Package leaflet

ACURMIL 25 mg/2.5 ml injectable solution for intravenous use, 50 mg/5 ml injectable solution for intravenous use

Atracurium besylate
PHARMACOTHERAPEUTIC CATEGORY
Peripherally acting muscle relaxants.
THERAPEUTIC INDICATIONS
ACURMIL is a highly selective non-depolarizing neuromuscular blocking agent used in anaesthesia to facilitate tracheal intubation and to achieve muscle relaxation during a wide range of surgical procedures requiring it, as well as during controlled ventilation. It is also indicated to facilitate controlled ventilation in patients admitted to Intensive Care Units.
ACURMIL is also suitable for maintaining muscle relaxation during caesarean section.
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.
Atracurium is contraindicated in patients with known hypersensitivity to atracurium, cisatracurium or benzenesulfonic acid.
PRECAUTIONS FOR USE
As with all other neuromuscular blocking agents, ACURMIL paralyses respiratory muscles as well as other skeletal muscles, but has no effect on consciousness. Therefore, it must be administered only under appropriate general anaesthesia and only by an anaesthetist or under his close supervision, and adequate means for endotracheal intubation and artificial ventilation must be available.
In susceptible patients, administration of ACURMIL may cause histamine release; therefore particular caution should be exercised when treating patients with severe cardiovascular diseases who may be more sensitive to the effects of transient hypotension, and in those with any history (e.g. severe hypersensitivity reactions to multiple allergens and asthma) in which histamine release could pose a significant risk. In particular, bronchospasm may occur in patients with a history of allergy and asthma. In such patients, slow intravenous injection in divided doses is recommended.
Caution is also required when administering atracurium to patients who have shown hypersensitivity to other neuromuscular blocking agents, since a high rate of cross-sensitivity (over 50%) has been reported among neuromuscular blocking agents (see section Contraindications).
ACURMIL should be used with caution in patients with myasthenia gravis, other neuromuscular disorders, carcinomatosis and severe electrolyte disturbances, since, as with other non-depolarizing neuromuscular blocking agents, increased sensitivity to atracurium may be expected in patients with myasthenia gravis, other neuromuscular diseases and severe electrolyte imbalance.
Atracurium should be administered over a period of 60 seconds in patients who may be unusually sensitive to drops in arterial pressure, for example in hypovolemic patients.
Within the recommended dosage range, atracurium has no significant vagal or ganglionic blocking properties. Consequently, within the recommended dosage range, atracurium does not produce clinically significant effects on heart rate and does not counteract bradycardia produced by many anaesthetics or vagal stimulation during surgical procedures.
If a small-calibre vein is chosen as the injection site, any residual ACURMIL should be flushed from the vein after injection by introducing a small amount of physiological saline solution.
When other anaesthetic drugs are administered through the same needle or indwelling cannula as ACURMIL, it is important to flush each drug with sterile pyrogen-free water or physiological saline solution.
INTERACTIONS
Inform your doctor or pharmacist if you have recently taken any other medicines, including those not requiring a prescription.
The neuromuscular blockade caused by ACURMIL may be enhanced by concomitant use of inhalational anaesthetics such as halothane, enflurane and isoflurane.
As with other non-depolarizing neuromuscular blocking agents, the extent and/or duration of a non-depolarizing neuromuscular blockade may be enhanced by interaction with:

• antibiotics, including aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin and clindamycin.
• Diuretics: furosemide and possibly mannitol, thiazide diuretics and acetazolamide
• Magnesium sulfate
• Ketamine
• Lithium salts
• Ganglion-blocking drugs: trimethaphan, hexamethonium.

In rare cases, certain drugs may worsen or unmask latent myasthenia gravis or induce a myasthenic syndrome; in such cases, increased sensitivity to atracurium would occur. These drugs include various antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmics (procainamide, quinidine), antirheumatics (chloroquine, D-penicillamine), trimethaphan, chlorpromazine, steroids, phenytoin and lithium.
In patients on chronic anticonvulsant therapy, onset of non-depolarizing neuromuscular blockade may take longer and its duration may be shorter.
Administration of combinations of non-depolarizing neuromuscular blocking agents with atracurium may result in a level of neuromuscular blockade greater than would be expected with an equieffective total dose of atracurium. Possible synergistic effects may vary depending on the drug combinations used.
Depolarizing muscle relaxants such as suxamethonium chloride should not be administered to prolong the neuromuscular blocking effects of non-depolarizing agents such as atracurium, as this could result in prolonged and complex blockade, difficult to reverse with anticholinesterase drugs.
Treatment with anticholinesterase agents, such as donepezil, commonly used in the treatment of Alzheimer's disease, may shorten the duration and reduce the extent of neuromuscular blockade induced by atracurium.
SPECIAL WARNINGS
When one of the metabolites of atracurium, laudanosine, is administered to laboratory animals, it may produce CNS excitatory-type effects.
While convulsive episodes have been reported in intensive care unit patients receiving ACURMIL, these were not considered attributable to either laudanosine or atracurium, even in cases where ACURMIL was administered by continuous infusion over long periods.
Atracurium is inactivated by high pH and therefore must not be mixed in the same syringe with thiopental or other alkaline agents.
Atracurium is hypotonic and must not be administered into the line of a blood transfusion.
Studies on malignant hyperthermia in susceptible animals (pig) and clinical studies in patients predisposed to malignant hypertheria indicate that atracurium does not trigger this syndrome.
As with other non-depolarizing neuromuscular blocking agents, resistance may develop in burned patients. Such patients may require higher doses depending on the time elapsed since the burn injury and the extent of the burn.
Intensive care patients. With administration of high doses in laboratory animals, laudanosine, a metabolite of atracurium, has been associated with transient hypotension and, in some species, with cerebral excitatory effects. Although seizures have been observed in intensive care patients who received atracurium, a causal relationship with laudanosine has not been established (see Undesirable effects).
Fertility, pregnancy and lactation
Fertility
No fertility studies have been conducted.
Pregnancy
Animal studies have indicated that ACURMIL does not produce adverse effects on fetal development. As with all neuromuscular blocking drugs, ACURMIL should be used during pregnancy only if the potential benefit to the mother outweighs any potential risk to the fetus.
ACURMIL may be used to maintain neuromuscular blockade during caesarean section, since, at recommended doses, it does not cross the placental barrier in clinically significant amounts.
However, the possibility of respiratory depression in the newborn should still be considered.
Lactation
It is not known whether ACURMIL is excreted in breast milk.
EFFECTS ON THE ABILITY TO DRIVE VEHICLES AND USE MACHINES
This precaution is not relevant for the use of atracurium. Atracurium is always used in conjunction with general anaesthesia and therefore the usual precautions regarding performance of tasks after general anaesthesia do not apply.
DOSAGE, ADMINISTRATION METHOD AND DURATION
ACURMIL must be administered exclusively by intravenous route.
It is recommended to administer ACURMIL slowly to avoid transient hypotensive effects that may occasionally follow rapid injection.
Adults

• Injection use Doses for adults range from 0.3 to 0.6 mg/kg depending on the required duration of complete blockade and provide adequate relaxation for periods ranging from 15 to 35 minutes. Complete blockade can be prolonged with supplemental doses of 0.1 - 0.2 mg/kg, as needed. Subsequent supplemental doses do not cause accumulation. Endotracheal intubation can generally be performed within 90 seconds after intravenous injection of 0.5 - 0.6 mg/kg of drug. The neuromuscular blockade caused by ACURMIL can be rapidly and permanently reversed by standard doses of anticholinesterase agents, such as neostigmine, in combination with an anticholinergic agent such as atropine. Recovery from complete blockade, without the use of neostigmine, occurs in approximately 35 minutes, measured from the return of tetanic response to 95% of normal neuromuscular function.
• Infusion use After an initial intravenous dose of 0.3 - 0.6 mg/kg, ACURMIL may be administered by continuous infusion at rates of 0.005 - 0.01 mg/kg/min to maintain neuromuscular blockade during prolonged surgical procedures. Accurate dosing of the drug administered by infusion can be achieved using a pump-driven syringe. ACURMIL may be administered by infusion during cardiopulmonary bypass procedures at the rates indicated above. Induced hypothermia at temperatures of 25°C or 26°C reduces the rate of inactivation of atracurium; therefore, at these temperatures, complete neuromuscular blockade can be maintained by halving the initial infusion rate. ACURMIL is compatible with the following infusion solutions for the stability periods indicated:

When diluted in these solutions to obtain concentrations of 0.5 to 0.9 mg/ml, ACURMIL infusions are stable under daylight conditions at temperatures up to 30°C.
ACURMIL may also be diluted in water for injections to achieve concentrations of 0.5–0.9 mg/ml, although its use in infusions is not recommended. Such dilutions are stable for 8 hours at temperatures up to 30°C.

Incompatibilities
ACURMIL must not be mixed in the same syringe with thiopental or any alkaline substance, as its high pH renders it inactive.

Children
The dosage for children over 1 month of age is the same as for adults, based on mg/kg of body weight.

Use in newborns
The use of ACURMIL is not recommended in newborns, as available data are insufficient.

Elderly
ACURMIL may be used at standard doses in elderly patients.

Use in patients with renal or hepatic impairment
ACURMIL may be used at standard doses in patients with renal or hepatic impairment.

Use in patients with severe cardiovascular diseases
In patients with severe cardiovascular diseases, the initial dose of ACURMIL should be administered slowly over 60 seconds.

Use in Intensive Care Units
Following an initial intravenous dose of 0.3–0.6 mg/kg, if required, ACURMIL may be administered by continuous infusion at doses of 11–13 μg/kg/min (0.65–0.78 mg/kg/hour) to maintain neuromuscular blockade. However, there is wide inter-patient variability in required doses (ranging from 4.5 μg/kg/min to 29.5 μg/kg/min). Available data indicate that ACURMIL requirements may increase during prolonged administration in intensive care units, more commonly in patients who develop peripheral edema.

Recovery from neuromuscular blockade (TOF > 0.75) after ACURMIL infusion is not influenced by the duration of administration. Spontaneous recovery occurs within approximately 60 minutes (range 32–108 min).

Hemofiltration and diafiltration have only minimal effects on plasma levels of atracurium and its metabolites, including laudanosine. The effects of hemodialysis or hemoperfusion on plasma levels of atracurium and its metabolites are unknown.

OVERDOSE
In case of accidental ingestion/overdose of ACURMIL, contact a physician immediately or go to the nearest hospital.

In cases of overdose or delayed recovery, atropine and neostigmine should be administered to the patient, while maintaining artificial ventilation until spontaneous respiration returns.

Signs and symptoms
Prolonged muscle paralysis and its consequences are the main signs of overdose.

Treatment
It is essential to maintain airway patency along with positive pressure assisted ventilation until spontaneous respiration is adequate. If consciousness is preserved, complete sedation may be required. Recovery may be accelerated by administration of anticholinesterase agents together with atropine or glycopyrrolate, as soon as spontaneous recovery becomes evident.

If you have any doubts about the use of ACURMIL, consult your doctor or pharmacist.

UNDESIRABLE EFFECTS
Like all medicines, ACURMIL can cause adverse effects, although not everyone experiences them.

ACURMIL has no significant vagal or ganglion-blocking properties. Therefore, vagomimetic effects of other concomitantly used anesthetic drugs may become more evident.

As with most neuromuscular blocking agents, ACURMIL may cause histamine release in susceptible patients.

The most frequently reported adverse reactions during treatment are: hypotension (mild, transient) and skin flushing, which are attributed to histamine release. Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients who received atracurium together with one or more anesthetics.

Adverse reactions are listed below, classified by system organ class and frequency. Frequencies are defined as: very common > 1/10, common > 1/100 and <1/10, uncommon >1/1000 and <1/100, rare >1/10,000 and <1/1000, very rare <1/10,000. Frequencies "very common", "common", and "uncommon" were determined from clinical trial data. "Rare" and "very rare" frequencies were generally derived from spontaneous reports. The frequency category "Not known" was assigned to reactions for which frequency could not be estimated from available data.

Clinical trial data
Vascular disorders
Common: hypotension (mild, transient)#, skin flushing#
Respiratory, thoracic and mediastinal disorders
Uncommon: bronchospasm#

Post-marketing data
Immune system disorders
Very rare: anaphylactic reaction, anaphylactoid reaction, including shock, circulatory collapse, and cardiac arrest.
Severe anaphylactoid or anaphylactic reactions have very rarely been reported in patients who received atracurium together with one or more anesthetics.

Nervous system disorders
Not known: seizures
Cases of seizures have been reported in intensive care patients who received atracurium together with various other drugs. These patients generally had one or more underlying conditions predisposing them to seizures (e.g., head trauma, cerebral edema, viral encephalitis, hypoxic encephalopathy, uremia). A causal relationship with laudanosine has not been established. In clinical trials, no correlation appears to exist between plasma laudanosine concentration and the occurrence of seizures.

Skin and subcutaneous tissue disorders
Rare: urticaria

Musculoskeletal and connective tissue disorders
Not known: myopathy, muscle weakness
There have been a few reports of muscle weakness and/or myopathy following prolonged use of muscle relaxants in critically ill intensive care patients. Most of these patients were also receiving corticosteroids concurrently. These events have been observed infrequently with atracurium, and no causal relationship has been established.

Events attributed to histamine release are marked with a hash (#)

Following the instructions in this leaflet reduces the risk of adverse effects.

If any of the adverse effects worsens or if you notice any adverse effects not listed in this leaflet, inform your doctor or pharmacist.

EXPIRY DATE AND STORAGE
Expiry date: see the date printed on the packaging.
The expiry date refers to the product in its original, unopened packaging, stored correctly.

Warning: do not use the medicine after the expiry date stated on the packaging.

For ACURMIL 50 mg/5 ml: store and transport at a temperature between 2°C and 8°C.
For ACURMIL 25 mg/2.5 ml: store at a temperature between 2°C and 8°C.
Keep in the original container to protect from light.
Do not freeze.
Opened vials not used must be discarded.

Medicines must not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

COMPOSITION
ACURMIL 25:
One 2.5 ml vial contains:
Active substance:
Atracurium besilate 25 mg
Excipients:
Benzenesulfonic acid; water for injections.

ACURMIL 50:
One 5.0 ml vial contains:
Active substance:
Atracurium besilate 50 mg
Excipients:
Benzenesulfonic acid; water for injections.

PHARMACEUTICAL FORM AND CONTENT
Injectable solution for intravenous use containing 10 mg/ml of atracurium besilate.
ACURMIL 25: 5 vials of 25 mg/2.5 ml;
ACURMIL 50: 5 vials of 50 mg/5.0 ml.

MARKETING AUTHORISATION HOLDER AND MANUFACTURER
Lab. It. Biochim. Farm.co LISAPHARMA S.p.A.
Via Licinio, 11 - 22036 ERBA (CO)

REVISION OF THE PACKAGE LEAFLET BY THE ITALIAN MEDICINES AGENCY
August 2024