Sevorane

Package leaflet: Information for the user

SEVORANE 250 ml solution for inhalation

Sevoflurane
Please read this leaflet carefully before this medicine is administered to you because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you get any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet:

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

1. What Sevorane is and what it is used for

Sevorane contains the active substance sevoflurane. Sevoflurane is a general anaesthetic used in surgery, administered as an inhaled vapour.
Sevorane is indicated in adults and children to induce and maintain general anaesthesia (a state of deep sleep without perception of pain) during surgical procedures.

2. What you should know before Sevorane is administered to you

Sevorane must not be administered to you/the child

• If you/the child are allergic to sevoflurane and/or to other inhaled anesthetics similar to sevoflurane (e.g., if you/the child have experienced reactions after anesthesia with one of these medicines such as: liver problems with increased liver enzymes, fever, increased number of a type of white blood cells).
• If you/the child know or suspect having a predisposition to a condition called malignant hyperthermia (a sudden and dangerously high increase in body temperature during or immediately after surgery) (see section 4 “Possible side effects”).
• If there are medical reasons why you/the child should not undergo general anesthesia.

Warnings and precautions
This medicine will be administered only under strict supervision by qualified medical personnel (anesthesiologist).
Contact your doctor or nurse before Sevorane is administered if:

• you/the child suffer from a rare inherited disease causing progressive muscle weakness (Pompe disease),
• you/the child have a cellular disorder known as mitochondrial disorder,
• you/the child have or have had liver problems, for example hepatitis (liver inflammation), with or without yellowing of the skin (jaundice),
• you/the child are taking medicines that may cause liver problems (see section “Other medicines and Sevorane”),
• you/the child have been administered sevoflurane or an inhaled anesthetic belonging to the same group more than once within a short time interval (less than 3 months),
• you/the child suffer from a disease affecting nerves and muscles (particularly Duchenne muscular dystrophy),
• you/the child have reduced blood volume (hypovolemia),
• you/the child have low blood pressure (hypotension),
• you/the child suffer from circulatory disorders,
• you/the child suffer from coronary artery disease,
• you/the child have reduced kidney function,
• you/the child are at risk of developing increased pressure in the brain,
• you/the child are at risk of experiencing seizures (violent, uncontrolled contractions of body muscles) (see section “Children and adolescents” and section 4 “Possible side effects”),
• you are pregnant, breastfeeding, or if this medicine is to be administered during childbirth (see section “Pregnancy, breastfeeding and fertility”).

The doctor (the anesthesiologist) will discontinue sevoflurane administration and initiate supportive therapy if you/the child develop malignant hyperthermia (see section 4 “Possible side effects”).
Children
The use of sevoflurane has been associated with seizures in children (from 2 months of age) and adolescents; therefore, the doctor must exercise particular caution when using this medicine.
Other medicines and Sevorane
Inform your doctor/the anesthesiologist if you/the child are taking, have recently taken, or might take any other medicines.
Some medicines may interact when used together with Sevorane.
In particular:

• medicines acting primarily on the sympathetic nervous system, the system controlling internal organs (mainly circulation and heart), such as amphetamines, ephedrine, adrenaline, noradrenaline, epinephrine, isoprenaline. If you/the child are scheduled for surgery, your doctor may ask you to stop treatment with these medicines a few days before the procedure;
• medicines used to treat depression (non-selective monoamine oxidase inhibitors, MAOIs). If you/the child are scheduled for surgery, your doctor may ask you to stop treatment two weeks before;
• St. John’s wort, a herbal remedy used to treat depression;
• medicines with strong pain-relieving properties (opioids), such as alfentanil and sufentanil;
• calcium antagonists, verapamil, and beta-blockers (medicines acting on the heart), usually administered to treat high blood pressure or irregular heartbeat;
• isoniazid, a medicine used in the treatment of certain infections. If you/the child are scheduled for surgery, your doctor may ask you to stop treatment one week before and not restart until 15 days after;
• other medicines or substances (including alcohol) that increase the activity of a specific liver enzyme, the CYP2E1 isoenzyme of cytochrome P450;
• other medicines used during general anesthesia (e.g., vecuronium, pancuronium, atracurium, succinylcholine, nitrous oxide, halogenated inhaled anesthetics).

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor before this medicine is administered to you.
Pregnancy
Data on the use of sevoflurane in pregnant women are lacking or limited in number.
Animal studies have shown reproductive toxicity.
Sevorane should be used during pregnancy only if strictly necessary. The doctor (the anesthesiologist) will exercise particular caution when using sevoflurane during obstetric anesthesia.
Breastfeeding
It is not known whether sevoflurane is excreted in human breast milk.
The doctor (the anesthesiologist) will exercise particular caution when administering Sevorane to breastfeeding women.
Fertility
Animal studies have not shown any adverse effects on fertility.
Driving and using machines
After general anesthesia, the ability to drive vehicles (including bicycles) and use machinery may be impaired for a certain period. This means that until the doctor considers that you/the child have fully recovered your reaction capabilities, you/the child must not drive vehicles or operate machinery after surgery.
The doctor will assess whether you/the child should be accompanied when leaving the hospital.

3. How to use Sevorane

This medicine will only be administered under the close supervision of qualified medical personnel.
The appropriate dose for you/for the child will be determined by the anaesthetist (the doctor administering the anaesthesia), based on age, body weight, and general health status. The doctor will administer the correct dose of Sevorane to induce and maintain anaesthesia or to achieve the desired level of sedation, carefully monitoring your/your child's response and vital signs (pulse, respiration, blood pressure, etc.).

Use in children and adolescents
The dose will be determined by the anaesthetist based on the child's age and body weight.

Method of administration
Sevorane will be administered to you by inhalation.

If you are elderly or debilitated, or have heart and/or circulatory problems, kidney, liver problems, or are in a condition where you have reduced blood volume (hypovolaemia), your doctor/anaesthetist will consider whether an adjustment of the Sevorane dose is necessary.

If more Sevorane is administered than intended
It is highly unlikely that an excessive dose of Sevorane will be administered, as your doctor will closely monitor you during treatment.
However, if an overdose of Sevorane is administered, the doctor will provide appropriate supportive therapy.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
During administration of Sevorane, the following serious side effects may occur; in such cases, the doctor will immediately initiate appropriate treatment:

• effects on the heart (abnormal heart rhythms)
• malignant hyperthermia (a sudden and dangerously high increase in body temperature during or immediately after surgery). In this case, the doctor/anaesthetist will stop administration of sevoflurane and start suitable therapy (see section “Warnings and precautions”)
• allergic reactions which may include:
• difficulty breathing (dyspnoea)
• anaphylactic reaction
• wheezing during breathing (wheeze)
• skin rash (rash)
• skin inflammation (contact dermatitis)
• swelling and pain in the face (facial oedema)
• chest discomfort
• increased levels of potassium in the blood (hyperkalaemia), which may cause abnormal heart rhythms and can be fatal in children in the period following surgery.

The following are possible side effects reported by frequency that may occur with this medicine:
Very common (may affect more than 1 in 10 people)

• agitation
• slowing of the heartbeat (bradycardia)
• low blood pressure (hypotension)
• cough
• nausea, vomiting

Common (may affect up to 1 in 10 people)

• drowsiness, dizziness, headache
• fast heartbeat (tachycardia)
• high blood pressure (hypertension)
• breathing problems, contraction of throat muscles (laryngospasm)
• increased salivation (hypersalivation)
• chills, increased body temperature (pyrexia)
• abnormal results in certain laboratory tests: abnormal blood glucose levels, abnormal liver function tests, abnormal count of a type of blood cell (white blood cells), increased fluoride levels in the blood
• decreased body temperature (hypothermia)

Uncommon (may affect up to 1 in 100 people)

• complete block of heart contractions (complete atrioventricular block)

Not known (frequency cannot be estimated from the available data)

• uncontrolled body muscle movements (convulsions), especially in children from 2 months of age
• altered body movements (dystonia)
• cessation of heartbeat
• contraction of the bronchial muscles (bronchospasm)
• liver disorders (hepatitis, liver failure, hepatic necrosis)
• hives, itching

Reporting of side effects
If you/your child experience any side effects, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Sevorane

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the container after Exp. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Sevorane contains
The active substance is sevoflurane.
The medicine does not contain any other components.

Description of the appearance of Sevorane and contents of the pack
Sevorane is a clear, colourless liquid supplied in 250 ml bottles made of polyethylene naphthalate (PEN).
This medicine is available in the following pack sizes:

• 250 ml bottle with Pilfer Proof cap
• 250 ml Quik Fil bottle

Not all pack sizes may be marketed.

Marketing Authorisation Holder
AbbVie S.r.l.,
S.R. 148 Pontina km 52, snc
04011 Campoverde di Aprilia (LT)

Manufacturer
Aesica Queenborough Limited
Queenborough
Kent ME11 5EL
United Kingdom
AbbVie S.r.l.,
S.R. 148 Pontina km 52, snc
04011 Campoverde di Aprilia (LT)

The following information is intended exclusively for physicians or healthcare professionals:
This section contains practical information regarding administration. Please refer to the Summary of
Product Characteristics for complete information on dosage, method of administration, contraindications,
warnings, etc.

DOSAGE AND METHOD OF ADMINISTRATION

Premedication
Premedication should be administered according to the patient's characteristics and at the discretion of the anaesthesiologist.

Surgical anaesthesia
Sevorane must only be used with a vaporizer specifically calibrated for its use, in order to accurately control the concentration of inspired anaesthetic agent.

Induction
Dosage should be individualised and titrated according to the desired effect, as well as the patient's age and clinical condition. Induction may be performed with an intravenous short-acting barbiturate or another intravenous agent, followed by inhalation of Sevorane.

Induction with Sevorane can be carried out using oxygen alone or a mixture of oxygen and nitrous oxide. In adult patients and children, administration of Sevorane at concentrations up to 8% generally induces anaesthesia within less than two minutes.

Maintenance
Maintenance of surgical anaesthesia is achieved with Sevorane concentrations of 0.5–3%, with or without concomitant administration of nitrous oxide (see section "Other medicines and sevoflurane", Nitrous oxide).

In elderly patients, as with other inhaled anaesthetics, maintenance is usually achieved at lower concentrations.

The minimum alveolar concentration (MAC) should be evaluated for adult and paediatric patients according to age.

The MAC values (Minimum Alveolar Concentration) of sevoflurane decrease with age and with concomitant administration of nitrous oxide. The following table shows the average MAC values for different age groups.

Wake-up
Recovery times are generally short, which may necessitate the use of analgesics in the postoperative period.

Elderly
Minimum alveolar concentration (MAC) decreases with increasing age.
The average sevoflurane concentration required to achieve MAC in an 80-year-old patient is approximately half that required in a 20-year-old patient.

Paediatric population
Refer to Table 1 for MAC values in paediatric patients according to age.

INCOMPATIBILITIES

Degradation of sevoflurane
Sevoflurane is stable when stored under normal light conditions. No significant degradation of sevoflurane is detected in the presence of strong acids or heat. Sevoflurane is not corrosive toward stainless steel, brass, aluminium, nickel-coated brass, chrome-plated brass, or beryllium-copper alloy.

Chemical degradation may occur when inhaled anaesthetics come into contact with CO₂ absorbents within the anaesthesia machine. When used directly with fresh absorbents, degradation of sevoflurane is minimal and resulting degradation products are neither detectable nor toxic. Degradation of sevoflurane and the formation of related products increase with rising absorbent temperature, when the CO₂ absorbent is dehydrated (especially those containing potassium hydroxide), with increasing sevoflurane concentration, and with reduced fresh gas flow.

Sevoflurane may undergo alkaline degradation via two pathways. The first involves the loss of hydrogen fluoride, leading to the formation of pentafluoroisopropyl fluoromethyl ether (PIFE), more commonly known as Compound A. The second degradation pathway occurs only in the presence of dehydrated CO₂ absorbents and results in the dissociation of sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP has toxicity comparable to that of sevoflurane, is pharmacologically inactive, non-genotoxic, and is rapidly glucuronidated and eliminated. Formaldehyde is normally present in metabolic processes. Following exposure to a highly dehydrated absorbent, formaldehyde may be further degraded to methanol and formate.

Formate may contribute to the formation of carbon monoxide in the presence of high temperatures. Methanol may react with Compound A to form methoxylated Compound B. Compound B may then undergo further loss of hydrogen fluoride, forming Compounds C, D, and E. The formation of formaldehyde, methanol, carbon monoxide, Compound A, and possibly some of its degradation products (Compounds B, C, and D) may occur in the presence of highly dehydrated CO₂ absorbents, particularly those containing potassium hydroxide.

Degradation by Lewis acids
The presence of small amounts of water (at least 300 ppm) inhibits the formation of Lewis acids. No other additives or chemical preservatives are used.