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SEVOFLURANE BAXTER 100% INHALATION VAPOUR LIQUID

Active substance(s): SEVOFLURANE

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Warnings and precautions

What is in this leaflet:

Talk to your doctor or pharmacist before taking Sevoflurane Baxter if:
• you have previously been given an inhalation anaesthetic,
particularly if this was more than once over a short period of
time (repeated use).
• you have low blood pressure
• you are hypovolemic (reduced blood volume) or weak
• you have impaired kidney function
• you are pregnant or breastfeeding or when this medicinal
product is given for obstetrical anaesthesia (delivery of a baby)
(see also section entitled “Pregnancy and breastfeeding”)
• you have a coronary artery disease
• you have a risk of increased pressure within the brain
• you have or previously had liver problems, e.g. hepatitis
(inflamed liver) or jaundice
• you are being treated with a medicine that may cause liver
problems
• you are known to have or are at risk of developing convulsions
(seizures)
• 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 a neuromuscular disease e.g. Duchenne muscular
dystrophy.
• you have a disorder of the cells (a condition called
mitochondrial disorder)

1. What Sevoflurane Baxter is and what it is used for
2. What you need to know before you are given Sevoflurane
Baxter
3. How you will be given Sevoflurane Baxter
4. Possible side effects
5. How to store Sevoflurane Baxter
6. Contents of the pack and other information

1. What Sevoflurane Baxter is and what it is used for
Sevoflurane Baxter contains sevoflurane. Sevoflurane is a general
anaesthetic used in surgery in adults and children. It is an
inhalation anaesthetic (it is given to you as a vapour for you to
breathe in). Breathing in sevoflurane vapour causes you to fall into
a deep, painless sleep. It also maintains a deep, painless sleep
(general anaesthesia) during which you can undergo surgery.
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 Baxter
Sevoflurane should be administered only by healthcare
professionals appropriately trained in the administration of general
anaesthesia under the supervision of or by an anaesthetist.

Your anaesthetist (doctor) will not give you
Sevoflurane Baxter if:

Children

• you are allergic (hypersensitive) to sevoflurane or other
inhalation anaesthetics.
• you have a history of confirmed inflamed liver (hepatitis) due
to sevoflurane or other inhalation anaesthetics or you have a
history of unexplained liver problems with jaundice, fever, and
an increased number of a certain type of white blood cells.

• 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.

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DATE 16 Jan 2015
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If any of the above applies, please inform your anaesthetist (doctor)
before you are given this medicine.

Name

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or
pharmacist.
• If you get any side effects, talk to your doctor or pharmacist.
This includes any possible side effects not listed in this leaflet.
See section 4.

Country

• you have a known or suspected susceptibility to malignant
hyperthermia (a sudden and dangerously high increase in body
temperature during or shortly after surgery).
• there are medical reasons why you should not be given a
general anaesthetic.

RA TO APPROVE LAYOUT
AND FORMAT

Read all of this leaflet carefully before you start using this
medicine because it contains important information for you.

1st DRAFT

Active substance: sevoflurane

ARTWORK APPROVAL

Sevoflurane Baxter 100% Liquid Inhalation Vapour

EMEA ARTWORK DESIGN CENTRE

Package leaflet: Information for the user

Serious side effects (can be life-threatening)
• anaphylaxis and anaphylactoid reactions (see not known side
effects section for more information).
If these symptoms should occur whilst you are being given
Sevoflurane Baxter, your anaesthetist will take appropriate action.
Very common side effects (affects more than 1 user in 10)
• agitation (being restless and disturbed)
• slower heart rate
• low blood pressure
• cough
• nausea (feeling sick) and vomiting (being sick).

Sevoflurane Baxter with food and drink
Sevoflurane Baxter 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.

Common side effects (affects 1 to 10 users in 100)
• drowsiness or feeling very sleepy
• headache
• dizziness
• fast heart rate
• high blood pressure
• breathing disorder
• airway obstruction
• slow and shallow breathing
• throat cramping
• increased salivation
• fever
• chills
• increased or reduced number of white blood cells, which might
affect the immune system, i.e. increased susceptibility to
infections
• increased level of glucose (sugar) in the blood, as detected by a
blood sample test
• increases in liver enzymes, as detected by a blood sample test
• Increased level of fluoride in the blood, as detected by a blood
sample test
• reduced body temperature

Pregnancy, breast-feeding and fertility
If you are pregnant or breastfeeding, think you may be pregnant
or are planning to have a baby ask your doctor, surgeon or
anaesthetist for advice before this medicine is given to you.

Driving and using machines
Sevoflurane Baxter 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 you will be given Sevoflurane Baxter
Sevoflurane Baxter will be given to you by an anaesthetist. The
anaesthetist will decide on how much 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.
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Like all medicines, this medicine can cause side effects, although
not everybody gets them.
Most side effects are mild to moderate in their severity and are
brief but there may be some serious side effects.

Date:

4. Possible side effects

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

EMEA ARTWORK DESIGN CENTRE

If you receive more Sevoflurane Baxter than you
should

Date:

Your anaesthetist will decide when to stop giving you Sevoflurane
Baxter. You will then wake up in a few minutes.

Sign:

The medicines or active substances contained in the medicines
listed below may influence each other’s effect when used together
with Sevoflurane Baxter. Some of these medicines are given to
you during your surgery by your anaesthetist, as indicated in the
description.
• Nitrous oxide: This is a medicine used during general
anaesthesia that will cause you to sleep and will ease your pain.
• Opioids (e.g. morphine. fentanyl, remifentanil): These medicines
are strong pain killers and are often used during general
anaesthesia.
• Non-depolarising muscle relaxants (e.g. pancuronium,
atracurium): These medicines are used during general
anaesthesia to relax your muscles.
• 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.
• Adrenaline: This medicine is often used to treat allergic
reactions, but can also be used during general anaesthesia.
• 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.
• Beta-blockers (e.g. atenolol, propranolol): These are heart
medicines often given to treat a high blood pressure.
• Indirect sympathomimetic drugs e.g.: amphetamines (used
to treat attention-deficit hyperactivity disorder (ADHD) or
narcolepsy) or ephedrine (used as a decongestant and
commonly found in cough and cold medicines).
• Isoniazid: A medicine used to treat tuberculosis (TB).
• Alcohol.
• St John’s Wort: this is a herbal remedy used for depression.

Version: 01

Please inform your doctor, pharmacist, surgeon or anaesthetist
if you are taking, have recently taken or might take any other
medicines. This also applies to herbal medicinal products, vitamins
and minerals.

DATE 16 Jan 2015
PLANT APPROVAL
HALLE ONLY
N/A

Sevoflurane Baxter is produced from liquid sevoflurane in a
vaporiser, specifically designed for use with sevoflurane. You may
be asked to breathe the sevoflurane vapour through a mask to
make you asleep. You may also be given an injection of another
anaesthetic to make you sleep before being given Sevoflurane
Baxter through a mask or a tube in your throat.

1st DRAFT

Other medicines and Sevoflurane Baxter:

Do not use Sevoflurane Baxter after the expiry date that is printed
on the label. The expiry date refers to the last day of that month.
This medicine requires no special storage conditions.

6. Contents of the pack and other information

The active substance is sevoflurane 100% (250 ml in a 250 ml bottle).
There are no other ingredients.

What Sevoflurane Baxter looks like and contents of
the pack
Sevoflurane is a clear, colourless inhalation vapour, liquid.
It is supplied in 250 ml aluminium bottles with a protective lining
and a plastic screw-on cap.
Pack sizes of 1 and 6 bottles.
Not all pack sizes may be marketed.

MARKETING AUTHORISATION HOLDER AND MANUFACTURER
MARKETING AUTHORISATION HOLDER

Sometimes seizures (fits) are seen. These can occur when receiving
Sevoflurane Baxter, 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.

Baxter Healthcare Ltd
Caxton Way, Thetford
Norfolk IP24 3SE, UK.

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 normal.

Baxter SA,
Boulevard Rene Branquart 80,
B-7860 Lessines,
Belgium

MANUFACTURER

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

Baxter Manufacturing Sp. z o.o.,
42 B Wojciechowska Str.,
20-704 Lublin,
Poland
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1st DRAFT

Keep out of reach and sight of children.

What Sevoflurane Baxter contains

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5. How to store Sevoflurane Baxter

Date:

By reporting side effects you can help provide more information on
the safety of this medicine.

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Republic of Ireland:
Via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2;
Tel: +353 1 6764971;
Fax: +353 1 6762517;
Website: “http://www.hpra.ie”
E-mail: “mailto:medsafety@hpra.ie”

Not known (frequency cannot be estimated from the available
data)
• allergic reactions e.g.:
– rash
– redness of the skin
– urticaria (hives)
– itching
– 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 or wheezing
– 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 urine.
– 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

Version: 01

United Kingdom:
Via the Yellow Card Scheme at: “http://www.mhra.gov.uk/
yellowcard”

DATE 16 Jan 2015
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If you get any side effects, talk to your doctor or nurse. This
includes any possible side effects not listed in this leaflet. You can
also report side effects directly (see details below).

Name

Reporting of side effects

Uncommon side effects (affects 1 to 10 users in 1,000)
• confusion
• heart thumping or irregular heart beat
• AV blockade (a disorder of the electrical conduction of the heart)
• apnoea (when you stop breathing)
• asthma
• hypoxia (a low level of oxygen in the blood)
• increased blood creatinine levels (an indicator of poor kidney
function), as detected by a blood sample test.

Sevofluran Baxter Flüssigkeit zur Herstellung eines
Dampfs zur Inhalation

Greece

Sevoflurane Baxter

Hungary

Sevoflurane Baxter, folyadék inhalációs gőz
képzéséhez

Iceland

Sevofluran Baxter 100% innöndunargufa, vökvi

Ireland

Sevoflurane Baxter, 100%, inhalation vapour, liquid

Italy

Sevoflurane Baxter 100% Liquido per inalazione

Latvia

Sevoflurane Baxter 100% inhalācijas tvaiki, šķidrums

Lithuania

Sevoflurane Baxter 100% inhaliaciniai garai, skystis
Sevoflurane Baxter, vloeistof voor inhalatiedamp 100%

Netherlands
Norway

Sevofluran Baxter Væske Til Inhalasjonsdamp 100%
“Baxter”

Poland

Sevoflurane Baxter 100% płyn do
sporządzaniainhalacji parowej

Portugal

Sevoflurano Baxter

Romania
Slovenia

Sevofluran Baxter 100% lichid pentru vapori de
inhalat
Sevofluran Baxter 250 ml para za inhaliranje, tekočina

Slovak Republic

Sevoflurane Baxter

Spain

Sevoflurano 100% Baxter, Líquido para inhalación
del vapor

Sweden

Sevofluran Baxter, 100% inhalationsånga, vätska

United Kingdom

Sevoflurane Baxter 100% Inhalation Vapour, Liquid

Baxter is a trademark of Baxter International Inc.

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Germany

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Sevoflurane Baxter 1 ml/ml, Liquide pour Inhalation
par Vapeur

Date

Sevofluran Baxter 100%, inhalaatiohöyry, neste

France

Signature

Sevoflurane Baxter 100%

Finland

N/A

Sevofluran “Baxter”

Estonia

Name

Denmark

For information about Sevoflurane Baxter or to
request this leaflet in formats such as audio
or large print please contact the Marketing
Authorisation Holder:
Tel: +44 (0)1635 206345

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Sevoflurane Baxter

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Czech Republic

RA TO APPROVE LAYOUT
AND FORMAT

Sevoflurane Baxter 100%

1st DRAFT

Other sources of information

Bulgaria

ARTWORK APPROVAL

Sevoflurane Baxter 100%, liquide pour inhalation par
vapeur

Date:

This leaflet was last revised in January 2015.

Belgium

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Sevofluran “Baxter” Flüssigkeit zur Herstellung eines
Dampfs zur Inhalation

EMEA ARTWORK DESIGN CENTRE

Name

Austria

Date:

Member State

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For any information about this medicinal product,
please contact the local representative of the
Marketing Authorisation Holder.

Version: 01

This medicinal product is authorised in the Member
States of the EEA under the following names:

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 sevoflurane.
Induction with sevoflurane may be achieved by inhalation of 0.5 – 1.0% sevoflurane
in oxygen (O2) with or without nitrous oxide (N2O), 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 two minutes. In children, inspired concentrations of up to
7% sevoflurane usually produce surgical anaesthesia in less than two minutes.
Maintenance of anaesthesia
Surgical levels of anaesthesia may be maintained by inhalation of 0.5 – 3%
sevoflurane in O2 with or without concomitant use of N2O.
Table 1
MAC Values for Adults and Pediatric Patients According to Age
Age of Patient
(Years)

Sevoflurane
in Oxygen

Sevoflurane
in 65% N20/35% 02

0 – 1 months *

3.3%

1 – < 6 months

3.0%

6 months – < 3 years

2.8%

3 – 12

2.5%

25

2.6%

1.4%

40

2.1%

1.1%

60

1.7%

0.9%

80

1.4%

0.7%

2.0%@

* Neonates are full-term gestational age. MAC in premature infants has not
been determined.
@ In 1 – <3 year old pediatric patients, 60% N20/40% 02 was used.
Emergence
Emergence times are generally short following sevoflurane anesthesia. Therefore,
patients may require post-operative pain relief earlier.
Elderly
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 nitrous oxide.
4.3 Contraindications
Sevoflurane should not be used in patients with known or suspected hypersensitivity
to sevoflurane or to other halogenated anaesthetics (e. g. history of liver function
disorder, fever or leucocytosis of unknown cause after anesthesia with one of these
agents).

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Surgical anaesthesia
The concentration of sevoflurane being delivered from a vaporizer during
anaesthesia should be known. This may be accomplished by using a vaporizer
calibrated specifically for Sevoflurane.

Date

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 anaesthesiologist.

Signature

4.1 Therapeutic indications
Induction and maintenance of general anaesthesia in adults and children.

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4. CLINICAL PARTICULARS

Name

Inhalation vapour, liquid.
Clear, colourless liquid.

Country

4.4 Special warning and precautions for use
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 vaporizer must be known
exactly. As volatile anaesthetics differ in their physical properties, only vaporizers
specifically calibrated for sevoflurane must be used. The administration of general
anaesthesia must be individualized based on the patient’s response. Hypotension
and respiratory depression increase as anaesthesia is deepened.
During maintenance of anaesthesia, increasing the sevoflurane concentration
results in dose-dependent decreases in blood pressure. An excessive reduction in
blood pressure may be related to depth of anesthesia and in such instances may be
corrected by decreasing the inspired sevoflurane concentration. Due to sevoflurane’s
insolubility in blood, hemodynamic changes may occur more rapidly than with some
other volatile anaesthetics. Recovery from general anaesthesia should be assessed
carefully before patients are discharged from the post-anaesthesia care unit.
Emergence is generally rapid following sevoflurane anaesthesia; therefore, patients
may require early postoperative pain relief.
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).
Patients with coronary disease
As with all anaesthetics, maintenance of haemodynamic stability is important in
order to avoid myocardial ischaemia in patients with coronary artery disease.
Patients undergoing obstetrical procedures
Caution should be exercised in obstetric anaesthesia due to the relaxant effect of
sevoflurane on the uterus and increase in uterine haemorrhage (see Section 4.6).
Patients undergoing neurosurgical procedures
In patients at risk for elevations of ICP, sevoflurane should be administered
cautiously in conjunction with ICP-reducing maneuvers such as 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).
Patients with renal injury
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. 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.
The level of Compound A exposure at which clinical nephrotoxicity might be
expected to occur has not been established. 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.
Patients with renal impairment
Sevoflurane should be administered with caution to patients with impaired renal
function (serum creatinine ≥ 1.5 mg/dl or 135 micromol/l); renal function should be
monitored postoperatively.

3. PHARMACEUTICAL FORM

DATE 16 Jan 2015
PLANT APPROVAL
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Sevoflurane 100%
Excipient with known effect:
None
The medicinal product is comprised only of the active substance, see section 6.1.

RA TO APPROVE LAYOUT
AND FORMAT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1st DRAFT

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.
Sevoflurane should not be used in patients with known or suspected genetic
susceptibility to malignant hyperthermia.
Sevoflurane is contraindicated in patients in whom general anesthesia is
contraindicated.

Sevoflurane Baxter, 100%, inhalation vapour, liquid

ARTWORK APPROVAL

1. NAME OF THE MEDICINAL PRODUCT

EMEA ARTWORK DESIGN CENTRE

SUMMARY OF PRODUCT CHARACTERISTICS
for
Sevoflurane Baxter, 100%, Inhalation vapour, liquid

Benzodiazepines and opioids
Benzodiazepines and opiates are expected to decrease the MAC of sevoflurane
to the same manner as other inhaled anaesthetics. Sevoflurane administration
is compatible with benzodiazepines and opioids as commonly used in surgical
practice.
Opioids such as fentanyl, alfentanil and sufentail, when combined with sevoflurane,
may lead to a synergistic fall in heart rate, blood pressure and respiratory rate.

Replacement of dried-out CO2 absorbents
The exothermic reaction between sevoflurane and CO2 absorbent lime is reinforced
when the CO2 absorbent lime is dried out, e.g. after a longer period with current
of dry gas over the bottle with CO2 absorbent lime. Rare cases have been reported
of extreme heat, smoke and/or spontaneous fire from the anaesthesia vaporiser
during use of sevoflurane together with dried-out absorbent lime, specifically
those containing potassium hydroxide. An unexpected delay in increase of inspired
concentration of sevoflurane or an unexpected decrease of inspired concentration of
sevoflurane compared with the setting of the vaporiser may be a sign of overheating
of the CO2 absorbent lime bottle.
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 anesthesia
machine using desiccated CO2 absorbents and maximum sevoflurane concentrations
(8%) for extended periods of time (≥ 2 hours). Concentrations of formaldehyde
observed at the anesthesia 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 the treating physician suspects the CO2 absorbent lime to be dried-out, this
must be replaced before the administration of sevoflurane. The colour indicator on
most CO2 absorbent limes does not necessarily change when dried-out. Therefore
the absence of marked changed of colour should not be taken as a secure sign of
sufficient hydration. CO2 absorbents must be replaced regularly irrespective of the
colour indicator (see Section 6.6).

Beta blockers
Sevoflurane may increase the negative ionotropic, chronotropic and dromotropic
effects of beta blockers through blockade of cardiovascular compensation
mechanisms.
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 arrhythmias has been established at
5 microgram per Kg.
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.
Indirect-acting sympathomimetics
There is a risk of acute hypertensive episode with the concomitant use of
sevoflurane and indirect sympathomimetic medicinal products (amphetamines,
ephedrine).
Verapamil
Atrioventricular impairment of conduction was observed when verapamil and
sevoflurane were administered at the same time.
St John’s Wort
Severe hypotension and delayed emergence from anaesthesia with halogenated
inhalational anesthetics have been reported in patients treated long-term with St
John’s Wort.

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DATE 16 Jan 2015
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Neuromuscular blocking agents
As with other inhalational anesthetic agents, sevoflurane affects both the intensity
and duration of neuromuscular blockade by non-depolarizing muscle relaxants.
When used to supplement alfentanil-N2O anesthesia, 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 depolarizing neuromuscular blockade has not
been studied.
Dosage reduction of neuromuscular blocking agents during induction of anesthesia
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-depolarizing 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-depolarizing muscle
relaxants; and, (2) during maintenance of anesthesia, the dose of non-depolarizing
muscle relaxants is likely to be reduced compared to that during N2O/opioid
anesthesia. Administration of supplemental doses of muscle relaxants should be
guided by the response to nerve stimulation.

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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. Rare cases of malignant
hyperthermia have been reported with the use of sevoflurane (see also section 4.8).
The clinical syndrome is signalled by hypercapnia, and may include muscle rigidity,
tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure.
Some of these nonspecific signs may also appear during light anesthesia, acute
hypoxia, hypercapnia and hypovolemia. Fatal outcome of malignant hyperthermia
has been reported with sevoflurane. Treatment includes discontinuation of triggering
agents (e.g. sevoflurane), administration of intravenous dantrolene sodium, and
application of supportive therapy. Renal failure may appear later, and urine
production 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.
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 hyperkalemia and resistant
arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular
disease.

RA TO APPROVE LAYOUT
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Nitrous oxide
As with other halogenated volatile anesthetics, 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 pediatric patients
(see section 4.2 – Maintenance).

1st DRAFT

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.

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

EMEA ARTWORK DESIGN CENTRE

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).
Rapid emergence in children may briefly evoke a state of agitation and hinder
cooperation (in about 25% of anaesthetised children). Isolated cases of ventricular
arrhythmia were reported in paediatric patients with Pompe’s disease.
Dystonic movements, which disappear without treatment, are seen in children who
have received sevoflurane for anaesthesia induction. The relationship to sevoflurane
is uncertain.

Patients with liver disease
Very rare cases of mild, moderate or serious post-operative liver dysfunction
or hepatitis (with or without jaundice) have been reported from post marketing
experience. Clinical judgement should be exercised when sevoflurane is used in
patients with underlying liver problems or those who are receiving treatment with
medications known to cause liver 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 mitochondrial disorders
Caution should be exercised in administering general anesthesia, including
sevoflurane, to patients with mitochondrial disorders.
Patient circumstances that warrant consideration
Particular care must be taken when selecting the dosage for hypovolaemic,
hypotensive, weakened patients or otherwise hemodynamically compromised,
e.g., due to concomitant medications.
Patients with repeated exposures to halogenated hydrocarbons, including
sevoflurane, within a relatively short interval may have an increased risk of hepatic
injury.
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.

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

Metabolism And Nutrition
Disorders
Musculoskeletal
connective tissue and
bone disorders
Hepato-biliary disorders

4.7 Effects on ability to drive and use machines
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 anesthesia (see section 4.4). Patients should not drive
following sevoflurane anaesthesia for a period determined by the anaesthetist.
4.8 Undesirable effects
Summary of the safety profile
As with all potent inhalational anaesthetics, sevoflurane can produce dosedependent cardiac respiratory depression. Most of the adverse reactions are mild
to moderate in severity and transient in duration. Nausea and vomiting have been
reported in the post-operative period – common symptoms following surgery and
general anaesthesia – which may be due to the inhalational anaesthetic, other
agents administered intra-operatively or post-operatively, or the patient’s reaction 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
All reactions, at least possibly related to sevoflurane from clinical trials and postmarketing experience, are displayed in the Table below by MedDRA System Organ
Class, Preferred Term and frequency. The following frequency groupings are used:
very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1,000 and
<1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000), including isolated
reports. 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

Frequency

Psychiatric disorders

Very Common
Uncommon

Confusion

Nervous system disorders Common
Unknown

Cardiac disorders

Very Common
Common

Unknown

Muscle rigidity

Unknown

Hepatitis 1 2
Hepatic failure 1 2
Hepatic necrosis 1 2
Jaundice
Tubulointerstitial nephritis

Renal and Urinary
Disorders
Skin and subcutaneous
tissue disorders

Unknown

General disorders and
administration site
conditions

Common

Investigations

Injury, poisoning and
procedural complications

Unknown

Dermatitis contact 1
Pruritus
Rash 1
Swelling face 1
Urticaria
Chills
Pyrexia

Uncommon

Chest discomfort 1
Hyperthermia malignant 1 2
Edema
Blood glucose abnormal
Liver function test abnormal 5
White blood cell count abnormal
Blood fluoride increased1
Serum Creatinine increased

Common

Hypothermia

Common

1
2
3
4

See section 4.8 – Description of selected adverse reactions.
See section 4.4.
See section 4.8 – Paediatric population.
There have been very rare postmarketing reports of cardiac arrest in the setting
of sevoflurane use.
5 Occasional cases of transient changes in hepatic function tests were reported
with sevoflurane and reference agents.

Adverse Reactions
Anaphylactic reaction 1
Anaphylactoid reaction
Hypersensitivity 1
Agitation

Immune system disorders Unknown

Common
Unknown
Unknown

Nausea
Vomiting
Salivary hypersecretion
Pancreatitis
Hyperkalemia

Unknown

Summary of Most Frequent Adverse Drug Reactions in Sevoflurane Clinical Trials
and Post-marketing Experience
System Organ Class

Very Common

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.

Somnolence
Dizziness
Headache
Convulsion 2 3
Dystonia
Increased intracranial pressure
Bradycardia
Tachycardia

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).

Uncommon

Atrioventricular block complete,
Cardiac arrhythmias (including
ventricular arrhythmias), atrial
fibrillation, extrasystoles (ventricular,
supra-ventricular, bigeminy-linked),

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 reported
particularly in association with long-term occupational exposure to inhaled
anaesthetic agents, including sevoflurane.

Unknown

Cardiac arrest 4
Ventricular fibrillation
Torsades de pointes
Ventricular tachycardia,
Electrocardiogram QT prolonged

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).

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Gastrointestinal disorders

N/A

Breastfeeding
It is not known whether sevoflurane is excreted in human milk. Caution should be
exercised when sevoflurane is administered to a nursing woman.

Date

Unknown

Signature

Uncommon

Labour and delivery
In a clinical trial, the safety of sevoflurane was demonstrated for mothers and
infants when used for anesthesia during Cesarean section. The safety of sevoflurane
in labor 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.

N/A

Respiratory disorder
Respiratory depression
Laryngospasm
Airway obstruction
Apnoea
Asthma
Hypoxia
Bronchospasm
Dyspnoea 1
Wheezing 1
Breath holding

Name

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 wellcontrolled studies in pregnant women; therefore, sevoflurane should be used during
pregnancy only if clearly needed.

Country

Common

Respiratory, thoracic and
mediastinal disorders

4.6 Fertility, pregnancy and lactation

DATE 16 Jan 2015
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Hypotension
Hypertension
Cough

RA TO APPROVE LAYOUT
AND FORMAT

Adverse Reactions

Very Common
Common
Very Common

1st DRAFT

Frequency

Vascular disorders

ARTWORK APPROVAL

System Organ Class

EMEA ARTWORK DESIGN CENTRE

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.

5. PHARMACOLOGICAL PROPERTIES

6.3 Shelf life
2 years.

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anaesthetics, general; halogenated hydrocarbons.
ATC code: N 01 AB 08
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 dose-dependent.
Sevoflurane has a low blood/gas partition coefficient (0.65) leading to a rapid
recovery from anaesthesia.
Cardiovascular effects: Sevoflurane may produce concentration-related decrease
of blood pressure. Sevoflurane produces a sensitisation of the myocardium to the
arrhythmogenic effect of exogenously administered epinephrine. This sensitisation is
similar to that produced by isoflurane.

6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and content of container
250 ml aluminium bottles, lined with an internal epoxyphenolic resin protective
lacquer, and plastic screw-on caps with a polytetraflurorethylene (PTFE) laminate
inner liner.
Pack sizes of 1 and 6 bottles.
Not all pack sizes may be marketed.
6.6 Instructions for use and handling
Sevoflurane should be administered with a vaporiser calibrated specifically for
sevoflurane and with the use of a filling system with a key which is designed for the
sevoflurane special vaporiser or other filling systems suitable for the sevoflurane
special vaporiser. Only vaporisers demonstrated to be compatible with this medicinal
product should be used for administration. 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.
Carbon dioxide absorbents should not be allowed to dry out when inhalational
anaesthetics are being administered. If the CO2 absorbent is suspected to be
desiccated it should be replaced.

5.2 Pharmacokinetic properties
Sevoflurane is weakly soluble in blood and tissue, resulting in the rapid achievement
of a sufficient alveolar concentration to produce anaesthesia and a subsequent rapid
elimination until cessation of anaesthesia.
In humans, < 5% of sevoflurane absorbed is metabolised in the liver to
hexafluoroisopropanol (HFIP) with release of inorganic fluoride and carbon dioxide
(or a one carbon fragment). Once formed, HFIP is rapidly conjugated with glucuronic
acid and eliminated in the urine.
The rapid and extensive pulmonary elimination of sevoflurane minimises the
quantity available for metabolism. The metabolism of sevoflurane is not induced by
barbiturates.

7. MARKETING AUTHORISATION HOLDER
Baxter Healthcare Ltd
Caxton Way
Thetford
Norfolk
IP24 3SE
United Kingdom

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 liver and kidney
circulation is maintained well 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.

8. MARKETING AUTHORISATION NUMBER
PL 00116/0420
PA 167/140/1

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
UK – Date of first authorisation: 21st October 2009
Ireland – Date of first authorisation: 21st May 2010

10. DATE OF REVISION OF THE TEXT
May 2014
Baxter is a trademark of Baxter International Inc.

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Signature

Date

DATE 16 Jan 2015
PLANT APPROVAL
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N/A

Name

4.9 Overdose
Symptoms of overdose include respiratory depression and circulatory insufficiency.
In the event of apparent overdosage the following action should be taken:
Sevoflurane administration should be discontinued and supportive measures
provided: the patient’s airway should be maintained and artificial or controlled
ventilation with pure oxygen should be instituted, along with measures to maintain
stable cardiovascular function.

Country

6.2 Incompatibilities
In the clinical setting, through direct contact with CO2 absorbents (Soda lime
and barium hydroxide lime), sevoflurane can degrade producing low levels of
Compound A (pentafluoroisopropenyl fluoromethyl ether (PIFE)), and trace amounts
of Compound B (pentfluoromethoxy isopropyl fluoromethyl ether (PMFE)). The
interaction with CO2 absorbents is not unique to sevoflurane. The production of
degradants in the anaesthesia circuit results from the extraction of the acidic
proton in the presence of a strong base (potassium hydroxide (KOH) and/or sodium
hydroxide (NaOH)) forming an alkene (Compound A) from sevoflurane. No dose
adjustment or change in clinical practice is necessary when rebreathing circuits are
used.
Higher levels of Compound A are obtained when using barium hydroxide lime rather
than soda lime.

RA TO APPROVE LAYOUT
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6.1 List of excipients
None

1st DRAFT

6. PHARMACEUTICAL PARTICULARS

ARTWORK APPROVAL

Effects of sevoflurane on the central nervous system: 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 Compound A.

EMEA ARTWORK DESIGN CENTRE

Paediatric population
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 the Yellow Card Scheme.
Website: www.mhra.gov.uk/yellowcard
FREEPOST
Pharmacovigilance Section
Irish Medicines Board
Kevin O’Malley House
Earlsfort Centre
Earlsfort Terrace
Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie

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Source: Medicines and Healthcare Products Regulatory Agency

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.

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