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DIGIFAB 40MG/VIAL DIGOXIN IMMUNE FAB POWDER FOR SOLUTION FOR INFUSION

Active substance(s): DIGOXIN IMMUNE FAB (OVINE) / DIGOXIN IMMUNE FAB (OVINE) / DIGOXIN IMMUNE FAB (OVINE)

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
DigiFab®,



2

40 mg/vial digoxin immune Fab, Powder for solution for infusion

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each glass vial of DigiFab® contains 40 mg of digoxin immune Fab (ovine) protein as
a sterile, lyophilized, off white powder.
For a full list of excipients see Section 6.1

3

PHARMACEUTICAL FORM
Powder for Solution for Infusion

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
DigiFab® is indicated for the treatment of known (or strongly suspected) lifethreatening digoxin toxicity associated with ventricular arrhythmias or
bradyarrhythmias unresponsive to atropine where measures beyond withdrawal of
digoxin and correction of serum electrolyte abnormalities are considered necessary.

4.2

Posology and method of administration
It is advised to discuss management of patients with digoxin toxicity with the UK
National Poisons Information Service at the following contact phone number: 0844
892 0111

Management follows a step-wise decision process, as shown:

Step 1

Decide if digoxin poisoning is (i) acute, (ii) acute-on-chronic or (iii)
chronic.

Step 2

Is the patient (i) an adult or a child >20 kg or (ii) a child <20 kg?

Step 3

Is (i) the amount of digoxin ingested known or is (ii) the serum
concentration of digoxin known?

Step 1 (i) Acute digoxin poisoning
Half the estimated dose required for full neutralisation can be given initially followed
by monitoring for 6-12 hours if there is a full response. The remainder may be given
if there is no clinical response within 2 hours.
Rationale: in acute digoxin poisoning, the serum digoxin concentration does not
reflect total body load and complete neutralisation is not necessary in digoxin-naïve
patients.

Step 1 (ii) Acute-on-chronic digoxin poisoning
A full neutralisation dose of DigiFab® can be given if the amount of digoxin ingested
is known. If the amount of digoxin ingested is not known then a half-neutralising
dose of DigiFab® based on serum digoxin concentration should be used followed by
monitoring for 6-12 hours if there is a full response. The remainder may be given if
there is no clinical response within 2 hours.
The usual dose for adults and children over 20 kg may vary between one half of a vial
(20 mg DigiFab®) to 20 vials (800 mg DigiFab®). More vials may be needed
dependent upon the amount of digoxin consumed.
Step 1 (iii) Chronic digoxin poisoning
Half the estimated dose required for full neutralisation can be given initially followed
by monitoring for 6-12 hours. The remainder may be given if there is recurrence of
toxicity.

Rationale: in chronic digoxin poisoning, the dose of antibody required for full
neutralisation depends on the total body load of cardiac glycoside which has to be
counteracted. However, as these patients are receiving digoxin therapeutically, full
neutralisation is not necessary.

Dose calculation for full neutralisation in digoxin poisoning:

Step 2 (i) Adults and children > 20 kg

Step 3 (i)

Dose of digoxin ingested known
Full neutralisation dose of DigiFab® is:
Number of vials = Amount of digoxin ingested (mg) x 1.6
Round up to the nearest vial
To calculate the number of milligrams to be prescribed: multiply
the number of vials by 40 (as there are 40 mg/vial).

Step 3 (ii)

Serum digoxin concentration known
Full neutralisation dose of DigiFab® is:
Number of vials =
[ serum digoxin concentration (ng/mL) X weight (kg) ] / 100
Round up to the nearest vial
To calculate the number of milligrams to be prescribed: multiply
the number of vials by 40 (as there are 40 mg/vial).

Step 2 (ii) Children <20 kg

Step 3 (i)

Serum digoxin concentration known
Full neutralisation dose of DigiFab® is:
Number of vials =
[ serum digoxin concentration (ng/mL) X weight (kg) ] / 100
Round up to the nearest vial
To calculate the number of milligrams to be prescribed: multiply
the number of vials by 40 (as there are 40 mg/vial).

Step 3
Alternate for
children <20kg

Serum digoxin concentration not known
One vial of DigiFab® will usually be sufficient for full
neutralisation.

when serum
digoxin not
known

Converting units of digoxin ng/mL to / from nmol/L
ng/mL (or µg/L) x 1.28 = nmol/L
nmol/L x 0.781 = ng/mL (or µg/L)

Method of administration

DigiFab® should be reconstituted prior to administration according to the instructions
provided in section 6.6.
The final solution of DigiFab® should be infused intravenously over a 30 minute
period.

4.3

Contraindications
Hypersensitivity to the active substance or any of the excipients.

4.4

Special warnings and precautions for use
UK National Poisons Information Service
It is advised to discuss management of patients with digoxin toxicity with the UK
National Poisons Information Service at the following contact phone number: 0844
892 0111
General management of patients
Dosage estimates are based on a steady-state volume of distribution of 5 L/kg for
digoxin in order to convert serum digitalis concentration to the amount of digitalis in
the body. These volumes are population averages and vary widely among individuals.
Ordinarily, improvements in signs and symptoms of digoxin toxicity begin within 30
minutes following administration of DigiFab®.
Patients should have continuous electrocardiographic monitoring during and for at
least 24 hours after administration of DigiFab®. Temperature, blood pressure and
potassium concentration should be monitored during and after DigiFab®
administration.
Patients previously dependent on the inotropism of digoxin may develop signs of
heart failure when treated with DigiFab®. After successful management of poisoning,
digoxin has had to be reinstituted in some cases.
If, after several hours, toxicity has not adequately reversed or appears to recur, readministration of DigiFab® at a dose guided by clinical judgement may be required.
Failure of the patient to respond to DigiFab® should alert the physician to the
possibility that the clinical problem may not be due to digoxin toxicity.

Suicidal ingestion may involve more than one drug. Toxic effects of other drugs
or poisons should not be overlooked, particularly where failure to respond to
DigiFab® raises the possibility that the clinical problem is not caused by digoxin
intoxication. If there is no response to an adequate dose of DigiFab®, the
diagnosis of digoxin toxicity should be questioned.
There is no information on re-administration of DigiFab® to patients for a second
(or more) episode of digoxin toxicity.
Risk of infusion-related reactions or hypersensitivity
As with any intravenous protein product, infusion-related reactions or
hypersensitivity reactions are possible. It is recommended that patients are
monitored for signs and symptoms of anaphylaxis and an acute allergic reaction.
Medical support must be readily available when DigiFab® is administered.
If an anaphylactic reaction occurs during an infusion then administration of
DigiFab® must be stopped immediately.
The likelihood of an allergic reaction may be higher in subjects who:


are allergic to sheep-derived proteins (as may be found in cheeses and
meats). DigiFab® is produced from sheep protein.



are allergic to papain, an extract of the papaya fruit. Papain is used to
cleave the whole antibody into Fab and Fc fragments: traces of papain or
inactivated papain residues may be present in DigiFab®. Papain shares
allergenic structures with (i) chymopapain and other papaya extracts, (ii)
bromelain found in pineapple, (iii) dust mite allergens and (iv) latex
allergens.

Impaired renal function
It may be expected that excretion of the Fab-digoxin complexes from the body is
slowed in the presence of renal impairment and that digoxin may be released after
some days from retained Fab-digoxin complexes.
Impaired hepatic function
There is no information on the use of DigiFab® in subjects with hepatic
impairment.
Laboratory tests
Digoxin assay kits may not be able to measure accurately digoxin concentrations
greater than 5 ng/mL (6.4 mmol/L). Exercise caution when using digoxin
concentrations above these figures to calculate the dose of DigiFab® required.

Presence of the exogenous antibody fragments will interfere with immunoassay
measurements of digoxin. 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.
General handling
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Repeated use
There are not any data on repeated dosing of DigiFab®. Repeat dosing with
DigiFab® may give rise to an anaphylactic reaction. Repeat dosing must only be
done when it is considered that clinical benefit outweighs risk.

4.5

Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.

4.6

Fertility, Pregnancy and lactation
Pregnancy
There are no data on the use of DigiFab® in pregnant women. The use of DigiFab®
should be considered only if the expected clinical benefit of treatment to the mother
outweighs any possible risk to the developing foetus.
Lactation
It is not known whether DigiFab® is excreted in human milk
A risk to the suckling child cannot be excluded.
Breast-feeding should be discontinued during treatment with DigiFab®
Fertility
There are no fertility data

4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been
performed

Undesirable effects
Adverse reactions reported from 23 subjects in clinical studies are listed below
according to system organ class.
Adverse reactions are ranked by frequency, the most frequent first, using the
following convention: very common ( 1/10); common ( 1/100 to <1/10); uncommon
( 1/1,000 to <1/100); rare ( 1/10,000 to <1/1,000) very rare (<1/10,000), including
isolated reports.









4.8

Exacerbation of low cardiac output states and congestive heart failure or a rapid
ventricular response in patients with atrial fibrillation may occur owing to withdrawal
of effect of digoxin.

Adverse reactions may occur up to 14 days after the infusion has been administered.
System organ class

Frequency

Undesirable effect

Metabolism and nutrition disorders

Common

Hypokalaemia, hyperkalaemia

Nervous system disorders

Common

Headache, confusional state

Gastrointestinal disorders

Common

Nausea, vomiting, diarrhoea,
constipation, abdominal distension

Cardiac disorders

Common

Worsening of cardiac failure
Chest pain
Hypotension
Orthostatic hypotension

Musculoskeletal and connective
tissue disorders

Common

Influenza-like illness

Renal and urinary disorders

Common

Renal failure

General disorders and
administration site conditions

Common

Fatigue

4.9

Overdose
No case of overdose has been reported

Infusion site phlebitis

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
ATC Code: VO3A B24 Digitalis antitoxin
DigiFab® has a high affinity for digoxin.
DigiFab® binds digoxin and so reduces the concentration of free digoxin.
When DigiFab® is administered to a patient with digoxin toxicity, there is a reduction
in the serum concentration of free digoxin leading to a reduction in toxicity.

5.2

Pharmacokinetic properties
In a study of healthy volunteers who were administered 76 mg of DigiFab® iv 2 hours
after 1 mg digoxin iv, the serum elimination half-life of DigiFab® was (about) 15
hours.

5.3

Preclinical safety data
There are no preclinical safety data of relevance to the prescriber that are additional to
safety data already included in other sections of the SPC.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium acetate
Acetic acid
Mannitol

6.2

Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed
with other medicinal products.

6.3

Shelf life
3 years
From a microbiological point of view, the product should be used immediately after
reconstitution.

6.4

Special precautions for storage
Store between 2 & 8°C. Do not freeze.
Keep vial in outer carton in order to protect from light.
For storage conditions of the reconstituted medicinal product see section 6.3

6.5

Nature and contents of container
Single clear, neutral glass vial closed with a butyl rubber stopper and fitted with an
aluminum flip top seal. One glass vial containers in an outer pack.

6.6

Special precautions for disposal
Instructions for Disposal
Any unused product should be disposed of in accordance with local requirements.
General Instructions
For single use only. Use immediately after reconstitution. The reconstituted solution
should be a clear to slightly opalescent, colourless to pale yellow solution.
Method of Preparation for Administration
Each vial should be reconstituted with 4 mL of sterile Water for Injection by gentle
mixing. This produces an approximately isosmotic solution with a protein

concentration of 10 mg/mL that may be diluted further to any convenient volume
with sterile saline suitable for infusion.

7

MARKETING AUTHORISATION HOLDER
Protherics UK Limited
Blaenwaun, Ffostrasol,
Llandysul, Ceredigion, SA44 5JT

8

MARKETING AUTHORISATION NUMBER(S)
PL 21744/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/07/2011

10

DATE OF REVISION OF THE TEXT
01/07/2011

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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