Desflurane

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.

1.1Induction 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.

1.2Maintenance 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 ) ] .

The use of Desflurane 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 or to other halogenated agents [ see Warnings and Precautions ( 5.5 )].
• Patients with a history of moderate to severe hepatic dysfunction following anesthesia with Desflurane 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 )
• Patients with a history of moderate to severe hepatic dysfunction following anesthesia with halogenated agents and not otherwise explained. ( 4 )

• 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 )

5.1Malignant 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.

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 )

7.1Benzodiazepines 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 mcg/kg) and intravenous fentanyl (3-6 mcg/kg) in patients of two different age groups. Table 3 Desflurane MAC with Fentanyl or Midazolam Mean ± SD (percent reduction) Dose 18-30 years 31-65 years No fentanyl 6.4 ± 0.0 6.3 ± 0.4 3 mcg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%) 6 mcg/kg fentanyl 3.5 ± 1.9 (46%) 2.3 ± 1.0 (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%)

7.2Neuromuscular 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

0.65MAC 60% N 2 O/O 2 26

133 - -

1.25MAC 60% N 2 O/O 2 18

119 - -

1.25MAC 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.

Most common adverse reactions (incidence> 10%) are coughing, breath holding, apnea, nausea, vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, Piramal Critical Care, Inc. at 1-888-822-8431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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*, 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) *Incidence of events 3% - 10% 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