Branded Medicine

 

Injection 10 mg/ml

 

Composition:

Each ml contains:

Atracurium besylate 10 mg

 

Pharmacological properties:

 

Pharmacodynamic properties:

Atracurium is a highly selective, competitive (non-depolarising) neuromuscular blocking agent with an intermediate duration of action. Non-depolarising agents antagonize 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.

Atracurium has no direct effect on intraocular pressure, and is therefore suitable for use in ophthalmic surgery.

 

Pharmacokinetic properties:

The elimination half-life is approximately 20 minutes. Atracurium is inactivated by Hofmann elimination, a non-enzymatic process which occurs at physiological pH and temperature; and 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 monoquartenary 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 hours in patients with normal kidney and liver function. It is about 15 hours in renal failure and is about 40 hours 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.

The termination of the neuromuscular blocking action of atracurium is not dependent on its hepatic or renal metabolism or excretion. Its duration of action, therefore, is unlikely to be affected by impaired renal, hepatic or circulatory function.

Tests with plasma from patients with low levels of pseudocholinesterase show that the inactivation of atracurium proceeds unaffected.

Variations in the blood pH and body temperature of the patient within the physiological range will not significantly alter the duration of action of atracurium.

Hemofiltration and hemodiafiltration have a minimal effect on plasma levels of atracurium and its metabolites, including laudanosine. The effects of hemodialysis and hemoperfusion on plasma levels of atracurium and its metabolites are unknown.

Concentrations of metabolites are higher in ICU patients with abnormal renal and/or hepatic function. These metabolites do not contribute to neuromuscular block.

 

Indications:

As an adjunct to general anesthesia 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.

 

Contraindications:

Patients known to be hypersensitive to the drug.

 

Dosage and administration:

Route of administration: intravenous injection or continuous infusion.

Use in adults:

Administered by intravenous injection.

The recommended dose: 0.3 - 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 atracurium 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.

Administered by intravenous infusion:

After an initial bolus dose of 0.3 - 0.6 mg/kg, atracurium 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/hour.

Atracurium can be administered by infusion during cardiopulmonary bypass surgery at the recommended infusion rates. Induced hypothermia to a body temperature of 25oC to 26oC 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.

Atracurium is compatible with the following infusion for the times stated below:

 

 



Infusion solution

Period of stability

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

24 hours

Glucose Intravenous Infusion BP (5% w/v)

8 hours

Ringer's Injection USP

8 hours

Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous Infusion BP

8 hours

Compound Sodium Lactate Intravenous Infusion BP (Hartmann's solution for injection)

4 hours

 

 

When diluted in these solutions to give atracurium besylate 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 30oC.

 

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 the elderly:

Atracurium may be used at standard dosage.

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:

Atracurium 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 atracurium should be administered over a period of 60 seconds.

 

Use in Intensive Care Unit (ICU) patients:

After an optional initial bolus dose of atracurium of 0.3 to 0.6 mg/kg, atracurium can be used to maintain neuromuscular block by administering a continuous infusion at rates of between 11 and 13 microgram/kg/min (0.65 to 0.78 mg/kg/hr). There may be wide interpatient variability in dosage requirements and these may increase or decrease with time. Infusion rates as low as 4.5 microgram/kg/min (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 atracurium in ICU patients is independent of the duration of administration.

 

Monitoring:

In common with all neuromuscular blocking agents, monitoring of neuromuscular function is recommended during the use of atracurium in order to individualise dosage requirements.

 

Adverse reactions:

  • Skin flushing and mild transient hypotension or bronchospasm, which have been attributed to histamine release.

  • Very rarely: severe anaphylactoid reactions have been reported in patients receiving atracurium in conjunction with one or more anesthetic agents.

  • Rare 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 edema, viral encephalitis, hypoxic encephalopathy, uremia). 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.

  • 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. A causal relationship has not been established.

 

Warnings and Precautions:

  • DO NOT GIVE ATRACURIUM BY INTRAMUSCULAR ADMINISTRATION.

  • In common with all the other neuromuscular blocking agents, atracurium paralyses the respiratory muscles as well as other skeletal muscles but has no effect on consciousness. Atracurium should be administered only with adequate general anesthesia and only by or under the close supervision of an experienced anesthetist with adequate facilities for endotracheal intubation and artificial ventilation.

  • In common with other neuromuscular blocking agents, the potential for histamine release exists in susceptible patients during atracurium administration. Caution should be exercised in administering atracurium to patients with a history suggestive of an increased sensitivity to the effects of histamine.

  • Monitoring of serial creatinine phosphate (CPK) values should be considered in asmathic patients receiving high dose corticosteroids and neuromusculars blocking agents in ICU.

  • Atracurium does not have significant vagal or ganglionic blocking properties in the recommended dosage range. Consequently, atracurium has no clinically significant effects on heart rate in the recommended dosage range and it will not counteract the bradycardia produced by many anesthetic 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 neuromusculars disease and severe electrolyte imbalance.

  • As with other non-depolarising neuromuscular blockers hypophosphatemia may prolong recovery. Recovery may be hastened by correcting this condition.

  • Atracurium 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.

  • Atracurium 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, atracurium 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 atracurium it is important that each drug is flushed through with an adequate volume of physiological saline.

  • Atracurium besylate is hypotonic and must not be administered into the infusion line of a blood infusion.

  • Studies in malignant hyperthermia in susceptible animals (swine), and clinical studies in patients susceptible to malignant hyperthermia indicate that atracurium 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 atracurium, a causal relationship to laudanosine or atracurium has not been established.

  • Mutagenicity: Atracurium has been evaluated in 3 short term mutagenicity tests: It was not mutagenic in either the in vitro Ames Salmonella assay (at concentrations up to 1,000 μg/plate) or in an in vivo rat bone marrow assay (at doses up to those which resulted in neuromuscular blockade); in in vitro test, the mouse lymphoma assay, mutagenicity was not observed at doses up to 60 μg/ml which killed up to 50% of the treated cells, but it was moderately mutagenic at concentrations of 80 mcg/ml in the absence of metabolising agent and weakly mutagenic at a very high concentration (1,200 mcg/ml) when metabolizing enzymes were added, at both concentration over 80% of cells were killed.

The mutagenic risk to patients undergoing surgical relaxation with atracurium must be considered negligible.

  • Carcinogenicity: No studies have been performed.

  • Teratogenicity: Animal studies have indicated that atracurium has no significant effects on fetal development.

  • Fertility: No studies have been performed.

  • Pregnancy and lactation: in common with all neuromuscular blocking agents, atracurium should be used during pregnancy only if the potential benefit to the mother outweighs any potential risk to the fetus.

Atracurium 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 atracurium is not excreted in human milk.

 

Drug interactions:

  • The neuromuscular block produced by atracurium may be increased by the concomitant use of inhalational anesthetics 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); antiarrythmic drugs (propranolol, calcium channel blockers, lignocaine, procainamide and quinidine); diuretics (furosemide and possibly mannitol, thiazide diuretics and acetazolamide); magnesium sulfate; 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 atracurium would be consequent on such a development. Such drugs include various antibiotics, β-blockers (propranolol, oxprenolol), antiarrhytmic 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.

  • The administration of combinations of non-depolarising neuromuscular blocking agents in conjunction with atracurium may produce a degree of neuromuscular blockage in excess of that which may be expected were an equipotent total dose of atracurium 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 agents such as atracurium, as this may result in a prolonged and complex block which can be difficult to reverse with anticholinesterase drugs.

 

Overdosage:

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.

 

 

Presentation and reg no:

Box, 5 ampoule @ 2.5 ml, DKL0605040443A1

Box, 5 ampoule @ 5 ml, DKL0605040443A1

 

 

ON MEDICAL PRESCRIPTION ONLY

 

STORE IN THE REFRIGERATOR AT 2oC TO 8oC TO PRESERVE POTENCY.

DO NOT FREEZE

PROTECT FROM LIGHT

 

Manufactured by:

PT FERRON PAR PHARMACEUTICALS

CIKARANG - INDONESIA

 

For:

DEXA MEDICA