iple ventricular arrhythmias. isoflurane may lead to marked hypotension in patients treated with calcium antagonists. concomitant use of beta blockers may exaggerate the cardiovascular effects of inhalational anesthetics, including hypotension and negative inotropic effects. concomitant use of mao inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.

als, volatile anesthetic agents, including isoflurane, 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 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 , clinical pharmacology /pharmacogenomics] 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. hepatic reactions cases of mild, moderate and severe postoperative hepatic dysfunction or hepatitis with or without jaundice, 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. as with other halogenated anesthetic agents, isoflurane may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics (see contraindications ). 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. (see contraindications ). as with all halogenated anesthetics, repeated 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. evaluate the need for repeated exposure in each individual patient and adjust the dose of isoflurane based on signs and symptoms of adequate depth of anesthesia if repeated exposure in a short period of time is clinically indicated. hypersensitivity reactions allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with isoflurane. manifestations of such reactions have included hypotension, rash, difficulty breathing and cardiovascular collapse abortions increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions. qtc prolongation qtc prolongation, with rare instances of torsade de pointes, have been reported. monitor qt interval when administering isoflurane to susceptible patients. 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 precautions /pregnancy, pediatric use, and animal toxicology and/or pharmacology ). 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.

mportant to the avoidance of myocardial ischemia in patients with coronary artery disease. isoflurane can cause dose-dependent coronary vasodilation and has been shown to divert blood from collateral-dependent myocardium to normally perfused areas in an animal model (“coronary steal”). the extent to which coronary steal occurs in patients with steal- prone coronary anatomy is unclear. monitor for signs of inadequate myocardial perfusion via hemodynamic monitors (e.g., ecg, blood pressure) during isoflurane administration. consider additional cardiac monitoring in patients with known coronary artery disease, as clinically necessary. isoflurane causes a dose-dependent reduction in systemic vascular resistance and blood pressure. particular care must be taken when selecting the dosage for patients who are hypovolemic, hypotensive, or otherwise hemodynamically compromised, e.g., due to concomitant medications. isoflurane markedly increases cerebral blood flow at deeper levels of anesthesia to produce a transient increase in intracranial pressure. in patients with or at risk for elevations of intracranial pressure (icp), administer isoflurane in conjunction with icp-reducing strategies, as clinically appropriate. isoflurane, like some other inhalational anesthetics, can react with desiccated carbon dioxide (co 2 ) absorbents to produce carbon monoxide, which may result in elevated levels of carboxyhemoglobin in some patients. barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the co 2 absorber 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 isoflurane. the color indicator of most co 2 absorbents does not necessarily change as a result of desiccation. therefore, the lack of significant color change should not be taken as assurance of adequate hydration of the co 2 absorbent material. co 2 absorbents should be replaced routinely regardless of the state of color indicator following current manufacturer’s guidelines for use of anesthesiology equipment. the following reactions have been reported following occupational exposure to isoflurane: dyspnea, bronchospasm, stridor, cough, dizziness, paresthesia, hepatic reactions, flushing rash, contact dermatitis, erythema, periorbital edema, eye irritation, conjunctival hyperemia, and headache.

h holding, or 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 3.0% isoflurane usually produce surgical anesthesia in 7 to 10 minutes. maint enance: isoflurane mac values according to age are shown below: age average mac value in 100% oxygen average mac value in 30% oxygen and 70% n 2 o preterm neonates ˂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 1.0 to 2.5% concentration when nitrous oxide is used concomitantly. an additional 0.5 to 1.0% may be required when isoflurane is given using oxygen alone. if added relaxation is required, supplemental doses of muscle relaxants 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.

reflect the rates observed in practice. table 1: 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 muscle relaxants for intubation (i.e., patients receiving inhalation induction). 2 reflects the number of patients with recorded body temperature measurements. table 2: 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 muscle relaxants for intubation (i.e., patients receiving inhalation induction). table 3: 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 muscle relaxants for intubation (i.e., patients receiving inhalation induction). the following adverse reactions were observed, but due to limited data, frequency could not be determined. blood and lymphatic system disorders: white blood cell count increased metabolism and nutrition disorders: blood glucose increased psychiatric disorders: confused state, nervousness nervous system disorders: ataxia; dizziness; drowsiness; intellectual function decrease vascular disorders: hypotension (intraoperative); hypertension (intraoperative) hepatobiliary disorders: blood bilirubin increased; bromsulphthalein clearance decreased; alanine aminotransferase increased; aspartate aminotransferase increased; blood alkaline phosphatase increased; blood lactate dehydrogenase increased musculoskeletal, connective tissue and bone disorders: myalgia general disorders and administrative site conditions: asthenia; fatigue post-marketing adverse reactions the following adverse reactions have been reported in the post-marketing experience, listed by meddra system organ class (soc), then by preferred term in order of decreasing severity. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. blood and lymphatic system disorders: carboxyhemoglobin increased immune system disorders: anaphylactic reaction metabolism and nutrition disorders: hyperkalemia in patients with underlying myopathies psychiatric disorders: withdrawal syndrome (following multi-day exposure; symptoms include seizure, hallucination, ataxia, agitation, confusion ) nervous system disorders: brain edema, intracranial pressure increased, migraine, myoclonus, nystagmus, pupils unequal, headache cardiac disorders : cardiac arrest, ventricular fibrillation, torsade de pointes, myocardial infarction, myocardial ischemia, atrioventricular block complete, atrioventricular block second degree, atrial fibrillation, electrocardiogram qt prolonged, atrioventricular block first degree, ventricular tachycardia, ventricular extrasystoles, tachycardia, bradycardia, cardiac output decreased. vascular disorders : flushing respiratory, thoracic, and mediastinal disorders: apnea, hypoxia, bronchospasm, airway obstruction, respiratory depression, hypercapnia, stridor, hiccough gastrointestinal disorders: pancreatitis hepatobiliary disorders : hepatic necrosis, hepatic failure, hepatitis fulminant, cholestatic hepatitis, hepatitis, hepatic steatosis, jaundice, gamma- glutamyltransferase increased. skin and subcutaneous tissue disorders: rash musculoskeletal, connective tissue and bone disorders: rhabdomyolysis renal and urinary disorders: acute renal failure**, oliguria** general disorders and administration site conditions: malignant hyperthermia, hypothermia injury, poisoning, and procedural complications*: unwanted awareness during anesthesia; dyspnea, bronchospasm, stridor, cough, dizziness, paresthesia, hepatic reactions, flushing, rash, contact dermatitis, erythema, periorbital edema, eye irritation, conjunctival hyperemia, headache *all reactions categorized within this soc, with the exception of, unwanted awareness during anesthesia, were from occupational exposure in non-patients. **cases of acute renal failure and oliguria have been reported after isoflurane anesthesia. these events may be secondary to hypotension or other effects of isoflurane.

iple ventricular arrhythmias. isoflurane may lead to marked hypotension in patients treated with calcium antagonists. concomitant use of beta blockers may exaggerate the cardiovascular effects of inhalational anesthetics, including hypotension and negative inotropic effects. concomitant use of mao inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.

opulation, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. data animal data pregnant rats were exposed to isoflurane at concentrations of 0%, 0.1%, or 0.4% for two hours per day during organogenesis (gestational days 6-15). isoflurane did not cause malformations or clear maternal toxicity under these conditions. pregnant mice exposed to isoflurane at concentrations of 0%, 0.075%, or 0.30% for 2 hours per day during organogenesis (gestational days 6-15). isoflurane increased fetal toxicity (higher post implantation losses at 0.075 and 0.3% groups and significantly lower live-birth index in the 0.3% isoflurane treatment group). isoflurane did not cause malformations or clear maternal toxicity under these conditions. pregnant rats were exposed to concentrations of isoflurane at 0%, 0.1%, or 0.4% for 2 hours per day during late gestation (gd 15-20). animals appeared slightly sedated during exposure. no adverse effects on the offspring or evidence of maternal toxicity were reported. this study did not evaluate neurobehavioral function including learning and memory in the first generation (f1) of 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. (see warnings /pediatric neurotoxicity, precautions /pediatric use, and animal toxicology and/or pharmacology ).

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 (see warnings /pediatric neurotoxicity, precautions/ pregnancy, and animal toxicology and/or pharmacology ).

ntration 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 paco2, 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 muscle relaxants. all commonly used muscle relaxants are markedly potentiated with isoflurane, the effect being most profound with the nondepolarizing type. neostigmine reverses the effect of nondepolarizing muscle relaxants in the presence of isoflurane. all commonly used muscle relaxants 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 studies 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. 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. pharmacogenomics: ryr1 and cacna1s are polymorphic genes, and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (mhs) in patients receiving volatile anesthetic agents, including isoflurane. case reports as well as ex-vivo studies have identified multiple variants in ryr1 and cacna1s associated with mhs. variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence (see contraindications , warnings ).

1/8, and 1/2 mac) 2 hours per day for 14 consecutive days prior to mating. isoflurane had no effects on either male or female fertility.