AERRANE Liquid for inhalation Ref.[27630] Active ingredients: 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.

Vaporizers specially calibrated for isoflurane should be used so that the concentration of anesthetic delivered can be accurately controlled.

Hypotension and respiratory depression increase as anesthesia is deepened.

Since levels of anesthesia may be altered quickly and easily with isoflurane, only vaporizers which deliver a predictable output with reasonable 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 anesthetic depth.

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 anesthesia, including isoflurane, to patients with mitochondrial disorders.

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 anesthetics, 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.

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).

Relatively little metabolism of isoflurane occurs in the human body. In the post operative period only 0.17% of the isoflurane taken up can be recovered as urinary metabolites. Peak serum inorganic fluoride values usually average less than 5 micromol/litre and occur about four hours after anaesthesia, returning to normal levels within 24 hours. No signs of renal injury have been reported after isoflurane administration.

There is insufficient experience of use in repeated anaesthesia to make a definitive recommendation in this regard. As with all halogenated anaesthetics repeat anaesthesia within a short period of time should be approached with caution.

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 markedly increases cerebral blood flow at deeper levels of anesthesia. 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 AErrane should be administered with caution to patients who can develop bronchoconstriction since bronchospasms can occur (see section 4.8).

Use of isoflurane in hypovolemic, hypotensive and debilitated patients has not been extensively investigated. A lower concentration of isoflurane is recommended for use in these patients.

Regardless of the anesthetics employed, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia in patients with coronary artery disease.

In light of the fact that AErrane acts in an irritating manner on the mucous membranes, the product is difficult to use if inhalation anaesthesia is applied via mask. During the induction of anaesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of laryngospasms, particularly in children (see section 4.8).

Increased blood losses comparable with those found following anaesthesia with other inhalation agents have been recorded with isoflurane in patients undergoing induced abortion.

Isoflurane relaxes the uterus muscle, and the lowest possible concentration of isoflurane should be used in obstetrical operations (Please refer to section 4.6).

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 pressures. (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). PaO₂ and pH may decrease, and hyperkalemia and a base deficit may appear. Fatal outcome of malignant hyperthermia has been reported with isoflurane. 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-acid-base derangements. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later.

Isolated cases of increased carboxyhemoglobin 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 manufacturers' instructions for CO₂ absorbents.

Rare cases of extreme heat, smoke and/or spontaneous fire in the anesthesia machine have been reported during administration of general anesthesia 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 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 an assurance of adequate hydration. CO₂ absorbents should be replaced routinely regardless of the state of the color indicator.

Perioperative Hyperkalaemia:

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 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, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.

Isoflurane may cause a slight decrease in intellectual function for 2-4 days following anesthesia. 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).

All commonly used muscle relaxants are markedly potentiated by isoflurane, the effect being most profound with non-depolarizing agents.

During the induction of anesthesia, saliva flow and thracheobronchial secretion can increase and can be the cause of laryngospasm, particularly in children (see section 4.8).

Children Under Two Years of Age

Caution should be exercised when isoflurane is used in small children due to limited experience with this patient-group.

The simultaneous administration of isoflurane and the following products requires strict supervision of the clinical and biological condition of the patient;

Combinations advised against

Beta-sympathomimetics (isoprenaline) and alpha- and beta- sympathomimetics (epinephrine or adrenaline; norepinephrine or noradrenaline): should be used with caution during isoflurane narcosis, due to a potential risk of ventricular arrhythmia.

Nonselective MAOI: Risk of crisis and hemodynamic instability during the surgery or medical procedures. Treatment should be stopped 15 days prior to surgery.

Combinations requiring precautions in using

Beta-blockers: Concomitant use of beta blockers may exaggerate the cardiovascular effects of inhalational anesthetics, including hypotension and negative inotropic effects. Risk of blockage of the cardiovascular compensation mechanism, as a result of which negative inotropic effects are intensified. The action of beta-blockers can be suppressed during the operation with the use of beta-sympathomimetic agents. In general, any medication with a beta-blocker need not be stopped and an abrupt reduction of the dosage should be avoided.

Isoniazid: risk of potentiating the hepatotoxic effect, with increased formation of toxic metabolites of isoniazid. Treatment with isoniazid should be suspended one week before the operation and should not be resumed until 15 days afterwards.

Epinephrine (adrenaline) by sub-cutaneous or gingival injections: risk of serious ventricular arrhythmia as a consequence of increased heart rate, although the myocardial sensitivity with respect to epinephrine is lower with the use of isoflurane than in the case of halothane. Thus, the dosage should be limited to, for example, 0.1 mg epinephrine within 10 minutes or 0.3 mg within one hour in adults. Doses of adrenaline greater than 5 mcg/kg, when administered submucosally, may produce multiple ventricular arrhythmias.

Indirect-acting sympathomimetics (amphetamines and their derivatives; psychostimulants, appetite suppressants, ephedrine and its derivatives): risk of perioperative hypertension. In patients undergoing elective surgery, treatment should ideally be discontinued several days before surgery.

In the majority of cases where a drug treatment is indispensable, there is no reason to suspend it before general anaesthesia. It suffices to inform the anaesthetist about it.

All commonly used muscle relaxants are markedly potentiated by isoflurane, the effect being most profound with non-depolarizing agents

Thus it is recommended that approximately one third to one half of the usual dose of these substances be administered. The disappearance of the myoneural effect takes longer with isoflurane than with other conventional anaesthetics. Neostigmine has an effect on the non-depolarising relaxants, but has no effect on the relaxing action of isoflurane itself.

Opioids, benzodiazepines and other sedative agents are associated with respiratory depression, and caution should be exercised when concomitantly administered with isoflurane.

Calcium antagonists: isoflurane may lead to marked hypotension in patients treated with calcium antagonists, particularly dihydropyridine derivatives. Caution should be exercised when calcium antagonists are used concomitantly with inhalation anaesthetics due to the risk of additive negative inotropic effect.

MAC (minimum alveolar concentration) is reduced by concomitant administration of N20 in adults (see section 4.2).

Use in Pregnancy

There are no or limited amount of data from the use of isoflurane in pregnant women. Studies in animals have shown reproductive toxicity. Isoflurane should only be used during pregnancy if the benefit outweighs the potential risk. (see section 5.3)

Isoflurane relaxes the uterus muscle, and the lowest possible concentration of isoflurane should be used in obstetrical operations.

Use in Caesarean Section

Isoflurane, in concentrations up to 0.75%, has been shown to be safe for the maintenance of anesthesia for cesarean section (please refer to section 4.4).

Nursing Mothers

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.

The medicinal product can have influence on driving and using machines. The patient should not drive or use machines for at least 24 hours after anaesthesia with isoflurane. Changes in behaviour and intellectual function 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.

a. Summary of the safety profile

Adverse reactions encountered in the administration of isoflurane are in general dose dependent extensions of pharmacophysiologic effects and include respiratory depression, hypotension and arrhythmias. Potential serious undesirable effects include malignant hyperthermia, anaphylactic reactions and liver adverse reactions (please refer to section 4.4 and 4.8). Shivering, nausea, vomiting and ileus have been observed in the postoperative period.

Cardiac arrest has been observed with general inhalation anesthetic drugs including isoflurane.

b. Tabulated summary of adverse reactions

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”.

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 anesthesia. See 4.4.
⁵ Small changes in moods and symptoms may persist for up to 6 days. See 4.4.

c. Description of selected adverse reactions

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 anesthetic agents, including isoflurane. These reactions have been confirmed by clinical testing (e.g., methacholine challenge). The etiology of anaphylactic reactions experienced during inhalational anesthetic 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 anesthesia, 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.

d. Paediatric population

Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the postoperative period. (See 4.4.)

During the induction of anesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of laryngospasm. (See 4.4.)

e. Other special populations

Neuromuscular disease

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. Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease (See 4.4.)

Elderly

Lesser concentrations of isoflurane are normally required to maintain surgical anesthesia in elderly patients. (See 4.2.)

Reporting of suspected adverse reactions

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.

Not applicable.