Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3978
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Sevoflurane (Liquid)
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The concentration
of sevoflurane being delivered from a vaporizer during anesthesia should
be known. This may be accomplished by using a vaporizer calibrated
specifically for sevoflurane. The administration of general anesthesia
must be individualized based on the patient's response. REPLACEMENT OF
DESICCATED COABSORBENTS: When a clinician suspects that the
COabsorbent may be desiccated, it should be replaced.
The exothermic reaction that occurs with sevoflurane and COabsorbents is increased when the COabsorbent becomes desiccated, such as after an extended period of dry gas flow through the
COabsorbent canisters . PRE-ANESTHETIC
MEDICATION: No specific premedication is either indicated or
contraindicated with sevoflurane. The decision as to whether or not to
premedicate and the choice of premedication is left to the discretion of
the anesthesiologist. INDUCTION:
Sevoflurane has a nonpungent odor and does not cause respiratory
irritability; it is suitable for mask induction in pediatrics and
adults. MAINTENANCE:
Surgical levels of anesthesia can usually be achieved with
concentrations of 0.5-3% sevoflurane with or without the concomitant use
of nitrous oxide. Sevoflurane can be administered with any type of
anesthesia circuit. # Neonates are
full-term gestational age. MAC in premature infants has not been
determined. @ In 1 -<3
year old pediatric patients, 60% NO/40% Owas
used.<br/>Directions for
Filling Vaporizers: Sevoflurane
is provided with a keyed bottle collar and should be filled only
into vaporizers designed for use with sevoflurane using a keyed
adaptor.
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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 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 COabsorbents
(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 COabsorbents (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, CHFO),
also known as Compound A, and trace amounts of pentafluoromethoxy
isopropyl fluoromethyl ether, (PMFE,
CHFO), also known as Compound B. Thesecond pathway for degradation of sevoflurane, which occurs primarily in
the presence of desiccated COabsorbents, 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 COabsorbed,
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 COand Compound A production is illustrated in the following in vitro simulation where COwas added to a circle absorber system. Compound A
concentration in a circle absorber system increases as a function of
increasing COabsorbent 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
LCreported 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 incynomolgus 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 COabsorbents 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 COabsorbents 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 COabsorbents are no longer
commercially available, in the laboratory experiments, exposure of
sevoflurane to the desiccated KOH containing COabsorbent,
Baralyme, resulted in the detection of substantially greater degradant
levels.
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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).<br/>Pharmacokinetics:<br/>UPTAKE AND
DISTRIBUTION:<br/>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��M
and 90��M. As shown in Figure 6, peak concentrations
occur within 2 hours of the end of anesthesia and are
less than 25��M (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��M 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.<br/>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: Some of
these variables are summarized as follows: n = number
of patients with recording of events. n = number
of patients with recording of recovery events. *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.<br/>CARDIOVASCULAR EFFECTS: Sevoflurane was studied in 14 healthy volunteers (18-35
years old) comparing sevoflurane-O(Sevo/O) to
sevoflurane-NO/O(Sevo/NO/O) 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.<br/>Clinical Trials: Sevoflurane
was administered to a total of 3185 patients prior to
sevoflurane NDA submission. The types of patients are summarized
as follows: Clinical
experience with these patients is described below.<br/>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.<br/>PEDIATRIC
ANESTHESIA: The
concentration of sevoflurane required for maintenance of
general anesthesia is age-dependent . 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, therewere 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.<br/>CARDIOVASCULAR SURGERY:<br/>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 deliveryhas not been evaluated.<br/>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
NO-O-fentanyl anesthesia. During
progressive hyperventilation from PaCO= 40 to PaCO= 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.<br/>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% Oor up to 70%
NO/O. Neither drug adversely
affected hepatic function. No serum inorganic fluoride
level exceeded 45��M/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).<br/>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 .
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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.
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Sevoflurane,
Volatile Liquid for Inhalation, is available as: NDC 10019-651-64 -
Aluminum bottle containing 250 mL sevoflurane.<br/>Safety and Handling:<br/>OCCUPATIONAL CAUTION: There is no specific work exposure limit established
for sevoflurane. However, the National Institute for
Occupational Safety and Health has recommended an 8 hour
time-weighted average limit of 2 ppm for halogenated
anesthetic agents in general (0.5 ppm when coupled with
exposure to NO).<br/>Storage: Store at controlled room temperature
15��-30��C (59��-86��F) [see USP]. The bottle
cap should be replaced securely after each use of sevoflurane. Manufactured for Baxter Healthcare
Corporation Deerfield,
IL 60015 USA by: Baxter
Healthcare Corporation of Puerto Rico Guayama,
Puerto Rico 00784 For Product
Inquiry 1 800 ANA DRUG (1-800-262-3784) Regulatory
MLT-01308/3.0
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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 (seePRECAUTIONS,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.<br/>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.<br/>INTRAVENOUS
ANESTHETICS:: Sevoflurane administration is compatible with
barbiturates, propofol, and other commonly used
intravenous anesthetics.<br/>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.<br/>NITROUS
OXIDE:: As
with other halogenated volatile anesthetics, the
anesthetic requirement for sevoflurane is decreased when administered in combination with nitrous oxide. Using
50% NO, the MAC equivalent dose requirement
is reduced approximately 50% in adults, and
approximately 25% in pediatric patients .<br/>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-NO 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:<br/>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).<br/>Desiccated
COAbsorbents: An
exothermic reaction occurs when sevoflurane is exposed to COabsorbents. This reaction is increased when
the COabsorbent becomes desiccated, such as after
an extended period of dry gas flow through the COabsorbent 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 COabsorbent, specifically those
containing potassium hydroxide (e.g. Baralyme). KOH containing
COabsorbents 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
COabsorbent 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
COabsorbent may be desiccated, it should be
replaced. The color indicator of most COabsorbents
may not change upon desiccation. Therefore, the lack of
significant color change should not be taken as an assurance of
adequate hydration. COabsorbents should be replaced
routinely regardless of the state of the color
indicator.<br/>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,P 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).<br/>PREGNANCY:<br/>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.<br/>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.<br/>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 Interactionsand 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.<br/>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.
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In the event of
overdosage, or what may appear to be overdosage, the following action
should be taken: discontinue administration of sevoflurane, maintain a
patent airway, initiate assisted or controlled ventilation with oxygen,
and maintain adequate cardiovascular function.
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Sevoflurane
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Sevoflurane (Liquid)
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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. See WARNINGS
for information regarding malignant hyperthermia.<br/>Adverse Events
During Post-Marketing Experience:: Post-marketing reports indicate that sevoflurane use has been
associated with seizures. The majority of cases were in children
and young adults, most of whom had no medical history of
seizures. Several cases reported no concomitant medications, and at least one case was confirmed by EEG. Although many cases were
single seizures that resolved spontaneously or after treatment,
cases of multiple seizures have also been reported. Seizures
have occurred during, or soon after sevoflurane induction,
during emergence, and during post-operative recovery up to a day
following anesthesia. Rare cases
of malignant hyperthermia and allergic reactions, such as rash,
urticaria, pruritis, bronchospasm, anaphylactic or anaphylactoid
reactions have been reported. Very rare
cases of mild, moderate and severe post-operative hepatic
dysfunction or hepatitis with or without jaundice have been
reported. Histological evidence was not provided for any of the
reported hepatitis cases. In most of these cases, patients had
underlying hepatic conditions or were under treatment with drugs
known to cause hepatic dysfunction. Most of the reported events
were transient and resolved spontaneously . There have
been rare post-marketing reports of hepatic failure and hepatic
necrosis associated with the use of potent volatile anesthetic
agents, including sevoflurane. Due to the spontaneous nature of
these reports, the actual incidence and relationship of
sevoflurane to these events cannot be established with
certainty.<br/>Laboratory
Findings:: Transient
elevations in glucose, liver function tests, and white blood
cell count may occur as with use of other anesthetic
agents.
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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.<br/>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
COabsorbents are not recommended for use with
sevoflurane.
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| dailymed-instance:indicatio... |
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.
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| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Sevoflurane
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