Dormikum

General characteristics. Structure:

Active ingredient: 5 mg of midazolam.

Excipients: sodium chloride, Acidum hydrochloricum, sodium hydroxide, water for injections.

The hypnagogue of a benzodiazepine row which is characterized by bystry approach of action and its short duration. It also possesses anticonvulsant, anxiolytic and myorelaxation action.

Pharmacological properties:

Pharmacodynamics. Benzodiazepine of short action. Active agent of the drug Dormikum® - midazolam - concerns to group of imidobenzodiazepines. The free basis is lipophilic substance, badly soluble in water.

Existence of the main nitrogen atom in the provision 2 of an imidobenzodiazepine ring allows midazolam to form water soluble salts with acids. Pharmacological effect of drug differs in quick start and - because of bystry biotransformation - short duration. Thanks to the hypotoxicity, midazolam has a big therapeutic interval.

Action mechanism. Midazolam stimulates the ionotropny receptors of GAMKA located in the central nervous system. In the presence of GAMK midazolam contacts receptors of benzodiazepines on channels for chlorine ions that leads to activation of a receptor of GAMK and decrease in excitability of subcrustal structures of a brain. Thereof midazolam has sedative and somnolent effect, and also anxiolytic, anticonvulsant and central myorelaxation action. Several subtypes of receptors of GAMKA are described. Sedation, an ecmnesia and anticonvulsant activity are mediated through GAMKA the receptor which is generally containing α1 subunit, anxiolytic and myorelaxation activity is associated with impact on GAMKA the receptor which is generally containing α2 subunit.

Midazolam has very bystry sedative and expressed somnolent effect.

After parenteral administration there is a short ecmnesia (the patient does not remember the events which were taking place during the most intensive operation of active agent).

Pharmacokinetics. Absorption after intramuscular introduction. Midazolam is soaked up from muscular tissue quickly and completely. The maximum concentration in plasma is reached within 30 min. Absolute bioavailability after intramuscular introduction exceeds 90%.

Distribution. After intravenous administration the curve of concentration of midazolam in plasma is characterized by one or two accurately expressed distribution phases. Distribution volume in an equilibrium state makes 0.7-1.2 l/kg of body weight. Extent of linkng with proteins of plasma, mainly, with albumine, is equal to 96-98%. In cerebrospinal fluid midazolam passes slowly and in insignificant quantities. Midazolam slowly passes through a placental barrier and gets to a fruit blood stream; its small quantities are found in breast milk.

Metabolism. Midazolam is removed practically only by biotransformation. Midazolam is hydroxylated by an isoenzyme 3A4 of system of P450 cytochrome. The main metabolite in plasma and urine is a-hydroxymidazolam. Concentration of a-hydroxymidazolam in plasma makes 12% of concentration of midazolam. A-hydroxymidazolam has pharmacological activity, but only in the minimum degree (about 10%) causes effects of intravenously entered midazolam. Data on a role of genetic polymorphism in oxidizing metabolism of midazolam are absent.

Removal. At healthy volunteers the elimination half-life makes 1.5-2.5 h. The plasma clearance is equal to 300-500 ml/min. Removal of midazolam from an organism happens, generally kidneys: 60-80% of the received dose are removed with urine in the form of an a-hydroxymidazolam glucuronide. In the form of not changed drug in urine less than 1% of the accepted dose are found. The elimination half-life of a metabolite makes less than 1 hour. At intravenous drop administration of midazolam the kinetics of its removal does not differ from that after jet introduction.

Pharmacokinetics in special groups of patients. At patients 60 years are more senior the elimination half-life can increase by 4 times.

At children from 3 to 10 years the elimination half-life after intravenous administration is shorter, than at adults (1-1.5 h) that corresponds to the increased metabolic clearance of drug.

At newborns – it is possible, owing to immaturity of a liver – the elimination half-life is increased and makes, on average, 6-12 h, and the clearance of drug is slowed down.

People with obesity have an elimination half-life more (8.4 h), than at people with normal body weight, it is probable owing to increase in volume of the distribution corrected taking into account body lump, approximately for 50%. The clearance of drug is much not changed.

The drug elimination half-life at patients with cirrhosis can be extended, and the clearance – to decrease, in comparison with similar indicators at healthy volunteers.

The drug elimination half-life at patients with a chronic renal failure is similar to that at healthy volunteers.

At the patients who are in critical condition, the elimination half-life of midazolam increases.

At chronic heart failure the midazolam elimination half-life is also more, than at healthy faces.

Indications to use:

Adults. Sedation with preservation of consciousness before the diagnostic or medical procedures made under local anesthesia or without it and also during their carrying out.

Premedication before an introduction anesthesia.

Introduction anesthesia.

As a sedative component at the combined anesthesia.

Long sedation in an intensive care.

Children. Sedation with preservation of consciousness before the diagnostic or medical procedures made under local anesthesia or without it and also during their carrying out.

Premedication before an introduction anesthesia.

Long sedation in an intensive care.

Route of administration and doses:

Midazolam - the strong sedative demanding slow introduction and individual selection of a dose.

The dose should be selected individually, titration of a dose for safe achievement of the necessary sedative action which corresponds to clinical need, a physical state and age of the patient, and also the medicamentous therapy received by it is also strongly recommended.

At patients 60 years are more senior, the patients who are in critical condition and also with a high risk and at patients of children's age a dose should be chosen carefully, considering individual risk factors.

Effect of drug begins approximately in 2 minutes after intravenous administration. The maximum effect is reached within 5-10 minutes.

Sedation with consciousness preservation. For sedation with preservation of consciousness before the diagnostic or surgical procedure, the drug Dormikum® is administered intravenously. The dose should be selected individually, to carry out its titration; the drug cannot be administered quickly or struyno. Approach of sedation varies individually, depending on a condition of the patient and the mode of dosing (rate of administering, dose size). If necessary perhaps repeated introduction.

Дормикум® for sedation with preservation of consciousness it is necessary to apply with care at patients with disturbances of respiratory function (see the section "Special Instructions").

Adults. Дормикум® it is necessary to enter intravenously slowly, with a speed about 1 mg of 30 sec.
· Age <60 years. The initial dose makes 2-2.5 mg, is entered in 5-10 minutes prior to the procedure. If necessary perhaps repeated introduction in a dose of 1 mg. The average total dose is in an interval of 3.5-7.5 mg. Usually happens rather total dose which is not exceeding 5 mg.
· Age of ≥60 years; the patients who are in critical condition and also with a high risk. The initial dose is reduced to 0.5-1 mg and enter it in 5-10 min. prior to the procedure. If necessary carry out repeated introduction in a dose of 0.5-1 mg. As at these patients the maximum effect can be reached not so quickly, additional doses need to be titrated slowly and carefully. Usually happens rather total dose which is not exceeding 3.5 mg.

Children. Intravenous administration of the drug Dormikum® is carried out by slow titration before achievement of effect. The initial dose of the drug Dormikum® is entered within 2-3 minutes. Then, before starting the procedure or to enter a repeated dose, it is recommended to wait for 2-5 more minutes for sedation assessment. If sedation needs to be strengthened, the dose continues to be titrated small "steps" before achievement of necessary degree of sedation. To babies and children 5 years are younger high doses, than to children of advanced age and teenagers can be required considerably.

· <6 months
Children are younger than 6 months are especially inclined to obstruction of respiratory tracts and hypoventilation therefore use of the drug Dormikum® for sedation with preservation of consciousness at children is younger than 6 months it is not recommended, except cases when the possible advantage exceeds potential risks. In these cases it is extremely important to titrate a dose small "steps" before achievement of clinical effect, and also to watch carefully patients. The initial dose has to be minimum possible at the available technical characteristics of the used equipment.

· From 6 months to 5 years
The initial dose makes 0.05-0.1 mg/kg. For achievement of desirable effect the total dose can be increased to 0.6 mg/kg, however it should not exceed 6 mg. At introduction of higher doses development of long sedation and risk of hypoventilation is possible (see the section "Special Instructions").

· From 6 to 12 years
The initial dose makes 0.025-0.05 mg/kg, the total dose can be increased to 0.4 mg/kg, however it should not exceed 10 mg. At introduction of higher doses development of long sedation and risk of hypoventilation is possible (see the section "Special Instructions").

· From 13 to 16 years
Doses for children from 13 to 16 years – same, as for adults.

Intramuscular introduction (children from 1 year to 16 years). The recommended dose of 0.05-0.15 mg/kg, is entered in 5-10 minutes prior to the procedure. Usually happens rather total dose which is not exceeding 10 mg. At body weight less than 15 kg administration of solutions of midazolam with concentration more than 1 mg/ml is not recommended. Solutions with higher concentration need to be dissolved to concentration 1 mg/ml.

Anesthesia. Premedication. Premedication the drug Dormikum® shortly before the procedure has sedative effect (drowsiness emergence, and elimination of emotional pressure), and also causes preoperative amnesia. For premedication the drug is administered intravenously or intramusculary (it is deep in a muscle in 20-60 min. prior to an introduction anesthesia).

After administration of the drug Dormikum® identification of symptoms of overdose requires obligatory observation of the patient as individual sensitivity to drug can vary. 

Дормикум® it is possible to apply in combination with anticholinergics.
Adults <60 years and the estimates of the physical status belonging to the class I and II on the classification system accepted by the American Society of Anaesthesiologists. For preoperative sedation and elimination of memory on preoperative events drug, enter in a dose 1-2 mg intravenously, if necessary repeating introduction, or intramusculary - in a dose of 0.07-0.1 mg/kg of body weight.

Adult ≥60 years, patients in critical condition, patients with a high risk. Decrease and individual selection of a dose is required. The recommended initial dose at intravenous administration makes 0.5 mg, if necessary the dose is raised slow titration. Before entering a repeated dose, it is necessary to wait 2-3 minutes for effect assessment.
The recommended dose at intramuscular introduction makes 0.025-0.05 mg/kg (usually 2-3 mg) provided that the patient at the same time does not receive drugs.

The dose of the drug Dormikum® has to be lowered at its simultaneous introduction with narcotic analgetics.

Rather higher doses (at the rate on body weight kg), than the adult are required for children from 1 to 15 years.

Doses within 0.08-0.2 mg/kg at intramuscular introduction are effective and safe. The drug needs to be administered deeply in a large muscle in 30-60 min. prior to an introduction anesthesia.

Less than 15 kg are not recommended to children with body weight administration of solutions of midazolam with concentration more than 1 mg/ml. Solutions with higher concentration need to be dissolved to concentration 1 mg/ml.

Introduction anesthesia. If Dormikum® is used for an introduction anesthesia before administration of other anesthetics, individual reaction of patients can be various. The dose should be titrated before achievement of desirable effect according to age and a clinical condition of the patient. At introduction of Dormikuma® before or in a combination with other intravenous or inhalation drugs for an introduction anesthesia initial doses of each of drugs can be considerably reduced, sometimes to 25% of the established initial dose.

Desirable level of sedation is reached by step titration of a dose. The induction dose of the drug Dormikum® should be entered intravenously slowly, fractionally. Each subsequent administration of drug in number of no more than 5 mg, it is necessary to carry out within 20-30 seconds, doing 2 minute intervals between introductions.

Adults <60 years. The dose of 0.2 mg/kg is entered intravenously for 20-30 seconds, waiting for 2 minutes for effect assessment. Usually this dose is enough for achievement of satisfactory effect.

In the absence of premedication the dose can be increased to 0.3-0.35 mg/kg of body weight. It is entered intravenously for 20-30 seconds, waiting for 2 minutes for effect assessment. If necessary for completion of induction the drug is administered in addition in the number of equal about 25% of an initial dose. As an alternative for completion of induction it is possible to use liquid inhalation anesthetics. In immunity cases the induction dose of the drug Dormikum® can reach 0.6 mg/kg, however recovery of consciousness after such doses can be slowed down.

Adult ≥60 years, patients in critical condition, and also with a high risk. In the absence of premedication, the smallest induction doses of the drug Dormikum®, equal 0.15-0.2 mg/kg are required. In the presence of premedication, intravenous administration of 0.05-0.15 mg/kg for 20-30 seconds is recommended, waiting for 2 minutes for effect assessment. Usually this dose is enough.

Children. Дормикум® it is not recommended for an introduction anesthesia at children as experience of its use for this age group is limited.

As a sedative component at the combined anesthesia. Adults <60 years. Use of the drug Dormikum® as a sedative component at the combined anesthesia is carried out or by fractional intravenous administration of small doses (0.03-0.1 mg/kg), or by continuous intravenous infusion in a dose of 0.03-0.1 mg/kg an hour, usually in combination with analgetics. Doses and intervals between introductions depend on individual reaction of the patient.
Adult ≥60 years, patients in critical condition, and also with a high risk. For maintenance of an anesthesia smaller doses are required.

Children. Use of the drug Dormikum® as a sedative component at the combined anesthesia at children is not recommended as experience of its use is limited.        

Long sedation in an intensive care. The necessary sedation is reached by step titration of a dose then either continuous infusion, or fractional jet administration of drug, depending on clinical need, a condition of the patient, his age and at the same time administered drugs follows.

Adults. The intravenous load dose of 0.03-0.3 mg/kg is entered fractionally, slowly. Each repeated dose into 1-2.5 mg is entered during 20-30 sec., observing 2-minute intervals between introductions.

The patient with a hypovolemia, vasoconstriction or a hypothermia the load dose is reduced or not entered in general.

If Dormikum® apply along with strong analgetics (in particular, morphine, methadone, pethidine, fentanyl, alfentanil, buprenorphine, pentazocine and derivatives of each subgroup), the last should be entered to it the dose of the drug Dormikum® could be titrated safely at height of the sedation caused by an analgetic.

The intravenous maintenance dose can vary within 0.03-0.2 mg/kg an hour. The patient with a hypovolemia, vasoconstriction or a hypothermia the maintenance dose is reduced. If the condition of the patient allows, it is necessary to estimate sedation degree regularly. When carrying out long sedation tolerance development is possible owing to what the dose will need to be increased.

Children. Less than 15 kg are not recommended to the full-term and premature newborns, and also children with body weight administration of solutions of midazolam with concentration more than 1 mg/ml. Solutions with higher concentration need to be dissolved to concentration 1 mg/ml.

Children are younger than 6 months. The drug should be administered by continuous intravenous infusion. Newborns with gestational age <of Dormikum® should enter 32 weeks 0.03 mg/kg/h (0.5 mkg/kg/min.) in an initial dose.

The newborn with gestational age> 32 weeks and to children are younger than 6 months – in a dose of 0.06 mg/kg/h (1 mkg/kg/min.).

The intravenous load dose is not entered, instead in the first several hours carry out infusion slightly quicker for achievement of therapeutic concentration of drug in plasma. It is necessary to reconsider the speed of infusion often and carefully, especially in the first 24 h to enter the smallest effective dose and to lower a possibility of cumulation of drug. It is necessary to control carefully a respiration rate and saturation by oxygen.

Children are more senior than 6 months. To the children who are on artificial ventilation of the lungs, and also intubated for establishment of desirable clinical effect the load dose of 0.05-0.2 mg/kg is entered intravenously slowly not less than within 2-3 minutes (intravenously quickly it is impossible to enter). After that pass to continuous intravenous infusion in a dose 0.06-0.12 mg/kg/h (1-2 mkg/kg/min.). If necessary, for strengthening or maintenance of desirable effect, the speed of infusion can be increased or reduced (usually by 25% of initial or subsequent speed) or to enter additional doses of the drug Dormikum®.

If infusion of the drug Dormikum® is begun the patient with disturbances of a hemodynamics, the usual load dose needs to be titrated small "steps", controlling hemodynamic indicators (lowering of arterial pressure). These patients have a tendency to respiratory depression at drug Dormikum® use therefore careful control of a respiration rate and saturation by oxygen is necessary.

Dosing in special cases. Children. Less than 15 kg are not recommended to the full-term and premature newborns, and also children with body weight administration of solutions of midazolam with concentration more than 1 mg/ml. Solutions with higher concentration need to be dissolved to concentration 1 mg/ml.
To children 6 months are younger intravenous administration of midazolam as they are especially inclined to obstruction of respiratory tracts and hypoventilation, except for sedation cases in chambers of an intensive care is not recommended.

Дормикум® it is not shown to use for children for carrying out an introduction anesthesia, and also as a sedative component at the combined anesthesia as children have only limited data on these indications.

Patients are more senior than 60 years. Usually need lower doses of midazolam. Continuous monitoring of indicators of the vital functions is necessary.

Patients with a renal failure. The pharmacokinetics of free midazolam is similar that at healthy volunteers. However, it was shown that patients to chronic diseases of kidneys have an a-hydroxymidazolam accumulation that can lead to increase in duration of clinical effects of drug and to extension of sedation.

Patients with an abnormal liver function. At patients with an abnormal liver function reduction of clearance of midazolam after its intravenous administration and, therefore, increase in a final elimination half-life is observed that can lead to strengthening and increase in duration of its clinical effects. Such patients can need lower doses of midazolam, and also the corresponding monitoring of indicators of the vital functions.

Special instructions on dosing. Drug Dormikum® solution in ampoules it is possible to part 0.9% with solution of sodium chloride, 5% and 10% glucose solution (5% and 10% solution of a dextrose and 5% levuloza solution), Ringer's solution and Hartmann's solution in the ratio of 15 mg of midazolam on 100-1000 ml of infusion solution. These solutions remain physically and chemically stable during 24 h at the room temperature or 3 days at a temperature of 5 °C.

It is not necessary to part Дормикум® 6% with dextran solution with cf. a pier. weighing 50000-70000 Da in Dextrosum. It is impossible to mix Dormikum® with alkaline solutions as midazolam leaves a sediment with sodium bicarbonate.

Use of other solvents in addition to mentioned above should be avoided. From the microbiological point of view the prepared solution has to be used immediately. If drug is not used at once, then time and storage conditions of the prepared solution are responsibility of the user and should not exceed 24 h at a temperature from 2 °C to 8 °C and only if preparation of solution was carried out in controlled and validiruyemy aseptic conditions. Ampoules of the drug Dormikum® are intended only for disposable. Unused solution should be thrown out.

Before introduction it is necessary to examine solution. Only transparent solution without visible foreign particles is suitable for use.

After freezing loss of a deposit which is dissolved when stirring at the room temperature is possible.

Features of use:

Midazolam should be applied to parenteral administration only in the presence of the resuscitation equipment as its intravenous administration can oppress sokratitelny ability of a myocardium and cause an apnoea. In rare instances the heavy cardiorespiratory undesirable phenomena developed. They consisted in oppression, an apnoea and/or a cardiac standstill. The probability of such life-threatening reactions increases at too bystry administration of drug or at introduction in a high dose (see the section "Side effect").

When carrying out sedation with consciousness preservation by the doctor - not the anesthesiologist it is necessary to adhere to the existing practical recommendations.

When using the drug Dormikum® in the conditions of a hospital of one day the patient can be written out only after survey of the anesthesiologist. The patient can leave clinic only in the presence of the accompanying person.

When carrying out premedication after administration of midazolam careful observation of a condition of the patient as individual sensitivity to drug can differ is obligatory and development of symptoms of overdose is possible.

Extra care is necessary at parenteral administration of midazolam to patients with a high risk: 60 years, the disturbance of respiratory function, function of kidneys which is in critical condition, suffering, a liver, disturbance of cordial activity are more senior. Smaller doses (see the section "Route of Administration and Doses") and constant observation for the purpose of early identification of disturbances of the vital functions are required for this patients. At long use of the drug Dormikum® for sedation in the block of an intensive care some reduction of effect of drug is described.

As sharp drug withdrawal of Dormikum®, especially after long intravenous use (more than 2-3 days), can be followed by abstinence signs, its dose is recommended to be reduced gradually. The following abstinence signs can develop: a headache, muscle pain, the increased uneasiness, tension, a condition of excitement, confusion of consciousness, irritability, "ricochet" sleeplessness, differences of mood, a hallucination, spasm.

Дормикум® causes an ecmnesia. Long amnesia can represent a problem for patients who are going to be written out after the surgical or diagnostic procedure.

Cases of paradoxical reactions, such as agitation, involuntary physical activity (including toniko-clonic spasms and a muscular tremor), a hyperactivity, hostile mood, anger and aggression, excitement paroxysms are described. Similar reactions can develop in introduction cases enough high doses of midazolam, and also at bystry administration of drug. Some increased predisposition to similar reactions is described at children and at elderly patients at intravenous administration of high doses of midazolam.

The concomitant use of midazolam with drugs inhibitors/inductors of an isoenzyme CYP3A4 can lead to change of his metabolism owing to what need for corresponding change of a dose of midazolam can appear (see the section "Interaction with Other Medicines").

The elimination half-life of drug can be extended at patients with an abnormal liver function, low cordial emission, and also at newborns (see the section "Route of Administration and Doses", the subsection "Dosing in Special Cases").

Extra care is necessary when carrying out sedation at the premature newborns (who are given rise on duration of gestation less than 36 weeks) if they are not intubated, because of danger of an apnoea. It is required to avoid bystry administration of drug at this group of patients. Careful monitoring of a respiration rate and saturation by oxygen is necessary.

Children are younger than 6 months are especially inclined to obstruction of respiratory tracts and hypoventilation therefore in these cases it is extremely important to titrate a dose, raising it small "steps" to achievement of clinical effect, and also to carefully monitorirovat a respiration rate and saturation by oxygen.

It is necessary to avoid sharing of the drug Dormikum® with alcohol and/or drugs, the oppressing TsNS. In such cases strengthening of clinical effects of the drug Dormikum®, development of the expressed sedation, and also clinically significant oppression of respiratory and cardiovascular activity is possible (see the section "Interaction with Other Medicines").

It is necessary to avoid use of the drug Dormikum® for the patients having alcoholism, and also having drug addiction in the anamnesis.

As well as when using any drug, the oppressing TsNS and possessing myorelaxation action, extra care needs to be observed at administration of midazolam by the patient with myastenia gravis.

Influence on ability to driving of vehicles and work with cars and mechanisms. Sedation, amnesia, decrease in concentration of attention, disturbance of muscular functions exert negative impact on ability to driving of the car or work with mechanisms. It is not necessary to manage vehicles or to work with machines or mechanisms before complete cessation of effect of drug. Resuming of similar activity has to happen with the permission of the attending physician.

Data for assessment of safety of midazolam at pregnancy are not enough. Benzodiazepines should not be applied during pregnancy if only they do not have safer alternative. Purpose of drug in the last trimester of pregnancy or in high doses during the first period of childbirth leads to disturbances of a cordial rhythm at a fruit, hypotonia, to disturbance of suction, a hypothermia and moderate respiratory depression at the newborn. Moreover, at children whose mothers at late stages of pregnancy it is long received benzodiazepines, physical dependence with a certain risk of an abstinence syndrome in the post-natal period can be created.

As midazolam in small quantities gets into breast milk, nursing mothers are recommended to interrupt feeding with a breast during 24 h after midazolam reception.

With care. The age is more senior than 60 years, critical condition, respiratory insufficiency, a renal failure and a liver, heart failure, premature children (because of danger of an apnoea), newborns is younger than 6 months, miastenia gravis.

Side effects:

From immune system: reactions of generalized hypersensitivity (skin, cardiovascular reactions, bronchospasm), acute anaphylaxis.

From the mental sphere: confusion of consciousness, euphoria, hallucinations.

Cases of paradoxical reactions, such as agitation, involuntary physical activity (including toniko-clonic spasms and a muscular tremor), a hyperactivity, hostile mood, anger and aggression, excitement paroxysms, especially at children and patients of senile age are described.

Drug Dormikum® use, even in therapeutic doses, especially at long sedation, can lead to formation of physical dependence. The risk of emergence of dependence increases with increase in a dose of drug and duration of its use, and also at the patients having alcoholism and/or having drug addiction in the anamnesis. Drug withdrawal, especially sharp, after its prolonged intravenous use, can be followed by cancellation symptoms, including spasms.

From the central and peripheral nervous system: long sedation, decrease in concentration of attention, a headache, dizziness, an ataxy, postoperative drowsiness, an ecmnesia which duration directly depends on a dose. The ecmnesia can take place at the end of the procedure, in some cases it proceeds longer. Retrograde amnesia, uneasiness, drowsiness and nonsense at an exit from an anesthesia, the atetoidny movements, a sleep disorder, a dysphonia, the indistinct speech, paresthesia.

At premature children and newborns spasms are described.

From cardiovascular system: in rare instances the heavy cardiorespiratory undesirable phenomena developed. They consisted in a cardiac standstill, a lowering of arterial pressure, bradycardia, a vazodilatation. The probability of such life-threatening reactions above at adults is more senior than 60 years and at persons with the accompanying respiratory insufficiency or heart failure, especially if the drug is administered too quickly or in a high dose (see the section "Special Instructions"). Tachycardia, bigeminal pulse, premature reduction of ventricles, vazovagalny crisis, rhythm of atrioventricular connection.

From a respiratory organs: in rare instances the heavy cardiorespiratory undesirable phenomena developed. They consisted in oppression, an apnoea, development of an apnoea, диспноэ, a laryngospasm. The probability of such life-threatening reactions above at adults is more senior than 60 years and at persons with the accompanying respiratory insufficiency or heart failure, especially, if the drug is administered too quickly or in a high dose (see the section "Special Instructions"). Hiccups, bronchospasm, hyperventilation, goose breathing, shallow breathing, obstruction of respiratory tracts, tachypnea.

From digestive tract: nausea, vomiting, a lock, dryness in a mouth, acid smack in a mouth, hypersalivation, an eructation.

From skin and a hypodermic fatty tissue: skin rash, small tortoiseshell, itch.

General and local reactions: an erythema and pains in the place of an injection, thrombophlebitis, thrombosis, hypersensitivity.

From sense bodys: disturbance and deterioration in visual acuity, doubling, a nystagmus, a miosis, periodic twitchings a century, a preunconscious condition, disturbance of a refraction, a congestion in ears, balance loss.

Use of benzodiazepines increases risk of falling and changes. In a zone of extra risk there are patients accepting the accompanying sedative drugs (including alcoholic beverages), and also patients of advanced and senile age.

Interaction with other medicines:

Pharmacokinetic interactions. Metabolism of midazolam is mediated practically only by system of P4503A4 cytochrome (CYP3A4 isoform). Substances, inhibitors and inductors of an isoenzyme CYP3A4, have potentiality to increase and reduce plasma concentration and consequently also pharmakodinamichesky effects of midazolam. In addition to influence on activity of an isoenzyme of CYP3A4 other mechanism causing clinically significant changes in result of intermedicinal interaction of midazolam with other substances is not revealed. However, there is a theoretical possibility of replacement of drug from communication with proteins of plasma (albumine) at its simultaneous use with medicinal substances with rather high therapeutic concentration in a blood plasma. For example, such mechanism of intermedicinal interaction is supposed for midazolam and valproic acid. Cases of influence of midazolam on pharmacokinetics of other drugs are not revealed.

In view of the fact that strengthening and increase in duration of clinical effects of midazolam at its sharing with CYP3A4 isoenzyme substances-inhibitors is possible careful observation of clinical effects, and also of indicators of the vital functions is recommended. Depending on extent of the inhibiting influence on CYP3A4 isoenzyme the dose of midazolam can be considerably reduced. On the other hand, combined use of midazolam with drugs inductors of an isoenzyme CYP3A4 can result in need for increase in a dose of midazolam for achievement of desirable effect.

In case of induction of an isoenzyme of CYP3A4 or its irreversible inhibition (in this case there is an irreversible interaction to P450 cytochrome as a result of which the difficult inactivated complexes are formed) influence on pharmacokinetics of midazolam can remain within several days, up to several weeks after administration of inhibitors of an isoenzyme of CYP3A4. Use antibacterial (кларитромицин, erythromycin, an isoniazid), anti-hypertensive drugs (verapamil, diltiazem), drugs for treatment of HIV infection (HIV protease inhibitors, делавирдин), sex steroid hormones (гестоден) and modulators of their receptors (ралоксифен), and also some vegetable matters is an example of irreversible inhibition of an isoenzyme of CYP3A4 (бергамоттин which in particular contains in grapefruit). Unlike other irreversible inhibitors (see below) ethinylestradiol / Norgestrelum at its use as an oral contraceptive, and grapefruit juice (200 ml) do not exert considerable impact on the size of plasma concentration of midazolam at its intravenous administration.

Intensity of the inhibiting/inducing influence of drugs varies over a wide range. For example, antifungal drug кетоконазол is rather powerful inhibitor of an isoenzyme CYP3A4 and increases plasma concentration of intravenously entered midazolam by 5 times. Drug of tuberculostatic action rifampicin is one of the most powerful inductors of an isoenzyme CYP3A4 and its combined use with intravenous administration of midazolam leads to reduction of plasma concentration of midazolam approximately for 60%.

The midazolam route of administration also exerts impact on extent of changes of pharmacokinetic parameters owing to modulation of activity of an isoenzyme of CYP3A4. At intravenous administration it is possible to expect smaller extent of change of plasma concentration in comparison with a peroral route of administration as modulation of activity of an isoenzyme of CYP3A4 exerts impact not only on the general clearance, but also on bioavailability of midazolam at its oral administration. It should be noted that the researches directed to studying of influence of the changed activity of an isoenzyme of CYP3A4 on midazolam pharmacokinetics after its intramuscular introduction were not conducted. After intramuscular introduction drug comes to a system blood stream therefore it is considered that influence of the changed activity of an isoenzyme of CYP3A4 on pharmacokinetics will be same, as at intravenous administration at once. According to pharmacokinetic bases in clinical trials it was shown that after single intravenous administration of a dose of midazolam of change of size of the maximum clinical effect owing to the changed activity of an isoenzyme of CYP3A4 are insignificant while duration of this effect can increase. However, at further administration of drug (treatment continuation) against the background of inhibition of activity of an isoenzyme of CYP3A4 increase both the size, and duration of clinical effect.
Examples of chances of intermedicinal interaction of midazolam at intravenous administration with other medicines are included below. It is important to note that any drug at which ability to change activity of an isoenzyme of CYP3A4 in vitro and in vivo was revealed can change plasma concentration of midazolam and, therefore, its clinical performance. In the absence of data on joint reception of any drug with an intravenous form of midazolam, the data obtained in clinical trials of its joint reception with a peroral form of midazolam are provided. In this case it is important to note that change of plasma concentration of midazolam owing to change of activity of an isoenzyme of CYP3A4 is more expressed at its oral administration, than at intravenous administration.

CYP3A4 isoenzyme drugs-inhibitors. Antifungal means from group of azoles. Ketokonazol. By 5 times increases plasma concentration of intravenously entered midazolam, approximately by 3 times increases a final elimination half-life. Parenteral administration of midazolam together with ketokonazoly, powerful inhibitor of an isoenzyme CYP3A4, has to be carried out in intensive care unit or any other department where there are opportunities for careful clinical monitoring and necessary treatment in case of respiratory depression and/or development of long sedation. Individual selection of a dose of drug, and also step-by-step introduction, especially, in cases of more than single administration of midazolam is necessary. 

Flukonazol and итраконазол. By 2-3 times increase plasma concentration of intravenously entered midazolam. Increase a final elimination half-life of midazolam by 2.4 times (итраконазол) and by 1.5 times (флуконазол).
Pozakonazol. Increases plasma concentration of intravenously entered midazolam twice.

Macroleads. Erythromycin. Increases plasma concentration of intravenously entered midazolam by 1.6-2 times, approximately at 1.5-1.8 time increases a final elimination half-life.

Klaritromitsin. Increases plasma concentration of midazolam to 2.5 times, by 1.5-2 times increases a final elimination half-life.

Additional information for a peroral form of midazolam. Roksitromitsin. Exerts smaller impact on midazolam pharmacokinetics in comparison with erythromycin and klaritromitsiny. Increases a plasma kontsentartion of midazolam after oral administration by 50%. For comparison, erythromycin increases this indicator by 4.4 times, кларитромицин – by 2.6 times. Moderate influence on a final elimination half-life of midazolam, namely increase by 30%, allows to assume that influence of a roksitromitsin on pharmacokinetics of intravenously entered midazolam is insignificant.

HIV protease inhibitors. Sakvinavir and other inhibitors of HIV protease. At joint reception of midazolam with lopinaviry and ritonaviry (a booster combination) plasma concentration of intravenously entered midazolam increases by 5.4 times that is combined with the same increase in a final elimination half-life. Parenteral administration of midazolam together with inhibitors of HIV protease demands observance of certain conditions of hospitalization (see кетоконазол).

Blockers of N2-of histamine receptors. Cimetidinum. Increases equilibrium plasma concentration of midazolam by 26%.

Blockers of slow calcium channels. Diltiazem. The single dose of diltiazem increases plasma concentration of midazolam at its intravenous administration approximately by 25% and extends a final elimination half-life for 43%.

Additional information for a peroral form of midazolam. Verapamil / дилтиазем. Increase plasma concentration of a peroral form of midazolam in 3 and 4 times, respectively. Increase a final elimination half-life of midazolam by 41% and for 49%, respectively.

Other medicinal drugs / Phytodrugs. Atorvastatin. By 1.4 times increases plasma concentration of intravenously entered midazolam.

Additional information for a peroral form of midazolam. Fluvoksamin. Causes moderate increase in plasma concentration of midazolam after its oral administration (for 28%), and also doubles duration of a final elimination half-life.

Nefazodon. Increases plasma concentration of midazolam by 4.6 times, the final elimination half-life extends by 1.6 times.

Aprepitant. Dozozavisimo increases plasma concentration of the midazolam entered orally. Increase happens approximately by 3.3 times at reception of an aprepitant in a dose of 80 mg/day, and the final elimination half-life is extended twice.

Hlorzoksazon. Causes reduction of size of a ratio α-gidroksimidazolam/midazolam that the chloroxazone on CYP3A4 isoenzyme indicates the inhibiting effect.

Bikalutamid. Renders insignificant effect on plasma concentration of midazolam after oral administration. Increases plasma concentration by 27%.

Goldenseal Canadian (Hydrastis Canadensis). Causes reduction of size of a ratio to α-gidroksimidazolam/midazola approximately for 40% that indicates the inhibiting effect on CYP3A4 isoenzyme.

CYP3A4 isoenzyme drugs inductors. Rifampicin. After reception of rifampicin within 7 days in a dose of 600 mg a day plasma concentration of midazolam after its intravenous administration approximately decreases by 60%. The final elimination half-life decreases approximately by 5-60%.

Additional information for a peroral form of midazolam. Carbamazepine/Phenytoinum. Reception of repeated doses of carbamazepine or Phenytoinum causes reduction of plasma concentration of the midazolam entered orally by 90% and shortens a final elimination half-life for 60%.

Efavirenz. 5 multiple increase in a ratio of concentration of the α-hydroxymidazolam formed by means of CYP3A4 isoenzyme and midazolam demonstrate the inducing action on CYP3A4 isoenzyme.

Phytodrugs and food stuffs. Extract of a root of a purple cone-flower purple. Reduces plasma concentration of intravenously entered midazolam by 20%. The final elimination half-life decreases approximately by 42%.

St. John's Wort ordinary (made a hole). Reduces plasma concentration of intravenously entered midazolam approximately by 20-40%. The final elimination half-life decreases approximately by 15-17%.

Other interactions. Valproic acid. There is potentiality of replacement of midazolam from communication with proteins of plasma (albumine) valproic acid. It is impossible to exclude that owing to high therapeutic concentration of valproic acid in the blood serum reached after its introduction replacement of midazolam from communication with serum proteins is possible that can lead to change of clinical effect of the midazolam entered in the conditions of the emergency sedation towards its strengthening.

Pharmakodinamichesky interactions. Joint administration of midazolam with others sedative and hypnagogues, including alcohol, can lead to strengthening of sedative and somnolent effects. Similar interaction is possible at reception of opiates and opioids (at their reception as analgetics, antibechics, means of replacement therapy), antipsychotic means (neuroleptics), various benzodiazepines used as anxiolytics or hypnagogues, barbiturates, a propofol, Ketaminum, an etomidat, also at a concomitant use of midazolam with antidepressants with sedative action, anti-histamine means and antihypertensives of the central action. Midazolam reduces the minimum alveolar concentration of inhalation anesthetics.

Strengthening of effects of midazolam (sedation, influence on respiratory system and indicators of a hemodynamics) can happen at its simultaneous use to any drugs oppressing the central nervous system (CNS) including alcohol. At similar combined use of medicines adequate monitoring of indicators of the vital functions is necessary. It is necessary to avoid a concomitant use of midazolam and alcohol (see the section "Special Instructions").

Carrying out spinal anesthesia can strengthen midazolam sedation, at its intravenous administration. In that case reduction of a dose of midazolam is necessary. Also reduction of a dose of intravenously entered midazolam is necessary in cases of its simultaneous use with lidocaine or bupivacaine at their intramuscular introduction.

The drugs activating activity of a brain, improving memory, attention such as acetylcholinesterase inhibitor physostigmine can reduce somnolent effect of midazolam. In this way, 250 mg of caffeine are partially reduced by midazolam sedation. 

Incompatibility. It is not necessary to part Дормикум® 6% with dextran solution with an average molecular weight of 50000-70000 Da in Dextrosum. It is impossible to mix Dormikum® with alkaline solutions as midazolam leaves a sediment with sodium bicarbonate.

Contraindications:

Hypersensitivity to benzodiazepines or to any component of drug.

Acute respiratory insufficiency, acute pulmonary insufficiency.

Shock, coma, acute drunkenness with oppression of the vital functions.

Closed-angle glaucoma.

HOBL (heavy current).

Period of childbirth.

Overdose:

Simtpoma. Reception of benzodiazepines often is the reason of development of drowsiness, an ataxy, a dysarthtia and a nystagmus. The overdose of the drug Dormikum® at its isolated reception seldom threatens life, however, can lead to an areflexia, an apnoea, a lowering of arterial pressure, oppression of cardiorespiratory activity and in rare instances – to a coma. If there is a development of a coma, then this state usually proceeds within several hours. However, the coma can have a prolonged and recurrent current, especially at elderly patients. The oppressing influence of benzodiazepines on respiratory function is more expressed at patients with diseases of respiratory system. Benzodiazepines strengthen effect of drugs, the oppressing TsNS, including alcohol.

Treatment. At overdose it is necessary to control indicators of the vital functions. Depending on a condition of the patient carrying out a maintenance therapy can be required. In particular, performing the symptomatic therapy directed to maintenance of cardiovascular and respiratory activity, and also the TsNS functions can be required by patients.

If drug was accepted inside, it is necessary to prevent its absorption by the methods suitable for this purpose, in particular, reception of absorbent carbon not later than in 1-2 h. When using absorbent carbon at unconscious patients, protection of respiratory tracts is necessary. In case of a drug mix proglatyvaniye with something, the gastric lavage which, however, is not the measure which is standardly established for this case is recommended.

If oppression of TsNS reaches considerable degree, use of the antagonist of benzodiazepines – a flumazenil is possible (Анексат®). Introduction of a flumazenil needs to be carried out in the conditions of careful control of a condition of the patient. This drug has a short elimination half-life (about an hour) therefore it is necessary to monitorirovat a condition of the patients who received flumazenit, and after the termination of its action. With extra care flumazenit it is necessary to use along with the drugs reducing a convulsive threshold (for example, tricyclic antidepressants). Additional information on the correct use of a flumazenil (drug Aneksat®) can be obtained in the instruction for its use.

Storage conditions:

Period of validity of 5 years. Not to use after the period of validity specified on packaging.

According to rules of storage of the psychotropic substances entered in the List III of the list of the narcotic, psychotropic substances and their precursors which are subject to control in the Russian Federation. To store at a temperature not above 30ºС in the place protected from light. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous and intramuscular administration of 5 mg / 1 ml and 15 mg / 3 ml. On 1 ml or 3 ml of drug in ampoules from colourless glass (hydrolytic type 1 on EF) with a blue point of an otlom and marking rings. On an ampoule of 5 mg / 1 ml an upper ring of light blue color, the lower ring – violet-purple color; on an ampoule of 15 mg / 3 ml one ring of red color.

10 ampoules of 1 ml or 5 ampoules of 3 ml together with the application instruction place in a cardboard pack with cardboard partitions.