Myrodex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIRODEX

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 anesthetic and sedative agents.

ATC code N05CM18.

Pharmacological Properties

Pharmacodynamics

Dexmedetomidine is a highly selective alpha-2 receptor agonist with a broad range of pharmacological properties. It exerts a potent 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 (resembling natural non-rapid eye movement sleep) 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. Cardiovascular effects are dose-dependent; at lower infusion rates, central effects predominate, leading to reductions in heart rate and arterial blood pressure. At higher doses, peripheral vasoconstrictive effects prevail, resulting in increased systemic vascular resistance and arterial pressure, while bradycardic effects become more pronounced. Dexmedetomidine has minimal respiratory depressant effects.

Sedation in hospital settings (in intensive care, anesthesia, and resuscitation units)

According to literature data, evidence of efficacy in the pediatric population was obtained in a placebo-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 the treatment period, which lasted on average 20.3 hours and did not exceed 24 hours. Data on treatment duration exceeding 24 hours are unavailable. Data in neonates (28–44 weeks gestational age) are limited and pertain to the use of low doses (≤0.2 mcg/kg/hr). Neonates may be particularly sensitive to the bradycardic effects of Miradex under conditions of hypothermia and when heart rate is dependent 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.

According to literature data, 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 of the investigational drug 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 proportion 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. The 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.

According to literature data, in Study 2, patients undergoing awake fiberoptic intubation under local anesthesia were randomized to receive a loading infusion of dexmedetomidine at 1 mcg/kg (n = 55) or placebo (normal saline) (n = 50) over 10 minutes, 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 therapy, compared to 14% in the placebo group. The risk difference in the proportion of patients randomized to the dexmedetomidine group who did not require rescue midazolam therapy 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. According to literature data, dexmedetomidine exhibits a two-compartment distribution model. In healthy volunteers, it shows a rapid distribution phase with an estimated central distribution half-life (t_1/2α) of approximately 6 minutes. The estimated terminal elimination half-life (t_1/2) is approximately 2.1 (±0.43) hours, and the estimated steady-state volume of distribution (V_ss) is approximately 91 (±25.5) liters. The estimated plasma clearance (Cl) is approximately 39 (±9.9) L/hr. The mean body weight associated with these V_ss and Cl estimates was 69 kg. Plasma pharmacokinetics of dexmedetomidine are similar in intensive care unit patients after infusions lasting >24 hours. Estimated pharmacokinetic parameters are: t_1/2 ≈ 1.5 hours, V_ss ≈ 93 liters, 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 lasting up to 14 days. Dexmedetomidine is 94% bound to plasma proteins. Protein binding is constant over a 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 binding protein in plasma.

Dexmedetomidine is extensively metabolized in the liver. There are three initial metabolic pathways: direct N-glucuronidation, direct N-methylation, and oxidation catalyzed by cytochrome P450. The major circulating metabolites of dexmedetomidine are two isomeric N-glucuronides, one formed by 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 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 is excreted in urine. Approximately 28% of metabolites detected in urine are unidentified polar metabolites.

No significant pharmacokinetic differences related to patient sex or age have been 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) had reduced hepatic clearance and prolonged plasma elimination half-life (t_1/2). Mean clearance values in patients with mild, moderate, and severe hepatic impairment were 74%, 64%, and 53% of that in healthy volunteers, respectively. Mean t_1/2 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 a desired 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.

The 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 to 44 weeks gestational age) 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 (born at 28 to 44 weeks gestational age), decreasing with increasing 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 units, anesthesia and resuscitation departments) in 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 forms of interaction

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

Concomitant administration of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids may result in potentiation of their effects, such as sedation, anesthesia, and cardiopulmonary effects. This assumption has been 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, dosage reduction of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid may be necessary.

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

Induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 isoenzymes by dexmedetomidine was observed in vitro; therefore, such in vivo interactions cannot be excluded.

Potential for enhanced hypotensive and bradycardic effects should be considered in patients receiving other medicinal products causing such effects, e.g., β-adrenergic blockers (although additional effects in an interaction study using esmolol were moderate).

Special precautions for use

Midodex 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 Midodex infusion, cardiac function must be continuously monitored in all patients. In patients who have not undergone intubation, respiratory function should be monitored due to the risk of respiratory depression and, in some cases, apnea.

Recovery time after administration of dexmedetomidine is approximately 1 hour. When used in outpatient settings, careful monitoring should continue for at least 1 hour (or longer depending on the patient's condition), and medical supervision should be maintained for an additional hour for patient safety.

General warnings

Midodex should not be administered as a bolus injection, and loading doses are not recommended in intensive care units. Therefore, readiness to use an alternative sedative agent for immediate control of agitation or during procedures, especially during the first few hours of treatment, is essential. 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 Midodex, mild arousal has been observed, with rapid return to consciousness upon stimulation. In the absence of other clinical symptoms, this sign alone should not be considered as evidence of inadequate drug efficacy.

Dexmedetomidine typically does not cause deep sedation, allowing patients to be easily aroused. Therefore, dexmedetomidine is not suitable for patients requiring continuous deep sedation.

Midodex should not be used as a general anesthetic agent for intubation induction or to provide sedation when neuromuscular blocking agents are used.

Midodex is unlikely to suppress seizure activity; therefore, it 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.

Midodex is not recommended for patient-controlled sedation. Appropriate data are lacking. If Midodex is administered in outpatient settings, patient discharge should occur under third-party supervision. Patients should be advised to refrain from driving vehicles and other potentially hazardous activities and, if possible, to 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, and the patient's age and condition.

Caution is advised when administering dexmedetomidine to elderly patients. Patients aged 65 years and older are more prone to developing hypotension during dexmedetomidine administration, including during loading dose infusion and procedures. Dose reduction should be considered (see section "Dosage and administration").

Mortality in intensive care unit (ICU) patients aged ≤ 65 years

In the pragmatic randomized controlled SPICE III trial 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 dexmedetomidine group and the usual care group (mortality 29.1% in both groups), but there was heterogeneity in the effect of age on mortality. 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 sedatives. Although the mechanism is unclear, this age-related heterogeneity in mortality 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.

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 sedatives in younger patients.

Cardiovascular effects and warnings

Midodex reduces heart rate and blood pressure (central sympatholytic effect), but at higher concentrations causes peripheral vasoconstriction, leading to increased blood pressure. Therefore, Midodex is not suitable for patients with severe cardiovascular disease.

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 (e.g., atropine) and dose reduction. Athletes with low resting heart rates may be particularly sensitive to the negative chronotropic effects 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 vasopressors), including chronic hypotension, hypovolemia, or reduced functional reserve (e.g., patients with severe ventricular dysfunction and elderly patients), the hypotensive effect of Midodex may be more pronounced—requiring special care. Reduction in blood pressure usually does not require specific interventions, but readiness to reduce the dose, administer volume expanders, and/or vasopressors should be ensured.

Hemodynamic effects after administration of Midodex may be more pronounced in patients with peripheral autonomic nervous system dysfunction (e.g., due to spinal cord injury), who may require special care.

Transient increases in blood pressure with concomitant peripheral vasoconstrictive effects have been observed during 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.

Peripheral vasoconstriction at higher concentrations may be more significant in patients with ischemic heart disease or severe cerebrovascular disease; such patients require close monitoring. If signs of myocardial or cerebral ischemia occur, dose reduction or discontinuation of the drug should be considered.

Caution is advised when administering dexmedetomidine concomitantly with spinal or epidural anesthesia due to increased risk of hypotension or bradycardia.

Patients with hepatic impairment

Caution should be exercised in patients with severe hepatic insufficiency, as reduced dexmedetomidine clearance may lead to accumulation, resulting in adverse reactions and excessive sedation.

Patients with neurological disorders

Experience with the use of Midodex in severe neurological conditions such as head trauma 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 prescribing therapy, it should be noted that Midodex reduces cerebral blood flow and intracranial pressure.

Other warnings

After prolonged use of alpha-2 receptor agonists, withdrawal syndrome has rarely occurred upon abrupt discontinuation. Agitation and elevated blood pressure immediately after stopping dexmedetomidine should raise suspicion of withdrawal syndrome.

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 and urine osmolality should be checked.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially sodium-free.

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. Midodex should not be used during pregnancy unless the woman's clinical condition requires treatment with dexmedetomidine.

Breastfeeding. Dexmedetomidine passes into human breast milk, but levels fall below the limit of detection within 24 hours after discontinuation of administration. 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 therapy for the mother.

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

Effects on ability to drive and use machines

Patients are advised to refrain from driving vehicles or performing other potentially hazardous tasks for a certain period after administration of Midodex 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.

Dosing for adults

Patients who have already been intubated and are under sedation may be transitioned to Mirdex with an initial infusion rate of 0.7 mcg/kg/hr, which can be gradually adjusted within the 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 the lowest initial infusion rate. It should be noted that dexmedetomidine is a potent agent; therefore, infusion rates are specified per hour. After dosage adjustment, up to 1 hour may be required to achieve a stable level of sedation.

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

The use of a loading dose of Mirdex for sedation is not recommended, as it is associated with an increased incidence of adverse effects. If necessary, propofol or midazolam may be administered 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 Mirdex for periods longer than 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

Mirdex should be administered only by healthcare professionals qualified in anesthesia for patients in operating rooms or during diagnostic procedures. When Mirdex is used 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").

Provision of supplemental oxygen must be ensured and should be immediately available when indicated. Oxygen saturation should be monitored using pulse oximetry.

Mirdex 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 pharmacokinetic half-distribution period of Mirdex is approximately 6 minutes, which, along with the effects of other administered drugs, should be considered when estimating the appropriate time required to titrate to the desired clinical effect of Mirdex.

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 should generally be initiated at 0.6–0.7 mcg/kg/hr and titrated to achieve the desired clinical effect within the dosage 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"). However, elderly patients may have an increased risk of hypotension (see section "Special Warnings and 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. Mirdex is metabolized in the liver and should therefore be used with caution in patients with hepatic impairment. Consideration should be given to using a reduced maintenance dose.

Method of administration

Mirdex should be administered by personnel experienced in managing patients requiring intensive care. The drug must be administered only as a diluted intravenous infusion using a controlled infusion device.

Vials and ampoules are intended for individual use in a single patient only.

Preparation of solution

Prior to administration, Mirdex 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 preparing the infusion.

To achieve a concentration of 4 mcg/mL:

To achieve a concentration of 8 mcg/mL:

Shake carefully to ensure the solution is well mixed.

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

Midazolam is compatible with the following intravenous fluids and drugs: Ringer's lactate solution, 5% dextrose solution, 0.9% sodium chloride solution, 20% mannitol, sodium thiopental, etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium besylate, mivacurium chloride, rocuronium bromide, glycopyrrolate bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, norepinephrine, dobutamine, midazolam, morphine sulfate, fentanyl citrate, and plasma expanders.

Children

The safety and efficacy of Midazolam 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

Symptoms of overdose. Several cases of dexmedetomidine overdose have been reported during clinical trials and post-marketing use. The highest infusion rates in these cases were 60 mcg/kg/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 observed adverse reactions in overdose included bradycardia, arterial hypotension, arterial hypertension, excessive sedation, respiratory depression, and cardiac arrest.

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

Side effects

Sedation of adult patients in intensive care units

When dexmedetomidine was used for sedation in intensive care units, the most frequently reported adverse reactions were arterial hypotension, arterial hypertension, and bradycardia, occurring in approximately 25%, 15%, and 13% of patients, respectively. Arterial hypotension and bradycardia were also the most common serious treatment-related adverse reactions, occurring in 1.7% and 0.9% of randomized intensive care, anesthesia, and resuscitation patients, respectively.

Procedural sedation with preserved consciousness

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 arterial pressure, respiratory rate, and heart rate considered as adverse effects):

• Arterial hypotension (55% in the dexmedetomidine group vs. 30% in the placebo group. The placebo group received rescue therapy with midazolam and fentanyl);
• Respiratory depression (38% in the dexmedetomidine group vs. 35% in the placebo group. The placebo group received rescue therapy with midazolam and fentanyl);
• Bradycardia (14% in the dexmedetomidine group vs. 4% in the placebo group. The placebo group received rescue therapy with midazolam and fentanyl).

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).

Endocrine disorders

Unknown: diabetes insipidus.

Metabolism and nutrition disorders

Common: hyperglycemia, hypoglycemia.

Uncommon: metabolic acidosis, hypoalbuminemia.

Psychiatric disorders

Common: agitation.

Uncommon: hallucinations.

Cardiac disorders

Very common: bradycardia^1,2.

Common: myocardial ischemia or infarction, tachycardia.

Uncommon: atrioventricular block¹, decreased cardiac output, cardiac arrest¹.

Vascular disorders

Very common: arterial hypotension^1,2, arterial hypertension^1,2.

Respiratory, thoracic and mediastinal disorders

Very common: respiratory depression^2,3.

Uncommon: dyspnea, apnea.

Gastrointestinal disorders

Common: nausea², vomiting, dry mouth².

Uncommon: abdominal distension.

General disorders and administration site conditions

Common: withdrawal syndrome, hyperthermia.

Uncommon: drug inefficacy, thirst.

¹ See "Description of selected adverse reactions" below.
² Adverse reaction also observed in procedural sedation studies.
³ Frequency "common" in intensive care unit setting studies.

Description of selected adverse reactions

Clinically significant arterial hypotension or bradycardia should be managed according to recommendations in the "Instructions for use" section.

In relatively healthy individuals not in intensive care, dexmedetomidine administration has occasionally led to sinus node suppression or sinus pause. Symptoms resolved after placing the patient in a supine position with legs elevated above head level and administration of anticholinergic agents such as atropine or glycopyrrolate. In isolated cases, bradycardia progressed to periods of asystole in patients with prior history of bradycardia. Cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have also been reported. Arterial hypertension has been associated with loading dose administration. This reaction can be minimized by avoiding a loading dose, reducing infusion rate, or decreasing the size of the loading dose.

Pediatric population. Over infusion durations up to 24 hours in patients aged 1 month and older, predominantly postoperative, in intensive care units, the drug demonstrated a safety profile similar to that in adults. Data in neonates (born at 28 to 44 weeks of gestation) are limited, particularly regarding maintenance doses ≤ 0.2 mcg/kg/hour. A single case of hypothermic bradycardia in a neonate has been reported in scientific literature.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is an important procedure. It allows continuous 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 lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life

3 years.

Physical and chemical stability has been demonstrated for 24 hours at 25°C.

From a microbiological standpoint, Myrodex 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

Store in a light-protected place at a temperature not exceeding 25°C.

Keep out of reach of children.

Incompatibilities

Use only the diluents specified in the section "Dosage and administration".

Packaging

2 ml in a glass vial, 5 glass vials in a cardboard box.

Prescription status

Prescription only.

Manufacturer

LLC "Farmideya".

Manufacturer's location and address of business activity

Rupnica 4, Olaine, Olaine district, LV-2114, Latvia.