Suprane

6. ADVERSE REACTIONS Most common adverse reactions (incidence> 10%) are coughing, breath holding, apnea, nausea, vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-800-262-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 SUPRANE 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. Table2.jpg Image1.jpg 6.2 Post Marketing Experience The following adverse reactions have been identified during post-approval use of SUPRANE. 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 Eye Disorders: Ocular icterus Cardiac Disorders: Cardiac arrest, Torsade de pointes, ventricular failure, ventricular hypokinesia 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, 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, 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 *All of reactions categorized within this SOC were accidental exposures to non-patients.

4. CONTRAINDICATIONS The use of SUPRANE is contraindicated in the following conditions: Known or suspected genetic susceptibility to malignant hyperthermia. Patients in whom general anesthesia is contraindicated. Patients with known sensitivity to SUPRANE or to other halogenated agents [see Warnings and Precautions (5.5)]. Patients with a history of moderate to severe hepatic dysfunction following anesthesia with SUPRANE or other halogenated agents and not otherwise explained [see Warnings and Precautions (5.5)]. Patients with known or suspected genetic susceptibility to malignant hyperthermia (4) Patients in whom general anesthesia is contraindicated (4) Induction of anesthesia in pediatric patients (4) Patients with known sensitivity to halogenated agents (4, 5.5) Patients with a history of moderate to severe hepatic dysfunction following anesthesia with ahlogenated agents and not otherwise explained. (4, 5.5)

11. DESCRIPTION SUPRANE (desflurane, USP), a nonflammable liquid administered via vaporizer, is a general inhalation anesthetic. It is (±)1,2,2,2-tetrafluoroethyl difluoromethyl ether: SUPRANE (desflurane, USP) is nonflammable as defined by the requirements of International Electrotechnical Commission 601-2-13. SUPRANE (desflurane, USP) is a colorless, volatile liquid below 22.8°C. Data indicate that SUPRANE (desflurane, USP) is stable when stored under normal room lighting conditions according to instructions. SUPRANE (desflurane, USP) is chemically stable. The only known degradation reaction is through prolonged direct contact with soda lime producing low levels of fluoroform (CHF 3 ). The amount of CHF 3 obtained is similar to that produced with MAC-equivalent doses of isoflurane. No discernible degradation occurs in the presence of strong acids. SUPRANE (desflurane, USP) does not corrode stainless steel, brass, aluminum, anodized aluminum , nickel plated brass, copper, or beryllium. Formula1.jpg Image2.jpg

2. DOSAGE AND ADMINISTRATION Only persons trained in the administration of general anesthesia should administer SUPRANE. 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. SUPRANE 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 SUPRANE is deepened. The minimum alveolar concentration (MAC) of SUPRANE decreases with increasing patient age. The MAC for SUPRANE 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 SUPRANE [see Drug Interactions (7.1, Table 3)]. SUPRANE (desflurane, USP) also decreases the doses of neuromuscular blocking agents required [see Drug Interactions (7.2, Table 4)]. The dose should be adjusted accordingly. Suprane 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 Suprane. (2) The administration of general anesthesia must be individualized based on the patient's response, including cardiovascular and pulmonary changes. (2) Suprane 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) Patients with intracranial space occupying lesions (2.7) Table1.jpg 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 SUPRANE 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% SUPRANE, increased in 0.5-1.0% increments every 2 to 3 breaths. End-tidal concentrations of 4-11%, SUPRANE with and without N 2 O, produced anesthesia within 2 to 4 minutes. When SUPRANE 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, SUPRANE can be started at approximately 0.5-1 MAC, whether the carrier gas is O 2 or N 2 O/O 2 . Inspired concentrations of SUPRANE 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 2.5-8.5% SUPRANE (desflurane, USP) with or without the concomitant use of nitrous oxide. In children, surgical levels of anesthesia may be maintained with concentrations of 5.2-10% SUPRANE 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 SUPRANE 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 concentrations of SUPRANE produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be due to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE. Concentrations of SUPRANE exceeding 1 MAC may increase heart rate. Thus with this drug, an increased heart rate may not serve reliably as a sign of inadequate anesthesia. 2.4 Maintenance of Anesthesia in Intubated Pediatric Patients SUPRANE is indicated for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. SUPRANE (desflurane, USP), with or without N 2 O, and halothane, with or without N 2 O were studied in three clinical trials of pediatric patients aged 2 weeks to 12 years (median 2 years) and ASA physical status I or II. The concentration of SUPRANE (desflurane, USP) required for maintenance of general anethesia is age-dependent [see Clinical Studies (14.5)]. Changes in blood pressure during maintenance of and recovery from anesthesia with SUPRANE/N2O/O2 are similar to those observed with halothane/N 2 O/O 2. Heart rate during maintenance of anesthesia is approximately 10 beats per minute faster with SUPRANE than with halothane. Patients were judged fit for discharge from post-anesthesia care units within one hour with both SUPRANE and halothane. There were no differences in the incidence of nausea and vomiting between patients receiving SUPRANE or halothane. 2.5 Recovery The recovery from general anethesia should be assessed carefully before patients are discharged from the post anesthesia care unit (PACU). 2.6 Use in Patients with Coronary Artery Disease In patients with coronary artery disease, maintenance of normal hemodynamics is important to prevent myocardial ischemia. A rapid increase in desflurane concentration is associated with marked increase in pulse rate, mean arterial pressure and levels of epinephrine and norepinephrine. SUPRANE should not be used as the sole agent foranesthetic induction in patients with coronary artery disease or patients where increases in heart rate or blood pressure are undesirable. It should be used with other medications, preferably intravenous opioids and hypnotics [see Clinical Studies (14.2)]. 2.7 Neurosurgical Use SUPRANE may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with intracranial space occupying lesions. SUPRANE should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) until cerebral decompression in patients with known or suspected increases in CSFP. Appropriate attention must be paid to maintain cerebral perfusion pressure [see Clinical Studies (14.4)]. 2.8 Observations Related to Vaporizer Use Yellow discoloration of SUPRANE sometimes accompanied by particulates, has been observed through the vaporizer sight glass or after draining the vaporizer. The presence of discoloration or particulates in these situations, does not alter the quality or efficacy of SUPRANE. If observed, refer to the respective vaporizer Instructions For Use (IFU) for recommended actions or contact Baxter Product Surveillance.

1. INDICATIONS AND USAGE 1.1 Induction of Anesthesia SUPRANE is indicated as an inhalation agent for induction of anesthesia for inpatient and outpatient surgery in adults. SUPRANE 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 SUPRANE 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 SUPRANE, and tracheal intubation, SUPRANE is indicated for maintenance of anesthesia in infants and children. SUPRANE 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)]. Suprane 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 Suprane and intubation. 1.1 Induction of Anesthesia in Adults SUPRANE (desflurane, USP) is indicated as an inhalation agent for induction of anesthesia for inpatient and outpatient surgery in adults. SUPRANE is contraindicated as an inhalation agent for the induction of anesthesia in pediatric patients because of a high incidence of moderate to severe uppoer airway adverse events. 1.2 Maintenance of Anesthesia SUPRANE 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 SUPRANE, and tracheal intubation, SUPRANE is indicated for maintenance of anesthesia in infants and children. SUPRANE 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)].

10. OVERDOSAGE The symptoms of overdosage of SUPRANE can present as a deepening of anesthesia, cardiac and/or respiratory depression in spontaneously breathing patients, and cardiac depression in ventilated patients in whom hypercapnia and hypoxia may occur only at a late stage. In the event of overdosage, or suspected overdosage, take the following actions: discontinue administration of SUPRANE, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.

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 SUPRANE on the disposition of other drugs has not been determined. Similar to isoflurane, SUPRANE does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine. Concomitant use of N2O, benzodiazepines and/or opioids reduces the MAC of Suprane (desflurane, USP). Adjust dose accordingly. (7.1, 7.3) Suprane (desflurane, USP) 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 (25-50 ug/kg) and intravenous fentanyl (3-6 ug/kg) in patients of two different age groups. Table3.jpg 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. 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 SUPRANE. 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. Table4.jpg 7.3 Concomitant Use with N2O Concomitant administration of N2O reduces the MAC of SUPRANE [see Dosage and Administration (2), Table 1].

12. CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Changes in the clinical effects of SUPRANE rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for SUPRANE are given in the following tables: In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5-2.0 ug/kg), anesthesia was initiated with propofol 2.5 mg/kg, desflurane/N 2 O 60% in O 2 or desflurane/O 2 alone. Anesthesia was maintained with either propofol 1.5-9.0 mg/kg/hr, desflurane 2.6-8.4% in N 2 O 60% in O 2 , or desflurane 3.1-8.9% in O 2 . In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3-9 mg/kg or desflurane in O 2 . Anesthesia was maintained with isoflurane 0.7-1.4% in N 2 O 60%, desflurane 1.8-7.7% in N 2 O 60%, or desflurane 4.4-11.9% in O 2 . Recovery from anesthesia was assessed at 30, 60, and 90 minutes following 0.5 MAC desflurane (3%) or isoflurane (0.6%) in N 2 O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of the isoflurane group were able to perform the psychometric tests compared to 76% in the SUPRANE group (p < 0.05). SUPRANE was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO 2 38 mm Hg) were: When the same volunteers breathed spontaneously during desflurane anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation. During spontaneous ventilation in the same volunteers, increasing the concentration of SUPRANE from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N 2 O 60% with a given concentration of desflurane gave results similar to those with desflurane alone. Respiratory depression produced by desflurane is similar to that produced by other potent inhalation agents. The use of desflurane concentrations higher than 1.5 MAC may produce apnea. Image3.jpg Image4.jpg Image5.jpg Image6.jpg Figure1.jpg 12.3 Pharmacokinetics Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. SUPRANE (desflurane, USP) is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the desflurane absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Eight healthy male volunteers first breathed 70% N2O/30% O2 for 30 minutes and then a mixture of desflurane 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (FI and FA) were measured. The FA/FI (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N2O, 0.74 for isoflurane, and 0.58 for halothane (see Figure 2). The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane (see Figure 3). The washout for desflurane was more rapid than that of isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for desflurane is 1/20th of that for halothane or isoflurane. Figure2.jpg Figure3.jpg

12.2 Pharmacodynamics Changes in the clinical effects of SUPRANE rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for SUPRANE are given in the following tables: In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5-2.0 ug/kg), anesthesia was initiated with propofol 2.5 mg/kg, desflurane/N 2 O 60% in O 2 or desflurane/O 2 alone. Anesthesia was maintained with either propofol 1.5-9.0 mg/kg/hr, desflurane 2.6-8.4% in N 2 O 60% in O 2 , or desflurane 3.1-8.9% in O 2 . In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3-9 mg/kg or desflurane in O 2 . Anesthesia was maintained with isoflurane 0.7-1.4% in N 2 O 60%, desflurane 1.8-7.7% in N 2 O 60%, or desflurane 4.4-11.9% in O 2 . Recovery from anesthesia was assessed at 30, 60, and 90 minutes following 0.5 MAC desflurane (3%) or isoflurane (0.6%) in N 2 O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of the isoflurane group were able to perform the psychometric tests compared to 76% in the SUPRANE group (p < 0.05). SUPRANE was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO 2 38 mm Hg) were: When the same volunteers breathed spontaneously during desflurane anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation. During spontaneous ventilation in the same volunteers, increasing the concentration of SUPRANE from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N 2 O 60% with a given concentration of desflurane gave results similar to those with desflurane alone. Respiratory depression produced by desflurane is similar to that produced by other potent inhalation agents. The use of desflurane concentrations higher than 1.5 MAC may produce apnea. Image3.jpg Image4.jpg Image5.jpg Image6.jpg Figure1.jpg

12.3 Pharmacokinetics Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. SUPRANE (desflurane, USP) is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the desflurane absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Eight healthy male volunteers first breathed 70% N2O/30% O2 for 30 minutes and then a mixture of desflurane 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (FI and FA) were measured. The FA/FI (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N2O, 0.74 for isoflurane, and 0.58 for halothane (see Figure 2). The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane (see Figure 3). The washout for desflurane was more rapid than that of isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for desflurane is 1/20th of that for halothane or isoflurane. Figure2.jpg Figure3.jpg

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3. DOSAGE FORMS AND STRENGTHS Colorless, non-flammable, volatile liquid (below 22.8°C) for inhalation, 100% desflurane. Liquid (volatile): 100% (3)

Suprane Desflurane Desflurane Desflurane

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal carcinogenicity studies have not been performed with desflurane. In vitro and In vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by desflurane. Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay. Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility.

13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal carcinogenicity studies have not been performed with desflurane. In vitro and In vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by desflurane. Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay. Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility.

NDA020118

Suprane

Desflurane

52584-641

HUMAN PRESCRIPTION DRUG

RESPIRATORY (INHALATION)

SAMPLE PACKAGE LABELS Label1.jpg

16. HOW SUPPLIED/STORAGE AND HANDLING SUPRANE (desflurane, USP) is available in an amber-colored glass bottle or an aluminum bottle containing 240 mL of desflurane as follows: Image9.jpg 16.1 Safety and Handling Occupational Caution There is no specific work exposure limit established for SUPRANE. However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour. Principle routes of exposure include: Skin contact - May cause skin irritation. In case of contact, immediately flush skin with plenty of water. Remove contaminated clothing and shoes. Seek medical attention if irritation develops. Eye contact - May cause eye irritation. In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Seek medical attention if irritation develops. Ingestion - No specific hazards other than therapeutic effects. Do NOT induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an unconscious person. If large quantities of this material are swallowed, seek medical attention immediately. Inhalation - If individual smell vapors, or experience dizziness or headaches, they should be moved to an area with fresh air. Individuals could also experience the following: Cardiovascular effects: may include fluctuations in heart rate, changes in blood pressure, chest pain. Respiratory effects: may include shortness of breath, bronchospasms, laryngospasms, respiratory depression. Gastrointestinal effects: may include nausea, upset stomach, loss of appetite. Nervous System effects: may include ataxia, tremor, disturbance of speech, lethargy, headache, dizziness, blurred vision. The predicted effects of acute overexposure by inhalation of SUPRANE include headache, dizziness or (in extreme cases) unconsciousness [see Overdosage (10)]. There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors ( W aste A nesthetic G ases or WAGs) in the workplace. Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive. Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system; work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks. Consistent with clinical data, concentrations would need to reach 2-3% in inspired air before individuals would likely experience dizziness or other physiologic effects. 16.2 Storage Store at room temperature, 15°-30°C (59°-86°F). SUPRANE (desflurane, USP) has been demonstrated to be stable for the period defined by the expiration dating on the label. The bottle should be recapped after each use of SUPRANE (desflurane, USP).

14. CLINICAL STUDIES The efficacy of SUPRANE was evaluated in 1,843 patients including ambulatory (N=1,061), cardiovascular (N=277), geriatric (N=103), neurosurgical (N=40), and pediatric (N=235) patients. Clinical experience with these patients and with 1,087 control patients in these studies not receiving SUPRANE is described below. Althrough SUPRANE can be used in adults for the inhalation induction of anesthesia via mask, it produces a high incidence of respiratory irritation (coughing, breathholding, apnea, increased secretions, laryngospasm). Oxyhemoglobin saturation below 90% occurred in 6% of patients (from pooled data, N = 370 adults). 14.1 Ambulatory Surgery SUPRANE plus N 2 O was compared to isoflurane plus N 2 O in multicenter studies (21 sites) of 792 ASA physical status I, II, or III patients aged 18-76 years (median 32). Induction Anesthetic induction begun with thiopental and continued with SUPRANE was associated with a 7% incidence of oxyhemoglobin saturation of 90% or less (from pooled data, N = 307) compared with 5% in patients in whom anesthesia was induced with thiopental and isoflurane (from pooled data, N = 152). Maintenance & Recovery SUPRANE (desflurane, USP) with or without N 2 O or other anesthetics was generally well tolerated. There were no differences between SUPRANE and the other anesthetics studied in the times that patients were judged fit for discharge. In one outpatient study, patients received a standardized anesthetic consisting of thiopental 4.2-4.4 mg/kg, fentanyl 3.5-4.0 ug/kg, vecuronium 0.05-0.07 mg/kg, and N 2 O 60% in oxygen with either desflurane 3% or isoflurane 0.6%. Emergence times were significantly different; but times to sit up and discharge were not different (see Table 5). Table5.jpg 14.2 Cardiovascular Surgery SUPRANE was compared to isoflurane, sufentanil or fentanyl for the anesthetic management of coronary artery bypass graft (CABG), abdominal aortic aneurysm, peripheral vascular and carotid endarterectomy surgery in 7 studies at 15 centers involving a total of 558 patients. In all patients except the desflurane vs. sufentanil study, the volatile anesthetics were supplemented with intravenous opioids, usually fentanyl. Blood pressure and heart rate were controlled by changes in concentration of the volatile anesthetics or opioids and cardiovascular drugs if necessary. Oxygen (100%) was the carrier gas in 253 of 277 desflurane cases (24 of 277 received N 2 O/O 2 ). No differences were found in cardiovascular outcome (death, myocardial infarction, ventricular tachycardia or fibrillation, heart failure) among desflurane and the other anesthetics. Induction SUPRANE should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or any patients where increases in heart rate or blood pressure are undesirable. In the desflurane vs. sufentanil study, anesthetic induction with desflurane without opioids was associated with new transient ischemia in 14 patients vs. 0 in the sufentanil group. In the desflurane group, mean heart rate, arterial pressure, and pulmonary blood pressure increased and stroke volume decreased in contrast to no change in the sufentanil group. Cardiovascular drugs were used frequently in both groups: especially esmolol in the desflurane group (56% vs. 0%) and phenylephrine in the sufentanil group (43% vs. 27%). When 10 ug/kg of fentanyl was used to supplement induction of anesthesia at one other center, continuous 2-lead ECG analysis showed a low incidence of myocardial ischemia and no difference between desflurane and isoflurane. If desflurane is to be used in patients with coronary artery disease, it should be used in combinations with other medications for induction of anesthesia, preferably intravenous opioids and hypnotics. Maintenance & Recovery In studies where SUPRANE or isoflurane anesthesia was supplemented with fentanyl, there were no differences in hemodynamic variables or the incidence of myocardial ischemia in the patients anesthetized with desflurane compared to those anesthetized with isoflurane. During the precardiopulmonary bypass period, in the desflurane vs. sufentanil study where the desflurane patients received no intravenous opioid, more desflurane patients required cardiovascular adjuvants to control hemodynamics than the sufentanil patients. During this period, the incidence of ischemia detected by ECG or echocardiography was not statistically different between desflurane (18 of 99) and sufentanil (9 of 98) groups. However, the duration and severity of the ECG-detected myocardial ischemia was significantly less in the desflurane group. The incidence of myocardial ischemia after cardiopulmonary bypass and in the ICU did not differ between groups. Image7.jpg 14.3 Geriatric Surgery SUPRANE plus N 2 O was compared to isoflurane plus N 2 O in a multicenter study (6 sites) of 203 ASA physical status II or III elderly patients, aged 57-91 years (median 71). Induction Most patients were premedicated with fentanyl (mean 2 ug/kg), preoxygenated, and received thiopental (mean 4.3 mg/kg IV) or thiamylal (mean 4 mg/kg IV) followed by succinylcholine (mean 1.4 mg/kg IV) for intubation. Maintenance & Recovery Heart rate and arterial blood pressure remained within 20% of preinduction baseline values during administration of SUPRANE 0.5-7.7% (average 3.6%) with 50-60% N 2 O. Induction, maintenance, and recovery cardiovascular measurements did not differ from those during isoflurane/N 2 O administration or did the postoperative incidence of nausea and vomiting differ. The most common cardiovascular adverse event was hypotension occurring in 8% of the desflurane patients and 6% of the isoflurane patients. 14.4 Neurosurgery SUPRANE was studied in 38 patients aged 26-76 years (median 48 years), ASA physical status II or III undergoing neurosurgical procedures for intracranial lesions. Induction Induction consisted of standard neuroanesthetic techniques including hyperventilation and thiopental. Maintenance No change in cerebrospinal fluid pressure (CSFP) was observed in 8 patients who had intracranial tumors when the dose of SUPRANE was 0.5 MAC in N 2 O 50%. In another study of 9 patients with intracranial tumors, 0.8 MAC desflurane/air/O 2 did not increase CSFP above post induction baseline values. In a different study of 10 patients receiving 1.1 MAC desflurane/air/O 2 , CSFP increased 7 mm Hg (range 3-13 mm Hg increase, with final values of 11-26 mm Hg) above the pre-drug values. All volatile anesthetics may increase intracranial pressure in patients with intracranial space occupying lesions. In such patients, SUPRANE should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) in the period before cranial decompression. Appropriate attention must be paid to maintain cerebral perfusion pressure. The use of a lower dose of desflurane and the administration of a barbiturate and mannitol would be predicted to lessen the effect of desflurane on CSFP. Under hypocapnic conditions (PaCO 2 27 mm Hg) SUPRANE 1 and 1.5 MAC did not increase cerebral blood flow (CBF) in 9 patients undergoing craniotomies. CBF reactivity to increasing PaCO 2 from 27 to 35 mm Hg was also maintained at 1.25 MAC desflurane/air/O 2 . 14.5 Pediatric Surgery In a clinical safety trial conducted in children aged 2 to 16 years (mean 7.4 years), following induction with another agent, SUPRANE and isoflurane (in N 2 O/O 2 ) were compared when delivered via face mask or laryngeal mask airway (LMA TM mask) for maintenance of anesthesia, after induction with intravenous propofol or inhaled sevoflurane, in order to assess the relative incidence of respiratory adverse events. SUPRANE was associated with higher rates (compared with isoflurane) of coughing, laryngospasm and secretions with an overall rate of respiratory events of 39%. Of the pediatric patients exposed to desflurane, 5% experienced severe laryngospasm (associated with significant desaturation; i.e. SpO 2 of <90% for >15 seconds, or requiring succinylcholine), across all ages, 2-16 years old. Individual age group incidences of severe laryngospasm were 9% for 2-6 years old, 1% for 7-11 years old, and 1% for 12-16 years old. Removal of LMA TM mask under deep anesthesia (MAC range 0.6 - 2.3 with a mean of 1.12 MAC) was associated with a further increase in frequency of respiratory adverse events as compared to awake LMA TM mask removal or LMA TM mask removal under deep anesthesia with the comparator. The frequency and severity of non-respiratory adverse events were comparable between the two groups. The incidence of respiratory events under these conditions was highest in children aged 2-6 years. Therefore, similar studies under the age of 2 years were not initiated. Image8.jpg

8.5 Geriatric Use The minimum alveolar concentration (MAC) of SUPRANE decreases with increasing patient age. The dose should be adjusted accordingly. The average MAC for SUPRANE in a 70 year old patient is two-thirds the MAC for a 20 year old patient [see Dosage and Administration (2) Table 1 and Clinical Studies (14.3)].

8.2 Labor and Delivery The safety of desflurane during labor or delivery has not been demonstrated. SUPRANE is a uterine-relaxant.

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SUPRANE is administered to a nursing woman.

8.4 Pediatric Use Respiratory Adverse Reactions in Pediatric Patients SUPRANE is approved for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. It is not approved for maintenance of anesthesia of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing (26%), laryngospasm (13%), and secretions (12%) [see Clinical Studies (14.5)]. Children, particularly if 6 years old or younger, who are under an anesthetic maintenance of SUPRANE delivered via laryngeal mask airway (LMA TM mask)are at increased risk for adverse respiratory reactions, e.g., coughing and laryngospasm, especially with removal of the laryngeal mask airway under deep anesthesia [see Clinical Studies (14.5)]. Therefore, closely monitor these patients for signs and symptoms associated with laryngospasm and treat accordingly. When SUPRANE is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection, there is an increased risk for airway narrowing and increases in airway resistance. Therefore, closely monitor these patients for signs and symptoms associated with airway narrowing and treat accordingly.

8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies have been performed in rats at doses up to at 1 MAC hour for a minimum of 21 days and have revealed no evidence of impaired fertility or harm to the fetus due to SUPRANE. No teratogenic effect was observed at approximately 10 and 13 cumulative MAC-Hour exposures at 1 MAC-Hour per day during organogenesis in rats or rabbits. At higher doses increased incidences of post-implantation loss and maternal toxicity were observed. However, at 10 MAC-Hours cumulative exposure in rats, about 6% decrease in the weight of male pups was observed at preterm caesarean delivery. Rats exposed to SUPRANE at 1 MAC-Hour per day from gestation day 15 to lactation day 21, did not show signs of dystocia. Body weights of pups delivered by these dams at birth and during lactation were comparable to that of control pups. No treatment related behavioral changes were reported in these pups during lactation.

8. USE IN SPECIFIC POPULATIONS Pediatric: SUPRANE is not contraindicated as an induction agent in children and is not indicated for maintenance of anesthesia in non-intubated children due to an increased incidence of moderate to severe respiratory adverse reactions, including coughing, laryngospasm and secretions. (5.3, 8.4) Geriatric: The minimum alveolar concentration (MAC) of SUPRANE decreases with increasing patient age. (8.5) See 17 for PATIENT COUNSELING INFORMATION. 8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies have been performed in rats at doses up to at 1 MAC hour for a minimum of 21 days and have revealed no evidence of impaired fertility or harm to the fetus due to SUPRANE. No teratogenic effect was observed at approximately 10 and 13 cumulative MAC-Hour exposures at 1 MAC-Hour per day during organogenesis in rats or rabbits. At higher doses increased incidences of post-implantation loss and maternal toxicity were observed. However, at 10 MAC-Hours cumulative exposure in rats, about 6% decrease in the weight of male pups was observed at preterm caesarean delivery. Rats exposed to SUPRANE at 1 MAC-Hour per day from gestation day 15 to lactation day 21, did not show signs of dystocia. Body weights of pups delivered by these dams at birth and during lactation were comparable to that of control pups. No treatment related behavioral changes were reported in these pups during lactation. 8.2 Labor and Delivery The safety of desflurane during labor or delivery has not been demonstrated. SUPRANE is a uterine-relaxant. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SUPRANE is administered to a nursing woman. 8.4 Pediatric Use Respiratory Adverse Reactions in Pediatric Patients SUPRANE is approved for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. It is not approved for maintenance of anesthesia of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing (26%), laryngospasm (13%), and secretions (12%) [see Clinical Studies (14.5)]. Children, particularly if 6 years old or younger, who are under an anesthetic maintenance of SUPRANE delivered via laryngeal mask airway (LMA TM mask)are at increased risk for adverse respiratory reactions, e.g., coughing and laryngospasm, especially with removal of the laryngeal mask airway under deep anesthesia [see Clinical Studies (14.5)]. Therefore, closely monitor these patients for signs and symptoms associated with laryngospasm and treat accordingly. When SUPRANE is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection, there is an increased risk for airway narrowing and increases in airway resistance. Therefore, closely monitor these patients for signs and symptoms associated with airway narrowing and treat accordingly. 8.5 Geriatric Use The minimum alveolar concentration (MAC) of SUPRANE decreases with increasing patient age. The dose should be adjusted accordingly. The average MAC for SUPRANE in a 70 year old patient is two-thirds the MAC for a 20 year old patient [see Dosage and Administration (2) Table 1 and Clinical Studies (14.3)]. 8.6 Renal Impairment Concentrations of 1-4% SUPRANE in nitrous oxide/oxygen have been used in patients with chronic renal or hepatic impairment and during renal transplantation surgery. Because of minimal metabolism, a need for dose adjustment in patients with renal and hepatic impairment is not to be expected. Nine patients receiving desflurane (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either desflurane (N=28) or isoflurane (N=30) undergoing renal transplant. 8.7 Hepatic Impairment Eight patients receiving SUPRANE were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including enzymes and hepatic function evaluation, were seen.