Sevoflurane y-phyll
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEVORANE U-FILL (Sevoflurane U-Fill)
Composition:
Active substance: sevoflurane;
1 vial contains 100% sevoflurane.
Pharmaceutical form. Vapour for inhalation, liquid.
Main physicochemical properties: clear, colorless, volatile liquid.
Pharmacotherapeutic group. General anesthetics. Halogenated hydrocarbons. Sevoflurane. ATC code N01AB08.
Pharmacological Properties
Pharmacodynamics
Inhalation administration of the medicinal product for induction of anesthesia causes rapid loss of consciousness, which quickly recovers after termination of anesthesia. Induction of anesthesia is accompanied by minimal excitation or signs of irritation of the upper respiratory tract and does not cause increased tracheobronchial secretion or stimulation of the central nervous system (CNS). In pediatric studies (mask induction), the incidence of cough 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 hepatic or renal 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 rises rapidly after initiation and declines rapidly 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 carbon-containing fragment). 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 ions 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/L, but no clinical impact on renal function was observed.
Clinical Studies
Efficacy Studies
Numerous clinical studies of sevoflurane as an anesthetic agent have been 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 more rapid 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 demonstrated adequacy 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 outpatient and inpatient studies involving children (comparing sevoflurane and 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 cough 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 surgical procedures lasting more than 6 hours), along with assessment of laboratory parameters [such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, serum creatinine, blood urea nitrogen], and the incidence 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 worsen pre-existing hepatic or renal insufficiency in the studied patient population (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects"). Study data also demonstrated no statistically significant difference in the number of patients with changes in any clinical chemistry parameters when sevoflurane was compared to other inhalational anesthetics. The effect on renal function was comparable between sevoflurane and other inhalational anesthetics, regardless of anesthetic circuit type, anesthetic flow rate, and in patients with inorganic fluoride concentrations ≥ 50 μmol/L and < 50 μmol/L. 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.
Children
In some published studies involving children, cognitive deficits were observed after repeated or prolonged exposure to anesthetics at early stages of life. These studies have significant limitations, and it remains unclear whether the observed effects were due to the use of anesthetic/sedative agents or to other factors such as surgery or underlying illness. Furthermore, these findings have not been confirmed in later published registration trials. Published animal studies investigating certain anesthetic/sedative agents have reported adverse effects on brain development at early stages of life (see below "Non-clinical Safety Data").
Patients with Hepatic Insufficiency
In 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 insufficiency. Sevoflurane did not worsen pre-existing hepatic insufficiency. For hepatic adverse reactions observed in post-marketing studies, see sections "Special Warnings and Precautions for Use" and "Undesirable Effects".
Patients with Renal Insufficiency
The effect of sevoflurane was evaluated in patients with renal insufficiency and serum creatinine levels ≥ 1.5 mg/dL (130 μmol/L). Based on the frequency and magnitude of changes in creatinine concentration, sevoflurane did not impair renal function.
Pharmaceutical Characteristics
Formula for calculating saturated vapor pressure: Log₁₀ Pvapor = A + B/T,
where A = 8.086,
B = –1726.68,
T = °C + 273.16 °K (temperature on the Kelvin scale).
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 distribution coefficients of component/gas at 25 °C for polymers used for medical indications:
| butyl rubber |
7.7 |
| conductive rubber |
14.0 |
| polyethylene |
1.3 |
| polyvinyl chloride |
17.4 |
Sevoflurane is a non-flammable, non-explosive liquid administered by inhalation of vapor produced 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 conditions. No significant degradation occurs in the presence of strong acids or under thermal stress. Sevoflurane does not adversely affect 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 anesthetic apparatus. When fresh absorbents are used, sevoflurane degradation 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 the loss of hydrogen fluoride, resulting in the formation of compound A. The second degradation pathway occurs only in the presence of dry CO2 absorbent and leads to dissociation of sevoflurane into HFIP and formaldehyde. HFIP is an inactive, non-genotoxic substance that is rapidly glucuronidated and excreted, with toxicity comparable to that of sevoflurane. Formaldehyde is normally present in metabolic processes. When used with very dry absorbent, formaldehyde may degrade into methanol and formate. Formate (formic acid residue) may contribute to the formation of carbon monoxide 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, particularly those containing potassium hydroxide (e.g., Baralyme®), are used, formation of formaldehyde, methanol, carbon monoxide, compound A, and some of its degradation products, including 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.
Preclinical safety data
Animal studies have demonstrated that hepatic and renal circulations are well preserved with sevoflurane administration.
Sevoflurane reduces cerebral oxygen metabolism (CMRO2) in a manner similar to that observed with isoflurane. CMRO2 decreases by approximately 50% at sevoflurane concentrations approaching 2.0 MAC. Animal studies have shown that sevoflurane does not have a significant effect on cerebral blood flow.
In animals, sevoflurane markedly suppresses electrical brain activity (as measured by electroencephalography [EEG]), an effect comparable to that observed after administration of equivalent doses of isoflurane. There is no evidence that sevoflurane administration 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 not been successful.
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 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 soda lime is used as the CO2 absorbent.
Published studies in pregnant and juvenile animals indicate that anesthetic 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 alterations in synaptic morphology and neurogenesis following exposure exceeding 3 hours. These studies included anesthetic agents from various drug classes. The clinical significance of these non-clinical findings is still under investigation (see section "Pharmacodynamics").
Clinical characteristics.
Indications.
Induction and maintenance of general anesthesia in adult and pediatric patients undergoing inpatient and outpatient surgical procedures.
Contraindications.
- Confirmed or suspected hypersensitivity to sevoflurane or to other halogenated anesthetics (e.g., history of hepatic dysfunction, usually with elevated liver enzymes, fever, leukocytosis, and/or eosinophilia of unknown origin following administration of halogenated anesthetics).
- Confirmed or suspected genetic predisposition to malignant hyperthermia.
- 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.
Nonselective monoamine oxidase inhibitors (MAO inhibitors). There is a risk of crisis during surgery. In general, MAO inhibitor therapy should be discontinued at least 2 weeks prior to surgery.
Sevoflurane may cause marked arterial hypotension in patients receiving treatment with calcium channel antagonists, particularly dihydropyridine derivatives.
Caution is advised when calcium channel blockers are used concomitantly with inhaled anesthetics due to the risk of additive negative inotropic effects.
Rare cases of hyperkalemia have been reported following concomitant use of succinylcholine and inhaled anesthetics, leading to cardiac arrhythmias and death in pediatric patients during the postoperative period.
As with other medicinal products, lower concentrations of sevoflurane may be required following administration of intravenous anesthetic agents such as propofol.
Sevoflurane is safe and effective when administered 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 fluids, 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. Interaction between sevoflurane and sympathomimetics (e.g., amphetamine, ephedrine) may lead to 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 used concomitantly with sevoflurane.
St. John’s wort. Cases of severe hypotension and delayed emergence from anesthesia have been reported in patients who have chronically taken St. John’s wort.
Barbiturates. Sevoflurane is compatible 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 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, 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 enhance the metabolism of sevoflurane and lead to a significant increase in plasma fluoride concentrations (see section "Pharmacological properties"). Concomitant administration of sevoflurane and isoniazid may potentiate the hepatotoxic effects of isoniazid.
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.
In cases of supplemental alfentanil-N2O anesthesia, sevoflurane potentiates neuromuscular blockade caused by pancuronium, vecuronium, and atracurium. Dose adjustments for these muscle relaxants when co-administered with sevoflurane are similar to those required with isoflurane. The effect of sevoflurane on succinylcholine and the duration of action of depolarizing neuromuscular blockers has not been studied.
Reducing the dose of neuromuscular blockers during induction of anesthesia may delay the onset of conditions suitable for tracheal intubation or result in inadequate muscle relaxation, as potentiation of muscle relaxant effects occurs within several minutes after initiating sevoflurane administration.
Interactions with non-depolarizing neuromuscular blockers such as pancuronium, vecuronium, and atracurium have been studied. In the absence of specific recommendations, the dose of non-depolarizing muscle relaxants should not be reduced for endotracheal intubation. During maintenance of anesthesia, the dose of non-depolarizing muscle relaxants should be reduced as with N2O-opioid anesthesia. Additional doses of muscle relaxants should only be administered after assessing response to neurostimulation.
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 narcotic or other medicinal products causing respiratory depression.
Respiration must be monitored, and emergency medical assistance should be provided if necessary.
Sevoflurane must be administered only by personnel trained in the administration of general anesthesia. Equipment for maintaining airway patency, artificial ventilation, oxygen supply, and circulatory support 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 use with sevoflurane should be used. General anesthesia should be individualized based on the patient's response to anesthesia. As anesthesia deepens, arterial hypotension and respiratory depression increase.
There have been isolated reports of QT interval prolongation, very rarely associated with torsades de pointes, which in exceptional cases has been fatal. Sevoflurane should be used with caution in patients predisposed to such conditions.
Isolated cases of ventricular extrasystoles in children with Pompe disease have been reported.
General anesthesia, including sevoflurane, should be used with caution in patients with mitochondrial disorders.
All patients receiving sevoflurane anesthesia must be under continuous monitoring, including electrocardiogram (ECG), arterial pressure, oxygen saturation, and end-tidal CO2 partial pressure. The presence of concomitant risk factors should be considered.
During maintenance of anesthesia, increasing the concentration of sevoflurane leads to dose-dependent reduction in arterial pressure. Excessive reduction in arterial pressure may be related to the depth of anesthesia and can be corrected in such cases by reducing the inspired concentration of sevoflurane. Particular caution should be exercised when dosing patients with hypovolemia, hypotension, or other hemodynamic disturbances, for example, due to concomitant medications. As with any anesthetic agents, in patients with ischemic heart disease, it is important to maintain hemodynamic stability to prevent myocardial ischemia.
Recovery from anesthesia should be carefully assessed before transferring the patient from the postoperative unit.
Although recovery of consciousness after sevoflurane administration usually occurs within a few minutes, the effect on intellectual abilities has not been studied during the 2–3 days following anesthesia. As with other anesthetics, minor mood changes may occur during the first few days after anesthesia (see section "Ability to influence reaction speed 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").
Liver function impairment
In post-marketing studies, very rare cases of mild, moderate, and severe postoperative liver dysfunction or hepatitis, with or without jaundice, have been reported. A careful clinical assessment is required when using sevoflurane in patients with concomitant liver function impairment or those receiving medications that may impair liver function (see section "Adverse reactions").
There have been reports that prior use of halogenated hydrocarbon anesthetics may increase the risk of liver injury, particularly if the interval between administrations is less than 3 months.
Malignant hyperthermia
In susceptible individuals, potent inhalational anesthetic agents may trigger a hypermetabolic state in skeletal muscle, leading to increased oxygen demand and resulting in a clinical syndrome known as malignant hyperthermia. This clinical 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 has been reported in clinical trials. 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 must be monitored and maintained if possible.
Perioperative hyperkalemia
The use of inhaled anesthetic agents 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. Particularly susceptible patients 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 were also observed in these patients. Although these manifestations resemble malignant hyperthermia, no patient exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and intensive correction of hyperkalemia and treatment of resistant arrhythmias are recommended, followed by evaluation for latent neuromuscular disorders.
Patients with renal impairment
Due to the limited number of patients with renal impairment studied [baseline serum creatinine level above 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.
When sevoflurane comes into direct contact with CO2 absorbents, small amounts of Compound A (pentafluoroisopropenyl fluoromethyl ether, PIFFE) and negligible amounts of Compound B (pentafluoromethoxyisopropyl fluoromethyl ether, PMFE) are formed. Levels of Compound A increase with higher canister temperature, higher anesthetic concentration, lower gas flow rates, and are greater when potassium hydroxide (e.g., Baralyme®) is used compared to soda lime.
Compound A concentrations observed in clinical practice average 19 ppm in adults (maximum 32 ppm) when soda lime is used as the CO2 absorbent.
Although the use of sevoflurane in low-flow systems is limited, no evidence of renal dysfunction related to Compound A has been observed.
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 (see sections "Special precautions for use. 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 is required before administering sevoflurane to patients with risk factors. In children, the depth of anesthesia should be limited. EEG monitoring may help optimize sevoflurane dosing and prevent seizures in susceptible patients.
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 had no risk factors for seizures. A careful clinical decision should be made when using sevoflurane in patients who may be at risk of seizures (see section "Adverse reactions").
Bradycardia in Down syndrome
Episodes of severe bradycardia and cardiac arrest, not related to congenital heart defects, have been reported during induction of anesthesia with sevoflurane in children with Down syndrome. In most cases, bradycardia improved with reduction in sevoflurane concentration, airway maneuvers, or administration of anticholinergic agents or epinephrine.
Heart rate should be closely monitored during induction, and a gradual increase in inspired sevoflurane concentration to achieve adequate anesthesia should be considered. Anticholinergic agents and epinephrine should be readily available during induction in this patient group.
Replacement of dried CO2 absorbents
Rare cases of intense heating, smoke, and/or spontaneous ignition in anesthetic equipment have been reported during sevoflurane use in combination with desiccated CO2 absorbents, particularly those containing potassium hydroxide (e.g., Baralyme®). Unusually slow increases or unexpected decreases in inspired sevoflurane concentration compared to vaporizer settings may be associated with excessive heating of the CO2 absorbent canister.
Exothermic reactions, enhanced decomposition of sevoflurane, and formation of degradation products may occur when CO2 absorbent becomes desiccated, for example, after prolonged exposure to dry gas flow through the absorbent canisters. Degradation products of sevoflurane (methanol, formaldehyde, carbon monoxide, and Compounds A, B, C, and D) have been observed in the breathing circuit of experimental anesthetic systems using desiccated CO2 absorbents and maximum sevoflurane concentrations (8%) over prolonged periods (≥2 hours). Formaldehyde concentrations observed in the anesthetic breathing circuit (using absorbents containing sodium hydroxide) corresponded to levels known to cause mild respiratory irritation. The clinical significance of degradation products observed in this extreme experimental model is unknown.
The following clinical manifestations have been reported in association with these rare events: failed induction or inadequate depth of sevoflurane anesthesia; signs of airway irritation in the patient, such as coughing, hypoxia, increased airway pressure, labored breathing, marked airway edema and hyperemia, and elevated carboxyhemoglobin levels.
If excessive heating of the CO2 absorbent canister is observed, the clinical situation should be evaluated and consideration given to disconnecting the patient from anesthesia.
If a healthcare provider suspects that the CO2 absorbent is desiccated, it should be replaced before further use of volatile anesthetics (such as sevoflurane). It should be noted that color indicators do not always change after drying. Therefore, absence of significant color change should not be taken as a guarantee of adequate moisture. CO2 absorbents should be replaced regularly regardless of the color indicator status.
Anesthetic machines should be completely turned off after use, the integrity of packaging of new CO2 absorbents should be checked before use, and the temperature of CO2 absorbent canisters should be monitored during use.
Use during pregnancy or breastfeeding.
Pregnancy
There are no adequate and well-controlled studies of sevoflurane use in pregnant women; 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 "Pharmacological properties. 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, as reported in studies of its use during termination of pregnancy. Its use during labor is limited to one small study during cesarean section. A careful clinical decision should be made when using sevoflurane for obstetric anesthesia.
Lactation period
It is unknown whether sevoflurane or its metabolites are excreted in breast milk. Due to the lack of documented experience in women, breastfeeding should be discontinued for 48 hours after sevoflurane administration.
Fertility
Animal studies have not shown any evidence of impaired fertility with sevoflurane administration at doses up to 1 MAC.
Ability to influence reaction speed when driving or operating machinery.
As with other medicinal products, patients should be advised that activities requiring mental alertness, such as driving a vehicle or operating dangerous machinery, may be impaired for some time after general anesthesia (see section "Special precautions for use").
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 titrated and increased according to the desired effect, taking into account the patient's age and clinical status. A short-acting barbiturate or another intravenous induction agent may be administered initially, followed by inhalation of sevofluorane. For induction, sevoflurane can be administered in oxygen or in a mixture of oxygen with nitrous oxide.
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 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 (Minimum Alveolar Concentration) 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 that required in patients aged 20 years.
The table below provides average MAC values for different age groups.
Table 1
| MAC of sevoflurane in adults and children depending on patient age |
||
| Patient age |
Sevoflurane in oxygen |
Sevoflurane in 65% N2O/35% O2* |
| 0–1 month** |
3.3% |
2.0% |
| 1 month – <6 months |
3.0% |
|
| 6 months – <3 years |
2.8% |
|
| 3–12 years |
2.5% |
|
| 25 years |
2.6% |
1.4% |
| 40 years |
2.1% |
1.1% |
| 60 years |
1.7% |
0.90% |
| 80 years |
1.4% |
0.70% |
* For children aged 1 – < 3 years, 60% N2O/40% O2 was used.
** Term newborns. MAC has not been determined in preterm newborns.
Emergence from anesthesia
After sevoflurane anesthesia, emergence is usually rapid. Therefore, patients may require early postoperative analgesia.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Children.
Sevoflurane may be used in term neonates 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.
Adverse Reactions
Like all potent inhalational anesthetics, sevoflurane may cause dose-dependent respiratory and cardiac depression. Most adverse effects are mild and moderate in severity and transient in nature. Postoperatively, nausea, vomiting, and delirium are commonly observed. These events are often consequences of surgical intervention and general anesthesia, may be associated with the inhalational anesthetic, other drugs administered intra- or postoperatively, and the patient's response to surgery; their incidence is similar to that observed with other inhalational anesthetic agents.
Adverse reactions observed in patients during clinical trials
Adverse reactions are categorized by system organ class and frequency of occurrence (over 10% – very common, 1–10% – common, 0.1–1% – uncommon, 0.1–0.01% – rare, less than 0.01% – very rare, including isolated reports); frequency unknown (cannot be estimated from available data).
In adult patients, very common adverse reactions include nausea, vomiting, and arterial hypotension; in elderly patients – arterial hypotension, nausea, bradycardia; in pediatric patients – very common adverse reactions include nausea, vomiting, agitation, and cough. 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: leucopenia, leukocytosis.
Psychiatric disorders
Very common: agitation.
Uncommon: confusion.
Nervous system disorders
Common: dizziness, somnolence, headache.
Cardiac disorders
Very common: bradycardia.
Common: tachycardia.
Uncommon: complete atrioventricular block, atrial fibrillation, arrhythmia, ventricular extrasystoles, supraventricular extrasystoles, extrasystoles.
Frequency unknown: QT interval prolongation associated with torsade de pointes arrhythmia.
Vascular disorders
Very common: arterial hypotension.
Common: arterial hypertension.
Respiratory, thoracic and mediastinal disorders
Very common: cough.
Common: respiratory disorders, laryngospasm.
Uncommon: apnea, hypoxia, asthma.
Gastrointestinal disorders
Very common: nausea, vomiting.
Common: hypersalivation.
Renal and urinary disorders
Uncommon: urinary retention, glucosuria.
General disorders
Common: chills, fever, hypothermia.
Investigations
Common: changes in serum glucose levels, changes in liver function tests5, increased ALT, increased AST, changes in leukocyte count, transient increase in serum inorganic fluoride levels1.
Uncommon: increased creatinine, lactate dehydrogenase.
Injury, poisoning and procedural complications
Common: hypothermia.
Post-marketing experience with sevoflurane
Adverse reactions reported from spontaneous reports; frequency and causal relationship cannot be established.
Immune system disorders: anaphylactic reactions1, hypersensitivity1, anaphylactoid reactions.
Nervous system disorders: seizures2,3, muscle dystonia.
Cardiac disorders: cardiac arrest4, QT interval prolongation associated with torsade de pointes arrhythmia, bradycardia in patients with Down syndrome.
Respiratory, thoracic and mediastinal disorders: dyspnea1, wheezing1, bronchospasm, pulmonary edema, apnea.
Renal and urinary disorders: acute renal failure.
Hepatobiliary disorders: hepatitis1,2, liver failure1,2, hepatic necrosis1,2.
Skin and subcutaneous tissue disorders: rash1, contact dermatitis1, facial swelling1, urticaria, pruritus.
General disorders: chest discomfort1, malignant hyperthermia.
Musculoskeletal and connective tissue disorders: muscle twitching.
1 See section "Adverse Reactions. Description of selected adverse reactions".
2 See section "Special precautions for use".
3 See section "Adverse Reactions. Pediatrics".
4 Very rare cases of cardiac arrest have been reported with the use of sevoflurane.
5 Transient changes in liver function tests have been observed in rare cases during the use of sevoflurane and similar agents.
Description of selected adverse reactions
Transient increase in serum inorganic fluoride levels may occur during and after sevoflurane anesthesia. Peak concentrations are typically reached within 2 hours after the end of anesthesia and return to preoperative levels within 48 hours. In clinical studies, elevated fluoride concentrations were not associated with impaired renal function.
Rare cases of hepatitis have been reported in the postoperative period. Additionally, rare post-marketing reports of liver failure and hepatic necrosis have been associated with the use of potent volatile anesthetics, including sevoflurane; however, a definitive causal relationship with sevoflurane has not been established (see section "Special precautions for use").
Rare cases of hypersensitivity (including contact dermatitis, rash, dyspnea, wheezing, chest discomfort, facial swelling, or anaphylactic reaction) have been reported, particularly with prolonged use of inhalational anesthetics, including sevoflurane.
In susceptible individuals, potent inhalational anesthetic agents may trigger a hypermetabolic state in skeletal muscle, leading to increased oxygen demand and the development of a clinical syndrome known as malignant hyperthermia (see section "Special precautions for use").
Pediatrics
The use of sevoflurane has been associated with seizures. Many of these occurred in children from two months of age and young adults, most of whom had no identifiable risk factors for seizures. Clinical judgment should be exercised when administering sevoflurane to patients who may be at risk of developing seizures (see section "Special precautions for use").
Reporting of adverse reactions
Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions.
Keep out of reach of children. Store at temperatures not exceeding 25 °C in the original packaging. Do not freeze.
Packaging.
250 ml in aluminum bottles, hermetically sealed with U-Fill adapters for contact-free vaporizer filling. 1 bottle per cardboard box.
Prescription status. Prescription only.
Manufacturer.
LLC "Yuria-Pharm".
Manufacturer's address and location of operations.
108 Kobzarska Street, Cherkasy, Cherkasy region, Ukraine. Tel.: (044) 281-01-01.