Drug Detail:Ultane (Sevoflurane [ see-voe-floo-rane ])
Drug Class: General anesthetics
Related/similar drugs
fentanyl, lidocaine, ketamine, hyoscyamine, propofol, glycopyrrolateUltane - Clinical Pharmacology
Sevoflurane is an inhalational anesthetic agent for use in induction and maintenance of general anesthesia. Minimum alveolar concentration (MAC) of sevoflurane in oxygen for a 40-year-old adult is 2.1%. The MAC of sevoflurane decreases with age (see DOSAGE AND ADMINISTRATION for details).
Pharmacogenomics
RYR1 and CACNA1S are polymorphic genes, and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (MHS) in patients receiving volatile anesthetic agents, including sevoflurane. Case reports as well as ex-vivo studies have identified multiple variants in RYR1 and CACNA1S associated with MHS. Variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence (see CONTRAINDICATIONS, WARNINGS - Malignant Hyperthermia).
CLINICAL STUDIES
Sevoflurane was administered to a total of 3185 patients. The types of patients are summarized as follows:
Type of Patients | Number | Studied |
ADULT | 2223 | |
Cesarean Delivery | 29 | |
Cardiovascular and patients at risk of myocardial ischemia | 246 | |
Neurosurgical | 22 | |
Hepatic impairment | 8 | |
Renal impairment | 35 | |
PEDIATRIC | 962 |
Clinical experience with these patients is described below.
Adult Anesthesia
The efficacy of sevoflurane in comparison to isoflurane, enflurane, and propofol was investigated in 3 outpatient and 25 inpatient studies involving 3591 adult patients. Sevoflurane was found to be comparable to isoflurane, enflurane, and propofol for the maintenance of anesthesia in adult patients. Patients administered sevoflurane showed shorter times (statistically significant) to some recovery events (extubation, response to command, and orientation) than patients who received isoflurane or propofol.
Mask Induction
Sevoflurane has a nonpungent odor and does not cause respiratory irritability. Sevoflurane is suitable for mask induction in adults. In 196 patients, mask induction was smooth and rapid, with complications occurring with the following frequencies: cough, 6%; breathholding, 6%; agitation, 6%; laryngospasm, 5%.
Ambulatory Surgery
Sevoflurane was compared to isoflurane and propofol for maintenance of anesthesia supplemented with N2O in two studies involving 786 adult (18-84 years of age) ASA Class I, II, or III patients. Shorter times to emergence and response to commands (statistically significant) were observed with sevoflurane compared to isoflurane and propofol.
Sevoflurane/N2O | Isoflurane/N2O | Sevoflurane/N2O | Propofol/N2O | |
Mean Maintenance | 0.64 ± 0.03 | 0.66 ± 0.03 | 0.8 ± 0.5 | 7.3 ± 2.3 |
Anesthesia | MAC·hr. | MAC·hr. | MAC·hr. | mg/kg/hr. |
Exposure ± SD | (n = 245) | (n = 249) | (n = 166) | (n = 166) |
Time to Emergence (min) | 8.2 ± 0.4 (n = 246) | 9.3 ± 0.3 (n = 251) | 8.3 ± 0.7 (n = 137) | 10.4 ± 0.7 (n = 142) |
Time to Respond to Commands (min) | 8.5 ± 0.4 (n = 246) | 9.8 ± 0.4 (n = 248) | 9.1 ± 0.7 (n = 139) | 11.5 ± 0.7 (n = 143) |
Time to First Analgesia (min) | 45.9 ± 4.7 (n = 160) | 59.1 ± 6.0 (n = 252) | 46.1 ± 5.4 (n = 83) | 60.0 ± 4.7 (n = 88) |
Time to Eligibility for | 87.6 ± 5.3 | 79.1 ± 5.2 | 103.1 ± 3.8 | 105.1 ± 3.7 |
Discharge from | (n = 244) | (n = 252) | (n = 139) | (n = 143) |
Recovery Area (min) | ||||
n = number of patients with recording of recovery events. |
Inpatient Surgery
Sevoflurane was compared to isoflurane and propofol for maintenance of anesthesia supplemented with N2O in two multicenter studies involving 741 adult ASA Class I, II or III (18-92 years of age) patients. Shorter times to emergence, command response, and first post-anesthesia analgesia (statistically significant) were observed with sevoflurane compared to isoflurane and propofol.
Sevoflurane/N2O | Isoflurane/N2O | Sevoflurane/N2O | Propofol/N2O | |
Mean Maintenance | 1.27 MAC·hr. | 1.58 MAC·hr. | 1.43 MAC·hr. | 7.0 mg/kg/hr |
Anesthesia | ± 0.05 | ± 0.06 | ± 0.94 | ± 2.9 |
Exposure ± SD | (n = 271) | (n = 282) | (n = 93) | (n = 92) |
Time to Emergence (min) | 11.0 ± 0.6 (n = 270) | 16.4 ± 0.6 (n = 281) | 8.8 ± 1.2 (n = 92) | 13.2 ± 1.2 (n = 92) |
Time to Respond to Commands (min) | 12.8 ± 0.7 (n = 270) | 18.4 ± 0.7 (n = 281) | 11.0 ± 1.20 (n = 92) | 14.4 ± 1.21 (n = 91) |
Time to First Analgesia (min) | 46.1 ± 3.0 (n = 233) | 55.4 ± 3.2 (n = 242) | 37.8 ± 3.3 (n = 82) | 49.2 ± 3.3 (n = 79) |
Time to Eligibility for Discharge from Recovery Area (min) | 139.2 ± 15.6 (n = 268) | 165.9 ± 16.3 (n = 282) | 148.4 ± 8.9 (n = 92) | 141.4 ± 8.9 (n = 92) |
n = number of patients with recording of recovery events. |
Pediatric Anesthesia
The concentration of sevoflurane required for maintenance of general anesthesia is age-dependent (see DOSAGE AND ADMINISTRATION). Sevoflurane or halothane was used to anesthetize 1620 pediatric patients aged 1 day to 18 years, and ASA physical status I or II (948 sevoflurane, 672 halothane). In one study involving 90 infants and children, there were no clinically significant decreases in heart rate compared to awake values at 1 MAC. Systolic blood pressure decreased 15%-20% in comparison to awake values following administration of 1 MAC sevoflurane; however, clinically significant hypotension requiring immediate intervention did not occur. Overall incidences of bradycardia [more than 20 beats/min lower than normal (80 beats/min)] in comparative studies was 3% for sevoflurane and 7% for halothane. Patients who received sevoflurane had slightly faster emergence times (12 vs. 19 minutes), and a higher incidence of post-anesthesia agitation (14% vs. 10%).
Sevoflurane (n = 91) was compared to halothane (n = 89) in a single-center study for elective repair or palliation of congenital heart disease. The patients ranged in age from 9 days to 11.8 years with an ASA physical status of II, III, and IV (18%, 68%, and 13% respectively). No significant differences were demonstrated between treatment groups with respect to the primary outcome measures: cardiovascular decompensation and severe arterial desaturation. Adverse event data was limited to the study outcome variables collected during surgery and before institution of cardiopulmonary bypass.
Mask Induction
Sevoflurane has a nonpungent odor and is suitable for mask induction in pediatric patients. In controlled pediatric studies in which mask induction was performed, the incidence of induction events is shown below (see ADVERSE REACTIONS).
Sevoflurane (n = 836) | Halothane (n = 660) | |
Agitation | 14% | 11% |
Cough | 6% | 10% |
Breathholding | 5% | 6% |
Secretions | 3% | 3% |
Laryngospasm | 2% | 2% |
Bronchospasm | < 1% | 0% |
n = number of patients. |
Ambulatory Surgery
Sevoflurane (n = 518) was compared to halothane (n = 382) for the maintenance of anesthesia in pediatric outpatients. All patients received N2O and many received fentanyl, midazolam, bupivacaine, or lidocaine. The time to eligibility for discharge from post-anesthesia care units was similar between agents (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS).
Cardiovascular Surgery
Coronary Artery Bypass Graft (CABG) Surgery
Sevoflurane was compared to isoflurane as an adjunct with opioids in a multicenter study of 273 patients undergoing CABG surgery. Anesthesia was induced with midazolam (0.1-0.3 mg/kg); vecuronium (0.1-0.2 mg/kg), and fentanyl (5-15 mcg/kg). Both isoflurane and sevoflurane were administered at loss of consciousness in doses of 1.0 MAC and titrated until the beginning of cardiopulmonary bypass to a maximum of 2.0 MAC. The total dose of fentanyl did not exceed 25 mcg/kg. The average MAC dose was 0.49 for sevoflurane and 0.53 for isoflurane. There were no significant differences in hemodynamics, cardioactive drug use, or ischemia incidence between the two groups. Outcome was also equivalent. In this small multicenter study, sevoflurane appears to be as effective and as safe as isoflurane for supplementation of opioid anesthesia for coronary bypass grafting.
Non-Cardiac Surgery Patients at Risk for Myocardial Ischemia
Sevoflurane-N2O was compared to isoflurane-N2O for maintenance of anesthesia in a multicenter study in 214 patients, age 40-87 years who were at mild-to-moderate risk for myocardial ischemia and were undergoing elective non-cardiac surgery. Forty-six percent (46%) of the operations were cardiovascular, with the remainder evenly divided between gastrointestinal and musculoskeletal and small numbers of other surgical procedures. The average duration of surgery was less than 2 hours. Anesthesia induction usually was performed with thiopental (2-5 mg/kg) and fentanyl (1-5 mcg/kg). Vecuronium (0.1-0.2 mg/kg) was also administered to facilitate intubation, muscle relaxation or immobility during surgery. The average MAC dose was 0.49 for both anesthetics. There was no significant difference between the anesthetic regimens for intraoperative hemodynamics, cardioactive drug use, or ischemic incidents, although only 83 patients in the sevoflurane group and 85 patients in the isoflurane group were successfully monitored for ischemia. The outcome was also equivalent in terms of adverse events, death, and postoperative myocardial infarction. Within the limits of this small multicenter study in patients at mild-to-moderate risk for myocardial ischemia, sevoflurane was a satisfactory equivalent to isoflurane in providing supplemental inhalation anesthesia to intravenous drugs.
Cesarean Section
Sevoflurane (n = 29) was compared to isoflurane (n = 27) in ASA Class I or II patients for the maintenance of anesthesia during cesarean section. Newborn evaluations and recovery events were recorded. With both anesthetics, Apgar scores averaged 8 and 9 at 1 and 5 minutes, respectively.
Use of sevoflurane as part of general anesthesia for elective cesarean section produced no untoward effects in mother or neonate. Sevoflurane and isoflurane demonstrated equivalent recovery characteristics. There was no difference between sevoflurane and isoflurane with regard to the effect on the newborn, as assessed by Apgar Score and Neurological and Adaptive Capacity Score (average = 29.5). The safety of sevoflurane in labor and vaginal delivery has not been evaluated.
Neurosurgery
Three studies compared sevoflurane to isoflurane for maintenance of anesthesia during neurosurgical procedures. In a study of 20 patients, there was no difference between sevoflurane and isoflurane with regard to recovery from anesthesia. In 2 studies, a total of 22 patients with intracranial pressure (ICP) monitors received either sevoflurane or isoflurane. There was no difference between sevoflurane and isoflurane with regard to ICP response to inhalation of 0.5, 1.0, and 1.5 MAC inspired concentrations of volatile agent during N2O-O2-fentanyl anesthesia. During progressive hyperventilation from PaCO2 = 40 to PaCO2 = 30, ICP response to hypocarbia was preserved with sevoflurane at both 0.5 and 1.0 MAC concentrations. In patients at risk for elevations of ICP, sevoflurane should be administered cautiously in conjunction with ICP-reducing maneuvers such as hyperventilation.
Hepatic Impairment
A multicenter study (2 sites) compared the safety of sevoflurane and isoflurane in 16 patients with mild-to-moderate hepatic impairment utilizing the lidocaine MEGX assay for assessment of hepatocellular function. All patients received intravenous propofol (1-3 mg/kg) or thiopental (2-7 mg/kg) for induction and succinylcholine, vecuronium, or atracurium for intubation. Sevoflurane or isoflurane was administered in either 100% O2 or up to 70% N2O/O2. Neither drug adversely affected hepatic function. No serum inorganic fluoride level exceeded 45 µM/L, but sevoflurane patients had prolonged terminal disposition of fluoride, as evidenced by longer inorganic fluoride half-life than patients with normal hepatic function (23 hours vs. 10-48 hours).
Renal Impairment
Sevoflurane was evaluated in renally impaired patients with baseline serum creatinine > 1.5 mg/dL. Fourteen patients who received sevoflurane were compared with 12 patients who received isoflurane. In another study, 21 patients who received sevoflurane were compared with 20 patients who received enflurane. Creatinine levels increased in 7% of patients who received sevoflurane, 8% of patients who received isoflurane, and 10% of patients who received enflurane. Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 1.5 mg/dL) studied, the safety of sevoflurane administration in this group has not yet been fully established. Therefore, sevoflurane should be used with caution in patients with renal insufficiency (see WARNINGS).
Contraindications
- Known or suspected genetic susceptibility to malignant hyperthermia (see WARNINGS - Malignant Hyperthermia, CLINICAL PHARMACOLOGY - Pharmacogenomics).
- Known or suspected sensitivity to sevoflurane or to other halogenated inhalational anesthetics.
Warnings
Malignant Hyperthermia
In susceptible individuals, volatile anesthetic agents, including sevoflurane, may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand. Fatal outcomes of malignant hyperthermia have been reported. In clinical studies of ULTANE, 1 case of malignant hyperthermia was reported.
The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. ULTANE can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants (see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY - Pharmacogenomics).
Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity (e.g., jaw muscle spasm), tachycardia (e.g., particularly that unresponsive to deepening anesthesia or analgesic medication administration), tachypnea, cyanosis, arrhythmias, hypovolemia, and hemodynamic instability. Skin mottling, coagulopathies, and renal failure may occur later in the course of the hypermetabolic process.
Successful treatment of malignant hyperthermia depends on early recognition of the clinical signs. If malignant hyperthermia is suspected, discontinue all triggering agents (i.e., volatile anesthetic agents and succinylcholine), administer intravenous dantrolene sodium, and initiate supportive therapies. Consult prescribing information for intravenous dantrolene sodium for additional information on patient management. Supportive therapies include administration of supplemental oxygen and respiratory support based on clinical need, maintenance of hemodynamic stability and adequate urinary output, management of fluid and electrolyte balance, correction of acid base derangements, and institution of measures to control rising temperature.
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, 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.
Bradycardia in Down Syndrome
Episodes of severe bradycardia and cardiac arrest, not related to underlying congenital heart disease, have been reported during anesthesia induction with sevoflurane in pediatric patients with Down syndrome. In most cases, bradycardia improved with decreasing the concentration of sevoflurane, manipulating the airway, or administering an anticholinergic or epinephrine.
During induction, closely monitor heart rate, and consider incrementally increasing the inspired sevoflurane concentration until a suitable level of anesthesia is achieved. Consider having an anticholinergic and epinephrine available when administering sevoflurane for induction in this patient population.
Precautions
During the maintenance of anesthesia, 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 anesthetics. Excessive decreases in blood pressure or respiratory depression may be related to depth of anesthesia and may be corrected by decreasing the inspired concentration of sevoflurane.
Rare cases of seizures have been reported in association with sevoflurane use (see PRECAUTIONS - Pediatric Use, ADVERSE REACTIONS).
The recovery from general anesthesia should be assessed carefully before a patient is discharged from the post-anesthesia care unit.
Drug Interactions
In clinical studies, no significant adverse reactions occurred with other drugs commonly used in the perioperative period, including central nervous system depressants, autonomic drugs, skeletal muscle relaxants, anti-infective agents, hormones and synthetic substitutes, blood derivatives, and cardiovascular drugs.
Epinephrine
Epinephrine administered with sevoflurane may increase the risk of ventricular arrhythmias. Monitor the electrocardiogram and blood pressure and ensure emergency medications to treat ventricular arrhythmias are readily available.
Calcium antagonists
Sevoflurane may lead to marked hypotension in patients treated with calcium antagonists. Blood pressure should be closely monitored and emergency medications to treat hypotension should be readily available when calcium antagonists are used concomitantly with sevoflurane.
In animals, impairment of atrioventricular conduction has been observed when verapamil and sevoflurane are administered concomitantly.
Succinylcholine
See WARNINGS - Perioperative Hyperkalemia.
Non-selective MAO-inhibitors
Concomitant use of MAO inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.
Intravenous Anesthetics
Sevoflurane administration is compatible with barbiturates, propofol, and other commonly used intravenous anesthetics.
Benzodiazepines and Opioids
Benzodiazepines and opioids would be expected to decrease the MAC of sevoflurane in the same manner as with other inhalational anesthetics. Sevoflurane administration is compatible with benzodiazepines and opioids as commonly used in surgical practice.
Nitrous Oxide
As with other halogenated volatile anesthetics, the anesthetic requirement for sevoflurane is decreased when administered in combination with nitrous oxide. Using 50% N2O, the MAC equivalent dose requirement is reduced approximately 50% in adults, and approximately 25% in pediatric patients (see DOSAGE AND ADMINISTRATION).
Neuromuscular Blocking Agents
As is the case with other volatile anesthetics, sevoflurane increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants. When used to supplement alfentanil-N2O anesthesia, sevoflurane and isoflurane equally potentiate neuromuscular block induced with pancuronium, vecuronium or atracurium. Therefore, during sevoflurane anesthesia, the dosage adjustments for these muscle relaxants are similar to those required with isoflurane.
Potentiation of neuromuscular blocking agents requires equilibration of muscle with delivered partial pressure of sevoflurane. Reduced doses of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation.
Among available nondepolarizing agents, only vecuronium, pancuronium and atracurium interactions have been studied during sevoflurane anesthesia. In the absence of specific guidelines:
- For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants.
- During maintenance of anesthesia, the required dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N2O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation.
The effect of sevoflurane on the duration of depolarizing neuromuscular blockade induced by succinylcholine has not been studied.
Pregnancy
Risk Summary
There are no adequate and well-controlled studies in pregnant women.
In animal reproduction studies, reduced fetal weights were noted following exposure to 1 MAC sevoflurane for three hours a day during organogenesis. Developmental and reproductive toxicity studies of sevoflurane in animals in the presence of strong alkalies (i.e., degradation of sevoflurane and production of Compound A) have not been conducted. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Pregnant rats were treated with sevoflurane (0.22%, 0.66%, or 2.2% equals 0.1, 0.3, or 1.0 MAC) without CO2 absorbent for three hours per day during organogenesis (from Gestation Day 7 to 17). Fetuses obtained by Cesarean section were examined on Gestation Day 20 while some animals were maintained for littering and pups were examined for adverse effects. There were no adverse effects on fetuses at 0.3 MAC. Reduced fetal body weights and increased skeletal variations such as delayed ossifications in the presence of maternal toxicity (reduced food and water intake and body weight of the dams) were noted at 1 MAC. In dams allowed to litter, reduced pup bodyweight gain and evidence of developmental delays (slight delay in eyelid opening and increased incidence of nonreactive animals in the visual placing reflex test) were noted in the 1.0 MAC treatment group.
Pregnant rabbits were treated with sevoflurane (0.1, 0.3, or 1.0 MAC) without CO2 absorbent for three hours per day during organogenesis (from Gestation Day 6 to 18). There were no adverse effects on the fetus at any dose; the mid- and high-dose produced a 5% and 6% decrease in maternal body weight, respectively.
In another study, pregnant rats were administered sevoflurane (0.1, 0.3, or 1.0 MAC) from Gestation Day 17 to Postnatal Day 21. Pup body weights were reduced in the 1.0 MAC treatment group in the absence of maternal toxicity. There was no effect of sevoflurane on sensory function (visual, auditory, nociception, righting reflexes), motor (roto-rod), open field test, or learning tasks (shuttle box avoidance and water T-maze).
In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see WARNINGS - Pediatric Neurotoxicity, PRECAUTIONS - Pediatric Use, ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).
Pediatric Use
Induction and maintenance of general anesthesia with sevoflurane have been established in controlled clinical studies in pediatric patients aged 1 to 18 years (see CLINICAL STUDIES, ADVERSE REACTIONS). Sevoflurane has a nonpungent odor and is suitable for mask induction in pediatric patients.
The concentration of sevoflurane required for maintenance of general anesthesia is age dependent. When used in combination with nitrous oxide, the MAC equivalent dose of sevoflurane should be reduced in pediatric patients. MAC in premature infants has not been determined (see PRECAUTIONS - Drug Interactions, DOSAGE AND ADMINISTRATION for recommendations in pediatric patients 1 day of age and older).
The use of sevoflurane has been associated with seizures (see PRECAUTIONS, ADVERSE REACTIONS). The majority of these have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors. Clinical judgement should be exercised when using sevoflurane in patients who may be at risk for seizures.
Cases of life-threatening ventricular arrhythmias have been reported in pediatric patients with Pompe disease (also commonly known as glycogen storage disease type II or acid maltase deficiency). In a published case series about a clinical trial of patients with infantile-onset Pompe disease, six percent of patients (9 of 139, with 6 of 9 having received sevoflurane) experienced arrhythmias after induction of anesthesia. Reported arrhythmias included severe bradycardia, torsade de pointes, and fatal ventricular fibrillation, which usually resolved after treatment with pharmacologic agents and defibrillation. Avoid induction and maintenance of anesthesia using sole agents, such as sevoflurane, that decrease systemic vascular resistance or diastolic blood pressure.
Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as ULTANE, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.
In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see WARNINGS - Pediatric Neurotoxicity, PRECAUTIONS - Pregnancy, ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).
Use in Pediatric Patients with Down Syndrome
See WARNINGS - Bradycardia in Down Syndrome.
Ultane Dosage and Administration
The concentration of sevoflurane being delivered from a vaporizer should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane. The administration of general anesthesia must be individualized based on the patient's response.
SAFETY AND HANDLING
Occupational Caution
There is no specific work exposure limit established for sevoflurane. However, the National Institute for Occupational Safety and Health has recommended an 8 hour time-weighted average limit of 2 ppm for halogenated anesthetic agents in general (0.5 ppm when coupled with exposure to N2O) (see ADVERSE REACTIONS).
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
Published studies in animals demonstrate that the use of anesthetic agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life, but may extend out to approximately 3 years of age in humans.
In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates and young children who require procedures against the potential risks suggested by the nonclinical data (see WARNINGS - Pediatric Neurotoxicity, PRECAUTIONS - Pregnancy, PRECAUTIONS - Pediatric Use).
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Company LTD. 2-3-5, Fushimi-machi, Chuo-Ku, Osaka, Japan.
Novaplus is a registered trademark of Vizient, Inc.
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Ultane® is a registered trademark of AbbVie Inc.
20073740 August 2022
ULTANE
sevoflurane liquid |
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Labeler - AbbVie Inc. (078458370) |