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 ] .
The use of Desflurane, USP, Liquid for Inhalation is contraindicated in the following conditions: Known or suspected genetic susceptibility to malignant hyperthermia [See Warnings and Precautions (5.1), Clinical Pharmacology (12.5)] . 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 [See Warnings and Precautions (5.6) ] . 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 [See Warnings and Precautions (5.6) ] . 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 ) Patients with a history of moderate to severe hepatic dysfunction following anesthesia with halogenated agents and not otherwise explained. ( 4 )
AND PRECAUTIONS Malignant Hyperthermia: Malignant hyperthermia may occur, especially in individuals with known or suspected susceptibility based on genetic factors or family history. Discontinue triggering agents, administer intravenous dantrolene sodium, and apply supportive therapies. ( 5.1 )
Perioperative
Hyperkalemia: Perioperative hyperkalemia may occur. Patients with latent or overt neuromuscular disease, particularly with Duchenne muscular dystrophy, appear to be most vulnerable. Early, aggressive intervention is recommended. ( 5.2 )
Respiratory Adverse
Reactions in Pediatric Patients: - Not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions. Monitor and treat accordingly. ( 5.3 ) - May cause airway narrowing and increased airway resistance in children with asthma or a history of recent upper airway infection. Monitor and treat accordingly.( 5.3 ) QTc Prolongation: Carefully monitor cardiac rhythm when administering desflurane to susceptible patients. ( 5.4 ) Interactions with Desiccated Carbon Dioxide (CO 2 ) Absorbents: May react with desiccated CO 2 absorbents to produce carbon monoxide. Replace desiccated CO 2 absorbent before administration of desflurane. ( 5.5 )
Hepatobiliary
Disorders: May cause sensitivity hepatitis in patients sensitized by previous exposure to halogenated anesthetics. Approach repeated anesthesia with caution ( 5.6 )
Pediatric
Neurotoxicity: In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. ( 5.7 )
Postoperative
Agitation in Children: May cause postoperative agitation during emergence from anesthesia in children. ( 5.9 )
5.1 Malignant Hyperthermia In susceptible individuals, volatile anesthetic agents, including desflurane, may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand. Fatal outcomes of malignant hyperthermia have been reported. The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. Desflurane can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor ( RYR1 ) or dihydropyridine receptor ( CACNA1S ) variants [See Contraindications (4), Clinical Pharmacology (12.5)] . Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity (e.g., jaw muscle spasm), tachycardia (e.g., particularly that unresponsive to deepening anesthesia or analgesic medication administration), tachypnea, cyanosis, arrhythmias, hypovolemia, and hemodynamic instability. Skin mottling, coagulopathies, and renal failure may occur later in the course of the hypermetabolic process. Successful treatment of malignant hyperthermia depends on early recognition of the clinical signs. If malignant hyperthermia is suspected, discontinue all triggering agents (i.e., volatile anesthetic agents and succinylcholine), administer intravenous dantrolene sodium, and initiate supportive therapies. Consult prescribing information for intravenous dantrolene sodium for additional information on patient management. Supportive therapies include administration of supplemental oxygen and respiratory support based on clinical need, maintenance of hemodynamic stability and adequate urinary output, management of fluid and electrolyte balance, correction of acid base derangements, and institution of measures to control rising temperature.
5.2 Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.
5.3 Respiratory Adverse Reactions in Pediatric Patients Desflurane 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 Clinical Studies (14.5) ] . 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 [See Clinical Studies (14.5) ] . 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 .
5.4 QTc Prolongation QTc prolongation, associated with torsade de pointes, has been reported [See Adverse Reactions ( 6.2 )]. Carefully monitor cardiac rhythm when administering desflurane to susceptible patients (e.g., patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval).
5.5 Interactions with Desiccated Carbon Dioxide Absorbents Desflurane like some other inhalation anesthetics, can react with desiccated carbon dioxide (CO 2 ) absorbents to produce carbon monoxide that may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO 2 canister at high flow rates over many hours or days. When a clinician suspects that CO 2 absorbent may be desiccated, it should be replaced before the administration of desflurane.
5.6 Hepatobiliary Disorders With the use of halogenated anesthetics, disruption of hepatic function, icterus and fatal liver necrosis have been reported; such reactions appear to indicate hypersensitivity. As with other halogenated anesthetic agents, desflurane may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics [See Contraindications (4) ] . Cirrhosis, viral hepatitis or other pre-existing hepatic disease may be a reason to select an anesthetic other than a halogenated anesthetic. As with all halogenated anesthetics, repeated anesthesia within a short period of time should be approached with caution.
5.7 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, 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 three years of age in humans. [See Use in Specific Populations ( 8.1 , 8.4 ), Nonclinical Toxicology (13.2) ] . Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.
5.8 Laboratory Findings Transient elevations in glucose and white blood cell count may occur as with use of other anesthetic agents.
5.9 Postoperative Agitation in Children Emergence from anesthesia in children may evoke a brief state of agitation that may hinder cooperation.
5.4 QTc Prolongation QTc prolongation, associated with torsade de pointes, has been reported [See Adverse Reactions ( 6.2 )]. Carefully monitor cardiac rhythm when administering desflurane to susceptible patients (e.g., patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval).