Isoflurane

1 INDICATIONS AND USAGE Isoflurane USP may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia. Isoflurane USP, a general anesthetic, is an inhalation agent indicated for induction and maintenance of general anesthesia. ( 1 )

12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Induction of and recovery from isoflurane anesthesia are rapid. Isoflurane has a mild pungency which limits the rate of induction, although excessive salivation or tracheobronchial secretions do not appear to be stimulated. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia may be changed rapidly with isoflurane. Isoflurane is a profound respiratory depressant. As anesthetic dose is increased, tidal volume decreases and respiratory rate is unchanged. This depression is partially reversed by surgical stimulation, even at deeper levels of anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether and enflurane, although the frequency is less than with enflurane. Blood pressure decreases with induction of anesthesia but returns toward normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding decreases in blood pressure. Nitrous oxide diminishes the inspiratory concentration of isoflurane required to reach a desired level of anesthesia and may reduce the arterial hypotension seen with isoflurane alone. Heart rhythm is remarkably stable. With controlled ventilation and normal PaCO 2 , cardiac output is maintained despite increasing depth of anesthesia, primarily through an increase in heart rate which compensates for a reduction in stroke volume. The hypercapnia which attends spontaneous ventilation during isoflurane anesthesia further increases heart rate and raises cardiac output above awake levels. Muscle relaxation is often adequate for intra-abdominal operations at normal levels of anesthesia. Complete muscle paralysis can be attained with small doses of neuromuscular blocking agents. ALL COMMONLY USED NEUROMUSCULAR BLOCKING AGENTS ARE MARKEDLY POTENTIATED WITH ISOFLURANE, THE EFFECT BEING MOST PROFOUND WITH THE NONDEPOLARIZING TYPE. Neostigmine reverses the effect of nondepolarizing neuromuscular blocking agents in the presence of isoflurane. All commonly used neuromuscular blocking agents are compatible with isoflurane. Isoflurane can produce coronary vasodilation at the arteriolar level in selected animal models; the drug is probably also a coronary dilator in humans. Isoflurane, like some other coronary arteriolar dilators, has been shown to divert blood from collateral dependent myocardium to normally perfused areas in an animal model (“coronary steal”). Clinical trials to date evaluating myocardial ischemia, infarction and death as outcome parameters have not established that the coronary arteriolar dilation property of isoflurane is associated with coronary steal or myocardial ischemia in patients with coronary artery disease. 12.3 Pharmacokinetics Isoflurane undergoes minimal biotransformation in man. In the postanesthesia period, only 0.17% of the isoflurane taken up can be recovered as urinary metabolites. 12.5 Pharmacogenomics RYR1 and CACNA1S are polymorphic genes, and multiple pathogeni

2 DOSAGE AND ADMINISTRATION • Isoflurane USP should be administered only by persons trained in the administration of general anesthesia. Isoflurane USP should only be delivered using a vaporizer specifically designed and designated for use with isoflurane. ( 2 ) • The administration of general anesthesia must be individualized and titrated based on the patient’s age and clinical status. ( 2 ) 2.1 Important Dosage and Administration Information Isoflurane 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. Isoflurane is administered by inhalation. Isoflurane should be delivered from a vaporizer specifically designed for use with isoflurane. Dosage for induction and maintenance must be individualized and titrated to the desired effect according to the patient’s age and clinical status. With the exception of neonates, the minimum alveolar concentration (MAC) of isoflurane decreases with increasing patient age. Nitrous oxide decreases the MAC of isoflurane (see Table 1 ). Opioids decrease the MAC of isoflurane [see Drug Interactions (7) ]. Isoflurane potentiates the muscle relaxant effect of all neuromuscular blockers and decreases the required doses of neuromuscular blocking agents [see Drug Interactions (7) ] . The dose should be adjusted accordingly. All patients anesthetized with isoflurane should be continually monitored (e.g., monitoring of the electrocardiogram, blood pressure, oxygen saturation, and end tidal CO 2 ). Isoflurane is a profound respiratory depressant. Excessive respiratory depression may be related to depth of anesthesia and respond to decreasing the inspired concentration of isoflurane. The depressant effect is accentuated by concurrent use of opioids and other respiratory depressants. Respiration should be closely monitored and assisted or controlled ventilation employed when necessary. 2.2 Premedication Premedication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by Isoflurane USP, and the heart rate tends to be increased. 2.3 Induction Induction with isoflurane in oxygen or in combination with oxygen-nitrous oxide mixtures may produce coughing, breath holding, laryngospasm and bronchospasm, which increases with the concentration of isoflurane. These difficulties may be avoided by the use of a hypnotic dose of an ultra-short-acting barbiturate. Inspired concentrations of 1.5 to 3% isoflurane usually produce surgical anesthesia in 7 to 10 minutes. 2.4 Maintenance Isoflurane MAC values according to age are shown below: Table 1: Effect of Age on Minimum Alveolar Concentration of Isoflurane Age Average MAC Value In 100% Oxygen Average MAC Value In 30% Oxygen and 70% N 2 O Preterm neonates less than 32 weeks gestational age 1.28% Preterm neonates 32-37 weeks gestational age 1.41% 0-1 month 1.60% 1-6 months 1.87% 6-12 months 1.80% 1-5 years 1.60% 6-10 years 1.45% 11-18 years 1.38% 19-30 years 1.28% 0.56% 31-55 years 1.15% 0.50% 55-83 years 1.05% 0.37% Dosage for induction and maintenance must be individualized and titrated to the desired effect according to the patient’s age and clinical status. Surgical levels of anesthesia may be sustained with a 1 to 2.5% concentration when nitrous oxide is used concomitantly. An additional 0.5 to 1% may be required when isoflurane is given using oxygen alone. If added relaxation is required, supplemental doses of neuromuscular blocking agents may be used. The level of blood pressure during maintenance is an inverse function of isoflurane concentration in the absence of other complicating problems. Excessive decreases may be due to depth of anesthesia and in such instances may be corrected by lightening anesthesia. Isoflurane causes a dose-dependent reduction in systemic vascular resistance and blood pressure.

6 ADVERSE REACTIONS Most common adverse reactions (incidence > 5%) are agitation, cough, breath holding, nausea, chills/shivering, vomiting, laryngospasm, delirium. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Piramal Critical Care, Inc. at 1-888-822-8431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The following adverse reactions were identified from controlled clinical trials of adult and pediatric subjects exposed to Isoflurane USP. The trials were conducted using a variety of pre-medications, other anesthetics, and surgical procedures of varying lengths. The most serious reported adverse reactions in alphabetical order are agitation, arrhythmia, breath holding, elevated liver enzyme, hypotension and laryngospasm. The most frequent adverse reactions (incidence ³ 5%) described in Table 1 are agitation, breath holding, chills/shivering, cough, delirium, laryngospasm, nausea, and vomiting. Adverse reactions with an incidence between 1% and 5% are provided in Table 2. Adverse reactions with an incidence less than 1% are provided in Table 3. 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. Table 2: Adverse Reactions ≥ 5% System Organ Class (SOC) Adverse Reaction Frequency PSYCHIATRIC DISORDERS Delirium 6.2% (N=2830) NERVOUS SYSTEM DISORDERS Agitation (Excitement) Induction 51.8% (N=515) 1 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Breath holding Induction 23.9% (N=515) 1 Cough Induction 28.2% (N=515) 1 Laryngospasm Induction 8.0% (N=515) 1 GASTROINTESTINAL DISORDERS Nausea Recovery 15.4 % (N=2830) Vomiting Recovery 9.5% (N=2830) GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Chills/shivering 14.0% (N=1691) 2 1 Represents patients not receiving intravenous agents or neuromuscular blocking agents for intubation (i.e., patients receiving inhalation induction). 2 Reflects the number of patients with recorded body temperature measurements. Table 3: Adverse Reactions between 1% and 5% System Organ Class (SOC) Adverse Reaction Frequency NERVOUS SYSTEM DISORDERS Movement Maintenance 1.8% (N=2830) CARDIAC DISORDERS Ventricular arrhythmia (Intraoperative) Induction 2.1% (N=2161) Maintenance 2.7% (N=2253) Nodal arrhythmia (Intraoperative) Induction 4.0% (N=2161) Maintenance 1.7% (N=2253) Atrial arrhythmia (Intraoperative) Induction 1.6% (N=2161 Maintenance 2.2% (N=2253) Arrhythmia (Postoperative) 1.1% (N=2830) RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Breath holding Maintenance 1.1% (N=359) 1 Cough Maintenance 4.2 % (N=359) 1 1 Represents patients not receiving intravenous agents or neuromuscular blocking agents for intubation (i.e., patients receiving inhalation induction). Table 4: Adverse Reactions less than 1% System Organ Class (SOC) Adverse Reaction Frequency PSYCHIATRIC DISORDERS Mood changes 0.3% (N=2830) Nightmare 0.4% (N=2175) 1 NERVOUS SYSTEM DISORDERS Convulsive pattern on electroencephalogram 0.5% (N=200) 2 Seizure 0.04% (N=2830) VASCULAR DISORDERS Hypotension Postoperative 0.3% (N=2830) Hypertension Postoperative 0.1% (N=2830) RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Laryngospasm Maintenance 0.8% (N=359) 3 Secretions Induction 0.2% (N=515) 3 Maintenance 0.0% (N=359) 3 GASTROINTESTINAL DISORDERS Vomiting Induction 0.8% (N=515) 3 Retching Induction 1.0% (N=515) 3 Maintenance 0.8% (N=359) 3 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Diaphoresis Induction 0.2% (N=515) 3 Maintenance 0.0% (N=359) 3 1 Reflects the number of patients interviewed by a physician in the recovery period. 2 Reflects the number of recorded electroencephalograms. 3 Represents patients not receiving intravenous agents or neuromuscular blocking agents for intubation (i.e., patients receiving inhalation induction). The following adverse reactions (see Table 5 ) were observed, but d

5 WARNINGS 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 ) • Hepatic Reactions : May cause sensitivity hepatitis in patients sensitized by previous exposure to halogenated anesthetics. Approach repeated anesthesia with caution. ( 5.3 ) • Hypersensitivity Reactions : Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with isoflurane. ( 5.4 ) • Abortions : Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions. ( 5.5 ) • QT Prolongation : Carefully monitor cardiac rhythm when administering Isoflurane USP to susceptible patients. ( 5.6 ) • 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 Isoflurane USP. ( 5.7 ) • 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. ( 5.8 ) 5.1 Malignant Hyperthermia In susceptible individuals, volatile anesthetic agents, including Isoflurane USP, 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. Isoflurane 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 (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 el

4 CONTRAINDICATIONS Isoflurane USP is contraindicated in patients: • in whom general anesthesia is contraindicated. • with known sensitivity to Isoflurane USP or to other halogenated agents [see Warnings and Precautions ( 5.3 )]. • with known or suspected genetic susceptibility to malignant hyperthermia [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.5 )]. • 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. • Patients in whom general anesthesia is contraindicated ( 4 ) • Patients with known sensitivity to Isoflurane USP or other halogenated agents ( 4 ) • Patients with known or suspected genetic susceptibility to malignant hyperthermia ( 4 ) • Patients 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 USP or other halogenated inhalational anesthetics ( 4 )

10 OVERDOSAGE The symptoms of overdosage of Isoflurane USP 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 what may appear to be overdosage, the following action should be taken, as appropriate: Stop drug administration, establish a clear airway, and initiate assisted or controlled ventilation with pure oxygen. Monitor cardiovascular function and manage signs of poor end-organ perfusion as clinically indicated.