Sevo-anesteran

INSTRUCTION
for medical use of medicinal product

SEVO-ANESTERAN
(SEVO-ANESTERAN)

Composition:

Active substance: sevoflurane;

1 vial contains 100 ml or 250 ml of sevoflurane.

Pharmaceutical form. Inhalation liquid.

Basic physico-chemical properties: colorless transparent liquid.

Pharmacotherapeutic group.

General anesthetics. Halogenated hydrocarbons. 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 irritation of the upper respiratory tract and does not cause increased tracheobronchial tree secretion or central nervous system stimulation. In pediatric practice studies (mask induction), coughing incidence 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 CO2 reactivity.

Sevoflurane does not have clinically significant effects 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 low blood solubility of sevoflurane, alveolar concentration rapidly increases after administration and rapidly decreases after discontinuation of the anesthetic agent.

Rapid and extensive elimination of sevoflurane by the lungs minimizes the amount of anesthetic available for metabolism. In humans, < 5% of absorbed sevoflurane is metabolized via cytochrome P450 (CYP) 2E1, resulting in 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 observed. This is the only fluorinated volatile anesthetic not metabolized to trifluoroacetic acid.

Fluoride ion concentration depends on 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, inorganic fluoride concentrations exceeding 50 μM were detected, but no clinical impact on kidney function was observed.

Clinical studies

Efficacy studies

Numerous clinical studies of sevoflurane as an anesthetic agent have been conducted in children and adult patients. Study results demonstrated that sevoflurane causes smooth, rapid induction and 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 where induction was performed via mask, sevoflurane provided smooth and rapid induction anesthesia. In three outpatient studies and twenty-five inpatient studies involving 3591 adult patients (2022 received sevoflurane, 1196 isoflurane, 111 enflurane, and 262 propofol), sevoflurane was established as an effective agent for maintenance of anesthesia. Sevoflurane proved adequate for use in neurosurgery, cesarean section, aortocoronary bypass, and in patients without cardiac disease but at risk of myocardial ischemia.

Anesthesia in children

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

Safety studies

Clinical trials were conducted in various patient groups (children, adults, elderly patients, patients with renal or hepatic insufficiency, obese patients, patients undergoing cardiac bypass surgery, patients receiving aminoglycosides or metabolic inducers, patients with repeated surgeries, patients undergoing surgery longer than 6 hours). Laboratory parameter assessments (ALT, AST, alkaline phosphatase, total bilirubin, serum creatinine, blood urea nitrogen) along with adverse reaction rates (in studies) related to liver or kidney function showed that sevoflurane has no clinically significant effect on liver or kidney function and does not worsen existing renal or hepatic insufficiency in the studied population (see sections "Special precautions for use" and "Adverse reactions"). Study data also demonstrated no statistically significant difference in the number of patients with changes in any clinical-chemical parameters when sevoflurane was compared to other inhalational anesthetics. Renal function impact was comparable with sevoflurane and other inhalational anesthetics, regardless of anesthetic circuit type, anesthetic delivery rate, and in patients with inorganic fluoride concentrations ≥ 50 μM and < 50 μM. 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 corresponds to that in general surgical practice. In all cases, there was either an alternative cause or a justified explanation for renal dysfunction development.

Children

In some published studies involving children, cognitive deficits were observed after repeated or prolonged exposure to anesthetics at early life stages. These studies have significant limitations, and it remains unclear whether observed effects were due to anesthetic/sedative use or other factors such as surgery or underlying disease. Furthermore, these data were not confirmed in later published registration trials. Published animal studies investigating certain anesthetics/sedatives reported adverse effects on early-life brain development (see "Non-clinical safety data").

Patients with hepatic insufficiency

During clinical trials, 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 existing hepatic insufficiency. Hepatic adverse reactions observed in post-marketing studies are described in sections "Special precautions for use" and "Adverse reactions".

Patients with renal insufficiency

The impact of sevoflurane was evaluated in patients with renal insufficiency with serum creatinine levels ≥ 1.5 mg/dL (130 μmol/L). Based on frequency and amplitude of creatinine concentration changes, 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 on Kelvin scale).

Distribution 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 component/gas at 25 °C for polymers used for medical purposes:

electrical 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 if stored under normal room lighting. No significant degradation occurs in the presence of strong acids or heat exposure. 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 of the anesthesia machine. When using fresh absorbents, 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 CO2 absorbent (especially potassium hydroxide-containing, 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 with 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 and is comparable in toxicity to sevoflurane. Formaldehyde is present in normal metabolic processes. When used with very dry absorbent, formaldehyde may decompose into methanol and formate. Formate (formic acid residue) 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, 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.

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 during inpatient and outpatient surgeries.

Contraindications.

Confirmed or suspected genetic predisposition to malignant hyperthermia.

Confirmed or suspected increased sensitivity to sevoflurane or other halogen-containing anesthetics (e.g., history of liver function impairment, usually with elevated liver enzymes, fever, leukocytosis and/or eosinophilia, of unknown origin following administration of halogen-containing anesthetics).

When general anesthesia is contraindicated.

Interaction with other medicinal products and other types of interactions.

During sevoflurane anesthesia, beta-sympathomimetics such as isoprenaline, and alpha- and beta-sympathomimetics such as adrenaline and noradrenaline, should be used with caution due to potential risk of ventricular arrhythmia.

Non-selective MAO inhibitors: risk of crisis during surgery. Therapy should be discontinued 2 weeks before surgery.

Sevoflurane may cause pronounced arterial hypotension in patients receiving calcium channel antagonists – dihydropyridine derivatives.

Caution is advised when co-administering calcium channel antagonists with inhalational anesthetics due to risk of additive negative inotropic effect.

Concomitant use of succinylcholine and inhalational anesthetics rarely is associated with cases of elevated serum potassium levels leading to cardiac arrhythmia and fatal outcomes in pediatric patients during the postoperative period.

As with other medicinal products, after intravenous anesthetic administration (e.g., propofol), a lower concentration of sevoflurane may be required.

Sevoflurane is safe and effective when used with drugs commonly used in surgical practice, such as central nervous system-acting drugs, autonomic nervous system-acting drugs, 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 arrhythmogenic effects of exogenously administered adrenaline.

Indirect-acting sympathomimetics. Interaction of sevoflurane with sympathomimetics (amphetamine, ephedrine) carries 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 with concomitant use of verapamil and sevoflurane.

St. John's wort. Cases of severe hypotension and delayed emergence from anesthesia have been reported in patients who have taken St. John's wort for a prolonged period.

Metabolism of sevoflurane may be enhanced by known CYP2E1 inducers (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. Sevoflurane is compatible in combination with barbiturates commonly used in surgical practice.

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

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

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

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

In cases of additional anesthesia with alfentanil-N2O, sevoflurane potentiates neuromuscular blockade caused by pancuronium, vecuronium, atracurium. The effect of sevoflurane on succinylcholine and duration of action of depolarizing neuromuscular blockers has not been studied.

Reducing neuromuscular blocker doses 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 several minutes after initiation of sevoflurane administration.

Interactions with non-depolarizing neuromuscular blockers such as pancuronium, vecuronium, atracurium have been studied. In the absence of specific instructions for endotracheal intubation, non-depolarizing muscle relaxant doses should not be reduced; during maintenance of anesthesia, non-depolarizing muscle relaxant doses should be reduced as with N2O-opioid anesthesia. Additional muscle relaxant doses should be administered only after assessment of response to neurostimulation. As with other anesthetic use, after intravenous anesthetic administration (e.g., propofol), a lower concentration of sevoflurane may be required. Significant increase in plasma fluoride concentration has been observed after increased CYP 2E1 activity.

Special precautions for use.

Sevoflurane may cause respiratory depression, which is enhanced during premedication with narcotics or other respiratory depressant medicinal products.

Respiration must be monitored and emergency medical assistance provided if necessary. Sevoflurane should be administered only by medical personnel trained in general anesthesia. Equipment for maintaining airway patency, artificial ventilation, oxygen supply, and circulatory resuscitation must be available. The concentration of sevoflurane delivered from the vaporizer must be precisely known. Since volatile anesthetics differ in physical properties, only vaporizers specifically calibrated for sevoflurane use should be used. General anesthesia administration must be individualized based on patient response to anesthesia. With increasing anesthesia depth, arterial hypotension and respiratory depression increase.

There have been reports that prior use of anesthetics – halogenated hydrocarbons, especially if the interval between administrations was less than 3 months – may increase the potential risk of liver injury.

There have been isolated reports of QT interval prolongation, very rarely associated with torsades de pointes ventricular tachycardia, which in exceptional cases was 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.

Liver

Very rare cases of mild, moderate, and severe postoperative liver function impairment 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 function impairment or when using drugs causing liver function impairment (see section "Adverse reactions"). It has been reported that prior use of halogenated hydrocarbon anesthetics may increase the risk of liver injury, especially if the interval between administrations is less than 3 months.

General

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

Recovery after anesthesia must be carefully assessed before transferring the patient from the postoperative room.

Although recovery of consciousness after sevoflurane use usually occurs within several minutes, effects on intellectual abilities during 2–3 days after anesthesia have not been studied. As with other anesthetics, minor mood changes may be observed during several days after anesthesia (see section "Ability to influence reaction rate when driving vehicles or operating other machinery").

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

Sevoflurane use has been associated with seizures in children and young people up to 21 years of age, as well as in elderly individuals, regardless of presence of seizure predisposition risk factors. Clinical assessment of patients is required before sevoflurane use in cases of seizure risk. In children, anesthesia depth should be limited. Electroencephalography (EEG) can help optimize sevoflurane dosage and prevent seizure development in predisposed patients.

Malignant hyperthermia

In susceptible patients, potent inhalational anesthetics may trigger a hypermetabolic state in skeletal muscle, increasing oxygen demand and leading to a clinical syndrome known as malignant hyperthermia. This syndrome manifests as hypercapnia and may include non-specific signs such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmia, 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 development was reported in clinical trials. Malignant hyperthermia has also been observed in post-marketing studies. In some cases, fatal outcomes were reported.

Treatment of malignant hyperthermia includes discontinuation of triggering agents (e.g., sevoflurane), intravenous administration of sodium dantrolene (see sodium dantrolene instructions for medical use), and supportive therapy consisting of vigorous measures to normalize body temperature, support respiratory and circulatory function, and correct water-electrolyte imbalances.

Renal failure may develop later; therefore, diuresis must be monitored and maintained if possible.

Perioperative hyperkalemia

Use of inhalational anesthetics is associated with rare cases of elevated plasma potassium levels, which may manifest as arrhythmias; fatal cases in the postoperative period have occurred 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. In these patients, significant elevation of plasma CPK levels was also observed, and in some cases myoglobinuria. Despite similarities to malignant hyperthermia, no patient exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and intensive correction of hyperkalemia and arrhythmia treatment are recommended, followed by investigation for latent neuromuscular disorders.

Patients with renal insufficiency

Due to limited number of studied patients with renal insufficiency (baseline serum creatinine level – 133 μmol/L (1.5 mg/dL)), safety of sevoflurane use in this group has not been fully established. Therefore, sevoflurane should be prescribed with caution in patients with renal insufficiency.

In some rat studies, nephrotoxicity was observed in animals exposed to compound A (pentafluoroisopropenyl fluoromethyl ether (PIFE)) exceeding levels usually observed in routine clinical practice. The mechanism of this renal toxicity in rats is unknown, and its significance for humans has not been established.

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 taken.

Seizures

Rare cases of seizures during sevoflurane use have been reported (see special precautions for use in sections "Children" and "Adverse reactions").

There is an association between sevoflurane use and seizure development observed in children and young patients, as well as in elderly patients, both with and without seizure predisposition risk factors. Clinical assessment of seizure risk is required before sevoflurane use in patients with risk factors. In children, anesthesia depth should be limited. EEG monitoring may help optimize sevoflurane dosage and prevent seizure development in predisposed patients (see section "Children").

Children

Sevoflurane use has been associated with seizures. Many occurred in children from 2 months of age and young adults, most of whom had no seizure predisposition risk factors. Clinical judgment should be exercised when using sevoflurane in patients at risk of seizure development (see section "Special precautions for use" – "Seizures").

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

Replacement of dried CO2 absorbents

Rare cases of severe heating, smoke, and/or spontaneous ignition in anesthesia machines have been reported during sevoflurane use in combination with dried CO2 absorbents, particularly those containing potassium hydroxide (e.g., Baralyme). Unusually slow increase or unexpected decrease in inhaled sevoflurane concentration compared to vaporizer setting may be associated with excessive heating of the CO2 absorbent canister.

Exothermic reaction, enhanced sevoflurane decomposition, and formation of degradation products may occur when CO2 absorbent is dried, e.g., after prolonged dry gas flow through CO2 absorbent canisters. Degradation products of sevoflurane (methanol, formaldehyde, carbon monoxide, and compounds A, B, C, D) have been observed in the breathing circuit of experimental anesthesia machines using dried CO2 absorbents and maximum sevoflurane concentrations (8%) over prolonged periods (≥ 2 hours). Formaldehyde concentration observed in the anesthesia respiratory circuit (using absorbents containing sodium hydroxide) corresponded to levels known to cause mild respiratory tract irritation. Clinical significance of degradation products observed in this extreme experimental model is unknown.

If a healthcare professional suspects that the CO2 absorbent is dried, it should be replaced before subsequent use of volatile anesthetics such as sevoflurane. It should be noted that color indicators do not always change after desiccation. Therefore, absence of significant color change should not be considered a guarantee of adequate moisture. CO2 absorbents should be changed regularly regardless of color indicator status.

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 use. Adequately controlled clinical studies of sevoflurane use in pregnant women are lacking; therefore, the drug may be used in pregnant women only if clearly needed.

Published animal studies on use of certain anesthetics/sedatives have reported adverse effects on early-life brain development (see "Non-clinical safety data").

Safety of sevoflurane use 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 potential risk of uterine hemorrhage. Clinical judgment should be exercised when using sevoflurane in obstetric anesthesia.

It is unknown whether sevoflurane or its metabolites pass into breast milk. Due to lack of documented experience with drug use during breastfeeding, women should discontinue breastfeeding for 48 hours after sevoflurane administration.

Fertility

Studies in rats and rabbits did not reveal any signs of fertility impairment with sevoflurane use at doses up to 1 MAC.

Ability to influence reaction rate when driving vehicles or operating other machinery.

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

Method of administration and dosage.

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

Induction

Dose must be individually adjusted and increased to desired effect according to patient age and clinical status. A short-acting barbiturate or other intravenous induction agent may be administered, followed by inhalation of sevoflurane. For induction, sevoflurane may be inhaled in oxygen or in a mixture of oxygen with nitrous oxide.

In adults, surgical anesthesia is usually achieved within less than 2 minutes with sevoflurane inhalation at concentrations up to 5%. In children, surgical anesthesia is usually achieved within less than 2 minutes with sevoflurane inhalation at concentrations up to 7%.

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

Maintenance

Surgical level of anesthesia can be maintained with sevoflurane concentrations from 0.5% to 3% with or without nitrous oxide (see section "Interaction with other medicinal products and other types of interactions").

MAC of sevoflurane decreases with age and with addition of nitrous oxide. The average sevoflurane concentration required to achieve MAC in 80-year-old patients is approximately 50% of the concentration required for 20-year-old patients.

The table below shows 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.

Emergence from anesthesia

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

Children.

Sevoflurane may 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.

Adverse reactions.

Like all potent inhalational anesthetic agents, sevoflurane may cause dose-dependent respiratory and cardiac depression. The severity of most adverse reactions is mild to moderate and transient. In the postoperative period, nausea, vomiting, and delirium are commonly observed; these are often consequences of surgical intervention and general anesthesia, may be associated with the inhalational anesthetic, other intra- or postoperatively administered drugs, and the patient's response to surgery; their incidence is similar to that observed with other inhalational anesthetics.

Adverse reactions observed in patients during clinical trials

Adverse reactions are categorized by organ systems and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

In adult patients, nausea, vomiting, and arterial hypotension were very commonly observed; in elderly patients – arterial hypotension, nausea, bradycardia; in children – nausea, vomiting, agitation, and coughing 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; common – tachycardia; uncommon – complete atrioventricular block, atrial fibrillation, arrhythmia, ventricular extrasystoles, supraventricular extrasystoles, extrasystoles; frequency not known – cardiac arrest⁴, QT interval prolongation associated with Torsade de pointes arrhythmia.

Vascular disorders: very common – arterial hypotension; common – arterial hypertension.

Psychiatric disorders: very common – agitation; uncommon – confusion.

Nervous system disorders: common – dizziness, somnolence, headache; frequency not known – seizures^2,3, dystonia.

Respiratory, thoracic and mediastinal disorders: very common – cough; common – respiratory disorders, laryngospasm; uncommon – apnea, hypoxia, asthma; frequency not known – bronchospasm, dyspnea¹, wheezing¹, pulmonary edema.

Renal and urinary disorders: uncommon – urinary retention, glucosuria; frequency not known – acute renal failure.

General disorders: common – chills, fever, hypothermia; frequency not known – chest discomfort¹, malignant hyperthermia^1,2.

Investigations: common – change in serum glucose level, change in liver function tests⁵, increased ALT, AST (transient changes in liver function tests have been observed rarely with sevoflurane and similar agents), change in leukocyte count, transient increase in serum inorganic fluoride levels, which may occur during and after sevoflurane anesthesia (maximum inorganic fluoride concentration is usually reached 2 hours after the end of sevoflurane anesthesia and returns to preoperative levels within 48 hours; in clinical studies, elevated fluoride levels were not associated with impaired renal function); uncommon – increased creatinine, lactate dehydrogenase levels.

Adverse reactions reported via spontaneous reports; frequency and causal relationship cannot be established.

Immune system disorders: anaphylactic reactions¹, hypersensitivity¹ (may be associated with hypersensitivity reactions, especially with prolonged exposure to inhalational anesthetics), anaphylactoid reactions.

Hepatobiliary disorders: hepatitis^1,2, liver failure^1,2, and hepatic necrosis^1,2, although the link to sevoflurane has not been definitively established.

Skin and subcutaneous tissue disorders: rash, contact dermatitis¹, facial swelling¹ (may be associated with hypersensitivity reactions, especially with prolonged exposure to inhalational anesthetics), urticaria, pruritus.

Musculoskeletal and connective tissue disorders: muscle twitching.

¹See section "Adverse reactions" ("Description of selected adverse reactions").

²See section "Special precautions for use".

³See section "Adverse reactions" ("Children").

⁴Very rare post-marketing reports of cardiac arrest associated with sevoflurane use.

⁵Isolated cases of transient changes in liver function tests have been reported with sevoflurane and reference agents.

⁶Transient increase in serum inorganic fluoride levels may occur during and after sevoflurane anesthesia. See description of selected adverse reactions below.

Description of selected adverse reactions

Transient increase in serum inorganic fluoride levels may occur during and after sevoflurane anesthesia. Inorganic fluoride concentration usually peaks within two hours after the end of sevoflurane anesthesia and returns to preoperative levels within 48 hours. In clinical studies, elevated fluoride concentration was not associated with renal dysfunction.

There are rare reports of postoperative hepatitis. Additionally, rare post-marketing reports of liver failure and hepatic necrosis have been associated with the use of potent volatile anesthetics, including sevoflurane. However, the actual incidence and causal relationship to sevoflurane cannot be definitively established (see section "Special precautions for use").

Rare reports of hypersensitivity (including contact dermatitis, rash, dyspnea, wheezing, chest discomfort, facial swelling, or anaphylactic reaction) have been received, particularly in relation to prolonged occupational exposure to inhalational anesthetics, including sevoflurane.

In susceptible individuals, potent inhalational anesthetics may trigger a hypermetabolic state in skeletal muscles, leading to increased oxygen demand and a clinical syndrome known as malignant hyperthermia (see section "Special precautions for use").

Children

Sevoflurane use has been associated with seizures. Many of these occurred in children and young people from 2 months of age, most of whom had no predisposing risk factors. Clinical caution should be exercised when administering sevoflurane to patients who may be at risk of seizures (see section "Special precautions for use").

Preclinical safety data

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

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

In animals, sevoflurane markedly suppresses electrical brain activity (EEG findings), 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 were 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 comparable threshold limits for compound A-related nephrotoxicity in humans would be 150–200 ppm. Compound A concentrations recorded 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 periods of rapid brain growth or synaptogenesis, may lead to neuronal and oligodendrocyte cell loss in the developing brain, as well as changes in synaptic morphology and neurogenesis, particularly after exposures exceeding 3 hours. These studies involved anesthetic agents from various drug classes. The clinical significance of these non-clinical data is still being investigated
(see section "Pharmacodynamics").

Reporting suspected adverse reactions

Reporting adverse reactions after drug approval is of significant importance. 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 through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C, in the original packaging. Keep out of reach of children.

Packaging.

100 ml or 250 ml of solution in a vial with a ring (nebulizer adapter); 1 vial per cardboard box.

Prescription category.

By prescription only. For hospital use only.

Manufacturer.

K.T. ROMPHARM COMPANY S.R.L.

S.C. ROMPHARM COMPANY S.R.L.

Manufacturer's address and place of business.

1A Eroilor Street, Otopeni, 075100, Ilfov County, Romania – Rompharm 1 and Rompharm 2 buildings.