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SUMMARY OF PRODUCT CHARACTERISTICS

Sevoflurane

100% Inhalation Vapour, liquid

1.    NAME OF THE MEDICINAL PRODUCT

Sevoflurane 100% Inhalation Vapour, liquid

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Sevoflurane 100%.

Excipient with known effect:

None

The finished product is comprised only of the active ingredient, see section 6.1.

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 teim neonates (see section 4.2 for age details).

4.2    Posology and method of administration

Premedication should be selected according to the need of the individual patient, and at the discretion of the Anaesthetist Surgical Anaesthesia:

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 with age 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.The table below indicates average MAC values for different age groups.

Table 1: MAC values forAdults and Paediatric patients according to age

Sevoflurane 100%

Inhalation Vapour, liquid in Oxygen

0    - 1 months*    3.3%

1    - < 6 months    3.0%

6 months - < 3 years    2.8%

3 - 12    2.5%

25    2.6%

40    2.1%

60    1.7%

80    1.4%

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

** In 1 - <3 year old paediatric patients, 60% N₂O/40% O₂was used.

Anaesthesia 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 sevofluranes.

Induction with sevoflurane may be achieved by inhalation of 0.5-1.0% sevoflurane in oxygen (O₂) with or without nitrous oxide (N₂ O), increasing by increments of 0.5-1.0% sevoflurane, to a maximum of 8% in adults and children until the required depth ofanaesthesia is achieved.

Age of Patient (years)

Sevoflurane 100% Inhalation Vapour, liquid in 65% N₂O/35% O₂

2.0%**

1.4%

1.1%

0.9%

0.7%

In adults inspired concentrations of up to 5% Sevoflurane usually produce surgical anaesthesia in less than 2 minutes. In children, inspired concentrations of up to 7% sevoflurane usually produce surgical anaesthesia in less than 2 minutes.

Maintenance ofAnaesthesia

Surgical levels of anaesthesia may be maintained by inhalation of 0.5-3% sevoflurane in O with or without concomitant use of N O.

Emergence:

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

Elderly people:

MAC decreases with increasing age. The average concentration of sevoflurane to achieve MAC in an 80 year old is approximately 50% of that required in a 20 year old.

Paediatric population:

Refer to Table 1 for MAC values for paediatric patients according to age when used in oxygen with or without concomitant use of nitrus oxide.

Method of Administration

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 or suspected hypersensitivity to

sevoflurane or other halogenated anaesthetics (e.g. history of liver function disorder, fever or leucocytosis of unknown cause after anaesthesia with one of these agents)..

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

Sevoflurane is contraindicated in patients in whom general anaesthesia is contraindicated. 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.

Sevoflurane should not be used in patients with a history of confirmed hepatitis due to a halogenated inhalational anesthetic or a history of unexplained moderate to severe hepatic dysfunction with jaundice, fever, and eosinophilia after anaesthesia with sevoflurane.

4.4 Special warning and precautions for use

Sevoflurane 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.

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. All patients anaesthetised with sevoflurane should be constantly monitored, including electrocardiogram (ECG), blood pressure (BP), oxygen saturation and end tidal carbon dioxide (CO.)

The concentration of sevoflurane being delivered from a vaporiser must be known exactly. As volatile anaesthetics differ in their physical properties, only vaporises specifically calibrated for sevoflurane must be used. The administration of general anaesthesia must be individualised based on the patient's response. Hypotension and respiratory depression increase as anaesthesia is deepened.

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. The clinical syndrome is signalled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnoea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anaesthesia, acute hypoxia, hypercapnia and hypovolaemia.

In clinical trials, one case of malignant hyperthermia was reported. In addition, there have been postmarketing reports of malignant hyperthermia. Some of these reports have been fatal. Treatment includes discontinuation of triggering agents (e.g. sevoflurane), administration of intravenous dantrolene sodium (consult prescribing information for intravenous dantrolene sodium for additional information on patient management), 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 abnormalities. 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 pediatric patients during the postoperative period.

Perioperative Hyperkalemia

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 consistent with myoglobinuria. Despite the similarity in presentation to

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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

Isolated reports of QT prolongation, vety rarely associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering sevoflurane to susceptible patients.

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

Caution should be exercised in administering general anaesthesia, including sevoflurane, to patients with mitochondrial disorders.

Hepatic

Very rare cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from postmarketing experiences.

Clinical judgment should be exercised when sevoflurane is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction. In patients who have experienced hepatic injury, jaundice, unexplained fever or eosinophilia after administration of other inhalation anaesthetics, it is recommended to avoid administration of sevoflurane if anaesthesia with intravenous medicinal products or regional anaesthesia is possible (see section 4.8).

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

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. Due to sevoflurane's insolubility in blood, hemodynamic changes may occur more rapidly than with some other volatile anaesthetics. Particular care must be taken when selecting the dosage for patients who are hypovolaemic, hypotensive, or otherwise hemodynamically compromised, e.g., due to concomitant medications.

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

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).

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. Although recovery of consciousness following sevoflurane administration generally occurs within minutes, the impact on intellectual function for two or three days following anaesthesia has not been studied. As with other anaesthetics, small changes in moods may persist for several days following administration (see section 4.7). Rapid emergence in children may be associated with agitation and lack of co-operation (in about 25% of cases).

Replacement of Desiccated CO₂ Absorbents;

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 CO₂absorbent, specifically those containing potassium hydroxide (e.g Baralyme). An unusually delayed rise or unexpected decline of inspired sevoflurane concentration compared to the vaporiser setting may be associated with excessive heating of the CO₂absorbent canister.

An exothermic reaction, enhanced sevoflurane degradation, and production of degradation products can occur when the 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 CO absortients 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.

If a health care professional suspects that the CO absorbent has become desiccated, it must be replaced before subsequent use of volatile anaesthetics (such as sevoflurane). It must be taken into account that the colour indicator does not always change after desiccation has taken place. Therefore, the lack of significant colour change should not be taken as an assurance of adequate hydration. CO absorbents should be replaced routinely regardless ofthe state ofthe colour indicator (see Section 6.6).

Renal Impairment:

Although data from controlled clinical studies at low flow rates are limited, findings taken from patient and animal studies suggest there is a potential for renal injury, which is presumed due to Compound A. Therefore, sevoflurane should be used with caution in patients with renal insufficiency. Animal and human studies demonstrate that sevoflurane administered for more than 2 MAC hours and at fresh gas flow rates of <2 L/min may be associated with proteinuria and glycosuria. Also see Section 5.1.

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. Consider all of the factors leading to Compound A exposure in humans, especially duration of exposure, fresh gas flow rate, and concentration of sevoflurane.

Inspired sevoflurane concentration and fresh gas flow rate should be adjusted to minimize exposure to Compound A. Sevoflurane exposure should not exceed 2 MAC hours at flow rates of 1 to <2 L/min. Fresh gas flow rates <1 L/min are not recommended.

The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established. (See Section 5.3, Preclinical Safety Data for further details.)

Sevoflurane should be administered with caution to patients with impaired renal function (GFR <60 ml/min); renal function should be monitored postoperatively.

Neurosurgery & Neuromuscular Impairment:

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). Seizures:

Rare cases of seizures have been reported in association with sevoflurane use.

Use of sevoflurane has been associated 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 for seizures (see section 4.4-Paediatric population).

Paediatric population:

The use of sevoflurane has been associated with seizures. Many have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors. Clinical judgment should be exercised when using sevoflurane in patients who may be at risk for seizures (see section 4.4 - Seizures).

Dystonic movements in children have been observed (see section 4.8).

Down syndrome

A significantly higher prevalence and degree of bradycardia has been reported in children with Down syndrome during and following sevoflurane induction. Experience with 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.

4.5 Interaction with other medicinal products and other forms of interaction Sevoflurane has been shown to be safe and effective when administered concurrently with a wide variety of agents commonly encountered in surgical situations such as central nervous system agents, autonomic drugs, skeletal muscle relaxants, anti-infective agents including aminoglycosides, hormones and synthetic substitutes, blood derivatives and cardiovascular drugs, including epinephrine.

Epinephrine/Adrenaline

Sevoflurane is similar to isoflurane in the sensitisation of the myocardium to the arrhythmogenic effect of exogenously administered adrenaline, the threshold dose of adrenaline producing multiple ventricular anhythmias has been established at 5 microgram per

^Kg.

Indirect-acting Sympathomimetics

There is a risk of acute hypertensive episode with the concomitant use of sevoflurane and indirect-acting sympathomimetics products (amphetamines, ephedrine).

Beta blockers

Sevoflurane may increase the negative inotropic, chronotropic and dromotropic effects of beta blockers (by blocking cardiovascular compensatory mechanisms).

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Verapamil

Impairment of atrioventricular conduction was observed when verapamil and sevoflurane were administered at the same time.

Inducers of CYP2E1

Medicinal products and compounds that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may increase the metabolism of sevoflurane and lead to significant increases in plasma fluoride concentrations. Concomitant use of sevoflurane and isoniazid can potentiate the hepatotoxic effects of isoniazid.

St John's Wort

Severe hypotension and delayed emergence from anaesthesia with halogenated inhalational anaesthetics have been reported in patients treated long-term with St John's Wort.

Barbiturates

Sevoflurane administration is compatible with barbiturates, propofol and other commonly used intravenous anaesthetics. Lower concentrations of sevoflurane may be required following use of an intravenous anaesthetic.

Benzodiazepines and Opioids

Benzodiazepines and opioids are expected to decrease the MAC of sevoflurane in the same manner as with other inhalational anaesthetics. Sevoflurane administration is compatible with benzodiazepines and opioids as commonly used in surgical practice.

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

Nitrous Oxide

As with other halogenated volatile anaesthetics, the MAC of sevoflurane is decreased when administered in combination with nitrous oxide. The MAC equivalent is reduced approximately 50% in adult and approximately 25% in paediatric patients (see section 4.2 - Maintenance). Neuromuscular BlockingAgents

As with other inhalational anaesthetic agents, sevoflurane affects both the intensity and duration of neuromuscular blockade by non-depolarising muscle relaxants. When used to supplement alfentanil-N₂O anaesthesia, sevoflurane potentiates neuromuscular block induced with pancuronium, vecuronium or atracurium. The dosage adjustments for these muscle relaxants when administered with sevoflurane are similar to those required with isoflurane. The effect of sevoflurane on succinylcholine and the duration of depolarising neuromuscular blockade has not been studied.

Dosage reduction of neuromuscular blocking agents during induction of anaesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation because potentiation of neuromuscular blocking agents is observed a few minutes after the beginning of sevoflurane administration.

Among non-depolarising agents, vecuronium, pancuronium and atracurium interactions have been studied. In the absence of specific guidelines: (1) for endotracheal intubation, do not reduce the dose of non-depolarising muscle relaxants; and, (2) during maintenance of anaesthesia, the dose of non-depolarising muscle relaxants is likely to be reduced compared to that during N₂O/opioid anaesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation.

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 intraoperative collapse cannot be excluded as this has been observed with other halogenated inhalational anaesthetic agents.

4.6 Fertility, pregnancy and lactation Pregnancy

Reproduction studies in rats and rabbits at doses up to 1 MAC have revealed no evidence of harm to the fetus due to sevoflurane. There are no adequate and well-controlled studies in pregnant women; therefore, sevoflurane should be used during pregnancy only if clearly

Labour and Delivery

In a clinical trial, the safety of sevoflurane was demonstrated for mothers and infants when used for anaesthesia during Caesarean section. The safety of sevoflurane in labour and vaginal delivery has not been demonstrated. Caution should be exercised in obstetric anesthesia due to the relaxant effect of sevoflurane on the uterus and increase in uterine hemorrhage.

Breastfeeding

It is not known whether sevoflurane or its metabolites are excreted in human milk. Caution

should be exercised when sevoflurane is administered to nursing mothers

Fertility

Reproduction studies in rats and rabbits at doses up to 1 MAC have revealed no evidence of impaired fertility due to sevoflurane.

Sevoflurane should only be used in pregnancy if clearly indicated.

The increased risk for uterus bleeding due to a relaxation effect of Sevoflurane on the uterus. Use during labour and delivery is limited to one small study in Caesarian section.

Animal studies indicate that sevoflurane is not teratogenic.

Reproduction studies in rats and rabbits (doses up to 1 MAC) showed no effect on male and female reproductive capability. No sign of fetal toxicity was seen in animal studies.

4.7    Effects on ability to drive and use machines

As with other agents, patients should be advised that performance ofactivities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, may be impaired for some time after general anaesthesia(see section 4.4).

Patients should not be allowed to drive for a suitable period after sevoflurane anaesthesia.

4.8    Undesirable effects Summary of the safety profile

As with all potent inhaled anaesthetics, sevoflurane may cause dose-dependent cardiorespiratory depression. Most adverse reactions are mild to moderate in severity and are transient in duration. Nausea and vomiting are commonly observed in the post-operative period, at a similar incidence to those found with other inhalation anaesthetics. These effects are common sequelae of surgery and general anaesthesia which may be due to the inhalational anaesthetic, other agents administered intra-operatively or post-operatively and to the patient's response to the surgical procedure. The most commonly reported adverse reactions 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. Tabulated summary of adverse reactions

Adverse event data are derived from controlled clinical trials conducted in the United States and Europe in over 3,200 patients. The type, severity and frequency of adverse events in sevoflurane patients were comparable to adverse events in patients treated with other inhalation anaesthetics.

The most frequent adverse events associated with sevoflurane overall were nausea (24%) and

vomiting (17%). Agitation occurred frequently in children (23%).

All Adverse reactions at least possibly relating to sevoflurane from clinical trials and postmarketing experience are presented in the following table by MedDRA System Organ Class, Preferred Term and frequency. The following frequency categories are used: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. Post-marketing adverse reactions are reported voluntarily from a population with an unknown rate of exposure. Therefore it is not possible to estimate the true incidence of advese events and the frequency is "unknown”. The type, severity and frequency of adverse reactions in sevoflurane patients in clinical trials were comparable to adverse reactions in reference-drug patients.

Adverse Reaction Data Derived From Clinical Trials and Post-marketing Experience Summary of Most Frequent Adverse Drug Reactions in sevoflurane Clinical Trials and Post-marketing Experience System Organ Class

Immune system disorders

disorders

Psychiatric disorders

Nervous system disorders

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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 start using this medicine because

’    it contains important information for you..

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

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

I - If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell yourdoctor or nurse.

What is in this leaflet:

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

2.    What you need to know before you are given Sevoflurane 100% Inhalation Vapour, liquid

3.    How Sevoflurane 100% Inhalation Vapour, liquid will be given I 4. Possible side effects

|    5. How to store Sevoflurane 100% Inhalation Vapour, liquid

I 6. Contents of the pack and other information

1. What sevoflurane 100% inhalation vapour, liquid is and what it is used for

I    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 for you 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). You must talk to a doctor if you do not feel better or if you feel worse. 2. What you need to know before you are given sevoflurane 100% inhalation vapour, liquid

Sevoflurane should be administered only by healthcare professionals appropriately trained in the administration of general anaesthesia under the supervision of or by an anaesthetist.

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

doctor if:You have been told previously that you should not receive general anaesthesia.

•    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.

•    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. Sevoflurane has sometimes been known to cause these.

•    there are medical reasons why you should not be given a general anaesthetic Warnings and precautions

Talk to your doctor before taking 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 risk of liver problems

I

•    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 or vomiting or Pompe's disease in children

•    you have a coronary artery disease

•    you are hypovolemic (reduced blood volume) orweak

•    you have or previously had liver problems, e.g. hepatitis (inflamed liver) or jaundice

•    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.

•    you have a mitochondrial disorder, which is a disorder that people may be born with and may affect special cells of the heart, brain, and kidney.

•    intie rare and unforeseen instance you develop malignant hyperthermia (a sudden and dangerously high increase in body temperature during or shortly after surgery). In this case your anaesthetist (doctor) will stop the administration of sevoflurane and you will be given a medicine to treat the malignant hyperthermia (known as dantrolene) and you will receive other supportive therapy. Fatal outcome of malignant hyperthermia has been reported with sevoflurane.

Children

•    you have Down syndrome

If any of the above apply to you check with your doctor, nurse or pharmacist. You

may need to be checked carefully and your treatment may be changed.

Other medicines and Sevoflurane 100% Inhalation Vapour, liquid

Tell your doctor if you are taking or have recently taken any of the following:

The medicines or active substances contained in the medicines listed below may

influence each other's effect when used together with Sevoflurane 100%

Inhalation Vapour, liquid. Some of these medicines are given to you during your

surgery by youranaesthetist, as indicated in the description.

•    Amphetamines (stimulants): used to treat attention-deficit hyperactivity disorder (ADHD) or narcolepsy)

•    medicines that affect the heart such as adrenaline or epinephrine

•    beta blockers (e.g. atenolol, propranolol): These are heart medicines often given to treat a high blood pressure.

•    Alcohol

•    Barbiturates (depressant)

•    StJohn's Wort (a herbal remedy used to help with depression)

•    Decongestants (ephedrine): used as a decongestant and commonly found in cough and cold medicines

•    Non-selective monoamine oxidase (MAO) inhibitors (a type of antidepressants)

•    Calcium antangonists

•    Verapamil: This is a heart medicine, and it is given to treat a high blood pressure or when you suffer from an irregular heart beat.

•    tranquillisers (benzodiazepines e.g. diazepam, lorazepam): These are sedative medicines, which have a calming effect. They are used when you feel nervous for instance before your surgery.

•    strong painkillers such as morphine or codeine

•    Non-depolarising muscle relaxants (e.g. vecuronium, pancuronium,

atracurium): These medicines are used during general anaesthesia to relax your muscles.

•    isoniazid, used to treat tuberculosis (TB)

•    isoprenaline

•    other anaesthetics, e.g. nitrous oxide: This is a medicine used during general anaesthesia that will cause you to sleep and will ease your pain propofol, opioids (e.g. alfentanil and sufentanil: These medicines are strong pain killers and are often used during general anaesthesia 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 medicines obtained without a prescription. This also applies to herbal medicinal products, vitamins and minerals.

Sevoflurane 100% Inhalation Vapour, liquid with food and drink Sevoflurane 100% Inhalation Vapour, liquid is a medicine to make and keep you asleep so you can undergo surgery. You should ask your doctor, surgeon or anaesthetist when and what you can eat or drink after you wake up.

Pregnancy and breast feeding

Tell your doctor or anaesthetist if you are pregnant or think you may be Pregnant or are breast feeding. You should not receive Sevoflurane 100%Inhalation Vapour, liquid if you are pregnant unless it is essential.

Driving and using machines

Sevoflurane 100% Inhalation Vapour, liquid severely influences your ability to drive and operate tools. Do not drive or operate tools or machines until your doctor tells you it is safe. Receiving an anaesthetic may influence your alertness for several days. This may affect your ability to carry out tasks that require mental alertness. Ask your anaesthetist when it will be safe for you to drive and use machines again.

3.    How sevoflurane 100% inhalation vapour, liquid will be given

Sevoflurane 100% Inhalation Vapour, liquid will be given by a trained anaesthetist in a surgery or hospital. The anaesthetist will decide how much Sevoflurane you need and when it is to be given. The dose will vary according to your age, weight, the type of surgery you need, and other medicines given to you during surgery. Sevoflurane 100% Inhalation Vapour, 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. Once the anaesthetist stops you from inhaling Sevoflurane you will wake up within a few minutes.

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

If you receive more Sevoflurane 100% Inhalation Vapour, liquid than you should

Sevoflurane 100% Inhalation Vapour, liquid will be given to you by a healthcare professional and it is not likely that you will receive too much Sevoflurane 100% Inhalation Vapour, liquid. If you are given too much Sevoflurane 100% Inhalation Vapour, liquid, your anaesthetist will take any necessary measures.

4.    Possible side effects

Like all medicines, Sevoflurane 100% Inhalation Vapour, liquid can cause side effects, although not everybody gets them. It is however, important to consult your ward doctor, nurse or anaesthetist if you are feeling unwell.

Serious rare side effects (can be life-threatening):

- anaphylaxis and anaphylactoid reactions (see not known side effects section for more information).

The following side effects are serious and you may need immediate medical

Page 5

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 in families.

•    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 musculardystrophy.

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

Very common side effects (may affect more than 1 in 10 people)

•    restlessness (agitation) in children

•    slow heart rate

•    lowblood pressure

•    coughing

•    nausea and vomiting.

Common side effects (may affect up to 1 in 10 people)

•    restlessness (agitation) in adults

•    headache

•    drowsiness

•    dizziness

•    fast heart rate

•    increased blood pressure

•    breathing disorder

•    airway obstruction

•    slow and shallow breathing

•    throat spasm, respiratory problems

•    mouth watering

•    hypothermia, chills

•    fever

abnormal blood sugar level, liver function test or white blood cell counts i.e. increased susceptibility to infections

•    increased blood fluoride.

Uncommon side effects (may affect up to 1 to 100 people)

The frequency should be changed from ''

•    confusion

•    abnormal heart rhythm and abnormal heart beats

•    AVblockade (a disorder of the electrical conduction of the heart)

•    asthma, stopping breathing, low oxygen levels

•    retention of urine, glucose in the urine

•    increased or decreased number of white blood cells

•    abnormal blood enzyme levels.

•    increased blood creatinine levels (an indicator of poor kidney function), as detected by a blood sample test.

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

•    fluid on the lungs

-    allergic reactions e.g.:

-    rash

- redness of the skin

dose-dependent.

Sevoflurane has a low blood/gas partition coefficient (0.65) leading to a rapid recovery from anaesthesia.

Cardiovascular Effects

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. Sevoflurane produces a sensitisation of the myocardium to the arrhythmogenic effect of exogenously administered epinephrine. This sensitisation is similar to that produced by isoflurane.

Nervous System Effects

In patients with normal intracranial pressure (ICP), sevoflurane had minimal effect on ICP and preserved CO responsiveness. The safety of sevoflurane has not been investigated in patients with a raised ICP. In patients at risk for elevations of ICP, sevoflurane should be administered cautiously in conjunction with ICP-reducing 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 metabolisedsevoflurane is defluorinated via cytochrome p450(CYP)2E1in the liver, 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 acid and excreted in the urine. The rapid and extensive pulmonary elimination of sevoflurane minimises the quantity available for metabolism.

The metabolism of sevoflurane may be increased by known inducers of CYP2E1 (e.g. isoniazid and alcohol), but it is not inducible by barbiturates.

8.    MARKETING AUTHORISATION NUMBER

PL 29595/0002

9.    DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION

30/09/2014

10.    DATE OF REVISION OF THE TEXT

04/2016

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urticaria (hives)

swollen eyelids, breathing difficulties

anaphylaxis and anaphylactoid reactions. These allergic reactions occur

quickly and can be life-threatening. Symptoms of anaphylaxis include:

angioedema (swelling of the skin of the face, limbs, lips, tongue or throat)

breathing difficulties

low blood pressure

urticaria (hives)

epilepsy-like fits

sudden twitching movements

cardiac arrest

cramping of the airways

difficulty in breathing orwheezing

breath holding

shortness of breath

reduced liver function or hepatitis (inflamed liver), characterised by e.g. loss of appetite, fever, nausea, vomiting, abdominal discomfort, jaundice and dark

dangerously raised body temperature chest discomfort

a rise in the pressure inside the skull irregular heart beat or palpitations inflammation of the pancreas

Increases in blood potassium levels as detected by a blood sample test muscle stiffness yellow-looking skin

-    inflammation of the kidneys (symptoms may include fever, confusion or sleepiness, rash, swelling, more or less urine than normal, and blood in the urine)

-    swelling

Sometimes seizures (fits) are seen. These can occur when receiving Sevoflurane 100% Inhalation Vapour, liquid, or up to a day later during recovery. They occur mostly in children and young adults.

In children with Down Syndrome who receive sevoflurane, a slowing of the heart rate can occur.

Levels of fluoride in the blood may be raised slightly during and immediately after anaesthesia, but these levels are not thought to be harmful and soon return to

If any of the side effects gets serious, or if you notice any side effects not listed in the leaflet, please tell your doctoror pharmacist.

If you notice any change in the way you feel after receiving sevoflurane, please inform your doctor or pharmacist. Some side effects may need treatment.

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.gov.ukvellowcard. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store sevoflurane 100% inhalation vapour, liquid Keep out of the 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 of the pack and other information

What Sevoflurane 100%Inhalation Vapour, liquid contains:

Sevoflurane 100%Inhalation Vapour, liquid contains 100% of the active ingredient Sevoflurane.

There are no other ingredients.

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 (with orwithout an outer PVC coating).

Marketing Authorisation Holder and Manufacturer Piramal Healthcare UK Limited Whalton Road, Morpeth, Northumberland,

NE61 3YA, United Kingdom.

Tel: 0044 1670562400 Fax: 0044 1670562604

'This medicinal product is authorised in the Member States of the EEA under the following names:"Austria Sevofluran Piramal 100 % Flussigkeit zur Herstellung eines Dampfes zur 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 prfprave inhalace parou Denmark - Sojourn TM

Estonia - Sevoflurane- Piramal, inhalatsiooniaur, vedelik 100%

Finland - Sevoflurane Piramal 100 % inhalaatiohoyry, neste

Germany - Sevofluran Piramal 100 % Flussigkeit zur Herstellung eines Dampfs

zur Inhalation

Greece - Sojourn TM Sevoflurane 100% Inhalation Vapour, liquid Hungary - Sevoflurane Piramal folyadek inhalacios goz kepzesehez Iceland - Sevoflurane Piramal 100% innondunargufa, vokvi Ireland - Sevoflurane 100% Inhalation Vapour, liquid Italy - Sevoflurane Piramal

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

Malta - Sevoflurane 100% Inhalation Vapour, liquid

Netherlands - Sevoflurane 100% (Piramal), Vloeistof voor inhalatiedamp

Norway - Sevoflurane Piramal v*ske til inhalasjonsdamp

Poland - Sojourn

Portugal - Sevoflurano Ojourn 100% liquido para inalacSo por vaporizacSo Romania - Sojourn lichid pentru vapori de inhalat.

Slovakia - Sevoflurane Piramal

Slovenia - Sevofluran Piramal 250 ml para za inhaliranje, tekocina Spain - Sevoflurano Piramal 100% dquido para inhalacion del vapor Sweden - Sevoflurane Piramal inhalationsanga, vatska United Kingdom - Sevoflurane 100% Inhalation Vapour, liquid This leaflet was last revised in: 04/2016

INFORMATION FOR THE HEALTHCARE PROFESSIONAL

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Transient increases in serum inorganic fluoride levels may occur during and after sevoflurane anaesthesia. Generally, concentrations of inorganic fluoride peak within 2 hours of the end of sevoflurane anaesthesia and return within 48 hours to pre-operative levels.

5.3 Preclinical safety data

Preclinical data on single and repeated dose toxicity of sevoflurane showed no specific organ toxicity.

Reproductive studies: Studies on fertility performed in rats indicated a decrease in implantation and pregnancy rates after repeated exposure to anaesthetic doses. Developmental toxicity studies performed in rats and rabbits did not reveal any teratogenic effect. In sub-anaesthetic concentrations during the perinatal phase rats showed a prolongation of gestation.

Extensive in-vitro and in-vivo mutagenicity studies with sevoflurane yielded negative results. Carcinogenicity studies were not performed.

Effects on circulatory function and oxygen consumption: The results of studies conducted in dogs indicate that sevoflurane does not cause any coronary steal syndrome and does not exacerbate a pre-existing myocardial ischaemia. Animal studies have shown that hepatic and renal circulation are well maintained with sevoflurane.

Sevoflurane decreases the cerebral metabolic rate for oxygen (CMRO) in a fashion analogous to that seen with isoflurane. An approximately 50% reduction of CMRO 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.

Compound A: CompoundA is a degradation product of sevoflurane, which is generated in CO-

absorbers. Its concentration increases normally with increasing absorber temperature, sevoflurane concentration and lowering of the fresh gas flow rate.

Studies performed in rats have shown a dose and duration of exposure dependent, reversible, nephrotoxicity (single cell necrosis of the proximal tubule cells). In the rat evidence for nephrotoxicity could be found at 25-50 ppm following 6 and 12 hours exposure. The relevance to humans is unknown.

In clinical studies the highest concentration of Compound A (using soda lime as CO2 absortients in the circuit) was 15 ppm in children and 32 ppm in adults. In systems using barium lime as CO absorbents concentrations of up to 61 ppm were found. Although the experience with low-flow anaesthesia is limited, to date there is no evidence of kidney impairment due to Compound A.

6. PHARMACEUTICAL PARTICULARS

6.1    List of excipients

6.2    Incompatibilities

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 COabsorbent 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 CO absorbent(especiallypotassium hydroxide-containing, e.g. Baralyme®), increased sevofluraneconcentration and decreased fresh gas flow. Sevoflurane

can undergo alkaline degradation by two pathways. The first results from the loss of hydrogen fluoridewith the formation of pentafluoroisopropanyl fluoromethyl ether (PIFE or morecommonly known as Compound A). The second pathwayfor degradation ofsevoflurane occurs only in the presence of desiccated COabsorbents 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 absortients, 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 mayoccur.

6.3    Shelf life

5 years

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

6.4    Special precautions forstorage

Do not store above 25^OC. Do not refrigerate. Keep 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 or without an external PVC coating) with two component screw cap made up of outer black phenolic cover and inner translucent low density polyethylene cone. The pack is provided with an LDPE yellow-coloured collar.

6.6 Special precautions for disposal and other handling

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, CO 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) CO absorbent.If the CO2 absorbent is suspected to be desiccated it should be replaced. Sevoflurane has been found to undergo degradation in the presence of strong Lewis acids that may be formed on metal or glass surfaces under harsh conditions, and the use of vaporisers that contain such strong Lewis acids, or that may form them under conditions of normal use, must be avoided. Only bottles without a pungent odour should be used. In the event that a partially used bottle remains at the end of the procedure, the contents may be used for a period of up to 8 weeks.

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

7. MARKETING AUTHORISATION HOLDER

Piramal Healthcare UK Limited Whalton Road, Morpeth,

Northumberland NE61 3YA, United Kingdom Tel : 0044 1670562400 / Fax :0044 1670562604

Page 7

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Do not store above 25°C.

Do not refrigerate.

Keep bottle cap tightly closed due to the volatile nature of the anaesthetic. Keep out of the sight reach of children. Once opened, the contents of the bottle should be used within 8 weeks.

Read the package Leaflet before use. Inhalation use.

Store the bottle in an upright position. PL 29595/0002

MA Holder:

Piramal Healthcare UK Limited

Whalton Road, Morpeth, Northumberland, NE 61 3YA United Kingdom

Tel.: 0044 1670562400 Fax: 0044 1670562543

250 ml e

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SEVOFLURANE

100% Inhalation Vapour, Liquid

' Piramal I Healthcare -

Contains Sevoflurane 100% Non flammable. Non explosive.

Page 8

Pantone 108 C Pantone 1595 C | Pantone Black C Pantone 425 C

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