Dexanest concentrate for solution for infusion 100 mcg/ml ampoule 2 ml No. 5

Instructions Dexanest concentrate for solution for infusion 100 mcg/ml ampoule 2 ml No. 5

Composition

active ingredient: dexmedetomidine hydrochloride;

1 ml of solution contains dexmedetomidine hydrochloride 118 μg, equivalent to 100 μg of dexmedetomidine;

Excipients: sodium chloride, water for injections.

Dosage form

Concentrate for solution for infusion.

Main physicochemical properties: transparent colorless solution.

Pharmacotherapeutic group

Psycholeptics. Other hypnotics and sedatives.

ATX code N05C M18.

Pharmacological properties

Pharmacodynamics.

Dexmedetomidine is a highly selective alpha-2 receptor agonist with a broad spectrum of pharmacological properties. It has a strong sympatholytic effect by reducing the release of noradrenaline from sympathetic nerve endings. The sedative effects are due to reduced excitation of the macula lutea, the main noradrenergic nucleus located in the brainstem. By acting on this area, dexmedetomidine exerts a sedative effect (similar to natural non-rapid eye movement sleep), acquiring the ability to exert a sedative effect while allowing the patient to be awake and active. Dexmedetomidine has an anesthetic and moderate analgesic effect; analgesic effect has been demonstrated in patients with chronic low back pain. The effect on the cardiovascular system is dose-dependent; at lower infusion rates, the central effect dominates, causing a decrease in heart rate and blood pressure. At higher doses, peripheral vasoconstrictor effects predominate, contributing to an increase in systemic vascular resistance and blood pressure, while the bradycardic effect becomes more pronounced. Dexmedetomidine has practically no depressant effect on the respiratory system.

Sedation in hospital settings (in intensive care, anesthesiology and resuscitation departments)

Evidence of efficacy in the pediatric population was obtained in a placebo-controlled study in a large number of postoperative patients aged 1 month to ≤ 17 years. Approximately 50% of patients treated with dexmedetomidine did not require the addition of midazolam during the treatment period, which lasted an average of 20.3 hours and did not exceed 24 hours. Data on treatment durations longer than 24 hours are not available. Data in neonates (28–44 weeks of gestation) are limited and relate to low doses (≤ 0.2 μg/kg/h). Neonates may be particularly sensitive to the bradycardic effects of dexmedetomidine in hypothermia and in conditions where the heart rate is dependent on cardiac output.

Procedural sedation

The safety and efficacy of dexmedetomidine for the sedation of non-intubated patients before and/or during surgical and diagnostic procedures were evaluated in two randomized, double-blind, placebo-controlled, multicenter clinical trials.

Study 1 randomized patients undergoing elective surgical procedures under controlled anesthesia and local/regional anesthesia to receive a loading infusion of dexmedetomidine 1 μg/kg (n = 129) or 0.5 μg/kg (n = 134) or placebo (saline; n = 63) over 10 minutes, followed by a maintenance infusion starting at 0.6 μg/kg/h.

Study 2 randomized patients undergoing conscious fiberoptic endotracheal intubation under local anesthesia to receive a loading infusion of dexmedetomidine 1 μg/kg (n = 55) or placebo (saline) (n = 50) over 10 minutes followed by a fixed maintenance infusion of 0.7 μg/kg/h. To maintain a Ramsey sedation score > 2, 53% of patients receiving dexmedetomidine did not require midazolam rescue therapy compared with 14% of patients receiving placebo. The risk difference in the proportion of patients randomized to dexmedetomidine who did not require midazolam rescue therapy was 43% (95% CI: 23–57%) compared with placebo. The mean rescue dose of midazolam was 1.1 mg in the dexmedetomidine group and 2.8 mg in the placebo group. The difference in mean rescue dose of midazolam was -1.8 mg (95% CI: -2.7 to -0.86) in favor of dexmedetomidine.

Pharmacokinetics.

The pharmacokinetics of dexmedetomidine have been evaluated after short-term intravenous administration to healthy volunteers and after long-term infusion to intensive care unit patients. Dexmedetomidine exhibits a 2-compartment distribution pattern. In healthy volunteers, it exhibits a rapid distribution phase with a central estimated half-life (t1/2α) of approximately 6 min. The estimated terminal half-life (t1/2) is approximately 2.1 (± 0.43) hours and the estimated steady-state volume of distribution (Vss) is approximately 91 (± 25.5) liters. The estimated plasma clearance (Cl) is approximately 39 (± 9.9) l/h. The mean body weight associated with these Vss and Cl estimates was 69 kg. The plasma pharmacokinetics of dexmedetomidine are similar in intensive care patients after infusions > 24 hours. The estimated pharmacokinetic parameters are as follows: t1/2 is approximately 1.5 hours, Vss is approximately 93 liters and Cl is approximately 43 liters/hour. The pharmacokinetics of dexmedetomidine are linear over the dose range of 0.2–1.4 μg/kg/hour and do not accumulate during treatment for up to 14 days. Dexmedetomidine is 94% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.85–85 ng/mL. Dexmedetomidine binds to human serum albumin and alpha-1-acid glycoprotein, with serum albumin being the major binding protein for dexmedetomidine in plasma.

Dexmedetomidine is extensively metabolized by the liver. There are three types of initial metabolic reactions: direct N-glucuronidation, direct N-methylation and oxidation catalyzed by cytochrome P450. The most abundant circulating metabolites of dexmedetomidine are two isomeric N-glucuronides, one of which is formed by oxidation of the imidazole ring, and the other is the product of the following sequential processes: N-methylation, hydroxylation of the methyl group and O-glucuronidation. Available data indicate that the formation of the oxidized metabolites is mediated by CYP forms (CYP2A6, CYP1A2, CYP2E1, CYP2D6 and CYP2C19). These metabolites have little pharmacological activity.

Following intravenous administration of radiolabeled dexmedetomidine, an average of 95% of the radioactivity was recovered in the urine and 4% in the feces after nine days. The major metabolites in urine are two isomeric N-glucuronides, which together account for approximately 34% of the dose, and the N-methylated O-glucuronide, which accounts for 14.51% of the dose. Minor carboxylic acid metabolites, the 3-hydroxy and O-glucuronide metabolites, individually account for 1.11–7.66% of the dose. Less than 1% of the unchanged parent compound was recovered in the urine. Approximately 28% of the metabolites recovered in urine are unidentified polar metabolites.

No significant pharmacokinetic difference was observed depending on the gender or age of the patient.

Dexmedetomidine plasma protein binding is reduced in subjects with hepatic impairment compared to healthy volunteers. The mean percentage of unbound dexmedetomidine in plasma ranged from 8.5% in healthy volunteers to 17.9% in patients with severe hepatic impairment. Subjects with varying degrees of hepatic impairment (Child-Pugh class A, B or C) had reduced hepatic clearance of dexmedetomidine and a prolonged plasma elimination half-life (t1/2). The mean clearance in patients with mild, moderate and severe hepatic impairment was 74%, 64% and 53% of that in healthy volunteers, respectively. The mean t1/2 in patients with mild, moderate and severe hepatic impairment was prolonged to 3.9, 5.4 and 7.4 hours, respectively. Although dexmedetomidine is administered until the onset of effect, it may be appropriate to reduce the initial/maintenance dose in patients with hepatic impairment depending on the degree of impairment and clinical response.

The pharmacokinetics of dexmedetomidine in patients with severe renal impairment (creatinine clearance < 30 ml/min) are unchanged.

Data on use in children from neonates (born at 28 to 44 weeks of gestation) to 17 years are limited. The half-life of dexmedetomidine in children (1 month to 17 years) is likely to be similar to that in adults, but in neonates (born at 28 to 44 weeks of gestation) it is higher and decreases with age. In the age groups 1 month to 6 years, weight-adjusted plasma clearance is higher but decreases with age. Due to immaturity in neonates (under 1 month of age), plasma clearance may be lower (0.9 l/h/kg) than in older age groups.

Indication

For sedation in hospital settings (in intensive care, anesthesiology and resuscitation departments) of patients who require a level of sedation no deeper than awakening in response to vocal stimulation.

For sedation of patients during diagnostic or surgical procedures requiring sedation/procedural sedation.

Contraindication

Hypersensitivity to dexmedetomidine or to any of the excipients of the medicinal product.

Atrioventricular block II–III degree (in the absence of an artificial pacemaker).

Uncontrolled arterial hypotension.

Acute cerebrovascular pathology.

Interaction with other medicinal products and other types of interactions

Drug interaction studies have only been conducted in adults.

Concomitant use of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids may lead to potentiation of their effects, as confirmed in studies with isoflurane, propofol, alfentanil, and midazolam.

No pharmacokinetic interactions have been observed between dexmedetomidine and isoflurane, propofol, alfentanil and midazolam. However, due to possible pharmacodynamic interactions, a reduction in the dose of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic or opioid may be necessary when these agents are used in combination with dexmedetomidine.

Studies in human liver microsomes have examined the ability of dexmedetomidine to inhibit cytochrome P450, including the CYP2B6 isoenzyme. Based on in vitro studies, there is a potential for interactions between dexmedetomidine and substrates (mainly CYP2B6) in vivo.

Induction of dexmedetomidine by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A4 isoenzymes has been observed in vitro, therefore such an interaction in vivo cannot be excluded. The clinical significance is unknown.

The possibility of increased hypotensive and bradycardic effects should be considered in patients receiving other drugs that cause such effects, such as β-blockers (although the additional effects in the interaction study with esmolol were modest).

Application features

Dexanest is intended for use in hospital settings (in intensive care, anesthesiology, and resuscitation departments), operating rooms, and during diagnostic procedures; its use in other settings is not recommended.

During infusion of Dexamethasone, cardiac function should be monitored continuously in all patients. Respiratory function should be monitored in non-intubated patients due to the risk of respiratory depression and, in some cases, apnea.

The recovery time after administration of dexmedetomidine is approximately one hour. When used in an outpatient setting, close monitoring should continue for at least one hour (or longer depending on the patient's condition), with medical supervision continuing for an additional hour for patient safety.

General warnings

Dexanest should not be administered as a bolus and loading dose is not recommended in the intensive care unit. Therefore, users should be prepared to use an alternative sedative for immediate control of agitation or during procedures, especially during the first few hours of treatment. During procedural sedation, a small bolus dose of another sedative may be used if a rapid increase in sedation is required.

Some patients receiving dexmedetomidine have experienced mild awakening and rapid recovery after stimulation. In the absence of other clinical symptoms, this feature alone should not be considered a failure of the drug.

Dexmedetomidine does not usually cause deep sedation, so patients can be easily awakened. Therefore, dexmedetomidine is not suitable for patients who require continuous deep sedation.

Dexanest should not be used as a general anesthetic for induction of intubation or to provide sedation with muscle relaxants.

Dexanest is unlikely to suppress seizure activity and should therefore not be used as monotherapy in status epilepticus.

Caution should be exercised when administering dexmedetomidine concomitantly with medicinal products that have sedative effects or affect the cardiovascular system due to a possible additive effect.

Dexmedetomidine is not recommended for patient-controlled sedation. If Dexmedetomidine is used in an outpatient setting, the patient may be discharged under third-party supervision. Patients should refrain from driving or performing other hazardous tasks and, if possible, avoid the use of other sedatives (e.g., benzodiazepines, opioids, alcohol) for a period of time, depending on the effects of dexmedetomidine observed, the procedure, concomitant medications, age, and condition of the patient.

Mortality in intensive care unit patients aged ≤ 65 years

In the pragmatic SPICE III randomized controlled trial of 3904 adult critically ill intensive care unit patients, there was no overall difference in 90-day mortality between the dexmedetomidine group and the usual care group (mortality 29.1% in both groups), but there was heterogeneity in this effect related to age. Dexmedetomidine was associated with increased mortality in the age group ≤ 65 years (odds ratio 1.26; 95% confidence interval 1.02 to 1.56) compared with alternative sedative agents. Although the mechanism is unclear, this age-related heterogeneity in mortality was most pronounced in cases where high-dose dexmedetomidine was used early to achieve deep sedation in patients admitted for reasons other than postoperative care, and increased with increasing APACHE II scores. There was no effect on mortality when dexmedetomidine was used for light sedation. These findings should be weighed against the expected clinical benefit of dexmedetomidine compared with alternative sedative agents in younger patients.

Effects on the heart and blood vessels - warnings

Dexanest reduces heart rate and blood pressure (central sympatholytic action), but at higher concentrations causes peripheral vasoconstriction, leading to an increase in blood pressure. Therefore, Dexanest is not suitable for patients with severe cardiovascular disease.

Dexmedetomidine should be administered with caution to patients with concomitant bradycardia. Data on the effect of the drug in patients with heart rates < 60 are limited, so such patients should be closely monitored. Bradycardia usually does not require treatment, but is usually well controlled by the administration of m-cholinergic blockers and a reduction in the dose of the drug. Patients who are involved in sports and have a low heart rate may be particularly sensitive to the negative chronotropic effect of alpha-2 receptor agonists; cases of sinus node arrest have been described. Cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have also been reported.

In patients with concomitant arterial hypotension (especially refractory to vasoconstrictors), including chronic, hypovolemic or reduced functional reserve, such as patients with severe ventricular dysfunction and elderly patients, the hypotensive effect of Dexanest may be more pronounced - this requires special care for such patients. A decrease in blood pressure, as a rule, does not require special measures, but if necessary, one should be prepared to reduce the dose, administer volume expanders and/or vasoconstrictors.

In patients with damage to the peripheral autonomic nervous system (e.g. due to spinal cord injury), the hemodynamic effects after administration of Dexanest may be more pronounced and require special patient care.

A transient increase in blood pressure with concomitant peripheral vasoconstriction was observed with a loading dose of dexmedetomidine, therefore, the administration of a loading dose for sedation in a hospital setting (intensive care, anesthesiology and resuscitation departments) is not recommended. Treatment of elevated blood pressure is usually not necessary, but a reduction in the rate of administration should be considered.

Focal vasoconstriction at elevated concentrations may be more significant in patients with ischemic heart disease or severe cerebrovascular disease, and such patients should be carefully monitored. For patients with signs of myocardial or cerebral ischemia, dose reduction or discontinuation should be considered.

Caution should be exercised when administering dexmedetomidine together with spinal and epidural anesthesia due to an increased risk of hypotension and bradycardia.

Patients with hepatic impairment

Caution should be exercised in patients with severe hepatic impairment, as excessive administration of dexmedetomidine increases the risk of adverse reactions and excessive sedation as a result of reduced clearance of dexmedetomidine.

Patients with neurological disorders

Experience with Dexanest in severe neurological conditions such as head trauma and the postoperative period after neurosurgery is limited, so it should be used with caution in such conditions, especially if deep sedation is required. When choosing a therapy, it should be taken into account that Dexanest reduces cerebral blood flow and intracranial pressure.

Other caveats

Dexmedetomidine may cause hyperthermia that may be refractory to conventional cooling methods. Dexmedetomidine should be discontinued in the event of persistent fever of unknown etiology. Dexmedetomidine is not recommended for use in patients predisposed to malignant hyperthermia.

Diabetes insipidus has been reported in association with dexmedetomidine treatment. If polyuria occurs, it is recommended to discontinue dexmedetomidine and monitor serum sodium and urine osmolality.

Dexanest contains less than 1 mmol sodium (23 mg) per ml.

Use during pregnancy or breastfeeding

Pregnancy: There are no or limited amount of data from the use of dexmedetomidine in pregnant women. Animal studies have shown reproductive toxicity. Dexanest should not be used during pregnancy unless the clinical condition of the woman requires treatment with dexmedetomidine.

Breastfeeding. Dexmedetomidine is excreted in human milk, but levels are below the detection limit 24 hours after discontinuation of the drug. A risk to the infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue dexmedetomidine therapy taking into account the benefit of breast-feeding for the infant and the benefit of dexmedetomidine therapy for the mother.

Fertility: Fertility studies in rats have shown no effect of dexmedetomidine on male or female fertility. There are no data on the effect on human fertility.

Ability to influence reaction speed when driving vehicles or other mechanisms

Patients are advised to refrain from driving or performing other hazardous tasks for a period of time after administration of Dexanest for procedural sedation.

Method of administration and doses

For sedation in hospital settings (in intensive care, anesthesiology and resuscitation departments) of patients requiring a level of sedation no deeper than awakening in response to vocal stimulation.

For hospital use only.

Dosage for adults

Patients who are already intubated and sedated can be switched to Dexanest with an initial infusion rate of 0.7 mcg/kg/h, which can be gradually adjusted within the dose range of 0.2–1.4 mcg/kg/h to achieve the desired level of sedation. For debilitated patients, the lowest initial infusion rate should be considered. It is important to note that dexmedetomidine is very potent, so the infusion rate is indicated for one hour. After dose adjustment, it may take up to 1 hour to achieve a stable level of sedation.

The maximum dose of 1.4 mcg/kg/h should not be exceeded. Patients who fail to achieve adequate sedation with the maximum dose of Dexanest should be switched to an alternative sedative.

The use of a loading dose of Dexanest for sedation is not recommended as it is associated with an increased level of side effects. If necessary, propofol or midazolam can be used until the clinical effect of dexmedetomidine is achieved.

The duration of the course of use depends on the need for the patient to be in a state of sedation. There is no experience of using the drug Dexanest for a period of more than 14 days. When using the drug for more than 14 days, the patient's condition should be regularly assessed.

For sedation of patients during diagnostic or surgical procedures requiring sedation/procedural sedation.

Dexamethasone should only be administered by healthcare professionals who are qualified to administer anesthesia to patients in operating rooms or during diagnostic procedures. When Dexamethasone is administered for conscious sedation, patients should be under the constant supervision of persons not involved in the diagnostic or surgical procedure. Patients should be monitored closely for early signs of hypotension, hypertension, bradycardia, respiratory depression, airway obstruction, respiratory arrest, dyspnea, and/or oxygen desaturation (see section 4.8).

Supplemental oxygen should be available and administered immediately if indicated. Oxygen saturation should be monitored by pulse oximetry.

Dexmedetomidine is administered as a loading infusion followed by a maintenance infusion. Depending on the procedure, concomitant local anaesthesia or analgesia may be required to achieve the desired clinical effect. Additional analgesia or sedatives (e.g. opioids, midazolam or propofol) are recommended for painful procedures or when greater depth of sedation is required. The pharmacokinetic half-life of dexmedetomidine is approximately 6 minutes, which can be taken into account together with the effects of other administered medicinal products to estimate the appropriate time required for titration to the desired clinical effect of Dexmedetomidine.

Loading infusion of 1.0 mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg over 10 minutes may be used.

Maintaining procedural sedation.

Maintenance infusion is generally initiated at a dose of 0.6–0.7 mcg/kg/h and titrated to achieve the desired clinical effect in a dose range of 0.2 to 1 mcg/kg/h. The maintenance infusion rate should be adjusted until the target level of sedation is achieved.

Elderly patients: No dose adjustment is usually necessary for elderly patients (see section 5.2). Elderly patients are at increased risk of hypotension (see section 4.4), however, the limited available data on the outcome of procedural sedation do not indicate a clear dose-response relationship.

Renal impairment: Dosage adjustment is usually not required in patients with renal impairment.

Hepatic impairment: Dexanest is metabolized in the liver and should be used with caution in patients with hepatic impairment. A reduced maintenance dose should be considered.

Method of application

Dexanest should be administered by persons experienced in the treatment of patients requiring intensive care. The medicinal product should only be administered as a diluted intravenous infusion using a controlled infusion device.

Ampoules and vials are intended for individual use by one patient only.

Solution preparation

Before use, Dexanest can be diluted in 5% glucose solution, Ringer's solution, mannitol or 0.9% sodium chloride solution to achieve the desired concentration of 4 μg/ml or 8 μg/ml. The table below shows the volumes required for infusion.

To achieve a concentration of 4 μg/mL:

To achieve a concentration of 8 μg/mL:

Shake gently to mix the solution well.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration.

Dexanest is compatible with the following intravenous fluids and drugs: lactated Ringer's solution, 5% glucose solution, 0.9% sodium chloride solution, 20% mannitol, sodium thiopental, etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium besylate, mivacurium chloride, rocuronium bromide, glycopyrrolate bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, noradrenaline, dobutamine, midazolam, morphine sulfate, fentanyl citrate and plasma substitute (Haemaccel®).

Children

The safety and efficacy of Dexanest in children (aged 0 to 18 years) have not been established. Data on use in children are provided in the sections “Pharmacological properties” and “Adverse reactions”, but no dosage recommendations can be given.

Overdose

Several cases of overdose with dexmedetomidine have been reported in clinical and post-marketing studies. The reported infusion rates of dexmedetomidine in these cases were 60 mcg/kg/h over 36 minutes and 30 mcg/kg/h over 15 minutes in a 20-month-old child and an adult, respectively. The most common adverse reactions reported in association with overdose include bradycardia, hypotension, hypertension, excessive sedation, respiratory depression, and cardiac arrest.

In case of overdose with clinical symptoms, the infusion of Dexanest should be reduced or stopped. Cardiovascular effects are mainly expected and should be treated according to clinical indications. At high concentrations, hypertension may be more pronounced than hypotension. In clinical studies, cases of sinus node arrest resolved spontaneously or responded to treatment with atropine or glycopyrrolate. In isolated cases of severe overdose, leading to cardiac arrest, resuscitation measures were required.

Side effects

Sedation of adult patients in the intensive care unit.

The most commonly reported adverse reactions with dexmedetomidine in the intensive care unit setting are hypotension, hypertension and bradycardia, occurring in approximately 25%, 15% and 13% of patients, respectively. Hypotension and bradycardia were also the most common serious adverse reactions associated with dexmedetomidine, occurring in 1.7% and 0.9% of randomized patients in the intensive care unit, anesthesiology and intensive care units, respectively.

The most commonly reported adverse reactions with dexmedetomidine for procedural sedation are listed below (the phase III study protocols contained pre-specified thresholds for changes in blood pressure, respiratory rate and heart rate as adverse effects):

hypotension (55% in the dexmedetomidine group compared to 30% in the placebo group, who received backup therapy with midazolam and fentanyl);

respiratory depression (38% in the dexmedetomidine group compared to 35% in the placebo group, who received backup therapy with midazolam and fentanyl);

bradycardia (14% in the dexmedetomidine group compared to 4% in the placebo group, who received backup therapy with midazolam and fentanyl).

The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency unknown (cannot be estimated from the available data).

From the endocrine system.

Frequency unknown: diabetes insipidus.

From the side of metabolism and nutrition.

Common: hyperglycemia, hypoglycemia.

Uncommon: metabolic acidosis, hypoalbuminemia.

Mental disorders.

Often: agitation.

Uncommon: hallucinations.

From the heart.

Very common: bradycardia1,2.

Common: myocardial ischemia or infarction, tachycardia.

Uncommon: atrioventricular block, decreased cardiac output, cardiac arrest.

From the side of the vessels.

Very common: hypotension1,2, hypertension1,2.

On the part of the respiratory system.

Very common: respiratory depression2,3.

Uncommon: dyspnoea, apnoea.

From the digestive system.

Common: nausea2, vomiting, dry mouth2.

Uncommon: abdominal bloating.

General disorders and administration site reactions.

Common: withdrawal syndrome, hyperthermia.

Uncommon: drug ineffectiveness, thirst.

1 See “Description of selected adverse reactions” below.

2The adverse reaction was also observed in procedural sedation studies.

3Frequency “often” in studies in intensive care unit settings.

Description of selected adverse reactions

In relatively healthy volunteers who were not in the intensive care unit, bradycardia occasionally resulted in sinus node arrest or sinus pause with dexmedetomidine. Symptoms resolved with elevation of the lower extremities and administration of anticholinergic agents such as atropine or glycopyrrolate. In isolated cases, bradycardia progressed to periods of asystole in patients who had previously suffered from bradycardia.

Cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have also been reported.

Hypertension has been associated with the use of a loading dose. This reaction can be reduced by avoiding the loading dose or by reducing the infusion rate or reducing the loading dose.

Pediatric group. When administered for up to 24 hours in patients aged 1 month and older, mainly postoperative, who were in intensive care units, the drug demonstrates a safety profile similar to that in adults. Data on neonates (born between 28 and 44 weeks of gestation) are also limited by the maintenance dose range ≤ 0.2 μg/kg/h. A single case of hypothermic bradycardia in a neonate has been reported.

Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.

Expiration date

2 years.

From a microbiological point of view, this product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Storage conditions

Does not require special storage conditions.

Keep out of reach of children.

Incompatibility.

Use only those specified in the section "Method of administration and doses"