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TRACRIUM SOLUTION FOR INJECT 25MG/2.5ML 50MG/5ML 250MG/25ML

Active substance: ATRACURIUM BESILATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Tracrium Injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Atracurium Besilate HSE 10mg/ml

3.

PHARMACEUTICAL FORM
Injection

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Tracrium is a highly selective, competitive or non-depolarising neuromuscular
blocking agent. It is used as an adjunct to general anaesthesia or sedation in
the intensive care unit (ICU), to relax skeletal muscles, and to facilitate
tracheal intubation and mechanical ventilation.

4.2.

Posology and method of administration
Route of administration: Intravenous injection or continuous infusion.
Used by injection in adults: Tracrium is administered by intravenous injection.
The dosage range recommended for adults is 0.3 to 0.6 mg/kg (depending on
the duration of full block required) and will provide adequate relaxation for
about 15 to 35 minutes.
Endotracheal intubation can usually be accomplished within 90 seconds from
the intravenous injection of 0.5 to 0.6 mg/kg.
Full block can be prolonged with supplementary doses of 0.1 to 0.2 mg/kg as
required. Successive supplementary dosing does not give rise to accumulation
of neuromuscular blocking effect.

Spontaneous recovery from the end of full block occurs in about 35 minutes as
measured by the restoration of the tetanic response to 95% of normal
neuromuscular function.
The neuromuscular block produced by Tracrium can be rapidly reversed by
standard doss of anticholinesterase agents, such as neostigmine and
edrophonium, accompanied or preceded by atropine, with no evidence of
recurarisation.
Use as an infusion in adults: After an initial bolus dose of 0.2 to 0.6mg/kg,
Tracrium can be used to maintain neuromuscular block during long surgical
procedures by administration as a continuous infusion at rates of 0.3 to
0.6mg/kg/hour.
Tracrium can be administered by infusion during cardiopulmonary bypass
surgery at the recommended infusion rates. Induced hypothermia to a body
temperature of 25° to 26°C reduces the rate of inactivation of atracurium,
therefore full neuromuscular block may be maintained by approximately half
the original infusion rate at these low temperatures.
Tracrium is compatible with the following infusion solutions for the times
stated below:
Infusion solution stability

Period of

Sodium Chloride Intravenous Infusion BP (0.9% w/v)

24 hours

Glucose Intravenous Infusion BP (5% w/v)
Ringer’s Injection USP
Sodium Chloride (0.18%w/v) and Glucose (4% w/v)
Intravenous Infusion BP
Compound Sodium Lactate Intravenous Infusion BP
(Hartmann’s Solution for Injection)

8 hours
8 hours
8 hours
4 hours

When diluted in these solutions to give atracurium besilate concentrations of
0.5 mg/ml and above, the resultant solutions will be stable in daylight for the
stated periods at temperatures of up to 30°C.
Use in Children: The dosage in children over the age of one month is similar
to that in adults on a bodyweight basis.
Use in Neonates: The use of Tracrium is not recommended in neonates since
there are insufficient data available.
Use in the elderly: Tracrium may be used at standard dosage in elderly
patients. It is recommended, however, that the initial dose be at the lower end
of the range and that it be administered slowly.
Use in patients with reduced renal and/or hepatic function: Tracrium may be
used at standard dosage at all levels of renal or hepatic function, including end
stage failure.

Use in patients with cardiovascular disease: In patients with clinically
significant cardiovascular disease, the initial dose of Tracrium should be
administered over a period of 60 seconds.
Use in intensive care unit (ICU) patients: After an optional initial bolus dose
of Tracrium of 0.3 to 0.6 mg/kg, Tracrium can be used to maintain
neuromuscular block by administering a continuous infusion at rates of
between 11 and 13 microgram/kg/mm (0.65 to 0.78 mg/kg/hr). There may be
wide inter-patient variability in dosage requirements and these may increase or
decrease with time. Infusion rates as low as 4.5 microgram/kg/mm (0.27
mg/kg/hr) or as high as 29.5 microgram/kg/min (1.77 mg/kg/hr) are required
in some patients.
The rate of spontaneous recovery from neuromuscular block after infusion of
Tracrium in ICU patients is independent of the duration of administration.
Spontaneous recovery to a train-of-four ratio>0.75 (the ratio of the height of
the fourth to the first twitch in a train-of-four) can be expected to occur in
approximately 60 minutes. A range of 32 to 108 minutes has been observed in
clinical trials.
Monitoring: In common with all neuromuscular blocking agents, monitoring
of neuromuscular function is recommended during the use of Tracrium in
order to individualise dosage requirements.

4.3

Contraindications
Atracurium is contraindicated in patients known to be hypersensitive to
atracurium, cisatracurium or benzenesulfonic acid (see section 4.4, Special
Warnings and Precautions for Use).

4.4

Special warnings and precautions for use
Precautions: In common with all the 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 by or under the close supervision of an experienced anaesthetist
with adequate facilities for endotracheal intubation and artificial ventilation.
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.

High rates of cross-sensitivity between neuromuscular blocking agents have been
reported. Therefore, where possible, before administering atracurium,
hypersensitivity to other neuromuscular blocking agents should be excluded.
Atracurium should only be used when absolutely essential in susceptible patients.
Patients who experience a hypersensitivity reaction under general anaesthesia should
be tested subsequently for hypersensitivity to other neuromuscular blockers.
Monitoring of serial creatinine phosphate (cpk) values should be considered in
asthmatic patients receiving high dose corticosteroids and neuromuscular blocking
agents in ICU.
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.
In common with other non-depolarising neuromuscular blocking agents, increased
sensitivity to atracurium may be expected in patients with myasthenia gravis and
other forms of neuromuscular disease.
As with other neuromuscular blocking agents severe acid-base and/or serum
electrolyte abnormalities may increase or decrease the sensitivity of patients to
atracrium.
As with other non-depolarising neuromuscular blockers hypophosphataemia may
prolong recovery. Recovery may be hastened by correcting this condition.
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 thiopental 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. Atracurium besilate 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 hypothermia 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.
Intensive Care Unit (ICU) patients: When administered to laboratory animals in high
doses, Laudanosine, a metabolite of atracrium 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 Undesirable Effects).

Carcinogenicity: Carcinogenicity studies have not been performed.

4.5

Interaction with other medicinal products and other forms of interaction
The neuromuscular block produced by Tracrium may be increased by the
concomitant use of inhalational anaesthetics such as halothane, 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, including the aminoglycosides, polymyxins,
spectinomycin, tetracyclines, lincomycin and clindamycin; antiarrhythmic drugs,
propranolol, calcium channel blockers, lignocaine, procainamide and quinidine;
diuretics: furosemide and possibly mannitol, thiazide diuretics and acetazolamide;
magnesium sulphate, ketamine, lithium salts, ganglion blocking agents, trimetaphan,
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, -blockers
(propranolol, oxprenolol), antiarrhythmic drugs (procainamide, quinidine),
antirheumatic drugs (chloroquine, D-penicillamine), trimetaphan, chlorpromazine,
steroids, phenytoin 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.

β

The administration of combinations of non-depolarising neuromuscular blocking
agents in conjunction with Tracrium may produce a degree of neuromuscular
blockage 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 depolarising muscle relaxant such as suxamethonium chloride should not be
administered to prolong the neuromuscular blocking effects of non-depolarising
blocking agents such as atracurium, as this may result in a prolonged and complex
block which can be 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

Pregnancy and lactation
Fertility studies have not been performed.
Animal studies have indicated that Tracrium 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 relaxation during Caesarean section
as it does not cross the placenta in clinically significant amounts following
recommended doses.
It is not known whether Tracrium is excreted in human milk.

4.7

Effects on Ability to Drive and Use Machines
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 < 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
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
Prolonged muscle paralysis and its consequences are the main signs of
overdosage.
Treatment: It is essential to maintain a patient 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 by
atropine or glycopyrrolate, once evidence of spontaneous recovery is present.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties
Atracurium is a highly selective competitive (non-depolarising) neuromuscular
blocking agent with an intermediate duration of action. Non- depolarising
agents antagonise the neurotransmitter action of acetylcholine by binding with
receptor sites on the motor-end-plate. Atracurium can be used in a wide range
of surgical procedures and to facilitate controlled ventilation.

5.2

Pharmacokinetic Properties

The pharmacokinetics of Atracurium in man are essentially linear with the 0.30.6 mg/kg dose range . The elimination half-life is approximately 20 minutes,
and the volume of distribution is 0.16 L/kg. Atracurium is 82% bound to
plasma proteins.
Atracurium is degraded spontaneously mainly by a non-enzymatic
decomposition process (Hofmann elimination) which occurs at plasma pH and
at body temperature and produces breakdown products which are inactive.
Degradation also occurs by ester hydrolysis catalysed by non-specific
esterases. Elimination of atracurium is not dependent on kidney or liver
function.
The main breakdown products are laudanosine and a monoquaternary alcohol
which have no neuromuscular blocking activity. The monoquaternary alcohol
is degraded spontaneously by hofmann elimination and excreted by the
kidney. Laudanosine is excreted by the kidney and metabolised by the liver.
The half-life of laudanosine ranges from 3-6h in patients with normal kidney
and liver function. It is about 15h in renal failure and is about 40h in renal and
hepatic failure. Peak plasma levels of laudanosine are highest in patients
without kidney or liver function and average 4 µg/ml with wide variation.
Concentration of metabolites are higher in ICU patients with abnormal renal
and/or hepatic function (see Special Warnings and Special Precautions for
Use). These metabolites do not contribute to neuromuscular block.

5.3

Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to
that already included in other sections of the SmPC.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients
Benzene Sulphonic acid
Water for Injections

6.2.

Incompatibilities
None.

6.3.

Shelf life

24 months.

6.4.

Special precautions for storage
Store between 2 and 8°C. Do not freeze. Keep container in the outer carton.
Any unused Tracrium from opened ampoules or vials should be discarded.

6.5.

Nature and contents of container
Neutral glass ampoules or vials. Vials are closed with a rubber stopper, sealed
with an aluminium collar and fitted with a plastic flip-off top. Pack sizes:
Boxes of 5 x 2.5ml ampoules, 5 x 5ml ampoules and 2 x 25ml vials.

6.6

Special precautions for disposal
None.

7

MARKETING AUTHORISATION HOLDER
The Wellcome Foundation Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
Trading as
GlaxoSmithKline UK
Stockley Park West
Uxbridge
Middlesex UB11 1BT

8.

MARKETING AUTHORISATION NUMBER(S)
PL 00003/0166

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12th January 1999

10

DATE OF REVISION OF THE TEXT
08/01/2013

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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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