Tracrium 10mg/ml, Solution for Injection or Infusion, vials

Text in red = new text
Text strikethrough = deleted text

 

7.         MARKETING AUTHORISATION HOLDER

           

GlaxoSmithKline (Ireland) Limited

12 Riverwalk,

Citywest Business Campus,

Dublin 24

Aspen Pharma Trading Limited,

3016 Lake Drive,

Citywest Business Campus,

Dublin 24,

Ireland

 

 

8.         MARKETING AUTHORISATION NUMBER

 

PA 1077/81/2 PA 1691/029/002

 

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

 

            28 Jan 2016 August 2017

Text in red = new text
Text strikethrough = deleted text

 

7.         MARKETING AUTHORISATION HOLDER

           

GlaxoSmithKline (Ireland) Limited

12 Riverwalk,

Citywest Business Campus,

Dublin 24

Aspen Pharma Trading Limited,

3016 Lake Drive,

Citywest Business Campus,

Dublin 24,

Ireland

 

 

8.         MARKETING AUTHORISATION NUMBER

 

PA 1077/81/2 PA 1691/029/002

 

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

 

            28 Jan 2016 August 2017

QRD v9 updates to the following sections:

4.2       Posology and method of administration

4.3       Contraindications

4.8       Undesirable effects

QRD v9 updates to the following sections:

4.2       Posology and method of administration

4.3       Contraindications

4.8       Undesirable effects

Section 9 - renewal appproved and date added.

Section 9 - renewal appproved and date added.

Section 7 - change to Ireland MAH address

Section 7 - change to Ireland MAH address

Section 4.2 - reformatting eg "use in children" replaced "children"

Section 4.5 - spelling and grammer changes throughout

Section 5.1 - addition of headings, addition of ATC code

Section 5.2 - addition of headings and reformatting

Section 6.4 - additional wording on precautions for storage

Section 4.2 - reformatting eg "use in children" replaced "children"

Section 4.5 - spelling and grammer changes throughout

Section 5.1 - addition of headings, addition of ATC code

Section 5.2 - addition of headings and reformatting

Section 6.4 - additional wording on precautions for storage

Section 4.2 - additional wording on use in neonates
Section 5.1 - additional wording on paediatric population

Section 4.2 - additional wording on use in neonates
Section 5.1 - additional wording on paediatric population

Changes to:

Section 4.4 - Special warnings and precautions for use,
Section 4.5 - Interaction with other medicinal products and other forms of interaction,
Section 4.6 - Pregnancy and lactation,
Section 4.7 - Effects on ability to drive and use machines,
Section 6.6 - Special precautions for disposal

 

 

 

 

 

 

 

 

 

Changes to:

Section 4.4 - Special warnings and precautions for use,
Section 4.5 - Interaction with other medicinal products and other forms of interaction,
Section 4.6 - Pregnancy and lactation,
Section 4.7 - Effects on ability to drive and use machines,
Section 6.6 - Special precautions for disposal

 

 

 

 

 

 

 

 

 

1.         NAME OF THE MEDICINAL PRODUCT

 

            Tracrium 10mg/ml, Solution for Injection or Infusion, ampoules

 

Tracrium 10mg/ml, Solution for Injection or Infusion, vials

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

                                                            Each ml contains 10mg of Atracurium Besilate.

 

                                                            Ampoules

Each 2.5ml ampoule contains 25mg of Atracurium Besilate.

Each 5ml ampoule contains 50mg of Atracurium Besilate.

 

Vials

Each 25ml vial contains 250mg Atracurium Besilate.

                                                            For a full list of excipients, see section 6.1.    

           

4.4       Special Warnings and Precautions for Use

 

In common with all other neuromuscular blocking agents Tracrium paralyses the respiratory muscles as well as other skeletal muscles but has no effect on consciousness.  Tracrium should be administered only with adequate general anaesthesia and only under the close supervision of an experienced anaesthetist with adequate facilities for endotracheal intubation and artificial ventilation.

 

Where hypothermia is required, the neuromuscular block of atracurium is increased and decreases when re-warming the patient.

 

The potential for histamine release exists in susceptible patients during Tracrium administration.  Caution should be exercised in administering Tracrium to patients with a history suggestive of an increased sensitivity to the effects of histamine. In particular, bronchospasm may occur in patients with a history of allergy and asthma.

 

Caution should also be exercised when administering Tracrium to patients who have shown hypersensitivity to other neuromuscular blocking agents since a high rate of cross-sensitivity (greater than 50%) between neuromuscular blocking agents has been reported (See Contra-indications Section 4.3).

 

Tracrium does not have significant vagal or ganglionic blocking properties in the recommended dosage range.  Consequently, Tracrium has no clinically significant effects on heart rate in the recommended dosage range and it will not counteract the bradycardia produced by many anaesthetic agents or by vagal stimulation during surgery. 

 

Bradycardia has been reported in association with Tracrium use.

 

In common with other non-depolarising neuromuscular blocking agents, increased sensitivity to atracurium may be expected in patients with myasthenia gravis, other forms of neuromuscular disease and severe electrolyte imbalance.  The action of Tracrium may be slightly prolonged in severe acidosis.

 

Tracrium should be administered over a period of 60 seconds to patients who may be unusually sensitive to falls in arterial blood pressure, for example those who are hypovolaemic.

 

Tracrium is inactivated by high pH and so must not be mixed in the same syringe with thiopentone or any alkaline agent.

 

When a small vein is selected as the injection site, Tracrium should be flushed through the vein with physiological saline after injection.  When other anaesthetic drugs are administered through the same in-dwelling needle or cannula as Tracrium it is important that each drug is flushed through with an adequate volume of physiological saline.

 

Tracrium is hypotonic and must not be administered into the infusion line of a blood transfusion.

 

Studies in malignant hyperthermia in susceptible animals (swine) and clinical studies in patients susceptible to malignant hyperthermia indicate that Tracrium does not trigger this syndrome.

 

In common with other non-depolarising neuromuscular blocking agents, resistance may develop in patients suffering from burns.  Such patients may require increased doses dependent on the time elapsed since the burn injury and the extent of the burn.

 

Patients with carcinomatosis especially when associated with bronchial carcinoma, may exhibit a marked sensitivity to this agent, and the neuromuscular block produced may respond poorly to neostigmine.

 

The neuromuscular blockage of this agent may be rapidly reversed by a cholinesterase inhibiting agent (e.g. neostigmine) in an adequate dose together with atropine as an anticholinergic agent.

 

Patients with severe cardiovascular disease may be more susceptible to the effects of transient hypotension.  In these patients slow intravenous injection in divided doses is recommended.

 

Particular attention should be paid to the presence of adequate respiratory exchange, before the patient is discharged from the anaesthetist’s care.

 

In no circumstances must Tracrium be mixed with any other intravenous administered agent.  Such drugs must be adequately washed into the patient before Tracrium is administered.

 

            Injection:

Intensive Care unit (ICU) Patients: When administered to laboratory animals in high doses, laudanosine, a metabolite of atracurium, has been associated with transient hypotension and in some species, cerebral excitatory effects. Although seizures have been seen in ICU patients receiving atracurium, a causal relationship to laudanosine has not been established (see section 4.8).

 

4.5       Interaction with Other Medicinal Products and Other Forms of Interaction

 

            The neuromuscular block produced by Tracrium is increased by the concomitant use of inhalation anaesthetics such as halothane, ether, isoflurane and enflurane. 

 

            In common with all non-depolarising neuromuscular blocking agents the magnitude and/or duration of a non-depolarising neuromuscular block may be increased as a result of interaction with:

-          Antibiotics, of the polypeptide and aminoglycoside groups: polymyxins, spectinomycin, tetracycline, lincomycin and clindamycin.

-          Antiarrhythmic drugs: propranolol, calcium channel blockers, lignocaine, procainamide and quinidine,

-          Diuretics: frusemide and possibly mannitol, thiazide diuretics and acetazolamide;

-          Magnesium sulphate;

-          Ketamine;

-          Lithium salts;

-          Ganglion blocking agents: trimetaphan and hexamethonium.

 

Rarely, certain drugs may aggravate or unmask latent myasthenia gravis or actually induce a myasthenic syndrome; increased sensitivity to Tracrium would be consequent on such a development.  Such drugs include various antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmic drugs (procainamide, quinidine), antirheumatic drugs (chloroquine, D-penicillamine), trimetaphan, chlorpromazine, steroids, pheytoin and lithium.

 

The onset of non-depolarising neuromuscular block is likely to be lengthened and the duration of block shortened in patients receiving chronic anticonvulsant therapy.

 

The administration of combinations of non-depolarising neuromuscular blocking agents in conjunction with Tracrium may produce a degree of neuromuscular blockade in excess of that which might be expected were an equipotent total dose of Tracrium administered.  Any synergistic effect may vary between different drug combinations.

 

A depolarizing muscle relaxant such as suxamethonium chloride should not be administered to prolong the neuromuscular blocking effects of non-depolarising agents such as atracurium as this may result in a prolonged and complex block which is difficult to reverse with anticholinesterase drugs.

 

Treatment with anticholinesterases, commonly used in the treatment of Alzheimer’s disease e.g. donepezil, may shorten the duration and diminish the magnitude of neuromuscular blockade with atracurium.

 

4.6              Fertility, pregnancy and lactation

 

Fertility

            Fertility studies have not been performed.

 

Pregnancy

Animal studies have indicated that atracurium has no significant effects on foetal development.

 

In common with all neuromuscular blocking agents, Tracrium should be used during pregnancy only if the potential benefit to the mother outweighs any potential risk to the foetus.

 

Tracrium is suitable for maintenance of muscle may be used to maintain neuromuscular relaxation in during Caesarean section as it does not cross the placenta in clinically significant amounts.

           

            Breast-feeding

It is not known whether atracurium is excreted in human milk.

 

 

4.7       Effects on Ability to Drive and Use Machines

                       

                        No data

This precaution is not relevant to the use of atracurium. Atracurium will always be used in combination with a general anaesthetic and therefore the usual precautions relating to performance of tasks following general anaesthesia apply.                   

 

4.8       Undesirable Effects

 

The most commonly reported adverse reactions during treatment are hypotension (mild, transient) and skin flushing, these events are attributed to histamine release. Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving atracurium in conjunction with one or more anaesthetic agents.

 

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (> ≥1/10), common (> ≥1/100 and to < 1/10), uncommon (> ≥1/1000 and to < 1/100), rare (> ≥1/10,000 and to < 1/1000), very rare (< 1/10,000). Very common, common and uncommon frequencies were determined from clinical trial data. Rare and very rare frequencies were generally derived from spontaneous data. The frequency classification "Not known" has been applied to those reactions where a frequency could not be estimated from the available data.

 

Clinical Trial Data

 

Vascular Disorders
Events which have been attributed to histamine release are indicated by a hash (#).
Common	Hypotension (mild, transient)#, Skin flushing#
Respiratory, thoracic and mediastinal disorders
Events which have been attributed to histamine release are indicated by a hash (#).
Uncommon		Bronchospasm#

 

Postmarketing Data

 

Immune system disorders
Very rare	Anaphylactic reaction, anaphylactoid reaction
Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving atracurium in conjunction with one or more anaesthetic agents.
Nervous system disorder
Not known		Seizures
There have been reports of seizures in ICU patients who have been receiving atracurium concurrently with several other agents. These patients usually had one or more medical conditions predisposing to seizures (e.g. cranial trauma, cerebral oedema, viral encephalitis, hypoxic encephalopathy, uraemia). A causal relationship to laudanosine has not been established. In clinical trials, there appears to be no correlation between plasma laudanosine concentration and the occurrence of seizures.
Musculoskeletal and connective tissue disorders
Not known		Myopathy, muscle weakness
There have been some reports of muscle weakness and/or myopathy following prolonged use of muscle relaxants in severely ill patients in the ICU. Most patients were receiving concomitant corticosteroids. These events have been seen infrequently in association with atracurium and a causal relationship has not been established.

 

Clinical Trial Data
Vascular disorders
Common	Hypotension (mild, transient)#, Skin flushing#
Respiratory, thoracic and mediastinal disorders
Uncommon	Bronchospasm#
Postmarketing Data
Immune system disorders
Very rare	Anaphylactic reaction, anaphylactoid reaction including shock, circulatory failure and cardiac arrest
Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving atracurium in conjunction with one or more anaesthetic agents.
Nervous system disorder
Not known		Seizures
There have been reports of seizures in ICU patients who have been receiving atracurium concurrently with several other agents. These patients usually had one or more medical conditions predisposing to seizures (e.g. cranial trauma, cerebral oedema, viral encephalitis, hypoxic encephalopathy, uraemia). A causal relationship to laudanosine has not been established. In clinical trials, there appears to be no correlation between plasma laudanosine concentration and the occurrence of seizures.
Skin and subcutaneous tissue disorders
Rare		Urticaria
Musculoskeletal and connective tissue disorders
Not known	Myopathy, muscle weakness
There have been some reports of muscle weakness and/or myopathy following prolonged use of muscle relaxants in severely ill patients in the ICU. Most patients were receiving concomitant corticosteroids. These events have been seen infrequently in association with atracurium and a causal relationship has not been established.

 

Events which have been attributed to histamine release are indicated by a hash (#).

 

4.9        Overdose

 

                        Symptoms and Signs

                        Prolonged muscle paralysis and its consequences are the main signs of overdosage.

                       

                        Treatment

It is essential to maintain a patent airway together with assisted positive pressure ventilation until spontaneous respiration is adequate. 

 

Full sedation will be required since consciousness is not impaired. 

 

Recovery may be hastened by the administration of anticholinesterase agents accompanied be atropine or glycopyrrolate, once evidence of spontaneous recovery is present.

 

6.1               List of Excipients       

                                               

                        Benzenesulphonic Acid Solution 32% w/v, used for pH adjustment only

                        Water for Injections

                       

6.2               Incompatibilities

 

No data                       

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. For further information see section 4.4.

 

6.3       Shelf life

 

Unopened: 2 years

 

From a microbiological point of view, the product should be used immediately.  If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

 

Please see section 6.6 for further information regarding in-use shelf life

 

6.4       Special Precautions for Storage

 

Store at 2^oC to 8^oC.   Store in the original package in order to protect from light.  Do not freeze.

 

Please see section 6.6 for further information regarding in-use storage precautions

 

6.5       Nature and Contents of Container

 

                        Ampoules

2.5ml and 5ml presentations are available in Type I Ph. Eur., clear colourless glass ampoules.

Tracrium is available in packs containing 5 x 2.5ml ampoules and 5 x 5ml ampoules.

 

Vials

25ml presentation is available in Type I, clear glass vials closed with bromobutyl rubber stopper, sealed with an aluminium collar and fitted with a plastic flip-off top.

Tracrium is available in packs containing 2 x 25ml vials.

 

Not all pack sizes may be marketed.

 

6.6       Special precautions for disposal of a used medicinal product or waste materials derived         from such medicinal product and other handling of the product

 

In-use: must be used immediately. Any unused Tracrium from opened ampoules/vials should be discarded immediately after use. Any waste material should be discarded in accordance with local requirements.

 

In-use following dilution: Chemical and physical in-use stability for Tracrium has been demonstrated with the following infusion solutions, for the times stated below at 30°C:

Infusion Solution	Period of Stability at 30°C
- Sodium Chloride I.V. Infusion BP (0.9% w/v)	24 hours
- Glucose I.V. Infusion BP (5% w/v)	8 hours
- Ringer's Injection USP	8 hours
- Sodium Chloride (0.18% w/v) and Glucose (4% w/v) I.V. Infusion BP	8 hours
- Compound Sodium Lactate I.V. Infusion BP (Hartmann's Solution for Injection)	4 hours

 

From a microbiological point of view, the product should be used immediately.  If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

 

Please refer to section 6.3 for microbiological in-use information.

 

Ampoules

Instructions to open the ampoule:

Ampoules are equipped with the OPC (One Point Open) opening system and must be opened following the below instructions:

·         Hold with the hand the bottom part of the ampoule.

·         Put the other hand on the top of the ampoule positioning the thumb above the coloured point and press.

 

8.         MARKETING AUTHORISATION NUMBER

 

                        Ampoules:        PA 1077/81/1

                        Vials:               PA 1077/81/2

1.         NAME OF THE MEDICINAL PRODUCT

 

            Tracrium 10mg/ml, Solution for Injection or Infusion, ampoules

 

Tracrium 10mg/ml, Solution for Injection or Infusion, vials

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

                                                            Each ml contains 10mg of Atracurium Besilate.

 

                                                            Ampoules

Each 2.5ml ampoule contains 25mg of Atracurium Besilate.

Each 5ml ampoule contains 50mg of Atracurium Besilate.

 

Vials

Each 25ml vial contains 250mg Atracurium Besilate.

                                                            For a full list of excipients, see section 6.1.    

           

4.4       Special Warnings and Precautions for Use

 

In common with all other neuromuscular blocking agents Tracrium paralyses the respiratory muscles as well as other skeletal muscles but has no effect on consciousness.  Tracrium should be administered only with adequate general anaesthesia and only under the close supervision of an experienced anaesthetist with adequate facilities for endotracheal intubation and artificial ventilation.

 

Where hypothermia is required, the neuromuscular block of atracurium is increased and decreases when re-warming the patient.

 

The potential for histamine release exists in susceptible patients during Tracrium administration.  Caution should be exercised in administering Tracrium to patients with a history suggestive of an increased sensitivity to the effects of histamine. In particular, bronchospasm may occur in patients with a history of allergy and asthma.

 

Caution should also be exercised when administering Tracrium to patients who have shown hypersensitivity to other neuromuscular blocking agents since a high rate of cross-sensitivity (greater than 50%) between neuromuscular blocking agents has been reported (See Contra-indications Section 4.3).

 

Tracrium does not have significant vagal or ganglionic blocking properties in the recommended dosage range.  Consequently, Tracrium has no clinically significant effects on heart rate in the recommended dosage range and it will not counteract the bradycardia produced by many anaesthetic agents or by vagal stimulation during surgery. 

 

Bradycardia has been reported in association with Tracrium use.

 

In common with other non-depolarising neuromuscular blocking agents, increased sensitivity to atracurium may be expected in patients with myasthenia gravis, other forms of neuromuscular disease and severe electrolyte imbalance.  The action of Tracrium may be slightly prolonged in severe acidosis.

 

Tracrium should be administered over a period of 60 seconds to patients who may be unusually sensitive to falls in arterial blood pressure, for example those who are hypovolaemic.

 

Tracrium is inactivated by high pH and so must not be mixed in the same syringe with thiopentone or any alkaline agent.

 

When a small vein is selected as the injection site, Tracrium should be flushed through the vein with physiological saline after injection.  When other anaesthetic drugs are administered through the same in-dwelling needle or cannula as Tracrium it is important that each drug is flushed through with an adequate volume of physiological saline.

 

Tracrium is hypotonic and must not be administered into the infusion line of a blood transfusion.

 

Studies in malignant hyperthermia in susceptible animals (swine) and clinical studies in patients susceptible to malignant hyperthermia indicate that Tracrium does not trigger this syndrome.

 

In common with other non-depolarising neuromuscular blocking agents, resistance may develop in patients suffering from burns.  Such patients may require increased doses dependent on the time elapsed since the burn injury and the extent of the burn.

 

Patients with carcinomatosis especially when associated with bronchial carcinoma, may exhibit a marked sensitivity to this agent, and the neuromuscular block produced may respond poorly to neostigmine.

 

The neuromuscular blockage of this agent may be rapidly reversed by a cholinesterase inhibiting agent (e.g. neostigmine) in an adequate dose together with atropine as an anticholinergic agent.

 

Patients with severe cardiovascular disease may be more susceptible to the effects of transient hypotension.  In these patients slow intravenous injection in divided doses is recommended.

 

Particular attention should be paid to the presence of adequate respiratory exchange, before the patient is discharged from the anaesthetist’s care.

 

In no circumstances must Tracrium be mixed with any other intravenous administered agent.  Such drugs must be adequately washed into the patient before Tracrium is administered.

 

            Injection:

Intensive Care unit (ICU) Patients: When administered to laboratory animals in high doses, laudanosine, a metabolite of atracurium, has been associated with transient hypotension and in some species, cerebral excitatory effects. Although seizures have been seen in ICU patients receiving atracurium, a causal relationship to laudanosine has not been established (see section 4.8).

 

4.5       Interaction with Other Medicinal Products and Other Forms of Interaction

 

            The neuromuscular block produced by Tracrium is increased by the concomitant use of inhalation anaesthetics such as halothane, ether, isoflurane and enflurane. 

 

            In common with all non-depolarising neuromuscular blocking agents the magnitude and/or duration of a non-depolarising neuromuscular block may be increased as a result of interaction with:

-          Antibiotics, of the polypeptide and aminoglycoside groups: polymyxins, spectinomycin, tetracycline, lincomycin and clindamycin.

-          Antiarrhythmic drugs: propranolol, calcium channel blockers, lignocaine, procainamide and quinidine,

-          Diuretics: frusemide and possibly mannitol, thiazide diuretics and acetazolamide;

-          Magnesium sulphate;

-          Ketamine;

-          Lithium salts;

-          Ganglion blocking agents: trimetaphan and hexamethonium.

 

Rarely, certain drugs may aggravate or unmask latent myasthenia gravis or actually induce a myasthenic syndrome; increased sensitivity to Tracrium would be consequent on such a development.  Such drugs include various antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmic drugs (procainamide, quinidine), antirheumatic drugs (chloroquine, D-penicillamine), trimetaphan, chlorpromazine, steroids, pheytoin and lithium.

 

The onset of non-depolarising neuromuscular block is likely to be lengthened and the duration of block shortened in patients receiving chronic anticonvulsant therapy.

 

The administration of combinations of non-depolarising neuromuscular blocking agents in conjunction with Tracrium may produce a degree of neuromuscular blockade in excess of that which might be expected were an equipotent total dose of Tracrium administered.  Any synergistic effect may vary between different drug combinations.

 

A depolarizing muscle relaxant such as suxamethonium chloride should not be administered to prolong the neuromuscular blocking effects of non-depolarising agents such as atracurium as this may result in a prolonged and complex block which is difficult to reverse with anticholinesterase drugs.

 

Treatment with anticholinesterases, commonly used in the treatment of Alzheimer’s disease e.g. donepezil, may shorten the duration and diminish the magnitude of neuromuscular blockade with atracurium.

 

4.6              Fertility, pregnancy and lactation

 

Fertility

            Fertility studies have not been performed.

 

Pregnancy

Animal studies have indicated that atracurium has no significant effects on foetal development.

 

In common with all neuromuscular blocking agents, Tracrium should be used during pregnancy only if the potential benefit to the mother outweighs any potential risk to the foetus.

 

Tracrium is suitable for maintenance of muscle may be used to maintain neuromuscular relaxation in during Caesarean section as it does not cross the placenta in clinically significant amounts.

           

            Breast-feeding

It is not known whether atracurium is excreted in human milk.

 

 

4.7       Effects on Ability to Drive and Use Machines

                       

                        No data

This precaution is not relevant to the use of atracurium. Atracurium will always be used in combination with a general anaesthetic and therefore the usual precautions relating to performance of tasks following general anaesthesia apply.                   

 

4.8       Undesirable Effects

 

The most commonly reported adverse reactions during treatment are hypotension (mild, transient) and skin flushing, these events are attributed to histamine release. Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving atracurium in conjunction with one or more anaesthetic agents.

 

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (> ≥1/10), common (> ≥1/100 and to < 1/10), uncommon (> ≥1/1000 and to < 1/100), rare (> ≥1/10,000 and to < 1/1000), very rare (< 1/10,000). Very common, common and uncommon frequencies were determined from clinical trial data. Rare and very rare frequencies were generally derived from spontaneous data. The frequency classification "Not known" has been applied to those reactions where a frequency could not be estimated from the available data.

 

Clinical Trial Data

 

Vascular Disorders
Events which have been attributed to histamine release are indicated by a hash (#).
Common	Hypotension (mild, transient)#, Skin flushing#
Respiratory, thoracic and mediastinal disorders
Events which have been attributed to histamine release are indicated by a hash (#).
Uncommon		Bronchospasm#

 

Postmarketing Data

 

Immune system disorders
Very rare	Anaphylactic reaction, anaphylactoid reaction
Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving atracurium in conjunction with one or more anaesthetic agents.
Nervous system disorder
Not known		Seizures
There have been reports of seizures in ICU patients who have been receiving atracurium concurrently with several other agents. These patients usually had one or more medical conditions predisposing to seizures (e.g. cranial trauma, cerebral oedema, viral encephalitis, hypoxic encephalopathy, uraemia). A causal relationship to laudanosine has not been established. In clinical trials, there appears to be no correlation between plasma laudanosine concentration and the occurrence of seizures.
Musculoskeletal and connective tissue disorders
Not known		Myopathy, muscle weakness
There have been some reports of muscle weakness and/or myopathy following prolonged use of muscle relaxants in severely ill patients in the ICU. Most patients were receiving concomitant corticosteroids. These events have been seen infrequently in association with atracurium and a causal relationship has not been established.

 

Clinical Trial Data
Vascular disorders
Common	Hypotension (mild, transient)#, Skin flushing#
Respiratory, thoracic and mediastinal disorders
Uncommon	Bronchospasm#
Postmarketing Data
Immune system disorders
Very rare	Anaphylactic reaction, anaphylactoid reaction including shock, circulatory failure and cardiac arrest
Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving atracurium in conjunction with one or more anaesthetic agents.
Nervous system disorder
Not known		Seizures
There have been reports of seizures in ICU patients who have been receiving atracurium concurrently with several other agents. These patients usually had one or more medical conditions predisposing to seizures (e.g. cranial trauma, cerebral oedema, viral encephalitis, hypoxic encephalopathy, uraemia). A causal relationship to laudanosine has not been established. In clinical trials, there appears to be no correlation between plasma laudanosine concentration and the occurrence of seizures.
Skin and subcutaneous tissue disorders
Rare		Urticaria
Musculoskeletal and connective tissue disorders
Not known	Myopathy, muscle weakness
There have been some reports of muscle weakness and/or myopathy following prolonged use of muscle relaxants in severely ill patients in the ICU. Most patients were receiving concomitant corticosteroids. These events have been seen infrequently in association with atracurium and a causal relationship has not been established.

 

Events which have been attributed to histamine release are indicated by a hash (#).

 

4.9        Overdose

 

                        Symptoms and Signs

                        Prolonged muscle paralysis and its consequences are the main signs of overdosage.

                       

                        Treatment

It is essential to maintain a patent airway together with assisted positive pressure ventilation until spontaneous respiration is adequate. 

 

Full sedation will be required since consciousness is not impaired. 

 

Recovery may be hastened by the administration of anticholinesterase agents accompanied be atropine or glycopyrrolate, once evidence of spontaneous recovery is present.

 

6.1               List of Excipients       

                                               

                        Benzenesulphonic Acid Solution 32% w/v, used for pH adjustment only

                        Water for Injections

                       

6.2               Incompatibilities

 

No data                       

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. For further information see section 4.4.

 

6.3       Shelf life

 

Unopened: 2 years

 

From a microbiological point of view, the product should be used immediately.  If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

 

Please see section 6.6 for further information regarding in-use shelf life

 

6.4       Special Precautions for Storage

 

Store at 2^oC to 8^oC.   Store in the original package in order to protect from light.  Do not freeze.

 

Please see section 6.6 for further information regarding in-use storage precautions

 

6.5       Nature and Contents of Container

 

                        Ampoules

2.5ml and 5ml presentations are available in Type I Ph. Eur., clear colourless glass ampoules.

Tracrium is available in packs containing 5 x 2.5ml ampoules and 5 x 5ml ampoules.

 

Vials

25ml presentation is available in Type I, clear glass vials closed with bromobutyl rubber stopper, sealed with an aluminium collar and fitted with a plastic flip-off top.

Tracrium is available in packs containing 2 x 25ml vials.

 

Not all pack sizes may be marketed.

 

6.6       Special precautions for disposal of a used medicinal product or waste materials derived         from such medicinal product and other handling of the product

 

In-use: must be used immediately. Any unused Tracrium from opened ampoules/vials should be discarded immediately after use. Any waste material should be discarded in accordance with local requirements.

 

In-use following dilution: Chemical and physical in-use stability for Tracrium has been demonstrated with the following infusion solutions, for the times stated below at 30°C:

Infusion Solution	Period of Stability at 30°C
- Sodium Chloride I.V. Infusion BP (0.9% w/v)	24 hours
- Glucose I.V. Infusion BP (5% w/v)	8 hours
- Ringer's Injection USP	8 hours
- Sodium Chloride (0.18% w/v) and Glucose (4% w/v) I.V. Infusion BP	8 hours
- Compound Sodium Lactate I.V. Infusion BP (Hartmann's Solution for Injection)	4 hours

 

From a microbiological point of view, the product should be used immediately.  If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

 

Please refer to section 6.3 for microbiological in-use information.

 

Ampoules

Instructions to open the ampoule:

Ampoules are equipped with the OPC (One Point Open) opening system and must be opened following the below instructions:

·         Hold with the hand the bottom part of the ampoule.

·         Put the other hand on the top of the ampoule positioning the thumb above the coloured point and press.

 

8.         MARKETING AUTHORISATION NUMBER

 

                        Ampoules:        PA 1077/81/1

                        Vials:               PA 1077/81/2

4.8        Undesirable Effects

 

Associated with the use of Tracrium there have been reports of skin flushing, mild transient hypotension or bronchospasm, which have been attributed to histamine release.  Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving Tracrium in conjunction with one or more anaesthetic agents.

 

There have been rare reports of seizures in ICU patients who have been receiving Tracrium concurrently with several other agents.

 

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common > 1/10, common >1/100 and < 1/10, uncommon >1/1000 and < 1/100, rare >1/10,000 and < 1/1000, very rare < 1/10,000. Very common, common and uncommon frequencies were determined from clinical trial data. Rare and very rare frequencies were generally derived from spontaneous data. The frequency classification "Not known" has been applied to those reactions where a frequency could not be estimated from the available data.

 

Clinical Trial Data

Vascular Disorders
Events which have been attributed to histamine release are indicated by a hash (#).
Common	Hypotension (mild, transient)#, Skin flushing#
Respiratory, thoracic and mediastinal disorders
Events which have been attributed to histamine release are indicated by a hash (#).
Uncommon		Bronchospasm#

4.8        Undesirable Effects

 

Associated with the use of Tracrium there have been reports of skin flushing, mild transient hypotension or bronchospasm, which have been attributed to histamine release.  Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving Tracrium in conjunction with one or more anaesthetic agents.

 

There have been rare reports of seizures in ICU patients who have been receiving Tracrium concurrently with several other agents.

 

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common > 1/10, common >1/100 and < 1/10, uncommon >1/1000 and < 1/100, rare >1/10,000 and < 1/1000, very rare < 1/10,000. Very common, common and uncommon frequencies were determined from clinical trial data. Rare and very rare frequencies were generally derived from spontaneous data. The frequency classification "Not known" has been applied to those reactions where a frequency could not be estimated from the available data.

 

Clinical Trial Data

Vascular Disorders
Events which have been attributed to histamine release are indicated by a hash (#).
Common	Hypotension (mild, transient)#, Skin flushing#
Respiratory, thoracic and mediastinal disorders
Events which have been attributed to histamine release are indicated by a hash (#).
Uncommon		Bronchospasm#