 ng/mL: 1 vial

4 ng/mL: 2 vials

8 ng/mL: 3 vials

12 ng/mL: 5 vials

16 ng/mL: 7 vials

20 ng/mL: 8 vials

Patient weight 60 kg and serum digoxin concentration:

1 ng/mL: 0.5 vial

2 ng/mL: 1 vial

4 ng/mL: 3 vials

8 ng/mL: 5 vials

12 ng/mL: 7 vials

16 ng/mL: 10 vials

20 ng/mL: 12 vials

Patient weight 70 kg and serum digoxin concentration:

1 ng/mL: 1 vial

2 ng/mL: 2 vials

4 ng/mL: 3 vials

8 ng/mL: 6 vials

12 ng/mL: 9 vials

16 ng/mL: 11 vials

20 ng/mL: 14 vials

Patient weight 80 kg and serum digoxin concentration:

1 ng/mL: 1 vial

2 ng/mL: 2 vials

4 ng/mL: 3 vials

8 ng/mL: 7 vials

12 ng/mL: 10 vials

16 ng/mL: 13 vials

20 ng/mL: 16 vials

Patient weight 100 kg and serum digoxin concentration:

1 ng/mL: 1 vial

2 ng/mL: 2 vials

4 ng/mL: 4 vials

8 ng/mL: 8 vials

12 ng/mL: 12 vials

16 ng/mL: 16 vials

20 ng/mL: 20 vials

Chronic toxicity (serum digoxin concentration unavailable): IV:

Infants and Children ≤20 kg: 1 vial is adequate to reverse most cases of toxicity

Children >20 kg and Adolescents: 6 vials is adequate to reverse most cases of toxicity

Reconstitution

Reconstitute each vial to a concentration of 10 mg/mL by adding 4 mL SWFI; gently mix. Add reconstituted digoxin immune fab to an appropriate volume of NS.

Administration

IV: Administer by slow IV infusion over at least 30 minutes. May also be given by bolus injection if cardiac arrest is imminent (infusion-related reaction may occur). Stopping the infusion and restarting at a slower rate may help if an infusion-related reaction occurs.

Storage

Store vials at 2°C to 8°C (36°F to 46°F); do not freeze. Reconstituted solutions are stable for 4 hours when stored at 2°C to 8°C (36°F to 46°F). The following stability information has also been reported: May be stored at room temperature for up to 30 days (Cohen, 2007).

Drug Interactions

There are no known significant interactions.

Test Interactions

Digoxin immune fab may interfere with digitalis immunoassay measurements, thereby resulting in clinically misleading total serum digoxin concentrations until all Fab fragments are eliminated from the body (may take several days to >1 week after administration). Digoxin serum samples should be obtained before digoxin immune fab administration, if possible.

Adverse Reactions

Frequency not defined.

Cardiovascular: Orthostatic hypotension, phlebitis, ventricular tachycardia (patients with atrial fibrillation; due to digoxin withdrawal), worsening of heart failure (due to digoxin withdrawal)

Endocrine & metabolic: Hypokalemia

Hypersensitivity: Hypersensitivity reaction, serum sickness

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity reactions: Digoxin immune Fab is derived from ovine (sheep) Fab immunoglobulin fragments; hypersensitivity reactions (eg, anaphylactic or anaphylactoid reactions, delayed allergic reactions) are possible. Patients with allergies to sheep proteins and patients with prior exposure to ovine antibodies or ovine Fab may be at a higher risk for anaphylactic reactions. In patients who develop an anaphylactic reaction, discontinue the infusion immediately and administer emergency care; balance the need for epinephrine against its potential risk in the setting of digitalis toxicity.

Processed with papain and may cause hypersensitivity reactions in patients allergic to papaya, other papaya extracts, papain, chymopapain, or the pineapple-enzyme bromelain. There may also be cross allergenicity with dust mite and latex allergens.

• Potassium imbalance: Patients experiencing acute digitalis toxicity may present with significant hyperkalemia due to shifting of potassium into the extracellular space. Upon treatment with digoxin immune Fab, potassium shifts back into the intracellular space and may result in hypokalemia. Monitor potassium closely, especially during the first few hours after administration; treat hypokalemia cautiously when clinically indicated.

Disease-related concerns:

• Heart failure (HF): In patients chronically maintained on digoxin for HF, administration of digoxin immune Fab may result in exacerbation of HF symptoms due to a reduction in digoxin serum concentration. If reinitiation is required, consider postponing until Fab fragments have been eliminated completely; elimination may take several days or longer, especially in patients with renal impairment.
• Renal impairment: Use with caution in patients with renal failure (experience limited); the Fab-digoxin complex will be eliminated more slowly. Toxicity may recur; prolonged monitoring for recurrence of symptoms and evaluation of free (unbound) digoxin concentrations (if test available) may be warranted in this patient population.

Monitoring Parameters

Prior to the first dose of digoxin immune Fab evaluate serum potassium, serum digoxin concentration, and serum creatinine; closely monitor serum potassium (eg, hourly for 4 to 6 hours; at least daily thereafter; elevated serum potassium is associated with increased morbidity and mortality (Hauptman 2016; Rezai 2018). Monitor temperature, blood pressure, and electrocardiogram after administration. Total serum digoxin concentrations will rise precipitously following administration of digoxin immune Fab due to the presence of the Fab-digoxin complex; because digoxin bound to Fab fragments cannot result in toxicity, this rise has no clinical meaning. Therefore, avoid monitoring total serum digoxin concentrations until the Fab fragments have been eliminated completely; this may be several days to weeks in patients with renal impairment (Ujhelyi 1995). Monitor for volume overload in children <20 kg. Monitor for signs and symptoms of a hypersensitivity reaction.

Patients with renal failure may experience a recurrence of toxicity; prolonged monitoring for recurrence of symptoms and evaluation of free (unbound) digoxin concentrations (if test available) may be warranted in this patient population.

Pregnancy

Pregnancy Considerations

Animal reproduction studies have not been conducted. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey, 2003).

Patient Education

What is this drug used for?

• It is used to treat digoxin overdose.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe dizziness
• Passing out
• Fast heartbeat
• Cough
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.