Data Sheet

ISOFLURANE

Presentation

A clear, colourless, volatile, non-flammable liquid for general inhalation

anaesthesia.



Uses

Actions

ISOFLURANE is a halogenated volatile anaesthetic which induces and maintains

general anaesthesia by depression of the central nervous system and resultant

loss of consciousness.



Pharmacokinetics

The pharmacokinetics of ISOFLURANE are those of inhaled gaseous or volatile

anaesthetics for which blood concentrations are related to alveolar

concentrations through the established partition coefficients, and the

distribution to tissues is also determined by solubility coefficients which are

relatively constant under a wide variety of circumstances. ISOFLURANE shows very

low solubility in blood and body tissues, much lower than for enflurane and

halothane, thus its partial pressure (concentration) in alveolar gas or arterial

blood rises to 50% of the inspired partial pressure (concentration) within 4-8

minutes of the start of its inhalation, and to 60% within 15 minutes. This rate

of rise is slightly faster than that obtained with enflurane (a structural

isomer of ISOFLURANE) and considerably faster (40%) than the more soluble

halothane. Age significantly affects blood-gas partition coefficients for all

anaesthetics; the lower blood-gas partition coefficients in children explain in

part the more rapid increase in alveolar anaesthetic partial pressures in this

group.

Throughout maintenance of anaesthesia, a high proportion of the ISOFLURANE

inspired is eliminated by the lungs. When administration is stopped and inspired

concentration becomes zero, the bulk of the remaining ISOFLURANE is eliminated

unchanged from the lungs. In keeping with its low solubility, recovery from

ISOFLURANE anaesthesia in man is rapid.

Biotransformation of ISOFLURANE is significantly less than that of enflurane or

halothane. Humans and animals biotransform a small fraction of ISOFLURANE

administered. In man about 0.2% administered is evident as recoverable

metabolites (fluoride and organic fluorine), with approximately 50% of these

excreted in the urine, the principal metabolite being trifluoracetic acid.

Enzyme induction associated with pre-existing drug therapy would not appear to

be an important factor in the metabolism of ISOFLURANE in man, mainly because

the overall metabolism of ISOFLURANE is so low.



Indications

General anaesthetic for use in patients of all ages.

Dosage And Administration

ISOFLURANE has a slight pungent ethereal odour, which may limit the rate of gas

induction but, despite this, induction and particularly recovery are rapid.

Salivation and tracheo-bronchial secretions may be stimulated in children but

pharyngeal and laryngeal reflexes are quickly diminished. The use of

ISOFLURANE-specific vaporisers will facilitate accurate control of the

administered concentration of anaesthetic.

Pre-medication:

Pre-medication drugs should be selected according to the needs of the patient.

The ventilatory depressant effect of ISOFLURANE should be taken into account. As

ISOFLURANE causes increased heart rate and only weak stimulation of secretions,

the use of anticholinergic drugs is a matter of choice.



Induction:

As ISOFLURANE has a mild pungency, inhalation should usually be preceded by the

choice of a short-acting barbiturate, or other intravenous induction agent, to

prevent coughing. Salivation and coughing may be troublesome in small children

induced with Isoflurane. Alternatively, ISOFLURANE with oxygen or an

oxygen/nitrous oxide mixture may be administered. It is recommended that

induction with ISOFLURANE be initiated at a concentration of 0.5%.

Concentrations of 1.5-3.0% usually produce surgical anaesthesia in 7-10 minutes.

Blood pressure decreases during induction but this may be compensated by

surgical stimulation.



Maintenance:

Adequate anaesthesia for surgery may be sustained with an inspired ISOFLURANE

concentration of 1.0% - 2.5% in an oxygen/70% nitrous oxide mixture. Additional

inspired ISOFLURANE (0.5% - 1%) will be required with lower nitrous oxide

levels, or when ISOFLURANE is given with oxygen alone or air/oxygen mixtures.

Blood pressure decreases during maintenance anaesthesia in relation to the depth

of anaesthesia. That is, blood pressure is inversely related to the ISOFLURANE

concentration. Provided there are no other complicating factors this is probably

due to peripheral vasodilation.

Cardiac rhythm remains stable. Excessive falls in blood pressure may be due to

the depth of anaesthesia and in such circumstances can be corrected by reducing

the inspired ISOFLURANE concentration.

Induced hypotension can be achieved by artificially ventilating patients with

ISOFLURANE 2.5-4.0%. Pre-treatment with clonidine significantly decreases the

ISOFLURANE requirement for maintaining induced hypotension.



Recovery:

The concentration of ISOFLURANE can be reduced to 0.5% at the start of closing

the operation wound, and then to 0% at the end of surgery, provided that the

anaesthesiologist is satisfied that the effect of any neuromuscular blocking

drugs has been reversed and the patient is no longer paralysed.

After discontinuation of all anaesthetics, the airways of the patient should be

ventilated several times with oxygen 100% until complete recovery.

Contraindications

Known sensitivity to ISOFLURANE or to other halogenated agents, especially

patients with known or suspected susceptibility to malignant hyperthermia.

ISOFLURANE must not be used in patients who have developed an icterus and/or

fever of unknown origin after administration of ISOFLURANE or another

halogenated anaesthetic.



Warnings And Precautions

ISOFLURANE is a profound respiratory depressant, this effect being accentuated

by narcotic premedication or concurrent use of other respiratory depressants.

ISOFLURANE causes an increase in cerebral blood flow at deeper levels of

anaesthesia (1.5%); this may give rise to an increase in cerebral spinal fluid

pressure. Where appropriate, this can be prevented or reversed by

hyperventilating the patient before or during anaesthesia.

As with other halogenated anaesthetics, ISOFLURANE must be used with caution in

patients with increased intracranial pressure. Again, in such cases,

hyperventilation may be necessary.

ISOFLURANE is a powerful systemic and coronary arterial dilator. The effect on

systemic arterial pressure is easily controlled in the normal healthy patient

and has been used specifically as a means of inducing hypotension. However, the

phenomenon of "coronary steal" means that ISOFLURANE should be used with caution

in patients with coronary artery disease. In particular, patients with

subendocardial ischaemia might be anticipated to be more susceptible.

As with all general inhalation anaesthetics, it is advisable to allow 24 hours

from recovery to elapse before driving or operating machinery.

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 should be used. The degree of hypotension and ventilatory depression

may provide some indication as to the level of anaesthesia. The level of

anaesthesia may be changed quickly with ISOFLURANE. Heart rhythm remains stable

but spontaneous breathing should be monitored closely and supported where

necessary.

Salivation and tracheo-bronchial secretions may be stimulated in children but

pharyngeal and laryngeal reflexes are quickly diminished.

It is recommended that vapour from this and other inhalational gases are

efficiently extracted from the area of use.

As with all halogenated anaesthetics, repeat anaesthesia within a short period

of time should be approached with caution since the risk of hepatotoxicity is

not fully understood. There is insufficient experience of use in repeated

anaesthesia to make a definite recommendation in this regard.

Caution should be exercised with administering ISOFLURANE to patients with

pre-existing liver disease.

Although peak inorganic fluoride concentrations which result from the breakdown

of ISOFLURANE are generally much lower than those considered to be nephrotoxic,

no information is available on levels in patients with compromised renal

function. The drug should therefore be used with extreme caution in these

patients, or in those receiving nephrotoxic drugs concomitantly.

ISOFLURANE has been reported to interact with dry carbon dioxide absorbents

during closed circuit anaesthesia, to form carbon monoxide. Inhalation of carbon

monoxide may lead to formation of significant levels of carboxyhaemoglobin in

exposed patients.

Carboxyhaemoglobin is toxic even in low concentrations and is not easily

detected by standard anaesthesia monitors such as pulse oximeters. Direct

measurement of carboxyhaemoglobin should be carried out in the event that a

patient on closed circuit anaesthesia with an implicated agent develops oxygen

desaturation which does not respond to the usual therapeutic measures.

All necessary precautions should be taken to ensure that carbon dioxide

absorbents are not allowed to dry out.



Use during Pregnancy and Lactation:

Category B3.

Reproduction studies have been carried out on rats and rabbits after repeated

exposure to ISOFLURANE at anaesthetic concentrations. In both species there was

no effect on fertility, pregnancy or delivery. The viability of offspring was

unaffected and there was no evidence of teratogenicity. It is not known whether

the consequences for humans are the same.

There is an increasing volume of information on the use of ISOFLURANE in

pregnancy and obstetric anaesthesia but, with the exception of Caesarean

section, the place of ISOFLURANE is still under development. A suitable level of

anaesthesia for Caesarean section can be maintained with 0.5 - 0.75% ISOFLURANE

in oxygen/nitrous oxide.

Increased blood loss has been observed, comparable with other inhalation

anaesthetics (e.g. halothane), in patients undergoing induced abortions.

Should ISOFLURANE be administered during lactation, lactation is to be

interrupted after the anaesthesia. Lactation can be restarted after the drug has

been discharged from the circulation.

(See also INTERACTIONS)

Adverse Effects

Adverse reactions encountered with ISOFLURANE are similar to those observed with

other halogenated anaesthetics; these are hypotension, respiratory depression

and arrhythmias.

Other minor side-effects encountered while using ISOFLURANE are an increase in

the white blood cell count (even in the absence of surgical stress) and also

shivering, nausea and vomiting during the post-operative period. These

side-effects are observed in a similar proportion of patients to other

anaesthetics.

During marketing, there have been rare reports of mild, moderate and severe

(some fatal) post-operative hepatic dysfunction. The causal relationship is

unknown.



Interactions

ISOFLURANE produces sufficient muscle relaxation for some intra-abdominal

operations. ISOFLURANE is compatible with all commonly used muscle relaxants,

the effects of which may be markedly potentiated by ISOFLURANE. The effect is

most notable in non-depolarising agents, thus lower doses would be used in the

presence of ISOFLURANE. The effect of non-depolarising muscle relaxants can be

counteracted by administering neostigmine as this has no effect on the relaxant

properties of ISOFLURANE.

Adrenaline: Administration of adrenaline by any route, and some other β-

sympathomimetic drugs, may cause arrhythmias during ISOFLURANE anaesthesia.

Calcium Antagonists (and other vasodilators):

ISOFLURANE can cause marked hypotension in patients receiving concomitant

therapy with calcium antagonists, especially those of the dihydropyridine class,

(e.g. nifedipine, felodipine, amlodipine, isradipine). Patients receiving

chronic therapy with other vasodilators such as ACE-inhibitors (e.g. captopril,

enalapril, lisinopril) or α1-adrenoceptor antagonists (e.g. prazosin), may

show unpredictable hypotension with any type of anaesthesia.

Narcotic Analgesics:The anaesthetic effect of ISOFLURANE can be potentiated by

narcotic analgesics.



Overdosage

(See also PRECAUTIONS)

Overdosing with ISOFLURANE will result in marked depression of breathing, and a

marked decrease in blood pressure, the latter being predominantly due to a

peripheral vasodilatation rather than direct myocardial depression.

If it appears an overdose has been administered, stop drug inspiration

immediately, establish a clear airway and initiate controlled ventilation with

pure oxygen.



Pharmaceutical Precautions

ISOFLURANE is fully compatible with other anaesthetic gases and volatile agents,

but should be mixed and administered using agent-specific vapourising equipment.

Special precautions for storage: Room temperature (15 to 30°C). Keep container

well closed.

Shelf-life as presented in 100 mL or 250 mL bottle: 5 years. Shelf-life (after

first opening of container): If the container is left open, contents will

evaporate. If securely reclosed, shelf-life is unaffected. Shelf-life after

dilution or reconstruction is not applicable.



Medicine Classification

Prescription Medicine

Package Quantities

Bottles of 100 or 250 mL

Further Information

Isoflurane is a colourless non-flammable general inhalation anaesthetic which

contains no additive or stabiliser. It is 1-chloro-2,2,2-trifluoroethyl

difluoromethyl ether and has the structural formula:



Some physical constants of Isoflurane are:-

      Molecular weight184.5

      Boiling point °C at 760 mm Hg48.5

      Specific gravity at 25 °C1.496

      Refractive index n20 D1.2990 - 1.3005



      Vapour pressure mm Hg:

      at 20°C238

      at 25°C295

      at 30°C367

      at 35°C450



      Partition coefficients at 37°C

      Water/gas0.61

      Blood/gas1.43

      Oil/gas90.80



      Partition coefficients at 25°C for rubber and plastics:

      Polyolefin/gasca 1.1

      Polyurethane/gasca 1.4

      Polyethylene/gasca 2.0

      Butylacetate/gasca 2.5

      Conductive rubber/gas62.0

      Butyl rubber/gas75.0

      Polyvinylchloride/gas110.0



      Flammability in oxygen or nitrous oxide:

      at 9 joules/sec and 23°CNon-flammable

      at 900 joules/sec and 23°CNon-flammable at anaesthetic concentrations.





The MAC (Minimum Alveolar Concentration), the standard measure of potency for

anaesthetics, is 1.15% for middle-aged humans. There is an age-relationship, and

the MAC is significantly higher in children.

      MAC AGEAverage Conc. in Oxygen

      up to 12 months1.60 to 1.85%

      1 to 5 years1.50 to 1.60%

      mid-twenties1.25 to 1.30%

      mid-forties1.10 to 1.20%

      mid-sixties1.00 to 1.10%

       Stability:

      1. UV light - 30 hoursStable (No change)

      2. Indirect sunlight - 3 yearsStable (No change)



Name And Address

Distributed by:

Rhodia New Zealand Limited

P O Box 76214

Manukau City

Auckland

Ph: (09) 262 6943

Date Of Preparation

January 1999