Digoxin Immune Fab (Ovine) - DigiFab; ovine immune globulin Fab fragments
Status: marketed in U.S.; European filings pending/-expected
Organizations involved:
Protherics Inc. – Manuf.; R&D; Tech.
Protherics PLC – Parent
BTG plc – Parent; World mark.
Fougera, Inc. – Former
Nycomed Group – Parent; Former
Beacon Pharmaceuticals plc – ; Former
Altana Inc. – Former
ALTANA Pharma AG – Parent.; Former
Byk Gulden S.A. – Parent; Former
Cross ref.: See the Antivenin Products entry (#906) and the entry above (#913) for Digoxin Immune Fab (Ovine), Digibind, from GlaxoSmithKline (GSK).
Description: Digoxin Immune Fab (Ovine) from Protherics or DigiFab is a purified lyophilized formulation of digoxin-immune ovine (sheep) Fab (monovalent) immune globulin (antibody) Fab fragments. Digoxin-binding immune globulin Fab fragments are enzymatically derived from pooled digoxin-specific ovine (sheep) immune globulin containing polyclonal antibodies from digoxin-immunized sheep. The antibody fragments have a molecular weight of approximately 46,000 Da (46 kDa).
DigiFab, like DigiBind, is used for treatment (as an antidote) for digitalis (and digoxin) overdosage (poisoning). The Fab fragments in bind digitalis/digoxin molecules, making them unavailable for binding at their site of action on cells in the body. The complexes accumulate in the blood and are excreted by the kidneys. The net effect is to shift the equilibrium from binding of digoxin to its receptors in the body, reversing the drug’s toxic effects.
Each vial of DigiFab contains 40 mg of digoxin immune Fab (which will bind ~0.5 mg digoxin), ~75 mg of mannitol USP, and ~2 mg sodium acetate as a buffering agent. The product contains no preservatives and is intended for intravenous administration after reconstitution with 4 mL of Sterile Water for Injection USP. The dating period when stored at 2-8˚C (refrigerated) is 36 months from the date of manufacture, defined as the date of the initial sterile filtration of the formulated bulk.
Two unspecified viral clearance process steps of dissimilar mode of action are employed in the manufacturing process. This may refer to papain digestion and affinity chromatography for viral inactivation and elimination, respectively. Acetonitrile is a processing residual in DigiFab. The product meets the final CH guideline Q3C for residual solvents at a limit of detection of 1.4 ppm (1.4 pg/g). Mercury, a component of thimerosal used by Protherics in the manufacture of the similar product, CroFab, is assayed as a precaution.
Nomenclature: Digoxin Immune Globulin, ovine Fab/Protherics [BIO]; DigiFab [TR]; Digoxin Immune Fab (Ovine) [FDA]; ovine digoxin-specific antibody Fab fragments [SY]
Biological.: Digoxin (and digitalis) 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. DigiFab (and similarly, Digibind) 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 the toxic effects of digoxin are reversed by DigiFab, i.e., circulating digoxin removed from the circulation, potassium shifts back into the cell with a resulting decline in serum potassium concentration.
Companies.: DigiFab was developed and is manufactured by Protherics Inc. (Brentwood, TN) CBER/FDA est. no. 1575, a subsidiary of Protherics PLC. Sheep are raised and/or sheep blood is initially processed at facilities in Melbourne, Victoria, Australia.
Originally ,DigiFab was marketed in the U.S. by the Savage Laboratories, a division of ALTANA Pharma AG., a subsidiary of Byk Gulden S.A. At the start of 2007, Nycomed acquired ALTANA Pharma AG, and DigiFab is now marketed in the U.S. by Fougera, a subsidiary of Nycomed. Protherics receives 50% of total sales. U.S. marketing rights will revert to Protherics in 2010.
Beacon Pharmaceuticals plc has most continental European marketing rights. Protherics retains marketing rights in Germany and the Nordic countries.
In Nov. 2006, Protherics exclusively licensed marketing rights to Digitalis Antidot® from Hoffmann-La Roche., with Protherics intending to replace this product with DigiFab in early 2007.
In 2008, BTG plc acquired Protherics. BTG began U.S. sales in Oct. BTG now has exclusive marketing rights.
Manufacture: Healthy sheep are immunized with digoxindi-carboxymethoxylamine (DDMA), a digoxin analog containing a cyclopenta-per-hydro-phen-an-threne:lactone ring moiety (from digoxin) coupled to keyhole limpet hemocyanin (KLH) as a protein hapten to boost immune responses to the digoxin moiety. The sheep are from Australian pathogen and prion-free herds. The immunoglobulin fraction of the ovine serum is isolated and digested with papain. This enzyme derived from papaya cleaves whole immune globulin antibodies into Fab and Fc fragments. Digoxin-specific Fab fragments are isolated and purified by affinity chro-matography (presumably, using matrix-bound digoxin or DDMA).
FDA Class: Biologic BLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 20010813; BLA, first approval
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:
DigiFab is indicated for the treatment of patients with life-threatening or potentially life threatening digoxin toxicity or overdose. Although designed specifically to treat digoxin overdose, a product very similar to DigiFab (Digibind) has been used successfully to treat life-threatening digitoxin overdose. Since human experience is limited, and the consequences of repeated exposure are unknown, DigiFab is not indicated for milder cases of digitalis toxicity. Clinical conditions requiring administration of DigiFab include: Known suicidal or accidental consumption of fatal doses of digoxin, including ingestion of 10 mg or more of digoxin in previously healthy adults, 4 mg (or more than 0.1 mg/kg) in previously healthy children, or ingestion causing steady state serum concentrations greater than 10 ng/mL; Chronic ingestions causing steady-state serum digoxin concentrations exceeding 6 ng/mL in adults or 4 ng/mL in children; and Manifestations of life-threatening toxicity due to digoxin overdose, including severe ventricular arrhythmias (such as ventricular tachycardia or fibrillation), progressive bradycardia, and second or third degree heart block not responsive to atropine, serum potassium levels exceeding 5.5 mEq/L in adults or 6 mEq/L in children with rapidly progressive signs and symptoms of digoxin toxicity.
Status: In Sept. 2004, Protherics filed for approval of DigiFab in the U.K., in conjunction with Beacon Pharmaceuticals, its European distribution partner. In early 2007, U.K. approval was expected in the 1st-half 2007; approvals in several other European countries were expected in 2007 or early 2008, and Canadian approval was expected in 2008.
DigiFab was approved by FDA based primarily on small comparative, rather than large Phase III-type placebo-controlled, studies. In this context, with its abbreviated filing/approval, some might now call it a biogeneric, biosimilar, follow-on biologic, etc. product.
In “The FDA’s assessment of follow-on protein products: a historical perspective,” Nature Reviews Drug Discovery, published online 13 April 2007, FDA justified (rationalized) its prior biogeneric (follow on protein/biologic, biosimilar, biocomparable, etc)-like abbreviated approvals, including that for DigiFab. FDA stated, “The original product developed for this indication [treat life-threatening or potentially life-threatening overdoses with digoxin], Digibind (GlaxoSmithKline), was derived from sheep that were immunized with digoxin linked to albumin. The effectiveness of Digibind in reversing digoxin toxicity was demonstrated in a study of 150 subjects with life-threatening digitalis toxicity. DigiFab was determined to be safe and effective in reversing life-threatening digoxin toxicity in a study of 15 subjects (digoxin toxicity was completely resolved in 14 out of 15 subjects in 20 hours). The study demonstrated that the ability of DigiFab to reverse digoxin toxicity was comparable with historical data for Digibind. In addition, a study in healthy volunteers demonstrated that pharmacodynamic and pharmacokinetic properties of DigiFab and Digibind were comparable 2 hours after digoxin administration. Thus DigiFab was approved on the basis of a small study demonstrating its safety and effectiveness in reversing life-threatening digoxin toxicity, an understanding of its mechanism of action and data indicating that its pharmacodynamic and pharmacokinetic parameters were comparable with those for Digibind.”
Disease: Digoxin is a widely prescribed drug for the treatment of cardiac conditions, which has a narrow therapeutic range, and can cause life-threatening toxicity through overdose or a gradual build up in the body during normal treatment. About 7,500 cases of digoxin poisoning occur every year in Europe and the U.S., with an estimated market size of $20 million/year (according to Protherics), and the majority of use in the U.S.
Trials: Clinical trials with Digi-Fab met their primary endpoint, with serum free digoxin concentrations in all patients falling to undetectable levels following DigiFab administration. A comparative trial found similar pharmacokinetic profiles for DigiFab and Digibind. DigiFab and Digibind have similar volumes of distribution (0.3 L/kg and 0.4 L/kg, respectively), indicating considerable penetration from the circulation into the extracellular space; and similar elimination half-life values, 15 hours and 23 hours, respectively. Also, equi-valent responses were observed in rats tested with both DigiFab and DigiBind.
Medical: DigiFab is administered by intravenous infusion over 30 minutes, or as a bolus in the case of imminent cardiac arrest. The recommended dose is equimolar to the estimated amount of digoxin or digitoxin in the body. 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. 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.
DigiFab is also used for the treatment of oleander poisoning in Sri Lanka. Oleander, a plant commonly found in South East Asia, contains substances similar to digitalis.
Market: The 2007 Average Wholesale Price (AWP) is $600/vial (no change from 2004) (Red Book, 2007).
Protherics has estimated the potential market for DigiFab to be $25 million (2006 annual report).
For FY2006, Protherics reported revenue $5.1 million (from sales to Altana/Fougera for U.S. marekting), down from $6.7 million in FY2005. For FY2004, Protherics reported £6.0 million (~$10.5 million) in revenue received from Digibind and £1.2 million (~2.1 million) in 2003.
In FY2006, Protherics shipped 14,235 cartons of DigiFab, receiving £1.2 million on shipment, £1.3 million royalty on Fougera sales, and £0.2 million other sales.
DigiFab is the leading digoxin antidote in the U.S. (as reported by Protherics in Jan. 2007). The current market for DigiFab is on the order of $20 million/year, based on information from Protherics. In Jan. 2007, Protherics estimated that the market opportunity for digoxin antidotes outside of the US is approximately $-$10 million/year, and that “the digoxin antidote market [is]worth an estimated $30 million per annum.” In Sept. 2004, Protherics estimated the total digoxin antidotes market to be over $30 million. The company previously estimated that DigiFab held about two-thirds of the market (for digoxin/digitalis immune globulins), with DigiBind holding the other third. Contributing to this, Protherics sells DigiFab at a 20% discount relative to DigiBind.
Ongoing: A Phase IIb, double blind, placebo-controlled study is ongoing in the U.s. in 50 women with severe
pre-eclampsia.
Companies involvement:
Full monograph
914 Digoxin Immune Globulin, ovine Fab/Protherics
Nomenclature:
Digoxin Immune Globulin, ovine Fab/Protherics [BIO]
DigiFab [TR]
Digoxin Immune Fab (Ovine) [FDA]
ovine digoxin-specific antibody Fab fragments [SY]
FDA Class: Biologic PLA
Year of approval (FDA) = 1986
Date of 1st FDA approval = 19860422
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
antivenins
biopharmaceutical products
Biorex-70 resin
blood products
immune globulins, Fab fragments <!-- immunoglobulins -->
immune globulins, ovine <!-- immunoglobulins -->
ovine (sheep) immune globulins <!-- immunoglobulins -->
ovine (sheep) source materials
acetone
adw, hepatitis B virus subtype
cyanogen bromide (CNBr)
cyanogen bromide (CNBr)
digoxin (or digitoxin)
digoxin-albumin conjugate
immunoaffinity chromatography
keratinocytes, human
lyophilized (freeze-dried)
mannitol
meningitis prophylaxis
ovine (sheep) plasma
papain digestion
sodium acetate
Sterile Water for Injection
thimerosal (mercury derivative)
apheresis (hemapheresis)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
BHK-21 (C-13)
North American coral snake
EU001 EU application expected
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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