Sevoflurane

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 & 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 # 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.

ADVERSE REACTIONS 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-Marketing Experience The following adverse events have been identified during post-approval use of sevoflurane. Due to the spontaneous nature of these reports, the actual incidence and relationship of sevoflurane to these events cannot be established with certainty. Central Nervous System • Seizures - Post-marketing 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 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, swellin

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% 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: 1. For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants. 2. 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.