Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Piramal Critical Care Limited, Suite 4, Ground Floor, Heathrow Boulevard East Wing, 280 Bath Road, West Drayton, UB7 0DQ, United Kingdom
Isoflurane is contraindicated in patients with known sensitivity to Isoflurane or to other halogenated anaesthetics.
It is also contraindicated in patients with known or suspected genetic susceptibility to malignant hyperthermia.
Vaporisers specially calibrated for isoflurane should be used so that the concentration of anaesthetic delivered can be accurately controlled.
Hypotension and respiratory depression increase as anaesthesia is deepened.
Reports of QT prolongation, associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering isoflurane to patients at risk for QT prolongation.
Caution should be exercised in administering general anaesthesia, including isoflurane, to patients with mitochondrial disorders.
Isoflurane, like other inhalational agents, has relaxant effects on the uterus with the potential risk for uterine bleeding. Clinical judgement should be observed when using isoflurane during obstetric anaesthesia. Consideration should be taken to use the lowest possible concentration of isoflurane in obstetrical operations (please refer to section 4.6).
Isolated cases of increased carboxyhaemoglobin have been reported with the use of halogenated inhalation agents with a –CF2H moiety (i.e., desflurane, enflurane and isoflurane). No clinically significant concentrations of carbon monoxide are produced in the presence of normally hydrated absorbents. Care should be taken to follow manufacturer’s instructions for CO2 absorbents.
Isoflurane has been reported to interact with dry carbon dioxide absorbents during closed circuit anaesthesia, to form carbon monoxide. In order to minimize the risk of formation of carbon monoxide in rebreathing circuits and the possibility of elevated carboxyhaemoglobin levels, carbon dioxide adsorbents should not be allowed to dry out.
Rare cases of extreme heat, smoke and/or spontaneous fire in the anaesthesia machine have been reported during the administration of general anaesthesia with drugs in this class when used in conjunction with desiccated CO2 absorbents, specifically those containing potassium hydroxide (e.g. Baralyme).
When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced before administration of isoflurane. The colour indicator of most CO2 absorbents does not necessarily change as a result of desiccation. Therefore, the lack of significant colour change should not be taken as an assurance of adequate hydration. CO2 absorbents should be replaced routinely regardless of the state of the colour indicator.
Because levels of anaesthesia can be altered easily and quickly with Isoflurane, only vaporisers which produce a predictable concentration with a good degree of accuracy or techniques during which inspired or expired concentrations can be monitored, should be used. The degree of hypotension and respiratory depression may provide some indication of anaesthetic depth.
As with any potent general anaesthetic, isoflurane should only be administered in an adequately equipped anaesthetising environment by those who are familiar with the pharmacology of the drug and qualified by training and experience to manage the anaesthetised patient.
Reports demonstrate that Isoflurane can produce hepatic injury ranging from mild transient increases of liver enzymes to fatal hepatic necrosis in very rare instances.
It has been reported that previous exposure to halogenated hydrocarbon anaesthetics, especially if the interval is less than 3 months, may increase the potential for hepatic injury. Cirrhosis, viral hepatitis or other pre-existing liver disease can be a reason to select an anaesthetic other than a halogenated anaesthetic.
Regardless of the anaesthetics employed, maintenance of normal haemodynamics is important to the avoidance of myocardial ischaemia in patients with coronary artery disease.
Isoflurane markedly increases cerebral blood flow at deeper levels of anaesthesia. There may be a transient rise in cerebral spinal fluid pressure which is fully reversible with hyperventilation.
Isoflurane must be used with caution in patients with increased intracranial pressure. In such cases hyperventilation may be necessary.
Use of isoflurane in hypovolaemic, hypotensive and debilitated patients has not been extensively investigated. A lower concentration of isoflurane is recommended for use in these patients.
All commonly used muscle relaxants are markedly potentiated by isoflurane, the effect being most profound with non-depolarising agents.
Isoflurane may cause a slight decrease in intellectual function for 2-4 days following anaesthesia. Small changes in moods and symptoms may persist for up to 6 days after administration. This must be taken into account when patients resume normal daily activities, including driving or operating heavy machinery (please refer to section 4.7).
A potentiation of neuromuscular fatigue can be seen in patients with neuromuscular diseases, such as myasthenia gravis. Isoflurane should be used with caution in these patients.
Isoflurane should be administered with caution to patients who can develop bronchoconstriction since bronchospasm can occur (see section 4.8).
Isoflurane may cause respiratory depression which may be augmented by narcotic premedication or other agents causing respiratory depression.
Respiration should be supervised and if necessary, assisted (see section 4.8).
During the induction of anaesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of laryngospasm, particularly in children (see section 4.8).
Caution should be exercised when Isoflurane is used in small children due to limited experience with this patient group.
During the induction of anaesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of laryngospasm, particularly in children.
In susceptible individuals, isoflurane anaesthesia 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, tachypnoea, cyanosis, arrhythmias, and unstable blood pressures. (It should also be noted that many of these nonspecific signs may appear with light anaesthesia, 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). PaO2 and pH may decrease, and hyperkalaemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g. isoflurane), intravenous administration of 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-acidbase derangements. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later.
There have been postmarketing reports of malignant hyperthermia. Some of these reports have been fatal.
Use of inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric age group 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 creatine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, these patients did NOT have classical signs or symptoms of malignant hyperthermia such as muscle rigidity or hypermetabolic state. Prompt and vigorous treatment for hyperkalaemia and resistant arrhythmias is recommended as is subsequent evaluation for latent neuromuscular disease.
Beta-sympathomimetic agents like isoprenaline, and alpha and beta- sympathomimetic agents like adrenaline and noradrenaline should be used with caution during isoflurane narcosis, due to a potential risk of ventricular arrhythmia.
Non-selective MAO-inhibitors: Risk of crisis during the operation. Treatment should be stopped 15 days prior to surgery.
Indirect-acting sympathomimetics (amphetamines and their derivatives, psychostimulants, appetite suppressants, ephedrine and its derivatives): Risk of peri-operative hypertension. In patients undergoing elective surgery, treatment should ideally be discontinued several days before surgery.
Adrenaline, by subcutaneous or gingival injections: risk of serious ventricular arrhythmia as a consequence of increased heart rate, although the myocardial sensitivity with respect to adrenaline is lower with the use of Isoflurane than in the case of Halothane.
Isoflurane may lead to marked hypotension in patients treated with calcium antagonists.
Caution should be exercised when calcium antagonists are used concomitantly with inhalation anaesthetics due to risk of additive negative inotropic effect.
Beta-blockers: Cardiovascular compensation reactions may be impaired by beta- blockers.
Medicinal products and compounds that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may increase the metabolism of isoflurane and lead to significant increases in plasma fluoride concentrations.
Use of Isoflurane and Isoniazid can increase the risk of potentiation of the hepatotoxic effects.
Opioids, benzodiazepines and other sedative agents are associated with respiratory depression, and caution should be exercised when concomitantly administered with Isoflurane.
Concomitant use of succinylcholine with inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the post-operative period.
All commonly used muscle relaxants are markedly potentiated by Isoflurane. Neostigmine has an effect on the non-depolarising relaxants, but has no effect on the relaxing action of Isoflurane itself.
MAC (minimum alveolar concentration) is reduced by concomitant administration of N2O in adults (see section 4.2).
There are no or limited amount of data from the use of isoflurane in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Isoflurane should only be used during pregnancy if the benefit outweighs the potential risk.
Isoflurane, like other inhalational agents, has relaxant effects on the uterus with the potential risk for uterine bleeding. Clinical judgement should be observed when using isoflurane during obstetric anaesthesia. Consideration should be taken to use the lowest possible concentration of isoflurane in obstetrical operations.
Isoflurane, in concentrations up to 0.75%, has been shown to be safe for the maintenance of anaesthesia for caesarean section (please refer to section 4.4).
It is not known whether isoflurane/metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isoflurane is administered to a nursing woman.
Patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, may be impaired for 2-4 days after anaesthesia with isoflurane. As with other anaesthetics, small changes in moods and symptoms may persist for up to 6 days after administration (see Section 4.4).
Adverse reactions encountered in the administration of Isoflurane are in general dose dependent extensions of pharmaco-physiological effects and include hypotension, respiratory depression and arrhythmias. Potential serious undesirable effects include malignant hyperthermia, hyperkalaemia, elevated serum creatine kinase, myoglobinuria, anaphylactic reactions and liver adverse reactions (please refer to section 4.4 and 4.8). Shivering, nausea, vomiting, ileus, agitation and delirium have been observed in the post-operative period.
Cardiac arrest, bradycardia and tachycardia have been observed with general inhalation anaesthetic drugs including isoflurane.
Reports of QT prolongation, associated with torsade de pointes (in exceptional cases, fatal) have been received.
The following table displays adverse reactions reported in clinical trials and from post-marketing experience. Frequency cannot be estimated from the available data, therefore it is “not known”.
Not known: Carboxyhaemoglobinaemia2
Not known: Anaphylactic reaction1, Hypersensitivity1
Not known: Hyperkalaemia2, Blood glucose increased1
Not known: Agitation, Delirium, Mood altered5
Not known: Convulsion, Mental impairment4
Not known: Arrhythmia
Not known: Hypotension2, Haemorrhage3
Not known: Bronchospasm2, Dyspnoea1, Wheezing1, Respiratory depression2, Laryngospasm2
Not known: Ileus, Vomiting, Nausea
Not known: Hepatic necrosis2, Hepatocellular injury2, Blood bilirubin increased1
Not known: Swelling face1, Dermatitis contact1, Rash1
Not known: Blood creatinine increased1, Blood urea decreased1
Not known: Hyperthermia malignant2, Chest discomfort1, Chills
Not known: White blood cell count increased1, Hepatic enzyme increased2, Fluoride increased1, Electroencephalogram abnormal, Blood cholesterol decreased1, Blood alkaline phosphatase decreased1
1 See 4.8©.
2 See 4.4.
3 In patients undergoing induced abortion. See 4.4.
4 May cause a slight decrease in intellectual function for 2-4 days after anaesthesia. See 4.4.
5 Small changes in moods and symptoms may persist for up to 6 days. See 4.4.
Transient increases in blood bilirubin, blood glucose and serum creatinine with decrease in BUN, serum cholesterol and alkaline phosphatase have been observed. As with other general anaesthetics, transient elevations in white blood count have been observed even in the absence of surgical stress.
Rare reports of hypersensitivity (including dermatitis contact, rash, dyspnoea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, especially in association with long-term occupational exposure to inhaled anaesthetic agents, including isoflurane. These reactions have been confirmed by clinical testing (e.g., methacholine challenge). The etiology of anaphylactic reactions experienced during inhalational anaesthetic exposure is, however, unclear because of the exposure to multiple concomitant drugs, many of which are known to cause such reactions. Minimally raised levels of serum inorganic fluoride occur during and after isoflurane anaesthesia, due to biodegradation of the agent. It is unlikely that the low levels of serum inorganic fluoride observed (mean 4.4 µmol/l in one study) could cause renal toxicity, as these are well below the proposed threshold levels for kidney toxicity.
Use of inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the post-operative period. (See 4.4.)
During the induction of anaesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of laryngospasm. (See 4.4.)
Use of inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the post-operative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease (see section 4.4).
Lesser concentrations of isoflurane are normally required to maintain surgical anaesthesia in elderly patients. (See 4.2.)
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Isoflurane has been reported to interact with dry carbon dioxide absorbents to form carbon monoxide. In order to minimise the risk of formation of carbon monoxide in rebreathing circuits and the possibility of elevated carboxyhaemoglobin levels, carbon dioxide absorbents should not be allowed to dry out. (See also section 4.4).
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