Dexmedetomidine-darnitsa
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Dexmedetomidine-Darnytsia (Dexmedetomidine-Darnytsia)
Composition:
Active substance: dexmedetomidine;
1 ml of concentrate contains 118 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. Other anesthetic and sedative agents.
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 norepinephrine release from sympathetic nerve endings. Sedative effects are mediated by decreased neuronal activity in the locus coeruleus (locus coeruleus (L.) – a nucleus in the brainstem predominantly composed of noradrenergic neurons.
Dexmedetomidine provides analgesic action and reduces the required doses of anesthetics and analgesics. Cardiovascular effects are dose-dependent: at low infusion rates, central effects predominate, leading to decreased heart rate and arterial blood pressure. At higher doses, peripheral vasoconstrictive effects prevail, resulting in increased systemic vascular resistance and arterial pressure, as well as further enhancement of bradycardia. Dexmedetomidine has minimal respiratory depressant effects when administered as a monotherapy in healthy volunteers.
Sedation of adult patients in intensive care units (ICU).
In placebo-controlled studies involving ICU patients following surgery who required intubation and sedation with midazolam or propofol, dexmedetomidine significantly reduced the need for rescue sedation (with midazolam or propofol) and opioid use during sedation for up to 24 hours. Most patients receiving dexmedetomidine did not require additional sedative therapy. Patients could be successfully extubated without discontinuing dexmedetomidine infusion. Studies conducted outside the ICU setting have confirmed that dexmedetomidine hydrochloride can be safely administered to patients without endotracheal intubation, provided appropriate monitoring is in place.
Dexmedetomidine was comparable to midazolam (mean ratio 1.07; 95% confidence interval (CI) 0.971, 1.176) and propofol (mean 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 (from 0 to -3 on the Richmond Agitation-Sedation Scale (RASS)) for up to 14 days. It reduced duration of mechanical ventilation compared to midazolam and shortened time to tracheal extubation compared to both midazolam and propofol. Patients receiving dexmedetomidine awakened more easily, were more cooperative, and reported pain more reliably compared to those receiving midazolam or propofol. Arterial hypotension and bradycardia occurred more frequently in patients receiving dexmedetomidine compared to midazolam, while tachycardia was less common. Compared to the propofol group, tachycardia occurred more frequently in the dexmedetomidine group, while the incidence of arterial hypotension was approximately similar. CAM-ICU assessment showed lower delirium rates 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 level was higher in patients who were difficult to sedate with standard agents immediately before switching to an alternative sedative.
Evidence of efficacy in the pediatric population comes from a dose-controlled study in children aged 1 month to ≤17 years in the ICU following surgery. Approximately 50% of patients receiving dexmedetomidine did not require forced rescue sedation with midazolam during a treatment period with a median duration of 20.3 hours, but not exceeding 24 hours. Data on treatment beyond 24 hours in children are lacking. Data in neonates (28–44 weeks gestation) 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 when hypothermia is present or in 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 reported as mild in one case and moderate in three cases.
Procedural sedation / sedation with preserved consciousness.
The safety and efficacy of dexmedetomidine for sedation of non-intubated patients during and/or prior to 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 at 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 Activity Score) without requiring forced rescue sedation with 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 for the proportion of patients randomized to the 1 mcg/kg and 0.5 mcg/kg dexmedetomidine groups who did not require forced rescue sedation with midazolam was 48% (95% CI: 37–57%) and 40% (95% CI: 28–48%), respectively, compared to placebo. The median (range) dose of forced rescue sedation with midazolam 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 mean difference in forced rescue midazolam dose between 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. The median time to first administration of forced rescue sedation 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 intubation under local anesthesia 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 at 0.7 mcg/kg/hr. To maintain a sedation level >2 on the Ramsay Sedation Scale, 53% of patients receiving dexmedetomidine did not require forced rescue sedation with midazolam, compared to 14% in the placebo group. The risk difference for the proportion of patients randomized to the dexmedetomidine group who did not require forced rescue sedation with midazolam was 43% (95% CI: 23–57%) compared to placebo. The mean midazolam dose for forced rescue sedation was 1.1 mg in the dexmedetomidine group and 2.8 mg in the placebo group. The mean difference in forced rescue midazolam dose was -1.8 mg (95% CI: -2.7 to -0.86) in favor of dexmedetomidine.
Preclinical Safety Data
Preclinical data from standard safety pharmacology, single and repeated dose toxicity, and genotoxicity studies indicate no special hazard for humans.
In reproductive toxicity studies, dexmedetomidine did not affect fertility in male or female rats, and no teratogenic effects were observed in rats or rabbits. In rabbits, intravenous administration at the maximum dose of 96 mcg/kg/day achieved exposures similar to those observed clinically. In rats, subcutaneous administration at the maximum dose of 200 mcg/kg/day caused increased embryofetal mortality and reduced fetal body weight. These effects were associated with clear maternal toxicity. Reduced fetal body weight was also observed in a rat fertility study at a dose of 18 mcg/kg/day and was accompanied by delayed ossification at 54 mcg/kg/day. The concentrations observed in rats were below the clinical exposure range.
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 distribution model. In healthy volunteers, the drug exhibits a rapid distribution phase with a central distribution half-life (t1/2α) of approximately 6 minutes. The mean terminal elimination half-life (t1/2) is approximately 1.9–2.5 hours (range: 1.35 to 3.68 hours), and the mean steady-state volume of distribution (Vss) is approximately 1.16–2.16 L/kg (90–151 L). Mean plasma clearance (Cl) is 0.46–0.73 L/hr/kg (35.7–51.1 L/hr). The mean body weight of patients used for Vss and Cl calculations was 69 kg.
Plasma pharmacokinetics of dexmedetomidine in ICU patients receiving infusions longer than 24 hours were similar. Calculated pharmacokinetic parameters were: t1/2 ≈ 1.5 hours, Vss ≈ 93 L, and Cl ≈ 43 L/hour. Over the dose range of 0.2 to 1.4 mcg/kg/hour, dexmedetomidine pharmacokinetics are linear, and the drug does not accumulate with administration up to 14 days. Dexmedetomidine is 94% protein-bound in plasma. The degree of plasma protein binding remains constant over a concentration range of 0.85 to 85 ng/mL. Dexmedetomidine binds to both human serum albumin and α1-acid glycoprotein, with serum albumin being the primary plasma protein to which it binds.
Biotransformation and Elimination.
Dexmedetomidine is eliminated primarily via extensive hepatic metabolism. There are three initial metabolic pathways: direct N-glucuronidation, direct N-methylation, and cytochrome P450-catalyzed oxidation.
The major 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 of dexmedetomidine) and H-3 (formed by oxidation of the imidazole ring). Available data indicate that oxidized metabolite formation involves several cytochrome P450 isoenzymes (CYP2A6, CYP1A2, CYP2E1, CYP2D6, and CYP2C19). These metabolites lack significant pharmacological activity.
Approximately 95% of radioactivity was recovered in urine and 4% in feces within 9 days after intravenous administration of radiolabeled dexmedetomidine. The main urinary metabolites are two isomeric N-glucuronides, accounting for approximately 34% of the administered dose combined, 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.
Special Patient Populations.
No significant pharmacokinetic differences were observed based on sex or age. 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 impairment (Child–Pugh classes A, B, or C), hepatic clearance of dexmedetomidine was reduced and plasma elimination half-life (t1/2) prolonged. Mean plasma clearance values of unbound dexmedetomidine in patients with mild, moderate, and severe hepatic impairment were 59%, 51%, and 32% of those in healthy volunteers, respectively. Mean plasma elimination half-life (t1/2) in patients with mild, moderate, and severe hepatic impairment was prolonged to 3.9, 5.4, and 7.4 hours, respectively. Although dose titration should be based on clinical response, consideration should be given to reducing the initial or maintenance dose of dexmedetomidine in patients with hepatic impairment, depending on the severity 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 use in neonates (28–44 weeks gestation) and children up to 17 years of age are limited. The elimination half-life of dexmedetomidine in children (aged 1 month to 17 years) is similar to that in adults, but is slightly longer in neonates (up to 1 month of age).
In age groups from 1 month to 6 years, plasma clearance adjusted for body weight is higher, but decreases in older children. Due to immaturity, plasma clearance adjusted for body weight in neonates (up to 1 month of age) is lower (0.9 L/hr/kg) than in older age groups. Available data are summarized in the table below.
| Mean value (95% CI) |
|||
| Age |
N |
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.
Sedation of adult patients in intensive care 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 Richmond Agitation-Sedation Scale (RASS)).
Sedation of non-intubated adult patients before and/or during diagnostic or surgical procedures requiring sedation, i.e., procedural sedation (sedation with preserved 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 a 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 use of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids is likely to enhance their effects, including sedative, anesthetic, and cardiorespiratory effects. Enhanced effects of isoflurane, propofol, alfentanil, and midazolam have been confirmed in individual studies.
No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam were observed. However, due to possible pharmacodynamic interactions, when these agents are used concomitantly with dexmedetomidine, it may be necessary to reduce the dose of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.
In vitro studies using human liver microsomes have investigated the ability of dexmedetomidine to inhibit cytochrome P450, including the CYP2B6 isoenzyme. According to in vitro results, there is a potential for in vivo interaction between dexmedetomidine and substrates predominantly metabolized by the CYP2B6 isoenzyme.
In vitro induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 isoenzymes by dexmedetomidine has been observed; therefore, such induction in vivo cannot be excluded. The clinical significance of this induction is unknown.
Potential enhancement of hypotensive and bradycardic effects should be considered in patients receiving other medicinal products that cause such effects (e.g., β-adrenoblockers), although additional effects observed in interaction studies with esmolol were moderate.
Special precautions.
Dexmedetomidine-Darnytsia is intended for use in intensive care units, operating rooms, and during diagnostic procedures. The use of dexmedetomidine under other conditions is not recommended. During infusion of dexmedetomidine, continuous cardiac monitoring must be maintained in all patients.
Due to the risk of respiratory depression and isolated cases of apnea in non-intubated patients, respiratory function should be monitored (see section "Adverse reactions").
Available data indicate that recovery time after administration of dexmedetomidine is approximately 1 hour. When the medicinal product is used in an outpatient setting, careful patient monitoring should be performed for at least 1 hour (or longer depending on the patient's condition), followed by continued medical supervision for at least another 1 hour to ensure patient safety.
General warnings
The medicinal product must not be administered as a bolus. In intensive care units, the use of a loading dose is not recommended. Therefore, medical personnel should be prepared to use alternative sedative agents for immediate control of agitation or during procedures, especially during the first hours of treatment.
During procedural sedation, if a rapid increase in the level of sedation is required, administration of a small bolus of another sedative agent is permitted.
In some patients receiving dexmedetomidine, mild arousal and return of consciousness in response to stimulation have been observed.
In the absence of other clinical signs, this finding alone should not be considered as evidence of drug inefficacy.
Dexmedetomidine typically does not cause deep sedation, and patients awaken easily. Therefore, dexmedetomidine is not recommended for patients who require a different effect profile, such as those requiring prolonged deep sedation.
Dexmedetomidine-Darnytsia must not be used as an agent for induction of general anesthesia during intubation or for providing sedation when muscle relaxants are used.
Dexmedetomidine lacks the anticonvulsant activity characteristic of some other sedative agents and therefore will not suppress existing seizure activity.
Caution should be exercised when dexmedetomidine is used concomitantly with medicinal products having sedative effects or affecting the cardiovascular system due to the possibility of additive effects.
Dexmedetomidine is not recommended for patient-controlled sedation. Adequate data are lacking.
When the medicinal product is used in an outpatient setting, patients should generally be placed under the supervision of an appropriate third party. Patients should be advised to refrain from driving or operating machinery and, if possible, to avoid using other agents with sedative effects (e.g., benzodiazepines, opioids, alcohol) for an appropriate period of time, depending on the observed effects of dexmedetomidine, the procedure performed, concomitant medications, age, and patient condition.
Caution should be exercised when administering dexmedetomidine to elderly patients. Patients aged 65 years and older may be more prone to developing hypotension when dexmedetomidine is administered during procedures, including with loading dose administration. Dose reduction should be considered (see section "Dosage and administration").
Mortality in patients aged ≤ 65 years in intensive care units.
In the pragmatic randomized controlled SPICE III trial involving 3,904 critically ill adult patients in intensive care units, dexmedetomidine was used as the primary sedative agent and compared with usual care. No overall difference in 90-day mortality was observed between the dexmedetomidine group and the usual care group (mortality 29.1% in both groups), but there was evidence of heterogeneity in the effect of age on mortality.
Dexmedetomidine was associated with increased mortality in patients aged ≤ 65 years (odds ratio 1.26; 95% Bayesian confidence interval from 1.02 to 1.56) compared to alternative sedative agents. Although the mechanism is unclear, the heterogeneity in mortality effect by age was most pronounced in patients hospitalized for reasons other than postoperative care and increased with higher APACHE II scores and lower age. These data should be weighed against the expected clinical benefit of dexmedetomidine compared to alternative sedative agents in younger patients.
Cardiovascular effects and warnings
Dexmedetomidine reduces heart rate and blood pressure (due to central sympatholytic action), but at higher concentrations causes peripheral vasoconstriction, leading to increased blood pressure. Therefore, the medicinal product is not suitable for patients with severe cardiovascular disease.
Caution should be exercised when administering dexmedetomidine to patients with concomitant bradycardia. Data on the effect of the medicinal product in patients with heart rates < 60 beats/min are limited; therefore, such patients require special care. Bradycardia usually does not require treatment but can typically be reversed with administration of anticholinergic agents or dose reduction if necessary. Athletes with low resting heart rates may be particularly sensitive to the bradycardic effect of alpha-2 adrenergic agonists; cases of transient sinus arrest have been reported. Cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have also been reported (see section "Adverse reactions").
In patients with concomitant arterial hypotension (especially refractory to vasoconstrictors), hypovolemia, chronic arterial hypotension, or reduced functional reserve, such as patients with severe ventricular dysfunction and elderly patients, the hypotensive effect of dexmedetomidine may be more pronounced, requiring special monitoring. Reduction in blood pressure usually does not require treatment, but readiness to reduce the dose, administer volume expanders, and/or vasoconstrictors should be maintained if necessary.
Hemodynamic effects after initiation of dexmedetomidine infusion may be more pronounced in patients with peripheral autonomic nervous system dysfunction (e.g., due to spinal cord injury), requiring special monitoring.
Transient increases in blood pressure with concomitant peripheral vasoconstriction have been observed during administration of a loading dose of dexmedetomidine; therefore, administration of a loading dose for sedation in hospital settings (in intensive care, anesthesia, and resuscitation units) is not recommended.
Treatment of arterial hypertension is usually not required; however, consideration should be given to reducing the infusion rate.
Local vasoconstriction at higher drug concentrations may be more significant in patients with ischemic heart disease or severe cerebrovascular disease; such patients should be closely monitored.
If signs of myocardial or cerebral ischemia develop, consideration should be given to reducing the dose or discontinuing the drug.
Caution should be exercised when administering dexmedetomidine concomitantly with spinal or epidural anesthesia due to the potential increased risk of hypotension and bradycardia.
Patients with hepatic impairment
Caution should be exercised in patients with severe hepatic insufficiency, as reduced clearance of dexmedetomidine may lead to drug overdose, increasing the risk of adverse reactions, excessive sedation, or prolonged effect.
Patients with neurological disorders
Experience with the use of the medicinal product in severe neurological conditions such as traumatic brain injury and the postoperative period following 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 may reduce cerebral blood flow and intracranial pressure.
Other warnings
After abrupt discontinuation of alpha-2 adrenergic agonists following prolonged use, withdrawal syndrome has rarely occurred. Excitation and increased blood pressure immediately after discontinuation of dexmedetomidine should raise suspicion of such a condition.
Dexmedetomidine may cause hyperthermia, which may be resistant to conventional cooling methods. Administration of dexmedetomidine should be discontinued if persistent fever of unknown etiology develops. Dexmedetomidine is not recommended for patients prone to malignant hyperthermia.
Unused medicinal product and/or waste material should be disposed of in accordance with local requirements.
Important information on excipients
The medicinal product contains less than 1 mmol of sodium (23 mg) per 1 mL, i.e., it is practically sodium-free. Cases of diabetes insipidus have been reported in association with the use of dexmedetomidine. In the event of polyuria, dexmedetomidine administration should be discontinued and serum sodium levels and urine osmolality should be checked.
Use during pregnancy or breastfeeding.
Data on the use of dexmedetomidine in pregnant women are lacking 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 the use of dexmedetomidine.
Breastfeeding. Dexmedetomidine passes into human breast milk, but levels become undetectable within 24 hours after discontinuation of the drug. Risk to the infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue dexmedetomidine therapy should be made considering the benefits of breastfeeding for the infant and the benefits of dexmedetomidine treatment for the mother.
Fertility. Fertility studies in rats showed no effect of dexmedetomidine on fertility in males or females. 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 operating machinery for a certain period after administration of dexmedetomidine for procedural sedation.
Administration and Dosage
For sedation of adult patients in intensive care units, anesthesia, and resuscitation departments requiring a level of sedation no deeper than awakening in response to verbal stimulation (corresponds to a range of 0 to -3 on the Richmond Agitation-Sedation Scale (RASS)).
For hospital use only. The medicinal product must be administered by healthcare professionals experienced in managing patients requiring intensive care.
Dosage for adults
Patients who are already intubated and under sedation may be transitioned to dexmedetomidine with an initial infusion rate of 0.7 mcg/kg/hr, which may subsequently be gradually adjusted according to the patient's clinical response within a dosage 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 a lower initial infusion rate. It should be noted that dexmedetomidine is a highly potent agent; therefore, the infusion rate is specified per hour. After dose adjustment, a new steady sedation level may not be achieved earlier than 1 hour.
Maximum dose
The maximum dose of 1.4 mcg/kg/hr must not be exceeded. Patients who do not 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 in ICU settings 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.
Duration
There is no experience with the use of dexmedetomidine for periods longer than 14 days. When dexmedetomidine is used for more than 14 days, the continued need for this medicinal product should be regularly assessed.
For sedation of non-intubated patients before and/or during diagnostic or surgical procedures requiring procedural sedation/preserving consciousness sedation.
The medicinal product must be administered only by qualified healthcare professionals trained in anesthesia for patients in operating rooms or during diagnostic procedures. If the medicinal product is administered for sedation with consciousness preserved, 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 arterial hypotension, hypertension, bradycardia, respiratory depression, airway obstruction, apnea, dyspnea, and/or decreased oxygen saturation (see section "Adverse Reactions").
An oxygen delivery system must be available and ready for immediate use if indicated. Oxygen saturation should be monitored using pulse oximetry.
The medicinal product should be 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 distribution-phase pharmacokinetic half-life of dexmedetomidine is approximately 6 minutes, which should be considered along with the effects of other co-administered medicinal products when estimating the appropriate time required to titrate to the desired clinical effect of dexmedetomidine.
Initiating procedural sedation.
Loading infusion of 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 should generally be initiated at 0.6–0.7 mcg/kg/hr and titrated to achieve the desired clinical effect within a dosage range of 0.2 to 1 mcg/kg/hr. 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 precautions**"**), although limited available data on procedural sedation outcomes 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 (see sections "Special precautions**"** and "Pharmacokinetics").
Administration method
Dexmedetomidine must be administered by personnel experienced in the care of patients requiring intensive therapy. The medicinal product should be used only as a diluted intravenous infusion using a controlled infusion device.
Ampoules and vials are intended for single-patient use only.
Preparation of solution
Prior to administration, the medicinal product may be diluted in 5% (50 mg/mL) glucose solution, Ringer's solution, mannitol, or 0.9% (9 mg/mL) sodium chloride solution to achieve the desired concentration of 4 mcg/mL or 8 mcg/mL. The table below provides the volumes required to prepare the infusion.
To obtain the required concentration of 4 mcg/mL:
| Volume of the medicinal product Dexmedetomidine-Darnytsia, 100 mcg/mL, concentrate for infusion solution, mL |
Volume of diluent, mL |
Total volume |
| 2 |
48 |
50 |
| 4 |
96 |
100 |
| 10 |
240 |
250 |
| 20 |
480 |
500 |
For the required concentration of 8 mcg/mL:
| Volume of the medicinal product Dexmedetomidine-Darnytsia, 100 mcg/ml, 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.
The medicinal product should be inspected visually for the presence of foreign particles and discoloration prior to administration.
The medicinal product Dexmedetomidine-Darnytsia is compatible with the following intravenous fluids and medicinal products: Ringer's lactate solution, 5 % glucose solution, 0.9 % (9 mg/mL) sodium chloride solution, 20 % (200 mg/mL) mannitol, thiopental sodium, 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 plasma substitute (Haemaccel®).
Children.
The safety and efficacy of Dexmedetomidine-Darnytsia in children (aged 0 to 18 years) have not been established. Data on use in children are provided in the sections "Pharmacological properties" and "Side effects**"**, 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 commonly reported adverse reactions associated with overdose include bradycardia, arterial hypotension, arterial hypertension, excessive sedation, respiratory depression, and cardiac arrest.
In case of overdose with clinical symptoms, infusion of Dexmedetomidine-Darnytsia should be slowed or discontinued. Cardiovascular effects are predominantly expected and should be managed 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 glycopyrronium. Resuscitation measures were required in isolated cases of severe overdose leading to cardiac arrest.
Adverse Reactions
Sedation of adult patients in the intensive care unit (ICU).
The most commonly reported adverse reactions during administration of dexmedetomidine in the ICU 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 associated with dexmedetomidine use, occurring in 1.7% and 0.9% of randomized ICU patients, respectively.
Procedural sedation/preserving consciousness sedation.
The most commonly reported adverse reactions during procedural sedation with dexmedetomidine are listed below (Phase III study protocols included predefined threshold levels for changes in blood pressure, respiratory rate, and heart rate considered as adverse events):
- Hypotension (55% in the dexmedetomidine group vs. 30% in the placebo group receiving mandatory rescue sedation with midazolam and fentanyl);
- Respiratory depression (38% in the dexmedetomidine group vs. 35% in the placebo group receiving mandatory rescue sedation with midazolam and fentanyl);
- Bradycardia (14% in the dexmedetomidine group vs. 4% in the placebo group receiving mandatory rescue sedation 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).
Respiratory, thoracic and mediastinal disorders: very common: respiratory depression\textsuperscript{2,3}; uncommon: dyspnea, apnea.
Gastrointestinal disorders: common: nausea\textsuperscript{2}, vomiting, dry mouth\textsuperscript{2}; uncommon: abdominal distension.
Metabolism and nutrition disorders: common: hyperglycemia, hypoglycemia; uncommon: metabolic acidosis, hypoalbuminemia; frequency not known: diabetes insipidus.
Psychiatric disorders: common: agitation; uncommon: hallucinations.
Cardiac disorders: very common: bradycardia\textsuperscript{1,2}; arterial hypotension\textsuperscript{1,2}, arterial hypertension\textsuperscript{1,2}; common: myocardial ischemia or infarction, tachycardia; uncommon: atrioventricular block\textsuperscript{1}, decreased cardiac output, cardiac arrest\textsuperscript{1}.
General disorders and administration site conditions: common: withdrawal syndrome, hyperthermia; uncommon: lack of drug efficacy, thirst.
\textsuperscript{1}Description of individual adverse reactions.
\textsuperscript{2}Adverse reaction also observed in procedural sedation studies.
\textsuperscript{3}Frequency "common" in ICU setting studies.
Description of individual adverse reactions
Clinically significant arterial hypotension or bradycardia should be managed according to recommendations in the "Dosage and Administration" section.
In relatively healthy individuals not in ICU who received dexmedetomidine, bradycardia was occasionally accompanied by sinus arrest or sinus pause. Symptoms were alleviated by leg elevation and administration of 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. 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 administered for up to 24 hours to pediatric patients aged 1 month and older in ICU, primarily after surgical procedures, was similar to that in adults. Data in neonates (28–44 weeks gestation) are very limited and relate only to maintenance doses (< 0.2 mcg/kg/hr). One case of hypothermic bradycardia in a neonate has been described in the literature.
Reporting suspected adverse reactions.
Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and/or lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Physical and chemical 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 duration and conditions of storage during use are the responsibility of the medical staff and generally should not exceed 24 hours at 2°C to 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 the reach of children.
Incompatibilities.
The medicinal product should not be mixed with other medicinal products except those specified in the "Dosage and Administration" section.
Compatibility studies have revealed potential adsorption of dexmedetomidine by certain types of natural rubber. Although the dose of dexmedetomidine is titrated according to clinical effect, it is recommended to use infusion systems with components made of synthetic rubber or coated natural rubber.
Packaging.
2 ml in a vial; 5 vials in a blister pack; 1 blister pack in a carton.
Prescription status. Prescription only.
Manufacturer. JSC "Pharmaceutical Company "Darnitsya".
Manufacturer's address.
13, Boryspilska Street, Kyiv, 02093, Ukraine.
Marketing authorization holder.
JSC "Pharmaceutical Company "Darnitsya".
Address of the marketing authorization holder.
13, Boryspilska Street, Kyiv, 02093, Ukraine.