Dexmedetomidine ewer pharma

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXMEDETOMIDINE EVER PHARMA (DEXMEDETOMIDINE EVER PHARMA)

Composition:

Active substance: dexmedetomidine;

1 ml of solution contains 118.2 mcg of dexmedetomidine hydrochloride, equivalent to 100 mcg of dexmedetomidine;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Psycholeptics. Hypnotics and sedatives. Other hypnotics and sedatives. ATC code N05CM18.

Pharmacological Properties

Pharmacodynamics

Dexmedetomidine is a selective α2-adrenoceptor agonist with a broad spectrum of pharmacological properties. It exerts sympatholytic effects by reducing the release of norepinephrine from sympathetic nerve endings. Sedative effects are mediated by decreased excitation in the locus coeruleus—a nucleus rich in noradrenergic neurons located in the brainstem.

Dexmedetomidine provides analgesic action and allows for reduced doses of anesthetics and analgesics. Cardiovascular effects are dose-dependent. At low infusion rates, central effects predominate, leading to decreased heart rate and arterial pressure. With higher doses, peripheral vasoconstrictive effects prevail, resulting in increased systemic vascular resistance and arterial pressure, as well as further enhancement of bradycardia. Dexmedetomidine causes minimal respiratory depression when used as monotherapy in healthy volunteers.

Physiological responses mediated by α2-adrenoceptors vary depending on their localization. From an anesthesiological perspective, neuronal hyperpolarization is the key mechanism of action of α2-adrenoceptor agonists at both central and peripheral levels. Presynaptic activation of α2-adrenoceptors generally inhibits norepinephrine release, thereby interrupting the transmission of pain signals.

Postsynaptic activation of α2-adrenoceptors in the central nervous system (CNS) suppresses sympathetic activity, contributing to reduced arterial pressure and heart rate. Together, these effects provide analgesia, sedation, and anxiolysis. Dexmedetomidine combines all these effects, potentially avoiding some adverse reactions associated with multi-agent therapy. At least three different isoforms of α2-adrenoceptors have been identified, both in pharmacological studies (based on affinity for various α2-adrenoceptor antagonists) and through biological probes.

α2-Adrenoceptor effects are mediated via activation of guanine nucleotide-binding regulatory proteins (G-proteins). Activated G-proteins modulate cellular activity either by signaling through secondary messenger systems or by modulating ion channel activity. Activation of the secondary messenger system leads to inhibition of adenylate cyclase, resulting in reduced formation of 3',5'-cyclic adenosine monophosphate (cAMP). Specific cAMP-dependent kinases alter the activity of target proteins by modifying their phosphorylation state.

Modulation of ion channel activity leads to hyperpolarization of the cell membrane. Potassium efflux through activated channels increases membrane polarization and effectively suppresses neuronal activity. Stimulation of α2-adrenoceptors also inhibits calcium influx into nerve terminals, which may explain its inhibitory effect on neurotransmitter secretion.

Dexmedetomidine is an α2-adrenoceptor agonist with dose-dependent selectivity for α2-adrenoceptors.

Indication 1. Sedation of adult patients in intensive care units (ICU)

In placebo-controlled studies involving patients in the postoperative ICU who had previously been intubated and sedated with midazolam or propofol, dexmedetomidine significantly reduced the need for additional sedation (midazolam or propofol) and for opioids over 24 hours. Most patients receiving dexmedetomidine did not require additional sedative therapy. Patients could be successfully extubated without discontinuing dexmedetomidine infusion.

Dexmedetomidine was comparable to midazolam (risk ratio 1.07; 95% confidence interval (CI) 0.971; 1.176) and propofol (risk ratio 1.00; 95% CI 0.922; 1.075) in time spent within the target sedation range in predominantly medical ICU patients requiring prolonged sedation of mild to moderate depth (0 to -3 on the Richmond Agitation-Sedation Scale (RASS)) for up to 14 days. It shortened the duration of mechanical ventilation compared to midazolam and reduced time to tracheal extubation compared to both midazolam and propofol. Patients receiving dexmedetomidine awakened more easily, cooperated better with staff, and reported pain more effectively than those receiving midazolam or propofol. Arterial hypotension and bradycardia occurred more frequently in patients receiving dexmedetomidine, while tachycardia was less common compared to midazolam. Compared to the propofol group, tachycardia was more frequent and arterial hypotension occurred at a similar rate in the dexmedetomidine group. CAM-ICU assessment showed a lower incidence of delirium in patients receiving dexmedetomidine compared to midazolam, and delirium-related adverse events were less frequent in the dexmedetomidine group compared to propofol. Patients who discontinued dexmedetomidine due to inadequate sedation depth were switched to propofol or midazolam. The risk of insufficient sedation was higher in patients who were difficult to sedate with standard agents immediately before switching to another sedative.

Evidence of efficacy in the pediatric population comes from a dose-controlled study in the ICU involving a large postoperative population aged 1 month to 17 years. Approximately 50% of patients receiving dexmedetomidine did not require additional midazolam sedation during a treatment period averaging 20.3 hours, but not exceeding 24 hours. Data on treatment beyond 24 hours in children are lacking. Data in neonates (28–44 weeks gestational age) are very limited and pertain only to low doses (≤ 0.2 mcg/kg/hr) (see sections “Pharmacokinetics” and “Special Warnings and Precautions for Use”). Neonates may be particularly sensitive to the bradycardic effects of dexmedetomidine, especially in the presence of hypothermia or conditions where cardiac output is heart rate-dependent.

In double-blind controlled ICU studies, the incidence of cortisol suppression in patients receiving dexmedetomidine (n = 778) was 0.5%, compared to 0% in patients receiving midazolam (n = 338) or propofol (n = 275). This effect was mild in one case and of moderate severity in three cases.

Indication 2. Procedural Sedation with Consciousness Preserved

Two randomized, double-blind, placebo-controlled, multicenter clinical trials demonstrated the safety and efficacy of dexmedetomidine for sedation of non-intubated adult patients before and/or during diagnostic or surgical procedures.

In Study 1, the sedative properties of dexmedetomidine were evaluated in patients undergoing various elective procedures under monitored anesthesia care, by comparing the percentage of patients who did not require additional midazolam to achieve the target sedation level, assessed using a standardized observer-rated sedation/activity scale.

Patients were randomized to receive a 10-minute loading infusion of dexmedetomidine at 1 mcg/kg (n = 129), dexmedetomidine at 0.5 mcg/kg (n = 134), or placebo (normal saline) (n = 63), followed by a maintenance infusion starting at 0.6 mcg/kg/hr. The maintenance infusion dose could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the target sedation level (observer-rated sedation/activity scale score ≤ 4). Midazolam could be administered as rescue medication if needed to achieve and/or maintain a sedation score ≤ 4. After achieving the desired sedation level, local or regional anesthesia was performed. Demographic characteristics were similar between dexmedetomidine and placebo groups.

Efficacy results showed that dexmedetomidine was more effective than placebo for sedation of non-intubated patients. 54% of patients receiving dexmedetomidine at 1 mcg/kg and 40% of those receiving 0.5 mcg/kg did not require additional midazolam sedation, compared to only 3% in the placebo group.

In Study 2, dexmedetomidine was evaluated in patients undergoing fiberoptic intubation while conscious prior to a surgical or diagnostic procedure.

Sedative properties were assessed by comparing the percentage of patients requiring additional midazolam to achieve or maintain a Ramsay Sedation Scale score ≥ 2. Patients were randomized to receive a 10-minute loading infusion of dexmedetomidine at 1 mcg/kg (n = 55) or placebo (normal saline) (n = 50), followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired sedation level, local airway anesthesia was administered. Midazolam could be given as rescue medication if needed to achieve or maintain a Ramsay Sedation Scale score ≥ 2. Demographic characteristics were similar between groups. Efficacy results showed that dexmedetomidine was more effective than placebo for sedation of non-intubated patients. 53% of patients receiving dexmedetomidine at 1 mcg/kg did not require additional midazolam sedation, compared to 14% in the placebo group.

Pharmacokinetics

The pharmacokinetics of dexmedetomidine have been studied in healthy volunteers after short-term intravenous administration and in ICU patients receiving prolonged infusion.

Distribution. Dexmedetomidine pharmacokinetics are described by a two-compartment model. In healthy volunteers, a rapid distribution phase is observed with a mean distribution half-life (t_1/2α) of approximately 6 minutes. The mean terminal elimination half-life (t_1/2) is approximately 1.9–2.5 hours (range: 1.35–3.68 hours), and the mean steady-state volume of distribution (V_ss) is approximately 1.16–2.16 L/kg (90–151 L). Mean plasma clearance (Cl) ranges from 0.46 to 0.73 L/hr/kg (35.7–51.1 L/hr). The mean body weight of patients used to calculate V_ss and Cl parameters was 69 kg.

Plasma pharmacokinetics in ICU patients receiving infusions longer than 24 hours were similar. Calculated pharmacokinetic parameters were: t_1/2 ≈ 1.5 hours, V_ss ≈ 93 L, and Cl ≈ 43 L/hr. Over the dose range of 0.2 to 1.4 mcg/kg/hr, dexmedetomidine pharmacokinetics are linear, and no accumulation occurs with treatment up to 14 days. Dexmedetomidine is 94% plasma protein-bound. The extent of protein binding is constant over a concentration range of 0.85 to 85 ng/mL. It binds to both human serum albumin and α1-acid glycoprotein, primarily to albumin.

Biotransformation and Elimination. Dexmedetomidine is completely metabolized in the liver. There are three primary metabolic pathways: direct N-glucuronidation, direct N-methylation, and cytochrome P450-catalyzed oxidation. The main circulating metabolites in blood are two isomeric N-glucuronides. Metabolite H-1 (N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide) is also a significant product of dexmedetomidine biotransformation. Cytochrome P450 enzymes catalyze the formation of two minor circulating metabolites: 3-hydroxymethyldexmedetomidine (formed by hydroxylation of the 3-methyl group) and H-3 (formed by oxidation of the imidazole ring). Available data indicate that oxidized metabolites are formed via several cytochrome P450 isoenzymes (CYP2A6, CYP1A2, CYP2E1, CYP2D6, and CYP2C19). These metabolites lack significant pharmacological activity.

Nine days after intravenous administration of radiolabeled dexmedetomidine, approximately 95% of radioactivity was recovered in urine and 4% in feces. The main urinary metabolites are two isomeric N-glucuronides, accounting for approximately 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—each account for 1.11–7.66% of the dose. Less than 1% of dexmedetomidine is excreted unchanged in urine. Approximately 28% of urinary metabolites are unidentified minor metabolites.

Pharmacokinetics in Special Populations

Significant differences in dexmedetomidine pharmacokinetics across age and gender groups have not been observed.

Plasma protein binding of dexmedetomidine is reduced in patients with hepatic impairment compared to healthy volunteers. The mean fraction of unbound dexmedetomidine in plasma ranged from 8.5% in healthy volunteers to 17.9% in patients with severe hepatic impairment. In patients with varying degrees of hepatic dysfunction (Child-Pugh classes A, B, or C), hepatic clearance of dexmedetomidine was reduced and plasma elimination half-life (t_1/2) prolonged. Mean unbound plasma clearance values in patients with mild, moderate, and severe hepatic impairment were 59%, 51%, and 32% of those in healthy volunteers, respectively. Mean t_1/2 was prolonged to 3.9, 5.4, and 7.4 hours, respectively. Although dose titration of dexmedetomidine should be based on sedative effect, consideration should be given to reducing the initial or maintenance dose in patients with hepatic impairment, depending on the degree of impairment and clinical response.

Pharmacokinetics of dexmedetomidine in patients with severe renal impairment (creatinine clearance < 30 mL/min) are not altered compared to healthy volunteers.

Data on the use of the medicinal product in children from neonates (28–44 weeks gestational age) up to 17 years of age are limited. The elimination half-life of dexmedetomidine in children (1 month to 17 years) is comparable to that in adults, but is slightly longer in neonates (under 1 month). Plasma clearance adjusted for body weight is higher in children aged 1 month to 6 years but decreases in older children. Due to immaturity, plasma clearance adjusted for body weight is lower (0.9) in neonates (under 1 month) compared to older age groups. Available data are summarized in Table 1.

Table 1

Pharmacokinetics of Dexmedetomidine in Children

Clinical characteristics.

Indications.

Sedation of adult patients in intensive care, anesthesia, and resuscitation units who require a level of sedation no deeper than awakening in response to verbal stimulation (corresponds to a range from 0 to -3 on the RASS scale).

Sedation of non-intubated adult patients before and/or during diagnostic or surgical procedures requiring sedation, i.e., procedural sedation with preservation of consciousness.

Contraindications.

• Hypersensitivity to dexmedetomidine or to any of the excipients of the medicinal product.
• Second- or third-degree atrioventricular block (in the absence of an artificial cardiac pacemaker).
• Uncontrolled arterial hypotension.
• Acute cerebrovascular pathology.

Interaction with other medicinal products and other forms of interaction.

Studies on interactions with other medicinal products have been conducted only in adults.

Concomitant administration of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids may lead to potentiation of their effects, such as sedation, anesthesia, analgesia, and cardiopulmonary effects. Enhanced effects have been confirmed when used concomitantly with isoflurane, propofol, alfentanil, and midazolam.

Pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam have not been observed. However, due to potential pharmacodynamic interactions when these medicinal products are used in combination with dexmedetomidine, dosage reduction of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid may be necessary.

In vitro studies using human liver microsomes evaluated the ability of dexmedetomidine to inhibit CYP isoforms, particularly CYP2B6. According to in vitro studies, there is a potential for in vivo interaction between dexmedetomidine and substrates predominantly metabolized by CYP2B6.

In vitro induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 isoforms by dexmedetomidine has been observed; therefore, such in vivo interactions cannot be excluded. The clinical significance of this effect is unknown.

In patients receiving medicinal products that cause a reduction in blood pressure and bradycardia, such as β-blockers, the potential for enhanced effects should be considered (although additional potentiation of these effects observed in an interaction study with esmolol was moderate).

Special precautions for use.

Monitoring

Dexmedetomidine EVER Pharma is intended for use in hospital settings, specifically in intensive care, anesthesia and resuscitation units, operating rooms, and during diagnostic procedures. Its use in other settings is not recommended. During dexmedetomidine infusion, continuous cardiac monitoring is required in all patients.

In non-intubated patients, respiratory function should be monitored due to the risk of respiratory depression and, in some cases, apnea development.

The time required for recovery to normal physiological status after dexmedetomidine administration is approximately 1 hour. When used in ambulatory patients, careful monitoring of their condition is required for at least this period, followed by continued medical supervision for at least another hour to ensure patient safety.

General warnings

Dexmedetomidine EVER Pharma must not be administered as a bolus injection. In intensive care settings (ICU), administration of a loading dose is also not recommended. Medical personnel should be prepared to use alternative sedative agents to immediately manage agitation in ICU patients, especially during the first hours of treatment.

In some patients receiving dexmedetomidine, mild arousal has been observed, with rapid return to consciousness upon stimulation. In the absence of other clinical symptoms, this sign alone should not be interpreted as evidence of inadequate drug efficacy.

Dexmedetomidine typically does not induce deep sedation, allowing patients to be easily aroused. Therefore, Dexmedetomidine EVER Pharma should not be used in patients requiring continuous deep sedation.

Dexmedetomidine EVER Pharma should not be used as an induction agent for anesthesia during intubation or to provide sedation when neuromuscular blocking agents are administered.

Unlike some other sedatives, dexmedetomidine does not possess anticonvulsant activity and does not suppress existing seizure activity; therefore, it should not be used as monotherapy in status epilepticus.

Caution is required when dexmedetomidine is used concomitantly with medicinal products that have sedative effects or affect the cardiovascular system, due to the potential for additive effects.

Dexmedetomidine EVER Pharma is not recommended for patient-controlled sedation. Relevant data are lacking.

When administering the drug to ambulatory patients, the effects of dexmedetomidine, the procedure performed, concomitant medication use, patient age, and clinical status should be considered when providing final recommendations regarding:

• the need for accompaniment upon patient discharge;
• the time required to regain the ability to perform complex or hazardous tasks, such as driving;
• the use of other sedative medicinal products (e.g., benzodiazepines, opioids) or alcohol.

Elderly patients

Extreme caution is required when administering dexmedetomidine to elderly patients. Patients aged 65 years and older are more prone to arterial hypotension following dexmedetomidine administration; therefore, dose reduction should be considered in such cases (see section "Dosage and administration").

Mortality in ICU patients aged ≤ 65 years

In the pragmatic randomized controlled trial SPICE III, involving 3904 critically ill adult ICU patients, dexmedetomidine was used as the primary sedative and compared with usual care. Overall, no differences in 90-day mortality were observed between the dexmedetomidine group and the usual care group (mortality 29.1% in both groups), but there was heterogeneity in the effect of age on mortality. Dexmedetomidine was associated with increased mortality in patients aged ≤ 65 years (odds ratio 1.26; 95% CI 1.02–1.56) compared to alternative sedatives. Although the mechanism is not fully understood, this age-dependent mortality effect was most pronounced in patients hospitalized for non-postoperative reasons and increased with higher APACHE II scores (Acute Physiology and Chronic Health Evaluation II) and decreasing age. These data should be weighed against the expected clinical benefit of dexmedetomidine compared to alternative sedatives in younger patients.

Cardiovascular effects and warnings

Dexmedetomidine EVER Pharma reduces heart rate and blood pressure due to central sympatholytic action, but at higher concentrations, it causes peripheral vasoconstrictive effects, leading to increased arterial pressure (see section "Pharmacodynamics"). Dexmedetomidine typically does not cause deep sedation, and patients can be easily aroused. Therefore, Dexmedetomidine EVER Pharma should not be used in patients for whom such a profile is inappropriate, such as those requiring deep sedation or those with severe cardiovascular diseases.

Extreme caution is required when administering dexmedetomidine to patients with pre-existing bradycardia. Data on the drug's effects in patients with heart rates < 60 beats/min are very limited; therefore, such patients require particularly close monitoring. Bradycardia usually does not require treatment, but if necessary, anticholinergic agents may be used or the dose reduced. Athletes with low resting heart rates may be particularly sensitive to the bradycardic effects of α2-adrenoceptor agonists; cases of transient sinus node arrest have been reported. Cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have also been reported (see section "Adverse reactions").

The hypotensive effect of Dexmedetomidine EVER Pharma may be more pronounced in patients with pre-existing arterial hypotension (especially refractory to vasopressors), hypovolemia, chronic hypotension, or reduced functional reserves, such as patients with severe ventricular dysfunction and elderly patients, requiring particular attention in such cases (see section "Contraindications"). Arterial hypotension usually does not require specific treatment, but if necessary, dose reduction, administration of intravascular volume replacement solutions, and/or vasoconstrictor agents should be considered.

Hemodynamic effects after initiating dexmedetomidine treatment may be more pronounced in patients with peripheral autonomic nervous system dysfunction (e.g., due to spinal cord injury); therefore, caution is required in such cases.

Transient arterial hypertension with concomitant peripheral vasoconstriction has been observed during administration of a loading dose of dexmedetomidine; therefore, loading dose administration during ICU sedation is not recommended. Treatment of elevated blood pressure is usually not required, but reducing the infusion rate may be beneficial.

Local vasoconstriction at higher dexmedetomidine concentrations may be more significant in patients with ischemic heart disease or severe cerebrovascular disease; continuous patient monitoring is required in such cases. If signs of myocardial or cerebral ischemia appear, dose reduction or discontinuation of the drug should be considered.

Patients with hepatic impairment

Extreme caution is required when treating patients with severe hepatic insufficiency, as reduced dexmedetomidine clearance may lead to drug accumulation, increasing the risk of adverse reactions, excessive sedation, or prolonged effects.

Patients with neurological disorders

Experience with Dexmedetomidine EVER Pharma in severe neurological disorders, such as head trauma and the postoperative period following neurosurgical procedures, is limited; therefore, the drug should be used with caution in such conditions, especially when deep sedation is required. When selecting therapy, it should be considered that dexmedetomidine may reduce cerebral blood flow and intracranial pressure.

Other warnings

After abrupt discontinuation of α2-adrenoceptor agonists following prolonged use, withdrawal syndrome has occurred in isolated cases. This possibility should be considered if agitation and increased blood pressure occur immediately after discontinuation of dexmedetomidine.

Dexmedetomidine may cause hyperthermia, which may be resistant to conventional cooling methods. Dexmedetomidine administration should be discontinued if persistent fever of unknown etiology develops. Dexmedetomidine is not recommended for patients predisposed to malignant hyperthermia.

Cases of diabetes insipidus have been reported in association with dexmedetomidine treatment. If polyuria occurs, discontinuation of dexmedetomidine is recommended, along with assessment of serum sodium levels and urine osmolality.

Excipients with known effect

1 ml of concentrate contains less than 1 mmol (approximately 3.5 mg) of sodium.

Use during pregnancy or breastfeeding.

Pregnancy

Adequate data on the use of dexmedetomidine in pregnant women are lacking. Animal studies have shown reproductive toxicity of dexmedetomidine. Dexmedetomidine EVER Pharma is not recommended during pregnancy unless the woman's clinical condition requires treatment with dexmedetomidine.

Breastfeeding period

Available data indicate that dexmedetomidine or its metabolites pass into the milk of rats. Therefore, a risk to breastfed infants cannot be excluded. A decision should be made either to discontinue breastfeeding or to discontinue dexmedetomidine administration, taking into account the benefits of breastfeeding for the infant and the benefits of treatment for the mother.

Fertility

Animal studies in rats showed no effect of dexmedetomidine on male or female fertility. Data on effects on human fertility are lacking.

Ability to influence reaction speed when driving or operating machinery.

Patients are advised to refrain from driving or performing other hazardous tasks for a certain period after administration of Dexmedetomidine EVER Pharma for procedural sedation.

Administration and Dosage

Sedation of adult patients in intensive care, anesthesia, and resuscitation who require a level of sedation no deeper than awakening in response to vocal stimulation (corresponds to a range of 0 to -3 on the RASS scale).

For hospital use only.

Dosage for adults

Patients who have already been intubated and are under sedation may be switched to DEXMEDETOMIDINE EVER PHARMA with an initial infusion rate of 0.7 mcg/kg/hour, which can be gradually adjusted within the dose range of 0.2–1.4 mcg/kg/hour to achieve the desired level of sedation. For frail patients, consideration should be given to using the lowest initial infusion rate. Dexmedetomidine is a highly potent agent; therefore, the infusion rate is specified per hour. After dose adjustment, up to 1 hour may be required to establish a stable level of sedation.

The maximum dose of 1.4 mcg/kg/hour must not be exceeded. Patients who fail to achieve adequate sedation at the maximum dose of DEXMEDETOMIDINE EVER PHARMA should be switched to an alternative sedative agent.

The use of a loading dose of DEXMEDETOMIDINE EVER PHARMA for sedation is not recommended, as it is associated with an increased incidence of adverse reactions. If necessary, propofol or midazolam may be used until the clinical effect of dexmedetomidine is achieved.

The duration of treatment depends on the need for sedation. There is no experience with the use of DEXMEDETOMIDINE EVER PHARMA for periods exceeding 14 days. When treatment exceeds 14 days, the patient's condition must be regularly assessed.

Sedation of non-intubated adult patients before and/or during diagnostic or surgical procedures requiring sedation, i.e., procedural sedation with preserved consciousness. DEXMEDETOMIDINE EVER PHARMA must be administered only by healthcare professionals qualified in anesthesia for patients in operating rooms or during diagnostic procedures. When DEXMEDETOMIDINE EVER PHARMA is administered for sedation with preserved consciousness, patients must be continuously monitored by personnel not involved in performing the diagnostic or surgical procedure. Continuous monitoring is required to detect early signs of arterial hypotension, arterial hypertension, bradycardia, respiratory depression, airway obstruction, apnea, dyspnea, and/or oxygen desaturation (see section "Adverse Reactions").

Supplemental oxygen must be available and immediately administered when indicated. Oxygen saturation should be monitored using pulse oximetry.

DEXMEDETOMIDINE EVER PHARMA is administered as a loading infusion followed by a maintenance infusion. Depending on the procedure, concomitant local anesthesia or analgesia may be required to achieve the desired clinical effect. It is recommended to use additional analgesics or sedatives (e.g., opioids, midazolam, or propofol) during painful procedures or when deeper sedation is needed. The pharmacokinetic half-life of DEXMEDETOMIDINE EVER PHARMA is approximately 6 minutes, which, along with the effects of other administered drugs, should be considered when estimating the appropriate time required to titrate to the desired clinical effect of DEXMEDETOMIDINE EVER PHARMA.

Initiation of procedural sedation

The loading infusion is 1.0 mcg/kg over 10 minutes. For less invasive procedures, such as ophthalmologic surgeries, a loading infusion of 0.5 mcg/kg over 10 minutes may be used.

Maintenance of procedural sedation

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

Elderly patients. Dose adjustment is generally not required for elderly patients (see section "Pharmacokinetics"). Elderly patients may have an increased risk of developing arterial hypotension (see section "Special Warnings and Precautions for Use**"**), although limited available data on procedural sedation do not indicate a clear dose-dependent relationship.

Renal impairment. Dose adjustment is generally not required in patients with renal impairment.

Hepatic impairment. DEXMEDETOMIDINE EVER PHARMA is metabolized in the liver; therefore, it should be used with caution in patients with hepatic impairment. Consideration should be given to using a reduced maintenance dose.

Administration method

DEXMEDETOMIDINE EVER PHARMA must be administered by personnel experienced in managing patients requiring intensive care. The drug should be used only as a diluted intravenous infusion, administered via a controlled infusion device.

Ampoules and vials are intended for single-patient use only.

Preparation of solution

Prior to administration, DEXMEDETOMIDINE EVER PHARMA may be diluted with 5% dextrose solution, Ringer's solution, mannitol, or 0.9% sodium chloride solution to achieve a desired concentration of 4 mcg/mL or 8 mcg/mL. Table 2 provides the volumes required for infusion preparation.

Table 2

To achieve a concentration of 4 mcg/mL:

To achieve a concentration of 8 mcg/mL:

Shake carefully to mix the solution well.

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

Dexmedetomidine EVER Pharma is compatible with the following intravenous fluids and drugs: Ringer's lactate 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, glycopyrronium bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, noradrenaline, dobutamine, midazolam, morphine sulfate, fentanyl citrate, and blood plasma substitutes.

Children.

The safety and efficacy of Dexmedetomidine EVER Pharma in children under 18 years of age have not been established.

Available data on use in children are presented in the sections “Pharmacodynamics”, “Pharmacokinetics” and “Side effects”, however, dosage recommendations for children cannot currently be provided.

Overdose.

Symptoms of overdose. Several cases of dexmedetomidine overdose have been reported during clinical trials and post-marketing use. The highest infusion rates in these cases were 60 mcg/kg/hour for 36 minutes and 30 mcg/kg/hour for 15 minutes in a 20-month-old child and an adult, respectively. The most commonly reported adverse reactions in overdose included bradycardia, arterial hypotension, arterial hypertension, excessive sedation, respiratory depression, and cardiac arrest.

Treatment of overdose. In case of overdose with clinical symptoms, the infusion rate of dexmedetomidine should be reduced or administration discontinued. Cardiovascular effects are expected to predominate and should be treated according to clinical indications (see section “Special precautions for use”). With high doses, arterial hypertension may be more pronounced than arterial hypotension. During clinical trials, sinus arrest resolved spontaneously or responded to treatment with atropine and glycopyrronium. In isolated cases of severe overdose leading to cardiac arrest, resuscitation measures were required.

Adverse Reactions

Summary of Safety Profile

Sedation of adult patients in intensive care units (ICU)

When dexmedetomidine is used for sedation in the ICU, the most commonly observed adverse reactions are arterial hypotension, arterial hypertension, and bradycardia, occurring in approximately 25%, 15%, and 13% of patients, respectively. Arterial hypotension and bradycardia were also the most frequent serious treatment-related adverse reactions, occurring in 1.7% and 0.9% of randomized ICU patients, respectively.

Procedural sedation with preserved consciousness

When dexmedetomidine is used for procedural sedation, the most commonly reported adverse reactions are arterial hypotension (54% in the dexmedetomidine group vs. 30% in the placebo group), respiratory depression (37% in the dexmedetomidine group vs. 32% in the placebo group), and bradycardia (14% in the dexmedetomidine group vs. 4% in the placebo group).

The adverse reactions listed below are based on pooled data from clinical studies in intensive care involving 3137 randomized patients (1879 receiving dexmedetomidine, 864 receiving active comparator drugs, and 394 receiving placebo), and on pooled data from clinical studies of procedural sedation involving 431 randomized patients (381 receiving dexmedetomidine and 113 receiving placebo).

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), frequency not known (cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity.

Metabolism and nutrition disorders

Common: hyperglycemia, hypoglycemia.

Uncommon: metabolic acidosis*, hypoalbuminemia.

Psychiatric disorders

Common: agitation.

Uncommon: hallucinations.

Cardiac disorders

Very common: bradycardia1,2.

Common: myocardial ischemia or myocardial infarction, tachycardia.

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

Vascular disorders

Very common: arterial hypotension1,2, arterial hypertension1,2.

Respiratory, thoracic and mediastinal disorders

Very common: respiratory depression2,3.

Uncommon: dyspnea, apnea.

Gastrointestinal disorders

Common: nausea2, vomiting, dry mouth2.

Uncommon: abdominal distension.

Renal and urinary disorders

Frequency not known: polyuria.

Endocrine disorders

Frequency not known: diabetes insipidus.

General disorders and administration site conditions

Common: withdrawal syndrome, hyperthermia.

Uncommon: drug inefficacy, thirst.

1Description of individual adverse reactions.

2Adverse reaction also observed in procedural sedation studies.

3Frequency categorized as "common" in intensive care unit studies.

Description of individual adverse reactions

Clinically significant arterial hypotension or bradycardia should be managed according to recommendations provided in the "Dosage and Administration" section.

In relatively healthy individuals not in the ICU, administration of dexmedetomidine has occasionally caused bradycardia and sinus arrest. Symptoms were alleviated by elevating the legs above the level of the head and administering anticholinergic agents such as atropine or glycopyrrolate. In isolated cases, pre-existing bradycardia progressed to episodes of asystole. Cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have also been reported.

Arterial hypertension has been observed during administration of a loading dose of dexmedetomidine in the ICU setting. To reduce the incidence of this adverse reaction, avoid the loading dose, reduce the infusion rate, or lower the loading dose of the drug.

Adverse reactions in pediatric patients

The safety profile of dexmedetomidine in children aged 1 month and older, predominantly postoperative patients, was similar to that in adults when administered for up to 24 hours in the ICU. Data in neonates (28–44 weeks gestational age) are very limited and pertain only to low maintenance doses (≤ 0.2 mcg/kg/hour). One case of hypothermic bradycardia in a neonate has been described in the literature.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

The medicinal product in its original packaging: 4 years.

Storage conditions.

Store in the original packaging, in a place inaccessible to children. No special temperature conditions are required for storage of this medicinal product.

Incompatibilities.

The product should not be mixed with other medicinal products except those specified in the "Dosage and Administration" section.

Compatibility studies have revealed potentially possible adsorption of dexmedetomidine to certain types of natural rubber. Although dexmedetomidine is administered in doses necessary to achieve the desired clinical effect, it is recommended to use infusion systems with components made of synthetic rubber or natural rubber with a coating.

Packaging.

2 mL in an ampoule; 5 or 25 ampoules per cardboard box.

4 mL in an ampoule; 4 or 5 ampoules per cardboard box.

10 mL in an ampoule; 4 or 5 ampoules per cardboard box.

2 mL in a vial; 5 vials per cardboard box.

4 mL in a vial; 4 or 5 vials per cardboard box.

10 mL in a vial; 4 or 5 vials per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

EVER Pharma Jena GmbH, Germany.

Manufacturer's address and location of operations.

Otto-Schott-Strasse 15, Sued, Jena, Thuringia, 07745, Germany.

Marketing Authorization Holder.

EVER Valinject GmbH, Austria.

Address of the Marketing Authorization Holder.

Oberburgau 3, 4866 Unterach am Attersee, Austria.