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1.    Name of the medicinal product

Sevoflurane

100% Inhalation Vapour, liquid

2.    Qualitative and quantitative composition

Sevoflurane 100%.

The finished product is comprised only of the active ingredient,

3.    Pharmaceutical form Inhalation vapour, liquid Clear, colourless, volatile liquid

4.    Clinical particulars

4.1    Therapeutic indications

Induction and maintenance of general anaesthesia in adult and paediatric patients of all ages, including full term neonates (see section 4.2 forage details).

4.2    Posology and method of ad ministration

Sevoflurane should be delivered via a vaporizer specifically calibrated for use with Sevoflurane so that the concentration delivered can be accurately controlled. MAC (minimum alveolar concentration) values for sevoflurane decrease as the patient's age increases and with the addition of nitrous oxide. Dosage should be individualised and titrated to the desired effect according to

the patient's age and clinical status.

MAC values for Adults and Paediatric patients according to age

determined.

** in 1 ~<3 year old paediatric patients, 60% N₂0/4Q% O_zwas used.

Anaesthesia Induction

A short acting barbiturate or other intravenous induction agent may be administered fol lowed by inhalation of sevofl urane.

Induction with sevoflurane may be achieved by inhalation of 0.5-1,0% sevoflurane in oxygen (Oj) with or without nitrous oxide (N₂0), increasing by

increments of 0.5-1.0% sevoflurane, to a maximum of 8% in adults and children until the required depth of anaesthesia is achieved.

In adults inspired concentrations of up to 5% sevoflurane In children, inspired concentrations of up to 7% sevoflurane usually produce surgical anaesthesia in less than two minutes.

Maintenance of Anaesthesia

Surgical levels of anaesthesia may be maintained by inhalation of 0.5-3% sevoflu rane i n 0₂ with or without N₂ O.

Emergence:

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

Hepatic Dysfunction:

Sevoflurane should not be used in patients with a history of unexplained moderate/severe hepatic dysfunction with jaundice, fever, and/or eosinophililia in association with halogenated anesthetics.

Renal Insufficiency:

Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 133pmol/litre) studied, the safety of sevoflurane administration in this group has not been folly established. Therefore, sevoflurane should be used with caution in patients with renal insufficiency. In some studies in rats, nephrotoxicity was seen in animals exposed to levels of

Compound A (pentafluoroisopropenyl fluoromethyl ether (PIFE) in excess of those usually seen in routine clinical practice. The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established. (See Section 5.3, Predinical Safety Data tor further details.). Postoperative monitoring ofthe renal function Is recommended in renal patients.

Inhalation use. Sevoflurane has to be administered either via face mask or via endotracheal tube. 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. If the carbon dioxide absorbent may be desiccated, it must be replaced before the use of sevoflurane. (see section 4.4.)

4.3 Contraindications

Sevoflurane should not be used in patients with known hypersensitivity to sevoflurane or other halogenated anaesthetics.

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

Sevoflurane should not be used in patients with a history of unexplained

moderate/severe hepatic dysfunction with jaundice, fever, and/or eosinophililia in association with halogenated anesthetics.

4 A Special warnings and precautions for use

Hypotension and respiratory depression increase as anaesthesia is deepened.

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.

As with all anaesthetics, particular care should be taken when selecting the dose forhypovolaemic, hypotensive or weakened patients.

As with all anaesthetics, maintenance of haemodynamic stability is important to avoid myocardial ischaemia in patients with coronary artery disease.

In patients at risk from elevation of intra-cranial pressure, sevoflurane should be administered cautiously in conjunction with techniques to lower intra-cranial pressure (e.g. hyperventilation).

Caution should be observed when using sevoflurane during obstetric anaesthesia because the relaxant effect on the uterus could increase the risk of uterine bleeding (see section 4.6).

Malignant Hyperthermia: In susceptible individuals, potent inhalation anaesthetic agents may trigger a skeletal muscle hypermetabolic state leading

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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 anaesthetic agents has been associated with very rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in children during the postoperative period. The condition has been described in patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy. Use of suxamethonium has been associated with most, but not all of these cases. These patients showed evidence of muscle damage with increased serum creatine kinase concentration and myoglobinuria. These patients did NOT have classical signs of malignant hyperthermia such as muscle rigidity, rapid increase in body temperature, or increased oxygen uptake and carbon dioxide production. Prompt and vigorous treatment for hyperkalaemia and arrhythmias is recommended. Subsequent evaluation for latent neuromuscular disease is indicated.

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

Observe caution in patients with underlying liver disease (including viral hepatitis) (see sections 4.3 and 4.8). Patients with repeated exposures to halogenated hydrocarbons, including sevoflurane, within a relatively short

interval may have an increased risk of hepatic injury.

Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 133pmol/litre) studied, the safety of sevoflurane administration in this group has not been folly established. Therefore, sevoflurane should be used with caution in patients with renal insufficiency. In some studies in rats, nephrotoxicity was seen in animals exposed to levels of Compound A (pentafluoroisopropenyl fluoromethyl ether (PIFE) in excess of those usually seen in routine clinical practice. The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established. (See Section 5.3, Predinical Safety Data for further details.). Post-operative monitoring of the renal function is recommended in renal patients.

Use of sevoflurane has been an assodation with seizures occurring in children and young adults as well as older adults with and without predisposing risk factors. Clinical judgment is necessary before sevoflurane Is used in patients at risk of seizures. In children the depth of anaesthesia should be limited. EEG may permit the optimization of sevoflurane dose and help avoid the development of seizure activity in patients with a predisposition forseizures (section 4.8). Dystonic movements in children have been observed (see section 4.8).

The recovery from general anaesthesia should be assessed carefully before patients are discharged from the recovery room. Rapid emergence from anaesthesia is generally seen with sevoflurane so early relief of postoperative pain may be required. Rapid emergence in children may be associated with

agitation and lack of co-operation (in about25% of cases).

Experience wife repeat exposure to sevoflurane is very limited. However, there were no obvious differences in adverse events between first and subsequent exposures.

Sevoflurane should be used with caution in patients with Myasthenia Gravis.

Like other halogenated anaesthetics, sevoflurane may cause cough during induction.

Sevoflurane could cause QTc prolongation. In clinical practice, this rarely lead to Torsade des Pointes. Sevoflurane should be administered with caution to patients at risk, such as elderly and patients diagnosed with congenital QTc prolongation.

Potential Interactions with CO., Absorbents

An exothermic reaction with degradation of volatile anaesthetics canoccurwhen the carbon dioxide absorbent in the vaporizer becomes desiccated following an extended period of use as a result of dry gas flow through the circuit 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 C0₂ 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 heatingoftheC0₂absorbentcanister.

Sevoflurane degradants were observed in the respiratory circuit of an experimental anaesthesia machine using desiccated C0₂ absorbents and maximum sevoflurane concentrations (8%) for extended periods of time l>_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 underthis extreme experimental model is unknown.

It must be taken into account that the colour indicator does not always change after desiccation has taken place. The carbon dioxide absorbent should be routinely replaced irrespectively of the status. If a health care professional suspects that the carbon dioxide absorbent has become desiccated, it must be replaced beforesubsequentuseofvolatileanesthetics(suchas sevoflu rane).

4.5 Interaction with other medicinal products and other forms of

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

Sevoflurane is similar to isoflurane in the sensitisation ofthe myocardium to the arrhythmogeniceffect of exogenously administered adrenaline.

MAC values for sevoflurane decrease with the addition of nitrous oxide as indicated in the table on 'Effect of Age on MAC of sevoflurane' (see Dosage and Method ofAdministration).

Benzodiazepines and opiates are expected to reduce sevoflurane MAC. Opioids (e.g. alfentanil and sufentanil), used concomitantly with sevoflurane, may lead to a synergistic fall in heart rate, blood pressure and respiratory rate.

As with other agents, lesser concentrations of sevoflurane may be required following use of an intravenous anaesthetic e.g. propofol.

The metabolism of sevoflurane may be increased by known i nd ucers of CYP2E1 (e.g. isoniazid and alcohol), but it is not inducible by barbiturates. Significant increases in plasma fluoride concentrations have been observed following the increased activity ofCYP2E1. Sevoflurane may increase the negative inotropic, chronotropic and dromotropic effects of beta blockers (by blocking cardiovascular compensatory mechanisms). Patients should be warned against interruption of beta-blockers and in any case abrupt interruption of the medication is to be avoided. The anaesthetist should be informed of beta-blocker therapy. The dosage of adrenaline and noradrenaline utilised for local haemostatic action by subcutaneous or-gingival injections should be limited to, for example, 0.1 mg epinephrine within 10 minutes or 0.3 mg within one hour in adults. Parenteral administration of adrenaline and noradrenaline is not recommended. Serious rhythm disturbances are associated with the use of isoprenaline (increased cardiovascular reactivity). Not recommended. The use of amphetamines and derivatives as well as of ephedrine and derivatives can cause preoperative hypertensive crisis. It is preferable to interrupt treatments some days before surgery. Concomitant use of MAO inhibitors: A risk of

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tissue disorders    Rash****

Urticaria

Contact dermatitis****

Swelling face****

Unknown    Musde twitching

connective tissue disorders

Renal and Urinary disorders    Unknown    Renal failure acute

General disorders and Unknown Hyperthermia malignant administration site conditions    Chest discomfort****

‘Frequency is Very Common in paediatric population.

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

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

“ May be associated with hypersensitivity reactions, particularly in association ith long term occupational exposure to inhaled anaesthetics, including Sevoflurane.

Summary of Post-Marketing Adverse Drug Reactions System Organ Class    Adverse Reactions

Immune system disorders    Anaphylactic reaction****

Anaphylactoid reaction Hypersensitivity****

Nervous system disorders    Convulsion

Dystonia

Respi ratory, thoracic and mediastinal    Pulmonaryoedema

disorders    Bronchos pasm

Dyspnoea**** Wheezing****

Hepato-biliary disorders    Hepatitis

Hepatic failure Hepatic necrosis

Skin and subcutaneous tissue disorders    Pruritus

Rash****

Urticaria

Contact dermatitis**** Swelling face****

Musculoskeletal and connective tissue    Musde twitching

Renal and Urinary disord

Renal failure acute

General disorders and administration    Hyperthermia malignant

site conditions    Chest discomfort****

**** May be associated with hypersensitivity reactions, particularly in assodation with long term occupational exposure to inhaled anaesthetics, including Sevoflurane.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring ofthe benefit/risk balance of the medidnal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at

4.9 Overdose

Symptoms of overdose indude respiratory depression and circulatory insufficiency.

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

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmaco-therapeutic group: Halogenated hydrocarbons ATC code: N01AB08

Changes in the clinical effects of sevoflurane rapidly follow changes in the

inspired concentration.

As with all other inhalation agents sevoflurane depresses cardiovascular function in a dose related fashion. In one volunteer study, increases in sevoflurane concentration resulted in decrease in mean arterial pressure, but there was no change in heart rate. Sevoflurane did not alter plasma noradrenaline concentrations in this study.

Nervous System Effects

In patients with normal intracranial pressure (ICP), sevoflurane had minimal effect on ICP and preserved C0₂ responsiveness. The safety of sevoflu rane has not been investigated in patients with a raised ICP. In patients at risk far elevations of ICP, sevoflurane should be administered cautiously in conjunction with ICP-redudng manoeuvres.

5.2 Pharmacokinetic properties

The low solubility of sevoflurane in blood should result in alveolar concentrations which rapidly increase upon induction and rapidly decrease upon cessation of the inhaled agent.

In humans <5% of the absorbed sevoflurane is metabolised, The rapid and extensive pulmonary elimination of sevoflurane minimises the amount of anaesthetic available for metabolism, sevoflurane is defluorinated via cytochrome p450(CYP)2E1 resulting in the production of hexafluoroisopropanol

(HFIP) with release of inorganic fluoride and carbon dioxide (or a one carbon fragment). HFIP is then rapidly conjugated with glucuronic add and excreted in the urine. The metabolism of sevoflurane may be increased by known inducers of CYP2E1 (e.g. isoniazid and alcohol), but it is not inducible by barbiturates. Transient increases in serum inorganic fluoride levels may occur during and after sevoflurane anaesthesia. Generally, concentrations of inorganic fluoride peak within 2 hours ofthe end of sevoflurane anaesthesia and return within 48 hours to pre-operative levels.

5.3 Predinical safety date

Animal studies have shown that hepatic and renal draulation are well maintained with sevoflurane.

Sevoflurane decreases the cerebral metabolic rate for oxygen (CMROJ in a fashion analogous to that seen with isoflurane. An approximately 50% reduction of CMR0₂ 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 anflurane, attempts to elicit seizure-like EEG activity during hypocapnia with rhythmic auditory stimuli have been negative.

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Patient Info Section Pages 5 & 6

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INFORMATION FOR THE PATIENT

Sevoflurane 100%

Inhalation Vapour, liquid

Sevoflurane

Read all of this leaflet carefully before you are given this medicine.

-    Keep th is leaflet. You may need to read it again.

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

-    If any of the side effects get serious, or if you notice any side effects not listed i n this leaflet, please tellyourdoctorornurse.

In this leaflet:

1.    What Sevoflurane 100% Inhalation Vapour, liquid is and what it is used for

2.    Before you are given Sevoflurane 100% Inhalation Vbpour, liquid

3.    How Sevoflu rane 100% In halation Vapour, liquid will begiven

4.    Possible side effects

5.    How to store Sevoflu rane 100% I n halation Vapour, liquid

6.    Further information

1.    WHAT SEVOFLURANE 100% INHALATION VAPOUR, LIQUID IS AND WHAT IT IS USED FOR

The active ingredient in Sevoflurane 100% Inhalation Vapour, liquid is sevoflurane, which is a general anaesthetic used for surgical operations and other procedures.

It is an inhaled anaesthetic that is given to you as a vapour foryou to breathe in. It causes you to fall into a deep sleep (induction of anaesthesia). It also maintains a deep, painless sleep during which you can undergo surgery (maintenance of anaesthesia).

2.    WHAT YOU NEED TO KNOW BEFORE YOU ARE GIVEN SEVOFLURANE 100% INHALATION VAPOUR, UQUID

You should not be given Sevoflurane 100% Inhalation Vapour, liquid If any of the following applies to you, please tell your doctor If:

•    you are hypersensitive (or allergy) to sevoflurane or other similar anaesthetic.

•    you, or anyone in your family, are susceptible to a condition called malignant hyperthermia (rapid rise in body temperature) during anaesthesia.

•    you have reacted badly after previous anaesthesia with sevoflurane or similar anaesthetics, e.g. you developed liver

problems (such as jaundice), fever or blood problems.

Tell your doctor before you are given Sevoflurane 100%

Inhalation Vapour, liquid If:

•    you have previously had general anaesthetics, particularly if repeated over a short period of time. You may have an increased riskof liver problems

•    you are suffering from any illness, other than those connected with your operation, particularly any kidney or heart problems, low blood pressure, severe headaches, nausea orvomiting or Pompe’s disease in children

•    you suffer from a neuromuscular disease, particularly Duchenne muscular dystrophy

•    you have raised pressure in the skull (intracranial pressure), such as from a head injury or brain tumor

•    you are at risk of having seizures (fits)

•    you are pregnant or breastfeeding.

Taking or using other medicines

Tell your doctor if you are taking or have recently taken any ofthe

following:

•    medicines that affect the heart such as adrenaline or beta blockers

•    tranquillisers (benzodiazepines)

•    strong painkillers such as morphine or codeine

•    musde relaxants

•    isoniazid, used to treat infections

•    other anaesthetics, e.g. nitrous oxide, propofol, opioids (e.g. alfentanil and sufentanil), as sevoflurane may affect the way they work if they are given at the same time.

Please tell your doctor or nurse if you are taking or have recently taken any other medicines, including medidnes obtained without a prescription.

Pregnancy and breastfeeding

Tell your dodor or anaesthetist if you are pregnant or think you may be pregnant. You should not receive Sevoflurane 100% In halation Vapour, liquid if you are pregnant unless it is essential.

Sevoflurane 100%Inhalation Vapour, liquid may cause increased blood loss after operations involving the womb.

Caution should be exercised when Sevoflurane 100%lnhalation Vapour, liquid is administered to nursing mothers as it is not known whether sevoflurane is present in human milk after anaesthesia.

Driving and using machines

You should not drive or use machinery for at least 24 hours after you have had a general anaesthetic.

3.    HOW SEVOFLURANE 100% INHALATION VAPOUR, UQUID WILL BE GIVEN

Sevoflurane 100% Inhalation Vapour, liquid will be given by a trained anaesthetist in a surgery or hospital. The anaesthetist will dedde how much Sevoflurane you need and when it is to be given. Sevoflurane 100% Inhalation Vapour, liquid liquid is changed to vapour (gas) in a vapouriser. You will breathe it in as a vapour. It may be used to put you to sleep before your operation or, if you are put to sleep with an injection, it may be used to maintain anaesthesia during the operation.

If you have any further questions on the use of this product, ask your anaesthetist, doctor or n urea.

4.    POSSIBLE SIDE EFFECTS

Like all medicines, Sevoflurane 100% Inhalation Vapour, liquid can cause side efforts, although not everybody gets them. It is however, important to consult your ward doctor, nurse or anaesthetist ifyouarefeelingunwell.

Serious rare side effects:

The following side effects are serious and you may need

immediate medical attention. Hospital staff will monitor you throughout your anaesthesia and will give immediate assistance when necessary.

Tell the doctor or nurse immediately if you have any of the following:

•    Allergic reactions, which can be severe, with swelling of the face, tongue and throat and difficulty breathing.

•    Malignant hyperthermia (very high temperature), which may require intensive care and may be fatal. This condition may run infamilies.

•    Increased potassium levels in the blood (hyperkalaemia), which may result in abnormal heart rhythms and can be fatal in children during the post-operative phase. This has been seen in patients with neuromuscular disease, particularly Duchenne muscular dystrophy.

If you experience any of the following, tell your doctor or nurse:

Very common side effects (occurring in more than 1 in 10 patients)

•    restlessness (agitation) in children

•    slow heart rate

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•    low blood pressure

•    coughing

•    nausea and vomiting.

Common side effects (1 to 10 patients In 100)

•    restlessness (agitation) in adults

•    headache

■ drowsiness

•    dizziness

•    fast heart rate

•    increased blood pressure

•    throat spasm, respiratory problems

•    mouthwatering

•    hypothermia, chills

•    fever

•    abnormal blood sugar level, liver function test or white blood cell counts

•    increased blood fluoride.

Uncommon side effects (1 to 10 patients in 1,000)

The frequency should be changed from "

•    confusion

•    abnormal heart rhythm and abnormal heart beats

•    asthma .stopping breath ing, low oxygen levels

•    retention of urine, glucose in the urine

•    increased or decreased number of white blood cells

•    abnormal blood enzyme levels.

Other side effects [frequency not known (frequency cannnot be esti mated from available data)]

•    convulsions particularly in children

•    muscle twitching

•    fluid on the lungs

•    liverproblems

•    kidneyfailure

•    hypersensitivity reactions, which may cause skin rash, itching, shortness of breath, wheezing chest discomfort and swelling ofthe face.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet You can also report side effects directly via Yellow Card Scheme at: www.mhra.Qov.uk/vel lowcard.

By reporting side effects you can help provide more information

on the safety of th is medicine.

5.    HOW TO STORE SEVOFLURANE 100% INHALATION VAPOUR, UQUID

Keep out ofthe sight and reach of children.

Do not use Sevoflurane 100% Inhalation Vapour, liquid after the expiry date (MM-YYYY) which is stated on both the bottle label and carton. The expiry date refers to the last day of that month. The abbreviation, EXP is used for expiry date on the labels.

Do not store above 25'C.

Store the bottle in an upright position.

Once opened, the contents of the bottle should be used within 8 weeks.

Do not refrigerate.

Keep bottle cap tightly closed due to the volatile nature of the anaesthetic.

6.    CONTENTS OFTHE PACKAND OTHER INFORMATION What Sevoflurane 100%lnhalation Vapour, liquid contains:

Sevoflurane 100% In halation \fapour, liquid contains 100% ofthe active ingredient Sevoflurane.

What Sevoflurane 100% Inhalation Vapour, liquid looks like and contents of the pack:

Sevoflurane is a colourless liquid available in 250 ml amber

coloured glass bottles.

Marketing Authorisation Holder and Manufacturer Piramal Healthcare UK Limited

Whalton Road, Morpeth,

Northumberland, NE613YA, United Kingdom Tel: 00441670562400 Fax: 00441670562543 "This medicinal product Is authorised In the Member States of the EEA under the following names:"

Austria Sevofluran Piramal 100 % Flussigkeit zur Herstellung einesDampfeszur Inhalation

Belgium - Sevoflurane- Piramal Sevoflurane 100 % Inhalation Vapour, Liquid.

Bulgaria - Sevoflurane Piramal 100% Inhalation Vapour, liquid Cyprus - Sevoflurane- Piramal

Czech Republic - Sojourn 100% tekutina k pfipravS inhalace parau

Denmark-Sojourn TM

Estonia - Sevoflurane- Piramal, inhalatsrooniaur, vedelik 100% Finland - Sevoflurane Piramal 100 % inhalaatiohoyry, neste Germany - Sevofluran Piramal 100 % Flussigkett zur Herstellung eines Dampfazur Inhalation

Greece - Sojourn TM Sevoflurane 100% Inhalation Vbpour,

liquid

Hungary - Sevoflurane Piramal folyad£k inhafacids g5z k6pz6slhez

Iceland - Sevoflurane Piramal 100% innbndunargufa, vokvi Ireland-Sevoflurane 100% Inhalation Vapour, liquid Italy - Sevoflurane Piramal

Latvia - Sevoflurane Piramal 100 % Inhalation Vapour, liquid Lithuania - Sevoflurane Piramal 100% inhaliadniai garai skystis Luxemburg - Sevoflurane 100%

Malta - Sevoflurane 100% Inhalation Vapour, liquid Netherlands - Sevoflurane 100% (Piramal), Vloeistof voor inhalatiedamp

Nonray-Sevoflurane PiramalveBsketilinhalasjonsdamp Poland-Sojourn

Portugal - Sevoflurane Ojoum 100% llquido para inalagflo por vaporizagao

Romania - Sojourn lichid pentru vapori de inhalat.

Slovakia - Sevoflurane Piramal

Slovenia - Sevofluran Piramal 250 ml para za inhaliranje, tekocina

Spain - Sevoflurane Piramal 100% liquido para inhalation del vapor

Sweden - Sevoflurane Piramal inhalations&nga, vatska United Kingdom - Sevoflurane 100% Inhalation Vapour, liquid

This leaflet was last revised In:

01/2015

INFORMATION FOR THE HEALTHCARE PROFESSIONAL

Sevoflurane 100%

Inhalation Vapour, liquid

Sevoflurane

The complete SmPC will be supplied as a tear-off section ofthe extensia label / leaflet.

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Compound A was minimally nephrotoxic at concentrations of 50-114 ppm for 3 hours in a range of studies in rats.

The toxicity was characterised by sporadic single cell necrosis of the proximal tubule cells. The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established. Comparable human thresholds for Com pound A-related nephrotoxicity would be predicted to be 150-200 ppm.

The concentrations of Compound A found in routine clinical practice are on average 19 ppm in adults (maximum 32 ppm) with use of Soda lime as the C0₂ absorbent.

6. PHARMACEUTICAL PARTICULARS

6.1    List of Excipients

None.

6.2    Incompatibilities

Sevoflurane is stable when stored under normal room lighting conditions. No discernible degradation of sevoflurane occurs in the presence of strong adds 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 C0₂ absorbent within the anaesthesia machine. When used as directed with fresh absorbents, degradation of sevoflurane is minimal and degradants are undetectable or nontoxic.

Sevoflurane degradation and subsequent degradant formation are enhanced by increasing absorbent temperature, desiccated C0₂ 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 C0₂ absorbents and leads to the dissociation of sevoflurane into hexafluoroiso-propanol (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 Aand perhaps some of its degradants, Compounds B,C and D may occur.

6.3    Shelf-Life

5 years.

Once opened, the contents ofthe bottle should be used within 8 weeks.

6.4    Special precautions for storage

Do not store above 25®C. Do not refrigerate. Keep bottle cap tightly closed due to the volatile nature of the anaesthetic. Store the bottle In an upright position

6.5    Nature and contents of container

Type III, 250 ml amber coloured glass bottles with two component screw cap made up of outer black phenolic cover and inner translucent low density polyethylene cone. The pat* is provided with an LDPE yellow-coloured collar.

6.6    Special precautions for disposal

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 fill ing 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, C0₂ 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) C0₂ absorbent. If the C0₂ absorbent is suspected to be desiccated it should be replaced.

Only bottles without a pungent odour should be used.

In the event that a partially used bottle remains at the end ofthe procedure, the contents maybeusedforaperiodofupto8 weeks.

Any unused product or waste materialshouldbedisposedofin accordance with local requirements.

7.    MARKETING AUTHORISATION HOLDER

Piramal Healthcare UK Limited Whalton Road, Morpeth,

Northumberland NE613YA, United Kingdom Tel: 00441670562400 Fax:00441670562543

8.    MARKETING AUTHORISATION NUMBER(S):

PL29595/0002

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION:

09/2011/04/2015

10.    DATE OF REVISION OF THE TEXT:

06/02/2015

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