sevoflurane 1000 MG/ML Inhalation Solution

INDICATIONS AND USAGE Sevoflurane, USP is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery. Sevoflurane, USP should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Since level of anesthesia may be altered rapidly, only vaporizers producing predictable concentrations of sevoflurane, USP should be used.

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. Replacement of Desiccated 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 (see PRECAUTIONS ). Pre-anesthetic 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 anesthesiologist. Induction Sevoflurane has a nonpungent odor and does not cause respiratory irritability; it is suitable for mask induction in pediatrics and adults. Maintenance 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 Neonates are full-term gestational age. MAC in premature infants has not been determined. 3.3% 1 - < 6 months 3.0% 6 months - < 3 years 2.8% 2.0% In 1 - < 3 year old pediatric patients, 60% N 2 O/40% O 2 was used. 3 - 12 2.5% 25 2.6% 1.4% 40 2.1% 1.1% 60 1.7% 0.9% 80 1.4% 0.7% Directions for Filling Vaporizers Filling occurs directly from the bottle via an integrated valve or, in case of a bottle without an integrated valve, with the use of an appropriate adaptor designed specifically to fit the sevoflurane vaporizer.

WARNINGS Risk of Renal Injury 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 1 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. Risk of Respiratory Depression 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 (see PRECAUTIONS ). 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). 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 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. 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. Risk of Driving and Operating Machinery Performance of activities requirin

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.

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). Pharmacokinetics Uptake and Distribution Solubility Because of the low solubility of sevoflurane in blood (blood/gas partition coefficient @ 37°C = 0.63- 0.69), a minimal amount of sevoflurane is required to be dissolved in the blood before the alveolar partial pressure is in equilibrium with the arterial partial pressure. Therefore, there is a rapid rate of increase in the alveolar (end-tidal) concentration (F A ) toward the inspired concentration (F I ) during induction. Induction of Anesthesia In a study in which seven healthy male volunteers were administered 70% N 2 O/30% O 2 for 30 minutes followed by 1.0% sevoflurane and 0.6% isoflurane for another 30 minutes the F A /F I ratio was greater for sevoflurane than isoflurane at all time points. The time for the concentration in the alveoli to reach 50% of the inspired concentration was 4 - 8 minutes for isoflurane and approximately 1 minute for sevoflurane. F A /F I data from this study were compared with F A /F I data of other halogenated anesthetic agents from another study. When all data were normalized to isoflurane, the uptake and distribution of sevoflurane was shown to be faster than isoflurane and halothane, but slower than desflurane. The results are depicted in Figure 3. Recovery from Anesthesia The low solubility of sevoflurane facilitates rapid elimination via the lungs. The rate of elimination is quantified as the rate of change of the alveolar (end-tidal) concentration following termination of anesthesia (F A ), relative to the last alveolar concentration (FaO) measured immediately before discontinuance of the anesthetic. In the healthy volunteer study described above, rate of elimination of sevoflurane was similar compared with desflurane, but faster compared with either halothane or isoflurane. These results are depicted in Figure 4. Protein Binding 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 Sevoflurane is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO 2 . Once formed HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic 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 isoniazid 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 barbiturates. As shown in Figure 5, inorganic fluoride concentrations peak within 2 hours of the end of sevoflurane anesthesia and return to baseline concentrations within 48 hours post- anesthesia in the majority of cases (67%). The rapid and extensive pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism. Elimination 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 nonrenal (via fluoride being taken up into bone). Pharmacokinetics of 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. In studies where anesthesia was maintained purely with sevoflurane for periods ranging from 1 to 6 hours, peak fluoride concentrations ranged between 12 μM and 90 μM. As shown in Figure 6, peak concentrations occur within 2 hours of the end of anesthesia and are less than 25 μM (475 ng/mL) for the majority of the population after 10 hours. The half-life is in the range of 15-23 hours. It has been reported that following administration of methoxyflurane, serum inorganic fluoride concentrations > 50 μM were correlated with the development of vasopressin-resistant, polyuric, renal failure. In clinical studies with sevoflurane, there were no reports of toxicity associated with elevated fluoride ion levels. Fluoride Concentrations After Repeat Exposure and in Special Populations Fluoride concentrations have been measured after single, extended, and repeat exposure to sevoflurane in normal surgical and special patient populations, and pharmacokinetic parameters were determined. Compared with healthy individuals, the fluoride ion half-life was prolonged in patients with renal impairment, but not in the elderly. A study in 8 patients with hepatic impairment suggests a slight prolongation of the half-life. The mean half-life in patients with renal impairment averaged approximately 33 hours (range 21-61 hours) as compared to a mean of approximately 21 hours (range 10- 48 hours) in normal healthy individuals. The mean half-life in the elderly (greater than 65 years) approximated 24 hours (range 18-72 hours). The mean half-life in individuals with hepatic impairment was 23 hours (range 16-47 hours). Mean maximal fluoride values (C max ) determined in individual studies of special populations are displayed below. Table 1. Fluoride Ion Estimates in Special Populations Following Administration of Sevoflurane n Age (yr) Duration (hr) Dose (MACꞏhr) Cmax (µM) PEDIATRIC PATIENTS Anesthetic Sevoflurane-O 2 76 0-11 0.8 1.1 12.6 Sevoflurane-O 2 40 1-11 2.2 3.0 16.0 Sevoflurane/N 2 O 25 5-13 1.9 2.4 21.3 Sevoflurane/N 2 O 42 0-18 2.4 2.2 18.4 Sevoflurane/N 2 O 40 1-11 2.0 2.6 15.5 ELDERLY 33 65-93 2.6 1.4 25.6 RENAL 21 29-83 2.5 1.0 26.1 HEPATIC 8 42-79 3.6 2.2 30.6 OBESE 35 24-73 3.0 1.7 38.0 n = number of patients studied. Pharmacodynamics Changes in the depth of sevoflurane anesthesia rapidly follow changes in the inspired concentration. In the sevoflurane clinical program, the following recovery variables were evaluated: 1. Time to events measured from the end of study drug: • Time to removal of the endotracheal tube (extubation time) • Time required for the patient to open his/her eyes on verbal command (emergence time) • Time to respond to simple command (e.g., squeeze my hand) or demonstrates purposeful movement (response to command time, orientation time) 2. Recovery of cognitive function and motor coordination was evaluated based on: • psychomotor performance tests (Digit Symbol Substitution Test [DSST], Trieger Dot Test) • the results of subjective (Visual Analog Scale [VAS]) and objective (objective pain- discomfort scale [OPDS]) measurements • time to administration of the first post-anesthesia analgesic medication • assessments of post-anesthesia patient status 3. Other recovery times were: • time to achieve an Aldrete Score of ≥ 8 • time required for the patient to be eligible for discharge from the recovery area, per standard criteria at site • time when the patient was eligible for discharge from the hospital •time when the patient was able to sit up or stand without dizziness Some of these variables are summarized as follows: Table 2. Induction and Recovery Variables for Evaluable Pediatric Patients in Two Comparative Studies: Sevoflurane versus Halothane Time to End-Point (min) Sevoflurane Mean ± SEM Halothane Mean ± SEM Induction 2.0 ± 0.2 (n = 294) 2.7 ± 0.2 (n