Desflurane

1 INDICATIONS AND USAGE Desflurane, USP, Liquid for Inhalation, a general anesthetic, is an inhalation agent indicated: for induction and/or maintenance of anesthesia in adults ( 1.1 ) for maintenance of anesthesia in pediatric patients following induction with agents other than Desflurane, USP, Liquid for Inhalation and intubation. 1.1 Induction of Anesthesia Desflurane, USP, Liquid for Inhalation is indicated as an inhalation agent for induction of anesthesia for inpatient and outpatient surgery in adults. Desflurane, USP, Liquid for Inhalation is contraindicated as an inhalation agent for the induction of anesthesia in pediatric patients because of a high incidence of moderate to severe upper airway adverse events. 1.2 Maintenance of Anesthesia Desflurane, USP, Liquid for Inhalation is indicated as an inhalation agent for maintenance of anesthesia for inpatient and outpatient surgery in adults and in pediatric patients. After induction of anesthesia with agents other than Desflurane, USP, Liquid for Inhalation, and tracheal intubation, Desflurane, USP, Liquid for Inhalation is indicated for maintenance of anesthesia in infants and children. Desflurane, USP, Liquid for Inhalation is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm, and secretions [See Warnings and Precautions (5.3) and Clinical Studies (14.5) ] .

2 DOSAGE AND ADMINISTRATION Only persons trained in the administration of general anesthesia should administer Desflurane, USP, Liquid for Inhalation. Only a vaporizer specifically designed and designated for use with desflurane should be utilized for its administration. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Desflurane, USP, Liquid for Inhalation is administered by inhalation. The administration of general anesthesia must be individualized based on the patient’s response. Hypotension and respiratory depression increase as anesthesia with Desflurane, USP, Liquid for Inhalation is deepened. The minimum alveolar concentration (MAC) of Desflurane, USP, Liquid for Inhalation decreases with increasing patient age. The MAC for Desflurane, USP, Liquid for Inhalation is also reduced by concomitant N 2 O administration (See Table 1 ) . The dose should be adjusted accordingly. The following table provides mean relative potency based upon age and effect of N 2 O in predominately ASA physical status I or II patients. Benzodiazepines and opioids decrease the MAC of Desflurane, USP, Liquid for Inhalation [See Drug Interactions (7.1, Table 3) ] . Desflurane, USP, Liquid for Inhalation also decreases the doses of neuromuscular blocking agents required [See Drug Interactions (7.2, Table 4) ] . The dose should be adjusted accordingly. Table 1 Effect of Age on Minimum Alveolar Concentration of Desflurane Mean ± SD (percent atmospheres) Age N O 2 100% N N 2 O 60%/40% O 2 2 weeks 6 9.2 ± 0 - - 10 weeks 5 9.4 ± 0.4 - - 9 months 4 10 ± 0.7 5 7.5 ± 0.8 2 years 3 9.1 ± 0.6 - - 3 years - - 5 6.4 ± 0.4 4 years 4 8.6 ± 0.6 - - 7 years 5 8.1 ± 0.6 - - 25 years 4 7.3 ± 0 4 4 ± 0.3 45 years 4 6 ± 0.3 6 2.8 ± 0.6 70 years 6 5.2 ± 0.6 6 1.7 ± 0.4 N = number of crossover pairs (using up-and-down method of quantal response) Desflurane, USP, Liquid for Inhalation should be administered only by persons trained in the administration of general anesthesia. It should only be administered using a vaporizer specifically designed and designated for use with desflurane. ( 2 ) The administration of general anesthesia must be individualized based on the patient’s response, including cardiovascular and pulmonary changes. ( 2 ) Desflurane, USP, Liquid for Inhalation should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or where increases in heart rate or blood pressure are undesirable. ( 2.6 ) For dosing considerations in patients with intracranial space occupying lesions, see Full Prescribing Information. ( 2.7 ) 2.1 Preanesthetic Medication Issues such as whether or not to premedicate and the choice of premedication(s) must be individualized. In clinical studies, patients scheduled to be anesthetized with Desflurane, USP, Liquid for Inhalation frequently received IV preanesthetic medication, such as opioid and/or benzodiazepine. 2.2 Induction In adults, some premedicated with opioid, a frequent starting concentration was 3% Desflurane, USP, Liquid for Inhalation, increased in 0.5% to 1% increments every 2 to 3 breaths. End-tidal concentrations of 4% to 11%, Desflurane, USP, Liquid for Inhalation with and without N 2 O, produced anesthesia within 2 minutes to 4 minutes. When Desflurane, USP, Liquid for Inhalation was tested as the primary anesthetic induction agent, the incidence of upper airway irritation (apnea, breathholding, laryngospasm, coughing and secretions) was high. During induction in adults, the overall incidence of oxyhemoglobin desaturation (SpO 2 < 90%) was 6% [ See Adverse Reactions (6.1) ]. After induction in adults with an intravenous drug such as thiopental or propofol, Desflurane, USP, Liquid for Inhalation can be started at approximately 0.5 to 1 MAC, whether the carrier gas is O 2 or N 2 O/O 2 . Inspired concentrations of Desflurane, USP, Liquid for Inhalation greater than 12% have been safely administered to patients, particularly during induction of anesthesia. Such concentrations will proportionately dilute the concentration of oxygen; therefore, maintenance of an adequate concentration of oxygen may require a reduction of nitrous oxide or air if these gases are used concurrently. 2.3 Maintenance Surgical levels of anesthesia in adults may be maintained with concentrations of 2.5% to 8.5% Desflurane, USP, Liquid for Inhalation with or without the concomitant use of nitrous oxide. In children, surgical levels of anesthesia may be maintained with concentrations of 5.2% to 10% Desflurane, USP, Liquid for Inhalation with or without the concomitant use of nitrous oxide. During the maintenance of anesthesia with inflow rates of 2 L/min or more, the alveolar concentration of Desflurane, USP, Liquid for Inhalation will usually be within 10% of the inspired concentration [F A /F I , see Figure 2 in Clinical Pharmacology (12.3) ] . During the maintenance of anesthesia, increasing

6 ADVERSE REACTIONS Most common adverse reactions (incidence>10%) are coughing, breath holding, apnea, nausea, vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse event information is derived from controlled clinical trials, the majority of which were conducted in the United States. 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 2,143 patients exposed to desflurane in clinical trials, 370 adults and 152 children were induced with desflurane alone and 987 patients were maintained principally with desflurane. The frequencies given reflect the percent of patients with the event. Each patient was counted once for each type of adverse event. They are presented in alphabetical order according to body system. Table 2 Frequency of Events Occurring in Greater Than 1% of Clinical Trial Patients (in Reports Deemed “Probably Causally Related”) Induction (use as a mask inhalation agent) Adult Patients (N=370): Coughing 34%, breathholding 30%, apnea 15%, increased secretions Incidence of events 3% to 10% , laryngospasm , oxyhemoglobin desaturation (SpO 2 < 90%) , pharyngitis . Maintenance or Recovery Adult and Intubated Pediatric Patients (N=687): Body as a Whole Headache Cardiovascular Bradycardia, hypertension, nodal arrhythmia, tachycardia Digestive Nausea 27%, vomiting 16% Nervous system Increased salivation Respiratory Apnea , breathholding, cough increased , laryngospasm , pharyngitis Special Senses Conjunctivitis (conjunctival hyperemia) Frequency of Events Occurring in Less Than 1% of Patients (in Reports Deemed “Probably Causally Related”) Reported in 3 or more patients, regardless of severity Adverse reactions reported only from postmarketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized. Cardiovascular Arrhythmia, bigeminy, abnormal electrocardiogram, myocardial ischemia, vasodilation Digestive Hepatitis Nervous System Agitation, dizziness Respiratory Asthma, dyspnea, hypoxia Frequency of Events Occurring in Less Than 1% of Clinical Trial Patients (in Reports Deemed “Causal Relationship Unknown”) Reported in 3 or more patients, regardless of severity Body as a Whole Fever Cardiovascular Hemorrhage, myocardial infarction Metabolic and Nutrition Increased creatinine phosphokinase Musculoskeletal System Myalgia Skin and Appendages Pruritus 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of desflurane. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders : Coagulopathy Metabolism and Nutrition Disorders : Hyperkalemia, Hypokalemia, metabolic acidosis Nervous System Disorders : Convulsion, Post-operative agitation in children Eye Disorders: Ocular icterus Cardiac Disorders: Cardiac arrest, QTc prolongation, torsade de pointes, ventricular failure, ventricular hypokinesia, atrial fibrillation Vascular Disorders: Malignant hypertension, hemorrhage, hypotension, shock Respiratory, Thoracic and Mediastinal Disorders: Respiratory arrest, respiratory failure, respiratory distress, bronchospasm, hemoptysis Gastrointestinal Disorders : Pancreatitis acute, abdominal pain Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, hepatitis, cytolytic hepatitis, cholestasis, jaundice, hepatic function abnormal, liver disorder Skin and Subcutaneous Tissue Disorder : Urticaria, erythema Musculoskeletal, Connective Tissue and Bone Disorders: Rhabdomyolysis General Disorders and Administration Site Conditions: Hyperthermia malignant, asthenia, malaise Investigations: Electrocardiogram ST-T change, electrocardiogram T-wave inversion, tranaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, coagulation test abnormal, ammonia increased Injury, Poisoning, and Procedural Complications*: Tachyarrhythmia, palpitations, eye burns, blindness transient, encephalopathy, ulcerative keratitis, ocular hyperemia, visual acuity reduced, eye irritation, eye pain, dizziness, migraine, fatigue, accidental exposure, skin burning sensation, drug administration error *Reactions categorized within this System Organ Class (SOC) were accidental exposures to non-

7 DRUG INTERACTIONS No clinically significant adverse interactions with commonly used preanesthetic drugs, or drugs used during anesthesia (muscle relaxants, intravenous agents, and local anesthetic agents) were reported in clinical trials. The effect of desflurane on the disposition of other drugs has not been determined. Similar to isoflurane, desflurane does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine. Concomitant use of N 2 O, benzodiazepines and/or opioids reduces the MAC of desflurane. Adjust dose accordingly. ( 7.1 , 7.3 ) Desflurane decreases the doses of neuromuscular blocking agents required. Adjust dose accordingly. ( 7.2 ) 7.1 Benzodiazepines and Opioids (MAC Reduction) Benzodiazepines and opioids decrease the amount of desflurane (MAC) needed to produce anesthesia. This effect is shown in Table 3 for intravenous midazolam (25 mcg/kg to 50 mcg/kg) and intravenous fentanyl (3 mcg/kg to 6 mcg/kg) in patients of two different age groups. Table 3 Desflurane MAC with Fentanyl or Midazolam Mean ± SD (percent reduction) Dose 18 to 30 years 31 to 65 years No fentanyl 6.4 ± 0 6.3 ± 0.4 3 mcg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%) 6 mcg/kg fentanyl 3 ± 1.2 (53%) 2.3 ± 1 (64%) No midazolam 6.9 ± 0.1 5.9 ± 0.6 25 mcg/kg midazolam - 4.9 ± 0.9 (16%) 50 mcg/kg midazolam - 4.9 ± 0.5 (17%) 7.2 Neuromuscular Blocking Agents Anesthetic concentrations of desflurane at equilibrium (administered for 15 or more minutes before testing) reduced the ED 95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N 2 O/opioid anesthesia (See Table 4 ) . The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied. Table 4 Dosage of Muscle Relaxant Causing 95% Depression in Neuromuscular Blockade Desflurane Concentration Mean ED 95 (mcg/kg) Pancuronium Atracurium Succinylcholine Vecuronium 0.65 MAC 60% N 2 O/O 2 26 133 - - 1.25 MAC 60% N 2 O/O 2 18 119 - - 1.25 MAC O 2 22 120 360 19 Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of desflurane. Among nondepolarizing drugs, pancuronium, atracurium, and vecuronium interactions have been studied. In the absence of specific guidelines: For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine. During maintenance of anesthesia, the 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. 7.3 Concomitant use with N 2 O Concomitant administration of N 2 O reduces the MAC of desflurane [See Dosage and Administration (2), Table 1 ] .