Sevoflurane

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEVOFLURANE (SEVOFLURANE)

Composition:

Active substance: sevoflurane;

1 vial (250 ml) contains sevoflurane 100%.

Pharmaceutical form. Inhalation liquid.

Main physico-chemical properties: clear, colorless liquid.

Pharmacotherapeutic group.
Agents for general anesthesia. Halogenated hydrocarbons. Sevoflurane.

ATC Code: N01AB08.

Pharmacological properties.

Pharmacodynamics

Inhalation administration of the drug for induction anesthesia causes rapid loss of consciousness, which quickly recovers after anesthesia ends. 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 studies involving pediatric patients (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 has no clinically significant effect on liver or kidney function and does not exacerbate existing renal or hepatic insufficiency. Sevoflurane does not affect renal concentrating function even during prolonged anesthesia (approximately up to 9 hours).

Pharmacokinetics

Due to the low blood solubility of sevoflurane, alveolar concentration rapidly increases after initiation and rapidly decreases after discontinuation of the anesthetic agent.

Rapid and extensive pulmonary elimination of sevoflurane minimizes 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.

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

Clinical studies

Efficacy studies

Studies of sevoflurane as an anesthetic agent were conducted in both pediatric and adult patients. Study results demonstrated that sevoflurane provides smooth and rapid induction, as well as rapid emergence from anesthesia.

Use of sevoflurane in studies was associated with faster induction and faster emergence from anesthesia, response to commands, and orientation compared to control groups.

Anesthesia in adults

In adult patients undergoing mask induction, sevoflurane provided smooth and rapid induction of anesthesia. In outpatient and inpatient studies involving adult patients (comparing sevoflurane, isoflurane, enflurane, and propofol), sevoflurane proved to be an effective agent for maintenance of anesthesia. Sevoflurane has been shown to be adequate for use in neurosurgery, cesarean section, coronary artery bypass grafting, and in patients without cardiac disease but at risk of myocardial ischemia.

Anesthesia in children

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 involving 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, and patients undergoing procedures longer than 6 hours), along with laboratory parameter assessments (ALT, AST, alkaline phosphatase, total bilirubin, serum creatinine, blood urea nitrogen), and the incidence of adverse reactions related to liver or kidney function, demonstrated that sevoflurane has no clinically significant effect on liver or kidney function and does not worsen pre-existing renal or hepatic insufficiency. Study data also showed no statistically significant difference in the number of patients exhibiting changes in any clinical chemistry parameters when sevoflurane was compared to other inhalational anesthetics. Renal function effects were comparable between sevoflurane and other inhalational anesthetics across different anesthesia circuit types, different anesthetic fresh gas flow rates, and in patients with inorganic fluoride concentrations ≥50 µmol and <50 µmol. The incidence of renal dysfunction in comparative studies was <1% for both sevoflurane (0.17%) and other inhalational anesthetics (0.22% for 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 justified explanation for the development of renal dysfunction.

Patients with hepatic insufficiency

Sevoflurane is effective and well tolerated when used as the primary agent for maintenance of anesthesia in patients with Child-Pugh class A and B hepatic insufficiency. Sevoflurane does not worsen pre-existing hepatic insufficiency.

Patients with renal insufficiency

The effect of sevoflurane was evaluated in patients with renal insufficiency 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 vaporized liquid using a vaporizer. Sevoflurane is chemically stable. No significant chemical decomposition occurs in the presence of strong acids or elevated temperatures.

Sevoflurane degradation

Sevoflurane remains stable when stored under normal room lighting. 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 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 (residue of 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, Compounds B, C, and D, is possible.

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 increased sensitivity to sevoflurane or to other halogenated anesthetics (e.g., history of hepatic dysfunction 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 and noradrenaline, should be used with caution during sevoflurane anesthesia due to the potential risk of ventricular arrhythmias.

Non-selective monoamine oxidase inhibitors (MAO inhibitors). Risk of crisis during surgery. Therapy is generally recommended to be discontinued at least 2 weeks prior to surgery.

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

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

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

As with other medicinal products, after intravenous administration of an anesthetic agent 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, such as agents acting on the central nervous system, autonomic nervous system, muscle relaxants, antimicrobial agents including aminoglycosides, hormones, synthetic substitutes, blood derivatives, and cardiovascular drugs, including epinephrine.

Epinephrine/adrenaline. Sevoflurane, like isoflurane, increases myocardial sensitivity to the arrhythmogenic effects of exogenously administered adrenaline.

Indirect-acting sympathomimetics. Interaction between sevoflurane and sympathomimetics (e.g., amphetamine, ephedrine) may carry a risk of acute hypertensive episodes.

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 administered concomitantly with sevoflurane.

St. John’s wort (Hypericum perforatum). Cases of severe arterial hypotension and delayed emergence from anesthesia have been reported in patients who have been taking St. John’s wort for prolonged periods.

Inducers of CYP2E1. Medicinal products and compounds that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may enhance the metabolism of sevoflurane and lead to a significant increase in plasma fluoride concentration. Concomitant administration of sevoflurane and isoniazid may potentiate the hepatotoxic effects of isoniazid.

Barbiturates. Sevoflurane is compatible when used in combination with barbiturates commonly used in surgical practice.

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

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 induced by non-depolarizing muscle relaxants.

When additional alfentanil-N2O anesthesia is used, sevoflurane potentiates 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 lead to delayed onset of conditions suitable for tracheal intubation or inadequate muscle relaxation, as potentiation of muscle relaxant effects occurs within several 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 for endotracheal intubation, the dose of non-depolarizing muscle relaxants should not be reduced. 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 assessment of response to neurostimulation. As with other anesthetics, after administration of an intravenous anesthetic agent such as propofol, lower concentrations 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 can be enhanced during premedication with narcotic or other medicinal agents that cause respiratory depression. Respiration must be monitored and emergency medical intervention provided if necessary.

Sevoflurane must be administered only by personnel trained in the conduct of general anesthesia. Equipment for maintaining airway patency, artificial ventilation, oxygen delivery, and circulatory resuscitation must be readily available. The concentration of sevoflurane delivered from the vaporizer must be accurately known. Since volatile anesthetics differ in their physical properties, only vaporizers specifically calibrated for sevoflurane should be used. General anesthesia must be individualized and based on the patient's response to anesthetic induction. With increasing depth of anesthesia, arterial hypotension and respiratory depression increase.

Malignant hyperthermia

Potent inhalational anesthetics may trigger a hypermetabolic skeletal muscle state in susceptible patients, resulting in increased oxygen demand and the development of a clinical syndrome known as malignant hyperthermia. One case of malignant hyperthermia has been reported. This syndrome is characterized by hypercapnia and may include nonspecific signs such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable arterial pressure (some of these symptoms may also occur with light anesthesia, acute hypoxia, hypercapnia, and hypovolemia).

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

Treatment includes discontinuation of triggering agents (e.g., sevoflurane), intravenous administration of sodium dantrolene (see sodium dantrolene prescribing information), and supportive therapy involving vigorous measures to normalize body temperature, maintain respiratory and circulatory function, and correct fluid and electrolyte imbalances. Renal failure may develop later; therefore, urine output must be monitored and maintained if possible.

Perioperative hyperkalemia

Inhalational anesthetics have been associated with rare cases of elevated plasma potassium levels, which may manifest as arrhythmias. Fatal cases have occurred in children during the postoperative period. Particularly susceptible patients include those with latent or overt neuromuscular disorders, especially Duchenne muscular dystrophy. In most reported cases, succinylcholine was administered concomitantly. These patients also showed marked increases in plasma creatine phosphokinase levels and, in some cases, myoglobinuria. Although these manifestations resemble malignant hyperthermia, none of the patients exhibited muscle rigidity or hypermetabolic state. Early and aggressive correction of hyperkalemia and treatment of arrhythmias are recommended, followed by evaluation for latent neuromuscular disorders.

Isolated reports of QT interval prolongation, very rarely associated with torsades de pointes ventricular tachycardia, have been reported, with rare fatal outcomes. 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 used with caution in patients with mitochondrial disorders.

Liver

Isolated cases of postoperative liver function impairment or hepatitis, with or without jaundice of mild, moderate, or severe degree, have been reported. Clinical judgment should be exercised when administering sevoflurane to patients with concomitant liver dysfunction or those receiving drugs known to impair liver function (see section "Adverse reactions"). Previous use of halogenated hydrocarbon anesthetics may increase the risk of hepatic injury, particularly if the interval between administrations is less than 3 months.

General

During maintenance of anesthesia, increasing the concentration of sevoflurane leads to dose-dependent decreases in arterial pressure. Excessive hypotension may be related to the depth of anesthesia and can be corrected by reducing the inspired concentration of sevoflurane. Particular caution should be exercised when dosing patients with hypovolemia, hypotension, or other hemodynamic disturbances, such as those caused by concomitant medications. As with any anesthetic, maintaining hemodynamic stability is essential in patients with ischemic heart disease to prevent myocardial ischemia.

Recovery from anesthesia must 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 for 2–3 days following anesthesia. As with other anesthetics, minor mood changes may occur for several days after anesthesia (see section "Ability to influence the speed of reactions when driving or operating machinery").

Sevoflurane should be used with caution in obstetric anesthesia, as its uterine relaxant effect may increase the risk of uterine bleeding (see section "Use during pregnancy or breastfeeding").

Replacement of dried-out CO₂ absorbents

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

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

Patients with renal impairment

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

Neurosurgery

Sevoflurane should be administered with caution to 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 sevoflurane administration have been reported. Sevoflurane has been associated with seizures in children and young adults (up to age 21) as well as in elderly patients, regardless of the presence of risk factors for seizure development. Clinical evaluation of patients at risk of seizures should be performed before administering sevoflurane. In children, the depth of anesthesia should be limited. Electroencephalography (EEG) may help optimize sevoflurane dosing and prevent seizures in susceptible patients (see section "Children").

Children

The use of sevoflurane has been associated with seizures. Many of these occurred in children as young as two months of age and in young adults, most of whom had no known risk factors for seizure development. Clinical judgment should be exercised when administering sevoflurane to patients at potential risk of seizures.

Dystonic movements have been observed in children (see section "Adverse reactions").

Use in children with Down syndrome

Bradycardia in Down syndrome

Episodes of severe bradycardia and cardiac arrest, unrelated to congenital heart defects, have been reported during induction of anesthesia with sevoflurane in children with Down syndrome. In most cases, bradycardia symptoms improved with reduced sevoflurane concentration, airway maneuvers, or administration of anticholinergic agents or adrenaline.

During induction, heart rate should be closely monitored, and gradual increase in inspired sevoflurane concentration should be considered until the desired anesthetic depth is achieved. Anticholinergic agents and adrenaline should be readily available during sevoflurane induction in this patient group.

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 have been published on the use of certain anesthetics/sedatives, reporting adverse effects on early brain development (see section "Preclinical safety data").

The safety of sevoflurane for 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 milk. Due to the lack of documented experience during lactation, women should discontinue breastfeeding for 48 hours after sevoflurane administration.

Fertility

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

Ability to influence the speed of reactions when driving or operating machinery.

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

Administration and Dosage

Sevoflurane must be administered using a vaporizer specifically calibrated for sevoflurane, so that the delivered concentration can be accurately controlled.

Induction

The dose should be individually adjusted and increased according to the desired effect, taking into account the patient's age and clinical status. A short-acting barbiturate or another intravenous agent may be administered for induction, followed by inhalation of sevoflurane. In adults, surgical anesthesia is usually achieved within less than 2 minutes by inhaling sevoflurane at concentrations up to 5%. In pediatric patients, surgical anesthesia is usually achieved within less than 2 minutes by inhaling 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 section "Interaction with other medicinal products and other forms of interaction").

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

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

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

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

Recovery from anesthesia

Recovery from anesthesia following sevoflurane is generally rapid. Therefore, patients may require early postoperative analgesia.

Children

Sevoflurane 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 assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.

Side effects.

Like all potent inhaled anesthetics, sevoflurane may cause dose-dependent respiratory and cardiac depression. Most adverse effects are mild to moderate in severity and transient. Postoperatively, nausea and vomiting are frequently observed; these are often consequences of surgical intervention and general anesthesia, may be related to the inhaled anesthetic, other drugs administered intra- or postoperatively, and the patient's response to surgery. The incidence is similar to that observed with other inhaled anesthetic agents.

Adverse reactions observed in patients during clinical trials

Adverse reactions are categorized by system organ class and frequency of occurrence (>10% – very common; 1–10% – common; 0.1–1% – uncommon; 0.1–0.01% – rare; <0.01% – very rare, including isolated reports); frequency unknown (cannot be estimated from available data).

In adult patients, nausea, vomiting, and arterial hypotension were very commonly observed; in elderly patients, arterial hypotension, nausea, and bradycardia were very common; in pediatric patients, nausea, vomiting, agitation, and cough were very common. The type, severity, and frequency of adverse reactions in patients receiving sevoflurane are similar to those observed with other anesthetic 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 unknown – QT interval prolongation associated with Torsade de pointes arrhythmia.

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 – apnea, hypoxia, asthma.

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

General disorders:
Common – chills, shivering, hypothermia.

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 anesthesia (peak inorganic fluoride concentrations typically occur 2 hours after the end of anesthesia 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

Adverse reactions have been reported spontaneously; 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 inhaled anesthetics), anaphylactoid reactions.

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

Cardiac disorders:
Cardiac arrest (very rare reports from post-marketing surveillance with sevoflurane use), QT prolongation, bradycardia in patients with Down syndrome, Torsade de pointes arrhythmia.

Respiratory, thoracic and mediastinal disorders:
Dyspnea, stridor (may be associated with hypersensitivity reactions, especially with prolonged use of inhaled anesthetics), bronchospasm, pulmonary edema, apnea.

Hepatobiliary disorders:
Hepatitis, hepatic failure, and hepatic necrosis; however, a definitive link to 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 inhaled anesthetics), urticaria, pruritus.

Renal and urinary disorders:
Acute renal failure.

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

Musculoskeletal and connective tissue disorders:
Muscle twitching.

Preclinical safety data

Animal studies have demonstrated that hepatic and renal blood flows 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 seen 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 stimulation have been unsuccessful.

Compound A was minimally nephrotoxic at concentrations of 50–114 ppm for 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 in humans, the comparative threshold limits for nephrotoxicity related to Compound A would be 150–200 ppm. Compound A concentrations observed in clinical practice average 19 ppm in adults (maximum 32 ppm) when soda lime is used as the CO₂ absorbent.

Published studies in pregnant and juvenile animals indicate that anesthetic and sedative agents that block NMDA receptors and/or enhance GABA activity, when administered during the period of rapid brain growth or synaptogenesis, may trigger widespread neuronal and oligodendrocyte cell loss and alter synaptic morphology and neurogenesis following exposures exceeding 3 hours. These studies involved anesthetic agents from various drug classes. The clinical significance of these preclinical findings is currently under investigation (see section "Pharmacodynamics").

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 25°C in the original packaging.

Keep out of reach of children.

Packaging.

250 ml of solution in a bottle.

Prescription status. Prescription only.

Manufacturer.

Piramal Critical Care Inc.

Manufacturer’s address and place of business.

3950 Sheldon Circle, Bethlehem, Pennsylvania (PA) 18017, USA.