Quanadex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KVANADEX (KVANADEX)

Composition:

Active substance: dexmedetomidine hydrochloride;

1 ml contains dexmedetomidine hydrochloride 118 mcg, equivalent to 100 mcg of dexmedetomidine;

Excipients: sodium chloride, 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 range of pharmacological properties. It exerts sympatholytic effects by reducing norepinephrine release from sympathetic nerve endings. Sedative effects are mediated by reduced activation of the locus coeruleus, the primary noradrenergic nucleus located in the brainstem. Dexmedetomidine provides analgesic and anesthetic/analgesic-sparing 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 bradycardic effects become more pronounced. Dexmedetomidine has minimal respiratory depressant effects when used as monotherapy in healthy volunteers.

Sedation of adult patients in intensive care units

In placebo-controlled studies conducted in postoperative intensive care unit patients who were previously intubated and sedated with midazolam or propofol, dexmedetomidine significantly reduced the need for additional sedation (midazolam or propofol) and for opioids during 24-hour sedation. Most patients receiving dexmedetomidine did not require additional sedative therapy. Patients could be successfully extubated without discontinuing dexmedetomidine infusion. Studies conducted outside the intensive care unit have confirmed that dexmedetomidine can be safely administered to non-intubated patients when appropriate monitoring conditions are available.

Dexmedetomidine was comparable to midazolam (risk ratio 1.07; 95% CI [confidence interval]: 0.971, 1.176) and propofol (risk ratio 1.00; 95% CI: 0.922, 1.075) regarding time spent within the target sedation range in predominantly medical ICU patients requiring prolonged light to moderate sedation (RASS from 0 to –3) for up to 14 days; it reduced duration of mechanical ventilation compared to midazolam and shortened time to tracheal extubation compared to both midazolam and propofol. Compared to propofol and midazolam, patients receiving dexmedetomidine awakened more easily, cooperated better with healthcare staff, and were better able to communicate whether they experienced pain. Arterial hypotension and bradycardia occurred more frequently in patients receiving dexmedetomidine compared to those receiving midazolam, while tachycardia occurred more frequently compared to midazolam but arterial hypotension rates were similar compared to propofol. Assessment using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scale showed that the incidence of delirium was lower in patients receiving dexmedetomidine compared to midazolam, and delirium-related adverse events occurred less frequently in the dexmedetomidine group compared to the propofol group. Patients in whom sedation was discontinued due to inadequate sedation level were switched to propofol or midazolam. The risk of inadequate sedation level was higher in patients who were difficult to sedate with standard methods immediately prior to switching to an alternative method.

Evidence of efficacy in the pediatric population was obtained from a dose-controlled study conducted in an intensive care unit involving a large group of postoperative patients aged 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 and did not exceed 24 hours. Data on treatment beyond 24 hours are unavailable. Data in neonates (28–44 weeks gestation) are limited and pertain only to low doses (≤0.2 mcg/kg/hour) (see sections "Pharmacokinetics", "Special precautions for use"). Neonates may be particularly sensitive to the bradycardic effects of dexmedetomidine when hypothermia is present or when heart rate is dependent on cardiac output.

In double-blind, placebo-controlled studies conducted in intensive care units, 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 adverse event was reported as mild in one case and moderate in three cases.

Procedural sedation / sedation in conscious patients

The safety and efficacy of dexmedetomidine for sedation of non-intubated patients before and/or during surgical and diagnostic procedures were evaluated in two randomized, double-blind, placebo-controlled, multicenter clinical studies.

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 starting at 0.6 mcg/kg/hour.

The maintenance infusion dose of the investigational drug was titrated from 0.2 mcg/kg/hour to 1 mcg/kg/hour. The proportion of patients achieving the target sedation level (≤4 on the Sedation and Activity Score) without requiring additional midazolam administration was 54% in the 1 mcg/kg dexmedetomidine group and 40% in the 0.5 mcg/kg dexmedetomidine group, compared to 3% in the placebo group. The risk difference in the number of patients randomized to the 1 mcg/kg and 0.5 mcg/kg dexmedetomidine groups who did not require additional midazolam administration was 48% (95% CI: 37–57%) and 40% (95% CI: 28–48%), respectively, compared to placebo. Median (range) of additional midazolam dose administered 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 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, –2.5) and –2.7 mg (95% CI: –3.3, –2.1), respectively, in favor of dexmedetomidine. Mean time to first additional midazolam dose was 114 minutes in the 1.0 mcg/kg dexmedetomidine group, 40 minutes in the 0.5 mcg/kg dexmedetomidine group, and 20 minutes in the placebo group.

In Study 2, patients undergoing fiberoptic intubation under local anesthesia while conscious 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/hour. To maintain a sedation level ≥2 on the Ramsay Sedation Scale, 53% of patients receiving dexmedetomidine did not require additional midazolam compared to 14% in the placebo group. The risk difference in the number of patients randomized to the dexmedetomidine group who did not require additional midazolam administration was 43% (95% CI: 23–57%) compared to placebo. Mean midazolam dose was 1.1 mg in the dexmedetomidine group and 2.8 mg in the placebo group. The mean difference in additional midazolam dose was –1.8 mg (95% CI: –2.7, –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, 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 liters). The mean plasma clearance (Cl) is approximately 0.46–0.73 L/hour/kg (35.7–51.1 L/hour). The mean body weight of patients on which Vss and Cl were calculated was 69 kg. Plasma pharmacokinetics of dexmedetomidine in intensive care unit patients are similar after infusions lasting >24 hours. Calculated pharmacokinetic parameters are: t1/2 approximately 1.5 hours, Vss approximately 93 liters, and Cl approximately 43 L/hour. Dexmedetomidine pharmacokinetics are linear within the dose range of 0.2–1.4 mcg/kg/hour, and it does not accumulate with treatment 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 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 initial metabolic pathways: direct N-glucuronidation, direct N-methylation, and cytochrome P450-catalyzed oxidation. The major circulating metabolites of dexmedetomidine in blood are two isomeric N-glucuronides. Metabolite H-1 (N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide) is also one of the main biotransformation products of dexmedetomidine. Cytochrome P450 catalyzes 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 formation of oxidized metabolites is mediated by several cytochrome P450 isoenzymes (CYP2A6, CYP1A2, CYP2E1, CYP2D6, and CYP2C19). These metabolites have no significant pharmacological activity.

After intravenous administration of radiolabeled dexmedetomidine, on average 95% of radioactivity was recovered in urine and 4% in feces over 9 days. The main urinary metabolites are two isomeric N-glucuronides, which together account for approximately 34% of the administered dose, and N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide, which accounts for 14.51% of the dose. Minor metabolites, including 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 detected in urine. Approximately 28% of metabolites detected in urine are unidentified minor metabolites.

Special populations

Significant differences in dexmedetomidine pharmacokinetics between patients of different ages and genders were not 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. Patients with varying degrees of hepatic impairment (Child-Pugh classes A, B, or C) had reduced hepatic clearance of dexmedetomidine and prolonged plasma elimination half-life (t1/2). 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 t1/2 in patients with mild, moderate, and severe hepatic impairment was prolonged to 3.9, 5.4, and 7.4 hours, respectively. Although the dose of dexmedetomidine is determined by the level of sedative effect, consideration should be given to reducing the initial or 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) does not differ from that in individuals with normal renal function.

Data in neonates (born at 28–44 weeks gestation) and children up to 17 years of age are limited. The elimination half-life of dexmedetomidine in children (aged 1 month to 17 years) does not differ from that in adults, but it is likely prolonged in neonates (up to 1 month). In age groups from 1 month to 6 years, body weight-adjusted plasma clearance was higher but decreased in older children. In neonates (up to 1 month of age), body weight-adjusted plasma clearance was lower (0.9 L/hour/kg) than in older age groups due to immaturity.

Available data are presented in the table below:

Clinical Characteristics

Indications

For sedation of adult patients in anesthesia, intensive care and emergency departments (ICU) who require a level of sedation no deeper than awakening in response to vocal stimulation (corresponds to a range from 0 to –3 on the Richmond Agitation-Sedation Scale [RASS]).

For sedation of non-intubated patients before and/or during diagnostic or surgical procedures requiring sedation, i.e., procedural sedation / sedation in conscious patients.

Contraindications

Hypersensitivity to dexmedetomidine or to any of the excipients of the medicinal product.

Second- or third-degree atrioventricular block (in the absence of a permanent 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 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, or midazolam have been observed. However, due to possible pharmacodynamic interactions when these agents are used concomitantly with dexmedetomidine, it may be necessary to reduce the dose of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.

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

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

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

Special precautions for use

Monitoring

Kvadex is intended for use in intensive care units, operating rooms, and during diagnostic procedures; its use in other settings is not recommended. Continuous cardiac monitoring must be performed during infusion of the medicinal product. In non-intubated patients, respiratory monitoring is required due to the risk of respiratory depression and, in some cases, apnea (see section "Adverse reactions").

Recovery time following administration of dexmedetomidine has been reported to be approximately 1 hour. When used in an outpatient setting, 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 to ensure patient safety.

General warnings

Kvadex should not be administered as a bolus injection, and loading doses are not recommended in intensive care units. Therefore, healthcare providers should be prepared to use an alternative sedative agent to immediately control agitation or during procedures, especially during the first few hours of treatment. A small bolus dose of another sedative may be used during procedural sedation if a rapid increase in the level of sedation is required.

Some patients receiving dexmedetomidine may be arousable and respond to external stimuli upon stimulation. In the absence of other clinical symptoms, this sign alone should not be considered as evidence of treatment inefficacy.

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

Kvadex should not be used as a general anesthetic agent for intubation induction or to provide sedation when muscle relaxants are administered.

Dexmedetomidine does not possess the anticonvulsant properties associated with some other sedatives and therefore does not suppress underlying seizure activity.

Caution should be exercised when dexmedetomidine is used concomitantly with medicinal products that have sedative effects or affect the cardiovascular system, due to the potential for additive effects.

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

If Kvadex is used in an outpatient setting, patient discharge should only occur under the supervision of a third party. Patients should be advised to refrain from driving or performing other potentially hazardous tasks. If possible, the use of other sedative agents (e.g., benzodiazepines, opioids, alcohol) should be avoided for a certain period, depending on the observed effects of dexmedetomidine, the procedure performed, concomitant medications, and the patient’s age and condition.

Extreme caution should be exercised when administering dexmedetomidine to elderly patients. Patients aged 65 years and older may be more susceptible to developing hypotension with dexmedetomidine, including during loading dose administration for procedures. Dose reduction should be considered (see section "Dosage and administration").

Mortality in ICU patients aged ≤ 65 years

In the pragmatic randomized controlled SPICE III trial involving 3904 critically ill adult patients in intensive care units, dexmedetomidine was used as the primary sedative and compared with usual care. There was no overall difference in 90-day mortality between the dexmedetomidine group and the usual care group (mortality was 29.1% in both groups), but there was heterogeneity in the effect of age on mortality. Dexmedetomidine was associated with increased mortality in patients aged ≤ 65 years (odds ratio 1.26; 95% CI: 1.02, 1.56) compared with alternative sedatives. Although the mechanism is unclear, the 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 and decreasing patient age. These findings should be weighed against the expected clinical benefit of dexmedetomidine compared with alternative sedatives in younger patients.

Cardiovascular effects and precautions

Dexmedetomidine reduces heart rate and blood pressure (due to central sympatholytic effects), but at higher concentrations causes peripheral vasoconstriction, leading to increased blood pressure (see section "Pharmacodynamics"). Therefore, Kvadex is not suitable for patients with severe cardiovascular disease.

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; such patients require special attention.

Bradycardia is usually not clinically significant and does not require treatment, but if necessary, it can be managed with anticholinergic agents or dose reduction. Physically fit patients with low resting heart rates may be particularly sensitive to the negative chronotropic effects of α2-adrenoceptor agonists; cases of sinus node block have been reported. Cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have also been reported (see section "Adverse reactions").

In patients with concomitant arterial hypotension (especially refractory to vasopressors), including chronic hypotension, hypovolemia, or reduced functional reserve—particularly those with severe ventricular dysfunction or elderly patients—the hypotensive effect of dexmedetomidine may be more pronounced, and special caution is required (see section "Contraindications"). Reduction in blood pressure generally does not require specific intervention, but readiness to reduce the dose, administer volume expanders, and/or vasopressors should be maintained if necessary.

Hemodynamic effects after administration may be more pronounced in patients with impaired peripheral autonomic nervous system function (e.g., due to spinal cord injury), requiring special patient care.

Transient increases in blood pressure have been observed during loading dose administration of dexmedetomidine due to peripheral vasoconstrictor effects; therefore, loading doses for sedation in intensive care settings are not recommended. Treatment of elevated blood pressure is usually not required, but consideration should be given to reducing the infusion rate.

Local vasoconstriction at high concentrations may be more significant in patients with ischemic heart disease or severe cerebrovascular disorders; such patients require careful monitoring. Dose reduction or discontinuation of the medicinal product may be necessary in patients showing signs of myocardial or cerebral ischemia.

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

Patients with hepatic impairment

Caution should be exercised in patients with severe hepatic insufficiency, as reduced clearance of dexmedetomidine may increase the risk of adverse reactions and excessive sedation with prolonged administration.

Patients with neurological disorders

Experience with the use of dexmedetomidine in severe neurological conditions such as traumatic brain injury and the postoperative period following neurosurgical procedures is limited; therefore, it should be used with caution in such conditions, especially when deep sedation is required. When selecting therapy, it should be considered that dexmedetomidine may reduce cerebral blood flow and intracranial pressure.

Other warnings

After prolonged use of α2-adrenoceptor agonists, withdrawal syndrome has rarely occurred upon abrupt discontinuation. This possibility should be considered if a patient develops agitation and hypertension shortly after stopping 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 predisposed to malignant hyperthermia.

Cases of diabetes insipidus have been reported in association with dexmedetomidine treatment. If polyuria occurs, dexmedetomidine should be discontinued and serum sodium levels and urine osmolality should be checked.

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 ml, i.e., it is 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. The medicinal product should not be used during pregnancy unless the woman's clinical condition necessitates treatment with dexmedetomidine.

Breastfeeding

Dexmedetomidine passes into human breast milk, but its levels will be below the limit of detection 24 hours after discontinuation of the medicinal product. Risk to the infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue dexmedetomidine therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of dexmedetomidine therapy for the mother.

Fertility

In fertility studies in rats, dexmedetomidine did not affect male or female reproductive function. Data on effects on human reproductive function are lacking.

Ability to affect reaction speed when driving or operating machinery

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

Method of Administration and Dosage

For sedation of adult patients in anesthesia, intensive care and emergency departments (ICU), 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 - Richmond Agitation-Sedation Scale [RASS])

For hospital use only. The medicinal product Quanadex must be administered by healthcare professionals experienced in managing patients in intensive care settings.

Dosing

Patients who have already been intubated and are under sedation may be switched to Quanadex with an initial infusion rate of 0.7 mcg/kg/hr, which can be gradually adjusted within the 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 debilitated patients, consideration should be given to using the lowest initial infusion rate. Dexmedetomidine is a potent agent, and therefore its infusion rate is specified on an hourly basis. After dose adjustment, it may take up to one hour to achieve the appropriate level of sedation.

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

Loading dose administration of dexmedetomidine for sedation is not recommended, as it is associated with an increased incidence of adverse effects. If necessary, propofol or midazolam may be used until the clinical effect of dexmedetomidine is achieved.

Duration of administration.

There is no experience with Quanadex use beyond 14 days. When administering the drug for more than 14 days, the patient's condition should be regularly evaluated.

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

The medicinal product Quanadex must be administered by healthcare professionals experienced in procedural sedation, either in the operating room or during diagnostic procedures.

When Quanadex 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").

Oxygen therapy must be available and promptly administered when indicated. Blood oxygen saturation should be monitored using pulse oximetry.

Quanadex should be administered as a loading infusion followed by a maintenance infusion. Depending on the procedure, appropriate 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, propofol) during painful procedures or when deeper sedation is needed. The pharmacokinetic distribution half-life of dexmedetomidine is approximately 6 minutes. This parameter, together with the effects of other concurrently administered drugs, should be considered when estimating the required time to titrate to the desired clinical effect of Quanadex.

Initiation of procedural sedation

Loading infusion: 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 a dose range of 0.2 to 1 mcg/kg/hr. The maintenance infusion rate should be adjusted until the target sedation level is achieved.

Elderly patients.

Dose adjustment is generally not required for elderly patients (see section "Pharmacokinetics"). However, elderly patients have an increased risk of developing arterial hypotension (see section "Special precautions"), although limited available data from procedural sedation do not clearly indicate a dose-dependent relationship.

Renal impairment.

Dose adjustment is generally not required for patients with renal impairment.

Hepatic impairment.

Quanadex is metabolized in the liver; therefore, it should be used with caution in patients with hepatic impairment. Consideration should be given to using a reduced maintenance dose (see sections "Special precautions", "Pharmacokinetics").

Method of administration

The medicinal product must be administered only 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, Quanadex may be diluted with 5% glucose solution, Ringer's solution, mannitol, or 0.9% sodium chloride solution to achieve the desired concentration of either 4 mcg/mL or 8 mcg/mL. The volumes required to prepare the infusion solution of the appropriate concentration are provided below.

To achieve a concentration of 4 mcg/mL:

To achieve a concentration of 8 mcg/ml:

After dilution, gently shake the solution to ensure uniform mixing.

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

Quandex is compatible with the following intravenous solutions and drugs: Ringer's lactate solution, 5 % glucose solution, 0.9 % sodium chloride solution, 20 % mannitol, atropine sulfate, dopamine, norepinephrine, dobutamine, midazolam, morphine sulfate, fentanyl citrate, and plasma substitutes.

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

Children

The safety and efficacy of Quandex 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. The 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 common adverse reactions reported in association 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 (see section "Special precautions for use"). With high concentrations, arterial hypertension may be more pronounced than hypotension. In clinical studies, cases of sinus node arrest were transient 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 intensive care settings are hypotension, hypertension, and bradycardia, occurring in approximately 25%, 15%, and 13% of patients, respectively.

Hypotension and bradycardia were also the most frequent serious adverse reactions associated with dexmedetomidine, occurring in 1.7% and 0.9% of randomized patients in the ICU, respectively.

Procedural sedation / sedation during wakefulness

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 effects):

• Hypotension (55% in the dexmedetomidine group vs. 30% in the placebo group, both groups additionally receiving midazolam and fentanyl);
• Respiratory depression (38% in the dexmedetomidine group vs. 35% in the placebo group, both groups additionally receiving midazolam and fentanyl);
• Bradycardia (14% in the dexmedetomidine group vs. 4% in the placebo group, both groups additionally receiving midazolam and fentanyl).

The adverse reactions listed below are based on pooled data from clinical trials in ICU patients. The frequency of adverse reactions is categorized as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Endocrine 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 infarction, tachycardia.

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

Vascular disorders

Very common: Hypotension^1,2, 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 medicinal product, 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 hypotension and bradycardia should be managed as described in the section “Special precautions for use”.

In relatively healthy volunteers not in the intensive care unit, bradycardia associated with the use of the medicinal product occasionally led to sinus 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 pre-existing bradycardia. Cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have also been reported.

Arterial hypertension has been associated with the administration of loading doses. This reaction can be minimized by avoiding the use of a loading dose, reducing the infusion rate, or decreasing the loading dose.

Children

In patients aged 1 month and older, predominantly postoperative, in intensive care units, and with administration duration up to 24 hours, the medicinal product demonstrated a safety profile similar to that in adults. Data in neonates (born at 28 to 44 weeks of gestation) are limited, particularly 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 adverse reactions

Reporting of adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging. Keep ampoules in the cardboard box to protect from light.

Keep out of reach of children.

Incompatibilities

This medicinal product should 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 acts in a dose-dependent manner, it is advisable to use synthetic components or lined natural rubber stoppers.

Packaging. 2 ml in an ampoule; 5 ampoules in a blister pack; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "Yuria-Pharm".

Manufacturer's address and location of business activity. 108 Kobzarska Street, Cherkasy, Cherkasy Oblast, 18030, Ukraine.

Tel.: (044) 281-01-01.