Dexmedetomidine-baxter

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Dexmedetomidine-Baxter (Dexmedetomidine-Baxter)

Composition:

Active substance: dexmedetomidine;

1 ml 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: the solution should be clear, colorless, and practically free from visible particles.

Pharmacotherapeutic group. Psycholeptics. Other hypnotics and sedatives.

ATC code N05CM18.

Pharmacological Properties.

Pharmacodynamics.

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

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

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

In placebo-controlled studies in patients admitted to postoperative intensive care units who had previously been intubated and sedated with midazolam or propofol, dexmedetomidine significantly reduced the need for additional sedation (midazolam or propofol) and opioids for up to 24 hours. Most patients receiving dexmedetomidine did not require additional sedative therapy. Patients could be successfully extubated without discontinuing the dexmedetomidine infusion. Studies conducted outside the ICU setting confirmed that dexmedetomidine hydrochloride can be safely administered to patients without endotracheal intubation, provided appropriate monitoring is in place.

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

Evidence of efficacy in the pediatric population was obtained in a dose-controlled ICU study involving a large postoperative population aged from 1 month to ≤17 years. Approximately 50% of patients receiving dexmedetomidine did not require additional sedation with midazolam during the treatment period, which lasted on average 20.3 hours, but not longer than 24 hours. Data on treatment with the drug in children beyond 24 hours are lacking. Data for 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"). Neonates may be particularly sensitive to the bradycardic effects of dexmedetomidine in the presence of hypothermia or when 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 with preserved consciousness.

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

In the first study, 54% of patients receiving dexmedetomidine at a dose of 1 mcg/kg and 40% of patients receiving dexmedetomidine at a dose of 0.5 mcg/kg did not require additional midazolam sedation, compared to 3% in the placebo group.

In the second study, 53% of patients receiving dexmedetomidine at a dose of 1 mcg/kg did not require additional midazolam sedation, compared to 14% in the placebo group.

Pharmacokinetics.

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

Distribution.

Dexmedetomidine pharmacokinetics are described by a two-compartment model. In healthy volunteers, a rapid distribution phase is observed with a mean distribution half-life (t1/2α) of approximately 6 minutes. The mean terminal elimination half-life (t1/2) is approximately 1.9–2.5 hours (minimum 1.35 hours, maximum 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 to calculate Vss and Cl parameters was 69 kg.

Plasma pharmacokinetics of dexmedetomidine in ICU patients receiving infusions for more than 24 hours were similar. Calculated pharmacokinetic parameters were: t1/2 approximately 1.5 hours, Vss approximately 93 L, and Cl approximately 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 during treatment up to 14 days. 94% of dexmedetomidine is bound to plasma proteins. The degree of plasma protein binding is constant over a concentration range of 0.85 to 85 ng/mL. Dexmedetomidine binds to both human serum albumin and α1-acid glycoprotein, predominantly to serum albumin.

Biotransformation and elimination.

Dexmedetomidine is completely metabolized in the liver. There are three initial metabolic pathways: direct N-glucuronidation, direct N-methylation, and cytochrome P450-catalyzed oxidation. The main metabolites of dexmedetomidine in blood are two isomeric N-glucuronides. Metabolite H-1 (N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide) is also an important 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 the formation of oxidized metabolites involves several cytochrome P450 isoenzymes (CYP2A6, CYP1A2, CYP2E1, CYP2D6, and CYP2C19). These metabolites have no significant pharmacological activity.

Within 9 days after intravenous administration of radiolabeled dexmedetomidine, approximately 95% of radioactivity was recovered in urine and 4% in feces. The main urinary metabolites are two isomeric N-glucuronides, accounting for approximately 34% of the administered dose, and N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide, accounting for 14.51% of the dose. Minor metabolites—dexmedetomidine carboxylic acid, 3-hydroxymethyldexmedetomidine, and its O-glucuronide—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 groups.

Significant differences in the pharmacokinetics of dexmedetomidine in patients of different ages and genders have not been observed.

Plasma protein binding of dexmedetomidine is reduced in individuals with impaired liver function 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 the plasma elimination half-life (t1/2) was 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 of dexmedetomidine should be based on the degree of sedative effect, consideration should be given to reducing the initial or maintenance dose in patients with hepatic impairment, depending on the severity of impairment and clinical response to therapy.

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 children from neonates (28–44 weeks gestation) up to age 17 years are limited. The elimination half-life of dexmedetomidine in children (aged 1 month to 17 years) is comparable 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.

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 RASS scale).

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

Contraindications.

Hypersensitivity to dexmedetomidine or to any of the excipients.

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

No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam have been identified. 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.

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

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

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

Special precautions for use.

Monitoring

Dexmedetomidine-Baxter is intended for use in intensive care units, operating rooms, and during diagnostic procedures; its use under other conditions is not recommended. Continuous cardiac monitoring is required for all patients during dexmedetomidine infusion.

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"). The time required for recovery to normal physiological status after dexmedetomidine administration is approximately 1 hour. When used in ambulatory patients, careful monitoring should continue for at least 1 hour (or longer, depending on the patient's condition), followed by at least another hour of medical supervision to ensure patient safety.

General warnings

Dexmedetomidine-Baxter must not be administered as a bolus injection. In ICU settings, a loading dose of the drug is also not recommended. Medical personnel should be prepared to use alternative sedatives to immediately control agitation during procedures, particularly during the first hours of drug administration. During procedural sedation, small bolus injections of other sedatives may be useful for rapidly increasing the level of sedation when necessary.

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

Dexmedetomidine typically does not cause deep sedation, and patients awaken easily. Therefore, dexmedetomidine is not suitable for patients who do not fit this profile of effects, such as those requiring prolonged deep sedation.

Dexmedetomidine-Baxter should not be used as an induction agent for anesthesia during intubation or for providing sedation when muscle relaxants are administered.

Unlike some other sedatives, dexmedetomidine has no anticonvulsant effect and does not suppress existing seizure activity.

Caution is required when administering dexmedetomidine concomitantly with medicinal products that have sedative effects or affect the cardiovascular system, due to the possibility of additive effects.

Dexmedetomidine-Baxter is not recommended for patient-controlled sedation. Appropriate data are lacking.

When the medicinal product is used in ambulatory patients, discharge may be permitted under the supervision of an appropriate third party. Patients should be advised to refrain from driving vehicles or performing other hazardous tasks and, if possible, to avoid using other agents with sedative effects (e.g., benzodiazepines, opioids, alcohol) for a certain period of time, depending on the observed effects of dexmedetomidine, the procedure, concomitant medications, age, and patient condition.

Caution is required when administering dexmedetomidine to elderly patients. Patients aged 65 years and older are more prone to hypotension when receiving dexmedetomidine, including during loading doses administered during procedures; therefore, dose reduction should be considered in such cases (see section "Dosage and administration").

Mortality in ICU patients aged ≤ 65 years

In the pragmatic randomized controlled trial SPICE III involving 3904 critically ill adult ICU patients, no overall difference in 90-day mortality was observed between the dexmedetomidine group and the usual care group (mortality was 29.1% in both groups), but heterogeneity in the effect of age on mortality was observed. Dexmedetomidine was associated with increased mortality in the age group ≤ 65 years (odds ratio 1.26; 95% CI 1.02–1.56) compared to alternative sedatives. Although the mechanism is not fully understood, this age-dependent effect on mortality was most pronounced with early use of high-dose dexmedetomidine to achieve deep sedation in patients hospitalized for reasons unrelated to postoperative care, and increased with higher APACHE II scores (Acute Physiology and Chronic Health Evaluation II scale). This effect on mortality was not observed when dexmedetomidine was used for light sedation. These data should be weighed against the expected clinical benefit of dexmedetomidine compared to alternative sedatives 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 vasoconstrictive effects, leading to increased blood pressure (see section "Pharmacodynamics"). Therefore, Dexmedetomidine-Baxter is not suitable for patients with severe cardiovascular instability.

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

The hypotensive effect of Dexmedetomidine-Baxter may be more pronounced in patients with pre-existing arterial hypotension (especially refractory to vasopressor agents), hypovolemia, chronic hypotension, or reduced functional reserves, such as patients with severe ventricular dysfunction or elderly patients, requiring particular attention in such cases (see section "Contraindications"). Hypotension usually does not require specific treatment, but if medical intervention is needed, the dose may be reduced, volume replacement solutions administered, and/or vasoconstrictor agents given.

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

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

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

Caution is recommended when administering dexmedetomidine together with spinal or epidural anesthesia due to the potential increased risk of hypotension or bradycardia.

Patients with hepatic impairment

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

Patients with neurological disorders

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

Other warnings

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

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.

Cases of non-diabetic diabetes insipidus associated with dexmedetomidine use have been reported. If polyuria develops, dexmedetomidine administration should be discontinued, and serum sodium levels and urine osmolality should be checked.

One vial contains less than 1 mmol of sodium, i.e., the medicinal product is considered sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of dexmedetomidine in pregnant women are lacking or limited. Animal studies have shown reproductive toxicity of dexmedetomidine. Dexmedetomidine-Baxter is not recommended during pregnancy, except when the woman's clinical condition requires treatment with dexmedetomidine.

Breastfeeding

Dexmedetomidine passes into human breast milk, but levels become undetectable 24 hours after discontinuation of treatment. Risk to the infant cannot be excluded. Either breastfeeding should be discontinued or administration of the drug stopped, after weighing the benefits of breastfeeding for the child against the benefits of treatment for the mother.

Fertility

Animal 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 rate when driving vehicles or operating machinery.

Patients are advised to refrain from driving vehicles or performing other hazardous tasks for a certain period after administration of the medicinal product for procedural sedation.

Method of Administration and Dosage.

Sedation of adult patients in intensive care units requiring a level of sedation no deeper than awakening in response to verbal stimulation (corresponds to a range of 0 to -3 on the RASS scale).

Dexmedetomidine-Baxter is intended for use only in a hospital setting. Therapy with this medicinal product should be administered under the supervision of qualified physicians experienced in managing patients in intensive care.

Dosage

Previously intubated and sedated patients may be transitioned to dexmedetomidine at an initial infusion rate of 0.7 mcg/kg/hour, with subsequent dose adjustment within the range of 0.2–1.4 mcg/kg/hour to achieve the desired level of sedation, depending on patient response. Consideration should be given to using a lower initial infusion rate in frail patients. It should be emphasized that dexmedetomidine is a highly potent agent, and the infusion rate is expressed per 1 hour. After dose adjustment, a new steady-state level of sedation may be achieved within 1 hour.

Maximum Dose

The maximum dose of 1.4 mcg/kg/hour should not be exceeded. Patients who do not achieve the required level of sedation at the maximum dose of Dexmedetomidine-Baxter should be switched to an alternative sedative agent.

The administration of a loading dose of dexmedetomidine for sedation in intensive care settings is not recommended, as it increases the frequency of adverse reactions. If necessary, propofol or midazolam may be used until the desired clinical effect of Dexmedetomidine-Baxter is achieved.

Duration of Therapy

Experience with use of Dexmedetomidine-Baxter for longer than 14 days is limited. When treatment is prolonged, the patient's condition should be regularly evaluated.

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

Dexmedetomidine-Baxter should be administered only by qualified physicians experienced in anesthesia management in operating rooms or during diagnostic procedures.

When Dexmedetomidine-Baxter is used for sedation with preservation of consciousness, continuous patient monitoring is required. This monitoring must be performed by personnel not involved in the diagnostic or surgical procedure. Continuous observation for early signs of arterial hypotension, arterial hypertension, bradycardia, respiratory depression, airway obstruction, apnea, dyspnea, and/or oxygen desaturation must be maintained (see section "Adverse Reactions"). Oxygen delivery equipment must be available and ready for use if needed. Continuous monitoring of blood oxygen saturation by pulse oximetry is required.

Initially, a loading dose of Dexmedetomidine-Baxter should be administered, followed by maintenance doses. Depending on the procedure, concomitant local anesthesia or analgesia may be necessary to achieve the desired clinical effect. For painful procedures or when deep sedation is required, additional analgesia or sedative agents (e.g., midazolam, propofol, and opioids) are recommended. The pharmacokinetic distribution half-life of dexmedetomidine hydrochloride is approximately 6 minutes, which, along with the effects of other administered medicinal products, should be considered when determining the appropriate time required to titrate the dose to the desired clinical effect.

Initial Doses for Procedural Sedation

• Loading infusion dose of 1.0 mcg/kg over 10 minutes. For less invasive procedures, such as ophthalmic surgery, a loading infusion dose of 0.5 mcg/kg over 10 minutes may be appropriate.

Maintenance Doses for Procedural Sedation

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

Dosage in Special Patient Populations

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

Patients with Renal Impairment: dose adjustment is not required in patients with renal impairment.

Patients with Hepatic Impairment: dexmedetomidine is metabolized in the liver; therefore, caution is required when treating patients with hepatic dysfunction. Consideration should be given to reducing maintenance doses (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Method of Administration

Dexmedetomidine-Baxter must be administered only after dilution by intravenous infusion using controlled infusion equipment.

Vials are intended for single-patient use only.

Preparation of Infusion Solutions

Prior to administration, Dexmedetomidine-Baxter must be diluted with 5% (50 mg/mL) glucose solution, Ringer's solution, 20% mannitol solution, or 0.9% (9 mg/mL) sodium chloride injection solution to achieve the required concentration of either 4 mcg/mL or 8 mcg/mL. The tables below provide the volumes required to prepare infusion solutions.

Infusion Solution with Concentration of 4 mcg/mL

Infusion solution with a concentration of 8 mcg/mL

The prepared solution should be gently shaken to ensure complete mixing of its components.

The preparation should be visually inspected before administration. Only clear, colorless solutions free from visible particulate matter should be administered.

Dexmedetomidine-Baxter is pharmaceutically compatible with the following intravenous solutions and medicinal products: Ringer's lactate solution, 5% glucose solution, 0.9% (9 mg/mL) sodium chloride injection solution, 20% (200 mg/mL) mannitol solution, sodium thiopental, etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium besilate, mivacurium chloride, rocuronium bromide, glycopyrrolate bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, norepinephrine, dobutamine, midazolam, morphine sulfate, fentanyl citrate, and plasma substitutes.

It has been demonstrated that infusion solutions prepared by dilution of the product are chemically and physically stable for 24 hours when stored at 25 °C.

From a microbiological standpoint, the diluted preparation should be used immediately. If the infusion solution is not used immediately, the user is responsible for the duration and conditions of storage. Do not refrigerate.

Any unused medicinal product and waste material must be disposed of in accordance with local requirements.

Children.

The safety and efficacy of Dexmedetomidine-Baxter treatment in children under 18 years of age have not been established.

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

Overdose.

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

Treatment in case of overdose. In the event 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. In 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.

Adverse Reactions

Summary of Safety Profile

Sedation of adult patients in intensive care units (ICU)

When dexmedetomidine was used for sedation in the ICU, the most commonly 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 frequent serious treatment-related adverse reactions, occurring in 1.7% and 0.9% of randomized ICU 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 of changes in blood pressure, respiratory rate, and heart rate considered as adverse effects).

When dexmedetomidine was used for procedural sedation, the most frequently observed adverse reactions were arterial hypotension (55% in the dexmedetomidine group vs. 30% in the placebo group, where patients received rescue medications – midazolam and fentanyl), respiratory depression (38% in the dexmedetomidine group vs. 35% in the placebo group, where patients received rescue medications – midazolam and fentanyl), and bradycardia (14% in the dexmedetomidine group vs. 4% in the placebo group, where patients received rescue medications – midazolam and fentanyl).

The adverse reactions listed below were collected from pooled data of clinical studies in intensive care settings.

Adverse reactions are categorized by frequency as follows, starting with the most frequent: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Endocrine system disorders

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: Bradycardia^1,2.

Common: Myocardial ischemia or myocardial 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: Ineffectiveness of the drug, thirst.

¹ See section on description of individual adverse reactions.

² Adverse reaction also observed in procedural sedation studies.

³ "Frequent" frequency in intensive care unit studies.

Description of Selected Adverse Reactions

Clinically significant arterial hypotension or bradycardia should be managed according to recommendations in the section "Special Warnings and Precautions for Use".

In relatively healthy individuals not in ICU who received dexmedetomidine, bradycardia occasionally led to sinus arrest. Symptoms were resolved 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 the loading dose of dexmedetomidine. To reduce the frequency of this adverse reaction, avoid the loading dose, reduce the infusion rate, or lower the loading dose.

Adverse Reactions in Pediatric Patients

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

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf Life

24 months.

Storage Conditions

No special temperature storage conditions are required for this medicinal product. Store in a place inaccessible to children.

Incompatibilities

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

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

Packaging

2 mL in a vial; 5, 10, or 25 vials per cardboard box.

Prescription Status

Prescription only.

Manufacturer

BAXTER PHARMACEUTICALS INDIA PRIVATE LIMITED.

Manufacturer's Address and Place of Business

CHACHROD-VASANA, AHMEDABAD, 382213, INDIA.