Sevoflurane

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 (F_A) toward the inspired concentration (F_I) 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 F_A/F_I 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.

F_A/F_I data from this study were compared with F_A/F_I 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 (F_A), relative to the last alveolar concentration (Fa_O) 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.

Figure 3. Ratio of Concentration of Anesthetic in Alveolar Gas to Inspired Gas

Figure 4. Concentration of Anesthetic in Alveolar Gas Following Termination of Anesthesia

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.

Figure 5. Serum Inorganic Fluoride Concentrations for Sevoflurane and Other Volatile Anesthetics

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).

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 12μM and 90μM. As shown in Figure 6, peak concentrations occur within 2 hours of the end of anesthesia and are less than 25μM (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 > 50μM were correlated with the development of vasopressin-resistant, polyuric, renal failure. In clinical studies with sevoflurane, there were no reports of toxicity associated with elevated fluoride ion levels.

Figure 6. Fluoride Ion Concentrations Following Administration of Sevoflurane (mean MAC = 1.27, mean duration = 2.06 hr) Mean Fluoride Ion Concentrations (n = 48)

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 (C_max) determined in individual studies of special populations are displayed below.

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:

1. 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)

2. Recovery of cognitive function and motor coordination was evaluated based on:

• psychomotor performance tests (Digit Symbol Substitution Test [DSST], Trieger 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:

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:

Figure 7. Heart Rate

figure7-

Figure 8. Mean Arterial Pressure

figure8-

Figure 9. Systemic Vascular Resistance

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Figure 10. Cardiac Index

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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.

Pharmacogenomics

RYR1 and CACNA1S are polymorphic genes, and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (MHS) in patients receiving volatile anesthetic agents, including sevoflurane. Case reports as well as ex-vivo studies have identified multiple variants in RYR1 and CACNA1S associated with MHS. Variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence (see CONTRAINDICATIONS, WARNINGS - Malignant Hyperthermia).

Sevoflurane was administered to a total of 3185 patients. The types of patients are summarized as follows:

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.

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.

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).

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 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 (1-3 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).

In susceptible individuals, volatile anesthetic agents, including sevoflurane, may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand. Fatal outcomes of malignant hyperthermia have been reported. In clinical studies of sevoflurane, 1 case of malignant hyperthermia was reported.

The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. Sevoflurane can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants (see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY - Pharmacogenomics).

Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity (e.g., jaw muscle spasm), tachycardia (e.g., particularly that unresponsive to deepening anesthesia or analgesic medication administration), tachypnea, cyanosis, arrhythmias, hypovolemia, and hemodynamic instability. Skin mottling, coagulopathies, and renal failure may occur later in the course of the hypermetabolic process.

Successful treatment of malignant hyperthermia depends on early recognition of the clinical signs. If malignant hyperthermia is suspected, discontinue all triggering agents (i.e., volatile anesthetic agents and succinylcholine), administer intravenous dantrolene sodium, and initiate supportive therapies. Consult prescribing information for intravenous dantrolene sodium for additional information on patient management. Supportive therapies include administration of supplemental oxygen and respiratory support based on clinical need, maintenance of hemodynamic stability and adequate urinary output, management of fluid and electrolyte balance, correction of acid base derangements, and institution of measures to control rising temperature.

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 the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended as is subsequent evaluation for latent neuromuscular disease.

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans (see PRECAUTIONS -Pregnancy, PRECAUTIONS -Pediatric Use, ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

Episodes of severe bradycardia and cardiac arrest, not related to underlying congenital heart disease, have been reported during anesthesia induction with sevoflurane in pediatric patients with Down syndrome. In most cases, bradycardia improved with decreasing the concentration of sevoflurane, manipulating the airway, or administering an anticholinergic or epinephrine.

During induction, closely monitor heart rate, and consider incrementally increasing the inspired sevoflurane concentration until a suitable level of anesthesia is achieved. Consider having ananticholinergic and epinephrine available when administering sevoflurane for induction in this patient population.

Performance of activities requiring mental alertness, such as driving or operating machinery, may be impaired after sevoflurane anesthesia.

Risk of Driving and Operating Machinery

Advise patients that performance of activities requiring mental alertness, such as driving or operating machinery, may be impaired after sevoflurane anesthesia (see WARNINGS).

Effect of anesthetic and sedation drugs on early brain development

Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs (see WARNINGS -Pediatric Neurotoxicity).

In clinical studies, 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.

Epinephrine

Epinephrine administered with sevoflurane may increase the risk of ventricular arrhythmias. Monitor the electrocardiogram and blood pressure and ensure emergency medications to treat ventricular arrhythmias are readily available.

Calcium antagonists

Sevoflurane may lead to marked hypotension in patients treated with calcium antagonists. Blood pressure should be closely monitored and emergency medications to treat hypotension should be readily available when calcium antagonists are used concomitantly with sevoflurane.

In animals, impairment of atrioventricular conduction has been observed when verapamil and sevoflurane are administered concomitantly.

Succinylcholine

See WARNINGS - Perioperative Hyperkalemia.

Non-selective MAO-inhibitors

Concomitant use of MAO inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.

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 N₂O/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.

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 regarding these changes in hepatic function.

Cases of mild, moderate, and severe hepatic dysfunction or hepatitis (e.g., jaundice associated with fever and/or eosinophilia) after anesthesia with sevoflurane have been reported. 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).

It has been reported that previous exposure to halogenated hydrocarbon anesthetics may increase the potential for hepatic injury.

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

Studies on carcinogenesis have not been performed for either sevoflurane or Compound A.

Mutagenesis

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 the in 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).

Impairment of Fertility

In a study in which male rats were treated with sevoflurane (0.22%, 0.66%, 1.1%, or 2.2% equals 0.1, 0.3, 0.5, or 1.0 MAC) three hours per day every other day starting 64 days prior to mating and female rats were treated with the same dosing regimen 14 days prior to mating until Gestation Day 7, there was no clear impact on male or female fertility.

Risk Summary

There are no adequate and well-controlled studies in pregnant women.

In animal reproduction studies, reduced fetal weights were noted following exposure to 1 MAC sevoflurane for three hours a day during organogenesis. 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. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Pregnant rats were treated with sevoflurane (0.22%, 0.66%, or 2.2% equals 0.1, 0.3, or 1.0 MAC) without CO2 absorbent for three hours per day during organogenesis (from Gestation Day 7 to 17). Fetuses obtained by Cesarean section were examined on Gestation Day 20 while some animals were maintained for littering and pups were examined for adverse effects. There were no adverse effects on fetuses at 0.3 MAC. Reduced fetal body weights and increased skeletal variations such as delayed ossifications in the presence of maternal toxicity (reduced food and water intake and body weight of the dams) were noted at 1 MAC. In dams allowed to litter, reduced pup bodyweight gain and evidence of developmental delays (slight delay in eyelid opening and increased incidence of nonreactive animals in the visual placing reflex test) were noted in the 1.0 MAC treatment group.

Pregnant rabbits were treated with sevoflurane (0.1, 0.3, or 1.0 MAC) without CO2 absorbent for three hours per day during organogenesis (from Gestation Day 6 to 18). There were no adverse effects on the fetus at any dose; the mid-and high-dose produced a 5% and 6% decrease in maternal body weight, respectively.

In another study, pregnant rats were administered sevoflurane (0.1, 0.3, or 1.0 MAC) from Gestation Day 17 to Postnatal Day 21. Pup body weights were reduced in the 1.0 MAC treatment group in the absence of maternal toxicity. There was no effect of sevoflurane on sensory function (visual, auditory, nociception, righting reflexes), motor (roto-rod), open field test, or learning tasks (shuttle box avoidance and water T-maze).

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see WARNINGS -Pediatric Neurotoxicity, PRECAUTIONS -Pediatric Use, ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).

Sevoflurane has been used in clinical studies, as part of general anesthesia for elective cesarean section, in 29 women. There were no untoward effects in mother or neonate (see CLINICAL STUDIES). The safety of sevoflurane in labor and delivery has not been demonstrated.

Sevoflurane can cause uterine smooth muscle relaxation and may contribute to uterine atony.

It is not known whether sevoflurane or its metabolites are present in human milk. To minimize infant exposure to sevoflurane or its metabolites, a nursing mother may temporarily pump, and discard breast milk produced during the first 24 hours after administration of sevoflurane. Exercise caution when administering sevoflurane to a nursing mother.

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.

Induction and maintenance of general anesthesia with sevoflurane have been established in controlled clinical studies in pediatric patients aged 1 to 18 years (see CLINICAL STUDIES, 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, 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, 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.

Cases of life-threatening ventricular arrhythmias have been reported in pediatric patients with Pompe disease (also commonly known as glycogen storage disease type II or acid altase deficiency). In a published case series about a clinical trial of patients with infantile-onset Pompe disease, six percent of patients (9 of 139, with 6 of 9 having received sevoflurane) experienced arrhythmias after induction of anesthesia. Reported arrythmias included severe bradycardia, torsade de pointes, and fatal ventricular fibrillation, which usually resolved after treatment with pharmacologic agents and defibrillation. Avoid induction and maintenance of anesthesia using sole agents, such as sevoflurane, that decrease systemic vascular resistance or diastolic blood pressure.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as sevoflurane, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see WARNINGS -Pediatric Neurotoxicity, PRECAUTIONS -Pregnancy, ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).

Use in Pediatric Patients with Down Syndrome

See WARNINGS - Bradycardia in Down Syndrome.

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%

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%

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

Amblyopia, Pruritus, Taste Perversion, Rash, Conjunctivitis

Urogenital

Urination Impaired, Urine Abnormality, Urinary Retention, Oliguria
See WARNINGS for information regarding malignant hyperthermia.

The following adverse events have been identified during post-approval use of sevoflurane USP. Due to the spontaneous nature of these reports, the actual incidence and relationship of sevoflurane USP to these events cannot be established with certainty.

Central Nervous System

• Seizures — 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.
• Delirium

Cardiac

• Cardiac arrest
• QT prolongation associated with Torsade de Pointe
• Bradycardia in patients with Down syndrome

Hepatic

• 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 (see PRECAUTIONS).
• Hepatic necrosis
• Hepatic failure

Other

• Malignant hyperthermia (see CONTRAINDICATIONS, WARNINGS)
• Allergic reactions, such as rash, urticaria, pruritus, bronchospasm, and anaphylactic reactions (see CONTRAINDICATIONS)
• Reports of hypersensitivity (including contact dermatitis, rash, dyspnea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, particularly in association with long-term occupational exposure to inhaled anesthetic agents, including sevoflurane (see SAFETY AND HANDLING - Occupational Caution).

Laboratory Findings

• Transient elevations in glucose, liver function tests, and white blood cell count may occur as with use of other anesthetic agents.

When a clinician suspects that the CO₂ absorbent may be desiccated, it should be replaced. The exothermic reaction that occurs with sevoflurane and CO₂ absorbents is increased when the CO₂ absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO₂ absorbent canisters (see PRECAUTIONS).

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.

Sevoflurane has a nonpungent odor and does not cause respiratory irritability; it is suitable for mask induction in pediatrics and adults.

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.

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 N₂O) (see ADVERSE REACTIONS).

Store at controlled room temperature, 15° -30°C (59° -86°F). See USP.