Dexto^® (Concentrate) Instructions for Use

Marketing Authorization Holder

PSK Pharma, LLC (Russia)

ATC Code

N05CM18 (Dexmedetomidine)

Active Substance

Dexmedetomidine (Rec.INN registered by WHO)

Dosage Form

Dexto®

Concentrate for solution for infusion 100 mcg/ml: fl. 2 ml 5 or 25 pcs., fl. 4 ml or 10 ml 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion transparent, colorless.

Excipients : sodium chloride – 8.83 mg, water for injection – up to 1 ml.

2 ml – colorless glass bottles (5) – cardboard packs.
2 ml – colorless glass bottles (25) – cardboard packs.
4 ml – colorless glass bottles (1) – cardboard packs.
10 ml – colorless glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Sedative agent for intravenous anesthesia

Pharmacotherapeutic Group

Sedative

Pharmacological Action

Sedative agent, a highly selective α₂-adrenoceptor agonist with a broad spectrum of pharmacological properties. It has a strong sympatholytic effect due to reduced norepinephrine release from sympathetic nerve endings. The sedative effect is due to reduced excitation of the locus coeruleus, the main noradrenergic nucleus located in the brainstem. By acting on this area, Dexmedetomidine produces a sedative effect (similar to natural sleep without rapid eye movement), while simultaneously allowing the patient to remain awake and active.

Dexmedetomidine has an anesthetic and moderate analgesic effect; the analgesic effect has been demonstrated in patients with chronic low back pain.

The effect on the cardiovascular system is dose-dependent; at lower infusion rates, the central action dominates, leading to a decrease in heart rate and blood pressure. At higher doses, peripheral vasoconstrictive effects predominate, leading to an increase in systemic vascular resistance and blood pressure, while bradycardia becomes more pronounced.

Dexmedetomidine has almost no depressant effect on the respiratory system.

Pharmacokinetics

The pharmacokinetics of dexmedetomidine were evaluated after rapid IV administration in healthy volunteers and during prolonged IV infusion in ICU patients.

The pharmacokinetics of dexmedetomidine is described by a 2-compartment model.

In healthy volunteers, the distribution half-life in the rapid distribution phase was about 6 min. The terminal T_1/2 is about 2.1±0.43 h, V_ss – about 91±25.5 L.

Plasma clearance is about 39(±9.9) L/h. The average body weight used to assess V_ss and plasma clearance was 69 kg. In ICU patients after dexmedetomidine infusion >24 h, the plasma pharmacokinetics had the same pattern. Pharmacokinetic parameters: T_1/2 – about 1.5 h, V_ss – about 93 L and plasma clearance – about 43 L/h. The pharmacokinetics of dexmedetomidine is linear within the dose range of 0.2-1.4 mcg/kg/h. Dexmedetomidine does not accumulate during therapy lasting up to 14 days.

The binding of dexmedetomidine within the concentration range of 0.85-85 ng/ml to plasma proteins is 94%. Dexmedetomidine binds to human serum albumin and α₁-acid glycoprotein, with serum albumin being the main binding protein for dexmedetomidine in plasma.

It is metabolized in the liver. Primary metabolites are formed through 3 types of initial metabolic reactions: direct N-glucuronidation, direct N-methylation, and oxidation, which occur with the participation of cytochrome P450 isoenzymes. The most abundant circulating metabolites of dexmedetomidine are two isomeric N-glucuronides, one of which is formed by oxidation of the imidazole ring, and the other is a product of sequential reactions of N-methylation, hydroxylation of the methyl group, and O-glucuronidation. Available data indicate that the formation of oxidized metabolites is CYP-mediated (CYP2A6, CYP1A2, CYP2E1, CYP2D6 and CYP2C19). These metabolites exhibit negligible pharmacological activity.

After IV administration of radiolabeled dexmedetomidine, an average of 95% of the radiolabeled substance was detected in urine and 4% in feces after 9 days. The main metabolites in urine are two isomeric N-glucuronides, which together account for about 34% of the dose, and the N-methylated O-glucuronide, which accounts for 14.51% of the dose. Minor metabolites of carboxylic acid, 3-hydroxy- and O-glucuronide metabolites, individually account for 1.11-7.66% of the dose. Less than 1% of the unchanged substance is detected in urine. About 28% of the metabolites identified in urine are unidentified polar metabolites.

The binding of dexmedetomidine to plasma proteins is reduced in individuals with impaired liver function compared to healthy volunteers. The unbound Dexmedetomidine in plasma averaged from 8.5% in healthy volunteers to 17.9% in patients with severe hepatic impairment. Patients with varying degrees of hepatic impairment (Child-Pugh class A, B, or C) had reduced hepatic clearance of dexmedetomidine and prolonged plasma T_1/2. The mean clearance values for individuals with mild, moderate, and severe hepatic impairment were 74%, 64%, and 53% of those in healthy volunteers, respectively. The mean T_1/2 for patients with mild, moderate, and severe hepatic impairment increased to 3.9, 5.4, and 7.4 h, respectively.

The pharmacokinetics of dexmedetomidine in patients with severe renal impairment (CrCl <30 ml/min) does not change compared to healthy volunteers.

Indications

For the purpose of achieving mild to moderate sedation in the ICU during or after intubation.

ICD codes

Dosage Regimen

For hospital use in adults only.

Administered intravenously as an infusion.

Patients who are already intubated and sedated can be switched to Dexmedetomidine with an initial IV infusion rate of 0.7 mcg/kg/h; this dose can be gradually adjusted within the range of 0.2-1.4 mcg/kg/h to achieve the desired level of sedation. For debilitated patients, using the minimum initial infusion rate may be appropriate.

A loading bolus dose is usually not required. For patients requiring more rapid onset of sedation, an infusion with a loading dose of 0.5-1 mcg/kg body weight over 20 minutes can be administered first, i.e., the initial infusion rate is 1.5-3 mcg/kg/h over 20 minutes.

The initial infusion rate after the loading dose infusion is 0.4 mcg/kg/h. The dose can be adjusted subsequently.

For patients with impaired renal function, dose adjustment is usually not required.

Use with caution in patients with impaired liver function. The appropriateness of using a low maintenance dose should be considered.

The duration of the course of application depends on the need for the patient to remain sedated. There is no experience with the use of dexmedetomidine for more than 14 days.

Adverse Reactions

Metabolism disorders common – hyperglycemia, hypoglycemia; uncommon – metabolic acidosis, hypoalbuminemia.

Psychiatric disorders common – agitation; uncommon – hallucinations.

Cardiovascular system disorders very common – bradycardia, arterial hypotension, arterial hypertension; common – myocardial ischemia or infarction, tachycardia; uncommon – first-degree AV block, decreased cardiac output.

Respiratory system disorders uncommon – dyspnea.

Digestive system disorders common – nausea, vomiting, dry mouth; uncommon – abdominal distension.

General disorders common – withdrawal syndrome, hyperthermia; uncommon – thirst.

Contraindications

Hypersensitivity to dexmedetomidine.

Use in Pregnancy and Lactation

Dexmedetomidine should not be used during pregnancy, except when the expected benefit to the mother outweighs the risk to the fetus. The potential risk to humans is unknown.

Breastfeeding should be discontinued during the period of use.

Special Precautions

Dexmedetomidine is intended for use in the ICU only.

Cardiovascular functions should be continuously monitored during the infusion.

In patients who are not intubated, respiratory function should be monitored.

Use with caution in combination with other drugs that have a sedative effect or affect the cardiovascular system due to the risk of additive effects.

Given the pharmacodynamic effects, Dexmedetomidine should be used with caution in patients with severe bradycardia, progressive heart block (second- or third-degree AV block, unless a pacemaker is in place), arterial hypotension, or in patients with severe ventricular dysfunction. Dexmedetomidine reduces sympathetic nervous system activity, so more pronounced arterial hypotension/bradycardia can be expected in patients with hypovolemia, chronic arterial hypertension, and elderly patients.

Physically fit patients with a low resting heart rate may be particularly sensitive to the bradycardic effects of α₂-adrenoceptor agonists; there are reports of temporary sinus node arrest.

Arterial hypotension and bradycardia usually do not require treatment, but if necessary, arterial hypotension should be treated with vasoconstrictors and/or fluid administration, and bradycardia with anticholinergic agents.

Use with caution in patients with coronary artery disease, as there is a risk of significant arterial hypo- or hypertension, since there is a theoretical possibility of reduced coronary blood flow due to peripheral vasoconstriction mediated by α₂-adrenoceptor stimulation. If signs of myocardial ischemia appear on the ECG, the appropriateness of reducing the dose or discontinuing the drug should be considered.

In patients with impaired autonomic nervous system activity (e.g., due to spinal cord injury), more pronounced hemodynamic changes may occur after starting dexmedetomidine, so Dexmedetomidine should be used with caution in such patients.

Transient arterial hypertension was observed mainly during the administration of the loading dose, which was associated with the peripheral vasoconstrictive effect of dexmedetomidine. Treatment of arterial hypertension was usually not required, but a reduction in the loading dose or infusion rate is recommended.

Compared to propofol and midazolam, patients who developed a sedative effect due to dexmedetomidine usually awaken more easily, interact better with the doctor, and are capable of better communication, while generally remaining calm and relaxed. However, the spectrum of clinical action means that Dexmedetomidine cannot be used as a sole agent when deep sedation or complete immobilization of the patient is required. If muscle relaxation is necessary (including during endotracheal intubation), an alternative sedative in therapeutic doses should be additionally used so that the patient does not regain consciousness during the procedure.

The administration of bolus doses of dexmedetomidine to abruptly increase the intensity of sedation has not been evaluated, so such use is not recommended. In case of insufficient sedative effect, especially during the first hours after switching to Dexmedetomidine, bolus doses of an alternative sedative can be used.

Dexmedetomidine probably does not suppress seizure activity and therefore is not used as the sole agent for the treatment of status epilepticus. Experience with dexmedetomidine in severe neurological disorders such as head trauma is limited, so it should be used with caution in such cases, especially if deep sedation is required.

Like other sedatives, Dexmedetomidine can reduce cerebral blood flow.

The development of withdrawal reactions upon sudden discontinuation of dexmedetomidine cannot be ruled out.

It is not recommended to use Dexmedetomidine in patients susceptible to malignant hyperthermia. In case of prolonged unexplained fever, the use of dexmedetomidine should be discontinued.

There is no experience with the use of dexmedetomidine for more than 14 days.

Use in pediatrics

Safety and efficacy in children have not been established.

Drug Interactions

Concomitant use of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids may lead to potentiation of their effects.

Special studies have confirmed the potentiation of effects when used concomitantly with sevoflurane, isoflurane, propofol, alfentanil, and midazolam.

No pharmacokinetic interaction between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam has been identified. However, due to possible pharmacodynamic interaction, when using such agents in combination with dexmedetomidine, a reduction in the dose of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid analgesic may be required.

The possibility of enhanced arterial hypotension and bradycardia in patients receiving other drugs that cause such effects should be considered.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.