Change to the Marketing Authorisation Holder for Malta

Section 6

• Under Manufacturer, removal of Aescica Queenborough site

Irish Sevorane pack is shared with Malta.

Section 4 has been updated to include the Competant Authority details in Malta (for the reporting of an adverse event)

Summary of Changes

Section 4.4

The statement:

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

has been amended to:

“It has been reported that previous exposure to halogenated hydrocarbon anaesthetics, especially if the interval is less than 3 months, may increase the potential for hepatic injury.”

Section 4.6

The following has been added:

“Studies in animals have shown reproductive toxicity (see section 5.3).”

Section 5.1

The following has been added:

“Pharmacotherapeutic Group: anaesthetics, general; halogenated hydrocarbons.

 ATC Code: N01AB08.”

Section 5.3

The following has been added:

“Published studies in animals (including primates) at doses resulting in light to moderate anaesthesia demonstrate that the use of anaesthetic agents during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain that can be associated with prolonged cognitive deficiencies. The clinical significance of these nonclinical findings is not known.”

Section 10

Date of Revision amended to February 2019

from

AbbVie Limited

Block B

Liffey Valley Office Campus

Quarryvale

Co. Dublin

to

AbbVie Limited

Citywest Business Park

Dublin 24

Ireland

Section 4.3 Contraindications:

Update the statement:

“Sevoflurane should not be used in patients with known or suspected sensitivity to sevoflurane or to other halogenated anaesthetics (e.g. history of liver function disorder, fever or leucocytosis of unknown cause after anaesthesia with one of these agents).”

to read:

“Sevoflurane should not be used in patients with known or suspected sensitivity to sevoflurane or to other halogenated inhalational anaesthetics (e.g. history of hepatotoxicity, usually including elevated liver enzymes, fever, leukocytosis and/or eosinophilia temporally related to anesthesia with one of these agents.”

Section 4.6 Fertility, Pregnancy and lactation

Inclusion of the following statement:

“Sevoflurane, like other inhalational agents, has relaxant effects on the uterus with the potential risk for uterine bleeding. Clinical judgment should be observed when using sevoflurane during obstetric anaesthesia.”

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.

Section 4.5
The following has been added:

Beta-sympathomimetic agents like isoprenaline and alpha- and beta-sympathomimetic agents like adrenaline and noradrenaline should be used with caution during Sevoflurane narcosis, due to a potential risk of ventricular arrhythemia.

Non-selective MAO-inhibitors: Risk of crisis during the operation. It is generally recommended that treatment should be stopped 2 weeks prior to surgery.

Sevoflurane may lead to marked hypotension in patients treated with calcium antagonists, in particular dihydropyridine derivates.

Caution should be exercised when calcium antagonists are used concomitantly with inhalation anesthetics due to the risk of additive negative inotropic effect.

Concomitant use of succinylcholine with 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 post-operative period.


Section 4.8
Delirium has been added to list of adverse reactions observed in postoperative period.
QT prolongation associated with Torsade  (frequency unknown) has been added to Table 2 (Summary of Most Frequent Adverse Drug Reactions in Sevoflurane Clinical Trials and Post-marketing Experience)

The following paragraph has been added:

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Section 6.6

The sentence

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

has been amended to:

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

Section 4.2     Posology and Method of Administration

• Formatting changes have been made to Table 1 (MAC Values for Adults and Paediatric Patients According to Age).

Section 4.4 Special Warnings and Special Precautions for Use

• The existing wording on malignant hyperthermia has been updated to inform physicians that post marketing reports of malignant hyperthermia, some fatal have been received.
• Additional language regarding supportive therapy for the treatment of malignant hyperthermia has been added.

Section 4.8 Undesirable Effects

• Table number added to Summary of Most Frequent Adverse Drug Reactions in Sevoflurane Clinical Trials and Post-marketing Experience

4.2 Posology and Method of Administration
Information on premedication added. Elderly and Paediatric Population subsections also added.

 4.3 Contraindications
The existing contraindication regarding use in patients with known sensitivity was updated with examples. Contraindiation in patients in whom general anaesthesia is contraindicated also added.

4.4 Warnings and Precautions
Warning added regarding patients who are hypovolemic, hypotensive, or otherwise hemodynamically compromised.
Warning added regarding maintenance of haemodynamic stability in patients with coronary artery disease.
Statement added that impact of sevoflurane on intellectual function for two or three days following anaesthesia has not been studied and as with other anaesthetics, small changes in moods may persist for several days following administration.
Symptoms of malignant hyperthermia added.
Warning added regarding use of sevoflurane in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction.
Neurosurgery, Seizures and Paediatric subsections added.

4.5 Drug Interactions
The Drug Interactions section updated to include information relating to 'Epinephrine/Adrenaline, Indirect-acting Sympathomimetics, beta blockers, Verapamil, Inducers of CYP2EI, St. John's Wort, Barbiturates, Benzodiazepines and Opioids, Nitrous Oxide and Neuromuscular Blocking Agents'.

4.6 Pregnancy and Lactation
Pregnancy, Labour and Delivery, Breast-feeding & Fertility subsections was added.

4.8 Adverse Reactions
Summary of most frequent adverse drug reactions in sevoflurane clincal trials and post-marketing experience have been combined in one table.  Hypothermia has been added as a common adverse drug reaction.  A subsection describing selected adverse events &  Paediatric Population was added.

4.9 Overdose
Minor revision to wording

• In Section 4.2 - The MAC values have been updated to align with the Company Core Data Sheet.
• In Section 4.4 -  A warning regarding repeat exposure to Sevorane within a short interval, potentially increasing the risk of liver damage has been added. Also, A statement regarding cases of ventricular arrhythmia reported in paediatric patients with Pompe's disease has also been added.
• In Section 4.5 - A warning regarding the use of Opioids such as alfentanil and sufentanil in combination with Sevorane can lead to a synergistc fall in heart rate, blood pressue and respiratory rate.
• In Section 4.8 - This whole section has been reformatted to use MedDRA system order calss terminology and frequency. Also, hypersensitivity and related reactions have been added to the post-marketing section.

6.5    Nature and Contents of Container

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

         Sevoflurane

        For excipients see 6.1.

4.4                Special Warnings and Special Precautions for Use

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 vaporizer setting may be associated with excessive heating of the CO₂ absorbent canister.An exothermic reaction , enhanced sevoflurane degragation, and production of degradation products can occur when 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 (³ 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.

4.8  Undesirable Effects

The most frequent adverse events (>1%) considered to be probably related to sevoflurane administration overall were: nausea, vomiting, increased cough, hypotension, agitation, somnolence, chills, bradycardia, dizziness, increased salivation, respiratory disorder, hypertension, tachycardia, laryngismus, and fever.

6.2  Incompatibilities

Sevoflurane is stable when stored under normal room lighting conditions. No discernible degradation of sevoflurane occurs in the presence of strong acids or heat. Sevoflurane is not corrosive to stainless steel, brass, alumimum, nickel-plated brass, chrome-plated brass or copper beryllium alloy.

Chemical degradation can occur upon exposure of inhaled anaesthetics to 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 (especially potassium hydroxide-containing, e.g. Baralyme^®), increased sevoflurane concentration and decreased fresh gas flow. Sevoflurane can undergo alkaline degradation by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropanyl fluoromethyl ether (PIFE or more commonly known as Compound A). The second pathway for degradation of sevoflurane occurs only in the presence of desiccated CO₂ absorbents and leads to the dissociation of sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic, rapidly glucoronidated, cleared and has toxicity comparable to sevoflurane. Formaldehyde is present during normal metabolic processes. Upon exposure to a highly desiccated absorbent, formaldehyde can further degrad 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 may occur.