DIGIFAB 40 MG / VIAL DIGOXIN IMMUNE FAB POWDER FOR SOLUTION FOR INFUSION - patient leaflet, side effects, dosage

Patient Information Leaflet

DigiFab®, 40 mg/vial, Powder for solution for infusion (referred to as DigiFab® hereafter in this leaflet).

digoxin immune Fab

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor.
• If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See Section 4.

In this leaflet:

• 1. What DigiFab® is and what it is used for

• 2. What you need to know before you are given DigiFab®

• 3. How DigiFab® will be given

• 4. Possible side effects

• 5. How DigiFab® will be stored

• 6. Contents of the pack and Further information

1. what digifab® is and what it 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. what you need to know beforeyou 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).

Warnings and precautions. Before you are given 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.

Children

There is limited information on the use of DigiFab in children.

Taking other medicines and DigiFab® Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

There is no information on the use of DigiFab® in pregnant women or women who are breastfeeding. 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®.

Driving and using machines

There is no information on whether DigiFab® affects the ability to drive or operate machines. Ask your doctor for advice.

• 3. HOW DIGIFAB® WILL BE GIVEN

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.

Use in children and adults

The usual dose for adults and children over 20kg may vary between one half of a vial (20mg DigiFab®) to 20 vials (800mg DigiFab®).

Your doctor will record the batch number of the DigiFab® given to you and this information will be kept in your patient file.

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.

SUMMARY OF PRODUCT CHARACTERISTICS (Information for the Healthcare Professional)

BTG

• 1. NAME OF THE MEDICINAL PRODUCT

DigiFab® (referred to as DIGIFAB) 40 mg/vial digoxin immune Fab, Powder for solution for infusion

• 2. 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) 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
  
  Posology

  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-naive 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 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)

Paediatric population

The safety and efficacy of DIGIFAB in children has not yet been established.

Method of administration

DIGIFAB should be reconstituted prior to administration according to the instructions provided in section 6.6.

The final solution of reconstituted and diluted DIGIFAB should be infused intravenously over a 30 minute period. Record the name of the patient and batch number of the product in order to maintain a link between the patient and the batch of the product.

• 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.

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. 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 the risk.

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). Digoxin immune Fab 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.

Immunoassay interference/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 is required. DIGIFAB may interfere with digoxin immunoassay measurements. Therefore, standard serum digoxin measurements may be clinically misleading until the Fab fragments are eliminated from the body. This may take several days or more than a week in patients with impaired renal function. The total serum digoxin concentration as measured by immunoassay may rise rapidly following administration of DIGIFAB. Serum digoxin will be almost entirely bound by DIGIFAB and therefore not able to react with receptors in the body.

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 completion of 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, re-administration 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

4. possible side effects

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.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

6. contents of the pack and other 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 Ltd, Blaenwaun, Ceredigion SA44 5JT, UK.

This leaflet was last approved in December 2017.

Distributed by: Protherics Medicines Development Ltd, 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.

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.

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.

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 no data on repeated dosing of DIGIFAB.

Paediatric population

There is limited information on the use of DIGIFAB in the paediatric population.

• 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.

Breastfeeding

It is not known whether DIGIFAB is excreted in human milk. A risk to the breast-feeding child cannot be excluded. Breastfeeding 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 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.

Summary of the safety profile

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

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.

Tabulated list of adverse reactions

Adverse reactions reported from 23 subjects in clinical studies are listed below according to system organ class.

System organ class	Frequency	Adverse reactions
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 Infusion site phlebitis

Paediatric population

No paediatric patients were included in the clinical studies in support of the indication.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at:.

• 4.9. Overdose

No case of overdose has been reported in adults or paediatrics.

• 5. PHARMACOLOGICAL PROPERTIES

  • 5.1. Pharmaco­dynamic properties

ATC Code: VO3A B24 Digitalis antitoxin

Mechanism of action

Digoxin immune Fab has a high affinity for digoxin.

Pharmacodynamic effect

Digoxin immune Fab binds digoxin and so reduces the concentration of free digoxin.

Clinical efficacy and safety

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.

Paediatric population

There is limited information on use in the paediatric population.

• 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.

Renal impairment

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.

Hepatic impairment

There is no information on the use of DIGIFAB in subjects with hepatic impairment.

Paediatric population

No data are available.

• 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 and 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 (0.9% NaCl) 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

First authorization: 01/07/2011

Renewal: 15/03/2016

• 10. DATE OF REVISION OF THE TEXT