Digifab 40mg/Vial Digoxin Immune Fab Powder For Solution For Infusion
Patient Information Leaflet
DigiFab®, 40 mg/vial digoxin immune Fab, Powder for solution for infusion (referred to as DigiFab® hereafter in this leaflet).
Read all of this leaflet carefully before you are given this medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.
In this leaflet:
1. What DigiFab® is and what it is used for
2. Before you are given DigiFab®
3. How DigiFab® will be given
4. Possible side effects
5. How DigiFab® will be stored
6. Further information
1. WHAT DIGIFAB® IS AND WHAT FT IS USED FOR
DigiFab® belongs to a group of medicines known as digitalis antitoxins. It is a preparation of protein fragments derived from antibodies produced in sheep. DigiFab® binds and neutralises digoxin.
DigiFab® solution is used to treat an overdose of digoxin when stopping taking digoxin and other measures are not sufficient.
2. BEFORE YOU ARE GIVEN DIGIFAB®
You should not be given DigiFab® if you
are allergic to DigiFab® or to any of the other ingredients of DigiFab® (for other ingredients see section 6 Other information).
Take special care with DigiFab®. Before you take DigiFab® you should tell your doctor if:
• You are allergic to papaya extracts, to pineapple or to sheep proteins (sheep protein may be found in cheeses and some meats).
• You are taking digoxin for heart problems. DigiFab® neutralises digoxin and may cause a worsening of your heart condition).
• You have been treated previously with DigiFab®. Repeat use of DigiFab® may be associated with a severe allergic reaction.
If any of the above apply to you then talk to your doctor who will decide what to do.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
There is no information on the use of DigiFab® in pregnant women or women who are breast-feeding. If you are pregnant, likely to become pregnant or are breast-feeding then you must tell your doctor before taking this medicine. Your doctor will have taken this into account before giving DigiFab®.
There is no information on whether DigiFab® affects the ability to drive or operate machines. Ask your doctor for advice.
Your doctor or nurse will usually give you DigiFab® by infusion into a vein. The powder in each vial will be dissolved in sterile water and may be further diluted with sterile saline solution.
Your doctor will calculate the amount of DigiFab® that you will be given depending on how much digoxin you have in your body.
The usual dose for adults and children over 20kg may vary between one half of a vial (20mg DigiFab®) to 20 vials (800mg DigiFab®).
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Technical Leaflet
(Information for the Healthcare Professional)
BTG
1. NAME OF THE MEDICINAL PRODUCT
DigiFab®T, 40 mg/vial digoxin immune Fab, Powder for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each glass vial of DigiFab9 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
DigiFab9 is indicated for the treatment of known (or strongly suspected) life-threatening 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
|
Step 1 |
Decide if diqoxin poisoninq 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? |
Management follows a step-wise decision process, as shown:_
Step 1 (i) Acute diooxin 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-nai've patients.
Step 1 (ii) Acute-on-chronic diooxin poisoning
A full neutralisation dose of DigiFab9 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 DigiFab9 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 DigiFab9) to 20 vials (800 mg DigiFab9). More vials may be needed dependent upon the amount of digoxin consumed.
Step 1 (iii) Chronic diooxin 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 tor 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 DigiFab9 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 when serum digoxin not known |
Serum digoxin concentration not known One vial of DigiFab® will usually be sufficient for full neutralisation. |
Converting units of digoxin ng/mL to / from nmol/L ng/mL (or pg/L) x 1.28 = nmol/L nmol/L x 0.781 = ng/mL (or pg/L)
Method of administration
DigiFab9 should be reconstituted prior to administration according to the instructions provided in section 6.6.
The final solution of DigiFab9 should be infused intravenously over a 30 minute period.
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 tor 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 DigiFab9.
Patients should have continuous electrocardiographic monitoring during and tor at least 24 hours after administration of DigiFab9. Temperature, blood pressure and potassium concentration should be monitored during and after DigiFab9 administration.
Patients previously dependent on the inotropism of digoxin may develop signs of heart failure when treated with DigiFab9. 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, re-administration of DigiFab9 at a dose guided by clinical judgement may be required.
Failure of the patient to respond to DigiFab9 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 DigiFab9 raises the possibility that the clinical problem is not caused by digoxin intoxication. If there is no response to an adequate dose of DigiFab9, the diagnosis of digoxin toxicity should be questioned.
There is no information on re-administration of DigiFab9 to patients tor 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 DigiFab9 is administered.
If an anaphylactic reaction occurs during an infusion then administration of DigiFab9 must be stopped immediately.
You will be monitored with blood tests and continuous heart monitoring during DigiFab® treatment and for at least 24 hours after DigiFab® treatment has been finished.
If you think you have been given too much DigiFab®
The MA holder is not aware of any patients who have suffered DigiFab® overdoses, so no information on overdose is available.
However, if you think you have been given too much DigiFab® tell a doctor or nurse or pharmacist immediately.
If you have further questions on the use of this product, ask your doctor or pharmacist.
Like all medicines, DigiFab® can cause side effects, although not everybody gets them.
The following side effects are important and will require immediate action if you experience them. Tell your doctor or nurse immediately if you experience any of the following symptoms (you may need to stop DigiFab®):
• a sudden allergic reaction with shortness of breath, rash, wheezing and drop of blood pressure
• allergic skin reactions such as rash, itchy skin, hives
• fever
The frequencies at which the above reactions occur are not stated.
The following side effects have also been reported:
Common, affecting up to 1 in 10 people:
• Worsening of heart failure causing retention of fluid
• Chest pain
• Low blood pressure
• Changes in blood test results for potassium (this may affect how the heart works or cause tiredness, weakness or pins and needles)
• Severe kidney disease
• Light-headedness on standing
• Inflammation of vein at site of infusion
• Flu-like symptoms
• Headache, feeling confused, feeling tired
• Nausea, vomiting, diarrhoea or constipation, abdominal distension
Symptoms may occur up to 14 days after the infusion.
If any of the side effects gets serious, or you notice any side effects not mentioned in this leaflet, please tell your doctor or nurse.
You will be given DigiFab® in a hospital. The hospital will store the medicine correctly between 2 and 8°C. Not to be stored in a freezer.
After DigiFab® has been made up, it should be used immediately.
DigiFab® must not be used after the expiry date on the vial and outer carton. The hospital pharmacist will check this before he/she dispenses DigiFab®.
All medicines should be kept out of the reach and sight of children.
6. FURTHER INFORMATION What DigiFab® contains
• The active substance is digoxin immune Fab.
• The other ingredients are sodium acetate, acetic acid and mannitol.
What DigiFab® looks like and contents of the pack
DigiFab® is supplied as a sterile, off-white powder in a clear glass vial, closed with a rubber stopper and aluminium flip top seal. Each vial contains 40mg digoxin immune Fab protein.
Each pack contains 1 vial.
Marketing Authorisation Holder and Manufacturer
The marketing authorisation holder is Protherics UK Limited, Blaenwaun, Ceredigion SA44 5JT, UK.
This leaflet was last approved in November
Distributed by:
Protherics Medicines Development Limited, A BTG International group company, 5 Fleet Place, London, EC4M 7RD
#
BTG
BTG and the BTG roundel logo are registered trademarks of BTG International Ltd
DigiFab® is a registered trademark of BTG International Inc.
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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. Interactions 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
4.8. 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 (S1/10); common (S1/100 to <1/10); uncommon (al/1,000to <1/100); rare (al/10,000 to <1/1,000) very rare (<1/10,000), including isolated reports.
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 orqan 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 diserders |
Common |
Worsening of cardiac failure Chest pain Flypotension Orthostatic hypotension |
|
Musculoskeletal and connective tissue disorders |
Common |
Influenza-like illness |
|
Renal and urinary disorders |
Common |
Renal failure |
|
General disorders and administration site |
Common |
Fatigue |
|
conditions |
Infusion site phlebitis |
4.9. Overdose
No case of overdose has been reported
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
ATC Code: V03A 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 preserver 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 container 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 PL 21744/0001
9. DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION
1 July 2011
10. DATE OF REVISION OF THE TEXT
1 July 2011
DigiFab® is a registered trademark of BTG International Inc.
BTG and the BTG roundel logo are registered trademarks of BTG International Ltd
P21744B Revision date Feb-12