Dexanest
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXANEST (DEXANEST)
Composition:
Active substance: dexmedetomidine hydrochloride;
1 ml of solution contains 118 μg of dexmedetomidine hydrochloride, 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 anxiolytics and sedatives.
ATC code N05CM18.
Pharmacological Properties.
Pharmacodynamics.
Dexmedetomidine is a highly selective alpha-2 receptor agonist with a broad spectrum of pharmacological properties. It exerts a strong sympatholytic effect by reducing norepinephrine release from sympathetic nerve endings. Sedative effects are mediated by reduced activation of the locus coeruleus, the primary noradrenergic nucleus located in the brainstem. Due to its action on this area, dexmedetomidine produces sedation (resembling natural sleep without rapid eye movement), while maintaining the ability to achieve a sedated yet easily arousable and cooperative state. Dexmedetomidine provides anesthetic and moderate analgesic effects; analgesic activity has been demonstrated in patients with chronic lower back pain. Effects on the cardiovascular system are dose-dependent: at lower infusion rates, central effects predominate, resulting in decreased heart rate and arterial blood pressure. At higher doses, peripheral vasoconstrictive effects prevail, leading to increased systemic vascular resistance and arterial blood pressure, while the bradycardic effect becomes more pronounced. Dexmedetomidine has minimal respiratory depressant effects.
Sedation in hospital settings (in intensive care, anesthesia, and resuscitation units)
Efficacy evidence in the pediatric population was obtained from a placebo-controlled study involving a large number of postoperative patients aged from 1 month to ≤17 years. Approximately 50% of patients receiving dexmedetomidine did not require additional midazolam during the treatment period, which averaged 20.3 hours and did not exceed 24 hours. Data on treatment lasting longer than 24 hours are unavailable. Data in neonates (28–44 weeks of gestation) are limited and pertain to low doses (≤0.2 mcg/kg/hr). Neonates may be particularly sensitive to the bradycardic effects of dexmedetomidine under conditions of hypothermia or when heart rate depends on cardiac output.
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 loading infusion of dexmedetomidine at 1 mcg/kg (n = 129) or 0.5 mcg/kg (n = 134) or placebo (normal saline; n = 63) over 10 minutes, followed by a maintenance infusion initiated 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 Assessment 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 proportion of patients randomized to the 1 mcg/kg and 0.5 mcg/kg dexmedetomidine groups who did not require rescue midazolam was 48% (95% CI [confidence interval]: 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 mean difference in 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. The 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 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 rescue midazolam compared to 14% in the placebo group. The risk difference in the proportion of patients randomized to dexmedetomidine who did not require rescue midazolam was 43% (95% CI: 23–57%) compared to placebo. The mean rescue midazolam dose was 1.1 mg in the dexmedetomidine group and 2.8 mg in the placebo group. The mean difference in rescue midazolam dose was –1.8 mg (95% CI: –2.7 to –0.86) in favor of dexmedetomidine.
Pharmacokinetics.
The pharmacokinetics of dexmedetomidine were evaluated after short-term intravenous administration in healthy volunteers and after prolonged infusion in intensive care unit patients. Dexmedetomidine exhibits a two-compartment distribution model. In healthy volunteers, it shows 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 2.1 (±0.43) hours, and the estimated steady-state volume of distribution (Vss) is approximately 91 (±25.5) liters. The estimated plasma clearance (Cl) is approximately 39 (±9.9) L/hr. The average body weight associated with these Vss and Cl estimates was 69 kg. Plasma pharmacokinetics of dexmedetomidine are similar in intensive care patients after infusions lasting >24 hours. Estimated pharmacokinetic parameters are: t1/2 — approximately 1.5 hours, Vss — approximately 93 liters, and Cl — approximately 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 lasting up to 14 days. Dexmedetomidine is 94% protein-bound in plasma. Protein binding is constant across the concentration range of 0.85–85 ng/mL. Dexmedetomidine binds to human serum albumin and alpha-1-acid glycoprotein, with serum albumin being the primary plasma binding protein.
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: one formed via oxidation of the imidazole ring, and the other resulting from sequential processes: N-methylation, hydroxylation of the methyl group, and O-glucuronidation. Available data indicate that the 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 nine days. The main urinary metabolites are two isomeric N-glucuronides, together accounting for approximately 34% of the dose, and the N-methylated 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 parent compound was found in urine. Approximately 28% of metabolites detected in urine are unidentified polar metabolites.
No significant pharmacokinetic differences related to patient sex or age were observed.
Plasma protein binding of dexmedetomidine is reduced in patients 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 and prolonged plasma elimination half-life (t1/2). Mean clearance values in patients with mild, moderate, and severe hepatic impairment were 74%, 64%, and 53% 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 achieve clinical effect, dose reduction of the initial and/or maintenance dose may be advisable 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 unchanged.
Data on use in pediatric patients—from neonates (born at 28–44 weeks of 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 is higher in neonates (28–44 weeks gestation) and decreases with age. In age groups from 1 month to 6 years, body weight-adjusted plasma clearance is higher but decreases with increasing age. Due to immaturity, plasma clearance in neonates (up to 1 month of age) may be lower (0.9 L/hr/kg) than in older age groups.
Clinical characteristics.
Indications.
For sedation in hospital settings (in intensive care, anesthesiology and resuscitation units) of patients requiring a level of sedation no deeper than awakening in response to verbal stimulation.
For sedation of patients 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 types of interactions.
Studies on interaction with other medicinal products have been conducted only in adults.
Concomitant use of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids may result in potentiation of their effects, as confirmed in studies with isoflurane, propofol, alfentanil, and midazolam.
No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, or midazolam were observed. However, due to possible pharmacodynamic interactions, when these agents are used in combination 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 evaluated the ability of dexmedetomidine to inhibit cytochrome P450, including the CYP2B6 isoenzyme. According to in vitro studies, there is a potential for interaction between dexmedetomidine and substrates (primarily 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. Clinical significance is unknown.
The possibility of enhanced hypotensive and bradycardic effects should be considered in patients receiving other medicinal products that cause such effects, e.g., β-adrenoblockers (although additional effects in an interaction study using esmolol were moderate).
Special precautions for use
Dexanest is intended for use in hospital settings (in intensive care, anesthesia and resuscitation units), operating rooms, and during diagnostic procedures. Its use in other settings is not recommended.
During infusion of Dexanest, cardiac function must be continuously monitored in all patients. In patients who have not been intubated, respiratory function should be monitored due to the risk of respiratory depression and, in some cases, the development of apnea.
Recovery time after administration of dexmedetomidine is approximately one hour. When used in outpatient settings, careful monitoring should continue for at least one hour (or longer, depending on the patient's condition). Medical supervision should be maintained for an additional hour for patient safety.
General warnings
Dexanest should not be administered as a bolus injection, and loading doses are not recommended in intensive care units. Therefore, users must be prepared to administer 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 receiving dexmedetomidine, light arousal has been observed, with rapid return to consciousness upon stimulation. In the absence of other clinical symptoms, this sign alone should not be considered as evidence of treatment inefficacy.
Dexmedetomidine typically does not induce deep sedation, allowing patients to be easily aroused. Therefore, Dexanest is not suitable for patients requiring continuous deep sedation.
Dexanest should not be used as a general anesthetic for intubation induction or to provide sedation when muscle relaxants are used.
Dexanest 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 having sedative effects or affecting the cardiovascular system, due to the possibility of additive effects.
Dexanest is not recommended for patient-controlled sedation. If Dexanest is used in outpatient settings, patient discharge should only occur under third-party supervision. Patients should refrain from driving or operating machinery and other hazardous tasks, and, if possible, avoid using other sedative agents (e.g., benzodiazepines, opioids, alcohol) for a certain period depending on the observed effects of dexmedetomidine, the procedure performed, concomitant medications, age, and patient condition.
Caution is advised when using dexmedetomidine in elderly patients. Patients aged over 65 years may be more prone to developing hypotension with dexmedetomidine, including during loading dose administration and procedures. Dose reduction should be considered (see section "Dosage and administration").
Mortality in ICU patients aged ≤ 65 years
In the pragmatic randomized controlled SPICE III trial involving 3904 critically ill adult ICU patients, there was no overall difference in 90-day mortality between the dexmedetomidine group and the usual care group (mortality was 29.1% in both groups). However, heterogeneity in this effect related to age was observed. Dexmedetomidine was associated with increased mortality in patients aged ≤ 65 years (odds ratio 1.26; 95% confidence interval 1.02 to 1.56) compared to alternative sedatives. Although the mechanism is unclear, this age-related heterogeneity in mortality impact was most pronounced with early use of high-dose dexmedetomidine to achieve deep sedation in patients hospitalized for reasons other than postoperative care, and increased with higher APACHE II scores. When dexmedetomidine was used for light sedation, no impact on mortality was observed. These findings should be weighed against the expected clinical benefit of dexmedetomidine compared to alternative sedatives in younger patients.
Cardiovascular effects — Warnings
Dexanest reduces heart rate and blood pressure (central sympatholytic effect), but at higher concentrations causes peripheral vasoconstriction, leading to increased blood pressure. Therefore, Dexanest is not suitable for patients with severe cardiovascular disorders.
Caution should be exercised when administering dexmedetomidine to patients with concomitant bradycardia. Data on the drug's effects in patients with heart rates < 60 bpm are limited; such patients require enhanced monitoring. Bradycardia usually does not require treatment but is typically well controlled with administration of anticholinergic agents (M-cholinergic blockers) and dose reduction. Athletes and others with low resting heart rates may be particularly sensitive to the negative chronotropic effect of alpha-2 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 vasopressors), including chronic hypotension, hypovolemia, or reduced functional reserve (e.g., patients with severe ventricular dysfunction and elderly patients), the hypotensive effect of Dexanest may be more pronounced, requiring special care. Reduction in blood pressure usually does not require specific intervention, but readiness to reduce the dose, administer volume expanders, and/or vasopressors should be ensured.
Hemodynamic effects after administration of Dexanest may be more pronounced in patients with peripheral autonomic nervous system dysfunction (e.g., due to spinal cord injury), requiring special patient monitoring.
Transient increases in blood pressure with concomitant peripheral vasoconstrictive effects have been observed after administration of a loading dose of dexmedetomidine. Therefore, loading doses for sedation in hospital settings (in intensive care, anesthesia, and resuscitation units) are not recommended. Treatment of elevated blood pressure is usually not required, but consideration should be given to reducing the infusion rate.
Central vasoconstriction at higher concentrations may be more significant in patients with ischemic heart disease or severe cerebrovascular disorders; such patients require close monitoring. Dose reduction or discontinuation of the drug should be considered in patients showing signs of myocardial or cerebral ischemia.
Caution is advised when administering dexmedetomidine concomitantly with spinal or epidural anesthesia due to increased risk of hypotension and bradycardia.
Patients with hepatic impairment
Caution is advised 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 Dexanest 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 Dexanest reduces cerebral blood flow and intracranial pressure.
Other warnings
After prolonged use of alpha-2 agonists, withdrawal syndrome has rarely occurred upon abrupt discontinuation. Agitation and elevated blood pressure immediately after stopping 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 predisposed to malignant hyperthermia.
Cases of non-diabetic diabetes insipidus have been reported in association with dexmedetomidine treatment. If polyuria occurs, dexmedetomidine should be discontinued and serum sodium levels and urine osmolality should be checked.
Dexanest contains less than 1 mmol of sodium (23 mg) per 1 mL.
Use during pregnancy or breastfeeding
Pregnancy. Data on the use of dexmedetomidine in pregnant women are lacking or limited. Reproductive toxicity has been observed in animal studies. Dexanest should not be used during pregnancy unless the woman's clinical condition requires treatment with dexmedetomidine.
Breastfeeding. Dexmedetomidine is excreted in human breast milk, but levels fall below the limit of detection 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 to the infant and the benefits of dexmedetomidine therapy to the mother.
Fertility. Fertility studies in rats did not show any effect of dexmedetomidine on male or female fertility. Data on effects on human fertility are lacking.
Ability to affect reaction speed when driving or operating machinery
Patients are advised to refrain from driving or operating machinery or performing other hazardous tasks for a certain period after administration of Dexanest 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.
For hospital use only.
Dosage for adults
Patients who have already been intubated and are under sedation may be transitioned to Dexanest 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. It is important to note that dexmedetomidine is a very 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 Dexanest should be switched to an alternative sedative agent.
The use of a loading dose of Dexanest 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 need for sedation. There is no experience with the use of Dexanest for periods exceeding 14 days. When treatment exceeds 14 days, the patient's condition should be regularly evaluated.
For sedation of patients during diagnostic or surgical procedures requiring sedation / procedural sedation.
Dexanest must be administered only by healthcare professionals qualified in anesthesia management for patients in operating rooms or during diagnostic procedures. When Dexanest 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 hypotension, hypertension, bradycardia, respiratory depression, airway obstruction, apnea, dyspnea, and/or oxygen desaturation (see section "Adverse Reactions").
Supplemental oxygen must be readily available and promptly administered when indicated. Oxygen saturation should be monitored using pulse oximetry.
Dexanest 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) for painful procedures or when deeper sedation is required. The pharmacokinetic distribution half-life of dexmedetomidine is approximately 6 minutes, which, along with the effects of other administered drugs, should be considered when estimating the appropriate time needed to titrate to the desired clinical effect of Dexanest.
Initiation of 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 is generally initiated at a dose of 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 in elderly patients (see section "Pharmacokinetics"). However, elderly patients are at increased risk of developing hypotension (see section "Special precautions**"**), although limited available data on 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. Dexanest 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
Dexanest must be administered by personnel experienced in managing patients requiring intensive care. 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, Dexanest may be diluted in 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. The table below provides the volumes required for infusion preparation.
To achieve a concentration of 4 mcg/mL:
| Volume of Dexanest, concentrate for solution for infusion, 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 Dexanest, concentrate for solution for infusion, ml |
Volume of diluent, ml |
Total volume |
| 4 |
46 |
50 |
| 8 |
92 |
100 |
| 20 |
230 |
250 |
| 40 |
460 |
500 |
Shake well to ensure adequate mixing of the solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Dexanest 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 besilate, mivacurium chloride, rocuronium bromide, glycopyrrolate bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, noradrenaline, dobutamine, midazolam, morphine sulfate, fentanyl citrate, and plasma substitute (Haemaccel®).
Children. The safety and efficacy of Dexanest in children (aged 0 to 18 years) have not been established. Data on use in children are provided in the sections "Pharmacological properties" and "Adverse reactions", but dosage recommendations cannot be given.
Overdose.
Several cases of dexmedetomidine overdose have been reported in clinical and post-marketing studies. Infusion rates of dexmedetomidine reported in these cases reached 60 mcg/kg/hr for 36 minutes and 30 mcg/kg/hr 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, the infusion of Dexanest 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 node arrest resolved spontaneously or responded to treatment with atropine or glycopyrrolate. In isolated cases of severe overdose leading to cardiac arrest, resuscitation measures were required.
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 associated with dexmedetomidine, occurring in 1.7% and 0.9% of randomized intensive care, anesthesiology, and resuscitation patients, respectively.
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 from available data).
Endocrine system.
Frequency not known: Diabetes insipidus.
Metabolism and nutrition disorders.
Common: Hyperglycemia, hypoglycemia.
Uncommon: Metabolic acidosis, hypoalbuminemia.
Psychiatric disorders.
Common: Agitation.
Uncommon: Hallucinations.
Cardiac disorders.
Very common: Bradycardia1,2.
Common: Myocardial ischemia or infarction, tachycardia.
Uncommon: Atrioventricular block, decreased cardiac output, cardiac arrest.
Vascular disorders.
Very common: Hypotension1,2, hypertension1,2.
Respiratory system.
Very common: Respiratory depression2,3.
Uncommon: Dyspnea, apnea.
Gastrointestinal disorders.
Common: Nausea2, vomiting, dry mouth2.
Uncommon: Abdominal distension.
General disorders and administration site conditions.
Common: Withdrawal syndrome, hyperthermia.
Uncommon: Ineffectiveness of the drug, thirst.
1 See "Description of selected adverse reactions" below.
2 This adverse reaction was also observed in procedural sedation studies.
3 Frequency "common" in intensive care unit setting studies.
Description of selected adverse reactions
In relatively healthy volunteers not in the intensive care unit, administration of dexmedetomidine occasionally led to sinus node arrest or sinus pause. Symptoms were resolved by 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 a loading dose. 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, and with administration duration up to 24 hours, the drug demonstrates 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. A single case of hypothermic bradycardia in a neonate has been reported in the literature.
Reporting of suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.
Shelf life. 2 years.
From a microbiological standpoint, this 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 a temperature of 2 to 8 °C, except when dilution is performed under controlled and validated aseptic conditions.
Storage conditions. No special storage conditions required.
Keep out of reach and sight of children.
Incompatibilities.
Use only the diluents specified in the section "Dosage and administration".
Packaging.
2 ml in a vial; 1 vial in a pack. 5 vials in a blister; 1 or 5 blisters in a pack.
4 ml in a vial; 1 vial in a pack. 4 vials in a blister; 1 blister in a pack.
10 ml in a vial; 1 vial in a pack. 4 vials in a blister; 1 blister in a pack.
Prescription status. Prescription only.
Manufacturer. JSC "Farmak".
Manufacturer's name and address of place of business.
74 Kyrylivska Street, Kyiv, 04080, Ukraine.