Dexmedetomidine EVER Pharma^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Ever Valinject, GmbH (Austria)

Manufactured By

Ever Pharma Jena, GmbH (Germany)

Contact Information

EVER Neuro Pharma LLC (Russia)

ATC Code

N05CM18 (Dexmedetomidine)

Active Substance

Dexmedetomidine (Rec.INN registered by WHO)

Dosage Form

Dexmedetomidine EVER Pharma®

Concentrate for solution for infusion 100 mcg/1 ml: amp. 2 ml 5 pcs.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion in the form of a transparent, colorless solution.

Excipients : sodium chloride – 9 mg, water for injections – up to 1 ml.

2 ml – ampoules of colorless glass (5) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Sedative agent for intravenous anesthesia

Pharmacotherapeutic Group

Sedative

Pharmacological Action

Pharmacodynamics

Dexmedetomidine is a selective α₂-adrenoreceptor agonist with a wide spectrum of pharmacological properties. It has a sympatholytic effect due to the reduction of norepinephrine release from sympathetic nerve endings. The sedative effect is due to reduced excitation in the locus coeruleus of the brainstem (a nucleus with a predominance of noradrenergic neurons).

Dexmedetomidine has analgesic and anesthetic/analgesic-sparing effects. Cardiovascular effects are dose-dependent: at low infusion rates, the central effect predominates, leading to a decrease in heart rate and blood pressure. When using high doses, peripheral vasoconstriction predominates, leading to an increase in total vascular resistance, blood pressure, and a further increase in bradycardia. Dexmedetomidine has virtually no ability to depress respiration when administered as monotherapy to healthy patients.

Sedation of adult patients in the anesthesiology, resuscitation, and intensive care unit (ARICU)

In placebo-controlled studies in patients in the postoperative intensive care unit, previously intubated and sedated with midazolam or propofol, Dexmedetomidine significantly reduced the need for additional sedation (midazolam or propofol) and opioids over 24 hours. Most patients receiving Dexmedetomidine did not require additional sedation. Patients could be successfully extubated without discontinuing the Dexmedetomidine EVER Pharma^® infusion. Studies conducted outside intensive care units confirmed that Dexmedetomidine can be safely administered to patients without tracheal intubation provided adequate monitoring conditions are available.

Dexmedetomidine was similar to midazolam (risk ratio 1.07; 95% CI: 0.971-1.176) and propofol (risk ratio 1.00; 95% CI: 0.922-1.075) in terms of time within the target sedation range in predominantly medical intensive care unit patients requiring long-term light to moderate sedation (RASS from 0 to -3) for up to 14 days; it reduced the duration of mechanical ventilation compared to midazolam and time to tracheal extubation compared to propofol and midazolam. Patients receiving Dexmedetomidine woke up more easily, cooperated better with staff, and reported pain intensity better compared to patients receiving midazolam or propofol.

Patients receiving Dexmedetomidine developed arterial hypotension and bradycardia more frequently, but tachycardia less frequently compared to patients receiving midazolam, and developed tachycardia more frequently, but the incidence of arterial hypotension was similar compared to patients receiving propofol. The incidence of delirium, assessed using the CAM-ICU (Confusion Assessment Method for the Intensive Care Unit) scale, was lower in the study compared to midazolam, and adverse events related to delirium occurred less frequently in the dexmedetomidine group compared to propofol. Those patients whose sedation was discontinued due to insufficient sedation level were switched to propofol or midazolam.

The risk of insufficient sedation level was higher in patients who were difficult to sedate with standard methods immediately compared to patients who were switched to another sedative method.

Sedation of children in the anesthesiology, resuscitation, and intensive care unit (ARICU)

The efficacy and safety of dexmedetomidine for sedation in the ARICU was studied in a group of children aged 12-17 years (n=57). Sedation with dexmedetomidine was administered for up to 5 days as an IV infusion without a loading dose, the initial dose was 0.7 mcg/kg/h with the possibility of titration in the range of 0.2-1.4 mcg/kg/h to achieve the target sedation value. 92% of patients (95% CI: 86.04-95.80%) were at the target sedation level, 98.2% of patients (95% CI: 87.76-99.77%) did not require additional therapy with sedative drugs.

Confirmation of the efficacy of dexmedetomidine was previously obtained in a dose-controlled study in the ARICU in a large postoperative population of children aged from 1 month to ≤ 17 years. Approximately 50% of patients receiving Dexmedetomidine did not require additional sedation with midazolam during the treatment period of 20.3 hours, but not exceeding 24 hours. There are no data on the use of the drug for more than 24 hours in the age group under 12 years. Information on the use of the drug in neonates (28-44 weeks gestation) is very limited and describes only the use of low doses (≤ 0.2 mcg/kg/hour). Neonates may be particularly sensitive to the bradycardic effect of Dexmedetomidine in the presence of hypothermia and in conditions where cardiac output is heart rate-dependent.

In double-blind comparator-controlled studies in the ARICU, the incidence of adrenal cortex suppression in patients receiving Dexmedetomidine (n=778) was 0.5% compared to 0% in patients receiving either midazolam (n=338) or propofol (n=275). This adverse event was noted as mild in 1 case and moderate in 3 cases.

Sedation during anesthetic management in adults during diagnostic and surgical procedures/conscious sedation

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

In the first study, patients undergoing certain operations/procedures under monitored anesthesia care and local/regional anesthesia were randomized to receive a loading dose of dexmedetomidine 1 mcg/kg (n=129), or 0.5 mcg/kg (n=134), or placebo (saline; n=63) over more than 10 minutes, followed by a maintenance infusion at a rate of 0.6 mcg/kg/h. The maintenance infusion rate of the study drug was titrated from 0.2 mcg/kg/h to 1 mcg/kg/h. The number of patients who achieved the target sedation level (Observer’s Assessment of Alertness/Sedation Scale, OAA/S ≤ 4), without the need for administration of the rescue sedative midazolam, was 54% of patients in the group receiving 1 mcg/kg dexmedetomidine and 40% in the group receiving 0.5 mcg/kg dexmedetomidine, compared to 3% of patients in the placebo group. The risk difference in the number of patients randomized to the dexmedetomidine 1 mcg/kg group and the dexmedetomidine 0.5 mcg/kg group, who did not require administration of the rescue sedative midazolam, was 48% (95% CI: 37-57%) and 40% (95% CI: 28-48%), respectively, compared to placebo. The median dose of the rescue sedative midazolam was 1.5 (0.5-0.7) mg in the dexmedetomidine 1.0 mcg/kg group, 2 (0.5-8.0) mg in the dexmedetomidine 0.5 mcg/kg group, and 4.0 (0.5-14.0) mg in the placebo group. The difference in mean values of the rescue midazolam dose in the dexmedetomidine 1 mcg/kg group and the dexmedetomidine 0.5 mcg/kg group compared to placebo was -3.1 mg (95% CI: -3.8 – -2.5) and -2.7 mg (95% CI: -3.3 – -2.1), respectively, in favor of dexmedetomidine. The mean time to administration of the first dose of rescue midazolam was 114 minutes in the dexmedetomidine 1 mcg/kg group, 40 minutes in the dexmedetomidine 0.5 mcg/kg group, and 20 minutes in the placebo group.

In the second study, patients undergoing awake fiberoptic tracheal intubation under local anesthesia were randomized to receive a loading infusion of dexmedetomidine at a dose of 1 mcg/kg (n=55) or placebo (saline) (n=50) over more than 10 minutes followed by a constant maintenance infusion at a rate of 0.7 mcg/kg/h. The number of patients in whom it was possible to achieve and maintain the target sedation level >2 on the RSS (Ramsay Sedation Scale) without administration of the rescue sedative midazolam was 53% in the Dexmedetomidine group compared to 14% in the placebo group. The risk difference in the number of patients randomized to the dexmedetomidine group who did not require rescue therapy with midazolam was 43% (95% CI: 23-57%) compared to placebo. The mean dose of the rescue sedative midazolam was 1.1 mg in the dexmedetomidine group and 2.8 mg in the placebo group. The difference in mean midazolam dose values was -1.8 mg (95% CI: -2.7 – -0.86) in favor of dexmedetomidine.

Pharmacokinetics

The pharmacokinetics of dexmedetomidine were studied in healthy volunteers after short-term IV administration and in ICU patients after long-term infusion administration of the drug.

Distribution

Dexmedetomidine follows a two-compartment distribution model. In healthy volunteers, Dexmedetomidine undergoes a rapid distribution phase with a distribution half-life (T_1/2α) of 6 min. The mean terminal half-life (T_1/2) is approximately 1.9-2.5 hours (min – 1.35 hours, max – 3.68 hours) and the mean steady-state volume of distribution (V_ss) is approximately 1.16-2.16 L/kg (90-151 L). The mean plasma clearance (Cl) is 0.46-0.73 L/h/kg (35.7-51.1 L/h). The mean body weight characteristic of the indicated V_ss and Cl was 69 kg.

The plasma pharmacokinetics of dexmedetomidine in ICU patients after drug administration >24 hours are comparable. The estimated pharmacokinetic parameters are: T_1/2 approximately 1.5 hours, V_ss approximately 93 L, and Cl approximately 43 L/h. In the dose range from 0.2 to 1.4 mcg/kg/h, the pharmacokinetics of dexmedetomidine are linear, and it does not accumulate during treatment lasting up to 14 days. Plasma protein binding of dexmedetomidine is 94%. The degree of plasma protein binding is constant in the concentration range from 0.85 to 85 ng/ml. Dexmedetomidine binds to both human serum albumin and α₁-acid glycoprotein, with serum albumin being the main protein to which Dexmedetomidine binds in plasma.

Metabolism and Excretion

Dexmedetomidine is completely metabolized in the liver. Initial metabolism proceeds via 3 metabolic pathways: direct N-glucuronidation, direct N-methylation, and cytochrome P450-mediated oxidation. The predominant metabolites in the bloodstream are two isomeric N-glucuronides.

Metabolite H-1 (N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide) is also a major circulating biotransformation product of dexmedetomidine. Cytochrome P450 catalyzes the formation of 2 minor circulating metabolites: 3-hydroxymethyldexmedetomidine is formed by hydroxylation of the 3-methyl group of dexmedetomidine and H-3 is formed by oxidation of the imidazole ring. According to available information, the formation of oxidized metabolites involves a number of cytochrome P450 isoenzymes (CYP2A6, CYP1A2, CYP2E1, CYP2D6, and CYP2C19). These metabolites do not possess significant pharmacological activity.

After IV administration of radiolabeled dexmedetomidine, approximately 95% of the radioactivity was detected in the urine and 4% in the feces after 9 days. The main metabolites in the urine are 2 isomeric N-glucuronides, accounting for 34% of the administered dose, and N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide, accounting for 14.51% of the dose. Minor metabolites: Dexmedetomidine-carboxylic acid, 3-hydroxymethyldexmedetomidine and its O-glucuronide account for 1.11-7.66% of the dose. Less than 1% of unchanged dexmedetomidine is found in the urine. About 28% of the metabolites in the urine are unidentified minor ones.

Pharmacokinetics in Special Patient Groups

There are no significant differences in pharmacokinetics depending on age and gender. Compared to healthy volunteers, individuals with hepatic impairment have a reduced degree of dexmedetomidine binding to plasma proteins. The mean fraction of unbound dexmedetomidine ranged from 8.5% in healthy volunteers to 17.9% in individuals with severe hepatic impairment. In patients with varying degrees of hepatic impairment (Child-Pugh classes A, B, and C), the hepatic clearance of dexmedetomidine was reduced and the plasma T_1/2 was prolonged. The mean plasma clearance values of unbound dexmedetomidine in individuals with mild, moderate, and severe hepatic impairment were 59%, 51%, and 32%, respectively, of those observed in healthy volunteers. The mean T_1/2 in individuals with mild, moderate, and severe hepatic impairment was prolonged to 3.9 hours, 5.4 hours, and 74 hours, respectively.

Although dexmedetomidine dosing is adjusted based on the degree of sedative effect, in patients with hepatic impairment, depending on the degree of impairment or clinical response, a reduction in the initial or maintenance dose of the drug should be considered.

Compared to healthy volunteers, the pharmacokinetics of dexmedetomidine are unchanged in patients with severe renal impairment (CrCl < 30 ml/min).

Data for children, from neonates (born at 28-44 weeks gestation) to children aged 17 years, are limited. The T_1/2 of dexmedetomidine in children (from 1 month to 17 years) corresponds to that observed in adults, but an increase is observed in neonates (under 1 month). In age groups from 1 month to 6 years, the plasma clearance period adjusted for body weight is longer than in older children. In neonates (under 1 month), the plasma clearance period adjusted for body weight is shorter (0.9 L/h/kg) compared to older children due to immaturity. The available data are presented in the table below.

Indications

• Sedation in adult patients and children over 12 years of age in the anesthesiology, resuscitation, and intensive care unit, whose required sedation depth does not exceed awakening in response to vocal stimulation (corresponding to a range from 0 to -3 points on the Richmond Agitation-Sedation Scale (RASS));
• Sedation in non-intubated adult patients before and/or during diagnostic or surgical interventions, i.e., sedation during anesthetic management/conscious sedation.

ICD codes

Dosage Regimen

Sedation in adult patients and children over 12 years of age in the ARICU, whose required sedation depth does not exceed awakening in response to vocal stimulation (corresponding to a range from 0 to -3 points on the Richmond Agitation-Sedation Scale (RASS))

For hospital use only.

Dexmedetomidine EVER Pharma^® should be used by specialists experienced in the treatment of patients in intensive care settings.

Patients who are mechanically ventilated and sedated can be switched to Dexmedetomidine with an initial infusion rate of 0.7 mcg/kg/h followed by dose adjustment within the dose range of 0.2 to 1.4 mcg/kg/h to achieve the desired level of sedation depending on the patient’s response. For debilitated patients, a lower initial infusion rate should be considered. Dexmedetomidine is a potent agent, so its rate of administration is calculated per hour. After dose adjustment, achieving the target sedation depth may take up to one hour.

The maximum drug dosage of 1.4 mcg/kg/h should not be exceeded. Patients who do not achieve an adequate level of sedation at the maximum drug dosage should be switched to an alternative sedative drug.

Administration of a loading dose of the drug in the ARICU is not recommended, as this increases the frequency of adverse reactions. If necessary, propofol or midazolam may be used until the clinical effect of dexmedetomidine is achieved.

There is no experience with the use of Dexmedetomidine EVER Pharma^® for more than 14 days. When using the drug for more than 14 days, the patient’s condition must be regularly assessed.

Special patient groups for sedation in adult patients and children over 12 years of age in the ARICU

Elderly patients

Dose adjustment is usually not required (see section “Pharmacokinetics”). Elderly patients may have an increased risk of hypotension (see section “Special Instructions”), but limited data available regarding sedation during anesthetic management do not suggest a clear dose-dependence of this risk.

Renal impairment

Dose adjustment is usually not required.

Hepatic impairment

Dexmedetomidine is metabolized in the liver, so it should be used with caution in patients with hepatic impairment. Such patients are indicated for a reduction in the maintenance dose (see sections “Pharmacokinetics” and “Special Instructions”).

Children

Age group from 0 to 11 years. The safety and efficacy of dexmedetomidine have not been sufficiently studied in children from 0 to 11 years. Current available studies are described in the sections “Adverse Reactions”, “Pharmacodynamics” and “Pharmacokinetics”, but recommendations for use and dosing regimens for this patient group cannot be provided.

Age group from 12 to 17 years. The dosing regimen corresponds to the dosing regimen for adults.

Sedation during anesthetic management/conscious sedation

Dexmedetomidine EVER Pharma^® can be used by specialists experienced in providing anesthetic management to patients, in the operating room or during therapeutic or diagnostic procedures.

When using dexmedetomidine for conscious sedation, patients must be continuously monitored by personnel not involved in performing the diagnostic or surgical intervention.

Continuous monitoring of patients is necessary to detect early signs of hypotension, hypertension, bradycardia, respiratory depression, airway obstruction, apnea, dyspnea and/or decreased oxygen saturation.

Oxygen therapy must be available and should be applied immediately if indicated. Oxygen saturation should be monitored by pulse oximetry.

Administration of dexmedetomidine begins with a loading dose, followed by a maintenance infusion. Depending on the type of intervention, appropriate local/regional anesthesia or analgesia may be required to achieve the desired clinical effect. Additional analgesia or sedative agents (e.g., opioids, midazolam, propofol) are recommended in case of painful interventions or if a deeper level of sedation is required. The pharmacokinetic distribution half-life of dexmedetomidine is estimated to be approximately 6 minutes. This should be considered together with the effects of other administered drugs to assess the time needed for titration to achieve the desired clinical effect of dexmedetomidine.

Initiation of sedation during anesthetic management

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

Maintenance of sedation during anesthetic management

Maintenance infusion is usually started at a dose of 0.6-0.7 mcg/kg/h and titrated to achieve the desired clinical effect within a dose range of 0.2 to 1 mcg/kg/h. The maintenance infusion rate must be adjusted to achieve the target level of sedation.

Special patient groups for sedation during anesthetic management/conscious sedation

Elderly patients

Dose adjustment is usually not required (see section “Pharmacokinetics”). Elderly patients may have an increased risk of hypotension (see section “Special Precautions”), but limited data available regarding sedation during anesthetic management do not suggest a clear dose-dependency of this risk.

Renal impairment

Dose adjustment is usually not required.

Hepatic impairment

Dexmedetomidine is metabolized in the liver, therefore it should be used with caution in patients with hepatic impairment. A reduced maintenance dose is indicated for such patients (see sections “Pharmacokinetics” and “Special Precautions”).

Children

The safety and efficacy of dexmedetomidine have not been sufficiently studied in children from 0 to 18 years. Current available studies are described in the sections “Adverse Reactions”, “Pharmacodynamics” and “Pharmacokinetics”, but recommendations for use and dosing regimens for this patient group cannot be provided.

Method of administration

Dexmedetomidine EVER Pharma^® should be administered only after dilution as intravenous infusions using special equipment (infusion pump). Each ampoule/vial of the drug is intended for single patient use only.

The drug should not be administered as a bolus (see section “Special Precautions”).

Solution preparation

To achieve the recommended concentration (4 mcg/ml or 8 mcg/ml), the drug can be diluted in 5% dextrose solution, Ringer’s solution, mannitol solution or 0.9% sodium chloride solution. The table below shows the volume of concentrate and the required volume of infusion medium.

If the required concentration is 4 mcg/ml

If the required concentration is 8 mcg/ml

The prepared solution should be gently shaken to ensure complete mixing of the components.

Before administration, the solution must be visually inspected for mechanical inclusions or changes in color.

Dexmedetomidine EVER Pharma^® is pharmaceutically compatible with the following medicinal products: lactated Ringer’s solution, 5% dextrose solution, 0.9% sodium chloride solution, 20% mannitol solution, thiopental sodium, etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium besylate, mivacurium chloride, rocuronium bromide, glycopyrronium bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, norepinephrine, dobutamine, midazolam, morphine sulfate, fentanyl citrate, plasma substitutes. Unused product should be disposed of in accordance with local requirements.

Adverse Reactions

Summary of the safety profile

For sedation in adult patients and children over 12 years of age in the ICU, whose required depth of sedation does not exceed arousal to verbal stimulation (corresponding to a range of 0 to -3 points on the Richmond Agitation-Sedation Scale (RASS))

The most frequently reported adverse reactions to dexmedetomidine administration in the ICU setting are decreased or increased blood pressure and bradycardia, occurring in approximately 25%, 15%, and 13% of patients, respectively.

Decreased blood pressure and bradycardia were also the most common dexmedetomidine-related serious adverse reactions, occurring in 1.7% and 0.9% of randomized intensive care unit patients, respectively.

For sedation in non-intubated adult patients before and/or during diagnostic or surgical interventions, i.e., sedation during anesthetic management/conscious sedation

The most frequently reported adverse reactions when using dexmedetomidine during sedation for anesthetic management are listed below (phase III study protocols had predefined limits for changes in blood pressure, respiratory rate, and heart rate, which are considered adverse events)

• Hypotension (55% in the dexmedetomidine group compared to 30% in the placebo group receiving midazolam and fentanyl rescue therapy);
• Respiratory depression (38% in the dexmedetomidine group compared to 35% in the placebo group receiving midazolam and fentanyl rescue therapy);
• Bradycardia (14% in the dexmedetomidine group compared to 4% in the placebo group receiving midazolam and fentanyl rescue therapy).

Summary of adverse reactions

The adverse reactions listed below are based on pooled data from clinical studies in intensive care unit patients.

Adverse reactions are grouped by frequency using the following classification: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10000 to <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from the available data).

Endocrine disorders frequency not known – diabetes insipidus.

Metabolism and nutrition disorders: common – hyperglycemia, hypoglycemia; uncommon – metabolic acidosis, hypoalbuminemia.

Psychiatric disorders common – agitation; uncommon – hallucinations.

Cardiac disorders very common: bradycardia^1,2; common – myocardial ischemia or infarction, tachycardia; uncommon – atrioventricular block¹, decreased cardiac output, cardiac arrest¹.

Vascular disorders very common – decreased^1,2 or increased blood pressure^1,2.

Respiratory, thoracic and mediastinal disorders very common – respiratory depression^2,3; uncommon – dyspnea, apnea.

Gastrointestinal disorders common – nausea², vomiting, dry mouth²; uncommon – abdominal distension.

General disorders and administration site conditions common: withdrawal syndrome, hyperthermia; uncommon – drug ineffectiveness, thirst.

Renal and urinary disorders frequency not known – polyuria.

¹See description of selected adverse reactions below.

²Adverse reaction was also observed in studies of sedation during anesthetic management.

³Frequency “common” in the study of sedation in the intensive care setting.

Description of selected adverse reactions

Clinically significant decreases in blood pressure and bradycardia should be managed as indicated in the “Special Precautions” section.

In relatively healthy individuals not in the intensive care unit, administration of dexmedetomidine sometimes led to sinus node block. Symptoms were resolved by raising the legs (above the level of the head) and administration of anticholinergic agents (atropine and glycopyrronium bromide).

In some cases, in patients with pre-existing bradycardia, it progressed to episodes of asystole. Cases of cardiac arrest, often with preceding bradycardia or atrioventricular block, have also been reported.

Increased blood pressure was associated with the administration of a loading dose, therefore it can be avoided by avoiding the loading dose or by reducing the infusion rate or loading dose.

Children

The safety profile of dexmedetomidine for sedation for up to 5 days in adolescents (12-17 years) was similar to that in adults.

Treatment of children over 1 month of age, predominantly post-surgery, in the ICU, for up to 24 hours was evaluated; a safety profile comparable to that in adults was demonstrated. Data in neonates (24-44 weeks gestation) are very limited, the maintenance dose was < 0.2 mcg/kg/h. Literature sources reported a single case of hypothermic bradycardia in a newborn infant.

Reporting of suspected adverse effects

It is important to report adverse effects after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are asked to report any suspected adverse effects observed during the use of the drug through national adverse reaction reporting systems and/or to the company address listed below.

Contraindications

• Hypersensitivity to the components of the drug;
• Second- or third-degree atrioventricular block (in the absence of a pacemaker);
• Uncontrolled arterial hypotension;
• Acute cerebrovascular disease;
• Children under 12 years of age (for the indication “sedation during anesthetic management/conscious sedation” – children under 18 years of age).

Use in Pregnancy and Lactation

Pregnancy

Data on the use of dexmedetomidine in pregnant women are absent or limited.

Animal studies have shown reproductive toxicity. Dexmedetomidine EVER Pharma^® should not be used during pregnancy unless the woman’s clinical condition requires treatment with dexmedetomidine.

Breast-feeding period

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

Fertility

In a fertility study in rats, Dexmedetomidine had no effect on male and female reproductive performance. There are no data regarding effects on human fertility.

Use in Hepatic Impairment

Dexmedetomidine is metabolized in the liver, therefore it should be used with caution in patients with hepatic impairment. A reduced maintenance dose is indicated for such patients.

Use in Renal Impairment

Dose adjustment is usually not required.

Pediatric Use

Contraindicated for use in children under 12 years of age. For the indication “sedation during anesthetic management/conscious sedation” – contraindicated in children under 18 years of age.

Geriatric Use

Dose adjustment is usually not required. Elderly patients may have an increased risk of hypotension, but limited data available regarding sedation during anesthetic management do not suggest a clear dose-dependency of this risk.

Special Precautions

Dexmedetomidine EVER Pharma^® is intended for use in anesthesiology, intensive care and resuscitation settings, as well as in the operating room and during diagnostic interventions; its use in other settings is not recommended. Continuous cardiac monitoring should be performed during drug infusion. In non-intubated patients, respiratory monitoring should be performed due to the risk of respiratory depression and, in some cases, apnea (see section “Adverse Reactions”).

The recovery time after dexmedetomidine administration is about 1 hour. When used in an outpatient setting, careful monitoring should be continued for at least 1 hour (or for a longer period depending on the patient’s condition), and medical supervision should continue for another 1 hour to ensure patient safety.

The drug Dexmedetomidine EVER Pharma^® should not be administered as a bolus and the use of a loading dose in the ICU setting is not recommended. Concurrent use of an alternative sedative agent is permitted, especially during the first hours of treatment for acute agitation or during medical procedures.

During sedation for anesthetic management, small doses of bolus injections of another sedative agent can be used to rapidly achieve the desired level of sedation.

Some patients receiving Dexmedetomidine were easily awakened and became responsive quickly after physical or verbal stimulation. In the absence of other clinical symptoms, this sign alone should not be considered as drug ineffectiveness.

Dexmedetomidine usually does not cause deep sedation, so patients can be easily awakened. Consequently, Dexmedetomidine is not suitable for patients requiring deep sedation.

Dexmedetomidine should not be used as a general anesthetic for intubation or to provide sedation when muscle relaxants are used.

Dexmedetomidine does not suppress seizure activity, therefore it should not be used as monotherapy for status epilepticus.

Caution should be exercised when dexmedetomidine is used concomitantly with drugs that have a sedative effect or affect the cardiovascular system, due to the possibility of an additive effect. Dexmedetomidine EVER Pharma^® is not recommended for patient-controlled sedation. Relevant data are not available.

When the drug is used in an outpatient setting, discharge of patients is possible under the supervision of a third party. Patients should be advised to refrain from driving a car or engaging in other potentially hazardous activities and, if possible, to avoid using other agents that may have a sedative effect (e.g., benzodiazepines, opioids, alcohol) for a sufficient time according to the observed effects of dexmedetomidine, depending on the procedure, medications used, age and condition of the patients.

Elderly patients

Caution should be exercised when using dexmedetomidine in elderly patients. When using dexmedetomidine, patients over 65 years of age may be more prone to hypotension, particularly when using a loading dose and during procedures. Dose reduction should be considered.

Effects on the cardiovascular system and precautions

Dexmedetomidine reduces heart rate and blood pressure (central sympatholytic effect), but at higher concentrations it causes peripheral vasoconstriction, leading to increased blood pressure (see section “Pharmacodynamics”). Therefore, the drug Dexmedetomidine EVER Pharma^® is not suitable for patients with significant hemodynamic instability.

Caution should be exercised when administering dexmedetomidine to patients with concomitant bradycardia. Data on the effect of the drug in patients with a heart rate < 60 beats/min are limited, so such patients require special control and observation.

Bradycardia usually does not require treatment; if necessary, it is well managed by administration of anticholinergic agents or by reducing the drug dose. Athletes with a low heart rate may be particularly sensitive to the negative chronotropic effect of α₂-adrenoceptor agonists; cases of sinus node block have been described.

Cases of cardiac arrest, often with preceding bradycardia or atrioventricular block, have also been reported (see section “Adverse Reactions”).

In patients with concomitant arterial hypotension (especially refractory to vasoconstrictors), including chronic hypotension, hypovolemia, or reduced functional reserve, such as patients with severe ventricular dysfunction and the elderly, the hypotensive effect of dexmedetomidine may be more pronounced, requiring special attention to such patients (see section “Contraindications”). Decreased blood pressure usually 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 autonomic nervous system impairment (e.g., due to spinal cord injury), hemodynamic effects after drug administration may be more pronounced and require special monitoring.

Transient arterial hypertension was observed primarily during the administration of the loading dose due to the peripheral vasoconstrictor effect of dexmedetomidine; therefore, the administration of a loading dose for sedation in the ICU is not recommended. Treatment of elevated BP is generally not required, but a reduction in the infusion rate of the drug should be considered.

Local vasoconstriction at high concentrations may be more significant for patients with coronary artery disease or severe cerebrovascular diseases. The condition of such patients should be carefully monitored. If signs of myocardial or cerebral ischemia appear, the dose of the drug should be reduced or its administration discontinued.

Dexmedetomidine should be used with caution in combination with spinal or epidural anesthesia due to a possible increased risk of hypotension and bradycardia.

Patients with impaired liver function

Caution should be exercised in patients with severe hepatic insufficiency, as a decrease in the clearance of dexmedetomidine with excessive administration of the drug in such patients may lead to an increased risk of adverse reactions, excessive sedation, and prolongation of effects.

Patients with neurological diseases

Experience with the use of dexmedetomidine in severe neurological conditions (traumatic brain injury, post-neurosurgical conditions) is limited, so the drug should be used with caution, especially when deep sedation is required.

When choosing therapy, it should be taken into account that Dexmedetomidine may reduce cerebral blood flow and intracranial pressure.

In the pragmatic randomized controlled SPICE III trial involving 3904 adult ICU patients, no overall difference in 90-day mortality was found between the group receiving Dexmedetomidine and the group receiving standard therapy (mortality 29.1% in both groups). However, heterogeneity in the effect of age on this outcome was observed. The use of dexmedetomidine was associated with increased mortality in the age group ≤ 65 years (odds ratio 1.26; 95% CI: 1.02 – 1.56) compared to the group using other sedatives. Although the mechanism is unclear, this heterogeneity in the effect of age on mortality was most noticeable in cases of early use of high doses of dexmedetomidine to achieve deep sedation in patients admitted to the ICU for reasons other than surgery and increased with higher APACHE II scores. Based on the above, the possible increased risk of death in patients under 65 years of age in intensive care units should be considered. When dexmedetomidine was used for light sedation, there was no effect on mortality. The expected clinical benefit of using dexmedetomidine should be weighed against the use of alternative sedatives in younger patients.

Patients with other diseases

With abrupt withdrawal of α₂-adrenergic receptor agonists after their long-term use, a withdrawal syndrome has rarely occurred. If agitation and increased BP develop immediately after discontinuation of dexmedetomidine, the possibility of this condition should be considered.

Dexmedetomidine can cause hyperthermia, which may be resistant to traditional cooling methods. Treatment with dexmedetomidine should be discontinued in case of prolonged unexplained fever and is not recommended for use in patients predisposed to malignant hyperthermia.

The development of diabetes insipidus associated with dexmedetomidine treatment has been reported. If polyuria occurs, it is recommended to discontinue dexmedetomidine, check serum sodium levels, and urine osmolality.

Dexmedetomidine EVER Pharma^® contains less than 1 mmol sodium (23 mg)/ml.

Effect on the ability to drive vehicles and operate machinery

Patients are advised to refrain from driving vehicles or performing other hazardous tasks for an appropriate period of time after using the drug for sedation during anesthesia.

Overdose

Symptoms

Several cases of dexmedetomidine overdose have been reported in clinical trials and post-marketing experience. According to available data, the infusion rate in such cases reached 60 mcg/kg/h for 36 minutes and 30 mcg/kg/h for 15 minutes in a 20-month-old child and an adult, respectively. The most frequent adverse reactions due to overdose in such cases were bradycardia, decreased BP, increased BP, excessive sedation, respiratory depression, and cardiac arrest.

Treatment

In case of an overdose manifesting with clinical symptoms, the administration of dexmedetomidine should be reduced or discontinued. The expected effects are primarily cardiovascular and should be managed according to clinical indications (see the “Special Instructions” section). At high concentrations, an increase in BP may predominate over its decrease. In clinical trials, sinus node arrest resolved spontaneously or in response to the administration of atropine and glycopyrronium bromide. In isolated cases of severe overdose accompanied by cardiac arrest, resuscitation measures were required.

Drug Interactions

The drug interaction study was conducted only in adults. Concomitant use of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioid analgesics enhances their effects, such as sedation, anesthesia, analgesia, and cardiorespiratory effects. Targeted studies have confirmed the enhancement of effects when used with isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam were identified.

However, due to possible pharmacodynamic interactions when used concomitantly with dexmedetomidine, a reduction in the dose of dexmedetomidine or the concomitantly used anesthetics, sedatives, hypnotics, or opioid analgesics may be required.

Inhibition of CYP enzymes, including CYP2B6, by dexmedetomidine was investigated by incubating human liver microsomal cells. According to in vitro studies, there is a potential for in vivo interaction between dexmedetomidine and substrates, primarily with CYP2B6.

Based on in vitro studies, Dexmedetomidine may induce the CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 isoenzymes; such a possibility in in vivo studies cannot be ruled out. The clinical significance is unknown.

In patients taking medications that cause decreased BP and bradycardia, for example, beta-blockers, the possibility of enhancement of these effects should be considered (however, additional enhancement of these effects in a study with esmolol was moderate).

Storage Conditions

The drug should be stored in the original packaging (cardboard box), in a place inaccessible to children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 4 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.