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Sevoflurane

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Sevoflurane 100% Inhalation Vapour, liquid

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Sevoflurane 100%. The finished product is comprised only of the active ingredient,

3 PHARMACEUTICAL FORM

Inhalation vapour, liquid Clear, colourless, volatile liquid

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Induction and maintenance of general anaesthesia in adult and paediatric patients of all ages, including full term neonates (see section 4.2 for age details).

4.2 Posology and method of administration

Sevoflurane should be delivered via a vaporizer specifically calibrated for use with Sevoflurane so that the concentration delivered can be accurately controlled. MAC (minimum alveolar concentration) values for sevoflurane decrease as the patient’s age increases and with the addition of nitrous oxide. Dosage should be individualised and titrated to the desired effect according to the patient’s age and clinical status.

MAC values for Adults and Paediatric patients according to age

Age of Patient (years)	Sevoflurane 100% Inhalation Vapour, liquid in Oxygen	Sevoflurane 100% Inhalation Vapour, liquid in 65% N2O/35% O2 *
0 - 1 months	3.3 %	2.0 %
1 - < 6 months	3.0 %
6 months - < 3 years	2.8 %
3 - 12	2.5 %
25	2.6 %	1.4 %
40	2.1 %	1.1 %
60	1.7 %	0.9 %
80	1.4 %	0.7 %

* 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.

Anaesthesia Induction

A short acting barbiturate or other intravenous induction agent may be administered followed by inhalation of sevoflurane.

Induction with sevoflurane only may be achieved by inhalation of 0.5-1.0% sevoflurane in oxygen (O2) with or without nitrous oxide (N2O), increasing by increments of 0.5-1.0% sevoflurane, to a maximum of 8% in adults and children until the required depth of anaesthesia is achieved.

In adults inspired concentrations of up to 5% sevoflurane usually produce surgical anaesthesia in less than two minutes. In children, inspired concentrations of up to 7% sevoflurane usually produce surgical anaesthesia in less than two minutes.

Maintenance of Anaesthesia

Surgical levels of anaesthesia may be maintained by inhalation of 0.5-3% sevoflurane in O2 with or without N2O.

Emergence:

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

As with other halogenated inhalational anaesthetic agents repeated use within a short period of time should be performed only with caution

Hepatic Dysfunction:

Sevoflurane should not be used in patients with a history of unexplained moderate/severe hepatic dysfunction with jaundice, fever, and/or eosinophililia in association with halogenated anesthetics.

Renal Insufficiency:

Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 133pmol/litre) studied, the safety of sevoflurane administration in this group has not been fully established. Therefore, sevoflurane should be used with caution in patients with renal insufficiency. In some studies in rats, nephrotoxicity was seen in animals exposed to levels of Compound A (pentafluoroisopropenyl fluoromethyl ether (PIFE) in excess of those usually seen in routine clinical practice. The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established. (See Section 5.3, Preclinical Safety Data for further details.). Post-operative monitoring of the renal function is recommended in renal patients.

Route of Administration:

Inhalation use. Sevoflurane has to be administered either via face mask or via endotracheal tube. Sevoflurane 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. Sevoflurane should be delivered via a vaporiser specifically calibrated for use with sevoflurane so that the concentration delivered can be accurately controlled. If the carbon dioxide absorbent may be desiccated, it must be replaced before the use of sevoflurane. (see section 4.4.)

4.3 Contraindications

Sevoflurane should not be used in patients with known hypersensitivity to sevoflurane or other halogenated anaesthetics.

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

Sevoflurane should not be used in patients with a history of unexplained moderate/severe hepatic dysfunction with jaundice, fever, and/or eosinophililia in

association with halogenated anesthetics.

4.4 Special warnings and precautions for use

Hypotension and respiratory depression increase as anaesthesia is deepened.

During the maintenance of anaesthesia, increasing the concentration of sevoflurane 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 sevoflurane.

As with all anaesthetics, particular care should be taken when selecting the dose for hypovolaemic, hypotensive or weakened patients.

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

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

Caution should be observed when using sevoflurane during obstetric anaesthesia because the relaxant effect on the uterus could increase the risk of uterine bleeding (see section 4.6).

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. Treatment includes discontinuation of triggering agents (e.g. sevoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Renal failure may appear later, and urine flow should be monitored and sustained if possible.

Use of inhaled anaesthetic agents has been associated with very rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in children during the postoperative period. The condition has been described in patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy. Use of suxamethonium has been associated with most, but not all of these cases. These patients showed evidence of muscle damage with increased serum creatine kinase concentration and myoglobinuria. These patients did NOT have classical signs of malignant hyperthermia such as muscle rigidity, rapid increase in body temperature, or increased oxygen uptake and carbon dioxide production. Prompt and vigorous treatment for hyperkalaemia and arrhythmias is recommended. Subsequent evaluation for latent neuromuscular disease is indicated. Isolated cases of ventricular arrhythmia were reported in paediatric patients with Pompe's disease.

Observe caution in patients with underlying liver disease (including viral hepatitis) (see sections 4.3 and 4.8). Patients with repeated exposures to halogenated hydrocarbons, including sevoflurane, within a relatively short interval may have an increased risk of hepatic injury.

Use of sevoflurane has been an association with seizures occurring in children and young adults as well as older adults with and without predisposing risk factors. Clinical judgment is necessary before sevoflurane is used in patients at risk of seizures. In children the depth of anaesthesia should be limited. EEG may permit the optimization of sevoflurane dose and help avoid the development of seizure activity in patients with a predisposition for seizures (section 4.8).

Dystonic movements in children have been observed (see section 4.8).

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 sevoflurane so early relief of postoperative pain may be required. Rapid emergence in children may be associated with agitation and lack of co-operation (in about 25% of cases).

Experience with repeat exposure to sevoflurane is very limited. However, there were no obvious differences in adverse events between first and subsequent exposures.

Sevoflurane should be used with caution in patients with Myasthenia Gravis.

Like other halogenated anaesthetics, sevoflurane may cause cough during induction. Sevoflurane could cause QTc prolongation. In clinical practice , this rarely lead to Torsade des Pointes. Sevoflurane should be administered with caution to patients at risk, such as elderly and patients diagnosed with congenital QTc prolongation.

Potential Interactions with CO2 Absorbents

An exothermic reaction with degradation of volatile anaesthetics can occur when the carbon dioxide absorbent in the vaporizer becomes desiccated following an extended period of use as a result of dry gas flow through the circuit. Rare cases of extreme heat, smoke, and/or spontaneous fire in the anaesthesia machine have been reported during sevoflurane 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 sevoflurane concentration compared to the vaporizer setting may be associated with excessive heating of the CO2 absorbent canister.

Sevoflurane degradants were observed in the respiratory circuit of an experimental anaesthesia machine using desiccated CO2 absorbents and maximum sevoflurane 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.

It must be taken into account that the colour indicator does not always change after desiccation has taken place. The carbon dioxide absorbent should be routinely replaced irrespectively of the status. If a health care professional suspects that the carbon dioxide absorbent has become desiccated, it must be replaced before subsequent use of volatile anesthetics (such as sevoflurane).

4.5 Interaction with other medicinal products and other forms of interaction

The action of non-depolarising muscle relaxants is potentiated with sevoflurane,

therefore, when administered with sevoflurane, dosage adjustments of these agents should be made.

Sevoflurane is similar to isoflurane in the sensitisation of the myocardium to the arrhythmogenic effect of exogenously administered adrenaline.

MAC values for sevoflurane decrease with the addition of nitrous oxide as indicated in the table on 'Effect of Age on MAC of sevoflurane' (see Dosage and Method of Administration).

Benzodiazepines and opiates are expected to reduce sevoflurane MAC. Opioids

(e.g. alfentanil and sufentanil), used concomitantly with sevoflurane, may lead to a synergistic fall in heart rate, blood pressure and respiratory rate.

As with other agents, lesser concentrations of sevoflurane may be required following use of an intravenous anaesthetic e.g. propofol.

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

Significant increases in plasma fluoride concentrations have been observed following the increased activity of CYP 2E1.

Sevoflurane may increase the negative inotropic, chronotropic and dromotropic effects of beta blockers (by blocking cardiovascular compensatory mechanisms). Patients should be warned against interruption of beta-blockers and in any case abrupt interruption of the medication is to be avoided. The anaesthetist should be informed of beta-blocker therapy.

The dosage of adrenaline and noradrenaline utilised for local haemostatic action by subcutaneous or-gingival injections should be limited to, for example, 0.1 mg epinephrine within 10 minutes or 0.3 mg within one hour in adults. Parenteral administration of adrenaline and noradrenaline is not recommended.

Serious rhythm disturbances are associated with the use of isoprenaline (increased cardiovascular reactivity). Not recommended.

The use of amphetamines and derivatives as well as of ephedrine and derivatives can cause preoperative hypertensive crisis. It is preferable to interrupt treatments some days before surgery.

Concomitant use of MAO inhibitors: A risk of intraoperative collapse cannot be excluded as this has been observed with other halogenated inhalational anaesthetic agents.

4.6 Fertility, Pregnancy and lactation

Pregnancy

Sevoflurane should only be used in pregnancy if clearly indicated.

It has a relaxant effect on the uterus, which can lead to increased uterine bleeding, as was reported in a study of its use during termination of pregnancy. Use during labour and delivery is limited to one small study in Caesarian section.

Animal studies indicate that sevoflurane is not teratogenic.

Reproduction studies in rats and rabbits (doses up to 1 MAC) showed no effect on

male and female reproductive capability. Reduced fetal body weight, with increased skeletal anomalies, were noted in rats at maternally toxic concentrations but no adverse fetal effects were noted in rabbit.

Lactation

Caution should be exercised when sevoflurane is administered to nursing mothers as it is not known whether it is excreted in human milk.

4.7 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 hazardous machinery, may be impaired for some time after general anaesthesia.

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

4.8 Undesirable effects

As with all potent inhaled anaesthetics, sevoflurane may cause dose-dependent cardio-respiratory depression. Most adverse events are mild to moderate in severity and are transient in duration. Nausea and vomiting 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.

Adverse event data are derived from controlled clinical trials conducted in the United States and Europe in over 3,200 patients. The type, severity and frequency of adverse events in sevoflurane patients were comparable to adverse events in patients treated with other inhalation anaesthetics.

The most frequent adverse events associated with sevoflurane overall were nausea (24%) and vomiting (17%). Agitation occurred frequently in children (23%).

All Adverse reactions at least possibly relating to sevoflurane from clinical trials are presented in the following table by body system and frequency. The following frequency categories are used:

Very common (>1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

not known (cannot be estimated from the available data)

The type, severity and frequency of adverse reactions in sevoflurane patients were comparable to adverse reactions in reference-drug patients.

Post-marketing Experience

Adverse reactions have been spontaneously reported during post-approval use of sevoflurane. 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.

System Organ Class	Frequency	Adverse Reactions
Blood and lymphatic system disorders	Uncommon	Leukopenia Leukocytosis
Psychiatric disorders	Common*	Agitation
Psychiatric disorders	Uncommon	Confusional state
Nervous system disorders	Common	Somnolence Dizziness Headache
Cardiac disorders	Very Common	Bradycardia
	Common	Tachycardia
	Uncommon	Atrioventricular block complete Atrial fibrillation Arrhythmia Ventricular extrasystoles Supraventricular extrasystoles Extrasystoles
Vascular disorders	Very Common	Hypotension
Vascular disorders	Common	Hypertension
Respiratory, thoracic and mediastinal disorders	Very Common	Cough
	Common	Laryngospasm Respiratory disorder
	Uncommon	Apnoea Hypoxia Asthma
Gastrointestinal disorders	Very Common	Vomiting Nausea
Gastrointestinal disorders	Common	Salivary hypersecretion
Renal and urinary disorders	Uncommon	Urinary retention Glycosuria
General disorders and administration site conditions	Common	Fever Hypothermia Chills

Investigations	Common	Aspartate aminotransferase increased Blood glucose abnormal Liver function test abnormal¹ ² White blood cell count abnormal Blood fluoride increased³
Investigations	Uncommon	Alanine aminotransferase increased Blood creatinine increased Blood lactate dehydrogenase increased
Post Marketing Experience
Immune system disorders	Unknown	** Anaphylactic reaction Anaphylactoid reaction ** Hypersensitivity
Nervous system disorders	Unknown	Convulsion Dystonia
Respiratory, thoracic and mediastinal disorders	Unknown	Pulmonary oedema Bronchospasm **** Dyspnoea Wheezing ⁴
Hepato-biliary disorders	Unknown	Hepatitis Hepatic failure Hepatic necrosis
Skin and subcutaneous tissue disorders	Unknown	Pruritus ** Rash Urticaria ** Contact dermatitis sjcjcjcsj: Swelling face
Musculoskeletal and connective tissue disorders	Unknown	Muscle twitching
Renal and Urinary disorders	Unknown	Renal failure acute
General disorders and administration site conditions	Unknown	Hyperthermia malignant Chest discomfort

Summary of Post-Marketing Adverse Drug Reactions

System Organ Class	Adverse Reactions
Immune system disorders	** Anaphylactic reaction Anaphylactoid reaction ** Hypersensitivity
Nervous system disorders	Convulsion Dystonia
Respiratory, thoracic and mediastinal disorders	Pulmonary oedema Bronchospasm ** Dyspnoea Wheezing **
Hepato-biliary disorders	Hepatitis Hepatic failure Hepatic necrosis
Skin and subcutaneous tissue disorders	Pruritus ** Rash Urticaria ** Contact dermatitis sjcjcsjcj: Swelling face
Musculoskeletal and connective tissue disorders	Muscle twitching
Renal and Urinary disorders	Renal failure acute
General disorders and administration site conditions	Hyperthermia malignant Chest discomfort

May be associated with hypersensitivity reactions, particularly in association with long term occupational exposure to inhaled anaesthetics, including Sevoflurane.

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 Yellow Card Scheme at:

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms of overdose include respiratory depression and circulatory insufficiency. 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Halogenated hydrocarbons ATC code: N01AB08

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

Cardiovascular Effects

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

Nervous System Effects

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

5.2 Pharmacokinetic properties

The low solubility of sevoflurane 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 sevoflurane is metabolised. The rapid and extensive pulmonary elimination of sevoflurane minimises the amount of anaesthetic available for metabolism. sevoflurane 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 sevoflurane 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 sevoflurane anaesthesia. Generally, concentrations of inorganic fluoride peak within 2 hours of the end of sevoflurane anaesthesia and return within 48 hours to preoperative levels.

5.3 Preclinical safety data

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

Sevoflurane 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 sevoflurane does not have a significant effect on cerebral blood flow.

In animals, sevoflurane significantly suppresses electroencephalographic (EEG) activity comparable to equipotent doses of isoflurane. There is no evidence that sevoflurane 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None.

6.2 Incompatibilities

Sevoflurane is stable when stored under normal room lighting conditions. No discernible degradation of sevoflurane occurs in the presence of strong acids or heat. sevoflurane is not corrosive to stainless steel, brass, alumimum, 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 sevoflurane is minimal and degradants are undetectable or non-toxic. Sevoflurane degradation and subsequent degradant formation are enhanced by increasing absorbent temperature, desiccated CO2 absorbent (especially potassium hydroxide-containing, e.g. Baralyme®), increased sevoflurane concentration and decreased fresh gas flow. Sevoflurane 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 sevoflurane occurs only in the presence of desiccated CO2 absorbents and leads to the dissociation of sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic, rapidly glucoronidated, cleared and has toxicity comparable to sevoflurane. 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.

6.3 Shelf-Life

5 years.

Once opened, the contents of the bottle should be used within 8 weeks.

6.4 Special precautions for storage

Do not store above 25°C. Do not refrigerate. Keep bottle cap tightly closed due to the volatile nature of the anaesthetic. Store the bottle in an upright position

6.5 Nature and contents of container

Type III, 250 ml amber coloured glass bottles with two component screw cap made

up of outer black phenolic cover and inner translucent low density polyethylene cone. The pack is provided with an LDPE yellow-coloured collar.

6.6 Special precautions for disposal

Sevoflurane should be administered via a vaporiser calibrated specifically for sevoflurane using a key filling system designed for sevoflurane specific vaporisers or other appropriate sevoflurane 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 rebreathing 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 sevoflurane 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.

Only bottles without a pungent odour should be used.

In the event that a partially used bottle remains at the end of the procedure, the contents may be used for a period of up to 8 weeks.

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

7 MARKETING AUTHORISATION HOLDER

Piramal Healthcare UK Limited Whalton Road,

Morpeth,

Northumberland NE61 3YA, United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 29595/0002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/02/2015

10 DATE OF REVISION OF THE TEXT

13/02/2015

Frequency is Very Common in paediatric population.

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

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

sjcjcjcj:

May be associated with hypersensitivity reactions, particularly in association with long term occupational exposure to inhaled anaesthetics, including Sevoflurane.