Mechanism of Action:

DigiFab has an affinity for digoxin in the range of 109 to 1010 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.

Animal Studies:

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 another ovine digoxin-specific immune Fab, Digibind® (manufactured by GlaxoSmithKline). 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.

Clinical Pharmacokinetics:

The pharmacokinetics 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 pharmacokinetic profiles of Fab were similar for both products.1 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).2-6 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.6

Clinical Studies:

There have been two controlled clinical trials conducted with DigiFab: a pharmacokinetic and pharmacodynamic study of DigiFab as compared to Digibind in healthy volunteers, and a prospective multi-center study of the efficacy of DigiFab in patients presenting with life-threatening digoxin toxicity.

The objective of the pharmacokinetic and pharmacodynamic study was to compare these parameters for DigiFab to those for Digibind.1 This trial was conducted in healthy volunteers who were administered a 1 mg intravenous dose of digoxin, followed 2 hours later by an equimolar neutralizing dose of either DigiFab or Digibind. The pharmacokinetics of both digoxin and Fab were determined (see Clinical Pharmacokinetics for Fab pharmacokinetic parameters). The primary outcome measure 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. In this study, no patients developed a measurable immune response (human anti-ovine antibodies) to DigiFab.

The objective of the efficacy study was to demonstrate safety and also to determine the pharmacokinetics of, and clinical response to, DigiFab in patients. Results were compared to historical data on another U.S. marketed ovine digoxin immune Fab product, Digibind. Fifteen patients received doses of DigiFab based on its theoretical binding capacity for digoxin, and based on the known amount of digoxin ingested or on blood concentrations of digoxin at the time of admission. This study was conducted in both the U.S. and in Finland.

The primary outcome of the study was met in that serum free digoxin concentrations in all patients fell to undetectable levels following DigiFab administration. This was an expected outcome that is consistent with data in the literature showing that free digoxin concentrations fall rapidly following administration of Digibind.2 In the DigiFab trial, an independent blinded review of each patient's ECG showed that 10 of the 15 patients studied had ECG abnormalities that improved within 4 hours after the DigiFab infusion. The remaining 5 patients had ECG abnormalities that were unchanged from baseline throughout the 24-hour assessment period, and in one case through the 30-day follow up period. Although the reason for the lack of ECG resolution could not be clearly determined in all cases, it is possible that the ECG abnormalities observed in these patients were not entirely due to digoxin toxicity, but rather to another underlying cardiac problem. Assessing all manifestations of toxicity, investigators classified 7 out of the 15 patients (47%) studied as having complete resolution of digoxin toxicity within 4 hours of DigiFab administration, and 14 patients (93%) were classified as having resolved their digoxin toxicity by 20 hours. The data for the proportion of patients who responded to treatment with DigiFab is similar to, and consistent with, historical data available for Digibind.2-3 In this study, where 2/15 patients had serum available for human anti-ovine antibody determination, there was no measurable immune response.

General:

Standard management of digitalis intoxication includes withdrawal of the intoxicating agent, correction of electrolyte disturbances (especially hyperkalemia), acid-base imbalances, hypoxia and treatment of cardiac arrhythmias.

Massive digitalis intoxication can cause hyperkalemia; administration of potassium supplements in the setting of digitalis intoxication may be hazardous. After treatment with DigiFab, the serum potassium concentration may drop rapidly and must be monitored frequently, especially after the first several hours after DigiFab is given (see Laboratory Tests).

Patients with poor cardiac function may deteriorate secondary to the withdrawal of the inotropic action of digoxin by DigiFab. If needed, additional support can be provided by using other intravenous inotropes such as dopamine, dobutamine or vasodilators. However, care must be taken not to aggravate the digitalis induced rhythm disturbances. Re-digitalization should be postponed, if possible, until the Fab fragments have been eliminated from the body, which may require several days, and patients with impaired renal function may require a week or longer.

Use of DigiFab in Renal Failure:

The elimination half-life of DigiFab in renal failure has not been clearly defined, although patients with renal dysfunction have been successfully treated with Digibind.3,12 There is no evidence to suggest that the time-course of therapeutic effect is any different in these patients than in patients with normal renal function, but excretion of the Fab fragment-digoxin complex from the body is probably delayed. There is one case report of recurrence of atrioventricular block due to digoxin in a functionally anephric patient 10 days after its initial reversal by ovine Fab therapy.12 This clinical event persisted for more than a week. In patients that are functionally anephric, failure to clear the Fab-digoxin complex from the blood by glomerular filtration and renal excretion may be anticipated. It is uncertain whether the failure to eliminate the Fab-digoxin complex in severe renal impairment may lead to re-intoxication with digoxin following the release of previously bound digoxin into the blood. However, patients with severe renal failure who receive DigiFab for digitalis toxicity should be monitored for a prolonged period for possible recurrence of toxicity. Monitoring of free (unbound) digoxin concentrations after the administration may be appropriate in order to establish recrudescent toxicity in renal failure patients.13

Formation of Antibodies to DigiFab:

Prior treatment with digoxin-specific ovine immune Fab carries a theoretical risk of sensitization to ovine serum protein (see WARNINGS) and possible diminution of the efficacy of the drug due to the presence of human antibodies against ovine Fab. Human antibodies to ovine Fab have been reported in some patients receiving Digibind, however, to date, there have been no clinical reports of human anti-ovine immunoglobulin antibodies causing a reduction in binding of ovine digoxin immune Fab or neutralization response to ovine digoxin immune Fab.

Laboratory Tests:

DigiFab will interfere with digitalis immunoassay measurements in the same way that has been reported for Digibind.14,15 Thus, standard serum digoxin concentration measurements may be clinically misleading until the Fab fragments are eliminated from the body. This may take several days or a week or more in patients with markedly impaired renal function. Therefore, serum samples for digoxin concentration should be obtained before DigiFab administration, if at all possible. Such measurements would establish the level of serum digoxin at the time of diagnosis of digitalis intoxication. At least 6 to 8 hours are required for equilibration of digoxin between serum and tissue, so absorption of the last dose may continue from the intestine. Therefore, serum measurements may be difficult to interpret if samples are drawn soon after the last digitalis dose. Patients should be closely monitored, including temperature, blood pressure, electrocardiogram, and potassium concentration, during and after administration of DigiFab. The total serum digoxin concentration may rise precipitously following administration of DigiFab, but this will be almost entirely bound to the Fab fragment and therefore not able to react with receptors in the body.

Digoxin causes a shift of potassium from inside to outside the cell, such that severe intoxication can cause a life-threatening elevation of serum potassium. This may lead to increased urinary excretion of potassium so that a patient may have hyperkalemia but a whole body deficit of potassium. When the toxic effects of digoxin are reversed by DigiFab, potassium shifts back into the cell with a resulting decline in serum potassium concentration. This hypokalemia may develop rapidly. For these reasons, serum potassium concentration should be followed closely, especially during the first several hours after DigiFab administration. Cautious potassium supplementation should then be given when necessary.

Information for Patients:

Patients should be advised to contact their physician immediately if they experience any signs and symptoms of delayed allergic reactions or serum sickness (e.g., rash, pruritus, urticaria) after hospital discharge.

Drug Interactions:

Studies of drug interactions have not been conducted with DigiFab.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

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

Pregnancy:

Pregnancy Category C. Animal reproduction studies have not been conducted with DigiFab. It is also not known whether DigiFab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DigiFab should be given to a pregnant woman only if clearly needed.

Nursing Mothers:

It is not known whether DigiFab is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when DigiFab is administered to a nursing woman.

Geriatric Use:

Specific studies in elderly patients have not been conducted. Of the 15 patients given DigiFab for digoxin toxicity in one clinical trial, the average age of all patients was 64 years and over half of the patients (8 of the 15) were 65 years of age or older. The oldest patient studied was 86 years old. There is no evidence that the efficacy of DigiFab would be altered due to advanced age alone, however elderly patients have a higher chance of having impaired renal function and therefore should be monitored more closely for recurrent toxicity (see PRECAUTIONS).

Pediatric Use:

Specific studies in pediatric patients have not been conducted and no pediatric patients were enrolled in the clinical studies of DigiFab. A similar digoxin ovine Fab product, Digibind, has been used successfully to treat infants.2 As with all drugs, the use of DigiFab in infants and children should be based on careful consideration of the benefits compared with the potential risks.

General Guidelines:

The dosage of DigiFab will vary according to the amount of digoxin or digitoxin to be neutralized.

Dosage for Acute Ingestion of Unknown Amounts of Digoxin or Digitoxin:

If a patient presents with life-threatening digitalis toxicity caused by an acute ingestion and neither a serum digitalis concentration nor an estimated ingestion amount is available, 20 vials of DigiFab may be administered. This amount should be adequate to treat most life-threatening overdoses in adults and children. However, in small children it is important to monitor for volume overload. In general, a larger dose of DigiFab has a faster onset of effect but may enhance the possibility of a febrile reaction. In such cases, 10 vials may be administered first with careful monitoring of the patient's response followed at the physician's discretion by 10 additional vials and continued monitoring. 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 for Toxicity During Chronic Therapy:

For adult patients who are in acute distress or for whom a serum digoxin concentration is not available, 6 vials (240 mg) should be adequate to reverse most cases of toxicity. For infants and small children (≤ 20 kg) on chronic therapy with digoxin and showing signs of toxicity, a single vial should be sufficient.

For Ingestion of Known Amount:

Each vial of DigiFab contains 40 mg of purified digoxin-specific Fab, which will bind 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. If digoxin tablets were ingested, 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:

Calculations Based on Steady-State Serum Digoxin Concentrations:

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:

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).

Administration:

Each vial of DigiFab should be reconstituted with 4 mL of Sterile Water for Injection USP and gently mixed to provide a solution containing approximately 10 mg/mL of digoxin immune Fab protein. The reconsituted product should be used promptly. If not used immediately, it may be stored under refrigeration at 2° to 8°C (36° to 46°F} for up to 4 hours. The reconstituted product may be added to an appropriate volume of 0.9% sodium chloride for injection.

DigiFab should be administered slowly as an intravenous infusion over at least 30 minutes. If infusion rate-related reactions occur, the infusion should be stopped and re-started at a slower rate. If cardiac arrest is imminent, DigiFab can be given by bolus injection. With bolus injection, an increased incidence of infusion-related reactions may be expected.

For infants and small children who may require very small doses, it is recommended that the 40 mg vial be reconstituted as directed and administered 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.

Storage Conditions:

The product should be stored at 2° to 8°C (36° to 46°F). Do not freeze. The product must be used within 4 hours after reconstitution.