Дексдор®

General characteristics. Structure:

Active ingredient: 118 mkg of a deksmedetomidin of a hydrochloride that is equivalent to 100 mkg of a deksmedetomidin in 1 ml of solution.

Excipients: sodium chloride, water for injections.

The sedative hypnagogue having anesthetizing and moderate the anesthetizing effect. Deksmedetomidin has unique ability of ensuring sedative action in "cooperation with the patient". The patients subjected to sedative influence deksmedetomidiny are quiet, but can be in case of need easily activated and well to interact with medical personnel.

Pharmacological properties:

Pharmacodynamics. Deksmedetomidin is the high-selection agonist α2-адренорецепторов with a wide range of pharmacological properties. Has strong sympatholytic effect thanks to decrease in release of Norepinephrinum from the terminations of sympathetic nerves. Sedation is caused by reduced excitement of a blue spot, main noradrenergichesky kernel which is in a brainstem. Influencing this site, дексмедетомидин renders sedation (similar to a natural dream without the bystry movement of eyes), at the same time at the same time allows the patient to be in the awakened and active state. Deksmedetomidin has the anesthetizing and moderate anesthetizing effect; the anesthetizing action was shown at patients with chronic lower back pain. Influence on cardiovascular system depends on a dose; at lower speeds of infusion the central action which leads to decrease in ChSS and the ABP dominates. At higher doses peripheral vasoconstrictive effects prevail that leads to increase in system vascular resistance and the ABP while bradycardia becomes more expressed. Deksmedetomidin has practically no the oppressing effect on respiratory system.

Pharmacokinetics. The pharmacokinetics of a deksmedetomidin was estimated after bystry at uses for healthy volunteers and long at infusions to patients in intensive care unit. Deksmedetomidin shows a 2-kompartmentny distribution model. At healthy volunteers дексмедетомидин shows a bystry phase of distribution with the semi-distribution period about 6 min. Terminal T1/2 makes about 2.1 (±0.43) h, and the volume of distribution (Vss) — about 91 (±25.5) l. The estimated size of plasma clearance (Cl) makes about 39 (±9.9) l/h. The average body weight on which indicators of Vss and Cl were estimated was equal to 69 kg. The plasma pharmacokinetics of a deksmedetomidin is similar at patients of intensive care units after infusion> 24 h. The estimated pharmacokinetic parameters following: T1/2 is about 1.5 h, Vss — about 93 l and Cl — about 43 l/h. The pharmacokinetics of a deksmedetomidin is linear within doses of 0.2-1.4 mkg/kg/h, it does not accumulate during therapy lasting up to 14 days.

Deksmedetomidin for 94% contacts proteins of a blood plasma. Linkng with proteins of a blood plasma within concentration of 0.85-85 ng/ml. Deksmedetomidin contacts a human seralbumin and α1-кислым a glycoprotein, and a seralbumin is the main protein of binding of a deksmedetomidin in a blood plasma.

Deksmedetomidin is generally metabolized by a liver. There are three types of initial metabolic reactions: the direct N-glyukuronidation, direct N-methylation and oxidation catalyzed by P450 cytochrome. The metabolites of a deksmedetomidin circulating in the greatest number are two isomeric N-glucuronides, one of which is formed by oxidation of an imidazolny ring, and another is a product consecutive N-methylations, hydroxylations of methyl group and O-glyukuronidatsii. The available data demonstrate that formation of the oxidized metabolites is mediated by CYP forms (CYP 2A6, CYP 1A2, CYP 2E1, CYP 2D6 and CYP 2C19). These metabolites show insignificant pharmacological activity.

Later in/in uses of the radio marked deksmedetomidin in 9 days on average 95% of the radio marked substance revealed in urine and 4% — in Calais. The main metabolites in urine are two isomeric N-glucuronides which together make about 34% of a dose, and N-metilirovanny O-glucuronide which is equal to 14.51% of a dose. Minor metabolites of carboxylic acid, 3-gidroksi-and O-glyukuronidnye metabolites separately make 1.11–7.66% of a dose. Less than 1% of not changed substance define in urine. About 28% of the metabolites revealed in urine are not identified polar metabolites.

Essential distinctions of pharmacokinetics of a deksmedetomidin depending on a floor or age are noted.

Linkng of a deksmedetomidin with proteins of a blood plasma is reduced at persons with an abnormal liver function in comparison with healthy volunteers. The average percent of an untied deksmedetomidin in a blood plasma made from 8.5% at healthy volunteers to 17.9% at patients with a heavy abnormal liver function. Patients with different degree of an abnormal liver function (the class A, B or C on a scale of Chayld-Pyyu) had reduced hepatic clearance of a deksmedetomidin and the extended T1/2 from a blood plasma. Average sizes of clearance for persons with an easy, moderate and heavy abnormal liver function made 74; 64 and 53% of those at healthy volunteers respectively. Average T1/2 for patients with an easy, moderate and heavy abnormal liver function increased to 3.9; 5.4 and 7.4 h respectively. Before use of a deksmedetomidin it is necessary to consider expediency of decrease in an initial/maintenance dose at patients with an abnormal liver function depending on extent of disturbance and the clinical answer.

Pharmacokinetics of a deksmedetomidin at patients with a heavy renal failure (the clearance of creatinine <30 ml/min.) is not changed in comparison with healthy volunteers.

Indications to use:

Sedation of easy and moderate degree in intensive care units in time or after an intubation.

Route of administration and doses:

Only for hospital use! A dose for adult patients. Patients to whom the intubation is carried already out and who are in a condition of sedation can be transferred on Deksdor with an initial speed to infusions 0.7 mkg/kg/h which can be korrigirovat gradually in limits - 0.2–1.4 mkg/kg/h for achievement of desirable level of sedation. For the weakened patients it is necessary to consider expediency of use of the lowest initial speed of infusion. It should be noted what дексмедетомидин is strong drug, therefore, the speed of infusion is specified for one hour.

Usually shock dose of saturation is not required. Patients who need more quick start of sedation can enter at first load infusion of 0.5-1.0 mkg/kg of body weight within 20 min., that is initial infusion of 1.5-3 mkg/kg/h within 20 min.

Speed of initial infusion after load infusion makes 0.4 mkg/kg/h which can be korrigirovat further.

Patients of advanced age. Dose adjustment usually is not required to patients of this age category.

Renal failure. Dose adjustment usually is not required to patients with a renal failure.

Abnormal liver function. Deksdor is metabolized in a liver therefore it should be applied with care at patients with an abnormal liver function. It is necessary to consider expediency of use of a low maintenance dose.

Duration of a course of use depends on need of stay of the patient for a condition of sedation. There is no experience of use of Deksdor more than 14 days.

Route of administration. Deksdor is entered only by the health worker who has experience of treatment of the patients demanding an intensive care. Drug is used only in the form of divorced in/in infusion, using the infusional device with regulation of rate of administering. Ampoules and bottles are intended only for individual use for one patient.

Solution preparation. Before use Deksdor it is possible to dilute in 5% dextrose solution, Ringer's solution, Mannitolum or 0.9% chloride sodium solution for achievement of desirable concentration of 4 mkg/ml. In the table the volumes necessary for infusion preparation are included below.
Table

Deksdor's volume, a concentrate for preparation of solution for infusions, ml	Volume of solvent, ml	Total amount of infusion, ml
2	48	50
4	96	100
10	240	250
20	480	500

After preparation it is careful to stir up well to mix solution.

Before use the prepared solution should be checked for existence of foreign particles and discoloration visually.

Deksdor is compatible to the following liquids and drugs: lactat solution of Ringer, 5% solution of a dextrose, 0.9% solution of sodium of chloride, 20% Mannitolum, sodium thiopental, этомидат, vekurony bromide, pankurony bromide, сукцинилхолин, atrakuriya бесилат, mivakuriya chloride, rokuroniya bromide, glycopyrolat bromide, Phenylephrinum hydrochloride, Atropini sulfas, dopamine, Norepinephrinum, Dobutaminum, midazolam, morphine sulfate, fentanyl citrate and plasma substitutes.

Features of use:

Deksdor it is not necessary to apply during pregnancy, except for cases when the advantage of use of drug for mother exceeds risk for the fruit/child. Data on use of a deksmedetomidin for pregnant women are limited.

Reproductive toxicity — the potential risk for people is unknown. For treatment stop feeding by a breast.

Deksdor is intended only for use in intensive care units. During Deksdor's infusion at all patients it is necessary to control function of heart constantly. Patients to whom the intubation is not carried out should control respiratory function.

As well as in a case with all sedative drugs, it is necessary to be careful at Deksdor's combination with other medicines having sedative effect or influencing cardiovascular system because of a possibility of development of the additive effects.

Owing to pharmakodinamichesky effects of Deksdor it is necessary to be careful at use of drug for patients with heavy bradycardia, the progressing heart block (AV blockade of the II-III degree, except for cases when the pacemaker), arterial hypotension is used or patients with heavy dysfunction of ventricles have hearts. Deksdor reduces activity of a sympathetic nervous system, and at patients with a hypovolemia, and at elderly people more expressed arterial hypotension / bradycardia can expect chronic AG. Patients with good physical training and low ChSS can be at rest especially sensitive to bradikardichesky effects of agonists α2-адренорецепторов; there are messages on a temporary stop of activity of a sinus node. Arterial hypotension and bradycardia usually do not demand treatment, but if it is necessary, arterial hypotension it is necessary to treat by means of vasoconstrictors and/or administration of liquid, and bradycardia — anticholinergics.

It is necessary to be careful to avoid considerable arterial hypo - or hypertensia at patients with coronary heart disease which apply Deksdor as there is a theoretical possibility of decrease in a coronary blood-groove because of α2-опосредованного narrowings of peripheral vessels. It is necessary to consider expediency of a dose decline or drug withdrawal at patients whose ECG confirms symptoms of ischemia of a myocardium.

At patients with disturbance of activity of the autonomic nervous system (for example because of damage of a spinal cord) can note more expressed hemodynamic changes after the beginning of use of Deksdor therefore it is necessary to use with care this drug at such patients.

Temporary AG was revealed preferential during introduction of a load dose that was associated with peripheral vasoconstrictive effect of Deksdor. Treatment of AG usually was not required, but decrease in a load dose or speed of infusion is recommended.

In comparison with propofoly and midazolam, the patients receiving sedation Deksdor waken usually easier, interact with the doctor better and are capable to the best communication, remaining in general at rest and slackness. However this clinical profile means that Deksdor as independent means cannot be choice drug if there is a speech about need of deep sedation or full obezdvizhimost of the patient. In need of relaxation of muscles (including when carrying out an endotracheal intubation) patients have to receive in addition alternative sedative in therapeutic doses that they did not recover consciousness procedure time.

Introduction of bolyusny doses of Deksdor for sharp increase in level of sedation was not estimated therefore it is not recommended to use. In case of insufficient sedation, especially for the first hours after transition on Deksdor, it is possible to apply bolyusny doses of alternative sedative.

Deksdor probably does not oppress convulsive activity, and therefore cannot be applied as the only remedy for the epileptic status. Experience of use of Deksdor at heavy neurologic disturbances, such as a head injury, is limited therefore in such cases it should be applied with care, especially if deep sedation is necessary. As well as other sedatives, Deksdor can reduce cerebral circulation.

Agonists α2-адренорецепторов seldom were associated with reactions of cancellation at the sudden termination of prolonged use. The possibility of it should be considered if at the patient agitation and AG soon after phase-out of Deksdor develops.

It is unknown whether Deksdor's use for the persons sensitive to a malignant hyperthermia therefore such patients are not recommended to apply it is safe. In case of long inexplicable fever treatment by drug should be stopped.

There is no experience of use of Deksdor more than 14 days.

Ability to influence speed of response at control of vehicles and work with other mechanisms. Drug is shown for use in the conditions of a hospital.

Side effects:

At Deksdor's use it was most often reported about arterial hypotension, AG and bradycardia which arose approximately at 25; 15 and 13% of patients respectively. Arterial hypotension and bradycardia were also the most frequent serious side reactions connected with Deksdor which arose at 1.7 and 0.9% according to randomized patients of intensive care units.

Frequency of emergence of side reactions has the following classification: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); seldom (≥1/10 000, <1/1000); very seldom (<1/10 000); frequency is unknown (it is impossible to determine by the available data).

From metabolism and food. Often: hyperglycemia, hypoglycemia; infrequently: metabolic acidosis, hypoalbuminemia.

Mental disorders. Often: agitation; infrequently: hallucinations.

From cardiovascular system. Very often: bradycardia, arterial hypotension; often: ischemia or myocardial infarction, tachycardia; infrequently: AV blockade of the I degree, reduction of minute volume of heart.

From respiratory system. Infrequently: asthma.

From the alimentary system. Often: nausea, vomiting, dryness in a mouth; infrequently: abdominal distention.

The general disturbances and reactions in an injection site. Often: withdrawal, hyperthermia; infrequently: inefficiency of drug, thirst.

Description of separate side reactions: in the main clinical trials of Deksdor the frequency of ischemia and myocardial infarction was close to the lower bound of category of frequent side effects (1/100) and significantly did not differ from that for a propofol and midazolam. The sympatholytic effect of Deksdor reduces ChSS, the ABP and the need of a myocardium for oxygen. The central vazodilatation and lengthening of the period of a diastole which is also caused by Deksdor's use can improve a coronary blood stream and promote characteristic of agonists α2-адренорецепторов to cardioprotection at myocardium ischemia, even in the conditions of decrease in the ABP and a tendency to decrease in a coronary blood-groove. Nevertheless at administration of drug it is necessary to be careful, especially at patients with myocardium ischemia, and at its development to lower a dose or to stop Deksdor's introduction.

Withdrawal frequency at use Deksdora was lower in comparison with propofoly. For example, in clinical trial of Prodex 4 cases (1.6%) of a withdrawal in Deksdor's group (251 patients) and 7 cases (2,8%, р =0,544) in group of a propofol (247 patients) were registered. Withdrawal symptoms at Deksdor's use usually were not heavy and did not cause considerable therapeutic problems.

At rather healthy volunteers who were not in intensive care unit at Deksdor's use sometimes noted oppression of activity of a sinus node or a sinus pause, and also bradycardia. Symptoms were eliminated after a pripodnimaniye of the lower extremities and use of anticholinergics, such as atropine or glycopyrolat. In some cases bradycardia progressed before emergence of an asystolia at patients at who bradycardia cases were fixed earlier.

AG was associated using a load dose. Expressiveness of this reaction can be reduced, avoiding a load dose or reducing infusion speed, or reducing the volume of a load dose.

Interaction with other medicines:

Simultaneous use of Deksdor with anesthetics, sedatives, somnolent drugs and opioids can lead to potentiation of their effects. Specific researches confirmed potentiation of effects at simultaneous use with sevoflurany, izoflurany, propofoly, alfentanily and midazolam.

Pharmacokinetic interaction between Deksdory and izoflurany, propofoly, alfentanily and midazolam is not revealed. However because of possible pharmakodinamichesky interactions at use of such means in a combination with Deksdor there can be necessary a dose decline of Deksdor or the accompanying anesthetic, sedative, somnolent drug or opioid.

It is necessary to consider a possibility of strengthening of hypotensive and bradikardichesky effects at the patients receiving other medicines which cause such effects though additional effects in an interaction research using an esmolol were moderate.

Contraindications:

Hypersensitivity to a deksmedetomidin or to any of drug excipients.

Overdose:

In clinical and post-market researches it was reported about several cases of overdose of a deksmedetomidin.

The maximum speed of infusion of a deksmedetomidin about which it was reported in these cases reached 60 mkg/kg/h within 36 min. and 30 mkg/kg/h — within 15 min. at the 20-month-old child and at the adult respectively. The most frequent side reactions about which it was reported in connection with overdose in these cases included bradycardia, arterial hypotension, excessive sedation, drowsiness and a cardiac standstill.

In overdose cases with clinical symptoms the speed of infusion of Deksdor should be lowered or stopped. Preferential cardiovascular effects which treatment is carried out according to clinical indications are expected. At high concentration of drug AG there can be more expressed, than arterial hypotension. Cases of a stop of activity of a sinus node passed in clinical trials spontaneously or answered treatment with atropine or glycopyrolat. In some cases heavy overdose which led to a cardiac standstill resuscitation actions were required. Any of cases of overdose did not lead to a lethal outcome.

Storage conditions:

At a temperature of 15-25 °C. After cultivation. Physical and chemical stability is shown during use during 24 h at a temperature of 25 °C.

From the microbiological point of view this product should be applied immediately. If not to apply it immediately, the period of storage and storage conditions during use are responsibility of the user and usually do not exceed 24 h at a temperature of 2-8 °C, except for cases when cultivation happens in controlled and validirovanny aseptic conditions.

Issue conditions:

According to the recipe

Packaging:

2 ml - ampoules (5) - planimetric strip packagings plastic (1) - packs cardboard. 5 ml - ampoules (5) - planimetric strip packagings plastic (5) - packs cardboard. 4 ml - bottles glass (1) - packs cardboard. 10 ml - bottles glass (1) - packs cardboard.