Sevoflurano baxter

Overdose

In the event of overdosage, the following action should be taken: Stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen and maintain adequate cardiovascular function.

In the event of overdosage, or what may appear to be overdosage, the following action should be taken: discontinue administration of sevoflurane, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.

Contraindications

Sevoflurano Baxter should not be used in patients with known or suspected sensitivity to Sevoflurano Baxter or other halogenated anaesthetics (e.g. history of liver function disorder, fever or leucocytosis of unknown cause after anaesthesia with one of these agents).

Sevoflurano Baxter is also contraindicated in patients with known or suspected genetic susceptibility to malignant hyperthermia.

Sevoflurano Baxter is contraindicated in patients in whom general anaesthesia is contraindicated.

Sevoflurane can cause malignant hyperthermia. It should not be used in patients with known sensitivity to sevoflurane or to other halogenated agents nor in patients with known or suspected susceptibility to malignant hyperthermia.

Incompatibilities

Sevoflurano Baxter is stable when stored under normal room lighting conditions. No discernible degradation of Sevoflurano Baxter occurs in the presence of strong acids or heat. Sevoflurano Baxter is not corrosive to stainless steel, brass, aluminum nickel-plated brass, chrome-plated brass or copper beryllium alloy.

Chemical degradation can occur upon exposure of inhaled anaesthetics to CO2 absorbent within the anaesthesia machine. When used as directed with fresh absorbents, degradation of Sevoflurano Baxter is minimal and degradants are undetectable or non-toxic. Sevoflurano Baxter degradation and subsequent degradant formation are enhanced by increasing absorbent temperature, desiccated CO2 absorbent (especially potassium hydroxide-containing, e.g. Baralyme®), increased Sevoflurano Baxter concentration and decreased fresh gas flow. Sevoflurano Baxter can undergo alkaline degradation by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropanyl fluoromethyl ether (PIFE or more commonly known as Compound A). The second pathway for degradation of Sevoflurano Baxter occurs only in the presence of desiccated CO2 absorbents and leads to the dissociation of Sevoflurano Baxter into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic, rapidly glucoronidated, cleared and has toxicity comparable to Sevoflurano Baxter. Formaldehyde is present during normal metabolic processes. Upon exposure to a highly desiccated absorbent, formaldehyde can further degrade into methanol and formate. Formate can contribute to the formation of carbon monoxide in the presence of high temperature. Methanol can react with compound A to form the methoxy addition product Compound B. Compound B can undergo further HF elimination to form Compounds C,D and E. With highly desiccated absorbents, especially those containing potassium hydroxide (e.g Baralyme®) the fomation of formaldehyde, methanol, carbon monoxide, Compound A and perhaps some of its degradants, Compounds B,C and D may occur.

Undesirable effects

Summary of the safety profile

As with all potent inhaled anaesthetics, Sevoflurano Baxter may cause dose-dependent cardio-respiratory depression. Most adverse reactions are mild to moderate in severity and are transient in duration. Nausea, vomiting and delirium are commonly observed in the post-operative period, at a similar incidence to those found with other inhalation anaesthetics. These effects are common sequelae of surgery and general anaesthesia which may be due to the inhalational anaesthetic, other agents administered intra-operatively or post-operatively and to the patient's response to the surgical procedure.

The most commonly reported adverse reactions were as follows:

In adult patients: hypotension, nausea and vomiting;

In elderly patients: bradycardia, hypotension and nausea; and

In paediatric patients: agitation, cough, vomiting and nausea.

Tabulated summary of adverse reactions

All adverse reactions at least possibly relating to Sevoflurano Baxter from clinical trials and post-marketing experience are presented in the following table by MedDRA System Organ Class, Preferred Term and frequency. The following frequency categories are used: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. Post-marketing adverse reactions are reported voluntarily from a population with an unknown rate of exposure. Therefore it is not possible to estimate the true incidence of adverse events and the frequency is “unknown”. The type, severity and frequency of adverse reactions in Sevoflurano Baxter patients in clinical trials were comparable to adverse reactions in reference-drug patients.

Adverse Reaction Data Derived From Clinical Trials and Post-marketing Experience

- Description of selected adverse reactions.

- Paediatric population.

4 There have been very rare post-marketing reports of cardiac arrest in the setting of Sevoflurano Baxter use.

5 Occasional cases of transient changes in hepatic function tests were reported with Sevoflurano Baxter and reference agents.

6 Transient increases in serum inorganic fluoride levels may occur during and after Sevoflurano Baxter anaesthesia. See Description of selected adverse reactions below.

Description of selected adverse reactions

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

Rare reports of post-operative hepatitis exist. In addition, there have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile anaesthetic agents, including Sevoflurano Baxter. However, the actual incidence and relationship of Sevoflurano Baxter to these events cannot be established with certainty.

Rare reports of hypersensitivity (including contact dermatitis, rash, dyspnoea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, particularly in association with long-term occupational exposure to inhaled anaesthetic agents, including Sevoflurano Baxter.

In susceptible individuals, potent inhalation anaesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia.

Paediatric population

The use of Sevoflurano Baxter 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 risk factors. Clinical judgment should be exercised when using Sevoflurano Baxter in patients who may be at risk for seizures.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Adverse events are derived from controlled clinical trials conducted in the United States, Canada, and Europe. The reference drugs were isoflurane, enflurane, and propofol in adults and halothane in pediatric patients. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered.

Of the 5182 patients enrolled in the clinical trials, 2906 were exposed to sevoflurane, including 118 adults and 507 pediatric patients who underwent mask induction. Each patient was counted once for each type of adverse event. Adverse events reported in patients in clinical trials and considered to be possibly or probably related to sevoflurane are presented within each body system in order of decreasing frequency in the following listings. One case of malignant hyperthermia was reported in pre-registration clinical trials.

Bradycardia 5%, Hypotension 4%, Tachycardia 2%

Agitation 7%

Laryngospasm 8%, Airway obstruction 8%, Breathholding 5%, Cough Increased 5%

Tachycardia 6%, Hypotension 4%

Agitation 15%

Breathholding 5%, Cough Increased 5%, Laryngospasm 3%, Apnea 2%

Increased salivation 2%

Fever 1%, Shivering 6%, Hypothermia 1%, Movement 1%, Headache 1%

Hypotension 11%, Hypertension 2%, Bradycardia 5%, Tachycardia 2%

Somnolence 9%, Agitation 9%, Dizziness 4%, Increased salivation 4%

Nausea 25%, Vomiting 18%

Cough increased 11%, Breathholding 2%, Laryngospasm 2%

Asthenia, Pain

Arrhythmia, Ventricular Extrasystoles, Supraventricular Extrasystoles, Complete AV Block, Bigeminy, Hemorrhage, Inverted T Wave, Atrial Fibrillation, Atrial Arrhythmia, Second Degree AV Block, Syncope, S-T Depressed

Crying, Nervousness, Confusion, Hypertonia, Dry Mouth, Insomnia

Sputum Increased, Apnea, Hypoxia, Wheezing, Bronchospasm, Hyperventilation, Pharyngitis, Hiccup, Hypoventilation, Dyspnea, Stridor

Increases in LDH, AST, ALT, BUN, Alkaline Phosphatase, Creatinine, Bilirubinemia, Glycosuria, Fluorosis, Albuminuria, Hypophosphatemia, Acidosis, Hyperglycemia

Leucocytosis, Thrombocytopenia

Amblyopia, Pruritus, Taste Perversion, Rash, Conjunctivitis

Urination Impaired, Urine Abnormality, Urinary Retention, Oliguria See WARNINGS for information regarding malignant hyperthermia.

The following adverse events have been identified during post-approval use of Sevoflurano Baxter (sevoflurane USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of Sevoflurano Baxter to these events cannot be established with certainty.

Seizures — Post-marketing reports indicate that sevoflurane use has been associated with seizures. The majority of cases were in children and young adults, most of whom had no medical history of seizures. Several cases reported no concomitant medications, and at least one case was confirmed by EEG. Although many cases were single seizures that resolved spontaneously or after treatment, cases of multiple seizures have also been reported. Seizures have occurred during, or soon after sevoflurane induction, during emergence, and during post-operative recovery up to a day following anesthesia.

Cardiac arrest

• Cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported. Histological evidence was not provided for any of the reported hepatitis cases. In most of these cases, patients had underlying hepatic conditions or were under treatment with drugs known to cause hepatic dysfunction. Most of the reported events were transient and resolved spontaneously (see PRECAUTIONS).
• Hepatic necrosis
• Hepatic failure

• Malignant hyperthermia (see CONTRAINDICATIONS and WARNINGS)
• Allergic reactions, such as rash, urticaria, pruritus, bronchospasm, anaphylactic or anaphylactoid reactions (see CONTRAINDICATIONS)
• Reports of hypersensitivity (including contact dermatitis, rash, dyspnea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, particularly in association with long-term occupational exposure to inhaled anesthetic agents, including sevoflurane (see Occupational Caution).

• Transient elevations in glucose, liver function tests, and white blood cell count may occur as with use of other anesthetic agents.

Preclinical safety data

Animal studies have shown that hepatic and renal circulation are well maintained with Sevoflurano Baxter.

Sevoflurano Baxter decreases the cerebral metabolic rate for oxygen (CMRO2) in a fashion analogous to that seen with isoflurane. An approximately 50% reduction of CMRO2 is observed at concentrations approaching 2.0 MAC. Animal studies have demonstrated that Sevoflurano Baxter does not have a significant effect on cerebral blood flow.

In animals, Sevoflurano Baxter significantly suppresses electroencephalographic (EEG) activity comparable to equipotent doses of isoflurane. There is no evidence that Sevoflurano Baxter is associated with epileptiform activity during normocapnia or hypocapnia. In contrast to enflurane, attempts to elicit seizure-like EEG activity during hypocapnia with rhythmic auditory stimuli have been negative.

Compound A was minimally nephrotoxic at concentrations of 50-114 ppm for 3 hours in a range of studies in rats. The toxicity was characterised by sporadic single cell necrosis of the proximal tubule cells. The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established. Comparable human thresholds for Compound A-related nephrotoxicity would be predicted to be 150-200 ppm. The concentrations of Compound A found in routine clinical practice are on average 19 ppm in adults (maximum 32 ppm) with use of Soda lime as the CO2 absorbent.

Developmental toxicity studies have been performed in pregnant rats and rabbits at doses up to 1 MAC for three hours per day. Reduced foetal body weights concomitant with increased skeletal variations were noted in rats only at maternally toxic concentrations. No adverse foetal effects were observed in rabbits. In fertility studies in rats at doses up to 1 MAC no effects on male and female reproductive capabilities were observed.

Published studies in pregnant and juvenile animals suggest that the use of anaesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes. The clinical significance of these nonclinical findings is yet to be determined.

Therapeutic indications

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

Sevoflurane is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery.

Sevoflurane should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Since level of anesthesia may be altered rapidly, only vaporizers producing predictable concentrations of sevoflurane should be used.

Pharmacodynamic properties

Pharmaco-therapeutic group: Anaesthetics, general - ATC code: N01A

Changes in the clinical effects of Sevoflurano Baxter rapidly follow changes in the inspired concentration.

Cardiovascular Effects

As with all other inhalation agents Sevoflurano Baxter depresses cardiovascular function in a dose related fashion. In one volunteer study, increases in Sevoflurano Baxter concentration resulted in decrease in mean arterial pressure, but there was no change in heart rate. Sevoflurano Baxter did not alter plasma noradrenaline concentrations in this study.

Nervous System Effects

No evidence of seizure was observed during the clinical development programme.

In patients with normal intracranial pressure (ICP), Sevoflurano Baxter had minimal effect on ICP and preserved CO2 responsiveness. The safety of Sevoflurano Baxter has not been investigated in patients with a raised ICP. In patients at risk for elevations of ICP, Sevoflurano Baxter should be administered cautiously in conjunction with ICP-reducing manoeuvres such as hyperventilation.

Paediatric

Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/sedation drug administration or other factors such as the surgery or underlying illness. In addition, more recent published registry studies did not confirm these findings.

Pharmacokinetic properties

The low solubility of Sevoflurano Baxter in blood should result in alveolar concentrations which rapidly increase upon induction and rapidly decrease upon cessation of the inhaled agent.

In humans <5% of the absorbed Sevoflurano Baxter is metabolised. The rapid and extensive pulmonary elimination of Sevoflurano Baxter minimises the amount of anaesthetic available for metabolism. Sevoflurano Baxter is defluorinated via cytochrome p450(CYP)2E1 resulting in the production of hexafluoroisopropanol (HFIP) with release of inorganic fluoride and carbon dioxide (or a one carbon fragment). HFIP is then rapidly conjugated with glucuronic acid and excreted in the urine.

The metabolism of Sevoflurano Baxter may be increased by known inducers of CYP2E1 (e.g. isoniazid and alcohol), but it is not inducible by barbiturates.

Transient increases in serum inorganic fluoride levels may occur during and after Sevoflurano Baxter anaesthesia. Generally, concentrations of inorganic fluoride peak within 2 hours of the end of Sevoflurano Baxter anaesthesia and return within 48 hours to pre-operative levels.

Solubility

Because of the low solubility of sevoflurane in blood (blood/gas partition coefficient @ 37°C = 0.63-0.69), a minimal amount of sevoflurane is required to be dissolved in the blood before the alveolar partial pressure is in equilibrium with the arterial partial pressure. Therefore there is a rapid rate of increase in the alveolar (end-tidal) concentration (FA) toward the inspired concentration (FI) during induction.

Induction of Anesthesia

In a study in which seven healthy male volunteers were administered 70% N2O/30%O2 for 30 minutes followed by 1.0% sevoflurane and 0.6% isoflurane for another 30 minutes the FA/FI ratio was greater for sevoflurane than isoflurane at all time points. The time for the concentration in the alveoli to reach 50% of the inspired concentration was 4-8 minutes for isoflurane and approximately 1 minute for sevoflurane.

FA/FI data from this study were compared with FA/FI data of other halogenated anesthetic agents from another study. When all data were normalized to isoflurane, the uptake and distribution of sevoflurane was shown to be faster than isoflurane and halothane, but slower than desflurane. The results are depicted in Figure 3.

Recovery from Anesthesia

The low solubility of sevoflurane facilitates rapid elimination via the lungs. The rate of elimination is quantified as the rate of change of the alveolar (end-tidal) concentration following termination of anesthesia (FA), relative to the last alveolar concentration (FaO) measured immediately before discontinuance of the anesthetic. In the healthy volunteer study described above, rate of elimination of sevoflurane was similar compared with desflurane, but faster compared with either halothane or isoflurane. These results are depicted in Figure 4.

Figure 3: Ratio of Concentration of Anesthetic in Alveolar Gas to Inspired Gas

Figure 4: Concentration of Anesthetic in Alveolar Gas Following Termination of Anesthesia

Yasuda N, Lockhart S, Eger EI II, et al: Comparison of kinetics of sevoflurane and isoflurane in humans. Anesth Analg 72:316, 1991.

Protein Binding

The effects of sevoflurane on the displacement of drugs from serum and tissue proteins have not been investigated. Other fluorinated volatile anesthetics have been shown to displace drugs from serum and tissue proteins in vitro. The clinical significance of this is unknown. Clinical studies have shown no untoward effects when sevoflurane is administered to patients taking drugs that are highly bound and have a small volume of distribution (e.g., phenytoin).

Sevoflurane is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Once formed HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. In vivo metabolism studies suggest that approximately 5% of the sevoflurane dose may be metabolized.

Cytochrome P450 2E1 is the principal isoform identified for sevoflurane metabolism and this may be induced by chronic exposure to isoniazid and ethanol. This is similar to the metabolism of isoflurane and enflurane and is distinct from that of methoxyflurane which is metabolized via a variety of cytochrome P450 isoforms. The metabolism of sevoflurane is not inducible by barbiturates. As shown in Figure 5, inorganic fluoride concentrations peak within 2 hours of the end of sevoflurane anesthesia and return to baseline concentrations within 48 hours post-anesthesia in the majority of cases (67%). The rapid and extensive pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism.

Figure 5: Serum Inorganic Fluoride Concentrations for Sevoflurane and Other Volatile Anesthetics

Cousins M.J., Greenstein L.R., Hitt B.A., et al: Metabolism and renal effects of enflurane in man. Anesthesiology 44:44; 1976* and Sevo-93-044+ .

Legend: Pre-Anesth. = Pre-anesthesia

Up to 3.5% of the sevoflurane dose appears in the urine as inorganic fluoride. Studies on fluoride indicate that up to 50% of fluoride clearance is nonrenal (via fluoride being taken up into bone).

Fluoride ion concentrations are influenced by the duration of anesthesia, the concentration of sevoflurane administered, and the composition of the anesthetic gas mixture. In studies where anesthesia was maintained purely with sevoflurane for periods ranging from 1 to 6 hours, peak fluoride concentrations ranged between 12 μM and 90 μM. As shown in Figure 6, peak concentrations occur within 2 hours of the end of anesthesia and are less than 25 μM (475 ng/mL) for the majority of the population after 10 hours. The half-life is in the range of 15-23 hours.

It has been reported that following administration of methoxyflurane, serum inorganic fluoride concentrations > 50 μM were correlated with the development of vasopressin-resistant, polyuric, renal failure. In clinical trials with sevoflurane, there were no reports of toxicity associated with elevated fluoride ion levels.

Figure 6: Fluoride Ion Concentrations Following Administration of Sevoflurane (mean MAC = 1.27, mean duration = 2.06 hr) Mean Fluoride Ion Concentrations (n = 48)

Fluoride concentrations have been measured after single, extended, and repeat exposure to sevoflurane in normal surgical and special patient populations, and pharmacokinetic parameters were determined.

Compared with healthy individuals, the fluoride ion half-life was prolonged in patients with renal impairment, but not in the elderly. A study in 8 patients with hepatic impairment suggests a slight prolongation of the half-life. The mean half-life in patients with renal impairment averaged approximately 33 hours (range 21-61 hours) as compared to a mean of approximately 21 hours (range 10-48 hours) in normal healthy individuals. The mean half-life in the elderly (greater than 65 years) approximated 24 hours (range 18-72 hours). The mean half-life in individuals with hepatic impairment was 23 hours (range 16-47 hours). Mean maximal fluoride values (Cmax) determined in individual studies of special populations are displayed below.

Table 1: Fluoride Ion Estimates in Special Populations Following Administration of Sevoflurane

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Sevoflurano Baxter may cause respiratory depression, which may be augmented by narcotic premedication or other agents causing respiratory depression. Respiration should be supervised and if necessary, assisted.

Sevoflurano Baxter should be administered only by persons trained in the administration of general anaesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment and circulatory resuscitation must be immediately available.

The concentration of Sevoflurano Baxter being delivered from a vaporiser must be known exactly. As volatile anaesthetics differ in their physical properties, only vaporisers specifically calibrated for Sevoflurano Baxter must be used. The administration of general anaesthesia must be individualised based on the patient's response. Hypotension and respiratory depression increase as anaesthesia is deepened.

Malignant Hyperthermia

In susceptible individuals, potent inhalation anaesthetic agents 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, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anaesthesia, acute hypoxia, hypercapnia and hypovolaemia.

In clinical trials, one case of malignant hyperthermia was reported. In addition, there have been postmarketing reports of malignant hyperthermia. Some of these reports have been fatal.

Treatment includes discontinuation of triggering agents (e.g. Sevoflurano Baxter), administration of intravenous dantrolene sodium (consult prescribing information for intravenous dantrolene sodium for additional information on patient management), 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 Hyperkalemia

Use of 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 postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatine kinase 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 arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.

Isolated reports of QT prolongation, very rarely associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering Sevoflurano Baxter to susceptible patients.

Isolated cases of ventricular arrhythmia were reported in paediatric patients with Pompe's disease.

Caution should be exercised in administering general anaesthesia, including Sevoflurano Baxter, to patients with mitochondrial disorders.

Hepatic

Very rare cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from postmarketing experiences.

Clinical judgment should be exercised when Sevoflurano Baxter is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction.

Patients with repeated exposures to halogenated hydrocarbons, including Sevoflurano Baxter, within a relatively short interval may have an increased risk of hepatic injury.

General

During the maintenance of anaesthesia, increasing the concentration of Sevoflurano Baxter 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 Sevoflurano Baxter. Particular care must be taken when selecting the dosage for patients who are hypovolaemic, hypotensive, or otherwise hemodynamically compromised, e.g., due to concomitant medications.

As with all anaesthetics, maintenance of haemodynamic stability is important to avoid myocardial ischaemia in patients with coronary artery disease.

Caution should be observed when using Sevoflurano Baxter during obstetric anaesthesia because the relaxant effect on the uterus could increase the risk of uterine bleeding.

The recovery from general anaesthesia should be assessed carefully before patients are discharged from the recovery room. Rapid emergence from anaesthesia is generally seen with Sevoflurano Baxter so early relief of postoperative pain may be required. Although recovery of consciousness following Sevoflurano Baxter administration generally occurs within minutes, the impact on intellectual function for two or three days following anaesthesia has not been studied. As with other anaesthetics, small changes in moods may persist for several days following administration. Rapid emergence in children may be associated with agitation and lack of co-operation (in about 25% of cases).

Replacement of Desiccated CO2 Absorbents:

Rare cases of extreme heat, smoke, and/or spontaneous fire in the anaesthesia machine have been reported during Sevoflurano Baxter use in conjunction with the use of desiccated CO2 absorbent, specifically those containing potassium hydroxide (e.g Baralyme). An unusually delayed rise or unexpected decline of inspired Sevoflurano Baxter concentration compared to the vaporiser setting may be associated with excessive heating of the CO2 absorbent canister.

An exothermic reaction, enhanced Sevoflurano Baxter degradation, and production of degradation products can occur when the CO2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2 absorbent canisters. Sevoflurano Baxter degradants (methanol, formaldehyde, carbon monoxide, and Compounds A, B, C, and D) were observed in the respiratory circuit of an experimental anaesthesia machine using desiccated CO2 absorbents and maximum Sevoflurano Baxter concentrations (8%) for extended periods of time (> 2 hours). Concentrations of formaldehyde observed at the anaesthesia respiratory circuit (using sodium hydroxide containing absorbents) were consistent with levels known to cause mild respiratory irritation. The clinical relevance of the degradants observed under this extreme experimental model is unknown.

If a health care professional suspects that the CO2 absorbent has become desiccated, it must be replaced before subsequent use of volatile anaesthetics (such as Sevoflurano Baxter). It must be taken into account that the colour indicator does not always change after desiccation has taken place. Therefore, the lack of significant colour change should not be taken as an assurance of adequate hydration. CO2 absorbents should be replaced routinely regardless of the state of the colour indicator.

Renal Impairment:

Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 1.5mg/dL) studied, the safety of Sevoflurano Baxter administration in this group has not been fully established. Therefore, Sevoflurano Baxter should be used with caution in patients with renal insufficiency.

Neurosurgery & Neuromuscular Impairment:

In patients at risk from elevation of intra-cranial pressure, Sevoflurano Baxter should be administered cautiously in conjunction with techniques to lower intra-cranial pressure (e.g. hyperventilation).

Seizures:

Rare cases of seizures have been reported in association with Sevoflurano Baxter use.

Paediatric population:

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

Dystonic movements in children have been observed.

Although data from controlled clinical studies at low flow rates are limited, findings taken from patient and animal studies suggest that there is a potential for renal injury which is presumed due to Compound A. Animal and human studies demonstrate that sevoflurane administered for more than 2 MAC·hours and at fresh gas flow rates of < 2 L/min may be associated with proteinuria and glycosuria.

While a level of Compound A exposure at which clinical nephrotoxicity might be expected to occur has not been established, it is prudent to consider all of the factors leading to Compound A exposure in humans, especially duration of exposure, fresh gas flow rate, and concentration of sevoflurane. During sevoflurane anesthesia the clinician should adjust inspired concentration and fresh gas flow rate to minimize exposure to Compound A. To minimize exposure to Compound A, sevoflurane exposure should not exceed 2 MAC·hours at flow rates of 1 to < 2 L/min. Fresh gas flow rates < 1 L/min are not recommended.

Because clinical experience in administering sevoflurane to patients with renal insufficiency (creatinine > 1.5 mg/dL) is limited, its safety in these patients has not been established.

Sevoflurane may be associated with glycosuria and proteinuria when used for long procedures at low flow rates. The safety of low flow sevoflurane on renal function was evaluated in patients with normal preoperative renal function. One study compared sevoflurane (N = 98) to an active control (N = 90) administered for ≥ 2 hours at a fresh gas flow rate of ≤ 1 Liter/minute. Per study defined criteria (Hou et al.) one patient in the sevoflurane group developed elevations of creatinine, in addition to glycosuria and proteinuria. This patient received sevoflurane at fresh gas flow rates of ≤ 800 mL/minute. Using these same criteria, there were no patients in the active control group who developed treatment emergent elevations in serum creatinine.

Sevoflurane may present an increased risk in patients with known sensitivity to volatile halogenated anesthetic agents. KOH containing CO2 absorbents are not recommended for use with sevoflurane.

Reports of QT prolongation, associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering sevoflurane to susceptible patients (e.g. patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval).

In susceptible individuals, potent inhalation anesthetic agents, including sevoflurane, may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. Sevoflurane can induce malignant hyperthermia in genetically susceptible individuals, such as those with certain inherited ryanodine receptor mutations. The clinical syndrome is signaled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia, acute hypoxia, hypercapnia, and hypovolemia.

In clinical trials, one case of malignant hyperthermia was reported. In addition, there have been postmarketing reports of malignant hyperthermia. Some of these cases have been fatal.

Treatment of malignant hyperthermia includes discontinuation of triggering agents (e.g., sevoflurane), administration of intravenous dantrolene sodium (consult prescribing information for intravenous dantrolene sodium for additional information on patient management), and application of supportive therapy. Supportive therapy may include efforts to restore body temperature, respiratory and circulatory support as indicated, and management of electrolytefluid-acid-base abnormalities. Renal failure may appear later, and urine flow should be monitored and sustained if possible.

Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatine kinase 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 hyperkalemia and resistant arrhythmias is recommended; as is subsequent evaluation for latent neuromuscular disease.

During the maintenance of anesthesia, increasing the concentration of sevoflurane produces dose-dependent decreases in blood pressure. Due to sevoflurane's insolubility in blood, these hemodynamic changes may occur more rapidly than with other volatile anesthetics. Excessive decreases in blood pressure or respiratory depression may be related to depth of anesthesia and may be corrected by decreasing the inspired concentration of sevoflurane.

Rare cases of seizures have been reported in association with sevoflurane use (see PRECAUTIONS - Pediatric Use and ADVERSE REACTIONS).

The recovery from general anesthesia should be assessed carefully before a patient is discharged from the post-anesthesia care unit.

Studies on carcinogenesis have not been performed for either sevoflurane or Compound A. No mutagenic effect of sevoflurane was noted in the Ames test, mouse micronucleus test, mouse lymphoma mutagenicity assay, human lymphocyte culture assay, mammalian cell transformation assay, 32P DNA adduct assay, and no chromosomal aberrations were induced in cultured mammalian cells.

Similarly, no mutagenic effect of Compound A was noted in the Ames test, the Chinese hamster chromosomal aberration assay and the in vivo mouse micronucleus assay. However, positive responses were observed in the human lymphocyte chromosome aberration assay. These responses were seen only at high concentrations and in the absence of metabolic activation (human S-9).

Reproduction studies have been performed in rats and rabbits at doses up to 1 MAC (minimum alveolar concentration) without CO2 absorbent and have revealed no evidence of impaired fertility or harm to the fetus due to sevoflurane at 0.3 MAC, the highest nontoxic dose. Developmental and reproductive toxicity studies of sevoflurane in animals in the presence of strong alkalies (i.e., degradation of sevoflurane and production of Compound A) have not been conducted. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, sevoflurane should be used during pregnancy only if clearly needed.

Sevoflurane has been used as part of general anesthesia for elective cesarean section in 29 women. There were no untoward effects in mother or neonate (see Pharmacodynamics - Clinical Trials). The safety of sevoflurane in labor and delivery has not been demonstrated.

The concentrations of sevoflurane in milk are probably of no clinical importance 24 hours after anesthesia. Because of rapid washout, sevoflurane concentrations in milk are predicted to be below those found with many other volatile anesthetics.

MAC decreases with increasing age. The average concentration of sevoflurane to achieve MAC in an 80 year old is approximately 50% of that required in a 20 year old.

Induction and maintenance of general anesthesia with sevoflurane have been established in controlled clinical trials in pediatric patients aged 1 to 18 years (see Pharmacodynamics - Clinical Trials and ADVERSE REACTIONS). Sevoflurane has a nonpungent odor and is suitable for mask induction in pediatric patients.

The concentration of sevoflurane required for maintenance of general anesthesia is age dependent. When used in combination with nitrous oxide, the MAC equivalent dose of sevoflurane should be reduced in pediatric patients. MAC in premature infants has not been determined (see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION for recommendations in pediatric patients 1 day of age and older).

The use of sevoflurane has been associated with seizures (see PRECAUTIONS and ADVERSE REACTIONS). The majority of these have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors. Clinical judgement should be exercised when using sevoflurane in patients who may be at risk for seizures.

Effects on ability to drive and use machines

As with other agents, patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, may be impaired for some time after general anaesthesia.

Patients should not be allowed to drive for a suitable period after Sevoflurano Baxter anaesthesia.

Dosage (Posology) and method of administration

Premedication should be selected according to the need of the individual patient, and at the discretion of the anaesthetist.

Surgical Anaesthesia:

Sevoflurano Baxter should be delivered via a vaporiser specifically calibrated for use with Sevoflurano Baxter so that the concentration delivered can be accurately controlled. MAC (minimum alveolar concentration) values for Sevoflurano Baxter decrease with age and with the addition of nitrous oxide. The table below indicates average MAC values for different age groups.

* Neonates are full term gestational age. MAC in premature infants has not been determined.

** In 1 - <3 year old paediatric patients, 60% N2O/40% O2 was used.

Induction:

Dosage should be individualised and titrated to the desired effect according to the patient's age and clinical status. A short acting barbiturate or other intravenous induction agent may be administered followed by inhalation of Sevoflurano Baxter. Induction with Sevoflurano Baxter may be achieved in oxygen or in combination with oxygen-nitrous oxide mixtures. In adults inspired concentrations of up to 5% Sevoflurano Baxter usually produce surgical anaesthesia in less than 2 minutes. In children, inspired concentrations of up to 7% Sevoflurano Baxter usually produce surgical anaesthesia in less than 2 minutes. Alternatively, for induction of anaesthesia in unpremedicated patients, inspired concentrations of up to 8% Sevoflurano Baxter may be used.

Maintenance:

Surgical levels of anaesthesia may be sustained with concentrations of 0.5 - 3% Sevoflurano Baxter with or without the concomitant use of nitrous oxide.

Emergence:

Emergence times are generally short following Sevoflurano Baxter anaesthesia. Therefore, patients may require early post-operative pain relief.

Older people:

MAC decreases with increasing age. The average concentration of Sevoflurano Baxter to achieve MAC in an 80 year old is approximately 50% of that required in a 20 year old.

Paediatric population:

Refer to Table 1 for MAC values for paediatric patients according to age.

The concentration of sevoflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane. The administration of general anesthesia must be individualized based on the patient's response.

When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced. The exothermic reaction that occurs with sevoflurane 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 (see PRECAUTIONS).

No specific premedication is either indicated or contraindicated with sevoflurane. The decision as to whether or not to premedicate and the choice of premedication is left to the discretion of the anesthesiologist.

Sevoflurane has a nonpungent odor and does not cause respiratory irritability; it is suitable for mask induction in pediatrics and adults.

Surgical levels of anesthesia can usually be achieved with concentrations of 0.5 - 3% sevoflurane with or without the concomitant use of nitrous oxide. Sevoflurane can be administered with any type of anesthesia circuit.

Table 9: MAC Values for Adults and Pediatric Patients According to Age

Special precautions for disposal and other handling

Sevoflurano Baxter should be administered via a vaporiser calibrated specifically for Sevoflurano Baxter using a key filling system designed for Sevoflurano Baxter specific vaporisers or other appropriate Sevoflurano Baxter specific vaporiser filling systems.

Carbon dioxide absorbents should not be allowed to dry out when inhalational anaesthetics are being administered. Some halogenated anaesthetics have been reported to interact with dry carbon dioxide absorbent to form carbon monoxide. However, in order to minimise the risk of formation of carbon monoxide in re-breathing circuits and the possibility of elevated carboxyhaemoglobin levels, CO2 absorbents should not be allowed to dry out. There have been rare cases of excessive heat production, smoke and fire in the anaesthetic machine when Sevoflurano Baxter has been used in conjunction with a desiccated (dried out) CO2 absorbent. If the CO2 absorbent is suspected to be desiccated it should be replaced.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements