sevoflurane
Generic Name: (
Sevoflurane)
Dosage Type: liquid
DESCRIPTION
Sevoflurane,
volatile liquid for inhalation, a nonflammable and nonexplosive liquid
administered by vaporization, is a halogenated general inhalation
anesthetic drug. Sevoflurane is fluoromethyl 2,2,2,-trifluoro-1-(trifluoromethyl) ethyl ether and its structural
formula is:
| Sevoflurane, Physical Constants
are: |
| Molecular weight |
200.05 |
| 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 |
|
|
|
| Distribution Partition
Coefficients at 37°C: |
| Blood/Gas |
0.63 - 0.69 |
| Water/Gas |
0.36 |
| Olive Oil/Gas |
47 - 54 |
| Brain/Gas |
1.15 |
|
|
|
| Mean Component/Gas Partition
Coefficients at 25°C for Polymers Used Commonly in
Medical Applications: |
| Conductive rubber |
14.0 |
| Butyl rubber |
7.7 |
| Polyvinylchloride |
17.4 |
| Polyethylene |
1.3 |
Sevoflurane is
nonflammable and nonexplosive as defined by the requirements of
International Electrotechnical Commission 601-2-13.
Sevoflurane is a
clear, colorless, liquid containing no additives. Sevoflurane is not
corrosive to stainless steel, brass, aluminum, nickel-plated brass,
chrome-plated brass or copper beryllium. Sevoflurane is nonpungent. It
is miscible with ethanol, ether, chloroform, and benzene, and it is
slightly soluble in water. Sevoflurane is stable when stored under
normal room lighting conditions according to instructions. No
discernible degradation of sevoflurane occurs in the presence of strong
acids or heat. When in contact with alkaline CO2 absorbents
(e.g. Baralyme® and to a lesser extent soda lime) within the
anesthesia machine, Sevoflurane can undergo degradation under certain
conditions. Degradation of sevoflurane is minimal, and degradants are
either undetectable or present in non-toxic amounts when used as
directed with fresh absorbents. Sevoflurane degradation and subsequent
degradant formation are enhanced by increasing absorbent temperature
increased sevoflurane concentration, decreased fresh gas flow and
desiccated CO2 absorbents (especially with potassium
hydroxide containing absorbents e.g. Baralyme).
Sevoflurane
alkaline degradation occurs by two pathways. The first results from the
loss of hydrogen fluoride with the formation of pentafluoroisopropenyl
fluoromethyl ether, (PIFE, C4H2F6O),
also known as Compound A, and trace amounts of pentafluoromethoxy
isopropyl fluoromethyl ether, (PMFE,
C5H6F6O), also known as Compound B. Thesecond pathway for degradation of sevoflurane, which occurs primarily in
the presence of desiccated CO2 absorbents, is discussed
later.
In the first
pathway, the defluorination pathway, the production of degradants in the
anesthesia circuit results from the extraction of the acidic proton in
the presence of a strong base (KOH and/or NaOH) forming an alkene
(Compound A) from sevoflurane similar to formation of
2-bromo-2-chloro-1,1-difluoro ethylene (BCDFE) from halothane.
Laboratory simulations have shown that the concentration of these
degradants is inversely correlated with the fresh gas flow rate (See
Figure 1).
Since the reaction
of carbon dioxide with absorbents is exothermic, the temperature
increase will be determined by quantities of CO2 absorbed,
which in turn will depend on fresh gas flow in the anesthesia circle
system, metabolic status of the patient, and ventilation. The
relationship of temperature produced by varying levels of CO2
and Compound A production is illustrated in the following in vitro simulation where CO2 was added to a circle absorber system.
Compound A
concentration in a circle absorber system increases as a function of
increasing CO2 absorbent temperature and composition
(Baralyme producing higher levels than soda lime), increased body
temperature, and increased minute ventilation, and decreasing fresh gas
flow rates. It has been reported that the concentration of Compound A
increases significantly with prolonged dehydration of Baralyme. Compound
A exposure in patients also has been shown to rise with increased
sevoflurane concentrations and duration of anesthesia. In a clinical
study in which sevoflurane was administered to patients under low flow
conditions for =2 hours at flow rates of 1 Liter/minute, Compound A
levels were measured in an effort to determine the relationship between
MAC hours and Compound A levels produced. The relationship between
Compound A levels and sevoflurane exposure are shown in Figure 2a.
Compound A has been
shown to be nephrotoxic in rats after exposures that have varied in
duration from one to three hours. No histopathologic change was seen at
a concentration of up to 270 ppm for one hour. Sporadic single cell
necrosis of proximal tubule cells has been reported at a concentration
of 114 ppm after a 3-hour exposure to Compound A in rats. The
LC50 reported at 1 hour is 1050-1090 ppm (male-female) and,
at 3 hours, 350-490 ppm (male-female).
An experiment was
performed comparing sevoflurane plus 75 or 100 ppm Compound A with an
active control to evaluate the potential nephrotoxicity of Compound A in
non-human primates. A single 8-hour exposure of Sevoflurane in the
presence of Compound A produced single-cell renal tubular degeneration
and single-cell necrosis in cynomolgus monkeys. These changes are
consistent with the increased urinary protein, glucose level and enzymic
activity noted on days one and three on the clinical pathology
evaluation. This nephrotoxicity produced by Compound A is dose and
duration of exposure dependent.
At a fresh gas flow
rate of 1 L/min, mean maximum concentrations of Compound A in the
anesthesia circuit in clinical settings are approximately 20 ppm
(0.002%) with soda lime and 30 ppm (0.003%) with Baralyme in adult
patients; mean maximum concentrations in pediatric patients with soda
lime are about half those found in adults. The highest concentration
observed in a single patient with Baralyme was 61 ppm (0.0061%) and 32
ppm (0.0032%) with soda lime. The levels of Compound A at which toxicityoccurs in humans is not known.
The second pathway
for degradation of sevoflurane occurs primarily 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 glucuronidated and cleared by the
liver. 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 that
can be associated with desiccated Baralyme®. 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.
Sevoflurane
degradants were observed in the respiratory circuit of an experimental
anesthesia machine using desiccated CO2 absorbents and
maximum sevoflurane concentrations (8%) for extended periods of time
(>2 hours).
Concentrations of formaldehyde observed with desiccated soda lime in
this experimental anesthesia respiratory circuit were consistent with
levels that could potentially result in mild respiratory irritation.
Although KOH containing CO2 absorbents are no longer
commercially available, in the laboratory experiments, exposure of
sevoflurane to the desiccated KOH containing CO2 absorbent,
Baralyme, resulted in the detection of substantially greater degradant
levels.
CLINICAL PHARMACOLOGY
Sevoflurane is an
inhalational anesthetic agent for use in induction and maintenance of
general anesthesia. Minimum alveolar concentration (MAC) of sevoflurane
in oxygen for a 40-year-old adult is 2.1%. The MAC of sevoflurane
decreases with age (see DOSAGE AND
ADMINISTRATION for details).
Pharmacokinetics
UPTAKE AND
DISTRIBUTION
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 (Fa0) 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.
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).
Metabolism
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.
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
Elimination
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).
PHARMACOKINETICS OF FLUORIDE ION
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.
Fluoride Concentrations After Repeat Exposure and
in Special Populations
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 SpecialPopulations Following Administration of
Sevoflurane
|
|
n |
Age
(yr) |
Duration
(hr) |
Dose
(MAC•hr) |
Cmax
(µM) |
| PEDIATRIC
PATIENTS |
|
|
|
|
|
| Anesthetic |
|
|
|
|
|
| Sevoflurane-O2 |
76 |
0 - 11 |
0.8 |
1.1 |
12.6 |
| Sevoflurane-O2 |
40 |
1 - 11 |
2.2 |
3.0 |
16.0 |
| Sevoflurane/N2O |
25 |
5 - 13 |
1.9 |
2.4 |
21.3 |
| Sevoflurane/N2O |
42 |
0 - 18 |
2.4 |
2.2 |
18.4 |
| Sevoflurane/N2O |
40 |
1 - 11 |
2.0 |
2.6 |
15.5 |
| ELDERLY |
33 |
65 - 93 |
2.6 |
1.4 |
25.6 |
| RENAL |
21 |
29 - 83 |
2.5 |
1.0 |
26.1 |
| HEPATIC |
8 |
42 - 79 |
3.6 |
2.2 |
30.6 |
| OBESE |
35 |
24 - 73 |
3.0 |
1.7 |
38.0 |
n
= number of patients studied.
Pharmacodynamics
Changes in
the depth of sevoflurane anesthesia rapidly follow changes in
the inspired concentration.
In the
sevoflurane clinical program, the following recovery variables
were evaluated:
- Time to events measured from the end of study drug:
- Time to removal of the endotracheal tube
(extubation time)
- Time required for the patient to open his/her eyes
on verbal command (emergence time)
- Time to respond to simple command (e.g., squeeze
my hand) or demonstrates purposeful movement
(response to command time, orientation time)
- Recovery of cognitive function and motor coordination was
evaluated based on:
- psychomotor performance tests (Digit Symbol
Substitution Test [DSST], Treiger Dot Test)
- the results of subjective (Visual Analog Scale
[VAS]) and objective (objective pain-discomfort
scale [OPDS]) measurements
- time to administration of the first
post-anesthesia analgesic medication
- assessments of post-anesthesia patient
status
- Other recovery times were:
- time to achieve an Aldrete Score of greater than
or equal to 8
- time required for the patient to be eligible for
discharge from the recovery area, per standard
criteria at site
- time when the patient was eligible for discharge
from the hospital
- time when the patient was able to sit up or stand
without dizziness
Some of
these variables are summarized as follows:
Table 2:
Induction and Recovery Variables for Evaluable Pediatric
Patients in Two Comparative Studies: Sevoflurane versus
Halothane
| Time to End-Point
(min) |
Sevoflurane Mean ±
SEM |
Halothane Mean ±
SEM |
| Induction |
2.0 ± 0.2 (n=294) |
2.7 ± 0.2 (n=252) |
| Emergence |
11.3 ± 0.7 (n=293) |
15.8 ± 0.8 (n=252) |
| Response to command |
13.7 ± 1.0 (n=271) |
19.3 ± 1.1 (n=230) |
| First analgesia |
52.2 ± 8.5 (n=216) |
67.6 ± 10.6 (n=150) |
| Eligible for recovery
discharge |
76.5 ± 2.0 (n=292) |
81.1 ± 1.9 (n=246) |
n = number
of patients with recording of events.
Table 3:
Recovery Variables for Evaluable Adult Patients in Two
Comparative Studies: Sevoflurane versus Isoflurane
| Time to Parameter:
(min) |
Sevoflurane Mean ±
SEM |
Isoflurane Mean ±
SEM |
| Emergence |
7.7 ± 0.3 (n=395) |
9.1 ± 0.3 (n=348) |
| Response to command |
8.1 ± 0.3 (n=395) |
9.7 ± 0.3 (n=345) |
| First analgesia |
42.7 ± 3.0 (n=269) |
52.9 ± 4.2 (n=228) |
| Eligible for recovery
discharge |
87.6 ± 5.3 (n=244) |
79.1 ± 5.2 (n=252) |
n = number
of patients with recording of recovery events.
Table 4:
Meta-Analyses for Induction and Emergence Variables for
Evaluable Adult Patients in Comparative Studies: Sevoflurane
versus Propofol
| Parameter |
No. of Studies |
Sevoflurane Mean ±
SEM |
Propofol Mean ±
SEM |
| Mean maintenance
anesthesia exposure |
3 |
1.0 MAC•hr ± 0.8 (n=259) |
7.2 mg/kg/hr ± 2.6
(n=258) |
| Time to induction: (min) |
1 |
3.1 ± 0.18* (n=93) |
2.2 ± 0.18** (n=93) |
| Time to emergence: (min) |
3 |
8.6 ± 0.57 (n=255) |
11.0 ± 0.57 (n=260) |
| Time to respond to
command: (min) |
3 |
9.9 ± 0.60 (n=257) |
12.1 ± 0.60 (n=260) |
| Time to first analgesia:
(min) |
3 |
43.8 ± 3.79 (n=177) |
57.9 ± 3.68 (n=179) |
| Time to eligibility for
recovery discharge: (min) |
3 |
116.0 ± 4.15 (n=257) |
115.6 ± 3.98
(n=261) |
*Propofol induction of one sevoflurane group = mean of 178.8 mg ± 72.5 SD
(n=165)
**Propofol
induction of all propofol groups = mean of 170.2 mg ± 60.6 SD
(n=245)
n = number
of patients with recording of events.
CARDIOVASCULAR EFFECTS
Sevoflurane was studied in 14 healthy volunteers (18-35
years old) comparing sevoflurane-O2
(Sevo/O2) to
sevoflurane-N2O/O2
(Sevo/N2O/O2) during 7 hours
of anesthesia. During controlled ventilation,
hemodynamic parameters measured are shown in Figures
7-10:
Sevoflurane is a dose-related cardiac depressant.
Sevoflurane does not produce increases in heart rate at
doses less than 2 MAC.
A
study investigating the epinephrine induced
arrhythmogenic effect of sevoflurane versus isoflurane
in adult patients undergoing transsphenoidal
hypophysectomy demonstrated that the threshold dose of
epinephrine (i.e., the dose at which the first sign of
arrhythmia was observed) producing multiple ventricular
arrhythmias was 5 mcg/kg with both sevoflurane and
isoflurane. Consequently, the interaction of sevoflurane
with epinephrine appears to be equal to that seen with
isoflurane.
Clinical Trials
Sevoflurane
was administered to a total of 3185 patients prior to
sevoflurane NDA submission. The types of patients are summarized
as follows:
Table 5:
Patients Receiving Sevoflurane in Clinical Trials
| Type of Patients |
Number Studied |
| ADULT |
2223 |
| Cesarean Delivery |
29 |
|
| Cardiovascular and
patients at risk of myocardial ischemia |
246 |
|
| Neurosurgical |
22 |
|
| Hepatic impairment |
8 |
|
| Renal impairment |
35 |
|
| PEDIATRIC |
962 |
Clinical
experience with these patients is described below.
ADULT
ANESTHESIA
The
efficacy of sevoflurane in comparison to isoflurane,
enflurane, and propofol was investigated in 3 outpatient
and 25 inpatient studies involving 3591 adult patients.
Sevoflurane was found to be comparable to isoflurane,
enflurane, and propofol for the maintenance of anesthesia in adult patients. Patients administered sevoflurane showed shorter times (statistically
significant) to some recovery events (extubation,
response to command, and orientation) than patients who
received isoflurane or propofol.
Mask Induction
Sevoflurane has a nonpungent odor and does not
cause respiratory irritability. Sevoflurane is
suitable for mask induction in adults. In 196
patients, mask induction was smooth and rapid,
with complications occurring with the following
frequencies: cough, 6%; breathholding, 6%;
agitation, 6%; laryngospasm, 5%.
Ambulatory Surgery
Sevoflurane was compared to isoflurane and
propofol for maintenance of anesthesia supplemented with N2O in two studies
involving 786 adult (18-84 years of age) ASA
Class I, II, or III patients. Shorter times to
emergence and response to commands
(statistically significant) were observed with
sevoflurane compared to isoflurane and propofol.
Table 6: Recovery Parameters in Two
Outpatient Surgery Studies: Least Squares
Mean ± SEM
|
|
Sevoflurane/N2O |
Isoflurane/N2O |
Sevoflurane/N2O |
Propofol/N2O |
| Mean
Maintenance Anesthesia Exposure ± SD |
0.64 ± 0.03 MAC•hr (n=245) |
0.66 ±
0.03 MAC•hr (n=249) |
0.8 ± 0.5
MAC•hr (n=166) |
7.3 ± 2.3
mg/kg/hr (n=166) |
| Time to
Emergence (min) |
8.2 ± 0.4
(n=246) |
9.3 ± 0.3
(n=251) |
8.3 ± 0.7
(n=137) |
10.4 ± 0.7
(n=142) |
| Time to
Respond to Commands (min) |
8.5 ± 0.4
(n=246) |
9.8 ± 0.4 (n=248) |
9.1 ± 0.7
(n=139) |
11.5 ± 0.7
(n=143) |
| Time to
First Analgesia (min) |
45.9 ± 4.7
(n=160) |
59.1 ± 6.0
(n=252) |
46.1 ± 5.4
(n=83) |
60.0 ± 4.7
(n=88) |
| Time to
Eligibility for Discharge from
Recovery Area (min) |
87.6 ± 5.3
(n=244) |
79.1 ± 5.2
(n=252) |
103.1 ± 3.8 (n=139) |
105.1 ±
3.7 (n=143) |
n
= number of patients with recording of recovery
events.
Inpatient Surgery
Sevoflurane was compared to isoflurane and
propofol for maintenance of anesthesia
supplemented with N2O in two
multicenter studies involving 741 adult ASA
Class I, II or III (18-92 years of age)
patients. Shorter times to emergence, command
response, and first post-anesthesia analgesia
(statistically significant) were observed with
sevoflurane compared to isoflurane and propofol.
Table 7: Recovery Parameters in Two
Inpatient Surgery Studies: Least Squares
Mean ± SEM
|
|
Sevoflurane/N2O |
Isoflurane/N2O |
Sevoflurane/N2O |
Propofol/N2O |
| Mean
Maintenance Anesthesia Exposure ± SD |
1.27
MAC•hr ± 0.05 (n=271) |
1.58
MAC•hr ± 0.06 (n=282) |
1.43
MAC•hr ± 0.94 (n=93) |
7.0
mg/kg/hr ± 2.9 (n=92) |
| Time to
Emergence (min) |
11.0 ± 0.6 (n=270) |
16.4 ± 0.6
(n=281) |
8.8 ± 1.2
(n=92) |
13.2 ± 1.2
(n=92) |
| Time to
Respond to Commands (min) |
12.8 ± 0.7
(n=270) |
18.4 ± 0.7
(n=281) |
11.0 ±
1.20 (n=92) |
14.4 ±
1.21 (n=91) |
| Time to
First Analgesia (min) |
46.1 ± 3.0
(n=233) |
55.4 ± 3.2
(n=242) |
37.8 ± 3.3
(n=82) |
49.2 ± 3.3
(n=79) |
| Time to
Eligibility for Discharge from
Recovery Area (min) |
139.2 ±
15.6 (n=268) |
165.9 ±
16.3 (n=282) |
148.4 ±
8.9 (n=92) |
141.4 ±
8.9 (n=92) |
n
= number of patients with recording of recovery
events.
PEDIATRIC
ANESTHESIA
The
concentration of sevoflurane required for maintenance of
general anesthesia is age-dependent (see DOSAGE AND ADMINISTRATION). Sevoflurane
or halothane was used to anesthetize 1620 pediatric
patients aged 1 day to 18 years, and ASA physical status
I or II (948 sevoflurane, 672 halothane). In one study
involving 90 infants and children, there were no
clinically significant decreases in heart rate compared
to awake values at 1 MAC. Systolic blood pressure
decreased 15-20% in comparison to awake values following
administration of 1 MAC sevoflurane; however, clinically
significant hypotension requiring immediate intervention
did not occur. Overall incidences of bradycardia [more
than 20 beats/min lower than normal (80 beats/min)] in
comparative studies was 3% for sevoflurane and 7% for
halothane. Patients who received sevoflurane had
slightly faster emergence times (12 vs. 19 minutes), and
a higher incidence of post-anesthesia agitation (14% vs.
10%).
Sevoflurane (n=91) was compared to halothane (n=89) in
a single-center study for elective repair or palliation
of congenital heart disease. The patients ranged in age
from 9 days to 11.8 years with an ASA physical status of
II, III, and IV (18%, 68%, and 13% respectively). No
significant differences were demonstrated between
treatment groups with respect to the primary outcome
measures: cardiovascular decompensation and severe
arterial desaturation. Adverse event data was limited to
the study outcome variables collected during surgery and
before institution of cardiopulmonary
bypass.
Mask Induction
Sevoflurane has a nonpungent odor and is
suitable for mask induction in pediatric patients. In controlled pediatric studies in
which mask induction was performed, the
incidence of induction events is shown below
(see ADVERSE REACTIONS).
Table 8: Incidence of Pediatric Induction
Events
|
|
Sevoflurane (n=836) |
Halothane
(n=660) |
| Agitation |
14% |
11% |
| Cough |
6% |
10% |
| Breathholding |
5% |
6% |
| Secretions |
3% |
3% |
| Laryngospasm |
2% |
2% |
| Bronchospasm |
<1% |
0% |
n
= number of patients.
Ambulatory Surgery
Sevoflurane (n=518) was compared to halothane
(n=382) for the maintenance of anesthesia in
pediatric outpatients. All patients received
N2O and many received fentanyl,
midazolam, bupivacaine, or lidocaine. The time
to eligibility for discharge from
post-anesthesia care units was similar between
agents (see CLINICAL PHARMACOLOGY and ADVERSE REACTIONS).
CARDIOVASCULAR SURGERY
Coronary Artery Bypass Graft (CABG) Surgery
Sevoflurane was compared to isoflurane as an
adjunct with opioids in a multicenter study of
273 patients undergoing CABG surgery. Anesthesia
was induced with midazolam (0.1-0.3 mg/kg);
vecuronium (0.1-0.2 mg/kg), and fentanyl (5-15
mcg/kg). Both isoflurane and sevoflurane were
administered at loss of consciousness in doses
of 1.0 MAC and titrated until the beginning of
cardiopulmonary bypass to a maximum of 2.0 MAC.
The total dose of fentanyl did not exceed 25 mcg/kg. The average MAC dose was 0.49 for
sevoflurane and 0.53 for isoflurane. There were
no significant differences in hemodynamics,
cardioactive drug use, or ischemia incidence
between the two groups. Outcome was also
equivalent. In this small multicenter study,
sevoflurane appears to be as effective and as
safe as isoflurane for supplementation of opioid
anesthesia for coronary bypass
grafting.
Non-Cardiac Surgery Patients at Risk for Myocardial
Ischemia
Sevoflurane-N2O was compared to
isoflurane-N2O for maintenance of
anesthesia in a multicenter study in 214 patients, age 40-87 years who were at
mild-to-moderate risk for myocardial ischemia
and were undergoing elective non-cardiac
surgery. Forty-six percent (46%) of the
operations were cardiovascular, with the
remainder evenly divided between
gastrointestinal and musculoskeletal and small
numbers of other surgical procedures. The
average duration of surgery was less than 2
hours. Anesthesia induction usually was
performed with thiopental (2-5 mg/kg) and
fentanyl (1-5 mcg/kg). Vecuronium (0.1-0.2
mg/kg) was also administered to facilitate
intubation, muscle relaxation or immobility
during surgery. The average MAC dose was 0.49
for both anesthetics. There was no significant
difference between the anesthetic regimens for
intraoperative hemodynamics, cardioactive drug
use, or ischemic incidents, although only 83
patients in the sevoflurane group and 85
patients in the isoflurane group were
successfully monitored for ischemia. The outcome
was also equivalent in terms of adverse events,
death, and postoperative myocardial infarction.
Within the limits of this small multicenter
study in patients at mild-to-moderate risk for myocardial ischemia, sevoflurane was a
satisfactory equivalent to isoflurane in
providing supplemental inhalation anesthesia to
intravenous drugs.
CESAREAN
SECTION
Sevoflurane (n=29) was compared to isoflurane (n=27) in
ASA Class I or II patients for the maintenance of
anesthesia during cesarean section. Newborn evaluations
and recovery events were recorded. With both
anesthetics, Apgar scores averaged 8 and 9 at 1 and 5 minutes, respectively.
Use
of sevoflurane as part of general anesthesia for
elective cesarean section produced no untoward effects
in mother or neonate. Sevoflurane and isoflurane
demonstrated equivalent recovery characteristics. There
was no difference between sevoflurane and isofluranewith regard to the effect on the newborn, as assessed by
Apgar Score and Neurological and Adaptive Capacity Score
(average=29.5). The safety of sevoflurane in labor and
vaginal delivery has not been evaluated.
NEUROSURGERY
Three studies compared sevoflurane to isoflurane for
maintenance of anesthesia during neurosurgical
procedures. In a study of 20 patients, there was no difference between sevoflurane and isoflurane with
regard to recovery from anesthesia. In 2 studies, a
total of 22 patients with intracranial pressure (ICP)
monitors received either sevoflurane or isoflurane.
There was no difference between sevoflurane and
isoflurane with regard to ICP response to inhalation of
0.5, 1.0, and 1.5 MAC inspired concentrations of
volatile agent during
N2O-O2-fentanyl anesthesia. During
progressive hyperventilation from PaCO2 = 40 to PaCO2 = 30, ICP response to hypocarbia was
preserved with sevoflurane at both 0.5 and 1.0 MAC
concentrations. In patients at risk for elevations of
ICP, sevoflurane should be administered cautiously in
conjunction with ICP-reducing maneuvers such as
hyperventilation.
HEPATIC
IMPAIRMENT
A
multicenter study (2 sites) compared the safety of
sevoflurane and isoflurane in 16 patients with
mild-to-moderate hepatic impairment utilizing the
lidocaine MEGX assay for assessment of hepatocellular
function. All patients received intravenous propofol
(1-3 mg/kg) or thiopental (2-7 mg/kg) for induction and
succinylcholine, vecuronium, or atracurium for
intubation. Sevoflurane or isoflurane was administered
in either 100% O2 or up to 70%
N2O/O2. Neither drug adversely
affected hepatic function. No serum inorganic fluoride
level exceeded 45 µM/L, but sevoflurane patients had
prolonged terminal disposition of fluoride, as evidenced
by longer inorganic fluoride half-life than patients
with normal hepatic function (23 hours vs. 10-48
hours).
RENAL
IMPAIRMENT
Sevoflurane was evaluated in renally impaired patients
with baseline serum creatinine >1.5 mg/dL.
Fourteen patients who received sevoflurane were compared
with 12 patients who received isoflurane. In another
study, 21 patients who received sevoflurane were
compared with 20 patients who received enflurane.
Creatinine levels increased in 7% of patients who
received sevoflurane, 8% of patients who received
isoflurane, and 10% of patients who received enflurane.
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 yet been fully
established. Therefore, sevoflurane should be used with
caution in patients with renal insufficiency (see WARNINGS).
INDICATIONS AND USAGE
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.
CONTRAINDICATIONS
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.
WARNINGS
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 postoperative period. Patients with latent as
well as overt neuromuscular disease, particular 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
creatinine 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 of hypermetabolic state. Early and aggressive
intervention to treat the hyperkalemia and resistant arrhythmias is
recommended, as is subsequent evaluation for latent neuromuscular
disease.
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.
Malignant
Hyperthermia
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. 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 nonspecific signs may also appear during light anesthesia,
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 dantrolene sodium intravenous for additional
information on patient management.) Renal failure may appear
later, and urine flow should be monitored and sustained if
possible.
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.
PRECAUTIONS
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.
Drug Interactions
In clinical
trials, no significant adverse reactions occurred with other
drugs commonly used in the perioperative period, including:
central nervous system depressants, autonomic drugs, skeletal
muscle relaxants, anti-infective agents, hormones and synthetic
substitutes, blood derivatives, and cardiovascular drugs.
INTRAVENOUS
ANESTHETICS:
Sevoflurane administration is compatible with
barbiturates, propofol, and other commonly used
intravenous anesthetics.
BENZODIAZEPINES AND OPIOIDS:
Benzodiazepines and opioids would be 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
anesthetic requirement for sevoflurane is decreased when administered in combination with nitrous oxide. Using
50% N2O, the MAC equivalent dose requirement
is reduced approximately 50% in adults, and
approximately 25% in pediatric patients (see DOSAGE AND ADMINISTRATION).
NEUROMUSCULAR BLOCKING AGENTS:
As
is the case with other volatile anesthetics, sevoflurane
increases both the intensity and duration of
neuromuscular blockade induced by nondepolarizing muscle
relaxants. When used to supplement
alfentanil-N2O anesthesia, sevoflurane and
isoflurane equally potentiate neuromuscular block
induced with pancuronium, vecuronium or atracurium.
Therefore, during sevoflurane anesthesia, the dosage
adjustments for these muscle relaxants are similar to
those required with isoflurane.
Potentiation of neuromuscular blocking agents requires
equilibration of muscle with delivered partial pressure
of sevoflurane. Reduced doses of neuromuscular blocking
agents during induction of anesthesia may result in
delayed onset of conditions suitable for endotracheal
intubation or inadequate muscle relaxation.
Among available nondepolarizing agents, only
vecuronium, pancuronium and atracurium interactions have
been studied during sevoflurane anesthesia. In the
absence of specific guidelines:
- For endotracheal intubation, do not reduce the
dose of nondepolarizing muscle relaxants.
- During maintenance of anesthesia, the required
dose of nondepolarizing muscle relaxants is likely
to be reduced compared to that during NO/opioid anesthesia. Administration of supplemental doses of
muscle relaxants should be guided by the response to
nerve stimulation. The effect of sevoflurane on the
duration of depolarizing neuromuscular blockade
induced by succinylcholine has not been
studied.
Hepatic Function
Results of
evaluations of laboratory parameters (e.g., ALT, AST, alkaline
phosphatase, and total bilirubin, etc.), as well as
investigator-reported incidence of adverse events relating to
liver function, demonstrate that sevoflurane can be administered
to patients with normal or mild-to-moderately impaired hepatic
function. However, patients with severe hepatic dysfunction were
not investigated.
Occasional cases of transient changes in postoperative hepatic function
tests were reported with both sevoflurane and reference agents.
Sevoflurane was found to be comparable to isoflurane with regard
to these changes in hepatic function.
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 judgement
should be exercised when sevoflurane is used in patients with
underlying hepatic conditions or under treatment with drugs
known to cause hepatic dysfunction (see ADVERSE
REACTIONS).
Desiccated
CO2 Absorbents
An
exothermic reaction occurs when sevoflurane is exposed to CO2 absorbents. This reaction is increased when
the CO2 absorbent becomes desiccated, such as after
an extended period of dry gas flow through the CO2
absorbent canisters. Rare cases of extreme heat, smoke, and/or
spontaneous fire in the anesthesia breathing circuit have been
reported during sevoflurane use in conjunction with the use of desiccated CO2 absorbent, specifically those
containing potassium hydroxide (e.g. Baralyme). KOH containing
CO2 absorbents are not recommended for use with
sevoflurane. 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 and chemical breakdown of sevoflurane.
As with
other inhalational anesthetics, degradation and production of
degradation products can occur when sevoflurane is exposed to
desiccated absorbents. When a clinician suspects that the
CO2 absorbent may be desiccated, it should be
replaced. The color indicator of most CO2 absorbents
may not change upon desiccation. Therefore, the lack of
significant color change should not be taken as an assurance of
adequate hydration. CO2 absorbents should be replaced
routinely regardless of the state of the color
indicator.
Carcinogenesis,
Mutagenesis, Impairment of Fertility
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 thein 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).
PREGNANCY
Pregnancy Category B:
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.
Labor and Delivery
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 CLINICAL
PHARMACOLOGY, Clinical Trials.) The safety of
sevoflurane in labor and delivery has not been
demonstrated.
Nursing Mothers
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.
Pediatric Use
Induction
and maintenance of general anesthesia with sevoflurane have been
established in controlled clinical trials in pediatric patients
aged 1 to 18 years (see 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 PRECAUTIONS, 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.
Geriatric Use
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.
ADVERSE REACTIONS
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.
| Adverse Events During the
Induction Period (from onset of anesthesia by mask
induction to surgical incision) Incidence>1% |
| Adult Patients (N = 118) |
| Cardiovascular: |
Bradycardia 5%, Hypotension 4%,
Tachycardia 2% |
| Nervous System: |
Agitation 7% |
| Respiratory System: |
Laryngospasm 8%, Airway
obstruction 8%, Breathholding 5%, Cough Increased 5% |
|
|
|
| Pediatric Patients (N =
507) |
| Cardiovascular: |
Tachycardia 6%, Hypotension
4% |
| Nervous System: |
Agitation 15% |
| Respiratory System: |
Breathholding 5%, Cough Increased
5%, Laryngospasm 3%, Apnea 2% |
| Digestive System: |
Increased salivation 2% |
|
|
|
| Adverse Events During Maintenance
and Emergence Periods, Incidence >1% (N =
2906) |
| Body as a whole: |
Fever 1%, Shivering 6%, Hypothermia 1%, Movement 1%, Headache 1% |
| Cardiovascular: |
Hypotension 11%, Hypertension 2%,
Bradycardia 5%, Tachycardia 2% |
| Nervous System: |
Somnolence 9%, Agitation 9%,
Dizziness 4%, Increased salivation 4% |
| Digestive System: |
Nausea 25%, Vomiting 18% |
| Respiratory System: |
Cough increased 11%, Breathholding
2%, Laryngospasm 2% |
|
|
|
| Adverse Events, All Patients in
Clinical Trials (N = 2906), All Anesthetic Periods,
Incidence <1% (reported in 3 or more
patients) |
| Body as a whole: |
Asthenia, Pain |
| Cardiovascular: |
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 |
| Nervous System: |
Crying, Nervousness, Confusion,
Hypertonia, Dry Mouth, Insomnia |
| Respiratory System: |
Sputum Increased, Apnea, Hypoxia,
Wheezing, Bronchospasm, Hyperventilation, Pharyngitis,
Hiccup, Hypoventilation, Dyspnea, Stridor |
| Metabolism and
Nutrition: |
Increases in LDH, AST, ALT, BUN,
Alkaline Phosphatase, Creatinine, Bilirubinemia, Glycosuria,
Fluorosis, Albuminuria, Hypophosphatemia, Acidosis,
Hyperglycemia |
| Hemic and Lymphatic System: |
Leucocytosis,
Thrombocytopenia |
| Skin and Special
Senses:< |