Sevoran

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CЕVORAN® (SEVORANE®)

Composition:

Active substance: 1 vial contains not less than 99.9875% and not more than 100% sevoflurane.

Pharmaceutical form. Inhalation liquid.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

General anesthetics. Halogenated hydrocarbons. Sevoflurane.

ATC code N01AB08.

Pharmacological Properties.

Pharmacodynamics. Inhalation administration of the medicinal product for induction of anesthesia results in rapid loss of consciousness, which quickly recovers after termination of anesthesia. Induction anesthesia is accompanied by minimal excitation or signs of upper airway irritation and does not cause increased tracheobronchial secretion or stimulation of the central nervous system. In pediatric studies (mask induction), the incidence of coughing with sevoflurane was significantly lower than with halothane. Like other inhalational anesthetics, sevoflurane causes dose-dependent respiratory depression and reduction in arterial pressure. In humans, the adrenaline-induced arrhythmogenic threshold level of sevoflurane corresponds to that of isoflurane and exceeds the threshold level of halothane.

Sevoflurane has minimal effect on intracranial pressure and does not reduce the response to CO₂.

Sevoflurane does not exert clinically significant effects on liver or kidney function and does not exacerbate existing hepatic or renal insufficiency. Sevoflurane does not affect renal concentrating ability even during prolonged anesthesia (approximately up to 9 hours).

Pharmacokinetics. Due to low blood solubility of sevoflurane, alveolar concentration rises rapidly after administration begins and declines rapidly after discontinuation of the anesthetic agent.

Rapid and extensive pulmonary elimination of sevoflurane contributes to minimizing the amount of anesthetic available for metabolism. In humans, less than 5% of absorbed sevoflurane is metabolized via cytochrome P450 (CYP) 2E1, resulting in the formation of hexafluoroisopropanol (HFIP) with release of inorganic fluoride and carbon dioxide (or one hydrocarbon moiety). HFIP is then rapidly conjugated with glucuronic acid and excreted in urine. No other metabolic pathways of sevoflurane have been identified. This is the only fluorinated volatile anesthetic that does not metabolize to trifluoroacetic acid.

The concentration of fluoride ion depends on duration of anesthesia, sevoflurane concentration, and composition of the anesthetic mixture. Defluorination of sevoflurane is not induced by barbiturates. In approximately 7% of adult patients during clinical trials, serum inorganic fluoride concentrations exceeding 50 μM were measured, but no clinical impact on renal function was observed.

Clinical Studies.

Efficacy Studies.

Numerous clinical studies have been conducted with sevoflurane as an anesthetic agent in both children and adult patients. Study results demonstrated that sevoflurane provides smooth, rapid induction and rapid emergence from anesthesia.

Use of sevoflurane in studies was associated with faster induction and more rapid recovery, response to commands, and orientation compared to control groups.

Anesthesia in Adults.

In adult patients undergoing mask induction, sevoflurane provided smooth and rapid induction anesthesia. In three outpatient and 25 inpatient studies involving 3591 adult patients (2022 received sevoflurane, 1196 isoflurane, 111 enflurane, and 262 propofol), sevoflurane proved to be an effective agent for maintenance of anesthesia. Sevoflurane demonstrated adequate performance when used in neurosurgery, cesarean section, coronary artery bypass grafting, and in patients without cardiac disease at risk of myocardial ischemia.

Anesthesia in Children.

In two outpatient and three inpatient studies involving 1498 children (837 received sevoflurane, 661 halothane), sevoflurane proved to be an effective agent for induction and maintenance of anesthesia. In pediatric studies (mask induction), induction time was statistically significantly shorter, and the incidence of coughing was significantly lower with sevoflurane compared to halothane.

Safety Studies.

Clinical studies conducted in various patient populations (children, adults, elderly patients, patients with renal or hepatic insufficiency, obese patients, patients undergoing cardiac bypass surgery, patients receiving aminoglycosides or metabolic inducers, patients undergoing repeated surgeries, patients undergoing surgical procedures lasting more than 6 hours), along with evaluation of laboratory parameters (such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, serum creatinine, blood urea nitrogen), and the frequency of adverse reactions (in studies) related to hepatic or renal function, showed that sevoflurane does not cause clinically significant effects on liver or kidney function and does not exacerbate pre-existing renal or hepatic insufficiency in the studied patient population (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects"). The study data also demonstrated no statistically significant difference in the number of patients exhibiting changes in any clinical chemistry parameters when sevoflurane was compared to other inhalational anesthetics. The effect on renal function was comparable with sevoflurane and other inhalational anesthetics, across different anesthesia circuit types, different anesthetic flow rates, and in patients with serum inorganic fluoride concentrations ≥ 50 μM and < 50 μM. The incidence of renal dysfunction in comparative studies was < 1% both with sevoflurane (0.17%) and with other inhalational anesthetics (0.22% with isoflurane, halothane, enflurane, propofol). This incidence is consistent with that observed in general surgical practice. In all cases, there was either an alternative cause or a plausible explanation for the development of renal dysfunction.

Children.

In some published studies involving children, cognitive deficits were observed after repeated or prolonged exposure to anesthetic agents at early stages of life. These studies have significant limitations, and it remains unclear whether the observed effects were due to anesthetic/sedative agents or to other factors such as surgery or underlying illness. Furthermore, these findings have not been confirmed in later published registry studies. Published animal studies investigating certain anesthetic/sedative agents have reported adverse effects on early brain development (see section "Non-clinical Safety Data").

Patients with Hepatic Impairment.

During clinical studies, sevoflurane was effective and well tolerated when used as the primary agent for maintenance of anesthesia in patients with Child-Pugh class A and B hepatic impairment. Sevoflurane did not exacerbate existing hepatic insufficiency. For adverse reactions affecting the liver observed in post-marketing studies, see sections "Special Warnings and Precautions for Use" and "Undesirable Effects."

Patients with Renal Impairment.

The effect of sevoflurane was evaluated in patients with renal impairment with serum creatinine levels ≥ 1.5 mg/dL (130 μmol/L). Based on the frequency and magnitude of changes in creatinine concentration, sevoflurane did not worsen renal function.

Pharmaceutical Characteristics.

Formula for calculating saturated vapor pressure: Log₁₀ P_vapor = A + B/T,

where A = 8.086,

B = –1726.68,

T = °C + 273.16 K (temperature in Kelvin).

Partition coefficients at 37°C:

water/gas 0.36,

blood/gas 0.63–0.69,

olive oil/gas 47.2–53.9,

brain/gas 1.15.

Average partition coefficients component/gas at 25°C for polymers used in medical applications:

electrical conductive rubber 14.0,

butyl rubber 7.7,

polyvinyl chloride 17.4,

polyethylene 1.3.

Sevoflurane is a non-flammable, non-explosive liquid administered by inhalation of vapor produced by a vaporizer. Sevoflurane is chemically stable. No significant chemical decomposition occurs in the presence of strong acids or elevated temperatures.

Degradation of Sevoflurane.

Sevoflurane remains stable when stored under normal room lighting conditions. No significant degradation occurs in the presence of strong acids or heat. Sevoflurane does not damage stainless steel, brass, aluminum, nickel-plated copper, chrome-plated copper, or copper-beryllium alloy. Chemical degradation may occur due to interaction of the anesthetic with the CO₂ absorbent in the anesthesia circuit. When fresh absorbents are used, degradation of sevoflurane is minimal and degradation products are either undetectable or non-toxic. Degradation of sevoflurane and subsequent formation of degradation products is enhanced by increased absorbent temperature, drying of the CO₂ absorbent (especially those containing potassium hydroxide, e.g., Baralyme®), increased sevoflurane concentration, and reduced fresh gas flow. Sevoflurane may undergo alkaline degradation via two pathways. The first pathway involves loss of hydrogen fluoride, forming Compound A. The second degradation pathway occurs only in the presence of dry CO₂ absorbent and leads to dissociation of sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is an inactive, non-genotoxic substance that is rapidly glucuronidated and excreted, with toxicity comparable to sevoflurane. Formaldehyde is normally present in metabolic processes. When used with very dry absorbent, formaldehyde may degrade to methanol and formate. Formate (residual formic acid) may contribute to carbon monoxide formation at high temperatures. Methanol may react with Compound A to form Compound B. Compound B undergoes further HF elimination to form Compounds C, D, and E. When very dry absorbents, especially those containing potassium hydroxide (e.g., Baralyme®), are used, formation of formaldehyde, methanol, carbon monoxide, Compound A and some of its degradation products, and Compounds B, C, and D is possible.

Lewis Acid Degradation.

The formulation contains at least 0.3% water as a Lewis acid inhibitor. No other chemical stabilizers are used.

Clinical characteristics.

Indications.

Induction and maintenance of general anesthesia in adult and pediatric patients undergoing inpatient and outpatient surgical procedures.

Contraindications.

Confirmed or suspected genetic predisposition to malignant hyperthermia.

Confirmed or suspected hypersensitivity to sevoflurane or to other halogenated anesthetics (e.g., history of hepatic dysfunction, typically with elevated liver enzymes, fever, leukocytosis, and/or eosinophilia of unknown origin following administration of halogenated anesthetics).

When general anesthesia is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Beta-sympathomimetics such as isoprenaline, and alpha- and beta-sympathomimetics such as adrenaline (epinephrine) and noradrenaline (norepinephrine), should be used with caution during sevoflurane anesthesia due to the potential risk of ventricular arrhythmias.

Non-selective MAO inhibitors: risk of crisis during surgery. In general, it is recommended to discontinue therapy at least 2 weeks prior to surgery.

Sevoflurane may cause marked hypotension in patients receiving treatment with calcium channel antagonists, particularly dihydropyridine derivatives.

Caution is advised when combining calcium channel blockers with inhaled anesthetics due to the risk of additive negative inotropic effects.

Concomitant use of succinylcholine and inhaled anesthetics has rarely been associated with elevated serum potassium levels leading to cardiac arrhythmias and death in pediatric patients during the postoperative period.

Following administration of intravenous anesthetic agents such as propofol, lower concentrations of sevoflurane may be required.

Sevoflurane is safe and effective when used in combination with drugs commonly used in surgical practice, including agents acting on the central nervous system, autonomic nervous system, neuromuscular blockers, antimicrobial agents (including aminoglycosides), hormones, synthetic substitutes, blood derivatives, and cardiovascular drugs, including epinephrine.

Epinephrine/Adrenaline. Like isoflurane, sevoflurane increases myocardial sensitivity to the arrhythmogenic effects of exogenously administered adrenaline.

Indirect-acting sympathomimetics. There is a risk of acute hypertensive episodes when sevoflurane is used concomitantly with indirect-acting sympathomimetics (e.g., amphetamines, ephedrine).

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

Verapamil. Impaired atrioventricular conduction has been observed when verapamil is used concomitantly with sevoflurane.

St. John’s wort. Cases of severe hypotension and delayed emergence from anesthesia have been reported in patients taking long-term St. John’s wort.

Metabolism of sevoflurane may be increased by known inducers of CYP2E1 (e.g., isoniazid and alcohol), but not by barbiturates. Concomitant use of sevoflurane and isoniazid may potentiate the hepatotoxic effect of isoniazid.

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

Barbiturates. Sevoran is compatible with barbiturates commonly used in surgical practice.

Benzodiazepines and opioids. A reduction in the minimum alveolar concentration (MAC) of Sevoran is expected, as with other inhaled anesthetics; Sevoran is compatible with benzodiazepines and opioids commonly used in surgical practice. Use of opioids such as alfentanil and sufentanil in combination with sevoflurane may result in synergistic reduction in heart rate, blood pressure, and respiratory rate.

Inducers of CYP2E1. Medicinal products and compounds that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may increase sevoflurane metabolism and lead to a significant rise in plasma fluoride concentration (see section "Pharmacological properties", pharmacokinetics, metabolism and fluoride ion).

Nitrous oxide. As with other inhaled anesthetics, the MAC of sevoflurane is reduced (by 50% in adults and by 25% in children).

Neuromuscular blockers. Like other inhaled anesthetics, sevoflurane affects both the intensity and duration of neuromuscular blockade caused by non-depolarizing muscle relaxants.

In cases where supplemental alfentanil-N2O anesthesia is used, sevoflurane enhances neuromuscular blockade induced by pancuronium, vecuronium, and atracurium. The effect of sevoflurane on succinylcholine and the duration of action of depolarizing neuromuscular blockers has not been studied.

Reducing the dose of neuromuscular blocking agents during induction anesthesia may delay achievement of conditions suitable for tracheal intubation or result in inadequate muscle relaxation, since potentiation of muscle relaxant effects occurs within minutes after initiation of sevoflurane administration.

Interactions with non-depolarizing neuromuscular blocking agents such as pancuronium, vecuronium, and atracurium have been studied. In the absence of specific recommendations, do not reduce the dose of non-depolarizing muscle relaxants for endotracheal intubation. During maintenance of anesthesia, the dose of non-depolarizing muscle relaxants should be reduced as in N2O/opioid anesthesia. Additional doses of muscle relaxants should be administered only after assessing response to neurostimulation. As with other neuromuscular blockers, following administration of an intravenous anesthetic agent such as propofol, a lower concentration of sevoflurane may be required. Marked increases in plasma fluoride concentrations have been observed following increased CYP2E1 activity.

Special precautions for use.

Sevoflurane may cause respiratory depression, which may be enhanced during premedication with opioids or other medicinal agents that cause respiratory depression.

Respiration must be monitored, and emergency medical assistance should be provided if necessary. Sevoflurane may be administered only by personnel trained in the administration of general anesthesia. Equipment for maintaining airway patency, artificial ventilation, oxygen delivery, and circulatory support must be readily available. The concentration of sevofluorane delivered from the vaporizer must be accurately known. Since volatile anesthetics differ in physical properties, only vaporizers specifically calibrated for sevoflurane should be used. General anesthesia should be individualized based on the patient's response to anesthetic agents. As anesthesia deepens, hypotension and respiratory depression increase.

There have been reports that prior use of anesthetic agents—halogenated hydrocarbons, particularly when the interval between administrations was less than 3 months—may increase the potential risk of hepatic injury.

Rare cases of QT interval prolongation, very rarely associated with torsades de pointes ventricular tachycardia, have been reported, which in exceptional cases proved fatal. Sevoflurane should be used with caution in patients predisposed to such conditions.

Isolated cases of ventricular extrasystoles have been reported in children with Pompe disease.

General anesthesia, including sevoflurane, should be administered with caution in patients with mitochondrial disorders.

Liver.

Very rare cases of mild, moderate, and severe postoperative liver dysfunction or hepatitis, with or without jaundice, have been reported in post-marketing studies. Clinical judgment should be exercised when using sevoflurane in patients with concomitant liver dysfunction or when using drugs that may cause hepatic impairment (see section "Adverse effects"). Previous use of halogenated hydrocarbon anesthetics may increase the risk of liver injury, especially if the interval between administrations is less than 3 months.

During maintenance of anesthesia, increasing the concentration of sevoflurane leads to dose-dependent reduction in arterial blood pressure. Excessive hypotension may be related to the depth of anesthesia and can be corrected in such cases by reducing the inhaled concentration of sevoflurane. As with any anesthetic agents, in patients with ischemic heart disease, it is important to maintain hemodynamic stability to prevent myocardial ischemia.

Recovery after anesthesia should be carefully assessed before transferring the patient from the post-anesthesia care unit.

Although recovery of consciousness after sevoflurane administration usually occurs within a few minutes, the effect on intellectual capacity has not been studied during the 2–3 days following anesthesia. As with other anesthetics, minor changes in mood may be observed for several days after anesthesia (see section "Effect on ability to drive or operate machinery").

Sevoflurane should be used with caution in obstetric anesthesia, as its uterine relaxant effect may increase the risk of uterine bleeding.

Seizures have been reported following the use of sevoflurane in children and young people (up to 21 years of age), as well as in elderly patients, regardless of the presence of risk factors for seizure development. A clinical assessment of seizure risk should be performed before administering sevoflurane. In children, the depth of anesthesia should be limited. Electroencephalographic (EEG) monitoring may help optimize the dose of sevoflurane and prevent seizures in patients predisposed to them.

Dystonic movements have been observed in children.

Malignant hyperthermia.

In susceptible individuals, potent inhalational anesthetics may trigger a hypermetabolic state in skeletal muscle, resulting in increased oxygen demand and the development of a clinical syndrome known as malignant hyperthermia. This syndrome manifests as hypercapnia and may include nonspecific signs such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable arterial blood pressure (some of these symptoms may also occur with light anesthesia, acute hypoxia, hypercapnia, and hypovolemia).

One case of malignant hyperthermia has been reported in clinical studies. Malignant hyperthermia has also been observed in post-marketing surveillance. In some cases, fatal outcomes have been reported.

Treatment of malignant hyperthermia includes discontinuation of triggering agents (e.g., sevoflurane), intravenous administration of sodium dantrolene (see the prescribing information for sodium dantrolene), and supportive therapy consisting of vigorous measures to normalize body temperature, support respiratory and circulatory function, and correct disturbances in fluid and electrolyte balance.

Renal failure may develop later; therefore, urine output should be monitored and maintained if possible.

Perioperative hyperkalemia.

The use of inhalational anesthetics has been associated with rare cases of elevated plasma potassium levels, which may manifest as arrhythmias. Fatal cases have occurred in the postoperative period in children. Patients particularly susceptible include those with latent or overt neuromuscular disorders, especially Duchenne muscular dystrophy. In most reported cases, succinylcholine was administered concomitantly. Marked increases in plasma creatine phosphokinase (CPK) levels and, in some cases, myoglobinuria have also been observed in these patients. Although these manifestations resemble malignant hyperthermia, none of the patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and intensive correction of hyperkalemia and treatment of arrhythmias are recommended, followed by evaluation for latent neuromuscular disorders.

Patients with renal impairment.

Due to the limited number of studied patients with renal impairment (baseline serum creatinine levels above 133 µmol/L (1.5 mg/dL)), the safety of sevoflurane in this patient group has not been fully established. Therefore, sevoflurane should be administered with caution in patients with renal impairment.

Neurosurgery.

Sevoflurane should be used with caution in patients at risk of increased intracranial pressure, and measures to reduce intracranial pressure, such as hyperventilation, should be implemented.

Seizures.

Rare cases of seizures during the use of sevoflurane have been reported (see "Special precautions in children" and "Adverse reactions").

There is an association between sevoflurane use and the occurrence of seizures observed in children and young patients, as well as in elderly patients, both with and without risk factors for seizures. A clinical assessment of seizure risk should be performed before administering sevoflurane to patients with risk factors. In children, the depth of anesthesia should be limited. EEG monitoring may help optimize the dose of sevoflururane and prevent seizures in patients predisposed to them (see section "Children").

Children.

The use of sevoflurane has been associated with seizures. Many of these occurred in children from two months of age and in young adults, most of whom did not have risk factors for seizures. Clinical judgment should be exercised when using sevoflurane in patients who may be at risk of developing seizures (see section "Adverse reactions").

Replacement of dried-out CO₂ absorbents.

When sevoflurane comes into direct contact with CO₂ absorbents, small amounts of Compound A (pentafluoroisopropyl fluoromethyl ether, PIFE) and trace amounts of Compound B (pentafluoromethoxyisopropyl fluoromethyl ether, PMFE) are formed. Levels of Compound A increase with higher container temperature, increased anesthetic concentration, reduced gas flow rate, and are higher when potassium hydroxide (e.g., Baralyme®) is used compared to soda lime.

Dried-out CO₂ absorbents should be replaced before administering sevoflurane to prevent exothermic reactions that enhance sevoflurane degradation.

Use during pregnancy or breastfeeding.

Reproductive studies in rats and rabbits at doses up to 1 MAC did not demonstrate impaired fertility or fetal harm with sevoflurane. Adequate and well-controlled studies of sevoflurane use in pregnant women are lacking; therefore, it should be used during pregnancy only if clearly needed.

Animal studies on the use of certain anesthetics/sedatives have reported adverse effects on early brain development (see section "Preclinical safety data").

The safety of sevoflurane for both mother and newborn has been demonstrated in clinical studies during cesarean section. Safety during labor has not been studied.

Sevoflurane, like other inhalational agents, has a uterine relaxant effect with a potential risk of uterine bleeding. Clinical judgment should be exercised when using sevoflurane for obstetric anesthesia.

It is unknown whether sevoflurane or its metabolites are excreted in human breast milk. Due to the lack of documented experience, women should discontinue breastfeeding for 48 hours after sevoflurane administration.

Fertility.

Studies in rats and rabbits revealed no evidence of impaired fertility following sevoflurane administration at doses up to 1 MAC.

Effect on ability to drive or operate machinery.

After sevoflurane anesthesia, patients should not drive or operate machinery for a period determined individually by the physician.

Administration and Dosage.

Sevoran must be administered using a vaporizer specifically calibrated for use with sevoflurane, allowing precise control of the delivered concentration.

Induction.

Dosage should be individualized and titrated to the desired effect according to the patient's age and clinical status. A short-acting barbiturate or another intravenous induction agent may be administered initially, followed by inhalation of sevoflurane. For induction, sevofluorane can be administered in oxygen or in an oxygen/nitrous oxide mixture.

In adults, surgical anesthesia is usually achieved within less than 2 minutes by inhalation of sevoflurane at concentrations up to 5%. In pediatric patients, surgical anesthesia is usually achieved within less than 2 minutes by inhalation of sevoflurane at concentrations up to 7%.

Alternatively, for induction in patients who have not received premedication, inhalation of sevoflurane at concentrations up to 8% may be used.

Maintenance.

Surgical levels of anesthesia can be maintained using sevoflurane concentrations between 0.5% and 3%, with or without nitrous oxide (see "Interaction with Other Medicinal Products and Other Forms of Interaction").

The minimum alveolar concentration (MAC) of sevoflurane decreases with age and when nitrous oxide is added. The average sevoflurane concentration required to achieve MAC in patients aged 80 years is approximately 50% of that required in patients aged 20 years.

The table below provides average MAC values for different age groups.

* For children aged 1 – < 3 years, 60% N2O/40% O2 was used.

** Term newborns. MAC has not been determined in preterm newborns.

Recovery from anesthesia.

After sevoflurane anesthesia, recovery time is usually short. Therefore, patients may require early postoperative analgesia.

Children. Sevoran can be used in term newborns from birth.

Overdose.

In case of overdose (respiratory and cardiac depression), the following measures should be taken: discontinue administration of the drug, ensure airway patency, initiate artificial assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.

Side effects

Like all potent inhalational anaesthetic agents, sevoflurane may cause dose-dependent depression of respiratory and cardiac function. The severity of most adverse effects is mild to moderate and transient. In the postoperative period, nausea, vomiting, and delirium are commonly observed. These effects are often consequences of surgical intervention and general anaesthesia, may be related to the inhalational anaesthetic, other intra- or postoperative medications, and the patient's response to surgery; their incidence is similar to that observed with other inhalational anaesthetics.

Adverse reactions observed in patients during clinical trials

Adverse reactions are categorized by organ system and frequency of occurrence (more than 10% – very common, 1–10% – common, 0.1–1% – uncommon, 0.1–0.01% – rare, less than 0.01% – very rare, including isolated reports).

In adult patients, nausea, vomiting, and arterial hypotension were very commonly observed; in elderly patients, arterial hypotension, nausea, and bradycardia were very common. In children, nausea, vomiting, agitation, and coughing were very commonly observed. The type, severity, and frequency of adverse reactions in patients receiving sevoflurane are similar to those observed in patients receiving other anaesthetic agents.

Blood and lymphatic system disorders:
Uncommon – leukopenia, leukocytosis.

Gastrointestinal disorders:
Very common – nausea, vomiting;
Common – hypersalivation.

Cardiac disorders:
Very common – bradycardia, arterial hypotension;
Common – tachycardia, arterial hypertension;
Uncommon – complete atrioventricular block, atrial fibrillation, arrhythmia, ventricular extrasystoles, supraventricular extrasystoles, extrasystoles;
Frequency not known – QT interval prolongation associated with torsade de pointes.

Psychiatric disorders:
Very common – agitation;
Uncommon – confusion.

Nervous system disorders:
Common – dizziness, somnolence, headache.

Respiratory, thoracic and mediastinal disorders:
Very common – cough;
Common – respiratory disorders, laryngospasm;
Uncommon – apnoea, hypoxia, asthma.

Renal and urinary disorders:
Uncommon – urinary retention, glucosuria.

General disorders:
Common – chills, fever, hypothermia.

Laboratory investigations:
Common – changes in serum glucose levels, changes in liver function tests, increased ALT and AST (transient changes in liver function tests have been observed rarely with sevoflurane and similar agents), changes in leukocyte count, transient increase in serum inorganic fluoride levels, which may occur during and after sevoflurane anaesthesia (peak serum fluoride concentrations are typically reached 2 hours after the end of anaesthesia and return to preoperative levels within 48 hours; in clinical studies, elevated fluoride levels were not associated with impaired renal function);
Uncommon – increased creatinine and lactate dehydrogenase levels.

Post-marketing experience

Information on adverse reactions comes from spontaneous reports; therefore, frequency and causal relationship cannot be established.

Immune system disorders:
Anaphylactic reactions, hypersensitivity (may be associated with hypersensitivity reactions, especially with prolonged use of inhalational anaesthetics), anaphylactoid reactions.

Nervous system disorders:
Seizures (see sections "Special precautions" and "Children"), muscle dystonia.

Cardiac disorders:
Cardiac arrest (very rare reports from post-marketing surveillance with sevoflurane use), QT prolongation, torsade de pointes-type arrhythmia.

Respiratory, thoracic and mediastinal disorders:
Dyspnoea, stridor (may be associated with hypersensitivity reactions, especially with prolonged use of inhalational anaesthetics), bronchospasm, pulmonary oedema, apnoea.

Hepatobiliary disorders:
Hepatitis, hepatic failure, and hepatic necrosis; however, a definitive link with sevoflurane has not been established.

Skin and subcutaneous tissue disorders:
Rash, contact dermatitis, facial swelling (may be associated with hypersensitivity reactions, especially with prolonged use of inhalational anaesthetics), urticaria, pruritus.

Renal and urinary disorders:
Acute renal failure.

General disorders:
Chest discomfort (may be associated with hypersensitivity reactions, especially with prolonged use of inhalational anaesthetics), malignant hyperthermia.

Musculoskeletal and connective tissue disorders:
Muscle twitching.

Safety preclinical data

Animal studies have demonstrated that hepatic and renal circulations are well preserved with sevoflurane.

Sevoflurane reduces cerebral metabolic rate for oxygen (CMRO₂) in a manner similar to that observed with isoflurane. CMRO₂ decreases by approximately 50% at sevoflurane concentrations approaching 2.0 MAC (minimum alveolar concentration). Animal studies have shown that sevoflurane has no significant effect on cerebral blood flow.

In animals, sevoflurane markedly suppresses electrical brain activity (as measured by electroencephalography, EEG), comparable to the effect observed after administration of equivalent doses of isoflurane. There is no evidence that sevoflurane is associated with epileptiform activity under conditions of normocapnia or hypocapnia. Unlike enflurane, attempts to elicit EEG activity resembling epileptic seizures during hypocapnia using rhythmic auditory stimuli have been unsuccessful.

Compound A showed minimal nephrotoxicity at concentrations of 50–114 ppm over 3 hours in several rat studies. Toxicity was characterized by sporadic single-cell necrosis of proximal tubular cells. The mechanism of this renal toxicity in rats is unknown, and its relevance to humans has not been established. It is presumed that comparable threshold limits for nephrotoxicity related to Compound A in humans would be 150–200 ppm. Concentrations of Compound A observed in clinical practice average 19 ppm in adults (maximum 32 ppm) when using soda lime as the CO₂ absorbent.

Published studies in pregnant and juvenile animals indicate that anaesthetic and sedative agents that block NMDA (N-methyl-D-aspartate) receptors and/or enhance GABA (gamma-aminobutyric acid) activity, when administered during periods of rapid brain growth or synaptogenesis, may trigger widespread neuronal and oligodendrocyte cell loss and changes in synaptic morphology and neurogenesis following exposures exceeding 3 hours. These studies included anaesthetic agents from various drug classes. The clinical significance of these non-clinical findings is still under investigation (see section "Pharmacodynamics").

Shelf life. 3 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 25 °C.
Do not freeze. Keep tightly closed.

Packaging. 250 ml in a plastic bottle with a Quik fill cap system and a shrink band covering the cap and neck of the bottle, including a company logo strip.
One bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer. AbbVie S.r.l., Italy.

Manufacturer's address and place of business.
S.R. 148 Pontina Km. 52, SNC - Campoverde di Aprilia (loc. Aprilia) – 04011 Aprilia (LT), Italy.