Ultane breathed in Liquid Liquid

ULTANE is indicated for induction and maintenance of general anaesthesia in adult and paediatric patients for inpatient and outpatient surgery.

The concentration of ULTANE being delivered from a vaporiser during anaesthesia should be known. This may be accomplished by using a vaporiser calibrated specifically for ULTANE. Induction: Dosage should be individualised and titrated to the desired effect according to the patientu2019s age and clinical status. A short acting intravenous induction agent may be administered, followed by inhalation of ULTANE. Induction with ULTANE may be achieved in oxygen or in combination with oxygen-nitrous oxide mixtures. Inspired concentrations of up to 8 % ULTANE usually produce surgical anaesthesia in less than 2 minutes in both adults and children. Maintenance: Surgical levels of anaesthesia may be sustained with concentrations of 0,5 - 3 % ULTANE with or without the concomitant use of nitrous oxide. Elderly: Lesser concentrations of ULTANE are normally required to maintain surgical anaesthesia.

ULTANE should not be used in patients with known or suspected hypersensitivity to ULTANE or to other halogenated agents (e.g. history of hepatotoxicity, usually including elevated liver enzymes, fever, leukocytosis and/or eosinophilia temporally related to anaesthesia with one of these agents). ULTANE should not be used in patients with known or suspected genetic susceptibility to malignant hyperthermia (See WARNINGS AND SPECIAL PRECAUTIONS). ULTANE should not be used in patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy. (See WARNINGS AND SPECIAL PRECAUTIONS).

Sevoflurane may cause respiratory depression, which may be augmented by narcotic pre-medication or other agents causing respiratory depression. Respiration should be supervised and if necessary, assisted. ULTANE should be administered only by persons trained in the administration of general anaesthesia. Facilities for maintenance of a patent airway, artificial ventilation and oxygen enrichment and circulatory resuscitation must be immediately available. Since levels of anaesthesia may be altered easily and rapidly, only vaporisers specifically calibrated for ULTANE should be used. Hypotension and respiratory depression increase as anaesthesia is deepened.

Malignant hyperthermia: In susceptible individuals ULTANE may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The clinical syndrome is signalled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnoea, cyanosis, dysrhythmias, and/or unstable blood pressure. Some of these non-specific signs may also appear during light anaesthesia, acute hypoxia, hypercapnia and hypovolaemia. Fatalities have occurred. Treatment of malignant hyperthermia includes discontinuation of ULTANE administration of intravenous dantrolene sodium and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base abnormalities. Renal failure may appear later, and urine flow should be monitored and sustained if possible.

Perioperative Hyperkalaemia: Use of inhaled anaesthetic agents, including ULTANE, has been associated with increases in serum potassium levels that have resulted in cardiac dysrhythmias and death in paediatric patients during the peri-operative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable (see CONTRA-INDICATIONS). Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatine phosphokinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalaemia and resistant dysrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. Reports of QT prolongation, associated with Torsades de Pointes, have been received. Caution should be exercised when administering ULTANE to susceptible patients.

Hepatic: Cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from post-marketing experiences. Caution should be exercised when ULTANE is used in patients with underlying hepatic conditions or under treatment with medicines known to cause hepatic dysfunction. (See SIDE-EFFECTS) It has been reported that previous exposure to halogenated hydrocarbon anaesthetics may increase the potential for hepatic injury.

General: During maintenance of anaesthesia, increasing the concentrations of ULTANE produces dose-dependent decreases in blood pressure. Excessive decrease in blood pressure may be related to depth of anaesthesia and in such instances may be corrected by decreasing the inspired concentration of ULTANE. Maintenance of haemodynamic stability is important to the avoidance of myocardial ischaemia in patients with coronary artery disease. The recovery from general anaesthesia should be assessed carefully before patients are discharged from the post-anaesthesia care unit. Although recovery of consciousness following ULTANE administration generally occurs within minutes, the impact on intellectual function for two or three days following anaesthesia has not been studied. Changes in mood may persist for several days following administration.

Replacement of Desiccated CO2 Absorbents: Cases of extreme heat, smoke and/or spontaneous fire in the anaesthesia machine have been reported during ULTANE use in conjunction with the use of desiccated CO2 absorbent. A delayed rise or unexpected decline of inspired ULTANE concentration compared to the vaporiser setting may be associated with excessive heating of the CO2 canister. The exothermic reaction that occurs with ULTANE and CO2 absorbents is increased when the CO2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2 absorbent canisters.

Renal Impairment: Because of the small number of patients with renal insufficiency studied (baseline serum creatinine greater than 15 mg/L (133 u03bcmol/L), the safety of ULTANE administration in this group has not yet been fully established. Therefore, ULTANE should be used with caution in patients with renal insufficiency.

Neurosurgery: In patients at risk for an increase in intracranial pressure, ULTANE should be administered cautiously in conjunction with measures to reduce intracranial pressure (such as hyperventilation).

Seizures: Cases of seizures have been reported in association with ULTANE use. (See SIDE-EFFECTS)

Paediatric use: The use of ULTANE has been associated with seizures. Many of these have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing factors. Clinical judgement should be exercised when using ULTANE in patients who may be at risk for seizures.

Hypersensitivity: Reports of hypersensitivity (including contact dermatitis, rash, dyspnoea, wheezing, chest discomfort, swelling face or anaphylactic reaction) have been received, including cases of association with long-term occupational exposure to ULTANE.

Beta-sympathomimetic agents like isoprenaline and alpha- and beta- sympathomimetic agents like adrenaline and noradrenaline should be used with caution during Sevoflurane narcosis, due to a potential risk of ventricular arrhythmia. Non-selective MAO-inhibitors: Risk of crisis during the operation. It is generally recommended that treatment should be stopped 2 weeks prior to surgery. Sevoflurane may lead to marked hypotension in patients treated with calcium antagonists, in particular dihydropyridine derivates. Caution should be exercised when calcium antagonists are used concomitantly with inhalation anaesthetics due to the risk of additive negative inotropic effect. Concomitant use of succinylcholine with inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the post-operative period. Barbiturates: ULTANE administration is compatible with barbiturates. Benzodiazepines and Opioids: Benzodiazepines and opioids decrease the MAC of ULTANE. ULTANE administration is compatible with benzodiazepines and opioids. Inducers of CYP2E1: Medicinal products and compounds that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may increase the metabolism of ULTANE and lead to significant increases in plasma fluoride concentrations. Nitrous oxide: The MAC of ULTANE is decreased when administered in combination with nitrous oxide. The MAC equivalent is reduced approximately 50 % in adult and approximately 25 % in paediatric patients. Altitude may affect the effects of nitrous oxide. Neuromuscular blocking agents: ULTANE affects both the intensity and duration of neuromuscular blockade by non-depolarising muscle relaxants. When used to supplement alfentanil N2O anaesthesia, ULTANE potentiates neuromuscular block induced with pancuronium, vecuronium or atracurium. The effect of ULTANE on succinylcholine and the duration of depolarising neuromuscular blockade has not been studied. Dosage reduction of neuromuscular blocking agents during induction of anaesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation because potentiation of neuromuscular blocking agents is observed a few minutes after the beginning of ULTANE administration. Among non-depolarising agents, vecuronium, pancuronium and atracurium interactions have been studied. In the absence of specific guidelines: (1) for endotracheal intubation, do not reduce the dose of non-depolarising muscle relaxants, (2) during maintenance of anaesthesia, the dose of non-depolarising muscle relaxants is likely to be reduced compared to that during N2O/opioid anaesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation.

Safety in pregnancy or lactation has not been established. The safety of ULTANE in labour and delivery has not been demonstrated. ULTANE may be used for anaesthesia during Caesarean section. Published animal studies of some anaesthetic/sedation drugs have reported adverse effects on brain development in early life (see PRE-CLINICAL SAFETY DATA). ULTANE has relaxant effects on the uterus with the potential risk for uterine bleeding. Caution should be observed when using ULTANE during obstetric anaesthesia. It is not known whether ULTANE is excreted in human milk. Caution should be exercised when ULTANE is administered to a breastfeeding woman.

Patients should be advised that performance of activities requiring mental alertness, such as decision making or operating a motor vehicle or hazardous machinery, may be impaired for some time after general anaesthesia.

Nausea, vomiting, and delirium have been observed in the postoperative period, common sequelae of surgery and general anaesthesia, which may be due to inhalational anaesthetic, other agents administered intra-operatively or post-operatively, and to the patient's response to the surgical procedure.

Adverse events are displayed in the following tables by System Organ Class and frequency, according to the following convention: Very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1000, < 1/100); rare (u2265 1/10 000, < 1/1000); and very rare (u2264 1/ 10 000).

CLASSIFICATION OF ADVERSE EVENTS REPORTED WITH SEVOFLURANE USE IN CONTROLLED CLINICAL TRIALS*

System Organ Class Frequency Adverse Reactions **

Psychiatric disorders Common Agitation

Nervous system disorders Common Somnolence Dizziness Headache

Cardiac disorders Very common Bradycardia

Common Tachycardia

Uncommon Atrioventricular block complete

Unknown QT prolongation associated with Torsade

Vascular disorders Very common Hypotension

Common Hypertension

Respiratory, thoracic and mediastinal disorders Very common Cough

Common Respiratory disorder Laryngospasm

Gastrointestinal disorders Very common Nausea Vomiting

Common Salivary hypersecretion

General disorders and administration site conditions Common Chills Pyrexia

Investigations Common Increased blood glucose Abnormal liver function test Increased white blood cell count Increased fluoride #

Injury, poisoning and procedural complications Common Hypothermia

# Increases in serum inorganic fluoride levels may occur during and after ULTANE anaesthesia. Concentrations of inorganic fluoride generally peak within two hours of the end of ULTANE anaesthesia and return within 48 hours to pre-operative levels. In clinical trials, elevated fluoride levels were not associated with impairment of renal function.

* Classification based on the reported incidence of adverse events in controlled clinical trials on sevoflurane use.

** Adverse event terms are listed in MedDRA 8.0 terminology.

CLASSIFICATION OF ADVERSE EVENTS REPORTED WITH SEVOFLURANE USE IN SPECIAL PATIENT GROUPS IN CONTROLLED CLINICAL TRIALS*

USE IN CHILDREN POST-SURGICALLY

System Organ Class Frequency Adverse Reactions **

Psychiatric disorders Very common Agitation

Respiratory, thoracic and mediastinal Very common Cough

disorders

Gastrointestinal disorders Very common Vomiting, nausea

USE IN ADULTS

System Organ Class Frequency Adverse Reactions **

Vascular disorders Very common Hypotension

Gastrointestinal disorders Very common Nausea, vomiting

USE IN ELDERLY PATIENTS

System Organ Class Frequency Adverse Reactions **

Cardiac disorders Very common Bradycardia

Vascular disorders Very common Hypotension

Gastrointestinal disorders Very common Nausea, vomiting

* Classification based on the reported incidence of adverse events in controlled clinical trials on sevoflurane use in children post-surgically, adults and elderly patients.

** Adverse event terms are listed in MedDRA 8.0 terminology.

Post-marketing reports Adverse reactions have been spontaneously reported during post-approval use of ULTANE. These events are reported voluntarily from a population of an unknown rate of exposure. Therefore it is not possible to estimate the true incidence of adverse events or establish a causal relationship to ULTANE exposure.

Immune system disorders Anaphylactic reaction, anaphylactoid reaction.

Nervous system disorders Convulsion, dystonia Seizure-like activity may occur on less frequent occasions following ULTANE administration. Reported events were of short duration and there was no evidence of any abnormality during emergence from anaesthesia or in the post-operative period.

Cardiac disorders Cardiac arrest There have been reports of QTc prolongation and cardiac arrest in the setting of ULTANE use.

Cardiac disorders Bradycardia in patients with Down syndrome.

Respiratory, thoracic and mediastinal disorders Bronchospasm.

Hepato-biliary disorders Cases of post-operative hepatitis have been reported. In addition, there have been post-marketing reports of hepatic failure and hepatic necrosis associated with the use of ULTANE. However, the actual incidence and relationship of ULTANE to these events cannot be established with certainty.

Skin and sub-cutaneous tissue disorders Pruritus, rash, urticaria.

General disorders and administration site conditions Malignant hyperthermia.

In the event of apparent overdosage, the following action should be taken: Discontinue administration of ULTANE, maintain a patent airway, initiate assisted or controlled ventilation with oxygen and maintain adequate cardiovascular function.