Tracrium

Leaflet accompanying the packaging: information for the user

Tracrium, 10 mg/ml, solution for injection or infusion

Atracurium besilate

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this leaflet, please inform your doctor or pharmacist. See section 4.

Table of contents of the leaflet

• 1. What Tracrium is and what it is used for
• 2. Important information before using Tracrium
• 3. How to use Tracrium
• 4. Possible side effects
• 5. How to store Tracrium
• 6. Contents of the pack and other information

1. What Tracrium is and what it is used for

Tracrium contains the active substance atracurium besilate, which is a highly specific, competitive (non-depolarizing) neuromuscular blocking agent with an intermediate duration of action.
Tracrium is indicated for use:

• during general anesthesia to facilitate endotracheal intubation,
• during surgical procedures or controlled ventilation to provide skeletal muscle relaxation,
• in intensive care units (ICU) to facilitate mechanical ventilation.

The medicine should only be administered by an experienced anesthesiologist or under their direct supervision, in conditions that allow for endotracheal intubation and artificial ventilation.

2. Important information before using Tracrium

When not to use Tracrium

• if the patient is allergic to atracurium, cisatracurium, or benzene sulfonic acid, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Before starting treatment with Tracrium, discuss it with your doctor, pharmacist, or nurse.
Like all other neuromuscular blocking agents, Tracrium paralyzes the respiratory muscles as well as other skeletal muscles, without affecting consciousness.
Tracrium should only be used in conjunction with appropriate general anesthetics.
During administration of Tracrium, some patients may experience histamine release. Therefore, Tracrium should be used with caution in patients with a history of hypersensitivity to histamine. In particular, patients with a history of allergy and asthma may experience bronchospasm.
Caution should also be exercised when administering Tracrium to patients who have shown hypersensitivity to other neuromuscular blocking agents, as there are reports of a high frequency of cross-sensitivity (greater than 50%) between neuromuscular blocking agents (see section "When not to use Tracrium").
Tracrium, when administered in recommended doses, does not have a significant effect on vagal nerve conduction and ganglionic transmission. Consequently, Tracrium, when administered within the recommended dose range, does not have a clinically significant effect on heart rate and does not counteract bradycardia induced by many anesthetics or vagal stimulation during surgery.
Patients with myasthenia, other neuromuscular transmission disorders, or severe electrolyte disturbances show increased sensitivity to the effect of atracurium, as with other non-depolarizing neuromuscular blockers.
Tracrium should be injected over at least 60 seconds to patients who are at risk of severe hypotension, such as those with hypovolemia (reduced blood volume).
Tracrium is inactivated at high pH and should not be mixed in the same syringe with thiopentone or other alkaline drugs.
When a small vein is chosen as the site of administration of Tracrium, the vein should be flushed with isotonic sodium chloride solution after injection. When Tracrium and other anesthetics are administered through a permanently inserted needle or cannula, each drug should be flushed with an appropriate volume of isotonic sodium chloride solution after administration.
Since Tracrium is a hypotonic compound, it should not be administered into a cannula intended for blood transfusion.
Studies on the occurrence of malignant hyperthermia in predisposed animals (pigs) and clinical studies on the occurrence of its symptoms in predisposed patients show that Tracrium does not cause this syndrome.
Burn patients may show resistance to the effect of atracurium and other non-depolarizing neuromuscular blockers. In such patients, higher doses of the drug may be required, depending on the time elapsed since the burn and its extent.

Tracrium and other medicines

Tell your doctor about all medicines you are taking or have recently taken, as well as any medicines you plan to take, including those available without a prescription.
Concomitant use of inhalational anesthetics, such as halothane, isoflurane, or enflurane, may enhance the neuromuscular blocking effect of Tracrium.
Like other non-depolarizing neuromuscular blockers, Tracrium may also enhance and/or prolong the neuromuscular blocking effect resulting from interactions with the following drugs: antibiotics (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, and ganglionic blockers (trimethaphan and hexamethonium).
Certain drugs may sometimes exacerbate or reveal latent myasthenia or even induce a myasthenic syndrome, resulting in increased sensitivity to the effect of Tracrium.
Such drugs include various antibiotics, beta-adrenergic blockers (propranolol, oxprenolol), antiarrhythmic drugs (procainamide, quinidine), antirheumatic drugs (chloroquine, D-penicillamine), trimethaphan, chlorpromazine, steroids, phenytoin, and lithium salts.
In patients receiving long-term anticonvulsant therapy, the onset of non-depolarizing neuromuscular blockade may be delayed and its duration shortened.
Administration of Tracrium in combination with other non-depolarizing neuromuscular blockers may result in a greater degree of neuromuscular blockade than would be expected from an equivalent dose of Tracrium alone. The degree of potentiation may vary depending on the combination of drugs used.
Depolarizing neuromuscular blockers, such as suxamethonium, should not be used to prolong neuromuscular blockade produced by non-depolarizing blockers, such as atracurium, as this may result in an excessively prolonged and complex blockade, which may be difficult to reverse with anticholinesterases.
Treatment with acetylcholinesterase inhibitors, commonly used in the treatment of Alzheimer's disease (such as donepezil), may shorten the duration and reduce the intensity of the neuromuscular blockade produced by Tracrium.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before taking this medicine.
Tracrium, like all neuromuscular blocking agents, is used in pregnant women only when the expected benefit to the mother outweighs the potential risk to the fetus.
Tracrium can be used to maintain muscle relaxation during cesarean section, as it does not cross the placenta in clinically significant amounts when administered in recommended doses.

Driving and using machines

This does not apply to the use of Tracrium. Tracrium is always used in conjunction with general anesthetics. The usual precautions related to the effects of general anesthesia on the patient's psychophysical fitness apply.

3. How to use Tracrium

Adults Intravenous injection

Tracrium is administered by intravenous injection. The dose for adults is 0.3 mg/kg body weight to 0.6 mg/kg body weight (depending on the required duration of complete non-depolarizing blockade) and provides adequate relaxation for 15-35 minutes.
Endotracheal intubation can usually be performed within 90 seconds of intravenous administration of a dose of 0.5 mg/kg body weight to 0.6 mg/kg body weight.
The duration of complete non-depolarizing blockade can be extended by administering additional doses of 0.1 mg/kg body weight to 0.2 mg/kg body weight as needed. Administration of additional doses does not potentiate the neuromuscular blocking effect. Spontaneous recovery of neuromuscular transmission, measured by the return of 95% of the response to tetanic stimulation, occurs after approximately 35 minutes from the end of complete blockade.
The neuromuscular blockade produced by Tracrium can be rapidly reversed without fear of recurarization by administering standard doses of anticholinesterase drugs, such as neostigmine and edrophonium, preceded by atropine or given concurrently with atropine.
Continuous infusion
After an initial dose of 0.3 mg/kg body weight to 0.6 mg/kg body weight administered by rapid intravenous injection, Tracrium can be administered by continuous infusion at a dose of 0.3 mg/kg body weight to 0.6 mg/kg body weight per hour to maintain neuromuscular blockade during prolonged surgical procedures.
Tracrium can be administered in recommended doses by continuous infusion during cardiopulmonary bypass surgery. Reduction of body temperature to 25-26°C reduces the rate of atracurium inactivation, so at such reduced body temperatures, complete neuromuscular blockade can be maintained by infusing approximately half the dose recommended for normothermia.

Patient in intensive care units

Administration of Tracrium can be started with an initial dose of 0.3 mg/kg body weight to 0.6 mg/kg body weight administered by rapid intravenous injection, followed by continuous infusion of Tracrium to maintain neuromuscular blockade at a dose of 11 µg/kg/min to 13 µg/kg/min (0.65 mg/kg/h to 0.78 mg/kg/h). However, during the use of Tracrium in intensive care units, there are large individual differences in effective doses - from very small, such as 4.5 µg/kg/min (0.27 mg/kg/h), to very large, such as 29.5 µg/kg/min (1.77 mg/kg/h). Also, the effective dose may change over time.
The duration of administration of Tracrium does not affect the rate of spontaneous recovery of neuromuscular transmission in patients in intensive care units. After approximately 60 minutes (range 32-108 minutes), spontaneous recovery of muscle twitch response to train-of-four stimulation occurs to a value > 0.75 (ratio of the amplitude of the fourth twitch to the first twitch).

Children and adolescents

The doses used in children over 1 month of age are the same as those used in adults, on a body weight basis.
The safety and efficacy of Tracrium in children under 1 month of age have not been established.

Older people

Older people should receive Tracrium in standard doses. However, it is recommended to administer the initial dose slowly, at a rate close to the lower end of the recommended dose range.

Patient with renal or hepatic impairment

Tracrium can be administered in standard doses to patients with renal or hepatic impairment at any stage, including severe impairment.

Patient with cardiovascular disease

Patients with clinically significant cardiovascular disease should receive the initial dose of Tracrium over at least 60 seconds.

Monitoring of patient

To determine the individual dose of Tracrium, the doctor should monitor neuromuscular transmission during administration of the drug, as with all other neuromuscular blocking agents.

Overdose of Tracrium

Symptoms
Prolonged muscle paralysis and its consequences.
Treatment
Until spontaneous recovery of adequate respiratory function, it is necessary to maintain a patent airway and to provide positive-pressure ventilation. Anesthetic drugs that produce full anesthesia should be used, as the patient's consciousness is not impaired. Administration of anticholinesterase inhibitors, such as neostigmine, with atropine or concurrently with atropine, may accelerate recovery when the first signs of spontaneous recovery of neuromuscular transmission appear.

4. Possible side effects

Like all medicines, Tracrium can cause side effects, although not everybody gets them.
The frequency of side effects is defined as follows: very common (affects more than 1 user in 10), common (affects 1 to 10 users in 100), uncommon (affects 1 to 10 users in 1,000), rare (affects 1 to 10 users in 10,000), very rare (affects less than 1 user in 10,000), and not known (frequency cannot be estimated from the available data).
Common side effects( may affect up to 1 in 10 people):

• Events related to histamine release, such as hypotension (mild, transient), flushing.

Uncommon side effects( may affect up to 1 in 100 people):

• Histamine-related bronchospasm.

Rare side effects( may affect up to 1 in 1,000 people):

• Urticaria.

Very rare side effects( may affect up to 1 in 10,000 people):

• Severe allergic reactions (anaphylactic reaction, anaphylactoid reaction, including anaphylactic shock, circulatory failure, cardiac arrest).

Very rare cases of severe anaphylactic or anaphylactoid reactions have been reported in patients receiving atracurium concomitantly with one or more anesthetic drugs.
Side effects with unknown frequency( frequency cannot be estimated from the available data):

• Seizures, muscle diseases (myopathy), muscle weakness.

There have been reports of seizures in patients treated in intensive care units who received atracurium concomitantly with multiple other drugs. These patients usually had other underlying conditions that may have predisposed them to seizures (e.g., head trauma, cerebral edema, viral encephalitis, hypoxic encephalopathy, or uremia). A causal relationship between seizures and laudanosine has not been established. Clinical studies have not demonstrated a correlation between plasma laudanosine concentrations and the occurrence of seizures.
There have been reports of muscle weakness and/or myopathy after prolonged administration of neuromuscular blocking agents in critically ill patients. Most of these patients received concomitant corticosteroids. These adverse events were infrequently associated with atracurium, and a causal relationship has not been established.

Reporting of side effects

If you experience any side effects, including those not listed in this leaflet, please inform your doctor or pharmacist, or nurse. You can also report side effects directly to the Pharmacovigilance Department, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl.
Side effects can also be reported to the marketing authorization holder or its representative.

5. How to store Tracrium

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the packaging after "EXP". The expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C). Do not freeze. Protect from light.
Any unused portion of Tracrium remaining in opened ampoules should be discarded.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What Tracrium contains

• The active substance of Tracrium is atracurium besilate. One ml of solution contains 10 mg of atracurium besilate.
• The other ingredients are: benzene sulfonic acid solution 32% w/v, water for injections.

What Tracrium looks like and contents of the pack

The pack contains:
Ampoules of 2.5 ml solution: 5 ampoules made of colorless glass (type I) in a cardboard box. One ampoule of 2.5 ml contains 25 mg of atracurium besilate.
Ampoules of 5 ml solution: 5 ampoules made of colorless glass (type I) in a cardboard box. One ampoule of 5 ml contains 50 mg of atracurium besilate.

Marketing authorization holder

Aspen Pharma Trading Limited
3016 Lake Drive
Citywest Business Campus
Dublin 24, Ireland
Tel: 0048 22 104 2100

Manufacturer

Aspen Pharma Ireland Limited
3016 Lake Drive, Citywest Business Campus
Dublin 24
Ireland
GlaxoSmithKline Manufacturing S.p.A.
Strada Provinciale Asolana, 90
43056 San Polo di Torrile
Parma
Italy

Manufacturer/Importer

Aspen Bad Oldesloe GmbH
Industriestrasse 32-36
23843 Bad Oldesloe
Germany

Date of last revision of the leaflet: 09/2023

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Information intended for healthcare professionals only

Instructions for preparation of the medicinal product for administration
Tracrium may be diluted with the following infusion solutions, in which it remains stable for the period indicated below:
Infusion solution
Stability
0.9% sodium chloride infusion solution
24 hours
5% glucose infusion solution
8 hours
Ringer's solution for intravenous injection
8 hours
0.18% sodium chloride and 4% glucose infusion solution
8 hours
Multi-electrolyte solution for infusion (Hartmann's solution for intravenous injection)
4 hours
After dilution with one of the above solutions to a concentration of atracurium besilate of 0.5 mg/ml or more, the resulting solutions are stable in daylight for the periods indicated above, provided they are stored at a temperature below 30°C.