Pharmacological properties
Pharmacodynamics. Dexmedetomidine is a selective α2-adrenergic agonist with a wide spectrum of pharmacological properties. It has a sympatholytic effect due to a decrease in the release of noradrenaline from sympathetic nerve endings. Sedative effects are due to a decrease in the severity of the disorder in the macula lutea - a nucleus with a predominance of noradrenergic neurons, which is located in the brainstem.
Dexmedetomidine has an analgesic effect and helps reduce the doses of anesthetics and analgesics used. Cardiovascular effects are dose-dependent. At low infusion rates, central effects predominate, which leads to a decrease in heart rate and blood pressure. When using the drug in high doses, peripheral vasoconstrictor effects predominate, which leads to an increase in systemic vascular resistance and blood pressure, as well as a further increase in bradycardia. Dexmedetomidine practically does not suppress respiration when used as monotherapy in healthy volunteers.
Indications 1. Sedation of adult patients in intensive care units (ICU)
In placebo-controlled studies in patients in the postoperative ICU who were previously intubated and sedated with midazolam or propofol, dexmedetomidine significantly reduced the need for both additional sedation (midazolam or propofol) and opioids for up to 24 hours. The majority of patients treated with dexmedetomidine did not require additional sedative therapy. Patients could be successfully extubated without stopping the dexmedetomidine infusion.
Dexmedetomidine was similar to MIDAZOLAM (hazard ratio 1.07; 95% confidence interval (CI) 0.971-1.176) and propofol (hazard ratio 1.00; 95% CI 0.922-1.075) in time spent in the target range of sedation in therapeutic (mainly ) ICU patients requiring prolonged mild to moderate sedation (0 to -3 Richmond Arousal-Sedation Scale (RASS)) for up to 14 days; it reduced the duration of mechanical ventilation compared with midazolam and reduced the time to tracheal extubation compared with midazolam and propofol. Patients receiving dexmedetomidine were more easily awakened, more cooperative with staff, and reported less pain compared with patients receiving midazolam or propofol. Patients receiving dexmedetomidine were more likely to develop hypotension and bradycardia, but less likely to develop tachycardia, compared with patients receiving midazolam. Compared with the propofol group, the incidence of tachycardia was higher in patients receiving dexmedetomidine and the incidence of hypotension was about the same. The CAM-ICU score showed that the incidence of delirium was lower in patients receiving dexmedetomidine compared with midazolam, and delirium-related adverse events were less common in the dexmedetomidine group compared with propofol. Those patients who were discontinued from dexmedetomidine due to insufficient depth of sedation were switched to propofol or midazolam. The risk of insufficient sedation was higher in patients who were difficult to sedate with standard agents immediately before switching to another sedative method.
Evidence of efficacy in the pediatric population was obtained in a dose-controlled study in the ICU in a large postoperative population aged 1 month to 17 years. Approximately 50% of patients treated with dexmedetomidine did not require additional sedation with midazolam during a treatment period lasting an average of 20.3 hours, but not more than 24 hours. Data on treatment of children with the drug for more than 24 hours are not available. Data in neonates (after 28-44 weeks of gestation) are very limited and only apply to low doses (≤0.2 μg/kg/h). Neonates may be particularly sensitive to the bradycardic effects of dexmedetomidine in the presence of hypothermia and in conditions where cardiac output is dependent on heart rate.
In double-blind, controlled studies in the ICU, the incidence of cortisol suppression in patients treated with dexmedetomidine (n = 778) was 0.5% compared with 0% in patients treated with midazolam (n = 338) or propofol (n = 275). This effect was reported as mild in 1 case and moderate in 3 cases.
Indication 2. Procedural sedation with preservation of consciousness
Two randomized, double-blind, placebo-controlled, multicenter clinical trials demonstrated the safety and efficacy of dexmedetomidine for the sedation of non-intubated adult patients before and/or during diagnostic or surgical procedures.
In the first study, 54% of patients receiving dexmedetomidine at a dose of 1 μg/kg body weight and 40% of patients receiving dexmedetomidine at a dose of 0.5 μg/kg did not require additional sedation with midazolam compared with 3% of patients in the placebo group.
In the second study, 53% of patients receiving dexmedetomidine at a dose of 1 μg/kg did not require additional sedation with midazolam compared with 14% of patients in the placebo group.
Distribution. The pharmacokinetics of dexmedetomidine are described by a two-compartment model. In healthy volunteers, a rapid distribution phase is observed with a T½α of approximately 6 min. T½ is approximately 1.9-2.5 h (minimum value - 1.35 h, maximum - 3.68 h), and Vss is approximately 1.16-2.16 l/kg (90-151 l). The mean clearance (Cl) is 0.46-0.73 l/h/kg (35.7-51.1 l/h). The mean body weight of the patients from whom Vss and Cl were calculated was 69 kg.
The plasma pharmacokinetics of dexmedetomidine in ICU patients administered by infusion over 24 hours were similar. The estimated pharmacokinetic parameters were: T½ - approximately 1.5 h, Vss - approximately 93 L and Cl - approximately 43 L/h. In the dose range from 0.2 to 1.4 μg/kg/h, the pharmacokinetics of dexmedetomidine are linear, it does not accumulate during treatment for up to 14 days. 94% of dexmedetomidine is bound to plasma proteins. The degree of binding to plasma proteins is constant in the concentration range of 0.85-85 ng/ml. Dexmedetomidine binds to both human serum albumin and α 1 acid glycoprotein, predominantly to serum albumin.
Biotransformation and elimination. Dexmedetomidine is completely metabolized in the liver. There are three types of initial metabolic reactions: direct N-glucuronidation, direct N-methylation and cytochrome P450-catalyzed oxidation. The main metabolites of dexmedetomidine in the blood are two isomeric N-glucuronides. Metabolite H-1 (N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide) is also an important product of dexmedetomidine biotransformation. 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 occurs with the participation of a number of cytochrome P450 isoenzymes (CYP2A6, CYP1A2, CYP2E1, CYP2D6 and CYP2C19). These metabolites do not have significant pharmacological activity.
Nine days after administration of radiolabeled dexmedetomidine, approximately 95% of the radioactivity was recovered in the urine and 4% in the feces. The major metabolites in the urine were two isomeric N-glucuronides, which together accounted for approximately 34% of the administered dose, and N-methyl-3-hydroxymethyldexmedetomidine O-glucuronide, which accounted for 14.51% of the dose. The minor metabolites dexmedetomidine carboxylic acid, 3-hydroxymethyldexmedetomidine, and its O-glucuronide accounted for 1.11-7.66% of the dose each. Less than 1% of dexmedetomidine was recovered in the urine as unchanged drug. Approximately 28% of the metabolites in the urine were unidentified minor metabolites.
Pharmacokinetics in special patient groups
No significant differences in the pharmacokinetic parameters of dexmedetomidine were observed in patients of different ages and genders.
The binding of dexmedetomidine to plasma proteins is reduced in subjects with impaired hepatic function compared with healthy volunteers. The mean proportion 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 class A, B or C), the hepatic clearance of dexmedetomidine was reduced and the half-life was increased.
The mean clearance of unbound dexmedetomidine in patients with mild, moderate and severe hepatic impairment was 59%, 51% and 32% of that in healthy volunteers, respectively. T½ in patients with mild, moderate and severe hepatic impairment was increased to 3.9, 5.4 and 7.4 h, respectively. Although dexmedetomidine dose selection is based on the degree of sedation, consideration should be given to reducing the initial or maintenance dose of the drug in patients with hepatic impairment, depending on the degree of impairment and clinical response to therapy.
The 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 newborns (after 28-44 weeks of gestation) to 17 years are limited. T½ of dexmedetomidine in children (aged 1 month to 17 years) is comparable to that in adults, but is slightly longer in newborns (aged < 1 month). In the age groups 1 month to 6 years, the weight-adjusted plasma clearance was higher, but decreased in older children. Due to immaturity, the weight-adjusted clearance in newborns (aged < 1 month) is lower (0.9) than in older age groups.
Indication
1. Sedation of adult patients in the ICU, anesthesiology and intensive care units who require a level of sedation no deeper than awakening in response to vocal stimulation (corresponding to a range of 0 to -3 points on the RASS scale).
2. Sedation of non-intubated adult patients before and/or during diagnostic or surgical procedures requiring sedation, i.e. conscious procedural sedation.
Application
Indications 1. Sedation of adult patients in the ICU, anesthesiology and intensive care unit who require a level of sedation no deeper than awakening in response to vocal stimulation (corresponding to a range of 0 to -3 points on the RASS scale)
Dexmedetomidine EVER Pharma is intended for use only in a hospital setting. Therapy should be carried out under the supervision of qualified physicians who have experience in treating patients in intensive care.
Previously intubated and sedated patients can be switched to dexmedetomidine at an initial infusion rate of 0.7 mcg/kg/h with subsequent dose adjustments within the range of 0.2-1.4 mcg/kg/h to achieve the desired level of sedation, depending on the patient's response. A low initial infusion rate should be considered for debilitated patients. It should be noted that dexmedetomidine is a very potent agent, so the infusion rate is given per 1 hour. After dose adjustments, a new steady-state level of sedation can be achieved within 1 hour.
Maximum dose
The maximum dose of 1.4 mcg/kg/h should not be exceeded. Patients who do not achieve the required level of sedation with the maximum dose of Dexmedetomidine EVER Pharma should be switched to an alternative sedative.
The introduction of a loading dose of dexmedetomidine for sedation in ICU conditions is not recommended, as this increases the frequency of adverse reactions. If necessary, propofol or midazolam can be used until the required clinical effect of Dexmedetomidine EVER Pharma is achieved.
duration of therapy
There is no experience with the use of Dexmedetomidine EVER Pharma for more than 14 days. With longer use of the drug, the patient's condition should be regularly assessed.
Indication 2. Sedation of non-intubated adult patients before and/or during diagnostic or surgical procedures requiring sedation, i.e. conscious procedural sedation
Dexmedetomidine EVER Pharma should only be used by qualified physicians who have experience in anesthetizing patients in operating room settings or during diagnostic procedures.
If Dexmedetomidine EVER Pharma is prescribed for conscious sedation, continuous monitoring of the patient's condition is necessary. It should be carried out by persons not involved in the diagnostic or surgical procedure. It is necessary to continuously monitor the appearance of early signs of hypotension, hypertension, bradycardia, respiratory depression, apnea, dyspnea and / or oxygen desaturation (see Side effects). An oxygen supply system should be available and ready to use if necessary. Monitoring of blood oxygen saturation is necessary.
A loading dose of Dexmedetomidine EVER Pharma should be administered first, followed by maintenance doses. Depending on the procedure, concomitant local anesthesia may be required to achieve the desired clinical effect. In the case of painful procedures or when deep sedation is required, additional analgesia or sedatives (e.g. midazolam, propofol, and opioids) are recommended.
Initial doses for procedural sedation
For adult patients: Infusion of a loading dose of 1.0 mcg/kg over 10 minutes. For less invasive procedures, such as ophthalmic surgery, an infusion of a loading dose of 0.5 mcg/kg over 10 minutes may be appropriate.
For fiberoptic intubation of conscious adult patients: infusion at a loading dose of 1 mcg/kg over 10 minutes.
For patients aged 65 years and over: a dose reduction should be considered.
For adult patients with impaired liver function, a dose reduction should be considered.
Maintenance doses for procedural sedation
For adult patients: maintenance infusion is usually started at a dose of 0.6 mcg/kg/h and titrated to achieve the desired clinical effect in the dose range of 0.2-1 mcg/kg/h. The maintenance infusion rate should be adjusted to achieve the desired level of sedation.
For fiberoptic intubation of conscious adult patients: maintenance infusion at a rate of 0.7 mcg/kg/h throughout the period until removal of the endotracheal tube.
For patients aged 65 years and over: a dose reduction should be considered.
For adult patients with impaired liver function, a dose reduction should be considered.
Doses for special patient groups
Elderly patients: a dose reduction should be considered (see Precautions).
Patients with renal impairment: No dose adjustment is required in patients with renal impairment.
Patients with hepatic impairment: Dexmedetomidine is metabolized in the liver, therefore caution should be exercised when treating patients with hepatic impairment. A reduction in maintenance doses should be considered (see Precautions and Pharmacokinetics).
Method of application
Dexmedetomidine EVER Pharma should only be administered after dilution by intravenous infusion using special equipment (infusomat). Dexmedetomidine EVER Pharma should not be administered as a bolus (see also Special warnings and precautions for use).
Ampoules and vials are intended for individual use by one patient only.
Preparation of infusion solutions
Before use, Dexmedetomidine EVER Pharma should be diluted with 5% glucose solution, Ringer's solution, mannitol solution or 0.9% sodium chloride solution to achieve the required concentration of 4 μg/ml or 8 μg/ml. The tables below show the volumes required for the preparation of infusion solutions.
Dexmedetomidine EVER Pharma, concentrate for preparation of solution for infusion, 100 mcg/ml
Solvent volume ml
Total volume
solution for infusions, ml
2 ml
48
50
4 ml
96
100
10 ml
240
250
20 ml
480
500
Solution for infusion with a concentration of 8 mcg/ml
Dexmedetomidine EVER Pharma, concentrate for preparation of solution for infusion, 100 mcg/ml
Solvent volume ml
Total volume
solution for infusions, ml
4 ml
46
50
8 ml
92
100
20 ml
230
250
40 ml
460
500
The prepared solution should be shaken gently to completely mix its components.
Before use, the drug should be visually inspected. Only clear, colorless solutions that do not contain visible mechanical inclusions can be administered.
Infusion solutions prepared by diluting the drug have been demonstrated to be chemically and physically stable for 48 hours when stored at 25°C or refrigerated (2-8°C).
From a microbiological point of view, the diluted product should be used immediately. If the solution for infusion is not used immediately, in-use storage times and conditions should be monitored by the person responsible. In general, in-use storage times should not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Dexmedetomidine EVER Pharma pharmaceutical is compatible with the following solutions and drugs: lactated Ringer's solution, 5% glucose solution, 0.9% sodium chloride solution, 20% mannitol solution, 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 blood plasma substitutes.
Unused drug residues and waste should be disposed of in accordance with applicable requirements.
children
The safety and efficacy of treatment with Dexmedetomidine EVER Pharma in children under the age of 18 have not been established.
Available data on use in children are presented in the sections Adverse Reactions, Pharmacodynamics and Pharmacokinetics, however, dosage recommendations for children cannot be provided at this time.
Contraindication
Hypersensitivity to dexmedetomidine or to any of the components of the drug.
AV block II-III degree (in the absence of an artificial pacemaker).
Uncontrolled arterial hypotension.
Acute cerebrovascular pathology.
Side effects
Summary of safety profile
Indications 1. Sedation of adult patients in the ICU
When dexmedetomidine was used for sedation in the ICU, the most common adverse reactions were hypotension, hypertension, and bradycardia, occurring in approximately 25%, 15%, and 13% of patients, respectively. Hypotension and bradycardia were also the most common serious adverse reactions associated with dexmedetomidine treatment, occurring in 1.7% and 0.9% of randomized ICU patients, respectively.
Indication 2. Procedural sedation with preservation of consciousness
When dexmedetomidine was used for procedural sedation, the most frequently reported adverse reactions were hypotension (54% in the dexmedetomidine group and 30% in the placebo group), respiratory depression (37% in the dexmedetomidine group and 32% in the placebo group), and bradycardia (14% in the dexmedetomidine group and 4% in the placebo group).
Depending on the frequency, adverse reactions are divided into the following categories: very common (≥1/10), common (≥1/100, 1/10), uncommon (≥1/1000, 1/100), rare (≥1/10,000, 1/1000), isolated (1/10,000).
Metabolism and nutrition disorders: often - hyperglycemia, hypoglycemia *; infrequently - metabolic acidosis *, hypoalbuminemia *.
From the psyche: often - agitation *; infrequently - hallucinations *.
From the heart: very often - bradycardia; often - myocardial ischemia or myocardial infarction *, tachycardia; infrequently - AV block I degree, decrease in cardiac output *.
From the vascular system: very often - arterial hypotension, arterial hypertension.
From the respiratory system, chest organs and mediastinum: very often - respiratory depression; infrequently - shortness of breath *, apnea *.
From the digestive system: often - nausea, vomiting, dry mouth; infrequently - bloating *.
General effects and local reactions: often - withdrawal syndrome, hyperthermia *; infrequently - ineffectiveness of the drug, thirst *.
* Adverse reactions observed during treatment only according to indications 1.
Description of selected adverse reactions
Clinically significant hypotension or bradycardia should be treated according to the recommendations in the Precautions section.
In healthy subjects not in the ICU, administration of dexmedetomidine has occasionally caused bradycardia and sinus arrest. Symptoms have been managed by elevating the legs above the head and using anticholinergics such as atropine or glycopyrrolate. In isolated cases, patients with preexisting bradycardia have progressed to episodes of asystole. Some patients with significant cardiac dysfunction may require resuscitation.
Hypertension has been reported with a loading dose of dexmedetomidine in the ICU. To reduce the incidence of this adverse reaction, the loading dose should be avoided, the infusion rate should be reduced, or the loading dose of the drug should be reduced.
The safety profile of dexmedetomidine in patients aged 1 month and older, mainly postoperative, was similar to that in adults when dexmedetomidine was administered for up to 24 hours in the ICU. Data in neonates (after 28-44 weeks of gestation) are very limited and only apply to low maintenance doses (≤0.2 μg/kg/h). One case of hypothermic bradycardia in a neonate has been reported in the literature.
Special instructions
monitoring
Dexmedetomidine EVER Pharma is intended for use in hospital settings, in intensive care units, anesthesiology and intensive care units, its use in other settings is not recommended. During dexmedetomidine infusion, cardiac function should be continuously monitored in all patients.
The recovery time after administration of dexmedetomidine is approximately 1 hour. When using the drug in outpatients, their condition should be closely monitored for at least this time, and then the patient should be observed for at least another 1 hour to ensure their safety.
general warnings
Dexmedetomidine EVER Pharma should not be administered as a bolus. It is also not recommended to administer a loading dose of the drug in ICU settings. Medical personnel should be prepared to use alternative sedatives for immediate control of agitation in ICU patients, especially in the first hours of drug administration.
Some patients treated with dexmedetomidine experienced mild arousal and recovered rapidly after stimulation. In the absence of other clinical symptoms, this finding alone should not be considered evidence of drug failure.
Dexmedetomidine EVER Pharma should not be used as a means of inducing anesthesia during intubation or to provide a sedative effect when using muscle relaxants.
Unlike some other sedatives, dexmedetomidine does not have an anticonvulsant effect, does not suppress existing seizure activity, and therefore should not be used as monotherapy in status epilepticus.
Caution should be exercised when administering dexmedetomidine concomitantly with medicinal products that have a sedative effect or affect the cardiovascular system due to a possible additive effect.
Dexmedetomidine EVER Pharma is not recommended for patient-controlled sedation. There are no relevant data.
When using the drug in outpatients, the effects of dexmedetomidine, the procedure, concomitant medications, age, and condition of the patient should be considered when making final recommendations regarding:
the appropriateness of accompanying the patient when leaving the hospital; the time to regain the ability to perform complex or dangerous tasks, such as driving; the use of other sedatives (e.g. benzodiazepines, sedatives, alcohol).
Elderly patients
Caution is required when using dexmedetomidine in the elderly. Patients over 65 years of age are more prone to hypotension when administered dexmedetomidine, therefore, in such cases, a dose reduction of the drug should be considered (see Method of administration).
Cardiovascular effects and precautions
Dexmedetomidine EVER Pharma reduces heart rate and blood pressure due to its central sympatholytic action, but at higher concentrations it causes peripheral vasoconstrictor effects, leading to an increase in blood pressure (see Pharmacodynamics). Dexmedetomidine does not usually cause deep sedation and patients can be easily awakened. Therefore, Dexmedetomidine EVER Pharma is not suitable for patients for whom this action profile cannot be used, for example those requiring deep sedation or those with severe cardiovascular disease.
When administering dexmedetomidine to patients with existing bradycardia, caution is required. Data on the effect of the drug in patients with a heart rate of 60 beats / min are very limited, so such patients require particularly careful monitoring. Bradycardia, as a rule, does not require treatment, but if necessary, anticholinergic agents can be used or the dose of the drug can be reduced. Young and adult patients who are involved in sports and have high vagal tone and low resting heart rate may be particularly sensitive to the negative chronotropic effect of α2-adrenoceptor agonists; cases of transient sinus node arrest have been described, mainly with non-recommended methods of administration of dexmedetomidine, in particular rapid IV and bolus.
In patients with damage to the peripheral autonomic nervous system (e.g. as a result of spinal cord injury), the hemodynamic effects after starting treatment with dexmedetomidine may be more pronounced, therefore caution is required in such cases.
Transient hypertension with concomitant peripheral vasoconstriction has been observed with a loading dose of dexmedetomidine, and therefore loading doses during sedation in the ICU are not recommended. Treatment of elevated blood pressure is not usually necessary, but a reduction in the rate of drug administration may be appropriate.
Local vasoconstriction at higher concentrations of dexmedetomidine may be more significant in patients with ischemic heart disease or severe cerebrovascular disease, in such cases, continuous monitoring of the patient's condition is necessary. If the patient develops signs of myocardial or cerebral ischemia, the feasibility of reducing the dose or discontinuing the drug should be considered.
Patients with hepatic impairment
Caution is required when treating patients with severe hepatic impairment, as excessive administration of dexmedetomidine may lead to an increased risk of adverse reactions, excessive sedation or prolonged effects as a result of reduced clearance of dexmedetomidine.
Patients with neurological disorders
Experience with the use of Dexmedetomidine EVER Pharma in severe neurological disorders, such as head trauma and in the postoperative period after neurosurgical operations, is limited, so it should be used in such conditions with caution, especially if deep sedation is required. When choosing a therapy, it should be taken into account that dexmedetomidine can reduce cerebral blood flow and intracranial pressure.
other warnings
Abrupt withdrawal of α2-adrenergic agonists after prolonged use has been reported in some cases. This should be considered if agitation and increased blood pressure develop in the patient immediately after discontinuation of dexmedetomidine. In patients with tachycardia and hypertension requiring treatment, less than 5% of cases occurred within 48 hours of discontinuation of the drug. In such cases, supportive therapy is indicated. In procedural sedation in adults, withdrawal symptoms were not observed after discontinuation of short-term infusions of dexmedetomidine (6 hours).
The safety of dexmedetomidine in patients prone to malignant hyperthermia has not been established, therefore, the administration of Dexmedetomidine EVER Pharma in this condition is not recommended. If persistent fever of unclear etiology develops, the drug should be discontinued.
The use of dexmedetomidine for more than 24 hours is associated with the development of habituation and tachyphylaxis and a dose-dependent increase in the frequency of adverse reactions.
Administration of the drug by continuous infusion should not exceed 24 hours.
Excipients with known effect
1 ml of concentrate contains less than 1 mmol (approximately 3.5 mg) sodium.
incompatibility
The drug should not be mixed with other drugs, except those specified in the USAGE section.
Compatibility studies have shown the potential for adsorption of dexmedetomidine to some types of natural rubber. Although dexmedetomidine is administered at doses necessary to achieve the desired clinical effect, it is recommended to use infusion sets with synthetic rubber or coated natural rubber components.
Use during pregnancy or breastfeeding
There are no adequate data on the use of dexmedetomidine in pregnant women. Animal studies have shown reproductive toxicity of dexmedetomidine. Dexmedetomidine EVER Pharma is not recommended for use in pregnant women and patients of reproductive age not using effective contraception.
According to available data, dexmedetomidine or its metabolites penetrate into the breast milk of rats. Therefore, a risk to the breast-fed child cannot be excluded. It is necessary to either discontinue breast-feeding or discontinue the drug, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.
Animal studies have not shown any effect of dexmedetomidine on male and female fertility.
The ability to influence the reaction speed when driving a vehicle or other mechanisms.
Dexmedetomidine EVER Pharma has a strong influence on the ability to drive and use machines.
Interactions
Drug interaction studies have only been conducted in adults.
Concomitant use of dexmedetomidine with anesthetics, sedatives, hypnotics, and depressants may lead to potentiation of their effects, such as sedation, anesthesia, analgesia, and cardiorespiratory effects. Studies have confirmed enhanced effects when used with sevoflurane, isoflurane, propofol, alfentanil, and midazolam.
Studies using human liver microsomes have examined the ability of dexmedetomidine to inhibit CYP isoenzymes, particularly CYP 2B6. Based on in vitro studies, there is a potential for in vivo interactions between dexmedetomidine and substrates that are primarily metabolized by CYP 2B6.
In vitro induction of dexmedetomidine by CYP 1A2, CYP 2B6, CYP 2C8, CYP 2C9 and CYP 3A4 has been observed, therefore the possibility of such an interaction in vivo cannot be excluded. The clinical relevance of this effect is unknown.
In patients taking drugs that cause a decrease in blood pressure and bradycardia, such as β-adrenergic blockers, the possibility of enhancing these effects should be considered (although the additional enhancement of these effects in the interaction study with esmolol was moderate).
In one study in 10 healthy adult volunteers, administration of dexmedetomidine over 45 min at a plasma concentration of 1 ng/mL did not cause a clinically significant increase in the neuromuscular blockade associated with rocuronium administration.
Overdose
Symptoms. Several cases of overdose with dexmedetomidine have been reported during clinical trials and post-marketing use. The highest rate of administration in these cases reached 60 mcg/kg/h for 36 minutes and 30 mcg/kg/h for 15 minutes in a 20-month-old child and an adult, respectively. The most common adverse reactions in overdose were bradycardia, hypotension, excessive sedation, drowsiness and cardiac arrest.
Treatment. In case of overdose with clinical symptoms, the infusion rate of dexmedetomidine should be reduced or stopped. Cardiovascular effects are expected, which should be treated according to clinical indications (see Features of use). At high doses, hypertension may be more pronounced than hypotension. During clinical studies, sinus arrest occurred spontaneously or was treated with atropine and glycopyrrolate. In rare cases of severe overdose, which caused cardiac arrest, resuscitation measures were required.
Storage conditions
In the original packaging, out of the reach of children. This medicinal product does not require any special temperature storage conditions.
