Universal reference book for medicines
Product name: DEXDOR ® (DEXDOR)

Active substance: dexmedetomidine

Type: Intravenous anesthetic drug

Manufacturer: ORION CORPORATION ORION PHARMA (Finland)
Composition, form of production and packaging
Concentrate for the preparation of solution for infusions is
transparent, colorless.

1 ml

dexmedetomidine hydrochloride 118 μg,

which corresponds to the content of dexmedetomidine 100 μg

Excipients: sodium chloride - 8.83 mg, water d / and - up to 1 ml.

2 ml - ampoules of colorless glass (5) - packs of cardboard.

2 ml - ampoules of colorless glass (25) - packs of cardboard.

4 ml - vials of colorless glass (1) - packs cardboard.

10 ml - vials of colorless glass (1) - packs cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2012.

PHARMACHOLOGIC EFFECT

Dexmedetomidine is a highly selective agonist?
2- adrenoreceptors with a wide range of pharmacological properties. Has a strong sympatholytic effect due to a decrease in the release of norepinephrine from the endings of the sympathetic nerves. The sedative effect is due to reduced excitation of the blue spot, the main noradrenergic nucleus, which is located in the brainstem. By acting on this site, dexmedetomidine has a sedative effect (similar to a natural sleep without rapid eye movement), while simultaneously allowing the patient to be in an awakened and active state. Dexmedetomidine has an anesthetic and moderate analgesic effect;analgesic effect was demonstrated in patients with chronic pain in the lower back. The effect on the cardiovascular system is dose dependent; at lower infusion rates, the central effect dominates, which leads to a decrease in heart rate and blood pressure. At higher doses, peripheral vasoconstrictive effects predominate, which leads to an increase in systemic vascular resistance and BP, while bradycardia becomes more pronounced. Dexmedetomidine has practically no inhibitory effect on the respiratory system.
PHARMACOKINETICS

The pharmacokinetics of dexmedetomidine was evaluated after rapid IV application in healthy volunteers and prolonged IV infusion in patients in the intensive care unit.
Dexmedetomidine shows a 2-compartmental distribution model. In healthy volunteers, dexmedetomidine exhibits a rapid distribution phase with a half-life period of about 6 minutes. The terminal T 1/2 is about 2.1 (± 0.43) h, and the volume of the distribution (V ss ) is about 91 (± 25.5) l. The estimated value of the plasma clearance (Cl) is about 39 (± 9.9) l / h. The average body weight, according to which the values ​​of V ss and Cl were estimated, was 69 kg. Plasma pharmacokinetics of dexmedetomidine is similar in intensive care patients after infusion> 24 h. The pharmacokinetic parameters evaluated are as follows: T 1/2 - about 1.5 h, V ss - about 93 l and Cl - about 43 l / h. The pharmacokinetics of dexmedetomidine is linear within doses of 0.2-1.4 μg / kg / h, it does not accumulate during therapy lasting up to 14 days.
Dexmedetomidine is 94% bound to blood plasma proteins.
Binding to blood plasma proteins within the concentration of 0.85-85 ng / ml. Dexmedetomidine binds to human serum albumin and? 1- acid glycoprotein, with serum albumin being the main protein of binding of dexmedetomidine in the blood plasma.
Dexmedetomidine is mainly metabolized by the liver.
There are three types of initial metabolic reactions: direct N-glucuronidation, direct N-methylation and oxidation catalyzed by cytochrome P450. The metabolites of dexmedetomidine circulating in the largest amount are two isomeric N-glucuronides, one of which is formed by oxidation of the imidazole ring, and the other is the product of successive N-methylation, hydroxylation of the methyl group, and O-glucuronidation. The available data indicate that the formation of oxidized metabolites is mediated by CYP-forms (CYP 2A6, CYP 1A2, CYP 2E1, CYP 2D6 and CYP 2C19). These metabolites exhibit little pharmacological activity.
After intravenous administration of radio-labeled dexmedetomidine, after 9 days an average of 95% of the radiolabelled substance was detected in urine and 4% in feces.
The main metabolites in urine are two isomeric N-glucuronide, which together constitute about 34% of the dose, and N-methylated O-glucuronide, which is equal to 14.51% of the dose. The secondary metabolites of carboxylic acid, 3-hydroxy- and O-glucuronide metabolites are separately 1.11-7.66% of the dose. Less than 1% of unchanged substance is detected in urine. About 28% of metabolites detected in urine are unidentified polar metabolites.
There were no significant differences in the pharmacokinetics of dexmedetomidine depending on sex or age.

The binding of dexmedetomidine to plasma proteins has been reduced in individuals with impaired liver function compared to healthy volunteers.
The average percentage of unrelated dexmedetomidine in blood plasma was from 8.5% in healthy volunteers to 17.9% in patients with severe hepatic impairment. Patients with varying degrees of impaired liver function (class A, B or C on the Child-Pugh scale) had reduced hepatic clearance of dexmedetomidine and elongated T 1/2 from plasma. The average clearance values ​​for individuals with mild, moderate and severe impairment of liver function were 74; 64 and 53% of those in healthy volunteers, respectively. The mean T 1/2 for patients with mild, moderate and severe impairment of liver function increased to 3.9; 5.4 and 7.4 hours respectively. Before the use of dexmedetomidine, it is necessary to consider the desirability of reducing the initial / maintenance dose in patients with impaired liver function, depending on the degree of impairment and the clinical response.
The pharmacokinetics of dexmedetomidine in patients with severe renal impairment (creatinine clearance <30 mL / min) is unchanged compared to healthy volunteers.

INDICATIONS

- sedation of mild to moderate degree in intensive care units during or after intubation.

DOSING MODE

Only for hospital use.

Dose for adult patients.

Patients who have already undergone intubation and who are in sedation can be transferred to Dexdor with an initial infusion rate of 0.7 μg / kg / h, which can be gradually adjusted within 0.2-1.4 μg / kg / h to achieve the desired level sedation.
For weakened patients, consideration should be given to using the lowest initial infusion rate. It should be noted that dexmedetomidine is a potent drug, therefore, the infusion rate is indicated for one hour.
Usually a shock dose of saturation is not required.
Patients who need a faster onset of sedation can first be given a loading infusion of 0.5-1.0 μg / kg body weight for 20 minutes, i.e. an initial infusion of 1.5-3 μg / kg / h for 20 min.
The rate of initial infusion after loading infusion is 0.4 μg / kg / h, which can then be corrected.

Patients of advanced age.

Patients of this age category do not usually need a dose adjustment.


Impaired renal function.

Patients with impaired renal function usually do not need dose adjustment.

Violation of the function of the liver.

Dexdor is metabolized in the liver, so it should be used with caution in patients with impaired liver function.
Consider the feasibility of using a low maintenance dose.
The duration of the course of treatment depends on the need for the patient to stay in a state of sedation.
There is no experience of Dexdor use for more than 14 days.
Mode of application


Dexdor is administered only by a medical professional who has experience in the treatment of patients requiring intensive care.
The drug is used only as a diluted intravenous infusion, using an infusion device with a regulation of the rate of administration. Ampoules and vials are intended only for individual use in one patient.
Preparation of r-ra


Before use Dexdor can be diluted in 5% of r-dextrose, r-re Ringer, mannitol or 0.9% of sodium chloride solution to achieve the desired concentration of 4 μg / ml.
The table below shows the volumes required for the preparation of the infusion.
Table

Volume of Dexdor, concentrate for preparation of r-ra for infusions, ml Volume of solvent, ml Total infusion volume, ml

2 48 50

4 96 100

10 240 250

20 480 500


After cooking, gently shake to mix well r.


Before use, the prepared rp should be visually checked for foreign particles and discoloration.

Dexdor is compatible with the following liquids and preparations: lactated Ringer's solution, 5% dextrose solution, 0.9% sodium chloride solution, 20% mannitol, sodium thiopental, etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atrakuria besilate, mivakuria chloride, rocuronium bromide, glycopyrrolate bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, norepinephrine, dobutamine, midazolam, morphine sulfate, fentanyl citrate and plasma substitutes.

SIDE EFFECT

With the use of Dexdor most often reported on arterial hypotension, AH and bradycardia, which occurred in about 25;
15 and 13% of patients, respectively. Arterial hypotension and bradycardia were also the most common serious side effects associated with Dexdor that occurred in 1.7 and 0.9% of randomly assigned intensive care unit patients, respectively.
The incidence of adverse reactions is as follows: very often (? 1/10);
often (? 1/100, <1/10); infrequently (? 1/1000, <1/100); rarely (? 1/10 000, <1/1000); very rarely (<1/10 000); frequency is unknown (can not be determined from available data).
From the side of metabolism and nutrition.
Often: hyperglycemia, hypoglycemia; infrequently: metabolic acidosis, hypoalbuminemia.
Mental disorders.
Often: agitation; infrequently: hallucinations.
From the cardiovascular system.
Very often: bradycardia, arterial hypotension; often: ischemia or myocardial infarction, tachycardia; infrequently: AV-blockade of the 1st degree, reduction of the minute volume of the heart.
From the respiratory system.
Infrequent: shortness of breath.
From the digestive system.
Often: nausea, vomiting, dry mouth; infrequently: bloating.
General disorders and reactions at the site of administration.
Often: withdrawal syndrome, hyperthermia; infrequently: inefficiency of the drug, thirst.
Description of individual adverse reactions: in the main clinical studies of Dexdor, the incidence of ischemia and myocardial infarction was close to the lower limit of the category of frequent side effects (1/100) and did not differ significantly from that for propofol and midazolam.
The sympathetic effect of Dexdor reduces heart rate, blood pressure and myocardial oxygen demand. Also caused by the use of Dexdor central vasodilation and lengthening of the period of diastole can improve coronary blood flow and promote the characteristic of agonists? 2- adrenoreceptors of cardioprotection in myocardial ischemia, even in conditions of lowering blood pressure and a tendency to decrease coronary blood flow. Nevertheless, when administering the drug, care must be taken, especially in patients with myocardial ischemia, and with its development to reduce the dose or stop the administration of Dexdor.
The frequency of withdrawal syndrome with the use of Dexdor was lower in comparison with propofol.
For example, 4 cases (1.6%) of the withdrawal syndrome in the Dexdor group (251 patients) and 7 cases (2.8%, p = 0.544) in the propofol group (247 patients) were recorded in the Prodex clinical trial. Symptoms of withdrawal syndrome in the use of Dexdor usually were not severe and did not cause significant therapeutic problems.
Relatively healthy volunteers who were not in the intensive care unit, sometimes with dexdor, depression of sinus node activity or sinus pause, as well as bradycardia, was noted.
Symptoms were eliminated after raising the lower limbs and using anticholinergics such as atropine or glycopyrolate. In some cases, the bradycardia progressed to the onset of asystole in patients who previously had cases of bradycardia.
AG was associated with the application of a loading dose.
The severity of this reaction can be reduced by avoiding a loading dose or reducing the infusion rate, or by reducing the loading dose volume.
CONTRAINDICATIONS

- hypersensitivity to dexmedetomidine or to any of the excipients of the drug.

PREGNANCY AND LACTATION

Dexdor should not be used during pregnancy, except when the benefits of using the drug for the mother exceed the risk to the fetus / child.
Data on the use of dexmedetomidine in pregnant women are limited.
Reproductive toxicity - the potential risk to humans is unknown.
For the period of treatment, stop breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER

Patients with impaired renal function usually do not need dose adjustment.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Dexdor is metabolized in the liver, so it should be used with caution in patients with impaired liver function.
Consider the feasibility of using a low maintenance dose.
APPLICATION FOR CHILDREN

Safety and efficacy not established.

APPLICATION IN ELDERLY PATIENTS

Patients of this age category do not usually need a dose adjustment.

SPECIAL INSTRUCTIONS

Dexdor is intended only for use in intensive care units.
During the infusion of Dexdor, all patients should constantly monitor the function of the heart. Patients who have not undergone intubation should monitor their respiratory function.
As with all sedatives, caution should be exercised when combining Dexdor with other drugs that have a sedative effect or affect the cardiovascular system due to the possibility of developing additive effects.

Due to the pharmacodynamic effects of Dexdor, care should be taken when using the drug in patients with severe bradycardia, progressive blockade of the heart (AV blockade II-III degree, except when the pacemaker is used), arterial hypotension or in patients with severe ventricular dysfunction.
Dexdor reduces the activity of the sympathetic nervous system, and in patients with hypovolemia, chronic hypertension and in elderly people, more pronounced arterial hypotension / bradycardia can be expected. Patients with good physical fitness and low heart rate at rest can be particularly sensitive to the bradycardic effects of agonists? 2- adrenoreceptors; there are reports of a temporary stop of the activity of the sinus node. Arterial hypotension and bradycardia usually do not require treatment, but if necessary, arterial hypotension should be treated with vasoconstrictor and / or fluid administration, and bradycardia with anticholinergics.
Care must be taken to avoid significant arterial hypo- or hypertension in patients with ischemic heart disease who use Dexdor, since there is a theoretical possibility of reducing coronary blood flow due to?
2- mediated narrowing of peripheral vessels. Consider the advisability of reducing the dose or discontinuing the drug in patients whose ECGs confirm the signs of myocardial ischemia.
In patients with a violation of the activity of the autonomic nervous system (for example, because of spinal cord injury), more marked hemodynamic changes can be noted after the onset of Dexdor's administration, so caution should be used in this patient.

Temporary hypertension was detected mainly during the administration of the loading dose, which was associated with the peripheral vasoconstrictor effect of Dexdor.
Treatment of AH is usually not required, but it is recommended to reduce the loading dose or the rate of infusion.
Compared to propofol and midazolam, patients who receive dexdor sedation are usually more likely to wake up, interact better with the doctor and are able to communicate better, while remaining generally at rest and relaxed.
However, this clinical profile means that Dexdor as an independent agent can not be a drug of choice, if it is a question of the need for deep sedation or complete immobilization of the patient. If it is necessary to relax the muscles (including endotracheal intubation), patients should additionally receive an alternative sedative in therapeutic doses so that they do not regain consciousness during the procedure.
The introduction of bolus doses of Dexdor for a sharp increase in sedation level was not evaluated, therefore it is not recommended for use.
In case of insufficient sedation, especially during the first hours after the transition to Dexdor, bolus doses of an alternative sedative can be used.
Dexdor probably does not suppress convulsive activity, and therefore can not be used as the sole means of treating epileptic status.
The experience with Dexdor in severe neurological disorders, such as head trauma, is limited, so in such cases it should be used with caution, especially if deep sedation is necessary. Like other sedatives, Dexdor can reduce cerebral circulation.
Agonists?
2- adrenoreceptors are rarely associated with cancellation reactions with a sudden discontinuation of prolonged use. The possibility of this should be taken into account if the patient develops agitation and AH shortly after ceasing the use of Dexdor.
It is unknown whether the use of safe Deksdora in individuals susceptible to malignant hyperthermia, so its use in these patients is not recommended. In the case of prolonged unexplained fever drug treatment should be discontinued.
No experience with Deksdora more than 14 days.
Ability to influence the reaction rate when driving and operating other machines.
The drug is indicated for use in a hospital environment.
OVERDOSE

In clinical studies and post-marketing reports of several cases of dexmedetomidine overdose.
Maximum dexmedetomidine infusion rate, which was reported in these cases reached 60 ug / kg / h for 36 minutes, and 30 ug / kg / h - for 15 min in 20-month old child and adult respectively. The most frequent adverse reactions that have been reported in connection with overdose in these cases included bradycardia, hypotension, excessive sedation, somnolence and cardiac arrest.
In cases of overdose with clinical symptoms of infusion rate Deksdora should be reduced or discontinued. Advantageously expected cardiovascular effects, treatment was performed for clinical reasons. At high drug concentrations hypertension may be more pronounced than hypotension. In clinical studies cases stop sinus node activity were spontaneously or respond to treatment with atropine or glycopyrolate. In some cases of severe overdose, which led to cardiac arrest, require resuscitation. None of the overdoses did not lead to death.
DRUG INTERACTION

Simultaneous application Deksdora with anesthetics, sedatives, hypnotics and opioid drugs may result in potentiation of their effects. Specific studies have confirmed the potentiation of effects while the use of sevoflurane, isoflurane, propofol, alfentanil and midazolam.
Pharmacokinetic interaction between Deksdorom and isoflurane, propofol, alfentanil and midazolam have been identified. However, due to possible pharmacodynamic interactions with the application of such agents in combination with Deksdorom may be necessary to decrease the dose of concomitant Deksdora or anesthetic, a sedative, hypnotic or opioid drug.
Should consider the possibility of strengthening the hypotensive and bradycardic effects in patients receiving other drugs that cause such effects, although additional effects in an interaction study with esmolol were modest.
TERMS OF RELEASE FROM PHARMACY

Only for hospital use.
TERMS AND CONDITIONS OF STORAGE

At a temperature of 15-25 ° C.
After dilution. Demonstrated physical and chemical stability during use for 24 hours at a temperature of 25 ° C.
From a microbiological point of view, the product should be used immediately. If not apply it immediately, storage period and storage conditions during use are the responsibility of the user and generally does not exceed 24 hours at 2-8 ° C, except in cases where dilution occurs in a controlled and validated aseptic conditions.
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