Abbott Laboratories Ireland Limited

Forane 99.9% w/w, inhalation vapour, liquid.

Isoflurane (not less than 99.9% w/w)

Inhalation vapour, liquid

-clear colourless liquid with slightly musty odour for vaporisation and administration as an inhalation gas.

Induction and maintenance of general anaesthesia in adults and children. Use of isoflurane in dental anaesthesia should be restricted to hospitals or day care units only (see section 4.3).

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

Overall, MAC values for Forane diminish with age. The table below indicates average MAC values for different age groups.

MAC (minimum alveolar concentrations in paediatric patients):

MAC (minimum alveolar concentrations in adult patients):

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

Induction: To avoid excitement an intravenous induction agent should be administered followed by inhalation of Forane. Forane with oxygen or with an oxygen/nitrous oxide mixture may be used.

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

Maintenance: surgical levels of anaesthesia may be maintained with 1.0 - 2.5% Forane in oxygen/nitrous oxide mixtures. An additional 0.5-1.0% Forane may be required when given with oxygen alone. For caesarian section, 0.5-0.75% Forane in a mixture of oxygen/nitrous oxide is suitable.

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

Elderly: as with other agents, lesser concentrations of Forane are normally required to maintain surgical anaesthesia in elderly patients. See above for MAC values.

Use in patients in whom liver dysfunction, jaundice or unexplained fever, leucocytosis or eosinophilia has occurred after a previous halogenated anaesthetic administration.

Forane is contra-indicated in patients with known sensitivity to Forane or other halogenated anaesthetics. It is also contraindicated in patients with known or suspected genetic susceptibility to malignant hyperthermia.

Forane is contraindicated in all patients (adults and children) undergoing dental procedures outside a hospital or day care unit (see section 4.4).

Since levels of anaesthesia may be altered quickly and easily with Forane, 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.

All patients anaesthetised with Forane should be constantly monitored, including ECG, BP, oxygen saturation and end tidal CO₂ in a setting where full resuscitative equipment is available and with staff fully trained in resuscitative techniques. The presence of additional risk factors should be taken into consideration (see section 4.8).

Forane is a profound respiratory depressant, which effect is accentuated by narcotic premedication or concurrent use of other respiratory depressants. Respiration should be closely monitored and assisted or controlled ventilation employed where necessary. Measurement of tidal volume may provide an indication of depth of anaesthesia in the spontaneously breathing patient.

Hypotension and myocardial depression are related to the depth of anaesthesia. The concomitant use of nitrous oxide and surgical stimulation may limit the extent of the hypotension. Excessive fall in blood pressure, unless due to hypovolaemia, should be corrected by lightening the depth of anaesthesia.

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

As with other halogenated agents, Forane must be used with caution in patients with increased intracranial pressure. Forane may cause a rise in cerebrospinal fluid pressure and cerebral blood flow, which may be reversible by hyperventilation. This should be borne in mind when considering use in neurosurgery.

Reports demonstrate that isoflurane can produce hepatic injury ranging from mild transient increases in liver enzymes to fatal hepatic necrosis in rare instances. Repeated exposure to halogenated hydrocarbon anaesthetics may increase the risk of hepatic injury, especially if the interval is less than 3 months.

Caution should be exercised when administering Forane to patients with pre-existing liver disease.

Malignant hyperthermia: In susceptible individuals, Forane (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 non-specific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressures. (It should also be noted that many of these non-specific 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 hyperkalemia and a base deficit may appear.

Treatment includes discontinuance of triggering agents (e.g. Forane). 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 and urine flow should be sustained if possible.

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 consistant with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity of hypermetabolic state. Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.

Although peak inorganic fluoride concentrations which result from the breakdown of isoflurane are generally much lower than those considered 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.

This agent should be administered cautiously to those on anti hypertensives or any drug which may influence the response of the sympathetic nervous system.

Some halogenated inhalation agents with a CH-F₂ moiety, i.e. desflurane, isoflurane and enflurane have been reported to interact with dry CO₂ absorbents to form carbon monoxide. In order to minimise the risk of formation of carbon monoxide in closed and re-breathing circuits, and the possibility of increased carboxyhaemoglobin levels in exposed patients, CO₂ absorbents should not be allowed to dry out.

Standard anaesthesia monitors such as pulse oximeters are not a reliable method for detecting carboxyhaemoglobin.

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.

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.

The action of non-depolarising relaxants is markedly potentiated with isoflurane. Isoflurane, as well as other general anaesthetics, may cause a slight decrease in intellectual function for two or three days following anaesthesia. As with other anaesthetics, small changes in moods and symptoms may persist for up to 6 days after administration.

Isoflurane markedly potentiates the effects of all commonly used muscle relaxants, especially the non-depolarising agents, and these agents should be used in reduced dosage. Care should also be exercised when using antibiotics of the aminoglycoside group e.g. neomycin, concurrently with isoflurane. Neostigmine does not antagonise the direct muscle relaxant effect of isoflurane.

Isoflurane does not sensitise the myocardium to the effects of catecholamines in dogs. Limited data suggests that subcutaneous infiltration of 0.25 mg (50 ml of 1:200,000 solution) adrenaline of 3.4 mcg/kg in a 70 kg adult, does not produce an increase in ventricular arrhythmias, provided there is no concomitant myocardial hypoxia. The utmost care must be used to prevent overdosage or unduly rapid adrenaline absorption.

Isoflurane should be administered with caution to patients on beta adrenergic blockers. Limited animal data suggests that isoflurane may be used safely in the presence of therapeutic levels of propranolol.

The MAC of isoflurane is decreased by the use of nitrous oxide (see section 4.2).

Reproduction studies have been carried out on animals after repeated exposures to anaesthetic concentrations of Forane. Studies with the rat demonstrated no effect on the fertility, pregnancy or delivery or on the viability of the offspring. No evidence of teratogenicity was revealed. Comparable experiments in rabbits produced similar negative results. The relevance of these studies to the human is not known. Safety in pregnancy has not been established. Adequate data have not been developed to establish the use of Forane in pregnancy or obstetrics other than for caesarian section.

It is not known whether isoflurane is excreted in human milk therefore caution should be exercised when isoflurane is administered to a nursing woman.

Gynaecological use: Blood losses comparable with those found following anaesthesia with other inhalation agents have been observed with Forane in patients undergoing uterine curettage.

The action of non-depolarizing relaxants is markedly potentiated with isoflurane.

Isoflurane, as well as other general anaesthetics, may cause a slight decrease in intellectual function for two or three days following anaesthesia. As with other anaesthetics, 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.

As with other halogenated anaesthetics, hypotension and respiratory depression have been observed. Close monitoring of blood pressure and respiration is recommended.

This agent causes a rise in blood sugar levels during anaesthesia. This should be borne in mind during administration to diabetic subjects.

*May be associated with hypersensitivity reactions, particularly in association with long-term occupational exposure to inhaled anaesthetic agents.

Supportive measures may be necessary to correct hypotension and respiratory depression resulting from excessively deep levels of anaesthesia.

ATC Code: N01AB06 Halogenated hydrocarbon.

Induction and particularly recovery are rapid. Although slight pungency may limit the rate of induction, excessive salivation and tracheobronchial secretions are not stimulated. Pharyngeal and laryngeal reflexes are diminished quickly. Levels of anaesthesia change rapidly with Forane. Heart rhythm remains stable.

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

Forane appears to sensitise the myocardium to adrenaline to an even lesser extent than enflurane. 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 Forane (See also Section 4.5).

Muscular relaxation may be adequate for some intra-abdominal 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 Forane, 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 Forane itself. All commonly used muscle relaxants are compatible with Forane (see also Section 4.5).

Forane undergoes minimal biotransformation in man. In the post-operative period only 0.17% of the Forane taken up can be recovered as urinary metabolites. Peak serum inorganic fluoride values usually average less than 5 µmol/litre and occur about four hours after anaesthesia, returning to normal levels within 24 hours. No signs of renal injury have been reported after Forane administration.

None stated.

None.

Some halogenated inhalation agents with a CH-F₂ moiety, i.e. desflurane, isoflurane and enflurane have been reported to interact with dry CO₂ absorbents to form carbon monoxide. In order to minimise the risk of formation of carbon monoxide in closed and re-breathing circuits, and the possibility of increased carboxyhaemoglobin levels in exposed patients, CO₂ absorbents should not be allowed to dry out (see also section 4.4).

5 years.

In-use stability: Use within 3 months from opening when stored in the original package and below 25°C.

Do not store above 25°C. Store in the original package in order to protect from light. Keep the bottle tightly closed.

100 ml and 250 ml Type III Ph.Eur amber glass bottles, closed with an aluminium cap with LDPE liner.

Not all pack sizes may be marketed.

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

It is recommended that vapour from this and other inhalation agents be efficiently extracted from the area of use.

Any unused product or waste material should be disposed of in accordance with local requirements.

Abbott Laboratories Ireland Limited,

4051 Kingswood Drive

Citywest Business Campus

Dublin 24

Ireland

PA 38/30/1

Date of first authorisation: 23rd June 1983

Date of last renewal: 23rd June 2008

01 November 2010