Abbott Laboratories Ireland Limited

Sevorane Inhalation gas

Sevoflurane

For excipients see 6.1.

Inhalation gas.

Non-flammable, volatile liquid for administration as an inhalation anaesthetic.

Sevoflurane is indicated for induction and maintenance of general anaesthesia in adult and paediatric patients. Use of Sevoflurane in dental anaesthesia should be restricted to hospitals or day care units only (see section 4.3).

Sevoflurane should be delivered via a vaporiser specifically calibrated for use with Sevoflurane so that the concentration delivered can be accurately controlled. MAC (minimum alveolar concentration) values for Sevoflurane decrease with age and with the addition of nitrous oxide. The table below indicates average MAC values for different age groups.

EFFECT OF AGE ON MAC OF SEVOFLURANE

*Neonates are full term gestational age. MAC in premature infants has not been determined

** In 1 - <3 year old paediatric patients, 60%N₂0/40%0₂ was used

Sevoflurane is similar to Isoflurane in the sensitisation of the myocardium to the arrhythmogenic effect of exogenously administered adrenaline.

Induction:

Dosage should be individualised and titrated to the desired effect according to the patient's age and clinical status. A short acting barbiturate or other intravenous induction agent may be administered followed by inhalation of Sevoflurane. Induction with Sevoflurane may be achieved in oxygen or in combination with oxygen-nitrous oxide mixtures. For induction of anaesthesia inspired concentrations of up to 8% Sevoflurane usually produces surgical anaesthesia in less than 2 minutes in both adults and children.

Maintenance:

Surgical levels of anaesthesia may be sustained with concentrations of 0.5 - 3% Sevoflurane with or without the concomitant use of nitrous oxide.

Elderly: As with other inhalation agents, lesser concentrations of Sevoflurane are normally required to maintain surgical anaesthesia.

Emergence:

Emergence times are generally short following Sevoflurane anaesthesia. Therefore, patients may require post operative pain relief earlier.

Sevoflurane should not be used in patients with known hypersensitivity to Sevoflurane. Sevoflurane is contraindicated in patients with known or suspected genetic susceptibility to malignant hyperthermia. Sevoflurane is also contraindicated in all patients (adults and children) undergoing dental procedures outside a hospital or day care unit (see section 4.4).

Sevoflurane should be administered only by persons trained in the administration of general anaesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment and circulatory resuscitation must be immediately available. Sevoflurane should be delivered via a vaporiser specifically calibrated for use with Sevoflurane so that the concentration delivered can be accurately controlled. Hypotension and respiratory depression increase as anaesthesia is deepened.

All patients anaesthetised with Sevoflurane 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).

During the maintenance of anaesthesia, increasing the concentration of Sevoflurane produces dose-dependent decreases in blood pressure. Excessive decrease in blood pressure may be related to depth of anaesthesia and in such instances may be corrected by decreasing the inspired concentration of Sevoflurane. The recovery from general anaesthesia should be assessed carefully before patients are discharged from the recovery room.

Patients with repeated exposures to halogenated hydrocarbons, including Sevoflurane, within a relatively short interval may have an increased risk of hepatic injury.

Malignant Hyperthermia: In susceptible individuals, potent inhalation anaesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. Treatment includes discontinuation of triggering agents (e.g. Sevoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Renal failure may appear later, and urine flow should be monitored and sustained if possible.

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. 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.

Isolated cases of ventricular arrhythmia were reported in paediatric patients with Pompe's disease.

Renal function: In clinical trials no effect on renal function was observed, including in-patients with pre-existing renal impairment. Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 1.5mg/dL) that have been studied, the safety of Sevoflurane administration in this group has not been fully established. Therefore, until further experience is obtained, Sevoflurane should be used with caution in patients with renal insufficiency.

Although clinical experience is limited no unusual or unexpected adverse events were seen in either an adult or a paediatric repeat use study.

Sevoflurane produces low levels of Compound A (pentafluoroisopropenyl fluoromethyl ether (PIFE)) and trace amounts of Compound B (pentafluoromethoxy isopropyl fluoromethyl ether (PMFE)), when in direct contact with CO₂ absorbents. Levels of Compound A increase with:- increase in canister temperature; increase in anaesthetic concentration; decrease in gas flow rate and increase more with the use of Baralyme rather than Soda lime. (See also Pharmaceutical Particulars.) The concentrations of Compound A found in routine clinical practice are on average 19ppm in adults (maximum 32ppm) with use of Soda lime as the CO₂ absorbent. Although exposure to Sevoflurane in low flow systems is limited, there has been no evidence of renal dysfunction attributable to Compound A.

Rare cases of extreme heat, smoke, and/or spontaneous fire in the anaesthesia machine have been reported during sevoflurane use in conjunction with the use of desiccated CO₂ absorbent,specifically those containing potassium hydroxide (e.g Baralyme). An unusually delayed rise or unexpected decline of inspired sevoflurane concentration compared to the vaporizer setting may be associated with excessive heating of the CO₂ absorbent canister.

An exothermic reaction , enhanced sevoflurane degragation, and production of degradation products can occur when CO₂ absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO₂ absorbent canisters. Sevoflurane degradants (methanol, formaldehyde, carbon monoxide, and Compounds A, B, C and D) were observed in the respiratory circuit of an experimental anaesthesia machine using desiccated CO₂ absorbents and maximum sevoflurane concentrations (8%) for extended periods of time ( 2 hours). Concentrations of formaldehyde observed at the anaesthesia respiratory circuit ( using sodium hydroxide containing absorbents) were consistent with levels known to cause mild respiratory irritation. The clinical relevance of the degradants observed under this extreme experimental model is unknown.

The following are clinical findings, which have been reported in association with these rare, isolated events. Failed inhalation induction or inadequate anaesthesia with Sevoflurane; patient signs of airway irritation, such as coughing, oxygen desaturation, increased airway pressures, difficult ventilation, severe airway oedema and erythema and elevated carboxyhemoglobin levels have been reported in association with these rare isolated events.

If excessive heat from the CO₂ absorbent canister is noted, the clinical situation should be evaluated and disconnecting the patient from the anaesthesia circuit should be considered.

When a clinician suspects that the CO₂ absorbent may be desiccated, it should be replaced. 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.

Anaesthetic machines should be completely shut off at the end of clinical use, the packaging integrity of new CO₂ absorbents should be verified prior to use and the temperature of CO₂ absorbents canisters monitored during use.

The action of non-depolarising muscle relaxants is potentiated with Sevoflurane, therefore, when administered with Sevoflurane, dosage adjustments of these agents should be made.

Opioids such as alfentanil and sufentail, when combined with sevoflurane, may lead to a synergistc fall in heart rate, blood pressure and respiratory rate.

Reproduction studies have been performed in rats and rabbits at doses up to 1 MAC and have revealed no evidence of impaired fertility or harm to the foetus due to Sevoflurane. There are no adequate and well-controlled studies in pregnant women therefore Sevoflurane should be used during pregnancy only if clearly needed.

The safety of Sevoflurane for anaesthesia during Caesarean section has been demonstrated in one multicentre trial. There are no studies of Sevoflurane in labour and delivery. It is not known whether Sevoflurane is excreted in human milk therefore caution should be exercised when Sevoflurane is administered to a nursing woman.

As with other agents, patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, may be impaired for some time after general anaesthesia.

As with all potent inhaled anaesthetics, Sevoflurane may cause dose- dependent cardio-respiratory depression. Most adverse events are mild to moderate in severity and are transient in duration.

Nausea and vomiting have been observed in the postoperative period. These effects are common sequelae of surgery and general anaesthesia which may be due to the inhalational anaesthetic, other agents administered intraoperatively or post-operatively and to the patient's response to the surgical procedure.

The most commonly reported adverse events were as follows;

In adult patients: hypotension, nausea and vomiting

In elderly patients: bradycardia, hypotension and nausea; and

In paediatric patients: agitation, cough, vomiting and nausea

All adverse events, at least possibly related to sevoflurane from clinical trials, are displayed in the Table below by MedDRA System Organ Class, Preferred Term and frequency. The following frequency groupings are used: very common (1/10); common (1/100 and <1/10); uncommon (1/1,000 and <1/100); rare (1/10,000 and <1/1,000); very rare (<1/10,000), including isolated reports. The type, severity, and frequency of adverse reactions in sevoflurane patients were comparable to adverse reactions in reference-drug patients.

Adverse Event Data Derived from Clinical Trials

*Occasional cases of transient changes in hepatic function tests were reported with sevoflurane and reference agents.

** Transient increases in serum inorganic fluoride levels my occur during and after sevoflurane anaesthesia. Concentrations of inorganic fluoride generally peak within two hours of the end of sevoflurane anaesthesia and return within 48 hours to pre-operative levels. In clinical trials, elevated fluoride concentrations were not associated with impairment of renal function.

Cardiac arrhythmias including ventricular arrhythmias have been reported during Sevoflurane anaesthesia.

Post Marketing Experience

Adverse reactions have been spontaneously reported during post-approval use of Sevoflurane. These events are reported voluntarily from a population of an unknown rate of exposure. Therefore, it is not possible to estimate the true incidence of adverse events or establish a causal relationship to Sevoflurane exposure.

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

In the event of overdosage, the following action should be taken: Stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen and maintain adequate cardiovascular function.

Changes in the clinical effects of Sevoflurane rapidly follow changes in the inspired concentration.

Recovery of cognitive function and motor co-ordination have been evaluated compared to reference drug using a meta - analysis of data generated in clinical trials. Patients administered Sevoflurane reached criteria required for discharge from the recovery room significantly sooner than those administered reference drug.

Cardiovascular Effects

As with all other inhalation agents Sevoflurane depresses cardiovascular function in a dose related fashion.

Nervous System Effects

No evidence of seizure was observed during the clinical development programme. Sevoflurane does not have any stimulating effect on the sympathetic nervous system.

Sevoflurane has minimal effect on ICP (intra-cranial pressure) and preserves CO₂ responsiveness. In patients at risk for elevations of ICP, Sevoflurane should be administered cautiously in conjunction with ICP-reducing manoeuvres such as hyperventilation.

The low solubility of Sevoflurane in blood would suggest that alveolar concentrations should rapidly increase upon induction and rapidly decrease upon cessation of the inhaled agent. This was confirmed in a clinical study where inspired and end-tidal concentrations of halogenated anaesthetics (F_I and F_A) were measured. The F_A/F_I (wash-in) value at 30 minutes for Sevoflurane was 0.85 and 0.73 for isoflurane. The wash-in was faster for Sevoflurane than isoflurane at all time points. The F_A/F_AO (wash-out) value at 5 minutes was 0.15 for Sevoflurane and 0.22 for isoflurane.

In humans <5% of Sevoflurane absorbed is metabolised, in the liver, to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and carbon dioxide (or a one carbon fragment). Once formed, HFIP is rapidly conjugated with glucuronic acid and excreted in the urine.

The rapid and extensive pulmonary elimination of Sevoflurane minimises the amount of anaesthetic available for metabolism. The metabolism of Sevoflurane is not inducible by barbiturates.

The results of studies in dogs indicate that Sevoflurane will not cause coronary steal nor will it exacerbate pre-existing myocardial ischemia.

Animal studies have shown that hepatic and renal circulation are well maintained with Sevoflurane.

Sevoflurane decreases the cerebral metabolic rate for oxygen (CMRO₂) in a fashion analogous to that seen with isoflurane. An approximately 50% reduction of CMRO₂ is observed at concentrations approaching 2.0 MAC. Animal studies have demonstrated that Sevoflurane does not have a significant effect on cerebral blood flow.

In animals, Sevoflurane significantly suppresses electroencephalographic (EEG) activity comparable to equipotent doses of isoflurane. There is no evidence that Sevoflurane is associated with epileptiform activity during normocapnia or hypocapnia. In contrast to enflurane, attempts to elicit seizure-like EEG activity during hypocapnia with rhythmic auditory stimuli have been negative.

Water (as a Lewis Acid inhibitor).

Sevoflurane is stable when stored under normal room lighting conditions. No discernible degradation of sevoflurane occurs in the presence of strong acids or heat. Sevoflurane is not corrosive to stainless steel, brass, alumimum, nickel-plated brass, chrome-plated brass or copper beryllium alloy.

Chemical degradation can occur upon exposure of inhaled anaesthetics to CO₂ absorbent within the anaesthesia machine. When used as directed with fresh absorbents, degradation of sevoflurane is minimal and degradants are undetectable or non-toxic. Sevoflurane degradation and subsequent degradant formation are enhanced by increasing absorbent temperature, desiccated CO₂ absorbent (especially potassium hydroxide-containing, e.g. Baralyme^®), increased sevoflurane concentration and decreased fresh gas flow. Sevoflurane can undergo alkaline degradation by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropanyl fluoromethyl ether (PIFE or more commonly known as Compound A). The second pathway for degradation of sevoflurane occurs only in the presence of desiccated CO₂ absorbents and leads to the dissociation of sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic, rapidly glucoronidated, cleared and has toxicity comparable to sevoflurane. Formaldehyde is present during normal metabolic processes. Upon exposure to a highly desiccated absorbent, formaldehyde can further degrade into methanol and formate. Formate can contribute to the formation of carbon monoxide in the presence of high temperature. Methanol can react with compound A to form the methoxy addition product Compound B. Compound B can undergo further HF elimination to form Compounds C,D and E. With highly desiccated absorbents, especially those containing potassium hydroxide (e.g Baralyme^®) the fomation of formaldehyde, methanol, carbon monoxide, Compound A and perhaps some of its degradants, Compounds B,C and D may occur.

The recommended shelf life is 3 years.

No special precautions for storage.

PEN bottle 100ml or 250ml with roll on pilfer-proof cap (ROPP) or Quik-fil MkI or MkII.

Sevoflurane should be administered via a vaporiser calibrated specifically for Sevoflurane using a key filling system designed for Sevoflurane specific vaporisers or other appropriate Sevoflurane specific vaporiser filling systems.

Carbon dioxide absorbents should not be allowed to dry out when inhalational anaesthetics are being administered. Some halogenated anaesthetics have been reported to interact with dry carbon dioxide absorbent to form carbon monoxide. However, in order to minimise the risk of formation of carbon monoxide in re-breathing circuits and the possibility of elevated carboxyhaemoglobin levels, CO₂ absorbents should not be allowed to dry out. There have been rare cases of excessive heat production, smoke and fire in the anaesthetic machine when Sevoflurane has been used in conjunction with a desiccated (dried out) CO₂ absorbent. If the CO₂ absorbent is suspected to be desiccated it should be replaced.

Abbott Laboratories Ireland Limited

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19 April 1995/19 April 2005

October 2009