Sevorane

Sevoflurane is a nonflammable liquid anesthetic agent administered by vaporization. It is a fluorinated derivative of methyl isopropyl ether. Sevoflurane is identified chemically as fluoromethyl 2, 2, 2-trifluoro-1-(trifluoromethyl) ethyl ether and has a molecular weight of 200.05.
Sevoflurane has the following physical and chemical properties: See Tables 1 and 2.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Sevoflurane is nonflammable and non-explosive as defined by the requirements of International Electrotechnical Commission 601-2-13.
Sevoflurane is a clear, colorless, liquid. Sevoflurane is nonpungent. It is miscible with ethanol, ether, chloroform and petroleum benzene, and it is slightly soluble in water.
Sevoflurane Degradation: Sevoflurane is stable when stored under normal room lighting conditions. No discernible degradation of sevoflurane occurs in the presence of strong acids or heat. Sevoflurane is not corrosive to stainless steel, brass, aluminum, nickel-plated brass, chrome-plated brass, or copper beryllium alloy. Chemical degradation can occur upon exposure of inhaled anesthetics to CO₂ absorbent within the anesthesia machine. When used as directed with fresh absorbents, degradation of sevoflurane is minimal, and degradants are undetectable or non-toxic. Sevoflurane degradation and subsequent degradant formation are enhanced by increasing absorbent temperature, desiccated CO₂ absorbent (especially potassium hydroxide-containing), increased sevoflurane concentration and decreased fresh gas flow. Sevoflurane can undergo alkaline degradation by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropanyl fluoromethyl ether (PIFE or more commonly known as Compound A). The second pathway for degradation of sevoflurane occurs only in the presence of desiccated CO₂ absorbents and leads to the dissociation of sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic, rapidly glucuronidated, cleared, and has toxicity comparable to sevoflurane. 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. 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. With highly desiccated absorbents, especially those containing potassium hydroxide, the formation of formaldehyde, methanol, carbon monoxide, Compound A and perhaps some of it's degradants, Compounds B, C, and D may occur.
Lewis Acid Degradation: At least 300 ppm of water is added as a Lewis acid inhibitor. No other additives or chemical stabilizers are utilized.
Formulation: Contains: Fluoromethyl 2, 2, 2-trifluoro-1 -(trifluoromethyl) ethyl ether (Sevoflurane) 250 mL Wet Formulation.

Pharmacology: Pharmacodynamics: In a variety of animal species including man, sevoflurane has been demonstrated to be a fast-acting, non-irritating agent. Administration has been associated with a smooth, rapid loss of consciousness during inhalational induction and a rapid recovery following discontinuation of anesthesia.
Induction is accomplished, with a minimum of excitement or signs of upper respiratory irritation, no evidence of excessive secretions within the tracheobronchial tree and no central nervous system stimulation. In pediatric studies in which mask induction was performed, the incidence of coughing was statistically significantly lower with sevoflurane than with halothane.
Like other potent inhalational anesthetics, sevoflurane depresses respiratory function and blood pressure in a dose-related manner.
In both dogs and humans, the epinephrine-induced arrhythmogenic threshold for sevoflurane was comparable to that of isoflurane and higher than that of halothane. Studies in dogs have demonstrated sevoflurane does not reduce collateral myocardial perfusion. In clinical studies, the incidence of myocardial ischemia and myocardial infarction in patients at risk for myocardial ischemia was comparable between sevoflurane and isoflurane.
Animal studies have shown regional blood flow (e.g., hepatic, renal, cerebral circulations) is well-maintained with sevoflurane. In both animal studies (dogs, rabbits) and clinical studies, changes in neurohemodynamics (intracranial pressure, cerebral blood flow/blood flow velocity, cerebral metabolic rate for oxygen, and cerebral perfusion pressure) were comparable between sevoflurane and isoflurane. Sevoflurane has minimal effect on ICP (intracranial pressure) and preserves CO₂ responsiveness.
Sevoflurane does not affect renal concentrating ability, even after prolonged anesthetic exposure, up to approximately nine hours.
Minimum Alveolar Concentration: The minimum alveolar concentration (MAC) is the concentration at which 50% of the population tested does not move in response to a single stimulus of skin incision. For MAC equivalents for sevoflurane for various age groups, see Dosage & Administration.
The MAC of sevoflurane in oxygen was determined to be 2.05% for a 40 year old adult. As with other halogenated agents, MAC decreases with age and with the addition of nitrous oxide.
Clinical Studies: Efficacy: Numerous clinical studies have been conducted with sevoflurane as the anesthetic agent for pediatric and adult patients. The results have shown sevoflurane provides smooth, rapid induction of, as well as rapid emergence from, anesthesia.
Sevoflurane was associated with faster times to induction and to such recovery events as emergence, response to command, and orientation compared to reference drugs.
Adult Anesthesia: Mask Induction: In adult studies in which mask induction was performed, sevoflurane was demonstrated to provide smooth and rapid induction of anesthesia.
Maintenance: In 3 outpatient and 25 inpatient studies involving 3591 adult patients (2022 sevoflurane, 1196 isoflurane, 111 enflurane, 262 propofol) sevoflurane was demonstrated to be an effective agent for the maintenance of anesthesia.
Sevoflurane was demonstrated to be an appropriate agent for use in neurosurgery, Cesarean section, patients undergoing coronary artery bypass surgery (CABG), and non-cardiac patients at risk for myocardial ischemia.
Pediatric Anesthesia: In two outpatient and three inpatient studies involving 1498 pediatric patients (837 sevoflurane, 661 halothane), sevoflurane was demonstrated to be an effective agent for the induction and maintenance of anesthesia.
Mask Induction: In pediatric studies in which mask induction was performed, the induction time was statistically significantly shorter and the incidence of coughing was statistically significantly lower with sevoflurane than with halothane.
Safety: Clinical studies were conducted in a wide variety of patient populations (children, adults, elderly, renally impaired, hepatically impaired, obese, patients undergoing cardiac by-pass surgery, patients treated with aminoglycosides or metabolic inducers, patients exposed to repeat surgeries, patients undergoing surgeries ≥6 hours in duration). The results of evaluation of laboratory parameters (e.g., SGPT, SGOT, alkaline phosphatase, total bilirubin, serum creatinine, BUN) as well as investigator-reported incidence of adverse events relating to hepatic and renal function, demonstrated sevoflurane did not have a clinically significant effect on liver or kidney function, nor did it exacerbate pre-existing renal and hepatic impairment within these study populations (see Hepatic under Precautions and Adverse Reactions). These studies also demonstrated there were no statistically significant differences between sevoflurane and reference agents in the proportions of patients showing changes in any clinical chemistry parameter.
The impact on renal function was comparable among sevoflurane and the reference drugs, between types of anesthesia circuits, among flow rates, and between patients with or without inorganic fluoride concentrations ≥50 μm.
The incidence of renal dysfunction was <1% for both sevoflurane (0.17%) and reference drugs (0.22%; isoflurane, halothane, enflurane, propofol) in comparative studies. This overall incidence is consistent with that of a general surgical population. In all cases, an alternate cause or reasonable explanation existed for the renal dysfunction.
Pediatric: Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anesthetic agents early in life. 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. In addition, more recent published registry studies did not confirm these findings.
Published animal studies of some anesthetic/sedation drugs have reported adverse effects on brain development in early life (see Pharmacology: Toxicology: Pre-Clinical Safety Data as follows).
Hepatically Impaired: During clinical development, sevoflurane was effective and well-tolerated when used as the primary agent for the maintenance of anesthesia in patients with impaired hepatic function, Child-Pugh Class A and B, and sevoflurane did not exacerbate pre-existing hepatic impairment.
For hepatic adverse events seen in postmarketing experience, see Hepatic under Precautions and Adverse Reactions.
Renally Impaired: Sevoflurane was evaluated in renally impaired patients with baseline serum creatinine ≥1.5 mg/dL (130 μmole/L). Based on the incidence and magnitude of changes in serum creatinine concentrations, sevoflurane did not further deteriorate renal function.
Pharmacokinetics: Solubility: The low solubility of sevoflurane in blood would suggest alveolar concentrations should rapidly increase upon induction and rapidly decrease upon cessation of the inhales agent. This was confirmed in a clinical study where inspired and end-tidal concentrations (F_I and F_A) were measured. The F_A/F_I (washin) value at 30 minutes for sevoflurane was 0.85. The F_A/F_AO (washout) value at five minutes was 0.15.
Distribution: 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: The rapid pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism. In humans <5% sevoflurane absorbed is metabolized via cytochrome P450 2E1 isoform to hexafluorisopropanol (HFIP), with release of inorganic fluoride and carbon dioxide (or a one carbon fragment). Once formed HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. It is the only fluorinated volatile anesthetic which is not metabolized to trifluoroacetic acid.
Fluoride Ion: Fluoride ion concentrations are influenced by the duration of anesthesia, the concentration of sevoflurane administered, and the composition of the anesthetic gas mixture.
The defluorination of sevoflurane is not inducible by barbiturates.
Approximately 7% of adults evaluated for inorganic fluoride concentrations in the Abbott Clinical Program experienced concentrations greater than 50 μm; no clinically significant effect on renal function was observed in any of these individuals (see Inducers of CYP2E1 under Interactions).
Toxicology: Pre-Clinical Safety Data: Sevoflurane has a low order of acute toxicity in rats, mice, rabbits, dogs and monkeys. Anesthesia induction was smooth and rapid, with no struggling, signs of gasping or other undesirable reactions. Deaths from exposure to lethal concentrations were due to respiratory arrest. Exposure was not associated with any specific organ toxicity or developmental toxicity in laboratory animals.
Fischer 344 rats were anesthetized within two to three minutes after start of exposure to sevoflurane (1.4%) for up to ten hours. There were no functional or morphologic defects following administration of sevoflurane. In a Segment I reproduction study, sevoflurane had no significant effects on male or female reproductive capabilities at exposure concentrations of up to 1.0 MAC (2.2%). Segment II and III studies in rats indicate sevoflurane is not a selective developmental toxicant.
Published studies in pregnant and juvenile animals suggest that the use of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anesthetic agents from a variety of drug classes. The clinical significance of these nonclinical findings is yet to be determined (see Pharmacology: Pharmacodynamics: Clinical Studies: Safety as previously mentioned).
Compound A: In Wistar rats the LC50 of Compound A was 1050 to 1090 ppm in animals exposed for one hour and 400 to 420 ppm in animals exposed for three 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 8-week chronic toxicity study (24 exposures, three 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). 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 of Compound A. Histological lesions were all reversible.
Since the uptake of inhalational 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 (β-Iyase) involved in haloalkene nephrotoxicity is ten-fold greater in the rat than it is in humans.
Compound A concentrations are reported to increase with increasing absorber temperature, increasing sevoflurane concentrations and decreasing fresh gas flow rates. It has been reported that the concentration of Compound A increases significantly with prolonged dehydration of Baralyme. In the clinical situation, the highest concentration of Compound A in the anesthesia circuit with soda lime as the CO₂ absorbent 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 as the CO₂ absorbent. The level of Compound A at which toxicity occurs in humans is not known. Although exposure to sevoflurane in low flow systems is limited, there has been no evidence of renal dysfunction attributable to Compound A.
Compound B: In the clinical situation, the concentration of Compound B detected in the anesthesia circuit did not exceed 1.5 ppm. Inhalation exposure to Compound B at concentrations of up to 2400 ppm (0.24%) for three hours resulted in no adverse effects on renal parameters or tissue histology in Wistar rats.
Carcinogenesis: 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.

Sevoflurane may be used for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery.

Premedication: Premedication should be selected according to the need of the individual patient, and at the discretion of the anesthesiologist.
Surgical Anesthesia: The concentration of sevoflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane.
Induction: Dosage should be individualized and titrated to the desired effect according to the patient's age and clinical status. A short acting barbiturate or other intravenous induction agent may be administered followed by inhalation of sevoflurane. Induction with sevoflurane may be achieved in oxygen or in combination with oxygen-nitrous oxide mixtures. For induction of anesthesia, inspired concentrations of up to 8% sevoflurane usually produces surgical anesthesia in less than two minutes in both adults and children.
Maintenance: Surgical levels of anesthesia may be sustained with concentrations of 0.5-3% sevoflurane with or without the concomitant use of nitrous oxide (see Nitrous Oxide under Interactions). (See Table 3.)

Click on icon to see table/diagram/image

Emergence: Emergence times are generally short following sevoflurane anesthesia. Therefore, patients may require post-operative pain relief earlier.
D and A-Geriatric: MAC (Minimum Alveolar Concentration) 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 the event of apparent 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 should not be used in patients with known or suspected genetic susceptibility to malignant hyperthermia.
Sevoflurane should not be used in patients with known or suspected sensitivity to sevoflurane or to other halogenated inhalational anesthetics (e.g. history of hepatotoxicity, usually including elevated liver enzymes, fever, leukocytosis and/or eosinophilia temporally related to anesthesia with one of these agents).

Sevoflurane may cause respiratory depression, which may be augmented by narcotic premedication or other agents causing respiratory depression. Respiration should be supervised and if necessary, assisted.
Sevoflurane should be administrated only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation and oxygen enrichment, and circulatory resuscitation must be immediately available.
The concentration of sevoflurane being delivered from a vaporizer must be known exactly. As volatile anaesthetics differ in their physical properties, only vaporizers specifically calibrated for sevoflurane must be used. The administration of general anaesthesia must be individualized based on the patient's response. Hypotension and respiratory depression increase as anaesthesia is deepened.
Isolated reports of QT prolongation, very rarely associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering sevoflurane to susceptible patients.
Isolated cases of ventricular arrhythmia were reported in pediatric patients with Pompe's disease.
Caution should be exercised in administering general anesthesia, including sevoflurane, to patients with mitochondrial disorders.
Hepatic: Very rare cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from post-marketing experiences.
Clinical judgment 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, especially if the interval is less than3 months, may increase the potential for hepatic injury.
Malignant Hyperthermia: In susceptible individuals, potent inhalation anesthetic agents, including sevoflurane, may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. 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 have been fatal.
Treatment of malignant hyperthermia includes discontinuation of triggering agents (e.g. sevoflurane), administration of intravenous dantrolene sodium (consult prescribing information for intravenous dantrolene sodium for additional information on patient management), and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, 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.
Preoperative 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 post-operative 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.
General: During maintenance of anesthesia, increasing the concentration of sevoflurane produces dose-dependent decreases in blood pressure. Excessive decrease in blood pressure may be related to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of sevoflurane.
As with all anesthetics, maintenance of hemodynamic stability is important to the avoidance of myocardial ischemia in patients with coronary artery disease.
The recovery from general anesthesia should be assessed carefully before patients are discharged from the post-anesthesia care unit.
Although recovery of consciousness following sevoflurane administration generally occurs within minutes, the impact on intellectual function for two or three days following anesthesia has not been studied. As with other anesthetics, small changes in moods may persist for several days following administration (see Effects on Ability to Drive and Use Machines as follows).
Replacement of Desiccated CO₂ Absorbents: 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, specifically those containing potassium hydroxide. 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.
An exothermic reaction, enhanced sevoflurane degradation, and production of degradation products (see Description) can occur when the CO₂ absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO₂ absorbent canisters. Sevoflurane degradants (methanol, formaldehyde, carbon monoxide, and Compounds A, B, C, and D) were observed in the respiratory circuit of an experimental anesthesia machine using desiccated CO₂ absorbents and maximum sevoflurane concentrations (8%) for extended periods of time (≥2 hours). Concentrations of formaldehyde observed at the anesthesia respiratory circuit (using sodium hydroxide containing absorbents) were consistent with levels known to cause mild respiratory irritation. The clinical relevance of the degradants observed under this extreme experimental model is unknown.
When a clinician suspects that the CO₂ absorbent may be desiccated, it should be replaced before administration of sevoflurane. 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.
Renal Impairment: 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.
Neurosurgery: In patients at risk for elevations of ICP, sevoflurane should be administered cautiously in conjunction with ICP-reducing maneuvers such as hyperventilation.
Seizures: Rare cases of seizures have been reported in association with sevoflurane use (see Use in Children as follows and Adverse Reactions).
Drug Abuse and Dependence: None known.
Effects on Ability to Drive and Use Machines: Patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, may be impaired for some time after general anesthesia.
Use in Children: The use of sevoflurane has been associated with seizures. Many of these have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors. Clinical judgment should be exercised when using sevoflurane in patients who may be at risk for seizures (see Adverse Reactions).

Pregnancy: Pregnancy Category B: Reproduction studies in rats and rabbits at doses up to 1 MAC have revealed no evidence of impaired fertility or harm to the fetus due to sevoflurane. There are no adequate and well-controlled studies in pregnant women; therefore, sevoflurane should be used during pregnancy only if clearly needed.
Published animal studies of some anesthetic/sedation drugs have reported adverse effects on brain development in early life (see Pharmacology: Toxicology: Pre-Clinical Safety Data under Actions).
Labor and Delivery: In a clinical trial, the safety of sevoflurane was demonstrated for mothers and infants when used for anesthesia during Cesarean section. The safety of sevoflurane in labor and vaginal delivery has not been demonstrated.
Sevoflurane, like other inhalational agents, has relaxant effects on the uterus with the potential risk for uterine bleeding. Clinical judgment should be observed when using sevoflurane during obstetric anesthesia.
Lactation: It is not known whether sevoflurane or its metabolites is excreted in human milk. Due to the absence of documented experience, women should be advised to skip breast-feeding for 48 hours after administration of sevoflurane and discard milk produced during this period.

As with all potent inhaled anesthetics, sevoflurane may cause dose-dependent cardio-respiratory depression. Most adverse events are mild or moderate in severity and transient in duration. Nausea, vomiting, and delirium have been observed in the postoperative period, common sequelae of surgery and general anesthesia, which may due to inhalational anesthetic, other agents administered intra-operatively or post-operatively, and to the patient's response to the surgical procedure.
ADR-Clinical Trials: As with all potent inhaled anesthetics, sevoflurane may cause dose-dependent cardio-respiratory depression. Most adverse events are mild or moderate in severity and transient in duration. Nausea and vomiting have been observed in the postoperative period, common sequelae of surgery and general anesthesia, which may due to inhalational anesthetic, other agents administered intra-operatively or post-operatively, and to the patient's response to the surgical procedure.
The most commonly reported adverse reactions were as follows: In adult patients: hypotension, nausea and vomiting.
In elderly patients: bradycardia, hypotension and nausea.
In pediatric patients: agitation, cough, vomiting and nausea.
All events, at least possibly related to sevoflurane from clinical trials, are displayed in the Table as follows by MedDRA System Organ Class, Preferred Term and frequency. The following frequency groupings are used: very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000), including isolated reports. The type, severity, and frequency of adverse events in sevoflurane patients were comparable to adverse events in reference-drug patients. (See Table 4.)

Click on icon to see table/diagram/image

ADR-Post-Marketing Experience: Adverse events have been spontaneously reported during post-approval use of sevoflurane. These events are reported voluntarily from a population of an unknown rate of exposure. Therefore it is not possible to estimate the true incidence of adverse events or establish a causal relationship to sevoflurane exposure. (See Table 5.)

Click on icon to see table/diagram/image

Beta-sympathomimetic agents like isoprenaline and alpha- and beta-sympathomimetic agents like adrenaline and noradrenaline should be used with caution during Sevoflurane narcosis, due to a potential risk of ventricular arrhythmia.
Non-selective MAO-inhibitors: Risk of crisis during the operation. It is generally recommended that treatment should be stopped 2 weeks prior to surgery.
Sevoflurane may lead to marked hypotension in patients treated with calcium antagonists, in particular dihydropyridine derivates.
Caution should be exercised when calcium antagonists are used concomitantly with inhalation anesthetics due to the risk of additive negative inotropic effect.
Concomitant use of succinylcholine with 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 post-operative period.
Sevoflurane has been shown to be safe and effective when administered concurrently with a wide variety of agents commonly encountered in surgical situations such as central nervous system agents, autonomic drugs, skeletal muscle relaxants, anti-infective agents including aminoglycosides, hormones and synthetic substitutes, blood derivatives and cardiovascular drugs, including epinephrine.
Barbiturates: Sevoflurane administration is compatible with barbiturates as commonly used in surgical practice.
Benzodiazepines and Opioids: Benzodiazepines and opioids are 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.
Inducers of CYP2E1: Medicinal products and compounds that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may increase the metabolism of sevoflurane and lead to significant increases in plasma fluoride concentrations (see Pharmacology: Pharmacokinetics: Metabolism and Fluoride Ion under Actions).
Nitrous Oxide: As with other halogenated volatile anesthetics, the MAC of sevoflurane is decreased when administered in combination with nitrous oxide. The MAC equivalent is reduced approximately 50% in adult and approximately 25% in pediatric patients (see Maintenance under Dosage & Administration).
Neuromuscular Blocking Agents: As with other inhalational anesthetics agents, sevoflurane affects both the intensity and duration of neuromuscular blockade by non-depolarizing muscle relaxants. When used to supplement alfentanil - N₂O anesthesia, sevoflurane potentiates neuromuscular block induced with pancuronium, vecuronium or atracurium. The dosage adjustments for these muscle relaxants when administered with sevoflurane are similar to those required with isoflurane. The effect of sevoflurane on succinylcholine and the duration of depolarizing neuromuscular blockade has not been studied.
Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation because potentiation of neuromuscular blocking agents is observed a few minutes after the beginning of sevoflurane administration.
Among non-depolarizing agents, vecuronium, pancuronium and atracurium interactions have been studied. In the absence of specific guidelines: (1) for endotracheal intubation, do not reduce the dose of non-depolarizing muscle relaxants; and, (2) during maintenance of anesthesia, the dose of non-depolarizing muscle relaxants is likely to be reduced compared to that during N₂O/opioid anesthesia. Administration of supplemental doses of muscles relaxants should be guided by the response to nerve stimulation.

Store at temperature not exceeding 30°C.

Anaesthetics - Local & General

N01AB08 - sevoflurane ; Belongs to the class of halogenated hydrocarbons. Used as general anesthetics.

Rx