Tracrium

Excipients/Inactive Ingredients: Benzenesulphonic acid solution.

Pharmacotherapeutic Group: Peripherally acting muscle relaxant; other quaternary ammonium compounds. ATC Code: M03AC04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Atracurium is a highly selective, competitive or 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-endplate. Atracurium can be used in a wide range of surgical procedures and to facilitate controlled ventilation.
Paediatric Population: The limited data in neonates from literature reports suggest variability in the time to onset and duration of action of atracurium in this population as compared to children (see Dosage & Administration).
Pharmacokinetics: The pharmacokinetics of Atracurium in man are essentially linear with the 0.3-0.6 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 3-6 hrs in patients with normal kidney and liver function. It is about 15 hrs in renal failure and is about 40 hrs 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 intensive care unit (ICU) patients with abnormal renal and/or hepatic function (see Precautions). These metabolites do not contribute to neuromuscular block.
Toxicology: Preclinical Safety Data: Carcinogenicity: Carcinogenicity studies have not been performed.

Tracrium is a highly selective, competitive or non-depolarising neuromuscular blocking agent which is used as an adjunct to general anaesthesia to enable tracheal intubation to be performed and to relax skeletal muscles during surgery or controlled ventilation and to facilitate mechanical ventilation in intensive care unit (ICU) patients.

Use by Injection in Adults: Tracrium is administered by IV injection. The dosage range for adults is 0.3 to 0.6 mg/kg (depending on the duration of full block required) and will provide adequate relaxation for 15 to 35 minutes.
Endotracheal intubation can usually be accomplished within 90 seconds from the IV 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 doses 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 0.3 to 0.6 mg/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 0.6 mg/kg/hr.
Tracrium can be administered by infusion during cardiopulmonary bypass surgery at the recommended infusion rates. Induced hypothermia to a body temperature of 25°C to 26°C reduces the rate of inactivation of Tracrium, 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 in the table. (See table.)

Click on icon to see table/diagram/image

When diluted in these solutions to give Tracrium 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.
Children: The dosage in children over the age of 1 month is the same as that in adults on a body weight basis.
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.
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.
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.
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 μg/kg/min (0.65-0.78 mg/kg/hr). However, there is wide inter-patient variability in dosage requirements. Dosage requirements may change with time. Infusion rates as low as 4.5 μg/kg/min (0.27 mg/kg/hr) or as high as 29.5 μg/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 greater than 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.
Administration: IV injection or continuous infusion.

Symptoms and Signs: 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.

Patients known to be hypersensitive to atracurium, cisatracurium or benzenesulfonic acid (see Precautions).

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 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 history of allergy and asthma.
High rates of cross-sensitivity between neuromuscular blocking agents have been reported. Therefore, where possible, before administering Tracrium, hypersensitivity to other neuromuscular blocking agents should be excluded. Tracrium 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 Tracrium 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 Tracrium.
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 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.
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 Tracrium, a causal relationship to laudanosine has not been established (see Adverse Reactions).
Effects on Ability to Drive and Use Machines: This precaution is not relevant to the use of Tracrium. Tracrium will always be used in combination with a general anaesthetic and therefore the usual precautions relating to performance of tasks following general anaesthesia apply.

Fertility: Fertility studies have not been performed.
Use in 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 relaxation during Caesarean section as it does not cross the placenta in clinically significant amounts following recommended doses.
Use in Lactation: It is not known whether Tracrium is excreted in human milk.

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 as follows by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 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: Common: Hypotension (mild, transient)#, skin flushing#.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Bronchospasm#.
Post-Marketing Data: Immune System Disorders: Very Rare: Anaphylactic reaction, anaphylactoid reaction.
Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving Tracrium 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 (eg, 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 (#).

The neuromuscular block produced by Tracrium may be increased by the concomitant use of inhalation anaesthetics eg, 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, β-blockers (propranolol, oxprenolol), anti-arrhythmic drugs (procainamide, quinidine), anti-rheumatic 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.
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 depolarising muscle relaxant eg, suxamethonium chloride should not be administered to prolong the neuromuscular blocking effects of non-depolarising agents eg, Tracrium, 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 eg, donepezil, may shorten the duration and diminish the magnitude of neuromuscular blockade with atracurium.

Incompatibilities: No data.

Store at temperatures between 2°C and 8°C. Protect from light. Do not freeze.
Any unused Tracrium from opened ampoules should be discarded.

Neuromuscular Blocking Agents

M03AC04 - atracurium ; Belongs to the class of other quaternary ammonium-containing agents used as peripherally-acting muscle relaxants.

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