Data Sheet

SEVORANE™

Sevoflurane

Presentation

Sevoflurane is a nonflammable and non-explosive liquid administered by vaporization. It is a clear, colorless, nonpungent liquid. At least 300ppm of water is present to provide protection from environmental Lewis acids. No other additives or chemical stabilizers are utilized. It is miscible with ethanol, ether, chloroform and petroleum benzene and is slightly soluble in water.

Uses

Actions

Sevoflurane has been demonstrated to be a fast-acting, non-irritating anaesthetic agent in a variety of animal species and in humans. Administration has been associated with a smooth, rapid loss of consciousness during inhalation induction and a rapid recovery following discontinuation of anaesthesia.

Induction is accomplished, with a minimum of excitement or of signs of upper respiratory irritation, no evidence of excessive secretions within the tracheobronchial tree and no central nervous system stimulation. In paediatric studies in which mask induction was performed, the incidence of coughing was statistically significantly lower with sevoflurane than with halothane.

The times for induction and recovery were also reduced in these patients.

Like other potent inhalational anaesthetics, sevoflurane depresses respiratory function and blood pressure in a dose-related manner. Sevoflurane has been demonstrated to be an appropriate agent for use in neurosurgery, caesarean section, coronary artery bypass surgery and in non-cardiac patients at risk for myocardial ischaemia.

The adrenaline-induced arrhythmogenic threshold for sevoflurane is comparable to that of isoflurane and higher than that of halothane. Studies in dogs have demonstrated that sevoflurane does not reduce collateral myocardial perfusion. In clinical studies, the incidence of myocardial ischaemia and myocardial infarction in patients at risk for myocardial ischaemia was comparable between sevoflurane and isoflurane.

Animal studies have shown that regional blood flow (e.g., hepatic, renal, cerebral circulations) is well-maintained with sevoflurane. In both animal studies (dogs, rabbits) and clinical studies, changes in neurohemodynamics (intracranial pressure, cerebral blood flow/blood flow velocity, cerebral metabolic rate for oxygen, and cerebral perfusion pressure) were comparable between sevoflurane and isoflurane. Sevoflurane has minimal effect on intra-cranial pressure and preserves CO₂ responsiveness.

Sevoflurane does not affect renal concentrating ability, even after prolonged anaesthetic exposure of up to approximately 9 hours.

For MAC equivalents for sevoflurane for various age groups, see DOSAGE and ADMINISTRATION section. As with other halogenated agents, minimum alveolar concentration (MAC) decreases with age and with the addition of nitrous oxide.

Pharmacokinetics

Solubility

The low solubility of sevoflurane in blood would suggest that alveolar concentrations should rapidly increase upon induction and rapidly decrease upon cessation of the inhaled agent. This was confirmed in a clinical study where inspired and end-tidal concentrations (F_I and F_A) were measured. The F_A/F_I (washin) value at 30 minutes for sevoflurane was 0.85. The F_A/F_AO (washout) value at 5 minutes was 0.15.

Distribution

The effects of sevoflurane on the displacement of medicines from serum and tissue proteins have not been investigated. Other fluorinated volatile anaesthetics have been shown to displace medicines 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 medicines that are highly bound and have a small volume of distribution (e.g. phenytoin).

Metabolism

The rapid pulmonary elimination of sevoflurane minimizes the amount of anaesthetic available for metabolism. In humans <5% of sevoflurane absorbed is metabolized to hexafluoroisopropanol (HFIP), with release of inorganic fluoride and carbon dioxide (or a one carbon fragment). Once formed HFIP is rapidly conjugated with glucuronic acid and eliminated. No other metabolic pathways for sevoflurane have been identified. It is the only fluorinated volatile anaesthetic that is not metabolized to trifluoroacetic acid.

Fluoride Ion

Fluoride ion concentrations are influenced by the duration of anaesthesia, the concentration of sevoflurane administered, and the composition of the anaesthetic gas mixture.

Inorganic fluoride concentrations peak within two hours of the end of sevoflurane anaesthesia and return to baseline concentrations within 48 hours post anaesthesia. Approximately 7% of adults evaluated for inorganic fluoride concentrations in Abbott clinical studies experienced concentrations greater than 50 M; no clinically significant effect on renal function was observed in any of these individuals.

The defluorination of sevoflurane is not inducible by barbiturates.

Indications

Sevoflurane may be used for induction and maintenance of general anaesthesia in adult and paediatric patients for inpatient and outpatient surgery.

Dosage and Administration

The concentration of sevoflurane being delivered from a vaporizer during anaesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane.

Premedication

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

Induction

Dosage should be individualized 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 Sevoflurane. Induction with sevoflurane may be achieved in oxygen or in combination with oxygen-nitrous oxide mixtures. For induction of anaesthesia, inspired concentrations of up to 8% sevoflurane usually produces surgical anaesthesia in less than two minutes in both adults and children.

Maintenance

Surgical levels of anaesthesia may be sustained with concentrations of 0.5 - 3% sevoflurane with or without the concomitant use of nitrous oxide (see table).

Elderly: As with other inhalation agents, lesser concentrations of sevoflurane are normally required to maintain anaesthesia.

Emergence

Emergence times are generally short following sevoflurane anaesthesia. Therefore, patients may require post-operative pain relief earlier.

Hepatic impairment

Sevoflurane is effective and well-tolerated when used as the primary agent for the maintenance of anaesthesia in patients with impaired hepatic function, Child-Pugh Class A and B. Sevoflurane did not exacerbate pre-existing hepatic impairment.

Renal impairment

See under Warnings and Precautions.

Contraindications

Sevoflurane should not be used in patients with known sensitivity to sevoflurane or to other halogenated agents or with known or suspected genetic susceptibility to malignant hyperthermia.

Warnings and Precautions

Sevoflurane 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 vaporizers specifically calibrated for sevoflurane should be used. Hypotension and respiratory depression increase as anaesthesia is deepened.

During 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 anesthetics, 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-anesthesia care unit.

Replacement of Desiccated CO₂ Absorbents:

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.

An exothermic reaction, enhanced sevoflurane degradation, and production of degradation products (See Further Information) can occur when the CO₂ absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO₂ absorbent canisters. Sevoflurane 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 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.

When a clinician suspects that the CO₂ absorbent may be desiccated, it should be replaced before administration of sevoflurane. The colour indicator of most CO₂ absorbents does not necessarily change as a result of desiccation. 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.

Compound A

The LC₅₀ of compound A in Wistar rats was 1050-1090ppm in animals exposed for 1 hour and 400-420ppm in animals exposed for 3 hours (median lethal concentrations were approximately 1070 and 330-490ppm, respectively). In rats exposed to 30, 60, or 120ppm of Compound A in a 8-week chronic toxicity study (24 exposures, 3 hours/exposure), no apparent evidence of toxicity was observed other than loss of body weight in females on the last study day.

Sprague-Dawley rats were administered Compound A via nose-only inhalation exposure in an open system (25, 50, 100 or 200ppm [0.0025-0.02%] of Compound A). Control groups were exposed to air. The threshold, at which reversible alterations in urinary and clinical parameters indicative of renal changes (concentration-dependent increases in BUN, creatinine, glucose, protein/creatinine ratios and N-acetyl-glucosamidase/creatinine ratios) were observed, was 114ppm of Compound A. Histological lesions were all reversible.

Since the uptake of inhalational agents in small rodents is substantially higher than in humans, higher levels of medicine, Compound A (degradant of sevoflurane) or 2-bromo-2-chloro-1, 1-difluoro ethylene (BCDFE) (degradant/metabolite of halothane) would be expected in rodents. Also, the activity of the key enzyme (β -lyase) involved in haloalkene nephrotoxicity is ten-fold greater in the rat than it is in humans.

Compound A concentrations are reported to increase with increasing absorber temperature, increasing sevoflurane concentrations and with decreasing fresh gas flow rates. It has been reported that the concentration of Compound A increases significantly with prolonged dehydration of Baralyme. In the clinical situation, the highest concentration of Compound A in the anaesthesia circuit with soda lime as the CO₂ absorbent was 15 ppm in paediatrics and 32 ppm in adults. However, concentrations to 61 ppm have been observed in patients attached to systems with Baralyme® as the CO₂ absorbent. The level of Compound A at which toxicity occurs in humans is not known. Although exposure to sevoflurane in low flow systems is limited, there has been no evidence of renal dysfunction attributable to Compound A.

Compound B

In the clinical situation, the concentration of Compound B detected in the anaesthesia circuit did not exceed 1.5 ppm. Inhalation exposure to Compound B at concentrations of up to 2400 ppm (0.24%) for 3 hours resulted in no adverse effects on renal parameters or tissue histology in Wistar rats.

Malignant Hyperthermia

In susceptible individuals, potent inhalation anaesthetic agents, including sevoflurane, may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In clinical trials, one case of malignant hyperthermia was reported. In genetically susceptible pigs, sevoflurane induced malignant hyperthermia. The clinical syndrome is signaled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these non-specific signs may also appear during light anaesthesia, acute hypoxia, hypercapnia and hypovolemia.

Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for intravenous dantrolene sodium for additional information on patient management). Renal failure may appear later, and urine flow should be monitored and sustained if possible.

Hyperkalaemic Cardiac Arrest in Paediatric Patients

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.

Carcinogenicity /Mutagenicity

Studies on carcinogenesis have not been performed. No mutagenic effect was noted in the Ames test and no chromosomal aberrations were induced in cultured mammalian cells.

Use in Pregnancy

Reproduction studies in rats and rabbits at doses up to 1 MAC have revealed no evidence of impaired fertility or harm to the foetus due to sevoflurane. 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.

The safety of sevoflurane has been demonstrated in a clinical trial of anaesthesia for caesarean section. The safety of sevoflurane in labor and vaginal delivery has not been demonstrated.

Use in Lactation

It is not known whether sevoflurane is excreted in human milk. Because many medicines are excreted in human milk, caution should be exercised when sevoflurane is administered to a nursing woman.

Elderly

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.

Renal Impairment

Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 1.5 mg/dL) 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.

Neurosurgery

In patients at risk for elevations of intracranial pressure (ICP), sevoflurane should be administered cautiously in conjunction with ICP-reducing maneuvers such as hyperventilation.

Adverse Effects

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

Nausea and vomiting 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 event data are derived from controlled clinical trials. The most frequent adverse events (≥ 10%) considered to be probably related to sevoflurane administration overall were: nausea, vomiting, increased cough and hypotension. In adult patients the most frequent adverse events (≥ 10%) were: nausea, vomiting and hypotension. In elderly patients the most frequent adverse events (≥ 10%) were: hypotension, nausea and bradycardia. In pediatric patients, the most frequent adverse events (≥ 10%) were: vomiting, agitation, increased cough, and nausea. The type, severity and frequency of adverse events in sevoflurane patients were comparable to adverse events in reference medicine patients.

The most frequently reported adverse events (> 1%) considered to be probably related to administration of this agent include: nausea, vomiting, increased cough, hypotension, agitation, somnolence, chills, bradycardia, dizziness, increased salivation, respiratory disorder, hypertension, tachycardia, laryngismus, and fever.

Transient elevations in glucose and white blood cell count may occur as with use of other anaesthetic agents.

Transient increases in serum inorganic fluoride levels may occur during and after sevoflurane anaesthesia. These have not been associated with impairment of renal function in clinical trials (see Uses). Occasional cases of transient changes in hepatic function tests have been reported.

In clinical studies administration of sevoflurane has not been associated with any clinically significant effect on liver or kidney function in a wide variety of patient populations including children, adults, elderly, renally impaired, hepatically impaired, obese, patients undergoing cardiac bypass surgery, patients treated with aminoglycerides or metabolic inducers, patients exposed to repeat surgeries, patients undergoing surgeries 6 hours in duration.

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 sevoflurane.  However, the actual incidence and relationship of sevoflurane to these events cannot be established with certainty.

As with other anaesthetic agents cases of dystonic movement with spontaneous resolution have been reported in children receiving sevoflurane for the induction of anaesthesia, with an uncertain relationship to sevoflurane seizure-like activity may occur on extremely rare occasions following sevoflurane administration. Reported events were of short duration and there was no evidence of any abnormality during emergence from anaesthesia or in the postoperative period rare events of malignant hyperthermia (See Contraindications and Warnings and Precautions) and allergic reactions, such as rash, urticaria, pruritus, bronchospasm, anaphylactic or anaphylactoid reactions have been reported (See Contraindications).

Interactions

Sevoflurane has been shown to be safe and effective when administered concurrently with a wide variety of agents commonly encountered in surgical situations such as central nervous system agents, autonomic medicines, smooth muscle relaxants, anti-infective agents including aminoglycosides, hormones and synthetic substitutes, blood derivatives and cardiovascular medicines including epinephrine. Sevoflurane administration is compatible with barbiturates as commonly used in surgical practice.

Benzodiazepines and Opioids

Benzodiazepines and opioids are expected to decrease the MAC of sevoflurane in the same manner as with other inhalational anesthetics. Sevoflurane administration is compatible with benzodiazepines and opioids as commonly used in surgical practice.

Nitrous Oxide

As with other halogenated volatile anesthetics, the MAC of sevoflurane is decreased when administered in combination with nitrous oxide. The MAC equivalent is reduced approximately 50% in adult and approximately 25% in pediatric patients.

Neuromuscular Blocking Agents

As with other inhalational anaesthetic agents, sevoflurane affects both the intensity and duration of neuromuscular blockade by non-depolarizing muscle relaxants. When used to supplement alfentanil-N₂O anaesthesia, sevoflurane potentiates neuromuscular block induced with pancuronium, vecuronium or atracurium. The dosage adjustments for these muscle relaxants when administered with sevoflurane are similar to those required with isoflurane. The effect of sevoflurane on suxamethonium chloride and the duration of depolarizing 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 sevoflurane administration.

Among non-depolarizing 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-depolarizing muscle relaxants, (2) during maintenance of anaesthesia, the dose of non-depolarizing 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.

Overdosage

In the event of 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.

Pharmaceutical Precautions

Sevoflurane should be stored at room temperature (Below 30°C). Sevoflurane has been demonstrated to be stable for the period defined by the expiration dating on the label.

Medicine Classification

Prescription Medicine

Package Quantities

Sevoflurane is packaged in 100 mL or 250 mL amber-coloured bottles.

Further Information

Sevoflurane is a fluorinated derivative of methyl isopropyl ether. The chemical name is fluoromethyl 2, 2, 2-trifluoro-1-(trifluoromethyl) ethyl ether and its structural formula is as follows:

Sevoflurane has the following physical and chemical properties:

**The equation for calculated vapor pressure in mm Hg:

Log₁₀P_vap=A+B/T

Distribution Partition Coefficients at 37°C:

Mean Component/Gas Partition Coefficients at 25°C for polymers commonly used in medical applications:

Sevoflurane is nonflammable and non-explosive as defined by the requirements of International Electrotechnical Commission 601-2-13.

Sevoflurane Degradation

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, aluminium, 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 formation of formaldehyde, methanol, carbon monoxide, Compound A and perhaps some of it's degradants, Compounds B, C and D may occur.

Name and Address

Abbott Laboratories (NZ) Ltd
4 Pacific Rise
Mt Wellington
Auckland

Date of Preparation

5 May 2006

Version 01