TERRELL Liquid for inhalation Ref.[50356] Active ingredients: Isoflurane

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.

Malignant Hyperthermia

In susceptible individuals, isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc.) An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO₂ absorption system (hot canister). PaO ₂ and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., isoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management). Renal failure may appear later, and urine flow should be sustained if possible. Fatal outcome of malignant hyperthermia has been reported with isoflurane.

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.

The following adverse reactions were identified from controlled clinical studies of adult and pediatric subjects exposed to isoflurane. The studies 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 ≥ 5%) described in Table 1 are agitation, breath holding, chills/shivering, cough, delirium, laryngospasm, nausea, and vomiting.

Adverse reactions with and 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 1. Adverse Reactions ≥5%:

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%:

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%:

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.

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.

As with any potent general anesthetic, isoflurane should only be administered in an adequately equipped anesthetizing environment by those who are familiar with the pharmacology of the drug and qualified by training and experience to manage the anesthetized patient.

All patients anesthetized with isoflurane should be continually monitored (e.g., monitoring of the electrocardiogram, blood pressure, oxygen saturation, and end tidal CO₂). 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.

With the exception of neonates, isoflurane MAC decreases with increasing age.

Regardless of the anesthetics employed, maintenance of normal hemodynamics is important 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 (CO₂) 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 CO₂ absorber canister at high flow rates over many hours or days. When a clinician suspects that CO₂ absorbent may be desiccated, it should be replaced before the administration of isoflurane.

The color indicator of most CO₂ 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 CO₂ absorbent material. CO₂ 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.

Isoflurane, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 or 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for up to 6 days after administration.

Effect of anesthetic and sedation drugs on early brain development

Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs (see WARNINGS/Pediatric Neurotoxicity).

Transient increases in BSP retention, blood glucose and serum creatinine with decrease in BUN, serum cholesterol and alkaline phosphatase have been observed.

Opioids decrease the Minimum Alveolar Concentration (MAC) of isoflurane. Opioids such as fentanyl and its analogues, when combined with isoflurane, may lead to a synergistic fall in blood pressure and respiratory rate.

Nitrous oxide decreases the MAC of isoflurane (see DOSAGE AND ADMINISTRATION).

Isoflurane potentiates the muscle relaxant effect of all muscle relaxants and decreases the required doses of neuromuscular blocking agents. In general, anesthetic concentrations of isoflurane at equilibrium reduce the ED95 of succinylcholine, atracurium, pancuronium, rocuronium and vecuronium by approximately 25 to 40% or more compared to N2O/opioid anesthesia. If added relaxation is required, supplemental doses of muscle relaxants may be used.

Isoflurane is similar to sevoflurane in the sensitization of the myocardium to arrhythmogenic effect of exogenously administered adrenaline. Doses of adrenaline greater than 5mcg/kg, when administered submucosally may produce multiple 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.

Risk Summary

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, embryofetal toxicity was noted in pregnant mice exposed to 0.075% (increased post implantation losses) and 0.3% isoflurane (increased post implantation losses and decreased live-birth index) during organogenesis.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [See Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, 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).

Due to insufficient information regarding the excretion of isoflurane in human milk, the potential risks and benefits for each specific patient should be carefully considered before isoflurane is administered to nursing women.

During the induction of anesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of larynogospasm, particularly in children.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Isoflurane, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, 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 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or 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).

Effects on Ability to Drive and Use Machines

Patients should be advised that performance of activities requiring mental alertness, such as driving a vehicle or operating machinery, may be impaired for some time after general anesthesia. Therefore, patients should not undertake hazardous tasks, such as driving, for at least 24 hours following administration of a general anesthetic.