Dexmedetomidine-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXMEDETOMIDINE-VISTA (DEXMEDETOMIDINE-VISTA)

Composition:

Active substance: dexmedetomidine hydrochloride;

1 ampoule (2 ml) contains dexmedetomidine (as dexmedetomidine hydrochloride) 0.2 mg;

Excipients: sodium chloride, sodium hydroxide, hydrochloric acid 37%, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Psycholeptics. Other hypnotics and sedatives.

ATC code N05CM18.

Pharmacological Properties.

Pharmacodynamics.

Dexmedetomidine is a selective α2-receptor agonist with a broad spectrum of pharmacological properties. It exerts a sympatholytic effect by reducing the release of norepinephrine from sympathetic nerve endings. The sedative effect is 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 (similar to natural sleep without rapid eye movement), enabling patients to achieve a sedated state while remaining easily arousable and cooperative. Dexmedetomidine provides anesthetic and moderate analgesic effects. Its effects on the cardiovascular system 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 blood pressure, while the bradycardic effect becomes more pronounced. Dexmedetomidine has minimal respiratory depressant effects. Sedation is administered in hospital settings (in intensive care, anesthesia, and resuscitation units). Efficacy data in the pediatric population were obtained from a dose-controlled ICU study in 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 averaged 20.3 hours and did not exceed 24 hours. Data on treatment durations longer than 24 hours are unavailable. Data in neonates (28–44 weeks gestation) are limited and restricted to low doses (≤0.2 mcg/kg/hr) (see sections "Pharmacokinetics", "Special Warnings and Precautions for Use"). Neonates may be particularly sensitive to the bradycardic effect 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 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 Observer’s Assessment of Alertness/Sedation 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: 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 dexmedetomidine group, and 4.0 (0.5–14.0) mg in the placebo group. The mean difference in rescue midazolam dose between the 1 mcg/kg and 0.5 mcg/kg dexmedetomidine groups compared to placebo was -3.1 mg (95% CI: -3.8 to -2.5) and -2.7 mg (95% CI: -3.3 to -2.1), respectively, in favor of dexmedetomidine. The median time to first 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 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 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 patients in intensive care units.

Distribution.

Dexmedetomidine exhibits a two-compartment distribution model. In healthy volunteers, it shows a rapid distribution phase with an estimated central half-life (t1/2α) of approximately 6 minutes. The estimated terminal elimination half-life (t1/2) is approximately 1.9–2.5 hours (minimum 1.35 hours, maximum 3.68 hours), and the estimated steady-state volume of distribution (Vss) is approximately 1.16–2.16 L/kg (90–151 liters). The estimated plasma clearance (Cl) is approximately 0.46–0.73 L/hr/kg (35.7–51.1 L/hr). The mean body weight associated with these Vss and Cl estimates was 69 kg. Plasma pharmacokinetics of dexmedetomidine are similar in ICU patients after infusions lasting >24 hours. Estimated pharmacokinetic parameters are: t1/2 ~1.5 hours, Vss ~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 up to 14 days. Dexmedetomidine is 94% bound to plasma proteins. Protein binding is consistent across concentrations ranging from 0.85 to 85 ng/mL. Dexmedetomidine binds to human serum albumin and α1-acid glycoprotein, with serum albumin being the primary binding protein in plasma.

Metabolism and Elimination.

Dexmedetomidine is extensively metabolized in the liver. There are three primary metabolic pathways: direct N-glucuronidation, direct N-methylation, and cytochrome P450-catalyzed oxidation. The major circulating metabolites are two isomeric N-glucuronides. Metabolite H-1 (N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide) is also a major circulating biotransformation product. Available data indicate that formation of oxidized metabolites is mediated by CYP isoforms (CYP2A6, CYP1A2, CYP2E1, CYP2D6, and CYP2C19). These metabolites have minimal pharmacological activity. After intravenous administration of radiolabeled dexmedetomidine, approximately 95% of radioactivity was recovered in urine and 4% in feces over 9 days. The major urinary metabolites are two isomeric N-glucuronides, accounting for approximately 34% of the dose, and N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide, accounting for 14.51% of the dose. Minor metabolites—carboxylic acid, 3-hydroxy, and O-glucuronide metabolites—individually account for 1.11–7.66% of the dose. Less than 1% of unchanged active substance was found in urine. Approximately 28% of metabolites detected in urine are unidentified polar metabolites.

Special Patient Groups.

No clinically significant pharmacokinetic differences were observed based on patient gender or age. Dexmedetomidine binding to plasma proteins 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. Patients with varying degrees of hepatic impairment (Child-Pugh classes A, B, or C) showed reduced hepatic clearance of dexmedetomidine and prolonged plasma elimination half-life (t1/2). The mean clearance of unbound dexmedetomidine in patients with mild, moderate, and severe hepatic impairment was 59%, 51%, and 32%, respectively, of that in healthy volunteers. The 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 based on clinical 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 compared to healthy volunteers. Data on the use of this medicinal product in children—from neonates (born at 28 to 44 weeks gestation) to 17 years—are limited. The elimination half-life of dexmedetomidine in children (aged 1 month to 17 years) is likely similar to that in adults, but appears to be longer in neonates (up to 1 month of age). In age groups from 1 month to 6 years, body weight-adjusted plasma clearance appears higher but decreases with increasing age. Due to immaturity, body weight-adjusted plasma clearance in neonates (up to 1 month of age) may be lower (0.9 L/hr/kg) than in older age groups.

Clinical characteristics.

Indications.

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 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 interaction with other medicinal products have been conducted only in adult patients.

Concomitant use of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids may lead to potentiation of their effects, including sedative, anesthetic, and cardiorespiratory effects. Targeted studies have confirmed enhanced effects when used in combination with isoflurane, propofol, alfentanil, and midazolam.

No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam were observed. However, due to possible pharmacodynamic interactions when these medicinal products 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 enzymes, including the CYP2B6 isoenzyme. According to in vitro data, there is a potential for interaction between dexmedetomidine and substrates (primarily CYP2B6 isoenzyme) in vivo.

Induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 isoenzymes by dexmedetomidine was observed in vitro, thus such interactions in vivo cannot be excluded. The clinical significance is unknown.

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

Special precautions for use.

Monitoring.

The medicinal product Dexmedetomidine-Vista is intended for use in hospital settings (in intensive care units, anesthesia and resuscitation departments), operating rooms, and during diagnostic procedures; its use in other settings is not recommended.

During infusion of the medicinal product, cardiac function should be continuously monitored in all patients. In patients who have not undergone intubation, respiratory function should be monitored due to the risk of respiratory depression and, in some cases, the development of apnea (see section "Side effects").

The recovery period 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 continue for an additional hour to ensure patient safety.

General warnings.

The medicinal product Dexmedetomidine-Vista should not be administered as a bolus injection, and loading doses are not recommended in intensive care units. Therefore, users should be prepared to use an alternative sedative agent for immediate control of 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 sedation level is required. Some patients receiving dexmedetomidine may exhibit light arousal and quickly regain consciousness upon stimulation. In the absence of other clinical symptoms, this sign alone should not be considered as evidence of drug inefficacy. Dexmedetomidine usually does not cause deep sedation, thus patients can be easily aroused. Therefore, dexmedetomidine should not be used in patients who cannot tolerate this profile of action, for example, patients requiring continuous deep sedation. The medicinal product Dexmedetomidine-Vista should not be used as a general anesthetic for intubation induction or for providing sedation when muscle relaxants are used. Dexmedetomidine is unlikely to suppress seizure activity and therefore should not be used as monotherapy in status epilepticus. Caution is required when dexmedetomidine is used concomitantly with medicinal products that have sedative effects or affect the cardiovascular system due to possible additive effects.

The medicinal product Dexmedetomidine-Vista is not recommended for patient-controlled sedation.

If this medicinal product is used in outpatient settings, patient discharge should occur under the supervision of a third party. Patients should be advised to refrain from driving vehicles and performing other hazardous tasks and, if possible, to avoid using other medicinal products with sedative effects (e.g., benzodiazepines, opioids) or consuming alcohol for a certain period of time, depending on the observed effects of dexmedetomidine, the procedure performed, concomitant medicinal products, age, and patient condition. Caution should be exercised when using dexmedetomidine in elderly patients. Patients aged 65 years and older may be more prone to developing hypotension with dexmedetomidine, including during loading dose administration and during procedures. Dose reduction should be considered (see section "Dosage and administration").

Mortality in patients aged ≤ 65 years in intensive care units.

In a pragmatic randomized controlled trial SPICE III involving 3904 critically ill adult patients in intensive care units, no overall difference in 90-day mortality was observed between the dexmedetomidine group and the usual care group (mortality 29.1% in both groups), but treatment effect heterogeneity was noted depending on age where mortality occurred. Use of dexmedetomidine was associated with increased mortality in the age group ≤ 65 years (odds ratio 1.26; 95% confidence interval 1.02–1.56) compared to alternative sedatives. Although the mechanism is unclear, the age-related heterogeneity in mortality impact was most evident 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 impact on mortality was observed when dexmedetomidine was used for light sedation. Based on this information, the expected clinical benefit of using dexmedetomidine compared to alternative sedatives should be carefully weighed in patients under 65 years of age.

Cardiovascular effects and precautions.

Dexmedetomidine reduces heart rate and blood pressure (due to central sympatholytic action), but at higher concentrations causes peripheral vasoconstriction, leading to increased blood pressure (see section "Pharmacodynamics"). Therefore, the medicinal product Dexmedetomidine-Vista should not be used in patients with severe cardiovascular diseases. Caution should be exercised when administering dexmedetomidine to patients with concomitant bradycardia. Data on the effects of the medicinal product in patients with heart rates < 60 beats per minute are limited; therefore, such patients require enhanced monitoring. Bradycardia usually does not require treatment but can be effectively managed with administration of anticholinergics (m-cholinoblockers) and dose reduction. Athletes and others with low resting heart rates may be particularly sensitive to the negative chronotropic effect of α2-receptor agonists; cases of sinus node arrest have been reported. Cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have also been reported (see section "Side effects").

In patients with concomitant arterial hypotension (especially refractory to vasopressors), including chronic hypotension, hypovolemia, or reduced functional reserve, such as patients with severe ventricular dysfunction and elderly patients, the hypotensive effect of dexmedetomidine may be more pronounced, requiring special care. Reduction in blood pressure usually does not require specific interventions, but readiness to reduce the dose, administer volume-expanding agents, and/or vasopressors should be ensured if needed. Hemodynamic effects after administration may be more pronounced in patients with peripheral autonomic nervous system impairment (e.g., due to spinal cord injury), requiring special monitoring. Transient increases in blood pressure with concomitant peripheral vasoconstrictive effects have been observed during administration of a loading dose of dexmedetomidine; therefore, administration of a loading dose for sedation in hospital settings (in intensive care, anesthesia, and resuscitation departments) is not recommended. Treatment of elevated blood pressure is usually not required, but consideration should be given to reducing the infusion rate. Central vasoconstriction at high concentrations may be more significant in patients with ischemic heart disease or severe cerebrovascular diseases; such patients require close monitoring. In patients showing signs of myocardial or cerebral ischemia, dose reduction or discontinuation of the medicinal product should be considered.

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

Patients with hepatic impairment.

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

Patients with neurological disorders.

Experience with dexmedetomidine use 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 selecting therapy, it should be considered that dexmedetomidine reduces cerebral blood flow and intracranial pressure.

Other warnings.

After abrupt discontinuation of α2-receptor agonists following prolonged use, withdrawal syndrome has rarely occurred. Agitation and increased blood pressure immediately after discontinuation of dexmedetomidine should raise suspicion of this 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 administration should be discontinued and serum sodium levels and urine osmolality should be checked.

Important information on excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Data on the use of dexmedetomidine in pregnant women are absent or limited. Reproductive toxicity has been observed in animal studies. The medicinal product should not be used during pregnancy unless the woman's clinical condition requires treatment with dexmedetomidine.

Breastfeeding period.

Dexmedetomidine passes into human breast milk, but its levels fall below the detection limit 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 risks of dexmedetomidine therapy for the mother.

Fertility.

Fertility studies in rats did not reveal any effect of dexmedetomidine on male or female fertility. Data on effects on human fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

Patients are advised to refrain from driving vehicles or performing other hazardous tasks for a certain period after administration of the medicinal product 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 (corresponding to the range of 0 to -3 on the Richmond Agitation-Sedation Scale (RASS)).

The medicinal product is intended for hospital use only and must be administered by qualified and specially trained medical personnel.

Dosage.

Patients who have already been intubated and are under sedation may be transitioned to DEXMEDETOMIDINE-VISTA 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, depending on the patient's response to the drug. For frail patients, consideration should be given to using the lowest initial infusion rate. Dexmedetomidine is a highly potent medicinal product; 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.

Maximum dose. The maximum dose of 1.4 mcg/kg/hr must not be exceeded. Patients who fail to achieve adequate sedation at the maximum dose should be switched to an alternative sedative agent. The use of a loading dose of dexmedetomidine for sedation is not recommended, as it is associated with an increased incidence of adverse reactions. If necessary, propofol or midazolam may be used until the clinical effect of dexmedetomidine is achieved.

Duration of administration. There is no experience with the use of DEXMEDETOMIDINE-VISTA for periods exceeding 14 days. Administration of the medicinal product beyond 14 days should be regularly re-evaluated.

For sedation of non-intubated patients before and/or during diagnostic or surgical procedures requiring sedation/procedural sedation.

DEXMEDETOMIDINE-VISTA must be administered only by medical personnel with appropriate qualifications and skills. When DEXMEDETOMIDINE-VISTA 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 of patients is required to detect early signs of hypotension, hypertension, bradycardia, respiratory depression, airway obstruction, apnea, dyspnea, and/or oxygen desaturation (see section "Adverse Reactions").

Supplemental oxygen must be readily available and immediately administered when indicated. Oxygen saturation should be monitored using pulse oximetry.

DEXMEDETOMIDINE-VISTA 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 the drug is approximately 6 minutes, which should be considered, along with the effects of other administered drugs, when determining the appropriate time required to titrate DEXMEDETOMIDINE-VISTA to the desired clinical effect.

Initiation of procedural sedation.

Loading infusion of 1.0 mcg/kg over 10 minutes. For less invasive procedures, such as ophthalmic 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 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"). Elderly patients may have an increased risk of developing arterial hypotension (see section "Special Warnings and Precautions for Use"), although limited available data from procedural sedation do not clearly indicate a dose-dependent relationship.

Renal impairment. Dose adjustment is generally not required in patients with renal impairment.

Hepatic impairment. Dexmedetomidine is metabolized in the liver; therefore, it should be used with caution in patients with hepatic impairment. Consideration should be given to using a reduced maintenance dose (see sections "Pharmacokinetics", "Special Warnings and Precautions for Use").

Method of administration.

The medicinal product should only be administered as a diluted intravenous infusion using a controlled infusion device.

Ampoules are intended for individual use in a single patient only. Preparation of solution.

Before administration, DEXMEDETOMIDINE-VISTA may be diluted in 5% dextrose solution, Ringer's solution, mannitol, or 0.9% sodium chloride solution to achieve a desired concentration of either 4 mcg/mL or 8 mcg/mL. The table below provides volumes required for preparation of the infusion.

To achieve a concentration of 4 mcg/mL:

To achieve a concentration of 8 mcg/mL:

Shake carefully to mix the solution well.

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

The medicinal product Dexmedetomidine-Vista is compatible with the following intravenous solutions and medicinal products: Ringer's lactate solution, 5 % glucose solution, 0.9 % sodium chloride solution, 20 % mannitol, sodium thiopental, etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium besylate, mivacurium chloride, rocuronium bromide, glycopyrrolate bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, noradrenaline, dobutamine, midazolam, morphine sulfate, fentanyl citrate, and plasma substitute.

Any unused medicinal product or waste materials should be disposed of in accordance with local requirements.

Children.

The safety and efficacy of the medicinal product Dexmedetomidine-Vista in children aged 0 to 18 years have not been established. Data on use in children are provided in the sections "Pharmacological properties" and "Side effects", but dosage recommendations cannot be given.

Overdose.

Symptoms. Several cases of dexmedetomidine overdose have been reported in clinical and post-marketing studies. Infusion rates 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.

Treatment. In cases of overdose with clinical symptoms, the infusion of the medicinal product should be reduced or discontinued. Cardiovascular effects are predominantly expected and should be treated according to clinical indications. At high concentrations, arterial hypertension may be more pronounced than arterial hypotension. In clinical studies, cases of sinus arrest resolved spontaneously or responded to treatment with atropine or glycopyrrolate. In individual 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, anesthesia, and resuscitation patients, respectively.

Procedural sedation.

The most commonly reported adverse reactions during procedural sedation with dexmedetomidine are listed below (Phase III study protocols included predefined threshold levels for changes in blood pressure, respiratory rate, and heart rate considered as adverse reactions):

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

The frequency of adverse reactions is classified as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (cannot be estimated based on available data).

Metabolism and nutritional disorders:

Common: Hyperglycemia, hypoglycemia.

Uncommon: Metabolic acidosis, hypoalbuminemia.

Frequency not known: Diabetes insipidus.

Psychiatric disorders:

Common: Agitation.

Uncommon: Hallucinations.

Cardiovascular disorders:

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

Common: Myocardial ischemia or infarction, tachycardia.

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

Respiratory, thoracic and mediastinal disorders:

Very common: Respiratory depression^2,3.

Uncommon: Dyspnea, apnea.

Gastrointestinal disorders:

Common: Nausea², vomiting, dry mouth².

Uncommon: Abdominal distension.

Renal and urinary disorders:

Frequency not known: Polyuria.

General disorders and administration site conditions:

Common: Withdrawal syndrome, hyperthermia.

Uncommon: Ineffectiveness of the medicinal product, thirst.

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

Description of individual adverse reactions.

Clinically significant arterial hypotension and bradycardia should be managed as described in the section "Special warnings and precautions for use".

In relatively healthy volunteers not in the intensive care unit, administration of the medicinal product occasionally led to sinus node arrest or sinus pause. Symptoms resolved after leg elevation and administration of anticholinergic agents such as atropine or glycopyrrolate. In isolated cases, bradycardia progressed to periods of asystole in patients with a prior history of bradycardia.

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 size of the loading dose.

Paediatric patients.

In patients aged 1 month and older, predominantly postoperative, in intensive care units, the medicinal product demonstrated a safety profile similar to that in adults when administered for up to 24 hours. Data in neonates (born at 28 to 44 weeks gestation) are limited, as are data within the maintenance dose range of ≤ 0.2 mcg/kg/hour. One case of hypothermic bradycardia in a neonate has been reported in the literature.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

No special temperature conditions for storage are required for this medicinal product. Store in the original packaging to protect from light. Keep out of the reach of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Compatibility studies have shown potential adsorption of dexmedetomidine to certain types of natural rubber. Although dexmedetomidine is administered in a controlled manner, it is advisable to use synthetic components or lined natural rubber stoppers.

Packaging.

2 ml concentrate in an ampoule; 5 or 25 ampoules in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

ALTA PHARMACEUTICALS, S.A.

Manufacturer's address and place of business.

1. Avda. de la Constitución, 198-199, Polígono Industrial Monte Boyal, Cazarrubios del Monte, Toledo, 45950, Spain.
2. Polígono Industrial de Bernedo, s/n, Bernedo, Álava, 01118, Spain.