Name: Sevoflurane


Mechanism of Action

Volatile liquid general anesthetic; may alter activity of neuronal ion channels, especially the fast synaptic neurotransmitter receptors including nicotinic acetylcholine, GABA, and glutamate receptors.


Onset: 2-3 min

Duration: Depends on blood concentration

Metabolism: Liver (3-5%); CYP2E1

Excretion: Respiratory exhaled gases


Increased incidence of malignant hyperthermia with use of volatile anesthetics or depolarizing neuromuscular blockers in patients with gene mutations in ryanodine receptor (RYR1) or calcium channel alpha (1S)- subunit gene (CACNA1S)

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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 Brand Names

Sevoflurane may be found in some form under the following brand names:

  • Petrem

  • SevoFlo

  • Sevosol

  • SevoThesia

  • Sojourn

  • Ultane

Sevoflurane Description

Sevoflurane, USP, volatile liquid for inhalation, a nonflammable and nonexplosive liquid administered by vaporization, is a halogenated general inhalation anesthetic drug. Sevoflurane, USP is fluoromethyl 2,2,2,-trifluoro-1-(trifluoromethyl) ethyl ether and its structural formula is:

Sevoflurane, USP, Physical Constants are:

Molecular weight


Boiling point at 760 mm Hg


Specific gravity at 20°C

1.520 - 1.525

Vapor pressure in mm Hg

157 mm Hg at 20°C

197 mm Hg at 25°C

317 mm Hg at 36°C

Distribution Partition Coefficients at 37°C:


0.63 - 0.69



Olive Oil/Gas

47 - 54



Mean Component/Gas Partition Coefficients at 25°C for Polymers Used Commonly in Medical Applications:

Conductive rubber


Butyl rubber






Sevoflurane, USP is nonflammable and nonexplosive as defined by the requirements of International Electrotechnical Commission 601-2-13.

Sevoflurane, USP is a clear, colorless, liquid containing no additives. Sevoflurane, USP is not corrosive to stainless steel, brass, aluminum, nickel-plated brass, chrome-plated brass or copper beryllium. Sevoflurane, USP is nonpungent. It is miscible with ethanol, ether, chloroform, and benzene, and it is slightly soluble in water. Sevoflurane, USP is stable when stored under normal room lighting conditions according to instructions. No discernible degradation of Sevoflurane, USP occurs in the presence of strong acids or heat. When in contact with alkaline CO2 absorbents (e.g. Baralyme and to a lesser extent soda lime) within the anesthesia machine, Sevoflurane, USP can undergo degradation under certain conditions. Degradation of Sevoflurane, USP is minimal, and degradants are either undetectable or present in non-toxic amounts when used as directed with fresh absorbents. Sevoflurane, USP degradation and subsequent degradant formation are enhanced by increasing absorbent temperature increased Sevoflurane, USP concentration, decreased fresh gas flow and desiccated CO2 absorbents (especially with potassium hydroxide containing absorbents e.g. Baralyme).

Sevoflurane, USP alkaline degradation occurs by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropenyl fluoromethyl ether, (PIFE, C4H2F6O), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether, (PMFE, C5H6F6O), also known as Compound B. The second pathway for degradation of Sevoflurane, USP, which occurs primarily in the presence of desiccated CO2 absorbents, is discussed later.

In the first pathway, the defluorination pathway, the production of degradants in the anesthesia circuit results from the extraction of the acidic proton in the presence of a strong base (KOH and/or NaOH) forming an alkene (Compound A) from Sevoflurane, USP similar to formation of 2-bromo-2-chloro-1,1-difluoro ethylene (BCDFE) from halothane. Laboratory simulations have shown that the concentration of these degradants is inversely correlated with the fresh gas flow rate (See Figure 1).

Since the reaction of carbon dioxide with absorbents is exothermic, the temperature increase will be determined by quantities of CO2 absorbed, which in turn will depend on fresh gas flow in the anesthesia circle system, metabolic status of the patient, and ventilation. The relationship of temperature produced by varying levels of CO2 and Compound A production is illustrated in the following in vitro simulation where CO2 was added to a circle absorber system.

Compound A concentration in a circle absorber system increases as a function of increasing CO2 absorbent temperature and composition (Baralyme producing higher levels than soda lime), increased body temperature, and increased minute ventilation, and decreasing fresh gas flow rates. It has been reported that the concentration of Compound A increases significantly with prolonged dehydration of Baralyme. Compound A exposure in patients also has been shown to rise with increased Sevoflurane, USP concentrations and duration of anesthesia. In a clinical study in which Sevoflurane, USP 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, USP exposure are shown in Figure 2a.

Compound A has been shown to be nephrotoxic in rats after exposures that have varied in duration from one to three hours. No histopathologic change was seen at a concentration of up to 270 ppm for one hour. Sporadic single cell necrosis of proximal tubule cells has been reported at a concentration of 114 ppm after a 3-hour exposure to Compound A in rats. The LC50 reported at 1 hour is 1050-1090 ppm (male-female) and, at 3 hours, 350-490 ppm (male-female).

An experiment was performed comparing Sevoflurane, USP 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, USP in the presence of Compound A produced single-cell renal tubular degeneration and single-cell necrosis in cynomolgus monkeys. These changes are consistent with the increased urinary protein, glucose level and enzymic activity noted on days one and three on the clinical pathology evaluation. This nephrotoxicity produced by Compound A is dose and duration of exposure dependent.

At a fresh gas flow rate of 1 L/min, mean maximum concentrations of Compound A in the anesthesia circuit in clinical settings are approximately 20 ppm (0.002%) with soda lime and 30 ppm (0.003%) with Baralyme in adult patients; mean maximum concentrations in pediatric patients with soda lime are about half those found in adults. The highest concentration observed in a single patient with Baralyme was 61 ppm (0.0061%) and 32 ppm (0.0032%) with soda lime. The levels of Compound A at which toxicity occurs in humans is not known.

The second pathway for degradation of Sevoflurane, USP occurs primarily in the presence of desiccated CO2 absorbents and leads to the dissociation of Sevoflurane, USP 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, USP degradants were observed in the respiratory circuit of an experimental anesthesia machine using desiccated CO2 absorbents and maximum Sevoflurane, USP 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 respiratory irritation. Although KOH containing CO2 absorbents are no longer commercially available, in the laboratory experiments, exposure of Sevoflurane, USP to the desiccated KOH containing CO2 absorbent, Baralyme, resulted in the detection of substantially greater degradant levels.


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, USP 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, USP. During Sevoflurane, USP 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, USP 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, USP to patients with renal insufficiency (creatinine >1.5 mg/dL) is limited, its safety in these patients has not been established.

Sevoflurane, USP may be associated with glycosuria and proteinuria when used for long procedures at low flow rates. The safety of low flow Sevoflurane, USP on renal function was evaluated in patients with normal preoperative renal function. One study compared Sevoflurane, USP (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, USP group developed elevations of creatinine, in addition to glycosuria and proteinuria. This patient received Sevoflurane, USP 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.

Sevoflurane, USP may present an increased risk in patients with known sensitivity to volatile halogenated anesthetic agents. KOH containing CO2 absorbents are not recommended for use with Sevoflurane, USP.

Reports of QT prolongation, associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering Sevoflurane to susceptible patients (e.g.patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval).

Malignant Hyperthermia

In susceptible individuals, potent inhalation anesthetic agents, including Sevoflurane, USP, may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. Sevoflurane can induce malignant hyperthermia in genetically susceptible individuals, such as those with certain inherited ryanodine receptor mutations. 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.

In clinical trials, one case of malignant hyperthermia was reported. In addition, there have been postmarketing reports of malignant hyperthermia. Some of these cases have been fatal.

Treatment of malignant hyperthermia includes discontinuation of triggering agents (e.g., Sevoflurane, USP), administration of intravenous dantrolene sodium (consult prescribing information for intravenous dantrolene sodium for additional information on patient management), and application of supportive therapy. Supportive therapy may include efforts to restore body temperature, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base abnormalities. Renal failure may appear later, and urine flow should be monitored and sustained if possible.

Perioperative Hyperkalemia

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.

Pediatric Neurotoxicity

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, and 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.

Adverse Reactions

Adverse events are derived from controlled clinical trials conducted in the United States, Canada, and Europe. The reference drugs were isoflurane, enflurane, and propofol in adults and halothane in pediatric patients. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered.

Of the 5182 patients enrolled in the clinical trials, 2906 were exposed to Sevoflurane, USP, 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, USP are presented within each body system in order of decreasing frequency in the following listings. One case of malignant hyperthermia was reported in pre-registration clinical trials.

Adverse Events During the Induction Period (from Onset of Anesthesia by Mask Induction to Surgical Incision) Incidence >1%

Adult Patients (N = 118)


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)


Tachycardia 6%, Hypotension 4%

Nervous System:

Agitation 15%

Respiratory System:

Breathholding 5%, Cough Increased 5%, Laryngospasm 3%, Apnea 2%

Digestive System:

Increased salivation 2%

Adverse Events During Maintenance and Emergence Periods, Incidence >1% (N = 2906)

Body as a whole:

Fever 1%, Shivering 6%, Hypothermia 1%, Movement 1%, Headache 1%


Hypotension 11%, Hypertension 2%, Bradycardia 5%, Tachycardia 2%

Nervous System:

Somnolence 9%, Agitation 9%, Dizziness 4%, Increased salivation 4%

Digestive System:

Nausea 25%, Vomiting 18%

Respiratory System:

Cough increased 11%, Breathholding 2%, Laryngospasm 2%

Adverse Events, All Patients in Clinical Trials (N = 2906), All Anesthetic Periods, Incidence <1% (Reported in 3 or more patients)

Body as a whole:

Asthenia, Pain


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


Urination Impaired, Urine Abnormality, Urinary Retention, Oliguria

See WARNINGS for information regarding malignant hyperthermia.

Post-Marketing Adverse Events

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, USP 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, USP induction, during emergence, and during post-operative recovery up to a day following anesthesia.


Cardiac arrest


• 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


• Malignant hyperthermia (see CONTRAINDICATIONS and WARNINGS) • Allergic reactions, such as rash, urticaria, pruritus, bronchospasm, anaphylactic or anaphylactoid 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 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.


In the event of overdosage, or what may appear to be overdosage, the following action should be taken: discontinue administration of Sevoflurane, USP, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.

Sevoflurane Dosage and Administration

The concentration of Sevoflurane, USP being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for Sevoflurane, USP. The administration of general anesthesia must be individualized based on the patient’s response.

Replacement of Desiccated CO2 Absorbents

When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced. The exothermic reaction that occurs with Sevoflurane, USP 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).

Pre-anesthetic Medication

No specific premedication is either indicated or contraindicated with Sevoflurane, USP. The decision as to whether or not to premedicate and the choice of premedication is left to the discretion of the anesthesiologist.


Sevoflurane, USP 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, USP with or without the concomitant use of nitrous oxide. Sevoflurane, USP can be administered with any type of anesthesia circuit.

Table 9: MAC Values for Adults and Pediatric Patients According to Age
* Neonates are full-term gestational age. MAC in premature infants has not been determined. † In 1 - <3 year old pediatric patients, 60% N2O/40% O2 was used.


Age of Patient (years)

Sevoflurane in

Sevoflurane in 65%
N2O/35% O2

0 - 1 months*



1 - <6 months



6 months - <3 years



3 - 12















Directions for Filling Vaporizers

Utilize an adapter, as appropriate, when filling the vaporizer with Sevoflurane, USP.