Sevoflurane

Risk of crisis during the operation. It is generally recommended that treatment should be stopped 2 weeks prior to surgery.

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

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.

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.

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

Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 1.5mg/dL) studied, the safety of sevoflurane administration in this group has not been fully established. Therefore, sevoflurane should be used with caution in patients with renal insufficiency.

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. The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established.

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

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.

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 sufentanil, when combined with sevoflurane, may lead to a synergistic fall in heart rate, blood pressure and respiratory rate.

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.

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.

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 arrhythmia.

Sevoflurane is similar to isoflurane in the sensitisation of the myocardium to the arrhythmogenic effect of exogenously administered adrenaline.

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.

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.

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

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 disease.

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

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).

Isolated cases of ventricular arrhythmia were reported in paediatric patients with Pompe’s disease.

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.

Sevoflurane has a relaxant effect on the uterus, which can lead to increased uterine bleeding, as was reported in a study of its use during termination of pregnancy. Use during labour and delivery is limited to one small study in caesarean section.

Studies in animals have shown reproductive toxicity.

There are no adequate and well-controlled studies in pregnant women; therefore, sevoflurane should be used during pregnancy only if clearly needed.

It is not known whether sevoflurane or its metabolites are excreted in human milk. Due to the absence of documented experience, women should be advised to skip breast-feeding for 48 hours after administration of sevoflurane and discard milk produced during this period.

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.

Fertility

A fertility study in rats has revealed no evidence of impaired fertility due to sevoflurane.

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.

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

Summary of the safety profile

As with all potent inhaled anaesthetics, sevoflurane may cause dose-dependent cardio-respiratory depression. Most adverse reactions are mild to moderate in severity and are transient in duration. Nausea, vomiting and delirium 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.

In paediatric patients: agitation, cough, vomiting and nausea.

Summary of adverse reactions

All adverse reactions at least possibly relating to sevoflurane from clinical trials and post-marketing experience are presented in the following list 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.

Immune system disorders

Unknown: Anaphylactic reaction¹, Anaphylactoid reaction, Hypersensitivity¹

Blood and lymphatic system disorders

Uncommon: Leukopenia, Leukocytosis

Psychiatric disorders

Very Common: Agitation

Uncommon: Confusional state

Nervous system disorders

Common: Somnolence, Dizziness, Headache

Unknown: Convulsion³, Dystonia

Cardiac disorders

Very Common: Bradycardia

Common: Tachycardia

Uncommon: Atrioventricular block complete, Atrial fibrillation, Arrythmia, Ventricular extrasystoles, Supraventricular extrasystoles, Extrasystoles

Unknown: Cardiac arrest⁴, QT prolongation associated with Torsade

Vascular disorders

Very Common: Hypotension

Common: Hypertension

Respiratory, thoracic and mediastinal disorders

Very Common: Cough

Common: Respiratory disorder, Laryngospasm

Uncommon: Apnoea, Hypoxia, Asthma

Unknown: Bronchospasm, Dyspnoea¹, Wheezing¹, Pulmonary oedema

Gastrointestinal disorders

Very Common: Nausea, Vomiting

Common: Salivary hypersecretion

Renal and urinary disorders

Uncommon: Urinary retention, Glycosuria

Unknown: Renal failure acute

Hepato-biliary disorders

Unknown: Hepatitis¹, Hepatic failure¹, Hepatic necrosis¹

Skin and subcutaneous tissue disorders

Unknown: Dermatitis contact¹, Pruritus, Rash¹, Swelling face¹, Urticaria

Musculoskeletal and connective tissue disorders

Unknown: Muscle twitching

General disorders and administration site conditions

Common: Chills, Pyrexia, Hypothermia

Unknown: Chest discomfort¹, Hyperthermia malignant¹

Investigations

Common: Blood glucose abnormal, Liver function test abnormal⁵, White blood cell count abnormal, Aspartate aminotransferase increased, Blood fluoride increased⁶

Uncommon: Alanine aminotransferase increased, Blood creatinine increased, Blood lactate dehydrogenase increased

Injury, poisoning and procedural complications

Common: Hypothermia

¹ See “Description of selected adverse reactions”.
³ See “Paediatric population”.
⁴ There have been very rare post-marketing 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.
⁶ Transient increases in serum inorganic fluoride levels may occur during and after sevoflurane anaesthesia. See Description of selected adverse reactions below.

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.

Rare reports of hypersensitivity (including contact dermatitis, rash, dyspnoea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) 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.

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. Clinical judgment should be exercised when using sevoflurane in patients who may be at risk for seizures.