SUMMARY OF PRODUCT CHARACTERISTICS

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1 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT ACURMIL 25 mg/2.5 ml solution for intravenous injection ACURMIL 50 mg/5 ml solution for intravenous injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION ACURMIL 25 mg/2.5 ml solution for injection a 2.5 ml ampoule contains: Active principle: atracurium besylate: 25 mg ACURMIL 50 mg/5 ml solution for injection a 5 ml ampoule contains: Active principle: atracurium besylate: 50 mg For the full list of excipients reference is made to section PHARMACEUTICAL FORM Solution for intravenous injection containing 10 mg/ml of atracurium besylate 4. CLINICAL PARTICULARS 4.1. Therapeutic Indications M03AC04 ACURMIL is a highly-selective nondepolarizing neuromuscular blocker used in general anesthesia to facilitate endotracheal intubation and to obtain muscle relaxation in a wide range of surgical procedures and in controlled ventilation. It is also indicated to facilitate controlled ventilation in Intensive Care Unit patients. In addition, ACURMIL is indicated for the maintenance of muscle relaxation during cesarean sections Dosage and Administration ACURMIL should be administered intravenously. To avoid a temporary pressure drop, as may occur following a bolus injection, ACURMIL should be administered by slow injection. Adults - Injection Adult doses range from 0.3 to 0.6 mg/kg according to the required duration of the complete block, determining a state of suitable relaxation for times varying from 15 to 35 minutes. Additional doses of mg/kg, as required, may be administered to prolong the complete block. Administration of successive additional doses does not induce any cumulative effects. As a rule, endotracheal intubation may be carried out within 90 seconds of the intravenous injection of mg/kg of the drug. The neuromuscular block induced by ACURMIL may be rapidly and permanently reversed with standard doses of such anticholinesterase agents as neostigmine, in conjunction with an anticholinergic agent such as atropine. Recovery from a complete block occurs, without neostigmine, within approximately 35 minutes calculated from the first recovery of muscle twitch to 95% recovery of the normal neuromuscular function.

2 - Use by intravenous infusion After administration of an initial dose of mg/kg i.v., ACURMIL may be administered by continuous intravenous administration at the dose of mg/kg/min. in order to maintain the muscular block during extended surgical procedures. Accurate dosing is best achieved by using an infusion pump. ACURMIL may be administered by continuous infusion at the above-mentioned rates to patients undergoing cardiopulmonary bypass. The induced hypothermia, with body temperatures of 25 C or 26 C, reduces the inactivation speed of Atracurium and therefore, at such temperatures, complete neuromuscular block can be maintained by reducing the initial infusion rate to one half. ACURMIL is compatible with the following infusion solutions, for the following stability periods: Infusion solutions Physiologic solution 0.9% w/v Glucose 5% w/v Ringer Glucose with sodium chloride I (respectively 4.7% w/v and 0.18% w/v) Ringer lactate Stability periods 24 hours 8 hours 8 hours 8 hours 4 hours The above-mentioned solutions may be admixed with ACURMIL to obtain 0.5 to 0.9 mg/ml solutions. These ACURMIL infusion solutions remain stable, in daylight, at temperatures of up to 30 C. ACURMIL may also be diluted with water for injectable preparations until concentrations of mg/ml are achieved, though their use for continuous infusion is not recommended. Such dilutions remain stable for 8 hours at temperatures not exceeding 30 C. Pediatric patients The dosage used for children over 1 month old is the same as for adults, based on mg/kg of body weight. Neonates Use of ACURMIL in neonates is not recommended, as there are no sufficient data available. Elderly patients ACURMIL may be used at standard doses in elderly patients. Patients with kidney or liver insufficiency ACURMIL may be used at standard doses in patients with kidney or liver insufficiency. Patients with serious cardiovascular diseases The initial dose of ACURMIL should be given slowly over a period of 60 seconds to patients with significant cardiovascular diseases.

3 Intensive Care Unit (ICU) patients After an initial bolus dose of mg/kg i.v., ACURMIL may be given by continuous infusion at the dose of µg/kg/min ( mg/kg/hour) in order to maintain a state of neuromuscular block. Anyway, there may be wide interpatient variability in dosage requirements (from 4.5 µg/kg/min to 29.5 µg/kg/min). The available data indicate that such requirements may increase in the course of prolonged administration in ICU patients; especially in patients developing peripheral edemas. Recovery from neuromuscular block (TOF> 0.75) after an infusion with ACURMIL does not depend on the duration of administration. Spontaneous recovery occurs in about 60 minutes (range min.). 4.3 Contraindications Hypersensitivity to the active principle or to any of the excipients. Atracurium is contraindicated for patients with known hypersensitivity to atracurium, cisatracurium and benzenesulfonic acid Special Warnings and Precautions for Use ACURMIL, like all other neuromuscular blockers, causes the paralysis of the respiratory and skeletal muscles, but does not affect the state of consciousness. Therefore, it should be administered only with suitable general anesthesia and by an anesthetist or under his/her direct surveillance. Besides, suitable endotracheal and artificial ventilation equipment must be directly available. In predisposed patients the administration of ACURMIL may cause the release of histamine; for this reason special caution should be applied in the treatment of patients with significant cardiovascular diseases who may be more sensitive to the effects of temporary hypotension and of patients whose history (e.g. severe hypersensitivity reactions to multiple allergens and asthma) suggests a greater risk of histamine release. In particular, bronchospasm might occur in patients with a history of allergy and asthma. In these patients, ACURMIL should be administered by slow i.v. injection of fractionated doses. Besides, caution is recommended in administering atracurium to patients with a history of hypersensitivity to other neuromuscular blocking agents, as a high rate of cross allergy (over 50%) was observed between neuromuscular blocking agents (see section 4.3). ACURMIL should be administered with caution to patients with myasthenia gravis, other neuromuscular diseases, carcinomatosis, or significant electrolyte disorders, because, as with other non-depolarizing agents, greater sensitivity to atracurium is to be expected in patients with myasthenia gravis, other neuromuscular diseases and severe electrolyte disorders. Atracurium should be administered over a period of 60 seconds to patients potentially prone to a drop in arterial pressure, such as hypovolemic patients. In the recommended dosage range, atracurium does not present any significant vagal or ganglionic blocking properties. Consequently, atracurium has no clinically relevant effects on heart rate in the recommended dosage range. Bradycardia induced by other anesthetics or by vagal stimulation during surgery will not be counteracted by atracurium.

4 If the injection site of choice is a small vein, all residues of ACURMIL must be washed away with a small quantity of physiologic solution. If other anesthetics are to be administered through the same needle or cannula used for administration of ACURMIL, it is important that each drug is removed by introducing some sterile pyrogen-free water or physiologic solution into the needle or cannula inbetween administrations. When given to laboratory animals, laudanosine, one of atracurium metabolites, may cause excitatory effects on the CNS. While cases of seizures have been reported in ICU patients to whom ACURMIL was administered, these were not ascribed to laudanosine or atracurium, also in those cases in which ACURMIL had been administered as continuous infusion over longer periods. Atracurium is inactivated by high ph and therefore must not be admixed in the same syringe with thiopentone or any alkaline agents. Atracurium is hypotonic and must not be administered via the infusion system of a blood transfusion. Studies in malignant hyperthermia in susceptible animals (swine) and clinical studies in patients susceptible to malignant hyperthermia indicate that atracurium does not trigger this syndrome. In common with other non-depolarizing 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. ICU patients. When given to laboratory animals at high doses, laudanosine, one of atracurium metabolites, may cause temporary hypotension and, in some species, excitatory effects on the brain. While cases of seizures have been reported in ICU patients to whom atracurium was administered, it was not possible to establish a cause-effect relationship with laudanosine (see section 4.8) Interaction with other medicinal products and other forms of interaction Drugs that, if contextually administered, may enhance the neuromuscular blocking action of ACURMIL include such inhalation anesthetics as halothane, enflurane and isoflurane. As with other non-depolarizing neuromuscular blocking agents, the extent and/or duration of a non-depolarizing muscular block may be enhanced by the interaction with: - antibiotics including the aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin, and clindamycin; - antiarrhythmic medicinal products: propranolol, calcium-antagonists, lignocaine, procainamide and quinidine; - diuretics: furosemide and possibly mannitol, thiazide diuretics and acetazolamide; - magnesium sulfate; - ketamine; - lithium salts; - ganglion blocking agents: trimethaphan, hexamethonium. Seldom, certain medicinal products may aggravate or unmask latent myasthenia gravis or actually induce a myasthenic syndrome; increased sensitivity to atracurium besylate would follow. Such medicinal products include various antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmics (procainamide, quinidine), antirheumatics

5 (chloroquine, D-penicillamine), trimethaphan, chlorpromazine, steroids, phenytoin, lithium. The onset of non-depolarizing neuromuscular block is likely to be lengthened and the duration of block shortened in patients receiving chronic anticonvulsant therapy. The administration of combinations of non-depolarizing neuromuscular blocking agents in conjunction with atracurium may produce a degree of neuromuscular blockade in excess of that which might be expected, were an equipotent total dose of atracurium administered. Any synergistic effect may vary between different medicinal product combinations. Depolarizing muscle relaxants such as suxamethonium chloride should not be administered to prolong the neuromuscular blocking effects of non-depolarizing blocking agents such as atracurium, as this may result in a prolonged and complex block, which can be difficult to reverse with anticholinesterase medicinal products. Anticholinesterase agents, such as donepezil, commonly used for the treatment of Alzheimer disease, may shorten the duration and reduce the extent of atracurium induced neuromuscular block Fertility, pregnancy and lactation Fertility No fertility studies have been conducted with atracurium besylate. Pregnancy Although animal studies indicate that ACURMIL has no negative effects on fetal development, however, as in the case of all neuromuscular blockers, ACURMIL should be used in pregnancy only if the potential benefit for the mother outweighs any potential risks for the fetus. ACURMIL may be used to maintain the neuromuscular block during a cesarean section, as within the recommended dose range it does not cross the placental barrier in clinically significant quantities. However, the possibility of respiratory depression in the newborn should be considered. Lactation It is not known whether ACURMIL is excreted in human milk Effects on the Ability to Drive and Operate Machines This precaution is not relevant for use of atracurium. As atracurium is always used in conjunction with a general anesthetic, the normal precautions concerning the performance of activities after general anesthesia apply Undesired effects ACURMIL exerts no appreciable vagal or ganglionic block effects. Therefore, the vagomimetic effects of the anesthetics used may be potentiated. As with most neuromuscular blockers, also with ACURMIL there is the possibility of histamine release in susceptible patients.

6 The adverse reactions most frequently observed during treatment are: hypotension (mild, transient) and flushing, both related to histamine release. More rarely serious anaphylactoid or anaphylactic reactions have been reported in patients who had received atracurium together with one or more anesthetics. Adverse reactions are classified by systems, organs and frequency. Frequency is defined as: very common > 1/10, common > 1/100 and < 1/10, uncommon > 1/1000 and < 1/100, rare > 1/ and < 1/1000, very rare < 1/ Very common, common and uncommon frequencies have been determined based on the data of clinical trials. Rare and very rare frequencies have been generally estimated based on spontaneous reports. Frequency defined as not known applied to those reactions that could not be estimated from the available data. Clinical trial data Vascular disorders Common: hypotension (mild, transient) #, flushing # Respiratory, thoracic and mediastinal disorders Uncommon: bronchospasm # Postmarketing data Immune system disorders Very rare: anaphylactic reaction, anaphylactoid reaction, including shock, circulatory failure and cardiac arrest. Very rarely serious anaphylactoid or anaphylactic reactions have been reported in patients who had received atracurium together with one or more anesthetics. Nervous system disorders Unknown: seizures There have been reports of seizures in patients in ICUs who had been receiving atracurium besylate simultaneously with other drugs. These patients generally had one or more medical conditions that made them susceptible to seizures (such as brain injury, cerebral edema, viral encephalitis, hypoxic encephalopathy, and uremia). It was impossible to establish a causative correlation with laudanosine. There appears to be no correlation between plasma laudanosine concentration and appearance of seizures in clinical trials. Skin and subcutaneous tissue disorders Rare: urticaria Musculoskeletal and connective tissue disorders Not known: myopathy, muscular weakness. After prolonged use of myorelaxants in severely ill ICU patients, myasthenia and/or myopathy have been observed. The majority of these patients received concomitant corticosteroids. Causal connection with atracurium besylate therapy is not established, as these events have been rarely observed with atracurium. # The events ascribed to histamine release have been marked with a # 4.9. Overdosage In case of overdosage or delayed recovery, patients must be given atropine and neostigmine, and should be artificially ventilated until spontaneous breathing is resumed. Signs and symptoms Prolonged muscle paralysis and its consequences are the main signs of overdose.

7 Treatment It is essential to maintain a patent airway together with assisted positive pressure ventilation until adequate spontaneous respiration reappears. Full sedation will be required if consciousness is not impaired. Recovery may be accelerated by the administration of anticholinesterase agents accompanied by atropine or glycopyrrolate, once evidence of spontaneous recovery is present. 5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic Properties Pharmacotherapeutic category: peripherally acting muscle relaxants ATC code: M03AC04. ACURMIL, atracurium besylate, acts on the neuromuscular junction competitively antagonizing the action of acetylcholine on the cholinergic receptors of the postsynaptic membrane, thus causing neuromuscular block. It has no effect on intraocular pressure, which makes it suitable for use in ophthalmic surgery. Pediatric population: Limited literature data on neonates suggest a variability in the onset time and duration of atracurium activity in this population as compared to older children (see section 4.2) 5.2. Pharmacokinetic Properties ACURMIL degradation to inactive metabolites is mainly carried out by a spontaneous mechanism of nonenzymatic decomposition called Hofmann elimination which takes place at physiological ph and temperature values. Reversal of ACURMIL-induced neuromuscular block is independent of its metabolism and excretion by liver or kidneys. Its action duration is probably not influenced by renal, liver or circulatory insufficiency. Degradation of a small ACURMIL aliquot is probably carried out by non-specific plasma esterases. Tests performed on the plasma of patients with low levels of pseudocholinesterase showed that ACURMIL inactivation proceeds without changes. Physiological changes in plasma ph or body temperature do not significantly influence the duration of ACURMIL action. Hemofiltration and hemodyalisis have minimal effects on the plasmatic levels of Atracurium and of its metabolites, including laudanosine. The effects of hemodyalisis and hemoperfusion on the plasmatic levels of Atracurium and its metabolites are not known Preclinical Safety Data No toxic effects were detected in patas monkeys following administration of nonparalyzing doses of 0.25 mg/kg of Atracurium s.c., administered 2-4 times a day for 28 days. 6. PHARMACEUTICAL PARTICULARS 6.1. List of Excipients Benzenesulfonic acid, water for injectable preparations

8 6.2. Incompatibilities ACURMIL should not be mixed in the same syringe with Thiopental or with any other alkaline substance, since high ph inactivates it Shelf-life 24 months 6.4. Special Storage Precautions Store at temperatures between 2 C and 8 C. Keep the ampoules in the outer carton in order to protect from light. Do not freeze Open, unused ampoules should be discarded Nature and contents of container Five 2.5 ml ampoules each containing 25 mg of Atracurium besylate Five 5.0 ml ampoules each containing 50 mg of Atracurium besylate 6.6 Instructions for Use See section Dosage and Administration 7. MARKETING AUTHORIZATION HOLDER Lab. It. Biochim.Farm.co LISAPHARMA S.p.A. Via Licinio ERBA (CO) 8. MARKETING AUTHORIZATION NUMBER(S) ACURMIL 25 five 2.5 ml ampoules AIC No ACURMIL 50 five 5.0 ml ampoules AIC No FIRST AUTHORIZATION /RENEWAL DATE / DATE OF THE LAST TEXT REVISION December 2013