ULTANE

ULTANE (sevoflurane), volatile liquid for inhalation, a nonflammable and nonexplosive liquid administered by vaporization, is a halogenated general inhalation anesthetic drug. Sevoflurane is fluoromethyl 2,2,2,-trifluoro-1-(trifluoromethyl) ethyl ether and its structural formula is: Sevoflurane, Physical Constants are: Molecular weight 200.05 Boiling point at 760 mm Hg 58.6°C Specific gravity at 20°C 1.520 - 1.525 Vapor pressure in mm Hg 157 mm Hg at 20°C 197 mm Hg at 25°C 317 mm Hg at 36°C Distribution Partition Coefficients at 37°C: Blood/Gas 0.63 - 0.69 Water/Gas 0.36 Olive Oil/Gas 47 – 54 Brain/Gas 1.15 Mean Component/Gas Partition Coefficients at 25°C for Polymers Used Commonly in Medical Applications: Conductive rubber 14.0 Butyl rubber 7.7 Polyvinylchloride 17.4 Polyethylene 1.3 Sevoflurane is nonflammable and nonexplosive as defined by the requirements of International Electrotechnical Commission 601-2-13. Sevoflurane is a clear, colorless, liquid containing no additives. Sevoflurane is not corrosive to stainless steel, brass, aluminum, nickel-plated brass, chrome-plated brass or copper beryllium. Sevoflurane is nonpungent. It is miscible with ethanol, ether, chloroform, and benzene, and it is slightly soluble in water. Sevoflurane is stable when stored under normal room lighting conditions according to instructions. No discernible degradation of sevoflurane occurs in the presence of strong acids or heat. When in contact with alkaline CO 2 absorbents (e.g., Baralyme ® and to a lesser extent soda lime) within the anesthesia machine, sevoflurane can undergo degradation under certain conditions. Degradation of sevoflurane is minimal, and degradants are either undetectable or present in non-toxic amounts when used as directed with fresh absorbents. Sevoflurane degradation and subsequent degradant formation are enhanced by increasing absorbent temperature increased sevoflurane concentration, decreased fresh gas flow and desiccated CO 2 absorbents (especially with potassium hydroxide containing absorbents e.g., Baralyme). Sevoflurane alkaline degradation occurs by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropenyl fluoromethyl ether, (PIFE, C 4 H 2 F 6 O), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether, (PMFE, C 5 H 6 F 6 O), also known as Compound B. The second pathway for degradation of sevoflurane, which occurs primarily in the presence of desiccated CO 2 absorbents, is discussed later. In the first pathway, the defluorination pathway, the production of degradants in the anesthesia circuit results from the extraction of the acidic proton in the presence of a strong base (KOH and/or NaOH) forming an alkene (Compound A) from sevoflurane similar to formation of 2-bromo-2-chloro-1,1-difluoro ethylene (BCDFE) from halothane. Laboratory simulations have shown that the concentration of these degradants is inversely correlated with the fresh gas flow rate (See Figure 1 ). Figure 1. Fresh Gas Flow Rate versus Compound A Levels in a Circle Absorber System Since the reaction of carbon dioxide with absorbents is exothermic, the temperature increase will be determined by quantities of CO 2 absorbed, which in turn will depend on fresh gas flow in the anesthesia circle system, metabolic status of the patient, and ventilation. The relationship of temperature produced by varying levels of CO 2 and Compound A production is illustrated in the following in vitro simulation where CO 2 was added to a circle absorber system. Figure 2. Carbon Dioxide Flow versus Compound A and Maximum Temperature Compound A concentration in a circle absorber system increases as a function of increasing CO 2 absorbent temperature and composition (Baralyme producing higher levels than soda lime), increased body temperature, and increased minute ventilation, and decreasing fresh gas flow rates. It has been reported that the concentration of Compound A increases significantly with prolonged dehydration of Baralyme. Compound A exposure in patients also has been shown to rise with increased sevoflurane concentrations and duration of anesthesia. In a clinical study in which sevoflurane was administered to patients under low flow conditions for ≥ 2 hours at flow rates of 1 Liter/minute, Compound A levels were measured in an effort to determine the relationship between MAC hours and Compound A levels produced. The relationship between Compound A levels and sevoflurane exposure are shown in Figure 2a. Figure 2a. ppm·hr versus MAC·hr at Flow Rate of 1 L/min Compound A has been shown to be nephrotoxic in rats after exposures that have varied in duration from one to three hours. No histopathologic change was seen at a concentration of up to 270 ppm for one hour. Sporadic single cell necrosis of proximal tubule cells has been reported at a concentration of 114 ppm after a 3-hour exposure to Compound A in rats. The LC 50 reported at 1 hour is 1050-1090 ppm (male-female) and, at 3 hours, 350-490 ppm (male-female). An experiment was performed comparing sevoflurane plus 75 or 100 ppm Compound A with an active control to evaluate the potential nephrotoxicity of Compound A in non-human primates. A single 8-hour exposure of Sevoflurane in the presence of Compound A produced single-cell renal tubular degeneration and single-cell necrosis in cynomolgus monkeys. These changes are consistent with the increased urinary protein, glucose level and enzymic activity noted on days one and three on the clinical pathology evaluation. This nephrotoxicity produced by Compound A is dose and duration of exposure dependent. At a fresh gas flow rate of 1 L/min, mean maximum concentrations of Compound A in the anesthesia circuit in clinical settings are approximately 20 ppm (0.002%) with soda lime and 30 ppm (0.003%) with Baralyme in adult patients; mean maximum concentrations in pediatric patients with soda lime are about half those found in adults. The highest concentration observed in a single patient with Baralyme was 61 ppm (0.0061%) and 32 ppm (0.0032%) with soda lime. The levels of Compound A at which toxicity occurs in humans is not known. The second pathway for degradation of sevoflurane occurs primarily in the presence of desiccated CO 2 absorbents and leads to the dissociation of sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic, rapidly glucuronidated and cleared by the liver. 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 that can be associated with desiccated Baralyme ® . 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. Sevoflurane degradants were observed in the respiratory circuit of an experimental anesthesia machine using desiccated CO 2 absorbents and maximum sevoflurane concentrations (8%) for extended periods of time (> 2 hours). Concentrations of formaldehyde observed with desiccated soda lime in this experimental anesthesia respiratory circuit were consistent with levels that could potentially result in respiratory irritation. Although KOH containing CO 2 absorbents are no longer commercially available, in the laboratory experiments, exposure of sevoflurane to the desiccated KOH containing CO 2 absorbent, Baralyme, resulted in the detection of substantially greater degradant levels. Chemical structure for sevoflurane Figure 1. Fresh Gas Flow Rate versus Compound A Levels in a Circle Absorber System Figure 2. Carbon Dioxide Flow versus Compound A and Maximum Temperature Figure 2a. ppm·hr versus MAC·hr at Flow Rate of 1 L/min

ULTANE is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery. ULTANE 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 should be used.

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 # 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 2 was used.

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 Trials Experience Adverse events are derived from controlled clinical studies conducted in the United States, Canada, and Europe. The reference drugs were isoflurane, enflurane, and propofol in adults and halothane in pediatric patients. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered. Of the 5182 patients enrolled in the clinical studies, 2906 were exposed to sevoflurane, including 118 adults and 507 pediatric patients who underwent mask induction. Each patient was counted once for each type of adverse event. Adverse events reported in patients in clinical studies and considered to be possibly or probably related to sevoflurane are presented within each body system in order of decreasing frequency in the following listings. One case of malignant hyperthermia was reported in pre-registration clinical studies. Adverse Events During the Induction Period (from Onset of Anesthesia by Mask Induction to Surgical Incision) Incidence > 1% Adult Patients (N = 118) Cardiovascular Bradycardia 5%, Hypotension 4%, Tachycardia 2% Nervous System Agitation 7% Respiratory System Laryngospasm 8%, Airway obstruction 8%, Breathholding 5%, Cough Increased 5% Pediatric Patients (N = 507) Cardiovascular Tachycardia 6%, Hypotension 4% Nervous System Agitation 15% Respiratory System Breathholding 5%, Cough Increased 5%, Laryngospasm 3%, Apnea 2% Digestive System Increased salivation 2% Adverse Events During Maintenance and Emergence Periods, Incidence > 1% (N = 2906) Body as a whole Fever 1%, Shivering 6%, Hypothermia 1%, Movement 1%, Headache 1% Cardiovascular Hypotension 11%, Hypertension 2%, Bradycardia 5%, Tachycardia 2% Nervous System Somnolence 9%, Agitation 9%, Dizziness 4%, Increased salivation 4% Digestive System Nausea 25%, Vomiting 18% Respiratory System Cough increased 11%, Breathholding 2%, Laryngospasm 2% Adverse Events, All Patients in Clinical Studies (N = 2906), All Anesthetic Periods, Incidence < 1% (Reported in 3 or More Patients) Body as a whole Asthenia, Pain Cardiovascular Arrhythmia, Ventricular Extrasystoles, Supraventricular Extrasystoles, Complete AV Block, Bigeminy, Hemorrhage, Inverted T Wave, Atrial Fibrillation, Atrial Arrhythmia, Second Degree AV Block, Syncope, S-T Depressed Nervous System Crying, Nervousness, Confusion, Hypertonia, Dry Mouth, Insomnia Respiratory System Sputum Increased, Apnea, Hypoxia, Wheezing, Bronchospasm, Hyperventilation, Pharyngitis, Hiccup, Hypoventilation, Dyspnea, Stridor Metabolism and Nutrition Increases in LDH, AST, ALT, BUN, Alkaline Phosphatase, Creatinine, Bilirubinemia, Glycosuria, Fluorosis, Albuminuria, Hypophosphatemia, Acidosis, Hyperglycemia Hemic and Lymphatic System Leucocytosis, Thrombocytopenia Skin and Special Senses Amblyopia, Pruritus, Taste Perversion, Rash, Conjunctivitis Urogenital Urination Impaired, Urine Abnormality, Urinary Retention, Oliguria See WARNINGS for information regarding malignant hyperthermia. Post m arketing Experience The following adverse events have been identified during post-approval use of Ultane (sevoflurane USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of Ultane to these events cannot be established with certainty. Central Nervous System Seizures: Postmarketing reports indicate that sevoflurane use has been associated with seizures. The majority of cases were in children and young adults, most of whom had no medical history of seizures. Several cases reported no concomitant medications, and at least one case was confirmed by EEG. Although many cases were single seizures that resolved spontaneously or after treatment, cases of multiple seizures have also been reported. Seizures have occurred during, or soon after sevoflurane induction, during emergence, and during post-operative recovery up to a day following anesthesia. Delirium Cardiac Cardiac arrest QT prolongation associated with Torsade de Pointe Bradycardia in patients with Down syndrome Pulmonary Diffuse Alveolar Hemorrhage: Hemoptysis, shortness of breath with chest X-ray findings, and increasing aliquots of frank blood on bronchoalveolar lavage have been reported following exposure to sevoflurane and in the absence of observed airway obstruction. Hepatic Cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported. Histological evidence was not provided for any of the reported hepatitis cases. In most of these cases, patients had underlying hepatic conditions or were under treatment with drugs known to cause hepatic dysfunction. Most of the reported events were transient and resolved spontaneously (see PRECAUTIONS ). Hepatic necrosis Hepatic failure Other Malignant hyperthermia (see CONTRAINDICATIONS , WARNINGS ) Allergic reactions, such as rash, urticaria, pruritus, bronchospasm, and anaphylactic reactions (see CONTRAINDICATIONS ) Reports of hypersensitivity (including contact dermatitis, rash, dyspnea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, particularly in association with long-term occupational exposure to inhaled anesthetic agents, including sevoflurane (see SAFETY AND HANDLING - Occupational Caution ). Laboratory Findings Transient elevations in glucose, liver function tests, and white blood cell count may occur as with use of other anesthetic agents.

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% N 2 O, 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-N 2 O 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 N 2 O/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.

Storage Store at controlled room temperature, 15° - 30°C (59° - 86°F). See USP.