A US Leader in Inhaled Anesthetics

SUPRANE (desflurane, USP) Volatile Liquid for Inhalation

INDICATIONS

• Induction of Anesthesia:  SUPRANE is indicated as an inhalation agent for induction of anesthesia for inpatient and outpatient surgery in adults.
• 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.

IMPORTANT RISK INFORMATION

DOSAGE AND ADMINISTRATION

• 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.
• The administration of general anesthesia must be individualized based on the patient’s response, including cardiovascular and pulmonary changes.
• 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.

CONTRAINDICATIONS

• Patients with known or suspected genetic susceptibility to malignant hyperthermia.
• Patients in whom general anesthesia is contraindicated.
• Induction of anesthesia in pediatric patients due to high incidence of upper airway adverse events.
• Patients with known sensitivity to SUPRANE or other halogenated agents.
• Patients with a history of moderate to severe hepatic dysfunction following anesthesia with SUPRANE or other halogenated agents and not otherwise explained.

WARNINGS AND PRECAUTIONS

• Malignant Hyperthermia:  In susceptible individuals, desflurane may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand.  Fatal outcomes have been reported.  The risk increases with the concomitant administration of succinylcholine and volatile anesthetic agents.  SUPRANE can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history.  Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, hypovolemia, and hemodynamic instability.  Skin mottling, coagulopathies, and renal failure may occur later.
  Successful treatment depends on early recognition of the clinical signs.  If malignant hyperthermia is suspected, discontinue all triggering agents, administer intravenous dantrolene sodium, and initiate supportive therapies.
• 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.
• Respiratory Adverse Reactions in Pediatric Patients:  Children, particularly if 6 years old or younger, who are under an anesthetic maintenance of SUPRANE delivered via laryngeal mask airway (LMA) are at increased risk for adverse respiratory reactions, especially with removal of the laryngeal mask airway under deep anesthesia.  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.  Closely monitor these patients for signs and symptoms associated with airway narrowing and treat accordingly.
• QT Prolongation:  QT prolongation, associated with torsade de pointes, has been reported.  Carefully monitor cardiac rhythm when administering SUPRANE to susceptible patients.
• Interactions with Desiccated Carbon Dioxide (CO₂) Absorbents:  Desflurane can react with desiccated CO₂ absorbents to produce carbon monoxide.  Replace desiccated CO₂ absorbent before administration of SUPRANE.
• 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, SUPRANE may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics.  Cirrhosis, viral hepatitis or other pre-existing hepatic disease may be a reason to select an anesthetic other than a halogenated anesthetic.  Repeated anesthesia within a short period of time should be approached with caution.
• 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.  Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.
• Postoperative Agitation in Children:  May cause postoperative agitation during emergence from anesthesia in children.
• Adverse Reactions:  The most common adverse reactions (incidence> 10%) are coughing, breath holding, apnea, nausea, and vomiting.
• Drug Interactions:
  • Concomitant use of N₂O, benzodiazepines and/or opioids reduces the MAC of SUPRANE. Adjust dose accordingly.
  • SUPRANE decreases the doses of neuromuscular blocking agents required.  Adjust dose accordingly.
  • Geriatric Use:  The minimum alveolar concentration (MAC) of SUPRANE decreases with increasing patient age. Adjust dose accordingly.

Please see full Prescribing Information for SUPRANE (desflurane, USP).

Sevoflurane, USP, Volatile Liquid for Inhalation

INDICATIONS

• Sevoflurane, USP is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery.
• Sevoflurane, USP should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Since level of anesthesia may be altered rapidly, only vaporizers producing predictable concentrations of sevoflurane, USP should be used.

IMPORTANT RISK INFORMATION 

• Contraindications:  Known or suspected genetic susceptibility to malignant hyperthermia. Known or suspected sensitivity to sevoflurane, USP or to other halogenated inhalational anesthetics.
• Risk of Renal Injury:  Findings taken from patient and animal studies suggest that there is a potential for renal injury which is presumed due to Compound A.  Animal and human studies demonstrate that sevoflurane, USP administered for more than 2 MAC-hours and at fresh gas flow rates of <2 L/min may be associated with proteinuria and glycosuria. To minimize exposure to Compound A, the clinician should adjust inspired concentration and fresh gas flow rate.  Sevoflurane, USP exposure should not exceed 2 MAC-hours at flow rates of 1 to <2 L/min.  Fresh gas flow rates <1 L/min are not recommended.
  Because clinical experience in administering sevoflurane, USP to patients with renal insufficiency (creatinine >1.5 mg/dL) is limited, its safety in these patients has not been established.
• Risk of Respiratory Depression:  Sevoflurane, USP may cause respiratory depression, which may be augmented by opioid premedication or other agents causing respiratory depression.  Monitor respiration and, if necessary, assist with ventilation.
• Risk of QT Prolongation:  Reports of QT prolongation, associated with torsade de pointes (in exceptional cases, fatal), have been received.  Caution should be exercised when administering sevoflurane, USP to susceptible patients (e.g., patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval).
• Malignant Hyperthermia:  Fatal outcomes have been reported.  The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents.  Sevoflurane, USP 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 or dihydropyridine receptor variants.  Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity, tachycardia, 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 depends on early recognition of the clinical signs. If malignant hyperthermia is suspected, discontinue all triggering agents, administer intravenous dantrolene sodium, and initiate supportive therapies.
• Perioperative Hyperkalemia:  Rare increases in serum potassium levels 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.  Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended; as is subsequent evaluation for latent neuromuscular disease.
• 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.  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.  Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.
• Bradycardia in Down Syndrome:  Episodes of severe bradycardia and cardiac arrest, not related to underlying congenital heart disease, have been reported during anesthesia induction with sevoflurane, USP in pediatric patients with Down syndrome.  In most cases, bradycardia improved with decreasing the concentration of sevoflurane, USP, manipulating the airway, or administering an anticholinergic or epinephrine.
  During induction, closely monitor heart rate, and consider incrementally increasing the inspired sevoflurane, USP concentration until a suitable level of anesthesia is achieved.  Consider having an anticholinergic and epinephrine available when administering sevoflurane, USP for induction in this patient population.
• Risk of Driving and Operating Machinery:  Performance of activities requiring mental alertness, such as driving or operating machinery, may be impaired after sevoflurane, USP anesthesia.
• Decreases in Blood Pressure:  During maintenance of anesthesia, increasing the concentration produces dose-dependent decreases in blood pressure.  These hemodynamic changes may occur more rapidly than with other volatile anesthetics.  Excessive decreases in blood pressure or respiratory depression may be related to depth of anesthesia and may be corrected by decreasing the inspired concentration of sevoflurane, USP.
• Seizures:  The majority of these have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors.  Clinical judgement should be exercised when using sevoflurane, USP in patients who may be at risk for seizures.
• Ventricular Arrhythmias in Pediatric Patients:  Cases of life-threatening ventricular arrhythmias have been reported in pediatric patients with Pompe disease (also commonly known as glycogen storage disease type II or acid maltase deficiency).  Reported arrhythmias included severe bradycardia, torsade de pointes, and fatal ventricular fibrillation, which usually resolved after treatment with pharmacologic agents and defibrillation.  Avoid induction and maintenance of anesthesia using sole agents, such as sevoflurane, USP, that decrease systemic vascular resistance or diastolic blood pressure.
• Hepatic Function:  Cases of mild, moderate, and severe hepatic dysfunction or hepatitis (e.g., jaundice associated with fever and/or eosinophilia) after anesthesia with sevoflurane, USP have been reported.  Clinical judgement should be exercised when sevoflurane, USP is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction.  It has been reported that previous exposure to halogenated hydrocarbon anesthetics may increase the potential for hepatic injury.
• Desiccated CO₂ Absorbents:  KOH (potassium hydroxide) containing CO₂ absorbents are not recommended for use with sevoflurane, USP.  Rare cases of extreme heat, smoke, and/or spontaneous fire in the anesthesia breathing circuit have been reported.
• Adverse Events:  Reported by ≥5% of the surgical patients receiving sevoflurane, USP during clinical studies during induction included: bradycardia, tachycardia, agitation, laryngospasm, airway obstruction, breath-holding, and increased cough; during maintenance and emergence: shivering, hypotension, bradycardia, somnolence, agitation, nausea, vomiting, and increased cough were reported.
• Drug Interactions:
  • Epinephrine:  Epinephrine administered with sevoflurane, USP may increase the risk of ventricular arrhythmias.  Monitor the electrocardiogram and blood pressure and ensure emergency medications to treat ventricular arrhythmias are readily available.
  • Calcium Antagonists:  Sevoflurane, USP may lead to marked hypotension in patients treated with calcium antagonists.  Blood pressure should be closely monitored and emergency medications to treat hypotension should be readily available.
  • Non-selective MAO Inhibitors:  Concomitant use of MAO inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.
  • Benzodiazepines and opioids:  Would be expected to decrease the MAC of sevoflurane, USP.  
  • Nitrous Oxide:  The anesthetic requirement for sevoflurane, USP is decreased when administered in combination with nitrous oxide.
  • Neuromuscular Blocking Agents:  Sevoflurane, USP increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants.

Please see full Prescribing Information for Sevoflurane, USP.

FORANE (isoflurane, USP) Liquid for Inhalation

INDICATIONS

FORANE, a general anesthetic, is an inhalation agent indicated for induction and maintenance of general anesthesia.  Adequate data have not been developed to establish its application in obstetrical anesthesia.
 

Dosage and Administration

• FORANE should be administered only by persons trained in the administration of general anesthesia.  FORANE should only be delivered using a vaporizer specifically designed and designated for use with isoflurane.
• The administration of general anesthesia must be individualized and titrated based on the patient’s age and clinical status.

IMPORTANT RISK INFORMATION 

• Contraindications:  FORANE is contraindicated in patients:
  • in whom general anesthesia is contraindicated.
  • with known sensitivity to FORANE or to other halogenated agents.
  • with known or suspected genetic susceptibility to malignant hyperthermia.
  • with a history of confirmed hepatitis due to a halogenated inhalational anesthetic, or a history of unexplained moderate to severe hepatic dysfunction (e.g., jaundice associated with fever and/or eosinophilia) after anesthesia with isoflurane or other halogenated inhalational anesthetics.
• Malignant Hyperthermia:  FORANE may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand.  Fatal outcomes have been reported.  The risk increases with the concomitant administration of succinylcholine and volatile anesthetic agents.  FORANE can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history.  Successful treatment depends on early recognition of the clinical signs.  If malignant hyperthermia is suspected, discontinue all triggering agents, administer intravenous dantrolene sodium, and initiate supportive therapies.
• 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.  Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs 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.
• Hepatic Reactions:  Cases of mild, moderate and severe postoperative hepatic dysfunction or hepatitis, including fatal hepatic necrosis and hepatic failure, have been reported with isoflurane.  Such reactions can represent hypersensitivity hepatitis, a known risk of exposure to halogenated anesthetics, including isoflurane.  FORANE may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics.  Clinical judgment should be exercised when isoflurane is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction.  Repeated halogenated anesthetics within a short period of time may result in increased effects, particularly in patients with underlying hepatic conditions, or additive effects in patients treated with drugs known to cause hepatic dysfunction.
• Hypersensitivity Reactions:  Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with isoflurane.
• Abortions:  Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions.
• QT Prolongation:  QT prolongation, with rare instances of torsade de pointes, have been reported.  Monitor QT interval when administering isoflurane to susceptible patients.
• Interactions with Desiccated carbon dioxide (CO₂) absorbents:  FORANE can react with desiccated carbon dioxide (CO₂) absorbents to produce carbon monoxide.  Replace desiccated CO₂ absorbent before administration of FORANE.
• 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.
• Adverse Reactions:  Most common adverse reactions (incidence ≥ 5%) are agitation, cough, breath holding, nausea, chills/shivering, vomiting, laryngospasm, delirium.
• Drug Interactions:
  • Concomitant use of N₂O and/or opioids reduces the MAC of FORANE.  Adjust dose accordingly.
  • FORANE decreases the doses of neuromuscular blocking agents required.  Adjust dose accordingly.
• Geriatric Use:  The minimum alveolar concentration (MAC) of FORANE decreases with increasing patient age.

Please see full Prescribing Information for FORANE (isoflurane, USP).