4.1. Therapeutic indications

AErrane is a volatile halogenated anaesthetic for general inhalation anaesthesia

4.2. Posology and method of administration

In order to be able to accurately control the precise concentration of isoflurane, vaporisers that have been specially calibrated for isoflurane should be used.

In order to be able to accurately control the precise concentration of isoflurane, vaporisers that have been specially calibrated for isoflurane should be used.

Induction of anaesthesia:

If isoflurane is used for induction of anaesthesia, a starting concentration of 0.5% is recommended. Concentrations of 1.3-3.0% usually bring about surgical anaesthesia within 7 to 10 minutes.

It is recommended that use be made of a hypnotic dose of a short acting barbiturate or another product such as propofol, etomidate, or midazolam in order to avoid coughing or laryngospasms, which can arise if induction is carried out with AErrane alone or in combination with oxygen or with an oxygen-nitrous oxide mixture.

Maintenance of anaesthesia:

Anaesthesia can be maintained during surgery using a concentration of 1.0-2.5% with the simultaneous administration of N2O and O2.

A higher concentration of 1.5-3.5% of AErrane is necessary if AErrane is administered with pure oxygen.

Recovery

The concentration of AErrane must be reduced to 0.5% at the end of the operation, or to 0% during closure of the wound to allow prompt recovery.

If all administration of anaesthetic agents has been stopped, the air passages of the patient should be ventilated several times with 100% oxygen until complete awakening occurs.

If the vector gas is a mixture of 50% O2 and 50% N2O, the value of the minimum alveolar concentration of isoflurane is approximately 0.65%.

ADULTS

Age

Average MAC Value in 100% Oxygen

70% N2O

26 ± 4 years

1.28%

0.56%

44 ± 7 years

1.15%

0.50%

64 ± 5 years

1.05%

0.37%

PAEDIATRIC POPULATION

Age

Average MAC Value in 100% Oxygen

Preterm neonates < 32 weeks gestational age

1.28%

Preterm neonates32-37 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%

Premedication:

Drugs used for premedication should be selected for the individual patient bearing in mind the respiratory depressant effect of isoflurane. The use of anticholinergic drugs is a matter of choice, but may be advisable for inhalation induction in paediatrics.

Induction of anaesthesia in children:

Isoflurane is not recommended for use as an inhalation induction agent in infants and children because of the occurrence of cough, breath-holding, desaturation, increased secretions and laryngospasm (see section 4.4).

4.3. Contraindications

• Isoflurane is contraindicated in patients with known sensitivity to isoflurane or other halogenated anaesthetics.

• It is also contraindicated in patients with known or suspected genetic susceptibility to malignant hyperthermia.

4.4. Special warnings and precautions for use

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.

4.5. Interaction with other medicinal products and other forms of interaction

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).

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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”.

Summary of Most Frequent Adverse Drug Reactions

SOC

Frequency

Adverse Reactions

Blood and lymphatic system disorders

Not known

Carboxyhaemoglobinaemia2

Immune system disorders

Not known

Anaphylactic reaction1

Not known

Hypersensitivity1

Metabolsim and nutrition disorders

Not known

Hyperkalaemia2

Not known

Blood glucose increased

Psychiatric disorders

Not known

Agitation

Not known

Delirium

Not known

Mood altered5

Nervous system disorders

Not known

Convulsion

Not known

Mental impairment4

Cardiac disorders

Not known

Arrhythmia

Not known

Bradycardia

Not known

Cardiac arrest

Not known

Electrocardiogram QT prolonged

Not known

Tachycardia

Not known

Torsade de pointes

Vascular disorders

Not known

Hypotension2

Not known

Haemorrhage3

Respiratory, thoracic and mediastinal disorders

Not known

Bronchospasm2

Not known

Dyspnoea1

Not known

Wheezing1

Not known

Respiratory depression2

Not known

Laryngospasm2

Gastrointestinal disorders

Not known

Ileus

Not known

Vomiting

Not known

Nausea

Hepatobiliary disorders

Not known

Hepatic necrosis2

Not known

Hepatocellular injury2

Not known

Blood bilirubin increased.

Skin and subcutaneous tissue disorders

Not known

Swelling face1

Not known

Dermatitis contact1

Not known

Rash1

Renal and urinary disorders

Not known

Blood creatinine increased

Not known

Blood urea decreased

General disorders and administration site conditions

Not known

Hyperthermia malignant2

Not known

Chest discomfort1

Not known

Chills

Investigations

Not known

White blood cell count increased1

Not known

Hepatic enzyme increased2

Not known

Fluoride increased1

Not known

Electroencephalogram abnormal

Not known

Blood cholesterol decreased

Not known

Blood alkaline phosphatase decreased

Not known

Blood creatine phosphokinase increased

Musculoskeletal and connective tissue disorders

Not known

Myoglobinuria

Not known

Rhabdomyolysis

1See 4.8(c)

2See 4.4

3In patients undergoing induced abortion. See 4.4.

4May cause a slight decrease in intellectual function for 2-4 days after anesthesia. See 4.4.

5Small 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

4.9. Overdose

In case of overdosage, stop administration of the anaesthetic agent.

Hypotension and respiratory depression have been observed. Close monitoring of blood pressure and respiration is recommended. Supportive measures may be necessary to correct hypotension and respiratory depression resulting from excessively deep levels of anaesthesia. Check whether air passages are open, and depending on the circumstances, continue with assisted or controlled respiration using pure oxygen.