SEVOFLURANE USP

Sevoflurane is an ether inhalation anesthetic agent used to induce and maintain general anesthesia.

It is a volatile, non-flammable compound with a low solubility profile and blood/gas partition coefficient.

Sevoflurane was patented in 1972, was approved for clinical use in Japan in 1990, and approved by the FDA in 1996.

Sevoflurane is three times more potent than desflurane, but has lower potency compared to halothane and isoflurane.

Unlike other volatile anesthetics, sevoflurane has a pleasant odor and does not irritate the airway.

The hemodynamic and respiratory depressive effects of sevoflurane are well tolerated, and most patients receiving this anesthetic agent present little toxicity.

Therefore, it can be used for inhalational induction in adults and children for a wide variety of anesthetic procedures.

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

Sevoflurane induces muscle relaxation and reduces sensitivity by altering tissue excitability with a fast onset of action.

It does so by decreasing the extent of gap junction-mediated cell-cell coupling and altering the activity of the channels that underlie the action potential.

Compared to halothane and isoflurane, sevoflurane has a shorter emergence time, as well as a shorter time to first analgesia.

To reach an equilibrium between alveolar and arterial partial pressure, only a minimal amount of sevoflurane needs to be dissolved in blood.

The use of sevoflurane can increase the risk of renal injury, respiratory depression, and QT prolongation.

Also, it can lead to malignant hyperthermia, perioperative hyperkalemia, and pediatric neurotoxicity.

Episodes of severe bradycardia and cardiac arrest have been reported in pediatric patients with Down Syndrome given sevoflurane.

Sevoflurane anesthesia may impair the performance of activities requiring mental alertness, such as driving or operating machinery.

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Sevoflurane is rapidly absorbed into circulation through the lungs; however, solubility in the blood is low (blood/gas partition coefficient at 37°C ranges from 0.63-0.69).

Therefore, a minimal amount of sevoflurane needs to be dissolved in blood in order to induce anesthesia.

Patients given low-flow sevoflurane anesthesia during maxillofacial surgery (n=16) had a peripheral volume of distribution of 1634 ml vapour /kg bw and a total volume of distribution of 1748 ml vapour /kg bw.

Sevoflurane is metabolized to hexafluoroisopropanol by cytochrome P450 2E1 in a reaction that promotes the release of inorganic fluoride and carbon dioxide.

Hexafluoroisopropanol is rapidly conjugated with glucuronic acid and eliminated in urine.

In vivo metabolism studies suggest that approximately 5% of the sevoflurane dose may be metabolized.

In most cases, inorganic fluoride reaches its highest concentration within 2 hours of the end of sevoflurane anesthesia, and returns to baseline levels within 48 hours.

Sevoflurane metabolism may be induced by chronic exposure to isoniazid and ethanol, and it has been shown that barbiturates do not affect it.

Hover over products below to view reaction partners Sevoflurane Carbon dioxide + Fluoride + Hexafluoroisopropanol.

The low solubility of sevoflurane facilitates its rapid elimination through the lungs, where 95% to 98% of this anesthetic is eliminated. 1, 8 Up to 3.5% of the sevoflurane dose appears in urine as inorganic fluoride, and as much as 50% of fluoride clearance is nonrenal (fluoride taken up into bone).

The terminal elimination half-life of sevoflurane from the peripheral fat compartment is approximately 20 hours.

In patients given low-flow sevoflurane anaesthesia during maxillofacial surgery (n=16), the transport clearance from the central to the peripheral compartment was 13.0 ml vapour /kg bw ⋅min.

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In the event of sevoflurane overdosage (or what may appear to be overdosage) discontinue administration, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.

Patients experiencing an overdose may be at an increased risk of severe adverse effects such as renal injury, respiratory depression, severe bradycardia and cardiac arrest.

Fatalities due to sevoflurane abuse have been reported as well.

Symptomatic and supportive measures are recommended.

Animal studies have shown that the use of anesthetic agents during periods of rapid brain growth or synaptogenesis results in alterations in synaptic morphology and neurogenesis.

In primates, anesthetic regimens of up to 3 hours did not increase neuronal cell loss, but regimens of 5 hours or longer did have a significant effect.

The oral

LD of sevoflurane is 10.8 g/kg in rats and 18.2 g/kg in mice.

Although data from controlled clinical studies at low flow rates are limited, findings taken from patient and animal studies suggest that there is a potential for renal injury which is presumed due to Compound A. Animal and human studies demonstrate that sevoflurane administered for more than 2 MAC·hours and at fresh gas flow rates of < 2 L/min may be associated with proteinuria and glycosuria.

While a level of Compound

A exposure at which clinical nephrotoxicity might be expected to occur has not been established, it is prudent to consider all of the factors leading to Compound A exposure in humans, especially duration of exposure, fresh gas flow rate, and concentration of sevoflurane.

During sevoflurane anesthesia the clinician should adjust inspired concentration and fresh gas flow rate to minimize exposure to Compound A. To minimize exposure to Compound A, sevoflurane exposure should not exceed 2 MAC·hours at flow rates of to < 2 L/min. Fresh gas flow rates < 1 L/min are not recommended.

Because clinical experience in administering sevoflurane to patients with renal insufficiency (creatinine >1.5 mg/dL) is limited, its safety in these patients has not been established.

Sevoflurane may be associated with glycosuria and proteinuria when used for long procedures at low flow rates.

The safety of low flow sevoflurane on renal function was evaluated in patients with normal preoperative renal function.

One study compared sevoflurane (N = 98) to an active control (N = 90) administered for ≥ 2 hours at a fresh gas flow rate of ≤ 1 Liter/minute.

Per study defined criteria, one patient in the sevoflurane group developed elevations of creatinine, in addition to glycosuria and proteinuria.

This patient received sevoflurane at fresh gas flow rates of ≤ 800 mL/minute.

Using these same criteria, there were no patients in the active control group who developed treatment emergent elevations in serum creatinine.

Sevoflurane may present an increased risk in patients with known sensitivity to volatile halogenated anesthetic agents.

KOH containing

CO 2 absorbents are not recommended for use with sevoflurane.

Sevoflurane may cause respiratory depression, which may be augmented by opioid premedication or other agents causing respiratory depression.

Monitor respiration and, if necessary, assist with ventilation.

Risk of QT Prolongation Reports of

QT prolongation, associated with torsade de pointes (in exceptional cases, fatal), have been received.

Caution should be exercised when administering sevoflurane to susceptible patients (e.g., patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval).

In susceptible individuals, volatile anesthetic agents, including sevoflurane, may trigger malignant hyperthermia,a skeletal muscle hypermetabolic state leading to high oxygen demand.

Fatal outcomes of malignant hyperthermia have been reported.

In clinical studies of sevoflurane, 1 case of malignant hyperthermia was reported.

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

Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity (e.g., jaw muscle spasm), tachycardia (e.g., particularly that unresponsive to deepening anesthesia or analgesic medication administration), tachypnea, cyanosis, arrhythmias, hypovolemia, and hemodynamic instability.

Skin mottling, coagulopathies, and renal failure may occur later in the course of the hypermetabolic process.

Successful treatment of malignant hyperthermia depends on early recognition of the clinical signs.

If malignant hyperthermia is suspected, discontinue all triggering agents (i.e., volatile anesthetic agents and succinylcholine), administer intravenous dantrolene sodium, and initiate supportive therapies.

Consult prescribing information for intravenous dantrolene sodium for additional information on patient management.

Supportive therapies include administration of supplemental oxygen and respiratory support based on clinical need, maintenance of hemodynamic stability and adequate urinary output, management of fluid and electrolyte balance, correction of acid base derangements, and institution of measures to control rising temperature.

Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period.

Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable.

Concomitant use of succinylcholine has been associated with most, but not all, of these cases.

These patients also experienced significant elevations in serum creatine kinase levels and, in some cases, changes in urine consistent with myoglobinuria.

Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state.

Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended as is subsequent evaluation for latent neuromuscular disease.

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans.

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

Episodes of severe bradycardia and cardiac arrest, not related to underlying congenital heart disease, have been reported during anesthesia induction with sevoflurane in pediatric patients with Down syndrome.

In most cases, bradycardia improved with decreasing the concentration of sevoflurane, manipulating the airway, or administering an anticholinergic or epinephrine.

During induction, closely monitor heart rate, and consider incrementally increasing the inspired sevoflurane concentration until a suitable level of anesthesia is achieved.

Consider having an anticholinergic and epinephrine available when administering sevoflurane for induction in this patient population.

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

• 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.

& 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.

CO 2 Absorbents When a clinician suspects that the CO 2 absorbent may be desiccated, it should be replaced.

The exothermic reaction that occurs with sevoflurane and CO 2 absorbents is increased when the CO 2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO 2 absorbent canisters.

No specific premedication is either indicated or contraindicated with sevoflurane.

The decision as to whether or not to premedicate and the choice of premedication is left to the discretion of the anesthesiologist.

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

Surgical levels of anesthesia can usually be achieved with concentrations of 0.5.

• 3% sevoflurane with or without the concomitant use of nitrous oxide.

Sevoflurane can be administered with any type of anesthesia circuit.

Table 9.

MAC Values for Adults and Pediatric Patients According to Age Age of Patient (years) Sevoflurane in Oxygen Sevoflurane in 65% N 2 O/35% O 2 0.

• 1 months # 3.3% 1.

• < 6 months 3.0% 6 months.

• < 3 years 2.8% 2.0%@ 3.

• 12 2.5% 25 2.6% 1.4% 40 2.1% 1.1% 60 1.7% 0.9% 80 1.4% 0.7% # Neonates are full-term gestational age.

MAC in premature infants has not been determined. @ In 1.

• < 3 year old pediatric patients, 60% N 2 O/40% O was used.

Sevoflurane, USP, Volatile Liquid for Inhalation, is packaged in amber-colored bottles containing 250 mL Sevoflurane, USP NDC 72162-2245-2: 250 mL in a BOTTLE Store at 20° to 25°C (68° to 77°F); excursions permitted to 15º to 30°C (59° to 86°F) .

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

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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 N 2 O) See ADVERSE REACTIONS.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15º to 30°C (59° to 86°F) .

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.

Pregnant rats were treated with sevoflurane (0.22%, 0.66%, or 2.2% equals 0.1, 0.3, or 1.0 MAC) without CO 2 absorbent for three hours per day during organogenesis (from Gestation Day 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 CO 2 absorbent for three hours per day during organogenesis (from Gestation Day 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 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.

It is not known whether sevoflurane or its metabolites are present in human milk.

To minimize infant exposure to sevoflurane or its metabolites, a nursing mother may temporarily pump, and discard breast milk produced during the first 24 hours after administration of sevoflurane.

Exercise caution when administering sevoflurane to a nursing mother.

Induction and maintenance of general anesthesia with sevoflurane have been established in controlled clinical studies in pediatric patients aged to 18 years.

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.

The use of sevoflurane has been associated with seizures.

The majority of these have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors.

Clinical judgement should be exercised when using sevoflurane in patients who may be at risk for seizures.

Cases of life-threatening ventricular arrhythmias have been reported in pediatric patients with Pompe disease (also commonly known as glycogen storage disease type II or acid altase deficiency).

In a published case series about a clinical trial of patients with infantile-onset Pompe disease, six percent of patients (9 of 139, with of 9 having received sevoflurane) experienced arrhythmias after induction of anesthesia.

Reported arrythmias included severe bradycardia, torsade de pointes, and fatal ventricular fibrillation, which usually resolved after treatment with pharmacologic agents and defibrillation.

Avoid induction and maintenance of anesthesia using sole agents, such as sevoflurane, that decrease systemic vascular resistance or diastolic blood pressure.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as sevoflurane, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine.

• treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data See WARNINGS – Pediatric Neurotoxicity, PRECAUTIONS – Pregnancy, ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY.

Use in Pediatric Patients with Down Syndrome See WARNINGS.

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.