Dexdor - instructions for use, dose, side effects, contraindications

Active substanceDexmedetomidineDexmedetomidine

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Dexdor®

concentrate d / infusion

Orion Corporation Orion Pharma Finland

Dosage form: & nbspconcentrate for solution for infusion

Composition:

Active substance: dexmedetomidine hydrochloride 118 μg, equivalent to dexmedetomidine 100 μg;

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

Description:

A clear, colorless solution.

Pharmacotherapeutic group:Sedative remedy

ATX: & nbsp

N.05.C.M Other sleeping pills and sedatives

N.05.C.M.18 Dexmedetomidine

Pharmacodynamics:

Dexmedetomidine is a selective α agonist₂- adrenoreceptors with a wide range of pharmacological properties.

Has a sympatholytic effect due to a decrease in the release of norepinephrine from the endings of the sympathetic nerves.

The sedative effect is due to a decrease in excitation in the blue spot of the brainstem (the nucleus with a predominance of noradrenergic neurons).

Dexmedetomidine has analgesic and anesthetic / analgesic-saving effects.

Cardiovascular effects are dose-dependent: at a low infusion rate, the central effect predominates, which leads to a decrease in the heart rate and blood pressure.When high doses are used, peripheral vasoconstriction predominates, leading to an increase in overall vascular resistance, arterial pressure, and a further increase in bradycardia.

Dexmedetomidine has practically no respiratory inhibition when taken as a monotherapy by healthy patients.

In placebo-controlled trials in patients in the postoperative intensive care unit previously incubated and sedated with midazolam or propofol, Dexdor® significantly reduced the need for additional sedation (midazolam or propofol) and opioids within 24 hours. Most patients who received dexmedetomidine, did not need additional sedation.

Patients could be successfully extubated without stopping the infusion of dexdor®. Studies conducted outside the intensive care unit confirmed that Dexdor® can be safely administered to patients without intubation of the trachea under conditions for adequate monitoring.

Dexmedetomidine was similar to midazolam (hazard ratio 1.07, 95% CI 0.971, 1.176) and propofol (risk ratio 1.00, 95% CI 0.922,1.075) by residence time in the target range of sedation in predominantly intensive intensive care patients requiring long-term mild to moderate sedation (RASS from 0 to -3) within 14 days; shortened the duration of artificial ventilation of the lungs compared with midazolam and time to extubation of the trachea compared to propofol and midazolam. Patients who received dexmedetomidine, wake up more easily, better cooperate with staff and better reported the intensity of pain compared with patients who received midazolam or propofol.

In patients who received dexmedetomidine, arterial hypotension and bradycardia most often developed, but less often tachycardia compared with patients receiving midazolam and tachycardia usually developed, but the rate of development of arterial hypotension was similar in comparison with patients receiving propofol.

The frequency of delirium development, estimated using a scale CAM-ICU (a method of assessing confusion in the intensive care unit) was lower in the study compared to midazolam, and undesirable events associated with delirium developed less frequently in the dexmedetomidine group than propofol.Those patients who stopped sedation due to insufficient sedation were transferred to propofol or midazolam.

The risk of an insufficient level of sedation was higher in patients who were difficult to sedate by standard methods immediately compared to patients who switched to another sedative method.

Evidence of effectiveness in children was revealed in a dose-controlled study in ICU on a large postoperative population aged 1 month to ≤ 17 years. Approximately 50% of patients who received dexmedetomidine, did not require additional sedation with midazolam during the treatment period of 20.3 hours, but not more than 24 hours. Data on treatment with the drug over 24 hours are not available.

Data for newborns (28-44 weeks of gestation) are very limited and cover only the use of low doses (≤ 0.2 μg / kg / h). Newborns can be particularly sensitive to the bradycardic effect of the drug Dexdor® in the presence of hypothermia and in conditions where cardiac output depends on the heart rate.

In double-blind controlled trials of the reference drug in ICU, the incidence of oppression of the adrenal cortex in patients receiving dexmedetomidine (n= 778) was 0.5% compared with 0% in patients receiving either midazolam (n= 338), or propofol (n= 275). This undesirable phenomenon was noted as mild in 1 case and of moderate severity - in 3 cases.

Pharmacokinetics:

The pharmacokinetics of dexmedetomidine was studied in healthy volunteers with short-term intravenous administration and in intensive care patients with prolonged infusion administration of the drug.

Distribution

Dexmedetomidine is subject to a two-chamber distribution model.

In healthy volunteers, it undergoes a rapid phase of distribution with a half-distribution period (T_1/2α) equal to 6 minutes. The mean value of the terminal half-life (T_1/2) is approximately 1.9-2.5 hours (min - 1,35, max - 3.68 hours) and the average value of the equilibrium volume of distribution (Vss) is approximately 1.16-2.15 l / kg (90-151 L). The average value of the plasma clearance (Cl) is 0.46-0.73 l / h / kg (35.7-51.1 l / h). The average body weight, characteristic for these Vss and Cl, was equal to 69 kg.

The plasma pharmacokinetics of dexdemetomidine in intensive care patients after administration of the drug> 24 h is comparable. Calculated pharmacokinetic parameters: T_1/2is about 1.5 hours, Vss is about 93 liters and Cl is about 43 liters / kg.In the dosage range of 0.2 to 1.4 μg / kg / h, the pharmacokinetics of dexmedetomidine is linear, it does not cumulate in treatment up to 14 days. The connection with plasma proteins of dexmedetomidine is 94%. The degree of binding to plasma proteins is constant in the concentration range from 0.85 to 85 ng / ml. Dexmedetomidine binds both to human serum albumin and to the α1-acid glycoprotein, serum albumin is the main protein with which dexmedetomidine binds in the blood plasma.

Metabolism and excretion

Dexmedetomidine is completely metabolized in the liver. The initial metabolism proceeds through three metabolic pathways: direct N- glucuronation, direct N-methylation and cytochrome P450-mediated oxidation.

The predominant metabolites of dexmedetomidine in the bloodstream are two isomeric N-glucuronide.

Metabolite H-1 (N-methyl-3-hydroxymethyl-undecomethomidine O-glucuronide) is also the main circulating product of the biotransformation of dexmedetomidine.

Cytochrome P450 catalyzes the formation of two secondary circulating metabolites: 3-hydroxymethyldecumededomidine is formed by hydroxylation of the 3-methyl group of dexmedetomidine and H-3 is formed by oxidation of the imidazole ring.According to the available information, 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.

After intravenous administration of radiolabeled dexmedetomidine after 9 days, approximately 95% of the radioactivity was detected in urine and 4% in feces. The main metabolites in urine are two isomeric N-glucuronide, which is 34% of the administered dose, and N-methyl-3-hydroxymethyldimededomidine O-glucuronide, which is 14.51% of the dose. Secondary metabolites: dexmedetomidine carboxylic acid, 3-hydroxymethyldite-medethomidine and its O-glucuronide constitute 1.11-7.66% of the dose. Less than 1% of unchanged dexmedetomidine is found in the urine. About 28% of metabolites in urine are uninstalled secondary.

Special Groups

There are no significant differences in pharmacokinetics depending on age and sex.

In comparison with healthy volunteers in people with hepatic insufficiency, the degree of binding of dexmedetomidine to plasma proteins decreases. The average fraction of the unbound fraction of dexmedetomidine ranged from 8.5% in healthy volunteers to 17.9% in patients with severe hepatic insufficiency.In patients with varying degrees of hepatic insufficiency (classes A, B and C on the Child-Pugh scale), hepatic clearance of dexmedetomidine decreased and T_1/2from the plasma. Average values of plasma clearance unrelated dexmedetomidine in persons with mild, moderate and severe hepatic insufficiency were respectively 59, 51 and 32% of those observed in healthy volunteers. Average T_1/2in persons with mild, moderate and severe hepatic insufficiency extended to 3.9, 5.4 and 7.4 h respectively.

Despite the fact that the choice of the dose of dexmedetomidine is carried out according to the degree of sedation, in patients with hepatic insufficiency, depending on the degree of disorder or clinical response, the possibility of reducing the initial or maintenance dose of the drug should be considered.

Compared with healthy volunteers in patients with severe renal insufficiency (creatinine clearance <30 ml / min), the pharmacokinetics of dexmedetomidine does not change.

Data on children, from newborns (born on the 28-44 week of pregnancy) to children age 17 are limited. The half-life period of dexmedetomidine in children (1 month to 17 years) corresponds to that observed in adults, but a longer period in newborns (up to 1 month).In the age groups from 1 month to 6 years, the plasma clearance period adjusted for body weight was longer, but in older children a shorter period was observed. In neonates (up to 1 month), the plasma clearance period adjusted for body weight was shorter (0.9 l / h / kg) than in the older groups due to immaturity. The available data are presented in the following table:

		Average value (SI 95%)
Age	N	Cl (l / h / kg)	T_1/2(h)
Younger than 1 month.	28	0,93 (0,76;U4)	4,47 (3,81;5,25)
1 - <6 months.	14	1,21 (0,99;1,48)	2,05 (1,59;2,65)
6 - <12 months.	15	1,11 (0,94;1,31)	2,01 (1,81;2,22)
12 - <24 months.	13	1,06 (0,87;1,29)	1,97 (1,62;2,39)
2 - <6 years	26	1,11 (1,00;1,23)	1,75 (1,57;1,96)
6 - <17 years	28	0,80 (0,69;0,92)	2,03 (1,78;2,31)

Indications:

Sedation in adult patients in the department of anesthesiology, resuscitation and intensive care, the necessary depth of sedation which does not exceed the awakening in response to voice stimulation (corresponds to the range from 0 to -3 points on the Richmond sedation-sedation scale (RASS)).

Contraindications:

Hypersensitivity to the components of the drug.

Atrioventricular block II-III degree (in the absence of an artificial pacemaker).

Uncontrolled arterial hypotension.

Acute cerebrovascular pathology.

Children under 18 years.

Pregnancy and lactation:

Pregnancy

Adequate data on the use of dexmedetomidine in pregnant women | women are absent.

In animal studies, reproductive toxicity has been identified. A potential risk to a person is not known. Dexdor® can be used during pregnancy, if it is absolutely necessary.

Breastfeeding period

According to available data dexmedetomidine or its metabolites penetrate the breast milk of rats. There is no risk of breastfeeding for infants. Taking into account the benefits of breastfeeding for a child and the benefit of treatment for the mother, it is necessary either to give up breastfeeding or stop the drug.

Fertility

In fertility studies in rats dexmedetomidine did not affect male and female fertility.

Dosing and Administration:

Only for hospital.

Dexdor® should be used by specialists with experience in treating patients in intensive care settings.

Patients who are mechanically ventilated and sedated can be transferred to dexmedetomidine with an initial infusion rate of 0.7 μg / kg / h followed by dose adjustment within the dose range of 0.2 to 1.4 μg / kg / hr, to achieve the desired level of sedation,depending on the patient's response. For impaired patients, a lower initial infusion rate should be considered. Dexmedetomidine is a powerful tool, so the speed of its introduction is based on hours. After correcting the dose for one hour, the target sedation depth may not be achieved.

Do not exceed the maximum dosage of the drug at 1.4 mcg / kg / h. Patients who do not achieve the proper level of sedation at the maximum dosage of dexdor® should be transferred to an alternative sedative.

The introduction of a saturating dose of the drug is not recommended, as this increases the frequency of unwanted drug reactions. If necessary, can be applied propofol or midazolam, until the clinical effect of the drug Dexdor® is established.

The experience of using the drug Dexdor® for more than 14 days is absent. When using the drug for more than 14 days, it is necessary to regularly assess the patient's condition.

Special patient groups

Elderly patients

Correction of the dose is usually not required.

Renal insufficiency

Correction of the dose is usually not required.

Liver failure

Dexmedetomidine it is metabolized in the liver, so in patients with hepatic insufficiency, it should be used with caution. Such patients showed a reduction in maintenance dose (see sections "Pharmacokinetics" and "Special instructions").

Method of administration

Dexdor^® should be administered only after dilution in the form of intravenous infusions with the help of special equipment (infusomat).

Each ampoule is only for one patient.

Preparation of the solution

To achieve the recommended concentration (4 μg / ml or 8 μg / ml), Dexdor® can be diluted in a 5% solution of dextrose, Ringer's solution, mannitol or 0.9% sodium chloride solution. Below is a table of the volume of the concentrate and the required volume of the infusion medium:

If the required concentration is 4 μg / ml

The volume of the drug Dexdor®, a concentrate for the preparation of a solution for infusions, 100 micrograms / ml	Scope infusion environment	Total infusion volume
2 ml	48 ml	50 ml
4 ml	96 ml	100 ml
10 ml	240 ml	250 ml
20 ml	480 ml	500 ml

If the required concentration is 8 μg / ml

The volume of the drug Dexdor®, a concentrate for the preparation of a solution for infusions, 100 micrograms / ml	The volume of the infusion medium	Total infusion volume
4 ml	46 ml	50 ml
8 ml	92 ml	100 ml
20 ml	230 ml	250 ml
40 ml	460 ml	500 ml

The prepared solution should be shaken gently for complete mixing its components.

Before administration, the solution must be visually checked for mechanical inclusions or discoloration.

Dexdor^® is pharmaceutically compatible with the following drugs: Ringer's lactate solution, 5% dextrose solution, 0.9% sodium chloride solution, 20% mannitol solution, sodium thiopental, ethomidate, vecuronium bromide, pancuronium bromide, suxamethonium, atracurium bezylate, miwakuria chloride, rocuronium bromide, glycopyrronium bromide, phenylephrine, atropine, dopamine, norepinephrine, dobutamine, midazolam, morphine, fentanyl, plasma-substituting agents.

The unused preparation should be disposed of in accordance with local regulations.

Side effects:

Summary of security profile

The most frequent reported undesirable drug reactions in response to the administration of dexmedetomidine are a decrease or increase in blood pressure and a bradycardia, occurring respectively in approximately 25%, 15% and 13% of patients. Decrease in blood pressure and bradycardia were also the most frequent dexmedetomidine-mediated serious adverse reactions,respectively, in 1,7 and 0,9% of randomized patients of intensive care unit.

Table summary of undesirable reactions

The undesired reactions listed below were obtained from clinical trials in 3,137 randomized intensive care unit patients (1,879 injected dexmedetomidine, 864 - active control and 394 - placebo).

Undesired reactions are grouped by frequency using the following gradation: very often (≥1 / 10), often (from 1≥100 to <1/10), infrequently (from ≥1 / 1,000 to <1/100), rarely (from ≥1 / 10,000 to <1/1 000), very rarely (<1/10 000).

See the table below:

	Highly often	Often	Infrequently	Rarely	Highly rarely	Frequency unknown
Metabolic and nutritional disorders		hyperglycemia, hypoglycemia	metabolic acidosis, hypoalbuminemia
Mental violations		agitation	hallucinations
Narushthe from the sidess hearts	bradycardia *	ischemia or myocardial infarction, tachycardia	atrioventriclarvaenaya blockade of I degree, reduction of cardiac output
Vascular disorders	decrease * or increased blood pressure *
Infringements from respiratory system, chest or mediastinum		oppression breathing	dyspnea, apnea
Infringements from gastrointestinal tract		nausea, vomiting, dryness of the oral mucosa	swelling belly
General violations and violations at the site of introduction		syndrome "cancellation", hyperthermia	inefficiency medicine, thirst

* See below for a description of individual unwanted reactions.

Description of individual adverse reactions

Clinically significant lowering of blood pressure and bradycardia should be stopped, as indicated in the section "Special instructions".

In relatively healthy individuals who were not in the intensive care unit, the administration of dexmedetomidine sometimes led to the arrest of the sinus node. Symptoms stopped when the legs were raised (above the level of the head) and the introduction of m-holinoblokatorov, such as atropine and glycopyrronium bromide.

In some cases, in patients with a previous bradycardia, it progressed to episodes of asystole. The increase in arterial pressure was associated with the introduction of a loading dose, so it can be avoided by avoiding the administration of a loading dose or by reducing the infusion rate or loading dose.

Children

An evaluation of the treatment of children younger than 1 month, mainly after the operation, in the ICU for up to 24 hours; A safety profile comparable to that of adults was demonstrated.

Overdose:

In clinical trials and post-registration use, several cases of dexmedetomidine overdose have been reported. According to the available data, the rate of administration in such cases reached 60 mcg / kg / h for 36 min and 30 mcg / kg / h for 15 min in a 20-month-old baby and adult, respectively. The most frequent undesirable drug reactions due to an overdose in such cases were bradycardia, lowering blood pressure, excessive sedation, drowsiness and cardiac arrest.

In the case of an overdose showing clinical symptoms, the administration of dexmedetomidine should be reduced or discontinued.

The expected effects are mainly cardiovascular and should be stopped according to clinical indications (see section "Special instructions"). At high concentrations, an increase in blood pressure may predominate over its decrease. In clinical studies, the arrest of the sinus node was resolved independently or in response to the administration of atropine and glycopyrronium bromide. In some cases of severe overdose accompanied by cardiac arrest, resuscitation was required.

Interaction:

The study of drug interactions was conducted only in adults.

The simultaneous use of dexmedetomidine with anesthetics, sedatives, hypnotics and narcotic analgesics leads to an increase in their effects, such as sedation, anesthesia, analgesia and cardiorespiratory effects.

Targeted studies have confirmed enhanced effects when used with isoflurane, propofol, alfentanil and midazolam.

Pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil and midazolam have not been revealed.

However, due to possible pharmacodynamic interactions with their simultaneous use with dexmedetomidine, a dose reduction of dexmedetomidine or concomitant means for anesthesia, sedatives, hypnotics or narcotic analgesics may be required.

Inhibition of CYP enzymes, including CYP2B6, with the help of dexmedetomidine was studied by incubating microsomal cells of the human liver. According to research in vitro there is a potential for interaction in vivo between dexmedetomidine and substrates, predominantly with CYP2B6.

Based on research results in vitro dexmedetomidine can induce isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A4, such an opportunity in research in vivo is not excluded. Clinical significance is unknown.

In patients taking medications that cause a reduction in blood pressure and a bradycardia, for example, βadrenoblockers, the possibility of enhancing these effects should be considered (however, the additional enhancement of these effects in the study with esmolol was moderate).

Special instructions:

Dexdor® is intended for use in anesthesia, intensive care and intensive care, and its use in other settings is not recommended. During the infusion of the drug, continuous monitoring of cardiac activity should be carried out. In non-intubated patients, respiratory monitoring should be monitored, due to the risk of respiratory depression and, in some cases, the development of apnea (see "Side effect").

Dexdor® should not be used as a means of inducing intubation or to provide sedation with the use of muscle relaxants.

Dexdor® lowers heart rate and blood pressure (central sympatholytic action), but at higher concentrations causes peripheral vasoconstriction, leading to increased blood pressure (see section "Pharmacodynamics"). Usually Dexdor^® Do not cause a deep sedation, so patients can be easily awakened. As a result, Dexdor® is not suitable for patients who need deep sedation, as well as patients with severe hemodynamic instability. Due to the fact that the saturating dose of the drug should not be administered or administered bolusily, alternative methods of immediate agitation control should be used or during the procedures, especially during the first hours of application of the drug.

Care should be taken when administering dexmedetomidine to patients with concomitant bradycardia. Data on the effect of the drug in patients with a heart rate <60 are limited, so these patients need special monitoring and follow-up.

Bradycardia, as a rule, does not require treatment, but is usually well-managed by the introduction of m-holinoblokatorov and a decrease in the dose of the drug.Patients engaging in sports and having a low heart rate may be particularly sensitive to the negative chronotropic effect of the α agonists₂-adrenoceptors; cases of stopping the sinus node have been described.

In patients with concomitant arterial hypotension (especially refractory to vasoconstrictors), including chronic, hypovolemia or reduced functional reserve, such as patients with severe ventricular dysfunction and elderly, hypotensive effect of the drug Dexdor® may be more pronounced, this requires special care for such patients (see the section "Contraindications"). Reduction of blood pressure, as a rule, does not require special measures, but if necessary, it is necessary to be ready to reduce the dose, introduce funds to replenish the volume of circulating blood and (or) vasoconstrictors.

In patients with a lesion of the vegetative system (for example, due to spinal cord injury), hemodynamic effects after the administration of Dexdor® can be more pronounced and require special control.

Transient arterial hypertension was observed, primarily, during a loading dose with a simultaneous peripheral effect, so the administration of a loading dose is not recommended.

Treatment of high blood pressure, as a rule, is not required, but one should consider the possibility of reducing the rate of administration of the drug. Focal vasoconstriction with increased concentration may be more important in patients with coronary heart disease or severe cerebrovascular disease, and continuous monitoring should be established for these patients.

Patients with signs of myocardial ischemia or brain should consider the possibility of reducing the dose of the drug or canceling its administration.

Care should be taken when concomitantly using dexmedetomidine with drugs that have a sedative effect or affect the cardiovascular system, due to a possible additive effect.

Some patients receiving Dexdor® were easily awakened and quickly contacted after physical or verbal stimulation. In the absence of other clinical symptoms, this symptom should not be considered as an ineffectiveness of the drug in isolation.

Care should be taken in patients with severe hepatic insufficiency,since excessive drug administration as a result of reduced clearance of dexmedetomidine can lead to an increased risk of unwanted reactions and excessive sedation.

Dexdor®, in all probability, does not suppress convulsive activity, and therefore should not be used in monotherapy with epileptic status.

Experience of using the drug Dexdor^® with severe neurological conditions such as head trauma and postoperative period after neurosurgical operations is limited, so it should be used with such precautions, especially when deep sedation is necessary.

When choosing a therapy, it should be noted that Dexdor® reduces cerebral blood flow and intracranial pressure.

With a sharp abolition of α₂-adrenoceptors after long-term use in rare cases, there was a syndrome of "cancellation." With the development of agitation and increased blood pressure immediately after the abolition of dexmedetomidine, the possibility of the onset of this condition should be considered.

The safety of the use of dexmedetomidine in persons prone to malignant hyperthermia has not been established, therefore, the use of the drug in this condition is not recommended.With the development of persistent unexplained fever, the use of Dexdor® should be discontinued.

Effect on the ability to drive transp. cf. and fur:

The drug is prescribed only in a hospital.

Form release / dosage:

Concentrate for solution for infusion, 100 μg / ml.

Packaging:

Ampoules of colorless glass type I 2 ml each.

Vials from colorless glass type I to 4 ml or 10 ml.

For 5 or 25 ampoules in a cardboard bundle.

For 1 bottle 4 ml or 10 ml in a cardboard bundle.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep in original packaging.

After dilution, the solution is stored at a temperature of 2 to 8 ° C for 24 hours.

Keep out of the reach of children.

Shelf life:

3 years.

Terms of leave from pharmacies:On prescription

Registration number:LP-001597

Date of registration:22.03.2012

Expiration Date:22.03.2017

The owner of the registration certificate:Orion Corporation Orion Pharma Orion Corporation Orion Pharma Finland

Manufacturer: & nbsp

ORION CORPORATION ORION PHARMA Finland

Representation: & nbspOrion Pharma LLCOrion Pharma LLC

Information update date: & nbsp22.04.2017

Illustrated instructions

Instructions

Dexdor® (Dexdor®)