ISOFLURANE INHALATION ANAESTHETIC, FORANE INHALATION ANAESTHETIC - patient leaflet, side effects, dosage

5. how to store isoflurane

Keep this medicine out of the sight and reach of children. Isoflurane should be stored in a tightly closed container not above 25°C. Do not use after the expiry date printed on the packaging.

Medicines should not be disposed of via wastewater or household waste.

6. contents of the pack and other information

What Isoflurane contains:

The active ingredient is Isoflurane and it is supplied as a pure liquid containing no other ingredients.

What Isoflurane looks like and contents of the pack:

Isoflurane is an inhalation anaesthetic with a mildly pungent odour. Isoflurane is available in 100ml and 250ml glass bottles.

Not all pack size may be marketed.

Marketing Authorisation and Manufacturer’s De­tails

Marketing Authorisation Holder: AbbVie Ltd

Maidenhead, SL6 4UB, UK Manufacturer:

Aesica Queenborough Limited, Queenborough, Kent,

ME11 5EL, United Kingdom.

This leaflet was last updated in November 2015

iiiiiiii

ISOFLURANE

\ IMPORTANT

-A- INFORMATION

all of this leaflet carefully you are given this medi

cine because it contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions , ask your anaesthetist, ward doctor or nurse.

If you get any side effects, talk to your anaesthetist, ward doctor or nurse. This includes any possible side effect not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What isoflurane is and what it is used for

• 2. What you need to know before you are given Isoflurane

• 3. How Isoflurane is used

• 4. Possible side effects

• 5. How to store Isoflurane

• 6. Contents of the pack and other information

cbbvie

1000009566

IIIIIIII IIIIIIII

1. what isoflurane is and what it is used for

Isoflurane belongs to a group of medicines called general anaesthetics. These work by temporarily reducing the activity of the body’s central nervous system. This causes a complete loss of sensation in the body, including loss of consciousness allowing surgery to be carried out without pain or distress.

Isoflurane is a clear colourless liquid that when put into a special anaesthetic machine (vaporiser) becomes a gas. This mixes with the oxygen you will be breathing in.

Once breathed in (inhaled), Isoflurane will induce and maintain a deep, pain-free sleep (general anaesthesia) in adults and children.

2. what you need to know before you are given isoflurane

You should not be given Isoflurane if:

• You have been told that you are allergic to Isoflurane or any other anaesthetic.
• You or any member of your family has experienced a rapid rise in body temperature during an operation (a condition called malignant hyperthermia).

Warnings and precautions

Tell your Ward Doctor, Surgeon or Anaesthetist if:

• You have previously received general anaesthetics, particularly if repeated over a short period of time (specifically in the last 3 months). Some anaesthetics can cause jaundice.
• If you have Cirrhosis, viral hepatitis or other liver disease
• If you have coronary heart disease
• You are suffering from any illness other than those connected with your operation, such as severe headaches, nausea, vomiting or a condition that affects muscles (a neuromuscular disease e.g. Duchenne muscular dystrophy or myasthenia gravis).
• You suffer with bronchoconstriction (a tightening of the lungs and airways leading to coughing, wheezing or shortness of breath).
• You are pregnant, could be pregnant or are breast feeding.
• You have ever had QT prolongation (prolongation of a specific time interval in an ECG) or torsade de pointes (a specific type of heart rhythm), which may also be associated with QT prolongation. Isoflurane has sometimes been known to cause these.
• You have a mitochondrial disease.

Other Medicines and Isoflurane

As with all drugs, it is important that you tell your ward doctor, surgeon or anaesthetist which medications you are taking. This is particularly important if you are taking the following drugs:

• Amphetamines (stimulants)
• Beta blockers (used to treat high blood pressure and certain heart conditions)
• Isoniazid (an antibiotic used to treat tuberculosis)
• Decongestants (ephedrine)
• Non-selective MAO-inhibitors (a type of anti-depressants). These should be stopped 15 days before surgery
• Calcium antagonists
• Opioids and other sedatives
• Sympathomimetic agents such as isoprenaline

Pregnancy, Breast Feeding and fertility

Tell your ward doctor, surgeon or anaesthetist if you are pregnant, could be pregnant or are breast feeding.

It is not known whether Isoflurane or its by-products are transferred into human milk.

Driving and using machines

You should not drive or operate machinery until your doctor advises that you may do so.

Your ability to drive or operate machinery may be impaired for 2–4 days. Do not drive or operate machinery if you are affected.

• 3. How Isoflurane is used

Isoflurane will always be administered to you by an anaesthetist. They will decide on the dose you will receive, depending on your age, weight and the type of operation you are having.

Your child should be monitored closely during the administration of Isoflurane.

Isoflurane has a strong smell, which is quite normal and will send you to sleep quickly.

Inducing sleep at the start of anaesthesia

Very occasionally you may be asked to breathe in the Isoflurane via a mask. Usually you will receive an injection of another anaesthetic to make you go to sleep before you receive Isoflurane.

Isoflurane is not recommended in infants and children for inducing sleep at the start of anaesthesia.

Medication before anaesthesia

Anaesthetist may decide to give your child medication to counter act the possible reduction in breathing and heart rate effects which may occur with the use of Isoflurane Maintaining sleep during anaesthesia

Under the observation of the anaesthetist you will continue to breathe in Isoflurane during the operation via a mask.

Waking-up after anaesthesia

Once the anaesthetist stops you from inhaling Isoflurane you will wake up within a few minutes.

4. possible side effects

As with all anaesthetics, Isoflurane can cause side effects. These can occur both during and after your or your childs’s operation. The following side effects with isoflurane are serious and will be managed by your surgeon or anaesthetist, as necessary, during the operation. If you or your child experience any of these side effects after an operation tell your doctor or anaesthetist immediately.The most commonly reported side effects are:

• A tightening of your lungs and airways causing a difficulty in breathing
• Increases in blood sugar levels or potassium levels. There have been rare reports of abnormal heartbeat (arrhythmias) and death associated with the use of inhaled anaesthetics in children shortly after surgery
• Allergic reaction 1000009566

ISOFLURANE

TECHNICAL LEAFLET

Composition and Description

Isoflurane is a non-flammable inhalational anaesthetic agent. It is 1-chloro-2,2,2-trifluoroethyl difluoromethyl et­her:

Some physical constants of isoflurane are:

Boiling point at 760 mm Hg 48.5oC

Refractive index nD20 1.2990–1.3005

Vapour pressure, mm Hg

Partition coefficients at 37oC:

Partition coefficients at 25oC for rubber and plastics:

Conductive rubber/gas 62.0

Butyl rubber/gas 75.0

Polyvinyl chloride/gas 110.0

Polyethylene/gas ca2.0

Polyurethane/gas ca1.4

Polyolefin/gas ca1.1

Butyl acetate/gas ca2.5

Purity by gas chromatography: better than 99.9%

Flammability in oxygen or nitrous oxide:

at 9 joules/sec. and 23oC non flammable

at 900 joules/sec. and 23oC non flammable at

anaesthetic concentrations.

Isoflurane is a stable, colourless liquid, with no added chemical stabiliser.

Isoflurane has a slightly pungent, ethereal odour. No change in the composition of samples exposed for 5 years to indirect sunlight in clear colourless bottles, nor in that of samples exposed for 30 hours to UV light was detectable by gas chromatography.

There was no consumption of alkali when isoflurane was exposed for more than 6 months to a 1 N sodium methoxide in methanol solution, demonstrating high stability to strong base. Isoflurane does not decompose in the presence of soda lime and does not attack aluminium, tin, brass, copper or iron.

Uses

Inhalation anaesthesia.

Properties

Induction and particularly recovery are rapid. Although slight pungency may limit the rate of induction, excessive salivation and tracheobronchial secretions do not appear to be stimulated. Pharyngeal and laryngeal reflexes are diminished quickly. Levels of anaesthesia change rapidly with isoflurane. Heart rhythm remains stable. Spontaneous respiration becomes depressed as depth of anaesthesia increases and should be closely monitored.

During induction there is a decrease in blood pressure which returns towards normal with surgical stimulation.

Blood pressure tends to fall during maintenance in direct relation to depth of anaesthesia, due to peripheral vasodilation, but cardiac rhythm remains stable. With controlled respiration and normal PaCO2, cardiac output tends to be maintained despite increasing depth of anaesthesia, primarily through a rise in heart rate. With spontaneous respiration, the resulting hypercapnia may increase heart rate and cardiac output above awake levels.

Cerebral blood flow remains unchanged during light isoflurane anaesthesia but tends to rise at deeper levels. Increases in cerebrospinal fluid pressure may be prevented or reversed by hyperventilating the patient before or during anaesthesia.

Electroencepha­lographic changes and convulsions are extremely rare with isoflurane.

Isoflurane appears to sensitise the myocardium to adrenaline. Limited data suggest that subcutaneous infiltration of up to 50 ml of 1:200,000 solution adrenaline does not induce ventricular arrhythmias in patients anaesthetised with isoflurane.

Muscular relaxation may be adequate for some intraabdominal operations at normal levels of anaesthesia, but should greater relaxation be required small doses of intravenous muscle relaxants may be used. All commonly used muscle relaxants are markedly potentiated by isoflurane, the effect being most profound with non-depolarising agents. Neostigmine reverses the effects of non-depolarising muscle relaxants but has no effect on the relaxant properties of isoflurane itself. All commonly used muscle relaxants are compatible with isoflurane.

Isoflurane may be used for the induction and maintenance of general anaesthesia. Adequate data are not available to establish its place in pregnancy or obstetric anaesthesia other than for caesarian section.

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 mmol/ 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.

Dosage and Administration

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

MAC values for isoflurane vary with age. The table below indicates average MAC values for different age groups: ADULTS

Age	Average MAC Value In 100%	70% N 2O
	Oxygen
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 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%

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 adults : a short-acting barbiturate or other intravenous induction agent is usually administered followed by inhalation of the isoflurane mixture. Alternatively, isoflurane with oxygen or with an oxygen/nitrous oxide mixture may be used.

It is recommended that induction with isoflurane be initiated at a concentration of 0.5%. Concentrations of 1.5 to 3.0% usually produce surgical anaesthesia in 7 to 10 minutes.

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 Warnings and Precautions ).

Maintenance: surgical levels of anaesthesia may be maintained with 1.0 – 2.5% isoflurane in oxygen/nitrous oxide mixtures. An additional 0.5–1.0% isoflurane may be required when given with oxygen alone.

For caesarian section, 0.5–0.75% isoflurane in a mixture of oxygen/nitrous oxide is suitable to maintain anaesthesia for this procedure.

Arterial pressure levels during maintenance tend to be inversely related to alveolar isoflurane concentrations in the absence of other complicating factors. Excessive falls in blood pressure may be due to depth of anaesthesia and, in these circumstances, should be corrected by reducing the inspired isoflurane concentration.

Older people: as with other agents, lesser concentrations of isoflurane are normally required to maintain surgical anaesthesia in elderly patients.

See above for MAC values related to age.

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.

Warnings and Precautions

Vaporizers 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 (see Fertility, pregnancy and lactation).

Isolated cases of increased carboxyhaemoglobin have been reported with the use of fluorinated inhalation agents (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 CO2absorbents.

Isoflurane has been reported to interact with dry carbon dioxide absorbents to form carbon monoxide. In order to minimise the risk of carbon monoxide in rebreathing circuits and the possibility of elevated carboxyhaemoglobin levels, carbon dioxide absorbents 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.

General

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.

Since levels of anaesthesia may be altered quickly and easily with isoflurane, only vaporisers 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 anaesthetic depth.

Reports demonstrate that isoflurane can produce hepatic injury ranging from mild transient increases in 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 nondepolarizing 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 (see Effects on ability to drive and use machines ).

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 Side-effects ).

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 Side-effects ).

During the induction of anaesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of laryngospasm, particularly in children (see Sideeffects ).

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.

Malignant Hyperthermia

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). 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-acid-base 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.

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 post-operative 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.

Drug interactions:

Combinations advised against:

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.

Combinations requiring precautions in using:

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.

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.

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 isoniazide can increase the risk of potentiation of the hepatotoxic effects.

Calcium antagonists, in particular dihydropyridine derivates: 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 the risk of additive negative inotropic effect.

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, the effect being most profound with nondepolarizing agents. Neostigmine has an effect on the nondepolarising relaxants, but has no effect on the relaxing action of isoflurane itself.

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

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 Warnings and Precautions ).

Use in Caesarean Section:

Isoflurane, in concentrations up to 0.75%, has been shown to be safe for the maintenance of anaesthesia for caesarean section (see Warnings and Precautions ).

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.

Effects on ability to drive and use machines

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 Warnings and Precautions ).

Side-effects

• a. Summary of the safety profile:

Adverse reactions encountered in the administration of isoflurane are in general dose dependent extensions of pharmaco-physiologic effects and include respiratory depression, hypotension and arrhythmias. Potential serious undesirable effects include malignant hyperthermia, hyperkalaemia, elevated serum creatinine kinase, myoglobinuria, anaphylactic reactions and liver adverse reactions (see Warnings and Precautions ). Shivering, nausea, vomiting, ileus, agitation and delirium have been observed in the postoperative 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.

• 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	Carboxyhaemoglo-binaemia2
Immune system disorders	Not known	Anaphylactic reaction1 Hypersensitivity1
Metabolism and nutrition disorders	Not known	Hyperkalaemia2 Blood glucose increased
Psychiatric disorders	Not known	Agitation Delirium Mood altered5
Nervous system disorders	Not known	Convulsion Mental impairment4
Cardiac disorders	Not known	Arrhythmia Bradycardia Cardiac arrest Electrocardiogram QT prolonged Tachycardia Torsade de pointes
Vascular disorders	Not known	Hypotension2 Haemorrhage3
Respiratory, thoracic and mediastinal disorders	Not known	Bronchospasm2 Dyspnoea1 Wheezing1 Respiratory depression2 Laryngospasm2
Gastrointestinal disorders	Not known	Ileus1 Vomiting1 Nausea1
Hepatobiliary disorders	Not known	Hepatic necrosis2 Hepatocellular injury2 Blood bilirubin increased1
Skin and subcutaneous tissue disorders	Not known	Swelling face1 Dermatitis contact1 Rash1
Renal and urinary disorders	Not known	Blood creatinine increased1 Blood urea decreased1
General disorders and administration site conditions	Not known	Malignant hyperthermia2 Chest discomfort1 Chills1
Investigations	Not known	White blood cell count increased Hepatic enzyme increased2 Fluoride increased1 Electroencepha­logram abnormal Blood cholesterol decreased1 Blood alkaline phosphatase decreased1
Musculoskeletal and connective tissue disorders	Not known	Myoglobinuria Rhabdomyolysis

• 1See section c below

• 2See Warnings and Precautions

• 3In patients undergoing induced abortion. See Warnings and Precautions

• 4May cause a slight decrease in intellectual function for 24 days after anaesthesia. See Warnings and Precautions. 5Small changes in moods and symptoms may persist for up to 6 days. See Warnings and Precautions

• c. Description of selected adverse reactions:

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 pmol/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 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 Warnings and Precautions ).

During the induction of anaesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of laryngospasm. (See Warnings and Precautions ).

• e. Other special populations: