Data Sheet



SEVORANEâ„?

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 (FI and FA) were measured. The FA/FI

(washin) value at 30 minutes for sevoflurane was 0.85. The FA/FAO (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 50microM; 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).

      MAC Values for Adults and Paediatric Patients According to Age

      Age of Patient (Years)Sevoflurane in OxygenSevoflurane in 65% N20/35% 02

      0 - 1 months*3.3%

      1 - <6 months3.0%

      6 months - <3 years2.8%2.0% @

      3 - 122.5%

      252.6%1.4%

      402.1%1.1%

      601.7%0.9%

      801.4%

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

      been determined.

      @ In 3 - <5 1 - <3 [1] year old paediatric patients, 60% N20/40% 02 was

      used.



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.

Sevoflurane through direct contact with CO2 absorbents produces low levels of

pentafluoroisopropenylfluoromethyl ether (PIFE), a haloalkene derivative,

commonly called Compound A and trace amounts of pentafluoromethoxyisopropyl

fluoromethyl ether (PMFE), commonly called Compound B.



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.

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, but with an uncertain

relationship to sevoflurane.

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 cases of

malignant hyperthermia have been reported (see WARNINGS AND PRECAUTIONS)



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:

Boiling Point at 760 mm Hg            58.6°C

Specific Gravity at 20°C                  1.520-1.525

Vapor pressure in mm Hg**            157 mm Hg at 20°C

          197 mm Hg at 25°C

          317 mm Hg at 36°C

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

Log10Pvap=A+B/T

Where:          A= 8.086

    B= -1726.68

                     T=°C + 273.16oK (Kelvin)

Distribution Partition Coefficients at 37°C:

  Blood/Gas                0.63-0.69

  Water/Gas              0.36

  Olive Oil/Gas           47.2-53.9

  Brain/Gas               1.15

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

medical applications:

  Conductive rubber 14.0

  Butyl rubber             7.7

  Polyvinyl chloride     17.4

  Polyethylene           1.3

Sevoflurane is nonflammable and non-explosive as defined by the requirements of

International Electrotechnical Commission 601-2-13.

Sevoflurane is stable when stored under normal room lighting conditions. No

discernible degradation occurs in the presence of strong acids or heat. The only

known degradation in the clinical setting is through direct contact with CO2

absorbants (soda lime and Baralyme®), producing pentafluoroisopropenyl

fluoromethyl ether (PIFE, C4H2F6O), a haloalkene derivative, also known as

Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether

(PMFE) C5H6F6O), also known as Compound B, Sevoflurane is not corrosive to

stainless steel, brass, aluminum, nickel plated brass, chrome plated brass, or

copper beryllium alloy.

Name and Address

Abbott Laboratories (NZ) Ltd

227 Cambridge Terrace

Naenae, Lower Hutt

(04) 5670 039

Date of Preparation

March 2001