SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 6 DRUG INTERACTIONS 11 DOSAGE AND ADMINISTRATION 12 OVERDOSAGE 14 ACTION AND CLINICAL PHARMACOLOGY 14 STORAGE AND STABILITY 18 DOSAGE FORMS, COMPOSITION AND PACKAGING 19
PHARMACEUTICAL INFORMATION 20 DETAILED PHARMACOLOGY 21 TOXICOLOGY 22 REFERENCES 26
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SEVOFLURANE
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Inhalation | Inhalation Anaesthetic/99.97% sevoflurane in 250mL bottles | None |
Sevoflurane is indicated for induction and maintenance of general anaesthesia in adult and paediatric patients for inpatient and outpatient surgery.
Sevoflurane is contraindicated in patients with known sensitivity to sevoflurane or to halogenated agents. Sevoflurane is contraindicated in patients in whom liver dysfunction jaundice, or unexplained fever, leucocytosis, or eosinophilia has occurred after previous halogenated anaesthetic administration (see WARNINGS AND PRECAUTIONS). Sevoflurane is contraindicated in patients with known or suspected genetic susceptibility to malignant hyperthermia, or in patients with a known or suspected history of malignant hyperthermia. Sevoflurane should not be used when general anaesthesia is contraindicated.
General
Sevoflurane should be administered only by persons trained in the administration of general anaesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Since levels of anaesthesia may be altered rapidly, only vaporizers producing predictable concentrations of sevoflurane should be used.
Compound A is produced when sevoflurane interacts with soda lime and Baralyme(r) (see ACTIONS AND CLINICAL PHARMACOLOGY). Its concentration in a circular absorber system increases with increasing absorber temperature and increasing sevoflurane concentration and with decreasing fresh gas flow rates. It has been reported that the concentration of Compound A increases significantly with prolonged dehydration of Baralyme(r). Although Compound A is a dose-dependent nephrotoxin in rats, there have been no cases of renal toxicity reported in humans, when sevoflurane is used as recommended.
When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced before administration of sevoflurane. The exothermic reaction that occurs with sevoflurane and CO2 absorbents is increased when 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 machine have been reported during sevoflurane use in conjunction with the use of desiccated CO2 absorbent. 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 canister. The color indicator of most CO2 absorbents does not necessarily change as a result of 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.
Malignant Hyperthermia
In susceptible individuals, potent inhalation anaesthetic 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, tachypnea, cyanosis, arrhythmias, and/or unstable, blood pressure. Some of these non-specific signs may also appear during light anaesthesia, 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 information for intravenous dantrolene sodium for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible.
Hepatic/Biliary/Pancreatic
In a limited number of patients with mild-to-moderate heptic impairment (N=16), the hepatic function was not affected by sevoflurane. The safety of sevoflurane in patients with severe hepatic impairment has not yet been demonstrated; therefore, sevoflurane should be used with caution in these patients. As with other halogenated anaesthetics, sevoflurane may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anaesthetics (see CONTRAINDICATIONS and ADVERSE EVENTS). Therefore, appropriate alternative anaesthetic agent(s) should be considered. This is especially important in patients with pre- existing hepatic conditions.
Neurologic
Due to limited number of patients who receive sevoflurane during neurosurgical procedures (N=22), safety in neurosurgery has not been fully established at this time and sevoflurane should be used with caution. In a study of 20 patients, there was no difference between sevoflurane and isoflurane with regard to recovery from anaesthesia. 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 regards to ICP response to inhalation of 0.5, 1.0, and 1.5 MAC inspired concentrations of volatile agent during N2O-O2-fentanyl anaesthesia. 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.
Peri-Operative Considerations
During the maintenance of anaesthesia, 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 anaesthetics. Excessive decreases in blood pressure or respiratory depression may be related to depth of anaesthesia and may be corrected by decreasing the inspired concentration of sevoflurane. The recovery from general anaesthesia should be assessed carefully before patient is discharged from the post-anaesthesia care unit.
Renal
Because clinical experience in administering sevoflurane in patients with renal insufficiencies (creatine > 1.5 mg/dL) is limited (N=35), its safety in these patients has not been established. Therefore, sevoflurane should be used with caution in patients with renal insufficiency. Limited pharmacokinetic data in these patients appear to suggest that the half-life of sevoflurane may be increased. The clinical significance is unknown at this time. (See ACTIONS AND CLINICAL PHARMACOLOGY.)
Special Populations
Pregnant Women
There are no adequate and well-controlled studies in pregnant women. Sevoflurane should be used during pregnancy only if clearly needed.
The safety of sevoflurane in Labour, Delivery and Nursing Mothers has not yet been demonstrated; therefore, sevoflurane should be used with caution in these patients. Due to the limited number of patients studied, safety in Caesarean section has not been fully established at this time and sevoflurane should be used with caution. Sevoflurane has been used as part of general anaesthesia for elective Caesarean section in 29 women. There were no untoward effects in mother or neonate.
The concentration of sevoflurane required for maintenance of general anaesthesia is age- dependent (see DOSAGE AND ADMINISTRATION). Incidences of bradycardia (more than 20 beats/min less than normal) is lower for sevoflurane (3%) than for halothane (7%). Emergence times for sevoflurane are faster than with halothane (12 vs 19 minutes, respectively). A higher incidence of agitation occurs with sevoflurane (208/637 patients or 25%) when compared with halothane (114/661 patients or 17%).
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. In adults, the incidence of bradycardia is greater with sevoflurane than with isoflurane.
Adverse Drug Reaction Overview
Adverse events are derived from controlled clinical trial conducted in the United States, Canada and Europe. The reference drugs were isoflurane, enflurane, and propofol in adults and halothane in paediatric patients. The studies were conducted using a variety of premedications, other anaesthetics, 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.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Of the 5,182 patients enrolled in the clinical trials, 2,906 were exposed to sevoflurane, including 118 adults and 507 paediatric patients who underwent mask induction. Each patient was counted once for each type of adverse event. Adverse events reported in patients in clinical trials are presented within each body system in order of decreasing frequency in the following listings (see Tables 1 to 4). One case of malignant hyperthermia was reported in pre-registration clinical trials.
| Table 1 ADVERSE EVENTS DURING THE INDUCTION PERIOD (from onset of anaesthesia by mask induction to surgical incision) POSSIBLY OR PROBABLY RELATED Incidence >1% | ||
| Body System | Adverse Event | Incidence |
| Adult Patients (N=118) | ||
| Cardiovascular Systems | Bradycardia | 5% |
| Hypotension | 4% | |
| Tachycardia | 2% | |
| Nervous System | Agitation | 7% |
| Respiratory System | Laryngospasm | 8% |
| Airway obstruction | 8% | |
| Breath holding | 5% | |
| Cough increased | 5% | |
| Paediatric Patients (N=507) | ||
| Cardiovascular System | Tachycardia | 6% |
| Hypotension | 4% | |
| Nervous System | Agitation | 15% |
| Increased Salivation | 2% | |
| Respiratory System | Breath holding | 5% |
| Cough Increased | 5% | |
| Laryngospasm | 3% | |
| Apnoea | 2% | |
NOTE: Similar incidence of adverse events was noted when all adverse reactions were recorded, not only possibly or probably related.
| Table 2 ADVERSE EVENTS FOR ALL PATIENTS DURING ALL ANAESTHIC PERIODS POSSIBLY OR PROBABLY RELATED Incidence > 1% (N=2906) | ||
| Body System | Adverse Event | Incidence |
| Body as a whole | Shivering | 6% |
| Fever | 1% | |
| Hypothermia | 1% | |
| Movement | 1% | |
| Headache | 1% | |
| Cardiovascular | Hypotension | 11% |
| Bradycardia | 5% | |
| Hypertension | 2% | |
| Tachycardia | 2% | |
| Digestive System | Nausea | 25% |
| Vomiting | 18% | |
| Nervous System | Somnolence | 9% |
| Agitation | 9% | |
| Dizziness | 4% | |
| Increased Salivation | 4% | |
| Respiratory System | Cough increased | 11% |
| Breath holding | 2% | |
| Laryngospasm | 2% | |
| Table 3 ALL ADVERSE EVENTS FOR ALL PATIENTS DURING ALL ANAESTHETIC PERIODS Incidence >1% | |||
| Body System | Adverse Event | Incidence Sevo (N=2906) | Incidence Ref. Agent (N=2276) |
| Body as a whole | Fever | 11% | 12% |
| Shivering | 7% | 8% | |
| Headache | 2% | 3% | |
| Hypothermia | 2% | 2% | |
| Movement | 1% | 1% | |
| Cardiovascular | Hypotension | 15% | 16% |
| Hypertension | 10% | 9% | |
| Bradycardia | 7% | 8% | |
| Tachycardia | 4% | 4% | |
| Digestive System | Nausea | 37% | 36% |
| Vomiting | 25% | 27% | |
| Nervous System | Somnolence | 14% | 17% |
| Agitation | 11% | 9% | |
| Dizziness | 8% | 9% | |
| Increased Salivation | 7% | 11% | |
| Respiratory System | Cough increased | 24% | 29% |
| Breath holding | 3% | 3% | |
| Laryngospasm | 2% | 3% | |
| Table 4 LESS COMMON CLINICAL TRIAL ADVERSE DRUG REACTIONS In addition the following adverse events were reported an incidence of <1% in controlled clinical trials (in more that 1 patient, with higher frequency than placebo). | |
| Body System | Adverse Event |
| Body as a whole | Asthenia Pain |
| Cardiovascular | Arrhythmia, Atrial Arrhythmia, Atrial Fibrillation, Bigeminy, Complete AV Block, Haemorrhage, Inverted T Wave, Second Degree AV Block, Supraventricular Extrasystoles, Syncope, S-T Depressed, and Ventricular Extrasystoles |
| Haemic and Lymphatic System | Leucocytosis, Thrombocytopenia |
| Metabolism and Nutrition | Acidosis, Albuminuria, Alkaline Phosphatase, Bilirubinemia, Creatinine, Fluorosis, Glycosuria, Hyperglycaemia, Hypophosphatemia, Increases in LDH, AST, ALT, BUN |
| Nervous System | Confusion, Crying, Dry Mouth, Hypertonia, Insomnia, Nervousness |
| Respiratory System | Apnoea, Bronchospasm, Dyspnea, Hiccup, Hyperventilation, Hypoventilation, Hypoxia, Pharyngitis, Sputum Increased, Stridor, Wheezing |
| Skin and Special Senses | Conjunctivitis, Pruritus, Rash, Taste Perversion |
| Urogenital | Oliguria, Urine Abnormality, Urination Impaired, Urine Retention |
See WARNINGS for information regarding malignant hyperthermia.
Abnormal Hematologic and Clinical Chemistry Findings
Transient elevations in glucose, liver function tests and white blood cell count may occur as with use of other anaesthetic agents.
Post-Marketing Adverse Reactions
There have been post-marketing reports of rare events of malignant hyperthermia (see WARNINGS). Rare events of allergic reactions, such as rash, urticaria, pruritus, bronchospasm, anaphylactic or anaphylactoid reactions have also been reported (see CONTRAINDICATIONS). Cases of dystonic movement with spontaneous resolution have been reported in children receiving sevoflurane for induction anaesthesia. Seizure-like activity may occur on extremely rare occasions following sevoflurane administration. Reported events were of short duration and there was no evidence of any abnormality during emergence from anaesthesia or in the postoperative period. There have also been reports of post-operative hepatitis. Due to the uncontrolled nature of these spontaneous reports, a casual relationship to sevoflurane has not been established.
Drug-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, including epinephrine.
Sevoflurane administration is compatible with barbiturates, non-barbiturates (such as propofol) and benzodiazepines.
Benzodiazepines and Opioids would be expected to decrease the MAC of sevoflurane in the same manner as with other inhalational anaesthetics. Sevoflurane administration is compatible with benzodiazepines and opioids as commonly used in surgical practices.
As with other halogenated volatile anaesthetics, the anaesthetic 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 paediatric patients (see DOSAGE AND ADMINISTRATION).
As is the case with other volatile anaesthetics, sevoflurane increases both the intensity and duration of neuromuscular blockade induced by non-depolarizing muscle relaxants. The effect of sevoflurane on succinylcholine and the duration of depolarizing neuromuscular blockade has not been studied.
Drug-Food Interactions
Interactions with foods have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
Dosing Considerations
Fresh gas flow rates of less than 2 L/min in a circle absorber system are not recommended, as safety at lower rates has not yet been established.
The concentration of Sevoflurane being delivered from a vaporizer during anaesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane.
The administration of general anaesthesia must be individualized based on the patient's response.
Pre-anaesthetic 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 anaesthesiologist.
Induction
Sevoflurane has a non-pungent odour and does not cause respiratory irritability; therefore, it is suitable for mask induction in paediatrics and adults.
Recommended Dose and Dosage Adjustment
Surgical levels of anaesthesia can usually be achieved with concentrations of 0.5 to 3% sevoflurane without the concomitant use of nitrous oxide. Sevoflurane can be administered with any type of anaesthesia circuit. MAC values according to age are presented in Table 5
| Table 5 MAC Values According to Age | |||
| Age of Patient | Number of Patients | MAC in Oxygen | MAC in 65% N 2 O/35% O 2 |
| Infants 1 - < 6 mo. 6 - < 12 mo. | 26 | 3.0% 2.8% | - - |
| Children 1 - < 3 years 3 - 12 years | 39 | 2.6% 2.5% | 2.0% - |
| Adults | 41 | 2.5% | 1.4% |
| 25 years | |||
| 40 years | 2.1% | 1.1% | |
| 60 years | 1.6% | 0.9% | |
| 80 years | 1.4% | 0.7% | |
Note 1: In 12 neonates of full-term gestational age, MAC was determined to be 3.3% Note 2: In 1 - < 3 yrs old paediatric patients, 60% N2O/40% O2 was used.
Administration
Sevoflurane is administered by vaporization. The concentration of Sevoflurane being delivered from a vaporizer during anaesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane. The administration of general anaesthesia must be individualized based on the patient's response. 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 anaesthesiologist. Sevoflurane has a non-pungent odour and does not cause respiratory irritability; therefore, it is suitable for mask induction in paediatrics and adults.
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.
Sevoflurane is an inhalation anaesthetic agent for use in induction and maintenance of general anaesthetics. Sevoflurane has a non-pungent odour and does not cause respiratory irritability. Sevoflurane is suitable for mask induction in adults and paediatrics. 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.)
Pharmacodynamics
Emergence times in paediatric patients are faster for sevoflurane (12 minutes) than for halothane (19 minutes). Time to first analgesia in paediatric patients is earlier in sevoflurane (approx. 52 minutes) than with halothane (approx. 68 minutes). The facts should be taken into account in cases where post-anaesthesia pain is anticipated.
Cardiovascular Effects
Sevoflurane was studied in 14 healthy volunteers (18-35 years old) comparing sevoflurane-O2 (Sevo/O2) to sevoflurane-N2O/O2 (Sevo/N2O/O2) during 7 hours of anaesthesia. During controlled ventilation, hemodynamic parameters measured are shown in Figures 1 to 4.
-Sevoflurane does not produce an increase in heart rate with or without nitrous oxide at doses less than 2 MAC.
- The decrease in mean arterial pressure seen with sevoflurane with or without nitrous oxide is dose dependent at all MAC values
- The decrease in systemic vascular resistance seen with sevoflurane with or without nitrous oxide is dose dependent at MAC values.
- Sevoflurane has a dose-related cardiac depressant effect with or without nitrous oxide
A study investigating the epinephrine-induced arrhythmogenic effect of sevoflurane versus isoflurane in adult patients undergoing transsphenoidal hypophysectomy (N=40) 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 ug/kg in both groups.
Cardiovascular Surgery/Coronary Artery Bypass Graft (CABG) Surgery
Sevoflurane was compared to isoflurane as an adjunct with opioids in a multicentre study of 273 patients undergoing CABG surgery. The average MAC dose was 0.49 for sevoflurane and 0.53 for isoflurane. No statistical differences were observed between the two treatment groups with respect to incidence (Sevoflurane 7%, Isoflurane 11%) and duration (Sevoflurane approx. 18 minutes, Isoflurane approx. 17 minutes) of ischemic events, number of patients with diagnosis of myocardial infarction (Sevoflurane 8%, Isoflurane 10%), time to hemodynamic stability (Sevoflurane approx. 5 hrs, Isoflurane approx. 6 hrs), or use of cardioactive drugs (Sevoflurane 53%, Isoflurane 47%).
Non-Cardiac Surgery Patients at Risk for Myocardial Ischemia
Sevoflurane-N2O was compared to isoflurane-N2O for maintenance in anaesthesia in a multicentre study of 214 patients who were mild-to-moderate risk for myocardial ischemia who underwent elective non-cardiac surgery. The average MAC dose was 0.49 for both drugs. No statistical differences were observed between the treatment groups for the incidence of any hemodynamic variation (tachycardia, bradycardia, hypertension, hypotension, and ischemia without hemodynamic abnormality). No statistical differences were observed between the two regimens with respect to intra-operative incidence of myocardial ischemia (Sevoflurane 6%, Isoflurane 3%) or post-operative incidence of ischemia events (Sevoflurane 10%, Isoflurane 16%). No statistical differences were observed between the treatment groups for the incidence of study drug-related adverse experience by body system or by COSTART term (Sevoflurane 60%, Isoflurane 61%). There was one death in Sevoflurane group while four deaths occurred in the Isoflurane group. None of these deaths were considered by the investigator to be drug-related.
Pharmacokinetics
Because of low solubility of sevoflurane in blood (blood/gas partition coefficient @ 37degC = 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 arterial partial pressure. Therefore there is a rapid rate of increase in the alveolar (end-tidal) concentration (FA) toward the inspired concentrations (F1) during induction and rapid elimination via the lungs when it is discontinued.
Sevoflurane is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIP) with the release of inorganic fluoride and CO2. Once formed, HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolite 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 isoniazide 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 barbituates. Inorganic fluoride concentrations peak within 2 hours of the end of sevoflurane anaesthesia and return to baseline concentrations within 48 hours post-anaesthesia in the majority of cases (67%). The rapid and extensive pulmonary elimination of sevoflurane minimizes the amount of anaesthesia available for metabolism. In 12 clinical trials with sevoflurane, approximately 7% (55 out of 886) of adults evaluated for inorganic fluoride had serum concentrations greater than 50 uM; there were no reports of toxicity associated with elevated fluoride ion levels.
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 non-renal (via fluoride being taken up into bone).
Special Populations and Conditions
The concentration of sevoflurane required for maintenance of general anaesthesia is age- dependent (see DOSAGE AND ADMINISTRATION). Incidences of bradycardia (more than 20 beats/min less than normal) is lower for sevoflurane (3%) than for halothane (7%). Emergence times for sevoflurane are faster than halothane (12 vs 19 minutes, respectively). A higher incidence of agitation occurs with sevoflurane (208/837 patients or 25%) when compared with halothane (114/661 patients or 17%).
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. In adults, the incidence of bradycardia is greater with sevoflurane than with isoflurane.
In a limited number of patients with mild-to-moderate heptic impairment (N=16), the hepatic function was not affected by sevoflurane. The safety of sevoflurane in patients with severe hepatic impairment has not yet been demonstrated; therefore, sevoflurane should be used with caution in these patients.
Limited pharmacokinetic data in these patients appear to suggest that the half-life of sevoflurane may be increased. The clinical significance is unknown at this time.
The only known degradation reaction in the clinical setting is through direct contact with CO2 absorbents (soda lime and Baralyme(r)) producing Compound A (pentafluoroisopropenyl fluoromethyl ether). The concentrations of Compound A measured in the anaesthesia circuit when sevoflurane is used as indicated are not known to be deleterious to humans. Fresh gas flow rates below 2 L/min in a circle absorber system are not recommended, as safety at lower rates has not yet been established.
Sevoflurane should be stored between 15 and 30EC. Sevoflurane is chemically stable under normal conditions, but can be degraded by some bases and Lewis acids under certain conditions. A degradation reaction occurs through direct contact with CO2 absorbents (soda lime and Baralyme(r)) producing pentafluoroisopropenyl fluoromethyl ether, [(PIFE), C4H2F6O] also known as Compound A and trace amounts of Compound B [pentafluoromethoxy isopropyl fluoromethyl ether, (PMFE) C5H6F6O] in the clinical setting. The interaction with CO2 absorbents is not unique to sevoflurane. The production of degradants in the anaesthesia 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. Sevoflurane is not corrosive to stainless steel, brass, aluminum, nickle plated brass, chrome plated brass or copper beryllium.
Dosage Form and Strength Inhalation Anaesthetic/99.97% sevoflurane in 250mL bottles. Sevoflurane is available in a 250mL aluminum bottle with an aluminum or polypropylene closure.
PART II: SCIENTIFIC INFORMATION
Drug Substance
Proper name: Sevoflurane Chemical name: Fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether Molecular formula and molecular mass: C4H3F7O 200.05 Structural formula:
F3C
H F3C
Physicochemical properties
C OCH2F
Sevoflurane, a nonflammable and nonexplosive liquid administered by vaporization, is a halogenated general inhalation anaesthetic drug. The boiling point is 58.6EC at 760 mm Hg, and the vapor pressure (in mm Hg) is 157 mm Hg at 20EC, 197 mm Hg at 25EC and 317 mm Hg at 36EC. Sevoflurane is nonpungent. It is miscible with ethanol, chloroform and petroleum benzene, and it is slightly soluble in water. Vapor pressure (mm Hg) can be calculated using the equation: Log10Pvap = A+B/T A = 8.086 B = -1726.68 T = EC + 273.16EK (Kelvin) The specific gravity is 1.520 - 1.525 at 20EC Distribution Partition Coefficients at 37EC: Blood/Gas 0.63 - 0.69 Water/Gas 0.36 Olive Oil/Gas 47.2 - 53.9 Brain/Gas 1.15 Mean Component/Gas Partition Coefficients at 25EC for polymers used commonly in medical applications:
| Conductive rubber | 14.0 |
| Butyl rubber | 7.7 |
| Polyvinyl chloride | 17.4 |
| Polyethylene | 1.3 |
Sevoflurane is a clear, colorless, liquid containing no additives or chemical stabilizers. The finished product is comprised only of the active drug substance, sevoflurane (about 99.975% w/w on anhydrous basis).
Methyl ethers have proven to be a successful series of anaesthetics because of several characteristics: molecular stability, non-flammability, lack of arrhythmogenicity, lack of neuronal excitation, relative cardiovascular stability, large lethal to anaesthetic concentration ratio, minimal effect on cerebral blood flow at low concentrations and minimal end-organ effects. In addition to these characteristics, Sevoflurane exhibits a low blood solubility with a blood gas partition coefficient of 0.63 to 0.69 at 37EC and has a pleasant, non-irritating odor. These qualities provide a rapid and smooth inhalation induction of, and rapid recovery from, anaesthesia. Equipotent doses of Sevoflurane and Isoflurane produce similar effects on cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), intracranial pressure (ICP) and electroencephalogram patterns (EEG). In contrast, after short-term exposure, Sevoflurane administration (1 MAC) produces a smaller increase in ICP than doses an equipotent concentration of Halothane. Anaesthesia with Sevoflurane is both time- and concentration-dependent and involves suppression of cerebral cortex activity (loss of awareness and motor reflex), suppression of the cerebellum and mesencephalon (loss of righting reflex, corneal reflex), suppression of the spinal cord (loss of the tail pinch response), suppression of the medulla oblongata (depression of respiration). Sevoflurane suppresses heart rate and arterial blood pressure in a dose-dependent fashion. In general, the hemodynamic/cardiovascular effects of Sevoflurane are comparable to those of Isoflurane. However, a more pronounced tachycardia was observed in dogs exposed to 1.2 MAC Sevoflurane than those animals exposed to 1.2 MAC Isoflurane. The magnitude of myocardial contractile depression observed in dogs during Sevoflurane anaesthesia was similar to those previously reported for Isoflurane and Desflurane; however, Sevoflurane appears to cause less depression of the inotropic state than that reported with Halothane. Sevoflurane does not appear to have any remarkable coronary vasodilatory effects, does not negatively affect the blood flow distribution in areas of local myocardial ischemia, and, therefore, does not appear to exacerbate myocardial ischemia. Sevoflurane does not reduce collaterally-derived myocardial perfusion or cause coronary steal. At clinical concentrations in the absence of pacing, Sevoflurane does not affect atrioventricular (A-V) conduction. Sevoflurane appears to have a lower risk for the potentiation of epinephrin- induced arrhymias, or other pressoramine-induced arrhythmias, than either Halothane or Enflurane. The administration of epinephrine during Sevoflurane anaesthesia does not appear to be associated with the production of ventricular arrhythmia. In a dog model, Halothane was more sensitizing to the myocardium in the presence of pressoramines than was Sevoflurane. Also, in the same dog model, ventricular fibrillation was observed with epinephrine and norepinephrine under Halothane anaesthesia; however, no ventricular fibrillation was produced under Sevoflurane anaesthesia in this study. Mean MAC for Sevoflurane has been determined as 2.2% in rats, 2.3% in mice, 3.61 to 3.7% in rabbits, 2.36% in dogs, 2.58% in cats, and 2.12% in newborn swine. Sevoflurane will trigger malignant hyperthermia (MH) in susceptible pigs; however, it is a weak trigger. The onset of MH is slow and easily reversible. In contrast, Halothane triggers MH in susceptible pigs much sooner and more strongly than does Sevoflurane.
Acute Toxicity
Five laboratory animal species (rat, mouse, rabbit, dog, monkey) have been studied to determine the acute toxic effects and median lethal concentrations of Sevoflurane via the inhalation route and, in rodents, by oral, and parenteral routes. Calculated median lethal concentration for 1-hour inhalation exposer ranged from 5.8% in the rat to 10.6% in rabbits. Prolongation of exposure lowered the LC50 within each species (See Table 6).
| Table 6 Summary of Calculated Median Lethal Concentrations | ||
| Species | Inhalation LC 50 (%) | |
| 1-Hour | 3-Hour | |
| Mouse | 8.3 | 2.9 |
| Rat | 5.8 | 2.9 |
| Rabbit | 10.6 | - |
| Dog | 7.3 | - |
| Monkey | - | 6.8 |
Sevoflurane was virtually non-toxic orally (LD50 10.8 - 24.3 mL/kg) and parenterally (LD50 6.3 - 11.7 mL/kg). No significant differences in response to Sevoflurane were detected between males and females. Neonatal rodents were shown to be more tolerant to acute exposure than adults. Dyspnea and cyanosis appeared to be the primary cause of death following acute inhalation exposure in all species studied. There was no clear organ pathology associated with acute Sevoflurane exposure in these studies even at lethal concentrations.
Subchronic Toxicity
Repeated exposure studies have confirmed the absence of any specific organ toxicity associated with non-lethal concentrations of Sevoflurane. Rats and monkeys have been exposed for up to 3 hours/day, 3 days/week, for 8 weeks at concentrations ranging from 0.1 to 1.0 MAC (0.22 to 2.2%) and 1.0 to 2.5 MAC (2 to 5%), respectively. Dogs have been repeatedly anesthetized (3 hours/day, 5 days/week for 2 weeks) at concentrations of up to 5%. Dogs and monkeys in these studies revealed no evidence of autonomic or central nervous system stimulation, cardiac arrhythmia or unexpected cardiorespiratory depression. Bradycardia was rarely reported in dogs, and was never observed in monkeys. Clinical observations, hematology and pathology were unremarkable, indicating no adverse events.
Reproduction and Teratology
There were no significant effects on male and female reproductive capabilities at exposure concentrations of up to 1.0 MAC (2.2%) in a classic Segment 1 reproduction study. Systemic toxicity, as manifested by reductions in body weight gain, was observed in the males at exposures > 0.5 MAC (1.1%) and at exposures > 0.3 MAC (0.66%) in females. Fetal body weights were slightly reduced at these maternally toxic exposure levels (>0.3 MAC), and an increase in skeletal variations at the highest exposure level, a common occurrence in this species, was also observed. Developmental toxicity (Segment II and III) studies in rats indicate that Sevoflurane is not a selective developmental toxicant. Similar to what was observed in the rat reproduction study, reductions in fetal and neonatal body weights and increased skeletal variations were observed only at maternally toxic concentrations of 1.0 MAC (2.2%). No effect on offspring viability, behaviour or reproductive capabilities was observed. In rabbits, no developmental toxicity was observed at maternally toxic concentrations of up to 1.0 MAC (1.8%). Mutagenicity studies indicate that Sevoflurane is not mutagenic when tested both in vitro and in vivo.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies on carcinogenesis have not been performed. No mutagenic effect was noted in the Ames test and no chromosomal aberrations were induced in cultured mammalian cells.
Special Toxicity Studies
In Wistar rats the LC50 of Compound A was 1050 to 1090 ppm in animals exposed for 1 hour and 400 to 420 ppm in animals exposed for 3 hours (median lethal concentrations were approximately 1070 and 330 to 490 ppm, respectively). In rats exposed to 30, 60, or 120 ppm of Compound A in an eight week chronic toxicity study (24 exposures, 3 hours/exposure), no apparent evidence of toxicity was observed other than loss of body weight in females on the last study day. Sprague-Dawley rats were administered Compound A via nose-only inhalation exposure in an open system (25,50, 100 or 200 ppm [0.0025 to 0.02%] of Compound A alone or in combination with 2.2% sevoflurane. Control groups were exposed to air. The threshold, at which reversible alterations in urinary and clinical parameters indicative of renal changes (concentration- dependent increases in BUN, creatinine, glucose, protein/creatinine ratios and N-acetyl- glucosamidase/creatinine ratios) were observed, was 114 ppm Compound A. Histological lesions were reversible as indicated by histological examinations and by urinalysis surrogate markers (ketones, occult blood, glucose, NAG/creatine, protein/creatinine). Since the uptake of inhalation agents in small rodents is substantially higher than in humans, higher levels of drug, Compound A (degradant of Sevoflurane) or 2-bromo-2-chloro-1, 1- difluoro ethylene (BCDFE) (degradant/metabolite of halothane) would be expected in rodents. Also, the activity of the key enzyme (b-lyase) involved in haloalkene nephrotoxicity is tenfold greater in the rat than it is in humans. In the clinical situation, the highest concentration of Compound A in the anaesthesia circuit with soda lime as the CO2 absorbant was 15 ppm in pediatrics and 32 ppm in adults. However, concentrations to 61 ppm have been observed in patients attached to systems with Baralyme(r) as the CO2 absorbant with no evidence of renal dysfunction.
In the clinical situation, the concentration of Compound B detected in the anaesthesia circuit did not exceed 1.5 ppm. Inhalation exposure to Compound B at concentrations of up to 2400 ppm (0.24%) for 3 hours resulted in no adverse effects on renal parameters or tissue histology in Wister rats.
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