Tracrium

Package leaflet: Information for the user

Tracrium, 10 mg/ml, solution for injection or infusion
Atracurii besilas
Please read all of this leaflet carefully before using this medicine because it contains
important information for you.

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

Leaflet contents

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, competitively blocking (causing non-depolarizing block) neuromuscular transmission agent with intermediate duration of action.
Tracrium is indicated for use:

• during general anaesthesia to facilitate endotracheal intubation,
• during surgical procedures or controlled ventilation to achieve skeletal muscle relaxation,
• in intensive care unit (ICU) patients to facilitate mechanical ventilation.

This medicine may be administered only by an experienced anaesthetist or under his or her strict supervision, in settings allowing for endotracheal intubation and artificial ventilation to be performed.

2. Important information before using Tracrium

When not to use Tracrium

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

Warnings and precautions
Before starting treatment with Tracrium, discuss this with your doctor, pharmacist, or
nurse.
Like all other neuromuscular blocking agents, Tracrium paralyzes respiratory muscles and other skeletal muscles without affecting consciousness.
Tracrium must be used only in combination with appropriate general anesthetics.
Administration of Tracrium may result in histamine release in some patients. Therefore, Tracrium should be used cautiously in patients with a history suggesting possible hypersensitivity to histamine. In particular, bronchospasm may occur in patients with a history of allergy or bronchial asthma.
Caution should also be exercised when administering Tracrium to patients who have shown hypersensitivity to other neuromuscular blocking agents, as reports indicate a high incidence of cross-sensitivity (greater than 50%) between neuromuscular blocking agents (see section When not to use Tracrium).
When administered in recommended doses, Tracrium does not exhibit significant effects on conduction in the vagus nerve or autonomic ganglia. Consequently, Tracrium administered within the recommended dose range does not have clinically significant effects on cardiac function and does not counteract bradycardia induced by various anesthetics or vagus nerve stimulation during surgery.
Patients with myasthenia gravis, other neuromuscular transmission disorders, or severe electrolyte imbalances show increased sensitivity to the effects of atracurium, as with other nondepolarizing muscle relaxants.
Tracrium should be injected over at least 60 seconds in patients at increased risk of sudden drop in arterial blood pressure, e.g., patients with hypovolemia (reduced circulating blood volume).
Tracrium is inactivated at high pH and therefore must not be mixed in the same syringe with thiopental or other alkaline drugs.
When a small vein is used for administration of Tracrium, the vein should be flushed after injection with isotonic sodium chloride solution. When Tracrium and other anesthetic drugs are administered through a permanent cannula or needle, each drug should be followed by flushing with an appropriate volume of isotonic sodium chloride solution.
Since Tracrium is a hypotonic solution, it must not be administered into a cannula intended for blood transfusion.
Studies on malignant hyperthermia in predisposed animals (pigs) and clinical studies on symptoms of this condition in predisposed patients have shown that Tracrium does not cause this syndrome.
Burned patients may exhibit resistance to the effects of atracurium and other nondepolarizing muscle relaxants. In such patients, increased doses of the drug may be required, depending on the time elapsed since the burn injury and its extent.
Patients in intensive care units: administration of high doses of laudanosine, one of the metabolites of atracurium, to laboratory animals has been associated with transient hypotension and, in some species, central nervous system excitation. Although seizures have been observed in patients receiving atracurium in intensive care units, a causal relationship between these seizures and laudanosine has not been established.

Tracrium and other medicines
Inform your doctor about all medicines currently used or recently used, as well as any medicines the patient plans to use, including those available without a prescription.
Concomitant use of inhaled anesthetics such as halothane, isoflurane, or enflurane may potentiate the neuromuscular blockade induced by Tracrium.
Like other nondepolarizing muscle relaxants, Tracrium may enhance and/or prolong neuromuscular blockade when used concomitantly with the following drugs: antibiotics (aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin, and clindamycin), antiarrhythmics (propranolol, calcium channel blockers, lidocaine, procainamide, and quinidine), diuretics (furosemide and possibly mannitol, thiazide diuretics, and acetazolamide), magnesium sulfate, ketamine, lithium salts, and ganglion-blocking agents (trimethaphan, hexamethonium).
Some drugs may occasionally exacerbate or unmask latent myasthenia gravis or even induce a myasthenic syndrome, which may result in increased sensitivity to Tracrium. Such drugs include various antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmics (procainamide, quinidine), antirheumatic drugs (chloroquine, D-penicillamine), trimethaphan, chlorpromazine, steroids, phenytoin, and lithium salts.
In patients receiving long-term anticonvulsant therapy, the onset of nondepolarizing neuromuscular blockade may be delayed and its duration shortened.
Administration of Tracrium in combination with other nondepolarizing neuromuscular blocking agents may result in a degree of neuromuscular blockade greater than expected from the administration of an equivalent dose of Tracrium alone. The extent of potentiation may vary depending on the combination used.
Depolarizing neuromuscular blocking agents such as suxamethonium should not be used to prolong muscle relaxation induced by nondepolarizing agents like atracurium, as this may lead to an excessively prolonged and complex blockade, which may be difficult to reverse with cholinesterase inhibitors.
Treatment with acetylcholinesterase inhibitors commonly used in Alzheimer's disease therapy (such as donepezil) may shorten the duration and reduce the intensity of neuromuscular blockade induced by Tracrium.

Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor before using this medicine.
Tracrium, like all neuromuscular blocking agents, should be used in pregnant women only when the expected benefit to the mother outweighs the potential risk to the fetus.
Tracrium may 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.
It is not known whether Tracrium passes into breast milk.

Driving and operating machinery
Not applicable to the use of Tracrium. Tracrium is always administered together with general anesthetics. Standard precautions related to the effects of general anesthesia on the patient's psychomotor performance apply.

3. How to use Tracrium

Adults
Intravenous injections
Tracrium is administered by intravenous injection. The adult dose is 0.3 mg/kg to 0.6 mg/kg body weight (depending on the required duration of complete non-depolarizing block) and provides adequate muscle relaxation for 15–35 minutes.
Endotracheal intubation can usually be performed within 90 seconds after intravenous administration of a dose of 0.5 mg/kg to 0.6 mg/kg body weight.
The duration of complete non-depolarizing block may be prolonged by administering additional doses of 0.1 mg/kg to 0.2 mg/kg body weight as needed. Repeated administration of additional doses does not intensify neuromuscular blocking effects. Spontaneous recovery of neuromuscular transmission, measured as achieving 95% response to tetanic stimulation, occurs approximately 35 minutes after termination of complete block.
Neuromuscular blockade induced by Tracrium can be rapidly reversed without risk of recurarization by using standard doses of cholinesterase inhibitors such as neostigmine and edrophonium, administered either after or simultaneously with atropine.

Continuous infusion
Following an initial intravenous bolus dose of 0.3 mg/kg to 0.6 mg/kg body weight, Tracrium may be administered as a continuous infusion at a rate of 0.3 mg/kg to 0.6 mg/kg body weight per hour to maintain neuromuscular blockade during prolonged surgical procedures.
Tracrium may be administered as a continuous infusion at recommended doses during cardiovascular surgery using cardiopulmonary bypass. Lowering body temperature to 25–26 °C reduces the rate of atracurium elimination; therefore, at such reduced body temperatures, full neuromuscular blockade can be maintained using approximately half the dose recommended under normothermic conditions.

Patients in intensive care units
Administration of Tracrium may be initiated with an intravenous bolus dose of 0.3 mg/kg to 0.6 mg/kg body weight, followed by continuous infusion to maintain neuromuscular blockade at a rate of 11 µg/kg body weight/min to 13 µg/kg body weight/min (0.65 mg/kg body weight/hour to 0.78 mg/kg body weight/hour). However, there is considerable individual variation in effective doses during Tracrium administration in intensive care units—ranging from very low, e.g., 4.5 µg/kg body weight/min (0.27 mg/kg body weight/hour), to very high, e.g., 29.5 µg/kg body weight/min (1.77 mg/kg body weight/hour). Furthermore, the effective dose may change over time.
Duration of Tracrium administration does not affect the rate of spontaneous recovery of neuromuscular transmission in intensive care patients. Spontaneous return of muscle contractile response, measured by the train-of-four method, to a value > 0.75 (ratio of the amplitude of the fourth twitch to the first) occurs after approximately 60 minutes (range: 32–108 minutes).

Children and adolescents
Doses used in children over 1 month of age are the same on a body weight basis as in adults.
The safety and efficacy of Tracrium have not been evaluated in children under 1 month of age.

Elderly patients
Tracrium is administered to elderly patients at standard doses. However, it is recommended that the initial dose be administered slowly and be close to the lower end of the recommended dose range.

Patients with renal or hepatic impairment
Tracrium may be administered at standard doses to patients at any stage of renal or hepatic impairment, including end-stage disease.

Patients with cardiovascular disorders
In patients with clinically significant cardiovascular disorders, the initial dose of Tracrium should be administered over at least 60 seconds.

Patient monitoring
To individually adjust the dose of Tracrium, the physician should monitor neuromuscular transmission during administration, as is done with all other neuromuscular blocking agents.

Overdose of Tracrium
Symptoms
Excessively prolonged muscle paralysis and its consequences.
Management
Until spontaneous adequate respiratory function returns, maintenance of airway patency and application of positive pressure ventilation are required. Agents inducing full anaesthesia should be administered, as patient awareness is not eliminated. Administration of acetylcholinesterase inhibitors together with atropine or glycopyrrolate, at the time when signs of spontaneous recovery of neuromuscular transmission appear, may accelerate recovery.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
The frequency of common and uncommon adverse reactions is based on data from clinical trials.
Rare and very rare adverse reactions are based on data from spontaneous reports received after the medicine was marketed.

Common adverse reactions (may occur in 1 to 10 out of 100 patients):

• Events related to histamine release, such as mild, transient decrease in blood pressure, sudden skin flushing.

Uncommon adverse reactions (may occur in 1 to 10 out of 1,000 patients):

• Bronchospasm related to histamine release.

Rare adverse reactions (may occur in 1 to 10 out of 10,000 patients):

• Urticaria (hives).

Very rare adverse reactions (may occur in less than 1 out of 10,000 patients):

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

Severe anaphylactic or pseudoallergic reactions have been very rarely reported in patients receiving atracurium together with one or more anaesthetic medicines.

Adverse reactions with unknown frequency (frequency cannot be estimated from the available data):

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

Seizures have been reported in patients treated in intensive care units who received atracurium together with multiple other medicines. These patients usually had additional predisposing factors for seizures (e.g. head trauma, cerebral edema, viral encephalitis, hypoxic encephalopathy or uremic encephalopathy). A causal relationship between seizure occurrence and laudanosine administration has not been established. Clinical studies have not shown a correlation between plasma laudanosine concentration and the occurrence of seizures.

Cases of muscle weakness and/or myopathy have been reported following prolonged administration of neuromuscular blocking agents in critically ill patients in intensive care units. Most of these patients were also receiving corticosteroids. These adverse events occurred infrequently in association with atracurium, and a causal relationship has not been established.

Reporting of adverse reactions

If any adverse reactions occur, including any adverse reactions not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, 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

Adverse reactions can also be reported to the marketing authorisation holder or its representative.

Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store the medicinal product Tracrium

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

6. Contents of the pack and other information

What Tracrium contains

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

What Tracrium looks like and contents of the pack
Pack contents:
2.5 ml vials: 5 vials of colourless glass (type I) in a cardboard carton. One 2.5 ml vial contains 25 mg of atracurium besilate.
5 ml vials: 5 vials of colourless glass (type I) in a cardboard carton. One 5 ml vial contains 50 mg of atracurium besilate.
Marketing Authorisation 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
{logo of the marketing authorisation holder}

Information intended exclusively for medical professionals

Instructions for preparation of the medicinal product for use
The Tracrium medicinal product may be diluted with the following infusion fluids, in which it remains stable for the period stated below:
Infusion fluid Stability
0.9% sodium chloride infusion solution 24 hours
5% glucose infusion solution 8 hours
Ringer's injection solution for intravenous use 8 hours
0.18% sodium chloride and 4% glucose infusion solution 8 hours
Multi-component sodium lactate infusion solution
(Hartmann's injection solution for intravenous use) 4 hours

After dilution with one of the listed fluids to a concentration of atracurium besylate of 0.5 mg/ml or higher, the resulting solutions are stable under daylight conditions as indicated above, provided they are stored at a temperature below 30 °C.