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DIGIBIND DIGOXIN ANTIBODY (F(AB)) FRAGMENTS 38 MG PER VIAL

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Product Summary
1.

Trade Name of the Medicinal Product

There is no approved SPC for this product

2.

Qualitative and Quantitative Composition
There is no approved SPC for this product

3.

Pharmaceutical Form
There is no approved SPC for this product

4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
DIGOXIN-SPECIFIC ANTIBODY FRAGMENTS ARE INDICATED FOR THE TREATMENT OF
KNOWN OR STRONGLY SUSPECTED DIGOXIN OR DIGITOXIN TOXICITY WHERE
MEASURES
BEYOND WITHDRAWAL OF THE DIGITALIS GLYCOSIDE AND CORRECTION OF ANY
SERUM ELECTROLYTE ABNORMALITY ARE FELT TO BE NECESSARY.
ADMINISTRATION BY INTRAVENOUS INFUSION.

4.2 Posology and Method of Administration
THE DOSAGE OF DIGIBIND VARIES ACCORDING TO THE AMOUNT OF DIGOXIN (OR DIG
OXIN) TO BE NEUTRALIZED.
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-SATE VOLUME OF DISTRIBUTION OF 5
L/K FOR DIGOXIN (0.5L/KG FOR DIGITOXIN) TO CONVERT SERUM DIGITALIS CONCE
NTRATION TO THE AMOUNT OF DIGITALIS IN THE BODY. THESE VOLUMES ARE POPU
LATION AVERAGES AND VERY WIDELY AMONG INDIVIDUALS. MANY PATIENTS MAY
REQ
UIRE HIGHER DOSES FOR COMPLETE NEUTRALIZATION. 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 NONSTEADY-STATE
SERUM
DIGITALIS CONCENTRATIONS. INACCURATE SERUM DIGITALIS CONCENTRATION
MEASUREMENTS ARE 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 NG/ML.
-IF AFTER SEVERAL HOURS TOXICITY HAS NOT ADEQUATELY REVERSED OR APPEARS
TO RECUR, READMINISTRATION OF DIGIBIND AT A DOSE GUIDED BY CLINICAL
JUDGEMENT MAY BE REQUIRED. (SEE PRECAUTIONS AND WARNINGS)

ACUTE INGESTION OF UNKNOWN AMOUNT OF GLYCOSIDE
ADULTS AND CHILDREN OVER 20 KG
IF A PATIENT PRESENTS WITH POTENTIALLY LIFE-THREATENING DIGITALIS TOXICI
TY AFTER ACUTE INGESTION OF AN UNKNOWN AMOUNT FO DIGOXIN, AND NEITHER A
SERUM CONCENTRATION NOR AN ESTIMATE OF THE INGESTED AMOUNT OF
GLYCOSIDE
IS AVAILABLE, 20 VIALS OF DIGIBIND CAN ADMINISTERED. THIS AMOUNT WILL
BE ADEQUATE TO TREAT MOST LIFE-THREATENING INGESTIONS IN ADULTS AND
LARG
E CHILDREN.
AS AN ALTERNATIVE, THE PHYSICIAN MAY CONSIDER ADMINISTERING 10 VIALS OF
DIGIBIND, OBSERVING THE PATIENT'S RESPONSE AND FOLLOWING WITH AN ADDITIO
NAL 10 VIALS IF CLINICALLY INDICATED.
INFANTS AND CHILDREN IN INFANTS AND SMALL CHILDREN ( ING DIGITALIS TOXICITY AFTER ACUTE INGESTION OF AN UNKNOWN AMOUNT OF
DIGOXIN OR DIGITOXIN, WHEN NEITHER A SERUM CONCENTRATION NOR AN
ESTIMATE
OF THE AMOUNT IS AVAILABLE, CLINICAL JUDGEMENT MSUT BE EXERCISED TO
ESTIMATE AN APPROPRIATE NUMBER OF VIALS OF DIGIBIND TO ADMINISTER.
THE ESTIMATE SHOULD BE BASED ON THE MAXIMUM LIKELY TOTAL BODY LOAD OF
AND THE NEUTRALISING CAPACITY OF DIGIBIND (ONE VIAL OF DIGIBIND PER 0.5
MG OF DIGOXIN OR DIGITOXIN-SEE DOSAGE 3.1.3.1) IT IS IMPORTANT TO MONITO
R FOR VOLUME OVERLOAD DURING ADMINISTRATION OF DIGIBIND.
ACUTE INGESTION OF KNOWN AMOUNT OF GLYCOSIDE
EACH VIAL DIGIBIND CONTAINS 38 MG OF PURIFIED DIGOXIN-SPECIFIC FAB
FRAGMENTS WHICH WILL BE 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
DOSE (IN NUMBER OF VIALS) = TOTAL BODY LOAD (MG)
0.5
"FOR FURTHER DETAILS SEE GOLD FILE"
4.3/4.9 Clinical particulars section
A) NONE KNOWN
B) INTERACTIONS
NO DRUG INTERACTION HAVE BEEN IDENTIFIED
C) EFFECTS ON ABILITY TO DRIVE AND TO USE MACHINES
NONE KNOWN
D) OTHER UNDESIRABLE EFFECTS
ALLERGIC RESPONSES OF POSSIBLE OR PROBABLE ATTRIBUTION TO DIGIBIND HAVE
BEEN REPORTED RARELY (SEE PRECAUTINS AND WARNINGS). THE DEVELOPMENT OF
A PRUITIC RASH (EITHER WITH OR WITHOUT FACIAL FLUSHING AND SWELLING) OR
SHAKING AND CHILLS WITHOUT FEVER, HAVE OCCURRED ON THE DAY OF
TREATMENT.
URTICARIA AND THROMBOCYTOPENIA HAVE OCCURED UP TO 16 DAYS POST
TREATMENT
. THERE ARE NO REPORTS OF ANY ALLERGIC REACTIONS TO READMINISTRATION OF
DIGIBIND IN SAME PATIENT, BUT THERE ARE FEW INSTANCE ON WHICH INFORMATIO
N IS AVAILABLE.
E) 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 INLY IF THE EXPECTED CLINICAL BENEFIT OF TREATMENT
TO THE MOTHER OUTWEIGHS ANY POSSIBLE RISK TO THE DEVELOPING FOETUS
F) OTHER SPECIAL WARNINGS
FAILURE TO RESPOND TO DIGIBIND RAISED THE POSSIBILITY THAT THE CLINICAL
PROBLEM IS NOT CAUSED BY DIGITALIS INTOXICATION. IF THERE IS NO RESPONS

E 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 RESPONSE IS DISTINCTLY GREATER
WHERE IS A HISTORY OF ALLERGY TO ANTIBIOTICS OR ASTHMA. SINCE PAPAIN IS
USED TO CLEAVE THE WHOLE ANTIBODY ANTIBODY INTO FAB AND FC FRAGMENTS,
AND TRACES OF PAPAIN OR INACTIVATED PAPAIN RESIDUES MAY BE PRESSENT IN
DIGIBIND, PATIENTS WITH KNOWN ALLERGIES TO PAPAIN, CHYMOPAPAIN OR OTHERE
PAPAYA EXTRACTS WOULD BE PARTICULARLY AT 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 DOSE AN INTACT IMMUNOGLOBULIN
MOLECULE.
MANY PATIENTS WITH MILD OR MODERATE RENAL DYSFUNCTION AND SOME WITH
SEVE
RE 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 FO SERIAL SERUM CREATININE MEASUREMENTS HAS BEEN ONE OF STABLE
OR IMPROVED RENAL FUNCTRION 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 FROM THE BODY IS SLOWED IN THIS SITUATION. A THEORETICAL POSSI
BILITY EXISTS THAT DIGOXIN COULD BE RELEASED AFTER SOME DAYS FROM FAB-DI
GOXIN COMPLEXES WHICH REMAINED IN THE CIRCULATION BECAUSE THEIR
EXCRETIO
N WAS PREVENTED BY RENAL FAILURE. HOWEVER, THIS PHENOMENON HAS PROVED
TO BE RARE.
PATIENTS PREVIOUSLY DEPENDENT ON THE INOTROPISM OF DIGOXIN COUOLD
DEVELO
P SIGNS OF HEART FAILURE WHEN TREATED WITH DIGIBIND. AFTER SUCCESSFUL
MANAGEMNT OF POISONING, DIGOXIN HAS HAD TO BE REINSTITUTED IN SOME CASES
. DURING MANAGMENT, ADDITIONAL INOTROPIC SUPPORT CAN BE OBTAINED FROM
INTRAVENOUS DOPAMINE OR DOBUTAMINE, BUT CAUTION IS REQUIRED AS
CATECHOLA
MINES CAN AGGRAVATE ARRHYTHMIAS CAUSED BY CARDIAC GLYCOSIDES.
LABORATORY TESTS
PATIENTS SHOULD HAVE CONTINUOUS ELECTROCARDIOGRAPHIC MONITORING
MONITORI
NG DURING AND FOR AT LEAST 24 HOURS AFTER ADMINISTRATION OF DIGIBIND.
PRESENCE OF THE EXOGENOUS ANTIBODY FRAGMENTS WILL INTERFERE WITH
RADIOIM
MUNOASSAY MEASUREMENTS OF DIGOXIN.
THE TOTAL SERM 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 RECEITORS IN THE
BODY.
SERUM POTASSIUM CONCENTRATIONS SHOULD BE FOLLOWED CAREFULLY. SEVERE
DIGITALIS INTOXICATION CAN CAUSE LIFE-THREATENING ELEVATION IN SERUM
POTASSIUM CONCENTRATION BY SHIFTING POTASSIUM FROM WITHIN THE CELLSL.
WHEN THE EFFECT OF DIGITALIS IS REVERSED BY DIGIBIND, POTASSIUM RETURNS
TO THE CELL CAUSING THE SERM POTASSIUM CONCENTRATIONS TO FALL. IT IS
POSSIBLE FOR THERE TO BE A TOTAL BODY DEFICIT OF POTASSIUM IN THE PRESEN
CE OF DIGITALIS TOXICITY-INDUCED HYPERKALAEMIA AND DIGIBIND TREATMENT
COULD RESULT IN A SIGNIFICANT HYPOKALAEMIA.

G) OVERDOSE
NOT RELEVANT
H) INCOMPATIBILITIES
NOT KNOWN.

No Data Held
No Data Held
No Data Held
4.6

Pregnancy and lactation
Pregnancy
Treatment of pregnant baboons with digoxin-specific antibody Fab fragments during
a period equivalent to the third trimester in humans showed no adverse effects on
pregnancy or viability of offspring (see Preclinical safety data). There are no animal
data to support use in the first and second trimester.
In the absence of adequate experience of administration of digoxin-specific antibody
Fab fragments to pregnant women, the potential benefit to the mother must be
weighed against the unknown risks to the foetus.
Lactation
It is unknown whether digoxin-specific antibody Fab fragments are excreted in
human milk. Data in animals have shown excretion of digoxin-specific antibody Fab
fragments in milk (see Preclinical safety data).
A risk to the suckling child cannot be excluded. A decision must be made whether to
discontinue breast-feeding or to discontinue digoxin-specific antibody Fab fragment
therapy taking into account the benefit of breast feeding for the child and the benefit
of therapy for the woman.

No Data Held
No Data Held
No Data Held
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
THE AFFINITY CONSTANT (K(D)) OF F(AB) FOR DIGOXIN IS HIGH (10(-10)M)
AND GREATER THAN THAT OF DIGOXIN FOR ITS RECEPTOR (NA-K ATPASE), WHICH
IS IMPLICATED IN THE DIGOXION TOXIC EFFECTS. THE AFFINITY CONSTANT OF
F(AB) FOR DIGITOXIN IS ALSO HIGH (10(-9)M). 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 KINETICS OF
RECEPTOR BINDING TO THAT GOVERNED BY THE KINETICS OF ACCESS AND
ELIMINATION OF F(AB).
IN ANIMALS F(AB) REVERSES DIGOXIN EFFECTS MUGH MORE QUICKLY THAN DOES
IGG. THERE IS A SUGGESTION THAT REVERSAL OF INOTROPY WITH F(AB) LAGS
BEHIND REVERSAL OF ELECTRICAL DYSRHYTHMIC EFFECTS. THIS COULD POSSIBLY

BE DUE TO CELLULAR DIFFERENCES BETWEEN CONTRACTILE AND CONDUCTING
TISSUE, OR TO DIFFERENCES IN ACCESSIBILITY.

5.2 Pharmacokinetic properties
THE PLASMA DISAPPEARANCE HALF-LIFE OF F(AB) IN THE BABOON IS 9-13H
AND THAT OF THE PARENT IGG ANTIBODY IS 61H. THE TOTAL VOLUME OF
DISTRIBUTION OF F(AB) IN THE BABOON IS 8.7 TIMES GREATER THAN THAT OF
IGG AND THE READIER DIFFUSION OF THE SMALLER MOIETY SUFFICIENTLY
ACCOUNTS FOR THIS.
ABOUT 93% OF RADIOACTIVITY LABELLED F(AB), INJECTED INTO BABOONS,
APPEARED IN THE URINE WITHIN 24H AND THE CORRESPONDING AMOUNT OF
DIGOXIN
SPECIFIC IGG WAS LESS THAN 1%. HOWEVER, MUCH OF THE URINARY F(AB) WAS
NOT INTACT. SMALL MOLECULAR WEIGHT PROTEINS ARE CATABOLISED BY THE
KIDNEY, AS AFTER FILTRATION THEY ARE TAKEN UP INTO PROXIMAL TUBULAR
CELLS. F(AB) ELIMINATION IS GREATLY PROLONGED IN NEPHRECTOMISED RATS,
BUT IS ACTUALLY ENHANCED IN RATS WHOSE RENAL TUBULES HAVE BEEN
DAMAGED
BY THE SPECIFIC TOXIN MALEATE.
CORRESPONDING INFORMATION ON HUMAN PATIENTS IS SPARSE, BUT THE
CLOSE RELATIONSHIP OF THERAPEUTIC PERFORMANCE TO PREDICTIONS SUGGESTS
THAT THE ANIMAL DATA WILL BE HELPFUL. THE HUMAN PLASMA DISAPPEARANCE
HALF-LIFE AFTER INTRAVENOUS ADMINISTRATION OF F(AB) IS ABOUT 16H WITH
GOOD RENAL FUNCTION.
SEVERAL PATIENTS WITH RENAL DYSFUNCITON HAVE RECEIVED DIGOXINSPECIFIC F(AB). (FOR FURTHER PARTICULARS PLEASE SEE PRODUCT FILE)

5.3

Preclinical safety data
Carcinogenesis, mutagenesis, impairment of fertility
There have been no long-term studies performed in animals to evaluate carcinogenic,
mutagenic potential or effects on fertility.
Reproductive toxicology
Treatment of 5 pregnant baboons with digoxin-specific antibody Fab fragments. by
intravenous infusion daily for 60 days from approximate Gestation Day 113, which is
equivalent to the third trimester in humans (duration of pregnancy in the baboon is
approximately 180 days), resulted in no treatment-related adverse effects on
tolerability, gestation, parturition or infant viability. Transient antibodies to digoxinspecific antibody Fab fragments were observed in 1 of 5 pregnant animals on Days 15
and 30 of the dosing period, but not later in gestation. Daily exposure to digoxinspecific antibody Fab fragments was at least 3 times higher than average human
exposure, based on dose. Plasma concentrations of digoxin-specific antibody Fab
fragments were detected in all viable infants on Days 7 and 21 postpartum and were 2
to 3 fold higher in infants nursed by mothers.

Pharmaceutical Particulars

6.1.

List of Excipients

There is no approved SPC for this product.

6.2.

Incompatibilities
There is no approved SPC for this product.

6.3.

Shelf Life
There is no approved SPC for this product.

6.4.

Special Precautions for Storage
There is no approved SPC for this product.

6.5.

Nature and Contents of Container
There is no approved SPC for this product.

6.6.

Instruction for Use/Handling
There is no approved SPC for this product.

7

MARKETING AUTHORISATION HOLDER
The Wellcome Foundation Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
Trading as
GlaxoSmithKline UK

Stockley Park West
Uxbridge
Middlesex UB11 1BT

8.

MARKETING AUTHORISATION NUMBER
PL 00003/0207

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF
AUTHORISATION
There is no approved SPC for this product.

10

DATE OF REVISION OF THE TEXT
08/01/2013

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Source: Medicines and Healthcare Products Regulatory Agency

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