Dexmedetomidine-novo
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXMEDETOMIDINE-NOVO (DEXMEDETOMIDINE-NOVO)
Composition:
Active substance: dexmedetomidine hydrochloride;
1 ml contains dexmedetomidine hydrochloride 118 µg, equivalent to 100 µg of dexmedetomidine;
Excipients: sodium chloride, water for injections.
Pharmaceutical form. Concentrate for solution for infusion.
Main physicochemical properties: clear, colorless solution.
Pharmacotherapeutic group. Psycholeptics. Other hypnotics and sedatives.
ATC code N05CM18.
Pharmacological Properties
Pharmacodynamics
Dexmedetomidine is a selective alpha-2 receptor agonist with a broad range of pharmacological properties. It exerts a strong sympatholytic effect by reducing norepinephrine release from sympathetic nerve endings. Sedative effects are mediated by decreased activation of the locus coeruleus, the primary noradrenergic nucleus located in the brainstem. Due to its action on this area, dexmedetomidine produces sedation (similar to natural non-rapid eye movement sleep) while maintaining the ability to rouse and remain responsive. Dexmedetomidine provides anesthetic and moderate analgesic effects; analgesic activity has been demonstrated in patients with chronic lower back pain. Cardiovascular effects are dose-dependent: at lower infusion rates, central effects predominate, resulting in reduced heart rate and arterial blood pressure. At higher doses, peripheral vasoconstrictive effects prevail, leading to increased systemic vascular resistance and arterial blood pressure, while bradycardic effects become more pronounced. Dexmedetomidine has minimal respiratory depressant effects.
Sedation in Hospital Settings (Intensive Care, Anesthesia, and Resuscitation Units)
In placebo-controlled studies in postoperative intensive care unit (ICU) patients previously intubated and sedated with midazolam or propofol, dexmedetomidine significantly reduced the need for both sedatives (midazolam or propofol) and opioids during 24 hours of sedation. Most patients receiving dexmedetomidine did not require additional sedative therapy. Patients could be successfully extubated without discontinuing the dexmedetomidine infusion. Studies conducted outside the ICU setting confirmed that dexmedetomidine can be safely administered to patients without endotracheal intubation under continuous monitoring.
Dexmedetomidine was non-inferior to midazolam (risk ratio 1.07; 95% CI [confidence interval] 0.971, 1.176) and to propofol (risk ratio 1.00; 95% CI 0.922, 1.075) in time to reach the target sedation range, primarily in ICU patients requiring prolonged light to moderate sedation (RASS 0 to -3) for up to 14 days; it reduced duration of mechanical ventilation (MV) compared to midazolam and shortened time to extubation compared to both midazolam and propofol.
Compared to propofol and midazolam, patients receiving dexmedetomidine awakened more easily, were more cooperative, and could communicate and report pain intensity. Arterial hypotension and bradycardia occurred more frequently with dexmedetomidine compared to midazolam, whereas tachycardia was less common; tachycardia occurred more frequently compared to propofol, but the incidence of arterial hypotension was similar. In a study assessing delirium, delirium incidence with dexmedetomidine, evaluated using the Confusion Assessment Method for the ICU (CAM-ICU), was lower than with midazolam, and delirium-related adverse effects were lower than with propofol. Patients who required discontinuation of sedation due to inadequate sedation level were switched to propofol or midazolam. The risk of inadequate sedation was higher in patients who were difficult to sedate with standard methods immediately prior to switching to an alternative method.
Evidence of efficacy in pediatric patients was obtained in a dose-controlled ICU study involving a large postoperative population aged from 1 month to ≤17 years. Approximately 50% of patients receiving dexmedetomidine did not require additional midazolam during a treatment period averaging 20.3 hours and not exceeding 24 hours. Data on treatment longer than 24 hours are unavailable. Data in neonates (28–44 weeks gestation) are limited and restricted to low doses (≤0.2 mcg/kg/hr) (see sections "Pharmacokinetics", "Special Warnings and Precautions"). Neonates may be particularly sensitive to bradycardic effects of dexmedetomidine under conditions of hypothermia or when heart rate depends on cardiac output.
In double-blind controlled studies in ICU settings, 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 adverse event was reported as mild in one case and moderate in three cases.
Procedural Sedation
The safety and efficacy of dexmedetomidine for sedation in non-intubated patients before and/or during surgical and diagnostic procedures were evaluated in two randomized, double-blind, placebo-controlled, multicenter clinical trials.
In Study 1, patients undergoing planned surgical procedures under monitored anesthesia care and local/regional anesthesia were randomized to receive a 10-minute loading infusion of dexmedetomidine 1 mcg/kg (n = 129) or 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 was titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr. The proportion of patients achieving the target sedation level (≤4 on the Sedation and Agitation Scale) without requiring rescue midazolam was 54% in the 1 mcg/kg dexmedetomidine group and 40% in the 0.5 mcg/kg group, compared to 3% in the placebo group. The risk difference in the number of patients randomized to the 1 mcg/kg and 0.5 mcg/kg dexmedetomidine groups who did not require rescue midazolam therapy was 48% (95% CI: 37–57%) and 40% (95% CI: 28–48%), respectively, compared to placebo. Median (range) rescue midazolam dose was 1.5 (0.5–7.0) mg in the 1.0 mcg/kg dexmedetomidine group, 2.0 (0.5–8.0) mg in the 0.5 mcg/kg group, and 4.0 (0.5–14.0) mg in the placebo group. The difference in mean rescue midazolam dose in the 1 mcg/kg and 0.5 mcg/kg dexmedetomidine groups compared to placebo was –3.1 mg (95% CI: –3.8 to –2.5) and –2.7 mg (95% CI: –3.3 to –2.1), respectively, in favor of dexmedetomidine. Mean time to first rescue dose was 114 minutes in the 1.0 mcg/kg dexmedetomidine group, 40 minutes in the 0.5 mcg/kg group, and 20 minutes in the placebo group.
In Study 2, patients undergoing awake fiberoptic tracheal intubation under local anesthesia were randomized to receive a 10-minute loading infusion of dexmedetomidine 1 mcg/kg (n = 55) or placebo (normal saline) (n = 50), followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. To maintain a sedation level ≥2 on the Ramsay Sedation Scale, 53% of patients receiving dexmedetomidine did not require rescue midazolam therapy 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 midazolam therapy was 43% (95% CI: 23–57%) compared to placebo. Mean rescue midazolam dose was 1.1 mg in the dexmedetomidine group and 2.8 mg in the placebo group. The difference in mean rescue midazolam dose was –1.8 mg (95% CI: –2.7 to –0.86) in favor of dexmedetomidine.
Pharmacokinetics
Dexmedetomidine pharmacokinetics were evaluated after short-term intravenous administration in healthy volunteers and after prolonged infusion in ICU patients.
Distribution
Dexmedetomidine pharmacokinetics are described by a two-compartment model. In healthy volunteers, it exhibits a rapid distribution phase with an estimated distribution half-life (t1/2α) of approximately 6 minutes. The estimated terminal elimination half-life (t1/2) is approximately 1.9–2.5 hours (minimum 1.35 hours, maximum 3.68 hours), and the estimated steady-state volume of distribution (Vss) is approximately 1.16–2.16 L/kg (90–151 L). Estimated plasma clearance (Cl) is approximately 0.46–0.73 L/hr/kg (35.7–51.1 L/hr). The average body weight associated with these Vss and Cl estimates was 69 kg. Plasma pharmacokinetics of dexmedetomidine are similar in ICU patients after infusion >24 hours. Estimated pharmacokinetic parameters are: t1/2 ≈ 1.5 hours, Vss ≈ 93 L, and Cl ≈ 43 L/hr. Dexmedetomidine pharmacokinetics are linear within the dose range of 0.2–1.4 mcg/kg/hr, and it does not accumulate during treatment up to 14 days. Dexmedetomidine is 94% bound to plasma proteins. Protein binding is constant over the concentration range of 0.85–85 ng/mL. Dexmedetomidine binds to human serum albumin and α1-acid glycoprotein, with serum albumin being the primary binding protein in plasma.
Metabolism and Elimination
Dexmedetomidine is extensively metabolized in the liver. There are three primary metabolic pathways: direct N-glucuronidation, direct N-methylation, and cytochrome P450-catalyzed oxidation. The major circulating metabolites are two isomeric N-glucuronides. Metabolite H-1 (N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide) is also a significant biotransformation product. Cytochrome P450 enzymes catalyze the formation of two minor circulating metabolites: 3-hydroxymethyldexmedetomidine (formed by hydroxylation of the 3-methyl group of dexmedetomidine) and H-3 (formed by oxidation of the imidazole ring). Available data indicate that formation of oxidized metabolites is mediated by CYP isoforms (CYP2A6, CYP1A2, CYP2E1, CYP2D6, and CYP2C19). These metabolites have minimal pharmacological activity.
After intravenous administration of radiolabeled dexmedetomidine, approximately 95% of radioactivity was recovered in urine and 4% in feces over 9 days. The main urinary metabolites are two isomeric N-glucuronides, together accounting for approximately 34% of the dose, and N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide, accounting for 14.51% of the dose. Minor metabolites—carboxylic acid, 3-hydroxy-, and O-glucuronide metabolites—individually account for 1.11–7.66% of the dose. Less than 1% of unchanged active substance was detected in urine. Approximately 28% of metabolites detected in urine are unidentified polar metabolites.
Special Populations
No significant pharmacokinetic differences were observed based on patient sex or age.
Plasma protein binding of dexmedetomidine is reduced in individuals with hepatic impairment compared to healthy volunteers. The mean percentage of unbound dexmedetomidine in plasma increased from 8.5% in healthy volunteers to 17.9% in patients with severe hepatic impairment. Subjects with varying degrees of hepatic impairment (Child-Pugh classes A, B, or C) showed reduced hepatic clearance of dexmedetomidine and prolonged plasma elimination half-life (t1/2). Mean unbound dexmedetomidine clearance in patients with mild, moderate, and severe hepatic impairment was 59%, 51%, and 32% of that in healthy volunteers, respectively. 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 to effect, consideration should be given to reducing the initial/maintenance dose in patients with hepatic impairment depending on the degree of impairment and clinical response.
Dexmedetomidine pharmacokinetics in patients with severe renal impairment (creatinine clearance <30 mL/min) are unchanged compared to healthy patients.
Data on use in pediatric patients—from neonates (born at 28–44 weeks gestation) to 17 years—are limited. The elimination half-life of dexmedetomidine in children (1 month to 17 years) is likely similar to that in adults, but appears higher in neonates (born at 28–44 weeks gestation), decreasing with age. Due to immaturity, body weight-adjusted plasma clearance in neonates (up to 1 month of age) may be lower (0.9 L/hr/kg) than in older age groups.
| Age |
N |
Mean value (95% CI) |
|
| Cl (L/h/kg) |
t1/2 (h) |
||
| Up to 1 month |
28 |
0.93 (0.76; 1.14) |
4.47 (3.81; 5.25) |
| From 1 to 6 months |
14 |
1.21 (0.99; 1.48) |
2.05 (1.59; 2.65) |
| From 6 to 12 months |
15 |
1.11 (0.94; 1.31) |
2.01 (1.81; 2.22) |
| From 12 to 24 months |
13 |
1.06 (0.87; 1.29) |
1.97 (1.62; 2.39) |
| From 2 to 6 years |
26 |
1.11 (1.00; 1.23) |
1.75 (1.57; 1.96) |
| From 6 to 17 years |
28 |
0.80 (0.69; 0.92) |
2.03 (1.78; 2.31) |
Clinical characteristics.
Indications.
For sedation in hospital settings (in intensive care units, anesthesia and resuscitation departments) of patients requiring a level of sedation no deeper than awakening in response to verbal stimulation (corresponds to the range from 0 to –3 on the Richmond Agitation-Sedation Scale (RASS)).
For sedation of non-intubated patients before and/or during diagnostic or surgical procedures requiring sedation/procedural sedation.
Contraindications.
Hypersensitivity to dexmedetomidine or to any of the excipients of the medicinal product.
Second- to third-degree atrioventricular block (in the absence of an artificial pacemaker).
Uncontrolled arterial hypotension.
Acute cerebrovascular pathology.
Interaction with other medicinal products and other forms of interaction.
Studies on interaction with other medicinal products have been conducted only in adult patients.
Concomitant use of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids may lead to potentiation of their effects, including sedative, anesthetic, and cardiorespiratory effects. Targeted studies have confirmed enhanced effects when used with isoflurane, propofol, alfentanil, and midazolam.
No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam were observed. However, due to possible pharmacodynamic interactions when these agents are used in combination with dexmedetomidine, dosage reduction of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid may be necessary.
The ability of dexmedetomidine to inhibit cytochrome P450, including the CYP2B6 isoenzyme, was studied in human liver microsomes. According to in vitro study results, there is a potential for interaction between dexmedetomidine and substrates (mainly of the CYP2B6 isoenzyme) in vivo.
Induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 isoenzymes by dexmedetomidine was observed in vitro, therefore such interaction in vivo cannot be excluded.
Potential enhancement of hypotensive and bradycardic effects should be considered in patients receiving other medicinal products causing such effects, e.g., β-adrenoblockers (although additional effects in an interaction study using esmolol were moderate).
Special precautions for use
The medicinal product is intended for use in a hospital setting (in intensive care, anaesthesiology and resuscitation units), operating rooms, and during diagnostic procedures; its use in other settings is not recommended.
During infusion of the medicinal product, cardiac function should be continuously monitored in all patients. In patients who have not undergone tracheal intubation, respiratory function should be monitored due to the risk of respiratory depression and, in some cases, the development of apnoea.
The recovery time after administration of dexmedetomidine is approximately one hour. When used in an outpatient setting, careful monitoring should continue for at least one hour (or longer, depending on the patient's condition), and medical supervision should be maintained for an additional hour for patient safety.
General warnings
The medicinal product should not be administered as a bolus. In intensive care unit settings, administration of a loading dose of the medicinal product is not recommended. Therefore, healthcare personnel should be prepared to use an alternative sedative agent to immediately control agitation or during procedures, especially during the first few hours of treatment. A small bolus dose of another sedative may be used during procedural sedation if a rapid increase in the level of sedation is required.
In some patients who received dexmedetomidine, mild arousal was observed, and they quickly regained consciousness after stimulation. In the absence of other clinical symptoms, this sign alone should not be considered as ineffectiveness of the medicinal product.
Dexmedetomidine usually does not cause deep sedation, so patients can be easily aroused. Therefore, dexmedetomidine is not suitable for patients requiring continuous deep sedation.
Dexmedetomidine should not be used as a general anaesthetic induction agent prior to intubation or to provide sedation when neuromuscular blockers are used.
Dexmedetomidine is unlikely to suppress seizure activity and therefore should not be used as monotherapy in status epilepticus.
Caution should be exercised when dexmedetomidine is used concomitantly with medicinal products that have sedative effects or affect the cardiovascular system due to the possibility of additive effects.
Dexmedetomidine is not recommended for patient-controlled sedation.
If dexmedetomidine is used in an outpatient setting, patient discharge may only occur under the supervision of a third party. Patients should be advised to refrain from driving vehicles and performing other hazardous tasks, and to avoid using other agents with sedative effects (e.g., benzodiazepines, opioids, alcohol) for a certain period of time, depending on the observed effects of dexmedetomidine, the procedure performed, concomitant medicinal products, age, and the patient's condition.
Caution should be exercised when administering dexmedetomidine to elderly patients. Patients over 65 years of age may be more prone to developing hypotension with dexmedetomidine, including during administration of a loading dose and during procedures. Dose reduction should be considered (see section "Dosage and administration").
Effects on the heart and blood vessels and precautionary measures
Dexmedetomidine reduces heart rate and arterial blood pressure (due to central sympatholytic action), but at higher concentrations causes peripheral vasoconstriction, leading to increased arterial pressure. Because of this, dexmedetomidine is not suitable for patients with severe cardiovascular disorders.
Caution should be exercised when administering dexmedetomidine to patients with concomitant bradycardia. Data on the effects of the medicinal product in patients with heart rates < 60 are limited; therefore, such patients require intensified monitoring. Bradycardia usually does not require treatment but is generally well corrected by administration of anticholinergic agents (muscarinic blockers) and dose reduction. Athletes with low heart rates may be particularly sensitive to the negative chronotropic effect of alpha-2 receptor agonists; cases of sinus arrest have been reported. 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 hypotension, hypovolemia, or reduced functional reserve, such as patients with severe ventricular dysfunction and elderly patients, the hypotensive effect of the medicinal product may be more pronounced—this requires special care for such patients. Reduction in blood pressure usually does not require specific interventions, but readiness to reduce the dose, administer volume-expanding agents, and/or vasoconstrictors should be ensured if necessary.
In patients with peripheral autonomic nervous system dysfunction (e.g., due to spinal cord injury), hemodynamic effects after administration of dexmedetomidine may be more pronounced and require special patient care.
Transient increase in arterial pressure with concomitant peripheral vasoconstrictive effect has been observed during administration of a loading dose of dexmedetomidine; therefore, administration of a loading dose for sedation in hospital settings (in intensive care, anaesthesiology and resuscitation units) is not recommended. Treatment of elevated blood pressure is usually not required; however, consideration should be given to reducing the infusion rate of the medicinal product.
Central vasoconstriction at higher concentrations may be more significant in patients with ischemic heart disease or severe cerebrovascular disorders; such patients require close monitoring. In patients with signs of myocardial or cerebral ischemia, dose reduction or discontinuation of the medicinal product should be considered.
Caution should be exercised when administering dexmedetomidine concomitantly with spinal or epidural anaesthesia due to increased risk of hypotension and bradycardia.
Mortality in intensive care unit (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 agent and compared with usual care. There was no overall difference in 90-day mortality between the group receiving dexmedetomidine and the group receiving usual care (mortality 29.1% in both groups), but there was heterogeneity in the effect of age on mortality. The use of dexmedetomidine was associated with increased mortality in patients aged ≤ 65 years (risk ratio 1.26; 95% confidence interval 1.02 to 1.56) compared to alternative sedative agents. Although the mechanism is unclear, this age-related heterogeneity in mortality was most evident with early use of high doses of dexmedetomidine to achieve deep sedation in patients hospitalized for reasons other than postoperative care, and increased with higher APACHE II scores.
No effect on mortality was observed when dexmedetomidine was used for light sedation. These results should be weighed against the expected clinical benefit of dexmedetomidine compared to alternative sedative agents in younger patients.
Patients with hepatic impairment
Caution should be exercised in patients with severe hepatic insufficiency, as reduced clearance of dexmedetomidine may lead to drug accumulation, increasing the risk of adverse reactions and excessive sedation.
Patients with neurological disorders
Experience with the use of dexmedetomidine in severe neurological conditions such as head trauma and the postoperative period after neurosurgical procedures is limited; therefore, it should be used with caution in such conditions, especially when deep sedation is required. When selecting therapy, it should be considered that dexmedetomidine reduces cerebral blood flow and intracranial pressure.
Other warnings
After abrupt discontinuation of alpha-2 receptor agonists following prolonged use, withdrawal syndrome has occurred rarely. The possibility of agitation and increased blood pressure immediately after discontinuation of dexmedetomidine should be considered.
Dexmedetomidine may cause hyperthermia, which may be resistant to traditional cooling methods. Administration of dexmedetomidine should be discontinued if persistent fever of unknown etiology develops. Dexmedetomidine is not recommended for use in patients prone to malignant hyperthermia.
Cases of diabetes insipidus have been reported during treatment with dexmedetomidine. If polyuria occurs, administration of dexmedetomidine should be discontinued and serum sodium and urine osmolality should be checked.
The medicinal product contains less than 1 mmol sodium (23 mg) per 1 mL, i.e., it is practically sodium-free.
Use during pregnancy or breastfeeding.
Pregnancy. Data on the use of dexmedetomidine in pregnant women are absent or limited. Reproductive toxicity has been observed in animal studies. The medicinal product should not be used during pregnancy unless the woman's clinical condition requires treatment with dexmedetomidine.
Breastfeeding period. Dexmedetomidine is excreted in human breast milk, but its levels fall below the limit of detection 24 hours after discontinuation of the infusion. Risk to the infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue therapy with dexmedetomidine should be made taking into account the benefits of breastfeeding for the infant and the benefits of dexmedetomidine therapy for the mother.
Fertility. Fertility studies in rats did not reveal any effect of dexmedetomidine on male or female fertility. Data on the effect on human fertility are lacking.
Ability to influence reaction speed when driving or operating machinery.
Patients are advised to refrain from driving vehicles or performing other hazardous tasks for a certain period after administration of dexmedetomidine for procedural sedation.
Method of Administration and Dosage
For sedation in hospital settings (in intensive care, anesthesia, and resuscitation units) of patients requiring a level of sedation no deeper than awakening in response to verbal stimulation.
The medicinal product is intended for hospital use only and must be administered by qualified and specially trained medical personnel.
Dosage for adults
Patients who have already been intubated and are under sedation may be transitioned to dexmedetomidine with an initial infusion rate of 0.7 mcg/kg/hr, which may be gradually adjusted within the dose range of 0.2–1.4 mcg/kg/hr to achieve the desired level of sedation. For debilitated 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/hr must not be exceeded. Patients who fail to achieve adequate sedation at the maximum dose of dexmedetomidine should be switched to an alternative sedative agent.
The use of a loading dose of dexmedetomidine for sedation is not recommended, as it is associated with an increased incidence of adverse effects. If necessary, propofol or midazolam may be used until the clinical effect of dexmedetomidine is achieved.
The duration of treatment depends on the necessity for the patient to remain sedated. There is no experience with the use of dexmedetomidine for periods longer than 14 days. When administering the medicinal product for more than 14 days, the patient's condition must be regularly evaluated.
For sedation of patients during diagnostic or surgical procedures requiring sedation / procedural sedation.
The medicinal product should be administered only by medical personnel qualified in anesthesia management for patients in operating rooms or during diagnostic procedures. When dexmedetomidine is administered for sedation with preserved consciousness, patients must be continuously monitored by individuals not involved in performing the diagnostic or surgical procedure. Continuous monitoring of patients is required to detect early signs of hypotension, hypertension, bradycardia, respiratory depression, airway obstruction, apnea, dyspnea, and/or oxygen desaturation (see section "Adverse Reactions").
Availability of supplemental oxygen must be ensured and promptly administered when indicated. Oxygen saturation should be monitored using pulse oximetry.
Dexmedetomidine 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) when performing painful procedures or when deeper sedation is needed. The pharmacokinetic distribution half-life of dexmedetomidine is approximately 6 minutes, which, along with the effects of other administered medicinal products, should be considered when estimating the appropriate time required to titrate to the desired clinical effect.
Initiation of procedural sedation
Loading infusion of 1.0 mcg/kg over 10 minutes. For less invasive procedures, such as ophthalmological 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/hr and titrated to achieve the desired clinical effect within the dose range of 0.2 to 1 mcg/kg/hr. The maintenance infusion rate should be adjusted until the target level of sedation 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 precautions for use"); however, limited available data from procedural sedation do not clearly indicate a dose-dependent relationship.
Renal impairment. Dose adjustment is generally not required in patients with renal impairment.
Hepatic impairment. Dexmedetomidine 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.
Method of administration
The medicinal product should be administered by personnel experienced in managing patients requiring intensive care. The medicinal product should only be used as a diluted intravenous infusion, administered via a controlled infusion device.
The vial of the medicinal product is intended for single-patient use only.
Preparation of the solution
Prior to administration, the medicinal product may be diluted in 5% dextrose solution, Ringer's solution, mannitol, or 0.9% sodium chloride solution to achieve the desired concentration of either 4 mcg/mL or 8 mcg/mL. The table below provides the volumes required to prepare the infusion.
To achieve a concentration of 4 mcg/mL:
| Volume of Dexmedetomidine-Novo, concentrate for infusion solution, ml |
Volume of diluent, ml |
Total volume |
| 2 |
48 |
50 |
| 4 |
96 |
100 |
| 10 |
240 |
250 |
| 20 |
480 |
500 |
To achieve a concentration of 8 mcg/mL:
| Volume of Dexmedetomidine-Novo, concentrate for infusion solution, ml |
Volume of diluent, ml |
Total volume |
| 4 |
46 |
50 |
| 8 |
92 |
100 |
| 20 |
230 |
250 |
| 40 |
460 |
500 |
Shake carefully to mix the solution well.
Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration.
Dexmedetomidine is compatible with the following intravenous fluids and medicinal products: Ringer's lactate solution, 5 % glucose solution, 0.9 % sodium chloride solution, 20 % mannitol, sodium thiopental, etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium besilate, mivacurium chloride, rocuronium bromide, glycopyrrolate bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, norepinephrine, dobutamine, midazolam, morphine sulfate, fentanyl citrate, and plasma substitutes.
Unused medicinal product and waste material must be disposed of in accordance with current requirements.
Children.
The safety and efficacy of dexmedetomidine 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 dosage recommendations cannot be given.
Overdose.
Several cases of dexmedetomidine overdose have been reported in clinical and post-marketing studies. Infusion rates reported in these cases reached 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 common adverse reactions reported in association with overdose include bradycardia, arterial hypotension, arterial hypertension, excessive sedation, respiratory depression, and cardiac arrest.
In the event of overdose with clinical symptoms, the infusion of dexmedetomidine should be reduced or discontinued. Cardiovascular effects are predominantly expected and should be treated according to clinical indications. At high concentrations, arterial hypertension may be more pronounced than arterial hypotension. In clinical studies, cases of sinus 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.
Adverse Reactions
Sedation of adult patients in the intensive care unit.
The most commonly reported adverse reactions during administration of dexmedetomidine in the intensive care unit setting 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 adverse reactions related to dexmedetomidine, occurring in 1.7% and 0.9% of randomized patients in intensive care, anesthesiology, and resuscitation units.
Procedural sedation.
The most commonly reported adverse reactions during administration of dexmedetomidine for procedural sedation are listed below (Phase III study protocols included predefined threshold levels for changes in blood pressure, respiratory rate, and heart rate considered as adverse effects):
- Hypotension (55% in the dexmedetomidine group compared to 30% in the placebo group receiving rescue therapy with midazolam and fentanyl);
- Respiratory depression (38% in the dexmedetomidine group compared to 35% in the placebo group receiving rescue therapy with midazolam and fentanyl);
- Bradycardia (14% in the dexmedetomidine group compared to 4% in the placebo group receiving rescue 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 not known (cannot be estimated based on available data).
Endocrine disorders.
Frequency not known: Diabetes insipidus.
Disorders of metabolism and nutrition.
Common: Hyperglycemia, hypoglycemia.
Uncommon: Metabolic acidosis, hypoalbuminemia.
Psychiatric disorders.
Common: Agitation.
Uncommon: Hallucinations.
Cardiac disorders.
Very common: Bradycardia1,2.
Common: Myocardial ischemia or infarction, tachycardia.
Uncommon: Atrioventricular block1, decreased cardiac output, cardiac arrest1.
Vascular disorders.
Very common: Hypotension1,2, 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.
General disorders and administration site conditions.
Common: Withdrawal syndrome, hyperthermia.
Uncommon: Ineffectiveness of the medicinal product, thirst.
1 See "Description of selected adverse reactions" below.
2 The adverse reaction was also observed in procedural sedation studies.
3 Frequency "common" in intensive care unit setting studies.
Description of selected adverse reactions.
Clinically significant arterial hypotension and bradycardia should be managed as described in the section "Special precautions for use".
In relatively healthy volunteers not in the intensive care unit, administration of dexmedetomidine has occasionally led to sinus node arrest or sinus pause. Symptoms resolved after leg elevation and administration of anticholinergic agents such as atropine or glycopyrrolate. In isolated cases, bradycardia progressed to periods of asystole in patients with a prior history of bradycardia.
Cases of cardiac arrest have also been reported, often preceded by bradycardia or atrioventricular block.
Arterial hypertension has been associated with the administration of loading doses. This reaction can be minimized by avoiding a loading dose, reducing the infusion rate, or decreasing the loading dose.
Pediatric population.
In patients aged 1 month and older, predominantly postoperative, in intensive care units, dexmedetomidine administered for up to 24 hours demonstrated a safety profile similar to that in adults. Data in neonates (born at 28 to 44 weeks of gestation) are limited and restricted to maintenance doses ≤ 0.2 mcg/kg/hour. One case of hypothermic bradycardia in a neonate has been reported in the literature.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after medicinal product registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Physicochemical stability has been demonstrated for 24 hours during use at 25°C.
From a microbiological standpoint, this medicinal product should be used immediately. If not used immediately, the storage duration and conditions during use are the responsibility of the user and generally should not exceed 24 hours at 2–8°C, except when dilution is performed under controlled and validated aseptic conditions.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25°C. Keep out of reach of children.
Incompatibilities.
This medicinal product must not be mixed with other medicinal products except those specified in the section "Instructions for use and dosage".
Compatibility studies have shown potential adsorption of dexmedetomidine to certain types of natural rubber. Although dexmedetomidine is administered in a controlled manner, it is advisable to use synthetic components or lined natural rubber stoppers.
Packaging.
2 ml in a vial; 5 vials in a blister pack; 1 blister pack in a cardboard carton.
Prescription status. Prescription only.
Manufacturer. Limited liability company "Novopharm-Biosyntez".
Manufacturer's address and location of operations.
Ukraine, 11700, Zhytomyr Oblast, Novohrad-Volynskyi, Zhитomirska St., 38.