Consumer medicine information

Atracurium besilate Medsurge

Atracurium besilate

BRAND INFORMATION

Brand name

Atracurium Besilate Medsurge

Active ingredient

Atracurium besilate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Atracurium besilate Medsurge.

SUMMARY CMI

Atracurium besilate Medsurge

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Atracurium besilate Medsurge?

Atracurium besilate Medsurge contains the active ingredient atracurium besilate. Atracurium besilate 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.

For more information, see Section 1. Why am I using Atracurium besilate Medsurge? in the full CMI.

2. What should I know before I use Atracurium besilate Medsurge?

Do not use if you have ever had an allergic reaction to atracurium besilate or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Atracurium besilate Medsurge? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with atracurium besilate and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Atracurium besilate Medsurge?

More instructions can be found in Section 4. How do I use Atracurium besilate Medsurge? in the full CMI.

Atracurium besilate Medsurge will be given into your vein as an injection or by a 'drip' (infusion). This will be done by an anaesthetist or a doctor with special training.

5. What should I know while using Atracurium besilate Medsurge?

Driving or using machines
  • If you are discharged early, following treatment with atracurium besilate or any other anaesthetic agent, do not drive or operate machinery
Looking after your medicine
  • Atracurium besilate Medsurge should be stored by the hospital's pharmacy between 2° and 8°C and protected from light. Do not freeze. Once removed from the fridge, the ampoules may be stored below 25°C, protected from light for up to 1 week only, provided the product is used before the printed expiry date. Thereafter discard the ampoules.

For more information, see Section 5. What should I know while using Atracurium besilate? in the full CMI.

6. Are there any side effects?

The most commonly reported side effects are skin flushing, lowering of blood pressure, changes in heart rate either increased or decreased, tight breathing, allergic reactions, skin rash, seizures (in certain patients), muscle weakness.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Atracurium besilate Medsurge

Active ingredient(s): atracurium besilate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Atracurium besilate Medsurge. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Atracurium besilate Medsurge.

Where to find information in this leaflet:

1. Why am I using Atracurium besilate Medsurge?
2. What should I know before I use Atracurium besilate Medsurge?
3. What if I am taking other medicines?
4. How do I use Atracurium besilate Medsurge?
5. What should I know while using Atracurium besilate Medsurge?
6. Are there any side effects?
7. Product details

1. Why am I using Atracurium besilate Medsurge?

Atracurium besilate Medsurge contains the active ingredient atracurium besilate. Atracurium besilate belongs to a group of medicines called neuromuscular blockers. Atracurium besilate works by blocking the effects of one of the body's chemical messengers called acetylcholine. Acetylcholine is involved in muscle contraction.

Atracurium besilate 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.

2. What should I know before I use Atracurium besilate Medsurge?

Do not use Atracurium besilate Medsurge if:

  • you are allergic to atracurium besilate, or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following:
    wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash ("hives") or fainting.

Check with your doctor if you:

  • have had any adverse reactions during an operation.
  • have had any type of allergic reaction to muscle relaxants, or to any medicines used during an operation.
  • are allergic to any other medicines or any other substance, such as foods, dyes or preservatives.
  • if you or a relative have had previous difficulties with anaesthetics.
  • you have or have ever had any of the following medical conditions:
    - asthma or any other breathing disorders
    - heart disease
    - kidney, liver disease or disease of the nervous system e.g. myaesthenia gravis

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor will discuss the possible risks and benefits of being given Atracurium besilate if you are pregnant or breast-feeding.

If you have not told your doctor about any of the above, tell them before you are given Atracurium besilate Medsurge.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Atracurium besilate may be affected by other medicines such as:

  • antibiotics
  • drugs for the heart
  • blood pressure tablets
  • magnesium
  • lithium
  • other muscle blockers (e.g. hexamethonium) and anaesthetics.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Atracurium besilate Medsurge.

4. How do I use Atracurium besilate Medsurge?

Atracurium besilate Medsurge can be given into a vein in two ways:

  • as an injection, or
  • as a slow infusion.

Atracurium besilate Medsurge will be administered by an anaesthetist or other doctor with special training. You will never be expected to give yourself this medication. The dosage will vary according to many factors such as your body weight and the type of operation you have.

5. What should I know while using Atracurium besilate Medsurge?

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Atracurium besilate affects you.

If you are discharged early, following treatment with Atracurium besilate or any other anaesthetic agents, do not drive or operate machinery.

Looking after your medicine

Atracurium besilate Medsurge should be stored by the hospital's pharmacy between 2° and 8°C and protected from light. Do not freeze.

Once removed from the fridge, the ampoules may be stored below 25°C, protected from light for up to 1 week only, provided the product is used before the printed expiry date. Thereafter discard the ampoules.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Check with your doctor as soon as possible if you have any problems after receiving atracurium besilate, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effectsWhat to do
  • skin flushing
  • lowering of blood pressure
  • changes in heart rate either increased or decreased
  • tight breathing
  • allergic reactions
  • skin rash
  • seizures (in certain patients)
  • muscle weakness
Call your doctor or nurse straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor, nurse or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

7. Product details

This medicine is only available with a doctor's prescription.

What Atracurium besilate Medsurge contains

Active ingredient
(main ingredient)		atracurium besilate
Other ingredients
(inactive ingredients)		benzenesulfonic acid,
water for injections
Potential allergensNone

Do not take this medicine if you are allergic to any of these ingredients.

What Atracurium besilate Medsurge looks like

Atracurium besilate Medsurge is clear, slightly yellow solution supplied in glass ampoules contains Atracurium besilate 25 mg/2.5 mL with pack size 5 x 2.5 mL ampoules (Aust R 400346).

Atracurium besilate Medsurge is clear, slightly yellow solution supplied in glass ampoules contains Atracurium besilate 50 mg/5 mL with pack size 5 x 5 mL ampoules (Aust R 400347).

Who distributes Atracurium besilate Medsurge

Medicianz Healthcare Pty Ltd
Unit 1&2, 6-7 Gilda Court
Mulgrave, Victoria 3170

Marketed and Distributed by Medsurge Healthcare.

Telephone: 1300 788 261
Website: www.medsurgehc.com

This leaflet was prepared in November 2023.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Atracurium Besilate Medsurge

Active ingredient

Atracurium besilate

Schedule

S4

 

Notes

Distributed by Medsurge Healthcare

1 Name of Medicine

Atracurium besilate.

2 Qualitative and Quantitative Composition

Atracurium Besilate Medsurge solution for injection, 10 mg atracurium besilate in each mL.
Each 2.5 mL glass ampoule contains 25 mg of atracurium besilate.
Each 5 mL glass ampoule contains 50 mg of atracurium besilate.
The pH is adjusted to 3.4-3.6 with benzenesulfonic acid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Atracurium Besilate Medsurge solution for injection is a sterile solution in water. It is clear, colourless or yellowish solution, free from visible particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Atracurium besilate 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.

4.2 Dose and Method of Administration

To avoid distress to the patient, atracurium besilate should not be administered before unconsciousness has been induced. Atracurium besilate should not be mixed in the same syringe, or administered simultaneously through the same needle, with alkaline solutions (e.g. barbiturate solutions).
Atracurium besilate injection should be administered intravenously. Do not give atracurium besilate intramuscularly. Intramuscular administration of atracurium besilate may result in tissue irritation and there is no clinical data to support this route of administration.

Bolus doses for intubation and maintenance of neuromuscular blockade.

Use in adults.

The initial dosage for adults ranges from 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.
An atracurium besilate dose of 0.5 to 0.6 mg/kg (2.2 to 2.6 times the ED95), given as an intravenous bolus injection provides suitable conditions for non-emergency intubation in 2 to 2.5 minutes in most patients which is comparable to other drugs of this class. Maximum neuromuscular blockade is achieved approximately 2 to 5 minutes after injection. Complete neuromuscular blockade generally lasts 20 to 35 minutes under balanced anaesthesia. Recovery to 25% of control is achieved approximately 35 to 45 minutes after injection, and recovery is usually complete 60 to 70 minutes after injection.
Atracurium besilate is potentiated by isoflurane or enflurane anaesthesia. The same initial atracurium besilate dose of 0.5 to 0.6 mg/kg may be used for intubation prior to administration of these inhalation agents; however, if atracurium besilate is first administered under steady state of isoflurane or enflurane, the initial atracurium besilate dose may be reduced by approximately one-third, i.e. 0.3 to 0.4 mg/kg, to adjust for the potentiating effects of these anaesthetic agents. With halothane, which has only a marginal (approximately 20%) potentiating effect on atracurium besilate, smaller dosage reductions may be considered.
Atracurium besilate doses of 0.08 to 0.10 mg/kg are recommended for maintenance of neuromuscular blockade during prolonged surgical procedures. The first maintenance dose will generally be required 20 to 45 minutes after the initial atracurium besilate, but the need for maintenance doses should be determined by clinical criteria. Because atracurium besilate lacks cumulative effects, maintenance doses may be administered at relatively regular intervals for each patient, ranging approximately from 15 to 25 minutes under balanced anaesthesia, slightly longer under isoflurane or enflurane. Higher atracurium besilate doses (up to 0.2 mg/kg) permit maintenance dosing at longer intervals.

Use in children.

No atracurium besilate dosage adjustments are required for paediatric patients two years of age or older. An atracurium besilate dose of 0.4 mg/kg is recommended as the initial dose for paediatric patients aged 1 month to 2 years of age under halothane anaesthesia. Maintenance doses may be required with slightly greater frequency in infants and children than in adults.
Safety and efficacy in children younger than one month have not been established.
In common with all neuromuscular blocking agents monitoring of neuromuscular function is recommended, particularly during long-term use, in order to individualise dosage requirements.

Special considerations.

Atracurium besilate may be used at standard dosage at all levels of renal or hepatic function, including end stage failure.
Atracurium besilate 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.
An initial atracurium besilate dose of 0.3 to 0.4 mg/kg, given slowly or in divided doses over one minute, is recommended for patients with significant cardiovascular disease (an increased incidence of hypotensive episodes has been seen in these patients) and for patients with any history (e.g. anaphylactoid reactions or asthma) suggesting a greater risk of histamine release.
Dosage reductions must be considered also in patients with neuromuscular disease, severe electrolyte disorders, or carcinomatosis in which potentiation of neuromuscular blockade or difficulties with reversal have been demonstrated. There has been no clinical experience with atracurium besilate in these patients, and no specific dosage adjustments can be recommended.
An initial atracurium besilate dose of 0.3 to 0.4 mg/kg is recommended following the use of suxamethonium for intubation under balanced anaesthesia. Further reductions may be desirable with the use of potent inhalation anaesthetics. The patient should be permitted to recover from the effects of suxamethonium prior to atracurium injection administration.

Reversal.

Reversal of neuromuscular blockade produced by atracurium besilate can be achieved with an anticholinesterase such as neostigmine in conjunction with an anticholinergic agent such as atropine. Under balanced anaesthesia, reversal can usually be attempted approximately 20 to 35 minutes after the initial atracurium besilate dose or approximately 10 to 30 minutes after a maintenance dose, when recovery of muscle twitch has started. Complete reversal is usually accomplished within 8 to 10 minutes of the administration of reversing agents. Rare instances of breathing difficulties, possibly related to incomplete reversal, have been reported following attempted pharmacological antagonism of atracurium-induced neuromuscular blockade. As with other agents in this class, the tendency for residual neuromuscular block is increased if reversal is attempted at deep levels of blockade or if inadequate doses of reversal agents are employed.

Use as an infusion.

An initial bolus dose of 0.3 to 0.6 mg/kg of atracurium besilate can be used to maintain neuromuscular block during long surgical procedures by administration as a continuous infusion. An initial infusion rate of 9 to 10 microgram/kg/min may be required to restore adequate neuromuscular block. Thereafter, a rate of 5 to 9 microgram/kg/min should be adequate to maintain continuous neuromuscular block in the range of 89 to 99% in most paediatric and adult patients under balanced anaesthesia. Occasional patients may require infusion rates as low as 2 microgram/kg/min or as high as 15 microgram/kg/min.
Atracurium besilate 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 temperatures.
Atracurium besilate is compatible with the following infusion solutions for the times stated in Table 1.
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 25°C.

Longer term use in intensive care unit (ICU) patients.

There is only limited information on the efficacy and safety of long-term (median duration approximately 90 hours) intravenous atracurium infusion to facilitate mechanical ventilation in the ICU (n = 58).
After an optional initial bolus dose of atracurium besilate of 0.3 to 0.6 mg/kg, atracurium besilate can be used to maintain neuromuscular block by administering a continuous infusion at rates of between 11 and 13 microgram/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 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 besilate 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 32-108 minutes has been observed in clinical trials.
Limited information is available on the plasma levels or clinical consequences of atracurium metabolites that may accumulate during days to weeks of atracurium administration in ICU patients. Laudanosine, a major biologically active metabolite of atracurium without neuromuscular blocking activity, produces transient hypotension and, in higher doses, cerebral excitatory effects (generalised muscle twitching and seizures) when administered to several animal species. Although seizures have been seen in ICU patients receiving atracurium, definite causality has not been attributable to laudanosine or atracurium. These patients usually had predisposing causes (such as cranial trauma, cerebral oedema, hypoxic encephalopathy, viral encephalitis, uraemia).

Monitoring.

In common with all neuromuscular blocking agents continuous monitoring of neuromuscular function is recommended during the use of atracurium besilate in order to individualise dosage requirements which may be variable over time.

4.3 Contraindications

Atracurium besilate is contraindicated in patients known to be hypersensitive to atracurium, cisatracurium or benzenesulfonic acid.

4.4 Special Warnings and Precautions for Use

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 anaesthesia or sedation/analgesia in the ICU and only by those skilled in the management of artificial respiration and only when facilities are instantly available for endotracheal intubation and for providing adequate ventilation of the patient, including the administration of oxygen under positive pressure and the elimination of carbon dioxide. The clinician must be prepared to assist or control respiration and anticholinesterase reversal agents should be immediately available.
Atracurium has the potential to cause histamine release. Anaphylactic and anaphylactoid reactions have been reported and have sometimes been life-threatening. For this reason it is essential that appropriate resuscitative equipment be immediately available. Caution should be exercised in administering atracurium besilate to patients with a history suggestive of an increased sensitivity to the effects of histamine.
Do not give atracurium besilate by intramuscular administration.
Atracurium besilate is hypotonic and must not be administered into the infusion line of a blood transfusion.
Atracurium besilate has no known effect on consciousness, pain threshold, or cerebration.
Atracurium besilate, which has an acid pH, should not be mixed with alkaline solutions (e.g. barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle. Depending on the resultant pH of such mixtures, atracurium besilate may be inactivated and a free acid may be precipitated.
Caution should also be exercised when administering atracurium to patients who have shown hypersensitivity to other neuromuscular blocking agents since cross-sensitivity between neuromuscular blocking agents has been reported (see Section 4.3 Contraindications).
Although atracurium is a less potent histamine releaser than d-tubocurarine, the possibility of histamine release in sensitive individuals must be considered. Special caution should be exercised in administering atracurium to patients in whom substantial histamine release would be especially hazardous (e.g. patients with clinically significant cardiovascular or respiratory disease) and in patients with any history (e.g. severe anaphylactoid reactions) suggesting a greater risk of histamine release. In these patients, the recommended initial atracurium besilate dose is lower (0.3 to 0.4 mg/kg) than for other patients and should be administered slowly or in divided doses over one minute. Limited clinical experience indicates that mean arterial pressure decreases in a substantial percentage of patients with a history of cardiovascular disease even at these doses.
Atracurium besilate 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 may have profound effects in patients with myasthenia gravis, Eaton-Lambert syndrome, or other neuromuscular diseases in which potentiation of non-depolarising agents has been noted. A reduced dosage of atracurium besilate and the use of a peripheral nerve stimulator for assessing neuromuscular blockade is especially important in these patients. Similar precautions should be taken in patients with severe electrolyte disorders or carcinomatosis.
The safety of atracurium has not been established in patients with bronchial asthma.
Atracurium does not have significant vagal or ganglion 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 anaesthetic agents and by vagal stimulation during surgery.
When a small vein is selected as the injection site, atracurium besilate 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 besilate it is important that each drug is flushed through with an adequate volume of physiological saline.
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.
Multiple factors in anaesthetic practice are suspected of triggering malignant hyperthermia (MH), a potentially fatal hypermetabolic state of skeletal muscle. Halogenated anaesthetic agents and suxamethonium are recognised as the principal pharmacological triggering agents in MH-susceptible patients; however, since MH can develop in the absence of established triggering agents, the clinician should be prepared to recognise and treat MH in any patient scheduled for general anaesthesia. Reports of MH have been rare in cases in which atracurium has been used. In a clinical study of MH-susceptible patients, atracurium did not trigger this syndrome.
One of the major metabolites of atracurium, laudanosine, when administered alone to laboratory animals, has been associated with transient hypotension and cerebral excitatory effects. Long-term atracurium administration may result in plasma laudanosine concentrations similar to those that produced seizure-like activity in rabbits. Although seizures have been seen in ICU patients receiving atracurium, definite causality has not been attributable to laudanosine or atracurium. These patients usually had predisposing causes (such as cranial trauma, cerebral oedema, hypoxic encephalopathy, viral encephalitis, uraemia).

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Special considerations.

Paediatric use.

Safety and effectiveness in paediatric patients below the age of one month have not been established. No dosage adjustments are required for paediatric patients two years of age or older. See Section 4.2 Dose and Method of Administration for recommendations of dose in patients between the ages of 1 month and 2 years.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Atracurium besilate is potentiated by isoflurane and by enflurane anaesthesia, and marginally potentiated by halothane (see Section 4.2 Dose and Method of Administration).
In common with other 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, lidocaine, procainamide and quinidine;
diuretics: furosemide and possibly mannitol, thiazide diuretics and acetazolamide;
magnesium sulfate;
ketamine;
lithium salts;
ganglion blocking agents: trimetaphan, hexamethonium.
If other muscle relaxants are used during the same procedure, the possibility of a synergistic or antagonistic effect should be considered.
The prior administration of suxamethonium does not enhance the duration, but quickens the onset and may increase the depth, of neuromuscular blockade induced by atracurium besilate. As with other non-depolarising neuromuscular blocking agents, it is advisable to await evidence of recovery from suxamethonium-induced neuromuscular block before administering atracurium besilate.
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, beta-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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
Atracurium has been shown to cross the placenta to a limited degree although the transfer of metabolites may be greater. Animal studies of teratogenic potential are limited to a single study in which pregnant rabbits received subcutaneous doses of 0.15 mg/kg once daily or 0.1 mg/kg twice daily during the period of organogenesis. There was no clear evidence of teratogenic activity at these doses, which are less than those used clinically, although there was some indication of fetotoxicity manifest as slight increases in the incidences of minor skeletal and visceral anomalies. There are no adequate and well controlled studies in pregnant women. In common with all neuromuscular blocking agents, atracurium besilate should be used in pregnant women only if in the opinion of the physician, the potential benefit outweighs any potential risk to the foetus.

Use in obstetrics.

In an open study, atracurium besilate was administered (0.3 mg/kg) to 26 pregnant women during delivery by Caesarean section. No harmful effects were attributable to atracurium in any of the newborn infants, although atracurium was shown to cross the placental barrier. The possibility of respiratory depression in the newborn infant should always be considered following Caesarean section during which a neuromuscular blocking agent has been administered. In patients receiving magnesium sulfate, the reversal of neuromuscular blockade may be unsatisfactory and atracurium besilate dose should be lowered as indicated.
 It is not known whether atracurium or its metabolites are excreted in milk of humans or animals. Because many drugs are excreted in human milk, caution should be exercised when atracurium besilate is administered to a nursing woman.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
In common with most neuromuscular blocking agents the potential exists for histamine release in susceptible patients. In clinical trials involving 875 patients there were reports of skin flushing ranging from 1% at doses less than 0.3 mg/kg to 29% at doses of 0.6 mg/kg or greater, and transient hypotension ranging from 1% to 14% respectively for the corresponding dosages. Bronchospasm and rarely anaphylactoid reactions have also been reported.
In a large scale muscle relaxant surveillance study in which 3,782 patients were treated with atracurium besilate, adverse reactions considered possibly or probably related to atracurium besilate were observed in approximately 10% of patients. Localised skin reactions, generalised flushing and hypotension each occurred in approximately 2 to 3% of patients. Hypertension, tachycardia and bradycardia were observed with an incidence of approximately 1%. Bronchospasm was observed in approximately 0.4% of patients.
There have been infrequent 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). In clinical trials no correlation was apparent between plasma laudanosine concentration and the occurrence of seizures. There have been reports of muscle weakness following prolonged use of muscle relaxants in severely ill patients in the ICU. This has very rarely been seen in association with atracurium besilate and a causal relationship has not been established.
Based on clinical practice experience in approximately 11 million patients who received atracurium besilate, spontaneously reported adverse reactions were uncommon. The following adverse reactions are among the most frequently reported, but there are insufficient data to support an estimate of their incidence. See Table 2.
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.

4.9 Overdose

There has been limited experience with atracurium besilate overdosage. The possibility of iatrogenic overdosage can be minimised by carefully monitoring muscle twitch response to peripheral nerve stimulation. Excessive doses of atracurium besilate can be expected to produce enhanced pharmacological effects. Overdosage may increase the risk of histamine release and cardiovascular effects, especially hypotension. If cardiovascular support is necessary, this should include proper positioning, fluid administration, and the use of vasopressor agents if necessary. The patient's airway should be maintained, with manual or mechanical ventilation as necessary. A longer duration of neuromuscular blockade may result from overdosage and a peripheral nerve stimulator should be used to monitor recovery. Full sedation will be required since consciousness is not impaired. Recovery may be facilitated by administration of an anti-cholinesterase reversing agent such as neostigmine, edrophonium or pyridostigmine, in conjunction with an anticholinergic agent such as atropine.

Further information.

Haemofiltration and haemodiafiltration have a minimal effect on plasma levels of atracurium and its metabolites, including laudanosine. The effects of haemodialysis and haemoperfusion on plasma levels of atracurium and its metabolites are unknown.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Atracurium besilate is an intermediate-duration, non-depolarising, skeletal muscle relaxant for intravenous administration.
Non-depolarising agents antagonise the neurotransmitter action of acetylcholine by binding competitively with cholinergic receptor sites on the motor end-plate. This antagonism is inhibited and neuromuscular block reversed, by acetylcholinesterase inhibitors such as neostigmine, edrophonium and pyridostigmine.
The duration of neuromuscular blockade produced by atracurium besilate is approximately one third to one half the duration seen with d-tubocurarine and pancuronium at equipotent doses. As with other non-depolarising neuromuscular blockers, the time to onset of paralysis decreases and the duration of maximum effect increases with increasing atracurium besilate doses.
The ED95 (dose required to produce 95% suppression of the muscle twitch response) averages 0.23 mg/kg. An initial atracurium besilate dose of 0.4 to 0.5 mg/kg generally produces maximum neuromuscular blockade within 3 to 5 minutes of injection, with suitable intubation conditions within 2 to 2.5 minutes. Recovery from neuromuscular blockade (under balanced anaesthesia) can be expected to begin approximately 20 to 35 minutes after injection. Recovery to 25% of control is achieved approximately 35 to 45 minutes after injection, and recovery is usually 95% complete 60 to 70 minutes after injection. The neuromuscular blocking action of atracurium besilate is enhanced in the presence of potent inhalation anaesthetics. Isoflurane and enflurane increase the potency of atracurium besilate and prolong neuromuscular blockade by approximately 35%; however, halothane's potentiating effect (approximately 20%) is marginal (see Section 4.2 Dose and Method of Administration).
Repeat administration of maintenance doses of atracurium besilate has no cumulative effect on the duration of neuromuscular blockade; therefore, doses can be administered at relatively regular intervals with predictable results. After an initial dose of 0.4 to 0.5 mg/kg under balanced anaesthesia, the first maintenance dose (suggested maintenance dose is 0.08 to 0.10 mg/kg) is generally required within 20 to 45 minutes, and subsequent maintenance doses are usually required at approximately 15 to 25 minute intervals. Repeated bolus dosing with atracurium does not give rise to prolongation of the neuromuscular blocking effect. This is reflected in the lack of accumulation.
Once recovery from atracurium's neuromuscular blocking effects begins, it proceeds more rapidly than recovery from d-tubocurarine, alcuronium and pancuronium. Regardless of atracurium besilate dose, the time from start of recovery (from complete block) to complete recovery, as measured by restoration of the tetanic response to 95% of normal, is approximately 30 minutes under balanced anaesthesia, and approximately 40 minutes under halothane, enflurane or isoflurane. Repeated doses have no cumulative effect on recovery rate.
Reversal of neuromuscular blockade produced by atracurium can be achieved with an anticholinesterase agent such as neostigmine, edrophonium, or pyridostigmine, in conjunction with an anticholinergic agent such as atropine. Under balanced anaesthesia, reversal can usually be attempted approximately 20 to 35 minutes after an initial atracurium besilate dose of 0.5 to 0.6 mg/kg, or approximately 10 to 30 minutes after 0.08 to 0.10 mg/kg maintenance dose, when recovery of muscle twitch has started. Complete reversal is usually accomplished within 8-10 minutes of the administration of reversing agents. There have been few reports of recurarization following reversal of atracurium-induced neuromuscular blockade, a finding consistent with the rapid elimination of atracurium.

Clinical trials.

See Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration.

5.2 Pharmacokinetic Properties

The pharmacokinetics of atracurium besilate in man are essentially linear within the 0.3 to 0.6 mg/kg dose range. The elimination half-life is approximately 20 minutes. The duration of neuromuscular blockade produced by atracurium does not correlate with plasma pseudocholinesterase levels and is not altered by the absence of renal function. This is consistent with the results of in vitro studies which have shown that atracurium is inactivated in plasma via two nonoxidative pathways: ester hydrolysis, catalyzed by nonspecific esterases; and Hofmann elimination, a nonenzymatic chemical process which occurs at physiological pH and body temperature. The rate of Hofmann elimination, which is the principal route of elimination for atracurium is increased at a higher pH or at higher temperatures and reduced at a lower pH or lower temperatures. Some placental transfer occurs in humans.
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.
Tests with plasma from patients with low levels of pseudocholinesterase show that the inactivation of atracurium injection proceeds unaffected.
The termination of the neuromuscular blocking action of atracurium is not dependent on hepatic or renal function. Its duration of action, therefore, is unlikely to be affected by impaired renal, hepatic or circulatory function.
The elimination half-life of atracurium is approximately 20 minutes, and the volume of distribution is 0.16 Uks. Atracurium is 82% bound to plasma proteins.
Radiolabel studies demonstrated that atracurium undergoes extensive degradation in cats, and that neither kidney nor liver plays a major role in its elimination. Biliary and urinary excretion were the major routes of excretion of radioactivity (totalling 90% of the labelled dose within 7 hours of dosing), of which atracurium represented only a minor fraction. The metabolites in bile and urine were similar, including products of Hofmann elimination and ester hydrolysis. A major metabolite is laudanosine which has the potential to accumulate in patients with end-stage liver failure who have received atracurium by infusion for several days to weeks. Laudanosine does not possess any neuromuscular blocking activity; CNS activating properties have been demonstrated in animals. Laudanosine is probably metabolised in the liver and is also cleared to a relatively small extent through the kidney. Accumulation is more likely in patients with hepatic and renal failure.
Plasma histamine levels were increased by 15% in a dose-dependent way with initial atracurium besilate doses up to 0.5 mg/kg, and haemodynamic changes were minor within this dose range. Histamine levels increased by 92% following 0.6 mg/kg of atracurium besilate and were shown to correlate with a transient (5 minutes) decrease in blood pressure and a brief (2 to 3 minutes) episode of skin flushing. While these effects are of little clinical significance in most patients, the possibility of substantial histamine release at recommended doses in sensitive individuals or in patients in whom substantial histamine release would be especially hazardous (e.g. patients with significant respiratory or cardiovascular disease) must be considered.
It is not known whether the prior use of other non-depolarising neuromuscular blocking agents has any effect on the activity of atracurium. The prior use of suxamethonium decreases by approximately 2 to 3 minutes the time to maximum blockade induced by atracurium, and may increase the depth of blockade.
Atracurium injection has no direct effect on intra-ocular pressure, and is therefore suitable for use in ophthalmic surgery.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for injections and benzenesulfonic acid.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store under refrigeration at 2°C to 8°C.
Do not freeze. Protect from light.
Any unused Atracurium Besilate Medsurge from opened ampoules should be discarded.
Once removed from the fridge, the ampoules may be stored below 25°C, protect from light, for up to 1 week only, provided that the product is used before printed expiry date. Thereafter discard the ampoules.
Contains no antimicrobial preservative. Use in one patient on one occasion only.

6.5 Nature and Contents of Container

2.5 mL or 5 mL glass ampoules.
Atracurium Besilate Medsurge atracurium besilate 25 mg/2.5 mL injection ampoule.
Atracurium Besilate Medsurge atracurium besilate 50 mg/5 mL injection ampoule.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Atracurium besilate is white or yellowish-white, slightly hygroscopic powder. Soluble in water, very soluble in acetonitrile, in ethanol (96 per cent) and in methylene chloride and is designated as 5-[3-[1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1-Hisoquinolin-2-ium-2-yl]propanoyloxy]pentyl3-[1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propanoate benzenesulfonate. It has a molecular weight of 1243.49, and its empirical formula is C53H72N2O12.2C6H5O3S.

Chemical structure.


CAS number.

64228-81-5.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine - Schedule 4.

Summary Table of Changes