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SEVOFLURANE 100% INHALATION VAPOUR LIQUID
Active substance(s): SEVOFLURANE / SEVOFLURANE / SEVOFLURANE
Sevoflurane 100% Inhalation Vapour, liquid
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Excipient with known effect:
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 term 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
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 for Adults and Paediatric patients according to age
Age of Patient (years)
liquid in Oxygen
liquid in 65% N2O/35% O2
0 – 1 months*
1 - < 6 months
6 months - < 3 years
3 – 12
* Neonates are full term gestational age. MAC in premature infants has not been determined.
** In 1 – <3 year old paediatric patients, 60% N2O/40% O2 was used.
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 of anaesthesia is achieved.
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 of Anaesthesia
Surgical levels of anaesthesia may be maintained by inhalation of 0.5-3% sevoflurane in O2 with
or without concomitant use of N2 O.
Emergence times are generally short following Sevoflurane . anaesthesia. Therefore, patients
may require early post operative pain relief.
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.
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.)
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
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 (CO2.)
The concentration of sevoflurane being delivered from a vaporiser must be known exactly. As
volatile anaesthetics differ in their physical properties, only vaporisers 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.
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-acidbase 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.
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
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, very 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.
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 CO2 absorbent,
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 CO2 absorbent 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 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.
If a health care professional suspects that the CO2 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. CO2 absorbents should be replaced routinely regardless of the state of the
colour indicator (see Section 6.6).
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).
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).
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).
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.
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 arrhythmias has been established at 5 microgram per
There is a risk of acute hypertensive episode with the concomitant use of sevoflurane and
indirect-acting sympathomimetics products (amphetamines, ephedrine).
Sevoflurane may increase the negative inotropic, chronotropic and dromotropic effects of beta
blockers (by blocking cardiovascular compensatory mechanisms).
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.
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.
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 Blocking Agents
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 betablocker 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
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
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
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
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 of activities 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
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 adverse 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
System Organ Class
Immune system disorders
Anaphylactic reaction 1
Blood and lymphatic system
Nervous system disorders
Headache Convulsion 2, 3
See section 4.8 – Paediatric population.
There have been very rare post-marketing reports of cardiac arrest in the setting of
Occasional cases of transient changes in hepatic function tests were reported with
sevoflurane and reference agents.
Description of selected adverse reactions
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 within 48 hours to pre-operative levels. In clinical trials,
elevated fluoride concentrations were not associated with impairment of renal function.
Rare reports of post-operative hepatitis exist. In addition, there have been rare post-marketing
reports of hepatic failure and hepatic necrosis associated with the use of potent volatile
anaesthetic agents, including sevoflurane. However, the actual incidence and relationship of
sevoflurane to these events cannot be established with certainty (see section 4.4).
Rare reports of hypersensitivity (including contact dermatitis, rash, dyspnoea, wheezing, chest
discomfort, swelling face, eyelid edema, erythema, urticaria, pruritis bronchospasm,
anaphylactic or anaphylactoid reactions) have been received, particularly in association with
long-term occupational exposure to inhaled anaesthetic agents, including sevoflurane.
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 (see section 4.4).
The use of sevoflurane has been associated with seizures. Many of these have occurred in
children and young adults starting from 2 months of age, most of whom had no predisposing
risk factors. Several cases reported no concomitant medications, and at least one case was
confirmed by electroencephalography (EEG). Although many cases were single seizures that
resolved spontaneously or after treatment, cases of multiple seizures have also been reported.
Seizures have occurred during, or soon after Sevoflurane induction, during emergence, and
during post-operative recovery up to a day following anaesthesia. Clinical judgment should be
exercised when using sevoflurane in patients who may be at risk for seizures (see section 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card
Scheme at: Website: www.mhra.gov.uk/yellowcard
Symptoms of overdose include respiratory depression and circulatory insufficiency.
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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: anaesthetics, general; Halogenated hydrocarbons
ATC code: N01 AB08
Changes in the clinical effects of sevoflurane rapidly follow changes in the inspired
concentration. Sevoflurane is a halogenated methyl isopropyl ether inhalational anaesthetic
which produces a rapid induction and recovery phase. MAC (minimum alveolar concentration)
is age specific (see Section 4.2).
Sevoflurane produces loss of consciousness, reversible abolition of pain and motor activity,
diminution of autonomic reflexes, respiratory and cardiovascular depression. These effects are
SUMMARY OF PRODUCT CHARACTERISTICS
100% Inhalation Vapour, liquid
Respiratory, thoracic and
Increased intracranial pressure
Atrioventricular block complete,
Cardiac arrhythmias (including
Cardiac arrest 4
Torsades de pointes
INFORMATION FOR THE PATIENT
100% Inhalation Vapour, liquid
Read all of this leaflet carefully before you start using this medicine because
it contains important information for you..
- Keep this 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
in this leaflet, please tell your doctor 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
3. How Sevoflurane 100% Inhalation Vapour, liquid will be given
4. Possible side effects
5. How to store Sevoflurane 100% Inhalation Vapour, liquid
6. Contents of the pack and other 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 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
Metabolism And Nutrition
Renal and urinary disorders
Skin and subcutaneous
connective tissue disorders
General disorders and
administration site conditions
Hepatitis 1, 2
Hepatic failure 1, 2
Hepatic necrosis 1, 2
Dermatitis contact 1
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
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
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
you have previously had general anaesthetics, particularly if repeated over a
short period of time. You may have an increased risk of liver problems
Swelling face 1
Chest discomfort 1
Hyperthermia malignant 1, 2
Blood glucose abnormal
Liver function test abnormal 5
White blood cell count abnormal
Blood fluoride increased1
Serum Creatinine increased
Blood lactate dehydrogenase
Injury, poisoning and
See section 4.8 – Description of selected adverse reactions.
See section 4.4.
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) or weak
you have or previously had liver problems, e.g. hepatitis (inflamed liver) or
you suffer from a neuromuscular disease, particularly Duchenne muscular
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.
in the 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.
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 your anaesthetist, 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.
St John'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
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
isoniazid, used to treat tuberculosis (TB)
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
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
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
The following side effects are seri
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
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 (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.
Compound A: Compound A is a degradation product of sevoflurane, which is generated in CO2-
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
absorbents in the circuit) was 15 ppm in children and 32 ppm in adults. In systems using barium
lime as CO2 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
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
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(especiallypotassium hydroxide-containing, e.g.
Baralyme®), increased sevofluraneconcentration and decreased fresh gas flow. Sevoflurane
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10. DATE OF REVISION OF THE TEXT
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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 CO2absorbents and leads to the dissociation of
sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, nongenotoxic, 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 mayoccur.
6.3 Shelf life
Once opened, the contents of the bottle should be used within 8 weeks.
6.4 Special precautions for storage
Do not store above 25OC. 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.
Sevoflurane has a low blood/gas partition coefficient (0.65) leading to a rapid recovery from
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 CO2 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.
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, 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. 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
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Tel : 0044 1670562400 / Fax :0044 1670562543
48 mm x 54 mm
Keep out of the sight reach of children.
Once opened, the contents of the bottle
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Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.