Digoxin antidote.

Digoxin-specific antibody

Each vial of Digibind contains a sterile, lyophilised, crystalline off-white powder, comprising 38 mg of antigen-binding fragments (Fab) derived from specific anti-digoxin antibodies raised in sheep, approximately 75 mg Sorbitol BP and approximately 28 mg Sodium Chloride BP.

Powder in viral

Digibind is indicated for the treatment of known or strongly suspected digoxin or digitoxin toxicity, where measures beyond the withdrawal of the digitalis glycoside and correction of any serum electrolyte abnormality are felt to be necessary.

Dosage: The dosage of Digibind varies according to the amount of digoxin (or digitoxin) to be neutralised. The average dose used during clinical testing was 10 vials. When determining the dose for Digibind, the following guidelines should be considered:

• Dosage estimates are based on a steady-state volume of distribution of 5 l/kg for digoxin (0.5 l/kg for digitoxin) to convert serum digitalis concentration to the amount of digitalis in the body. These volumes are population averages and vary widely among individuals. Many patients may require higher doses for complete neutralisation. Doses should ordinarily be rounded up to the next whole vial.
• Erroneous calculations may result from inaccurate estimates of the amount of digitalis ingested or absorbed or from non steady-state serum digitalis concentrations. Inaccurate serum digitalis concentration measurements are a possible source of error; this is especially so for very high values, since most digoxin assay kits are not designed to measure values above 5 nanogram/ml.
• If after several hours toxicity has not adequately reversed or appears to recur, re-administration of Digibind at a dose guided by clinical judgement may be required.

Acute ingestion of unknown amount of glycoside: Adults and children over 20 kg: If a patient presents with potentially life-threatening digitalis toxicity after acute ingestion of an unknown amount of digoxin or digitoxin, and neither a serum digoxin concentration nor an estimate of the ingested amount of glycoside is available, 20 vials of Digibind can be administered. This amount will be adequate to treat most life-threatening ingestions in adults and large children.

As an alternative, the physician may consider administering 10 vials of Digibind, observing the patient's response, and following with an additional 10 vials if clinically indicated.

Infants and children 20 kg: In infants and small children 20 kg) with potentially life- threatening digitalis toxicity after acute ingestion of an unknown amount of digoxin or digitoxin, when neither a serum concentration nor an estimate of the ingested amount is available, clinical judgement must be exercised to estimate an appropriate number of vials of Digibind to administer.

This estimate should be based on the maximum likely total body load of glycoside and the neutralising capacity of Digibind (one vial of Digibind per 0.5 mg of digoxin or digitoxin). It is important to monitor for volume overload during administration of Digibind.

Acute ingestion of known amount of glycoside: Each vial of Digibind contains 38 mg of purified digoxin-specific Fab fragments which will bind approximately 0.5 mg of digoxin or digitoxin. Thus one can calculate the total number of vials required by dividing the total digitalis body load in mg by 0.5 (see formula 1).

Formula 1

For toxicity from an acute ingestion, total body load in milligrams will be approximately equal to the amount ingested in milligrams for digitoxin, or the amount ingested in milligrams multiplied by 0.80 (to account for incomplete absorption) for digoxin. Table 1 gives Digibind doses based on an estimate of the number of digoxin tablets (0.25 mg) ingested as a single dose and is applicable to children or adults.

TABLE 1: Approximate Digibind Dose for Reversal of a Single Large Digoxin Overdose

Toxicity during chronic therapy: Adults and children over 20 kg: In adults and children over 20 kg with digitalis toxicity resulting from chronic digoxin or digitoxin therapy and for whom a steady-state serum concentration is not available, a dose of 6 vials of Digibind will usually be adequate to reverse toxicity.

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

Formula 2

TABLE 2: Adult Dose Estimate of Digibind (in number of vials) from Steady-State Serum Digoxin Concentration

v = vials

In patients for whom a steady-state serum digitoxin concentration is known the Digibind dose (in number of vials) can be approximated using the following formula:

Formula 3

Infants and children 20kg: In infants and small children with toxicity resulting from chronic digoxin or digitoxin therapy and for whom a steady-state serum concentration is not available, a dose of one vial of Digibind will usually suffice.

Clinical experience in children has indicated that the calculation of dose of Digibind from steady-state serum digoxin concentration may be carried out as for adults.

Table 3 (see next page) gives dosage estimates in milligrams for infants and small children based on the steady-state serum digoxin concentration. The Digibind dose represented in Table 3 can be estimated by multiplying the dose (in number of vials) calculated from Formula 2, by the amount of Digibind contained in a vial (38 mg/vial).

Formula 4

TABLE 3: Infants and Small Children Dose Estimates of Digibind (in mg) from Steady-State Serum Digoxin Concentration

* Dilution of reconstituted vial to 1 mg/ml may be desirable.

For very small doses, it may be necessary to dilute the reconstituted vial with sterile isotonic saline to achieve a concentration of 1 mg/ml, and to administer the dose with a tuberculin syringe.

Use in the elderly: Clinical experience has indicated that Digibind is effective and that calculation of dose may be carried out as for adults.

Use in renal impairment: See Precautions. The contents of each vial to be used should be dissolved in 4 ml of sterile Water for Injections BP, by gentle mixing, thus producing an approximately isosmotic solution with a protein concentration of between 8.5 and 10.5mg/ml. This may be diluted further to any convenient volume with sterile saline suitable for infusion.

Administration:

The final solution of Digibind should be infused intravenously over a 30 minute period. Infusion through a 0.22 micron membrane filter is recommended to remove any incompletely dissolved aggregates of Digibind. If cardiac arrest seems imminent, Digibind can be given as a bolus intravenous injection.

Pharmacology : The affinity constant (K_D) of Fab for digoxin is high (10¹¹M^-1) and greater than that of digoxin for its receptor (Na-K ATPase). The affinity constant of Fab for digitoxin is also high (fifteen fold lower than for digoxin). Digoxin and digitoxin are therefore attracted away from the receptor on heart tissue (and presumably other tissues as well, though this has not been studied) and their rate of elimination is changed from that governed by the kinetics of receptor binding to that governed by the kinetics of access and elimination of Fab.

In dogs, anti-digoxin Fab reverses arrhythmic manifestations of digoxin toxicity much more quickly than does IgG. There is a suggestion that reversal of inotropy with Fab lags behind reversal of cardiac electrophysiological effects.

The plasma elimination (ß) half-life of ovine digoxin-specific Fab in the baboon is 9 to l3h and that of the parent IgG antibody is 61h. The total volume of distribution of Digibind in the baboon appears to be about 9 times greater than that of IgG and more ready diffusion of the smaller moiety sufficiently accounts for this.

About 93% of radioactively labelled Fab, injected into baboons, was recovered in the urine within 24h and the corresponding amount of recoverable digoxin-specific IgG was less than 1%. Much of the urinary Fab was not intact; after glomerular filtration, low molecular weight proteins are taken into proximal renal tubular cells and catabolised.

Corresponding information on human patients is sparse, but the close relationship of therapeutic performance to predictions suggest that the animal data will be helpful. The human plasma elimination half-life after intravenous administration of Digibind is about l6 to 20h with good renal function.

Ordinarily, following administration of Digibind, improvements in signs and symptoms of digitalis intoxication begins within 30 minutes.

See data sheet.

Allergy to ovine protein.

Precautions: Failure to respond to Digibind raises the possibility that the clinical problem is not caused by digitalis intoxication. If there is no response to an adequate dose of Digibind, the diagnosis of digitalis toxicity should be questioned.

Although allergic reactions have been reported rarely, the possibility of anaphylactic, hypersensitive or febrile reactions should be borne in mind. The likelihood of an allergic reaction is distinctly greater where there is a history of allergy to antibiotics or asthma. Since papain is used to cleave the whole antibody into Fab and Fc fragments, and traces of papain or inactivated papain residues may be present in Digibind, patients with known allergies to papain, chymopapain or other papaya extracts would be at particular risk, as would those allergic to ovine proteins. However, as the Fab fragment of the antibody lacks the antigenic determinants of the Fc fragment it should present less of an immunogenic threat to patients than does an intact immunoglobulin molecule.

Many patients with mild or moderate renal dysfunction and some with severe renal dysfunction have been treated successfully with Digibind. There has been no evidence that administration of Digibind to patients with renal dysfunction will exacerbate that dysfunction; the dominant pattern of serial serum creatinine measurements has been one of stable or improved renal function after Digibind administration. The time course and general pattern of therapeutic effect have not been different in patients with severe renal dysfunction, although excretion of the Fab-digoxin complexes from the body is slowed in this situation. A theoretical possibility exists that digoxin could be released after some days from Fab-digoxin complexes which remained in the circulation because their excretion was prevented by renal failure. However, this phenomenon has proved to be rare.

Patients previously dependent on the inotropism of digoxin may develop signs of heart failure when treated with Digibind. After successful management of poisoning, digoxin has had to be reinstituted in some cases. If deemed absolutely necessary, additional inotropic support can be obtained from a non-glycoside inotropic drug such as dopamine or dobutamine, but caution is required as catecholamines and catecholamine analogues can aggravate arrhythmias caused by cardiac glycosides.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Monitoring and laboratory tests: Patients should have continuous electrocardiographic monitoring during and for at least 24 hours after administration of Digibind.

Presence of the exogenous antibody fragments will interfere with radioimmunoassay measurements of digoxin.

The total serum digoxin concentration may rise precipitously following administration of Digibind, but this will be almost entirely bound to the Fab fragment and therefore not able to react with receptors in the body.

Serum potassium concentrations should be followed carefully, since severe digitalis intoxication can cause life-threatening elevation in serum potassium concentration by shifting it from within the cells. When the effect of digitalis is reversed by Digibind, potassium returns to the cell causing the serum potassium concentrations to fall. It is possible for there to be a total body deficit of potassium in the presence of digitalis toxicity-induced hyperkalaemia and Digibind treatment could result in a significant hypokalaemia.

Use in pregnancy and lactation: To date there is no evidence that Digibind administered during human pregnancy causes foetal abnormalities; however, the use of Digibind should be considered only if the expected clinical benefit of treatment to the mother outweighs any possible risk to the developing foetus.

Carcinogenesis, mutagenesis, impairment of fertility: There have been no long-term studies performed in animals to evaluate carcinogenic or mutagenic potential or effects on fertility.

Drug interactions: No drug interactions have been identified.

Toxicity and treatment of overdosage: Not relevant.

Pharmaceutical precautions Store between 2 & 8°C. Protect from light. After reconstitution store between 2 and 8°C for up to 4 hours.

Reconstituted product should be used promptly. If it is not used immediately, it may be stored under refrigeration between 2 and 8°C for up to 4 hours. The reconstituted product may be diluted with sterile isotonic saline to a convenient volume.

No drug interactions have been identified

Allergic responses of possible or probable attribution to Digibind have been reported rarely. The development of a pruritic rash (either with or without facial flushing and swelling) or shaking or chills without fever, have occurred on the day of treatment. Urticaria and thrombocytopenia have occurred up to 16 days post treatment. There are no reports of any allergic reactions to re-administration of Digibind in the same patient, but there are few instances on which information is available.

GlaxoSmithKline(GSK)

(POM)

07 May 2009