Desflurane Drug Information

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

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-patients.

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%)

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.

Concomitant use with N 2 O

Concomitant administration of N 2 O reduces the MAC of desflurane .

Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, embryo-fetal toxicity (reduced viable fetuses and/or increased post-implantation loss) was noted in pregnant rats and rabbits administered 1 MAC desflurane for 4 hours a day (4 MAC-hours/day) during organogenesis. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Labor or Delivery The safety of desflurane during labor or delivery has not been demonstrated. Desflurane is a uterine-relaxant. Data Animal Data Pregnant rats were exposed to 8.2% desflurane (1 MAC; 60% oxygen) for 0.5, 1, or 4 hours (0.5, 1, or 4 MAC-hours) per day during organogenesis (Gestation Day 6 to 15). Embryo-fetal toxicity (increased post-implantation loss and reduced viable fetuses) was noted in the 4 hour treatment group in the presence of maternal toxicity (reduced body weight gain). There was no evidence of malformations in any group.

Pregnant rabbits were exposed to 8.9% desflurane (1 MAC; 60% oxygen) for 0.5, 1, or 3 hours per day during organogenesis (Gestation Days 6 to 18). Fetal toxicity (reduced viable fetuses) was noted in the 3 hour treatment group in the presence of maternal toxicity (reduced body weight). There was no evidence of malformations in any group. Pregnant rats were exposed to 8.2% desflurane (1 MAC; 60% oxygen) for 0.5, 1, or 4 hours per day from late gestation and through lactation (Gestation Day 15 to Lactation Day 21). Pup body weights were reduced in the 4 hours per day group in the presence of maternal toxicity (increased mortality and reduced body weight gain). This study did not evaluate neurobehavioral function including learning and memory or reproductive behavior in the first generation (F1) pups. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits .

Pediatric Use Respiratory Adverse Reactions in Pediatric Patients Desflurane is indicated for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than desflurane, and tracheal intubation. Is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing (26%), laryngospasm (13%) and secretions (12%) . Children, particularly if 6 years old or younger, who are under an anesthetic maintenance of desflurane delivered via laryngeal mask airway (LMA™ 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 . Therefore, closely monitor these patients for signs and symptoms associated with laryngospasm and treat accordingly. When desflurane 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. Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as desflurane, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, 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 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data .

The use of Desflurane, USP, Liquid for Inhalation is contraindicated in the following conditions: Known or suspected genetic susceptibility to malignant hyperthermia . Patients in whom general anesthesia is contraindicated. Induction of anesthesia in pediatric patients. Patients with known sensitivity to Desflurane, USP, Liquid for Inhalation or to other halogenated agents . Patients with a history of moderate to severe hepatic dysfunction following anesthesia with Desflurane, USP, Liquid for Inhalation or other halogenated agents and not otherwise explained . Patients with known or suspected genetic susceptibility to malignant hyperthermia Patients in whom general anesthesia is contraindicated Induction of anesthesia in pediatric patients Patients with known sensitivity to halogenated agents Patients with a history of moderate to severe hepatic dysfunction following anesthesia with halogenated agents and not otherwise explained.

The symptoms of overdosage of desflurane 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 desflurane, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.