DigiFab

Digoxin immune FAB is used as an antidote to treat a life-threatening overdose of digoxin or digitoxin.

Digoxin immune FAB is not for treating a mild digitalis overdose.

Digoxin immune FAB may also be used for purposes not listed in this medication guide.

• Tell all of your health care providers that you take DigiFab. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
• This medicine is used to reverse the effects of digoxin. Heart failure or atrial fibrillation (afib) may get worse with DigiFab. Tell your doctor right away if your health problem gets worse.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of low potassium levels like muscle pain or weakness, muscle cramps, or a heartbeat that does not feel normal.
• Very bad dizziness or passing out.
• Cough.
• A fast heartbeat.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

For Intravenous Use Only

Dosage

General Guidelines:

Adjust the dosage of Digifab ® according to the amount of digoxin to be neutralized.

Failure of the patient to respond to Digifab ® should alert the physician to the possibility that the clinical problem may not be caused by digitalis toxicity.

DOSAGE CALCULATION

General

Methods for calculating a neutralizing dose of Digifab ®, based on a known or estimated amount of digoxin or digitoxin in the body, are provided below. When using the dose calculation methods provided, the following guidelines should be considered:

• Inaccurate estimates of the amount of digitalis ingested or absorbed may occur due to non-steady state serum concentrations or due to digitalis assay limitations. Most serum digoxin assay kits are designed to measure concentrations less than 5 ng/mL; therefore, sample dilution is required to accurately measure serum concentrations > 5 ng/mL.
• Dosage calculations are based on a steady state volume of distribution of approximately 5 L/kg for digoxin, which is used to convert serum digoxin concentrations to total body burden of digoxin in milligrams. The volume of distribution is a population average and may vary among individuals. Many patients may require higher doses for complete neutralization and doses should usually be rounded up to the nearest whole vial.
• If toxicity has not adequately reversed after several hours, or appears to recur, re-administration of Digifab ®, at a dose guided by clinical judgment, may be necessary. If a patient is in need of re-administration of Digifab ® due to recurrent toxicity, or to a new toxic episode that occurs soon after the first episode, measurement of free (unbound) serum digitalis concentrations should be considered since Fab may still be present in the body.
• Failure of a patient to respond to Digifab ® treatment may indicate that the clinical problem is not caused by digitalis intoxication. If there is no response to an adequate dose of Digifab ®, the diagnosis of digitalis toxicity should be questioned.

Calculation for Ingestion of Known Amount:

• Each vial of Digifab ® (40 mg of purified digoxin-specific Fab) binds approximately 0.5 mg of digoxin.
• The total number of vials required can be calculated by dividing the total body load of digoxin in milligrams (mg) by 0.5 mg per vial (see Formula 1).
• Following an acute ingestion, total body load will be approximately equal to the amount ingested in milligrams for either digoxin capsules or digitoxin.
• In case of digoxin tablet ingestion , the total body load will be approximately equal to the amount ingested (in mg) multiplied by the bioavailability of the tablet preparation, which is 0.8.

Table 1 gives dosage estimates in number of vials for adults and children who have ingested a single large dose of digoxin and for whom the approximate number of tablets or capsules is known. The dose of Digifab ® (in number of vials) represented in Table 1 can be approximated using the following formula:

Formula 1

Dose             = total digitalis body load in mg
(in # of vials)    0.5 mg of digitalis bound/vial

If, after several hours, toxicity is not adequately reversed, or appears to recur, additional administration of Digifab ® at a dose guided by clinical judgment may be required.

Calculations Based on Steady-State Serum Digoxin Concentrations:

Adults

Table 2 gives dosage estimates in number of vials for adult patients for whom a steady-state serum digoxin concentration is known. The dose of Digifab® (in number of vials) represented in Table 2 can be approximated using the following formula:

Formula 2 (see Table 2)

Dose            = (Serum digoxin concentration in ng/mL)(weight in kg)
(in # of vials)                                     100

Children:

• Table 3 gives dosage estimates in milligrams for infants and small (< 20 Kg) children based on the steady-state serum digoxin concentration.
• The dose of Digifab ® represented in Table 3 can be estimated by multiplying the dose (in number of vials) calculated from Formula 2 by the amount of Digifab ® contained in a vial (40 mg/vial) (see Formula 3).
• Administer smaller doses in children < 20 Kg requiring doses < 1mL with a tuberculin syringe after reconstituting 40 mg.
• For very small doses, a reconstituted vial can be diluted with 36 mL of sterile isotonic saline to achieve a concentration of 1 mg/mL.

Formula 3 (see Table 3)

Dose (in mg)   = (Dose in # of vials) (40 mg/vial)

Calculation Based on Steady-State Digitoxin Concentrations:

The dose of Digifab ® for digitoxin toxicity can be approximated by using the following formula (which differs from Formula 2 in the denominator due to a 10-fold decrease in the volume of distribution of digitoxin as compared to digoxin).

Formula 4

Dose              = (Serum digitoxin concentration in ng/mL) (weight in kg)
(in # of vials)                                   1000

If in any case, the dose estimated based on ingested amount (Formula 1) differs substantially from that calculated based on the serum digoxin or digitoxin concentration (Formulas 2 and 4), it may be preferable to use the higher dose estimate.

Preparation and Administration

• Each vial contains 40 mg of digoxin immune Fab protein and is intended for one time use only as it contains no preservatives
• Reconstitute each vial of Digifab ® with 4 mL of Sterile Water for Injection USP and gently mix to provide a solution containing approximately 10 mg/mL of digoxin immune Fab protein.
• Use the reconstituted product promptly. If not used immediately, store under refrigeration at 2° to 8°C (36° to 46°F) for up to 4 hours. Add the reconstituted product to an appropriate volume of 0.9% sodium chloride for injection.
• Visually inspect reconstituted vials for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy, turbid or if it contains particulates.
• Administer Digifab ® slowly as an intravenous infusion over at least 30 minutes. Stop the infusion if infusion rate-related anaphylactoid-type reactions occur, such as hypotension, wheezing, or urticaria. The infusion can be re-started at a slower rate. Give Digifab ® by bolus injection, if cardiac arrest is imminent. An increased incidence of infusion-related reactions may be expected with bolus injection.
• For infants and small children who may require very small doses, reconstitute the 40 mg vial as directed and administer undiluted using a tuberculin syringe. For very small doses, a reconstituted vial can be diluted with an additional 36 mL of isotonic saline to achieve a concentration of 1 mg/mL.

Mechanism of Action

Digifab ® has an affinity for digoxin in the range of 10 9 to 10 10 M -1, which is greater than the affinity of digoxin for its sodium pump receptor, the presumed receptor for its therapeutic and toxic effects. When administered to the intoxicated patient, Digifab ® binds to molecules of digoxin reducing free digoxin levels, which results in a shift in the equilibrium away from binding to the receptors, thereby reducing cardio-toxic effects. Fab-digoxin complexes are then cleared by the kidney and reticuloendothelial system.

Pharmacokinetics

The pharmacokinetics and pharmacodynamics of Digifab ® were assessed in a randomized and controlled study of Digifab ® and Digibind ® (comparator Fab product for treatment of digoxin toxicity). Sixteen healthy subjects were given 1 mg of intravenous digoxin followed by an approximately equimolar neutralizing dose of either Digifab ® (n=8) or Digibind (n=8). The objective of the pharmacokinetic and pharmacodynamic study was to compare parameters for Digifab ® to those for Digibind. 7 The pharmacokinetics of both digoxin and Fab were determined and found to be similar for both products. The similar volumes of distribution (0.3 L/kg and 0.4 L/kg for Digifab ® and Digibind, respectively) indicate considerable penetration from the circulation into the extracellular space and are consistent with previous reports of ovine Fab distribution, as are the elimination half-life values (15 hours and 23 hours for Digifab ® and Digibind, respectively). 8-12 The elimination half-life of 15-20 hours in patients with normal renal function appears to be increased up to 10 fold in patients with renal impairment, although volume of distribution remains unaffected. 12

The primary outcome measure for this study was the serum level of free (unbound) digoxin. The results demonstrated that both products reduced the level of free digoxin in the serum to below the limit of assay quantitation for several hours after Fab administration. Cumulative urinary excretion of digoxin was comparable for both products and exceeded 40% of the administered dose by 24 hours. These results demonstrate that Digifab ® and Digibind have equivalent pharmacodynamic effects on the digoxin parameters that are relevant to the treatment of digoxin toxicity.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal carcinogenicity and reproduction studies have not been conducted with Digifab.

Animal Toxicology and/or Pharmacology

No toxic effects were observed when Digifab ® was administered to healthy male Sprague Dawley rats in equimolar doses sufficient to neutralize a 1 mg/kg dose of digoxin. In these studies, the physiologic changes produced by toxic serum concentrations of digoxin were ameliorated rapidly by the administration of Digifab ® or comparator product Digibind. Statistically equivalent responses were observed with both Digifab ® and Digibind to the following variables: PTQ index, heart rate, mean arterial pressure, ventilation, arterial blood gases, and serum potassium concentrations.

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8. Hickey AR, Wenger TL, Carpenter VP, et al. Digoxin immune fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study. J Am Coll Cardiol 1991; 17:590-598.
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Applies to digoxin immune fab: intravenous solution reconstituted