Drug Information for Sevoflurane (Halocarbon Products Corporation): 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).

  • Solubility

  • Because of the low solubility of sevoflurane in blood (blood/gas partition coefficient @ 37°C = 0.63 to 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 to 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 El 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 450 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 with in 48 hours postanesthesia 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 the 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 to 23 hours.

    It has been reported that following administration of methoxyflurane, serum inorganic fluoride concentration >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 to 61 hours) as compared to a mean of approximately 21 hours (range 10 to 48 hours) in normal healthy individuals. The mean half-life in the elderly (greater than 65 years) approximated 24 hours (range 18 to 72) hours). The mean half-life in individuals with hepatic impairment was 23 hours (range 16 to 47 hours). Mean maximal fluoride values (Cmax) determined in individual studies of special populations are displayed below.

    Table 1. Fluoride Ion Estimates in Special Populations Following Administration of Sevoflurane
    nAge (yr)Duration (yr)Dose (MAC∙hr)Cmax (µM)
    n = number of patients studied.
    Sevoflurane-O2760 to
    Sevoflurane-O2401 to
    Sevoflurane/N2O255 to 131.92.421.3
    Sevoflurane/N2O420 to
    Sevoflurane/N2O 401 to 112.02.615.5
    ELDERLY3365 to 932.61.425.6
    RENAL2129 to 832.51.026.1
    HEPATIC842 to 793.62.230.6
    OBESE524 to 733.01.738.0

  • Changes in the depth of sevoflurane anesthesia rapidly follow changes in inspired concentration.

    In the sevoflurane clinical program, the following recovery variables were evaluated:

    1. Time to events measured from the end of the 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)

    2. 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

    3. Other recovery times were:

    • Time to achieve an Aldrete Score of ≥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 ± SEMHalothane Mean ± SEM
    n = number of patients with recording of events.
    Induction2.0 ± 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 command13.7 ± 1.0 (n=271)19.3 ± 1.1 (n=230)
    First analgesia52.2 ± 8.5 (n=216)67.6 ± 10.6 (n=150)
    Eligible for recovery discharge76.5 ± 2.0 (n=292)81.1 ± 1.9 (n=246)
    Table 3. Recovery Variables for Evaluable Adult Patients in Two Comparative Studies: Sevoflurane versus Isoflurane
    Time to Parameter: (min)Sevoflurane Mean ± SEMIsoflurane Mean ± SEM
    n = number of patients with recording of recovery events.
    Emergence7.7 ± 0.3 (n=395)9.1 ± 0.3 (n=348)
    Response to command8.1 ± 0.3 (n=395)9.7 ± 0.3 (n=345)
    First analgesia42.7 ± 3.0 (n=269)52.9 ± 4.2 (n=228)
    Eligible for recovery discharge87.6 ± 5.2 (n=244)79.1 ± 5.2 (n=252)
    Table 4. Meta-Analyses for Induction and Emergence Variables for Evaluable Adult Patients in Comparative Studies: Sevoflurane versus Propofol
    ParameterNo. of studiesSevofluraneMean ± SEMPropofolMean ± SEM
    n = number of patients with recording of events
    Mean maintenance anesthesia exposure31.0 MAC∙hr. ± 0.8(n=259)7.2 mg/kg/hr. ± 2.6(n=258)
    Time to induction: (min)13.1 ± 0.18Propofol induction of one sevoflurane group = mean of 178.8 mg ± 72.5 SD (n=165)(n=93)2.2 ± 0.18Propofol induction of all Propofol groups = mean of 170.2 mg ± 60.6 SD (n=245)(n=93)
    Time to emergence: (min)38.6 ± 0.57(n=255)11.0 ± 0.57(n=260)
    Time to respond to command: (min)39.9 ± 0.60(n=257)12.1 ± 0.60(n=260)
    Time to first analgesia: (min)343.8 ± 3.79(n=177)57.9 ± 3.68(n=179)
    Time to eligibility for recovery discharge: (min)3116.0 ± 4.15(n=257)115.6 ± 3.98(n=261)
  • Cardiovascular Effects

  • Sevoflurane was studied in 14 healthy volunteers (18 to 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 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 PatientsNumber Studied
    Cesarean Delivery29
    Cardiovascular and patients at risk of myocardial ischemia246
    Hepatic impairment8
    Renal impairment35

    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 to 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
    n = number of patients with recording of recovery events.
    Mean Maintenance Anesthesia Exposure ± SD0.64 ± 0.03MAC∙hr.(n=245)0.66 ± 0.03MAC∙hr.(n=249)0.8 ± 0.5MAC∙hr.(n=166)7.3 ± 2.3mg/kg/hr.(n=168)
    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=83)11.5 ± 0.7(n=88)
    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)
  • 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 to 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
    n = number of patients with recording of recovery events.
    Mean Maintenance Anesthesia Exposure ± SD1.27 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=91)
    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)6.1 ± 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 ± 16.3(n=282)148.4 ± 8.9(n=92)141.4 ± 8.9(n=92)
  • 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 to 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 were 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)
    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).

  • 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 to 0.3 mg/kg); vecuronium (0.1 to 0.2 mg/kg), and fentanyl (5 to 15 mg/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 to 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 to 5 mg/kg) and fentanyl (1 to 5 mcg/kg). Vecuronium (0.1 to 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 isoflurane with 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 to 3 mg/kg) or thiopental (2 to 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 to 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).

  • Drug Information Provided by National Library of Medicine (NLM).