Dormicum® (Dormicum®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceMidazolamMidazolam
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  • Dormicum®
    solution w / m in / in 
    Hoffmann-La Roche Ltd.     Switzerland
  • Midazolam
    solution w / m in / in 
    MOSCOW ENDOCRINE FACTORY, FSUE     Russia
  • Midazolam Hamelin
    solution w / m in / in 
       
  • Fused
    solution w / m in / in 
    Ranbaxy Laboratories Limited     India
    • Dosage form: & nbspSolution for intravenous and intramuscular injection.
    Composition:1 ml of the preparation contains: active substance: midazolam 5 mg;
    Excipients: sodium chloride - 5 mg, hydrochloric acid - 2.76 mg, sodium hydroxide, water for injection.
    Description:Transparent colorless or slightly yellowish liquid.
    Pharmacotherapeutic group:The drug belongs to the List III of the list of narcotic, psychotropic substances and their precursors subject to control in the Russian Federation.
    ATX: & nbsp

    N.05.C.D.08   Midazolam

    Pharmacodynamics:Benzodiazepine short-acting.
    Active substance of preparation Dormikum® - midazolam - belongs to the group of imidobenzo-diazepines. The free base is a lipophilic substance that is poorly soluble in water.
    The presence of the main nitrogen atom in position 2 of the imidobenzodiazepine ring allows midazolam to form water-soluble salts with acids. Pharmacological action of the drug is characterized by a rapid onset and, due to rapid biotransformation, a short duration. Due to its low toxicity, midazolam has a large therapeutic interval.
    Mechanism of action
    Midazolam stimulates ionotropic GABA receptorsAlocated in the central nervous system. In the presence of GABA midazolam binds to benzodia-zepin receptors on the channels for chloride ions, which leads to activation of the GABA receptor and a decrease in the excitability of the subcortical structures of the brain. Consequently midazolam has a sedative and hypnotic effect, as well as anxiolytic, anticonvulsant and central muscle relaxant action. Several subtypes of GABA receptors have been describedA. Sedation, anterograde amnesia and anticonvulsant activity are mediated through GABAA a receptor mainly comprising α1 subunit, anxiolytic and myorelaxing activity is associated with exposure to GABAA a receptor mainly comprising α2 subunit.
    Midazolam has a very rapid sedative and pronounced sleeping pills. After parenteral administration there is a short anterograde amnesia (the patient does not remember the events that occurred during the most intensive action of the active substance).
    Pharmacokinetics:Suction after intramuscular injection
    Midazolam is absorbed from the muscle tissue quickly and completely. The maximum concentration in plasma is reached within 30 minutes. Absolute bioavailability after intramuscular injection exceeds 90%.
    Distribution
    After intravenous administration, the midazolam concentration curve in plasma is characterized by one or two clearly expressed distribution phases. The volume of distribution in the equilibrium state is 0.7-1.2 l / kg body weight. The degree of binding to plasma proteins, mainly with albumin, is 96-98%. D spinal fluid mi-dazolam passes slowly and in small amounts. Midazolam slowly passes through the placental barrier and enters the fetal bloodstream; small amounts are found in breast milk.
    Metabolism
    Midazolam is excreted almost exclusively by biotransformation. Midazolam is hydroxylated by the isoenzyme of the 4A system of cytochrome P450. The main metabolite in plasma and urine is a-hydroxyimidazoles. The concentration of a-hydroxyimidazole in plasma is 12% of the concentration of midazolam.α-Hydroxyimidazolum has pharmacological activity, but only to a minimal extent (about 10%) causes the effects of intravenously administered midazolam. Data on the role of genetic polymorphism in the oxidative metabolism of midazolam are absent.
    Excretion
    In healthy volunteers, the elimination half-life is 1.5-2.5 hours. The plasma clearance is 300-500 ml / min. Removal of midazolam from the body occurs mainly in the kidneys: 60-80% of the received dose is excreted in the urine in the form of glucuronide α-hydroxymidazolam. In the form of unchanged drug in urine, less than 1% of the dose is detected. The half-life of the metabolite is less than 1 hour. With the intravenous drip of midazolam, the kinetics of its excretion does not differ from that after inoculation.
    Pharmacokinetics in special patient groups
    In patients older than 60 years, the elimination half-life can be increased 4-fold.
    In children from 3 to 10 years, the half-life after intravenous administration is shorter than in adults (1-1.5 hours), which corresponds to an increased metabolic clearance of the drug.
    In newborns - perhaps due to the immaturity of the liver - the half-life is increased and is, on average, 6-12 hours, and the clearance of the drug is slowed.
    In obese people, the elimination half-life is longer (8.4 hours) than in people with normal body weight, probably due to an increase in the volume of distribution adjusted for total body weight by approximately 50%. Clearance of the drug is not significantly altered, the half-life of the drug in patients with cirrhosis of the liver may be prolonged, and the clearance - to decrease, compared with similar indicators in healthy volunteers.
    The half-life of the drug in patients with chronic renal failure is similar to that of healthy volunteers.
    In patients who are in a very serious condition, the half-life of midazolam increases.
    In chronic heart failure, the half-life of midazolam is also greater than in healthy individuals.
    Indications:Adults
    Sedation with preservation of consciousness before diagnostic or medical procedures, performed under local anesthesia or without it, and also during their conduct. Premedication before introductory anesthesia.
    Introductory anesthesia.
    As a sedative for combined anesthesia.
    Prolonged sedation in intensive care.
    Children
    Sedation with preservation of consciousness before diagnostic or medical procedures, performed under local anesthesia or without it, and also during their conduct. Premedication before introductory anesthesia.
    Prolonged sedation in intensive care.
    Contraindications:Hypersensitivity to benzodiazepines or to any component of the drug. Acute respiratory failure, acute pulmonary insufficiency.
    Shock, coma, acute alcohol intoxication with oppression of vital functions.
    Closed-angle glaucoma.
    COPD (severe course).
    Period of delivery.
    Carefully:Age over 60, extremely severe condition, respiratory failure, renal and hepatic impairment, heart failure, premature babies (due to the risk of apnea), newborns under 6 months of age, miastenia gravis.
    Pregnancy and lactation:Data for assessing the safety of midazolam in pregnancy is not enough. Benzodiazepines should not be used during pregnancy unless they have a safer alternative. Use of the drug in the last trimester of pregnancy or at high doses during the first stage of labor leads to heart rhythm abnormalities in the fetus, hypotension, a violation of sucking, hypothermia and moderate respiratory depression in the neonate.Moreover, in children whose mothers in the late stages of pregnancy have been receiving benzodiazepines for a long time, a physical dependence may be formed with a certain risk of the abstinence syndrome in the postnatal period.
    Because the midazolam in small quantities penetrates into breast milk, it is recommended that nursing mothers interrupt breastfeeding for 24 hours after taking midazolam.
    Dosing and Administration:Midazolam - a strong sedative, requiring slow administration and individual selection of a dose.
    The dose should be selected individually, and titration of the dose is strongly recommended to safely achieve the desired sedative effect, which corresponds to the clinical need, physical condition and age of the patient, as well as the medication he receives.
    In patients older than 60 years, patients in extremely serious condition, as well as with a high degree of risk and in patients of childhood, the dose should be chosen carefully, taking into account individual risk factors.
    The drug begins approximately 2 minutes after intravenous administration. The maximum effect is achieved within 5-10 minutes.
    Sedation with Consciousness
    For sedation with preservation of consciousness before a diagnostic or surgical procedure, the drug Dormikum® is administered intravenously. The dose should be selected individually, carry out its titration; the drug can not be injected quickly or in jet. The onset of sedation varies individually, depending on the patient's condition and dosing regimen (rate of administration, dose size). If necessary, repeated administration is possible.
    Dormicum ® for sedation with conscious consciousness should be used with caution in patients with impaired respiratory function (see section "Special instructions").
    Adults
    Dormicum® should be administered intravenously slowly, at a rate of approximately 1 mg per 30 seconds.
    - Age <60 years
    The initial dose is 2-2.5 mg, administered 5-10 minutes before the procedure. If necessary, repeated administration in a dose of 1 mg. The average total dose is in the range 3.5-7.5 mg. Usually there is enough of a total dose not exceeding 5 mg.
    - Age> 60 years; patients in extremely serious condition, as well as with a high degree of risk
    The initial dose is reduced to 0.5-1 mg and injected it 5-10 minutes before the procedure. If necessary, re-administered in a dose of 0.5-1 mg.Since in these patients the maximum effect can not be achieved so quickly, additional doses should be titrated slowly and cautiously. Usually there is enough of a total dose not exceeding 3.5 mg.
    Children
    Intravenous administration of Dormikum® is carried out by slow titration until the effect is achieved. The initial dose of Dormikum® is given within 2-3 minutes. Then, before proceeding with the procedure or introducing a second dose, it is recommended to wait another 2-5 minutes to assess the sedation effect. If sedation needs to be strengthened, the dose continues to be titrated with small "steps" until the necessary degree of sedation is achieved. Infants and children younger than 5 years of age may require significantly higher doses than older children and adolescents.
    - <6 months
    Children younger than 6 months are particularly prone to airway obstruction and hypoventilation, so the use of Dormikum® for sedation with conscious consciousness in children younger than 6 months is not recommended unless the potential benefit exceeds potential risks. In these cases, it is extremely important to titrate the dose in small "steps" to achieve a clinical effect, and also carefully monitor patients.The initial dose should be minimally possible with the available technical characteristics of the equipment used
    - From 6 months. up to 5 years
    The initial dose is 0.05-0.1 mg / kg. To achieve the desired effect, the total dose can be increased to 0.6 mg / kg, but it should not exceed 6 mg. With the introduction of higher doses, it is possible to develop prolonged sedation and the risk of hypoventilation (see section "Special instructions").
    - 6 to 12 years
    The initial dose is 0.025-0.05 mg / kg, the total dose can be increased to 0.4 mg / kg, but it should not exceed 10 mg. With the introduction of higher doses, it is possible to develop prolonged sedation and the risk of hypoventilation (see section "Special instructions").
    - From 13 to 16 years
    Doses for children from 13 to 16 years old are the same as for adults.
    Intramuscular injection (children from 1 year to 16 years of age)
    The recommended dose is 0.05-0.15 mg / kg, administered 5-10 minutes before the procedure. Usually there is enough of a total dose not exceeding 10 mg.
    At a body weight of less than 15 kg, the administration of solutions of midazolam with a concentration of more than 1 mg / ml is not recommended. Solutions with a higher concentration should be diluted to a concentration of 1 mg / ml.
    Anesthetic
    Premedication
    Premedication with Dormikum® shortly before the procedure has a sedative effect (the occurrence of drowsiness, and the elimination of emotional stress), and also causes pre-operative amnesia. For premedication, the drug is administered intravenously or intramuscularly (deep into the muscle 20-60 min before the anesthesia).
    After the administration of Dormikum® for the detection of symptoms of overdose, it is necessary to observe the patient, since the individual sensitivity to the drug can vary.
    Dormikum® can be used in combination with anticholinergics.
    Adults <60 years of age and belonging to the class lull according to the classification system of physical status assessment, adopted by the American Society of Anesthesiologists
    For preoperative sedation and removal of memory for preoperative events, the drug is administered in a dose of 1-2 mg intravenously, if necessary repeating the introduction, or intramuscularly - in a dose of 0.07-0.1 mg / kg body weight.
    Adults≥60 years, patients in extremely serious condition, patients with a high degree of risk
    Requires reduction and individual selection of the dose.
    The recommended initial dose for intravenous administration is 0.5 mg, if necessary, increase the dose by slow titration.Before introducing a second dose, wait 2-3 minutes to assess the effect.
    The recommended dose for intramuscular injection is 0.025-0.05 mg / kg (usually 2-3 mg), provided that the patient simultaneously does not receive narcotic drugs.
    The dose of Dormikum® should be reduced by simultaneous administration with narcotic analgesics.
    Children from 1 to 15 years old relatively higher doses are required (per kg body weight) than for adults.
    Doses in the range of 0.08-0.2 mg / kg for intramuscular injection are effective and safe. The drug must be injected deep into the large muscle 30-60 minutes before the anesthesia.
    Children with body weight less than 15 kg are not recommended to administer midazolam solutions with a concentration of more than 1 mg / ml. Solutions with a higher concentration should be diluted to a concentration of 1 mg / ml
    Introductory anesthesia
    If Dormikum® is used for introductory anesthesia before the introduction of other anesthetics, the individual response of patients may be different. The dose should be titrated until the desired effect is achieved in accordance with the age and clinical condition of the patient. When Dormikum® is administered before orcombination with other intravenous or inhalation preparations for anesthesia, the initial doses of each drug can be significantly reduced, sometimes up to 25% of the initial dose set. The desired level of sedation is achieved by stepwise titration of the dose. Induction dose of Dormikum® should be administered intravenously slowly, fractionally. Each subsequent administration of the drug in an amount of not more than 5 mg, should be done within 20-30 seconds, making 2-minute intervals between the administrations.
    Adults <60 years
    A dose of 0.2 mg / kg is given intravenously for 20-30 seconds, waiting for 2 minutes to assess the effect. Usually this dose is sufficient to achieve a satisfactory effect.
    In the absence of premedication, the dose may be increased to 0.3-0.35 mg / kg body weight. It is administered intravenously for 20-30 seconds, waiting for 2 minutes to assess the effect. If necessary, to complete the induction, the drug is administered additionally in amounts equal to approximately 25% of the initial dose. Alternatively, liquid inhalation anesthetics may be used to complete the induction. In cases of immunity, the induction dose of Dormikum® can reach 0.6 mg / kg,However, the restoration of consciousness after such doses may be slowed down.
    Adults> 60 years, patients in extremely serious condition, and also with a high degree of risk
    In the absence of premedication, the smallest induction doses of Dormikum®, 0.15-0.2 mg / kg, are required. In the presence of premedication, intravenous administration of 0.05-0.15 mg / kg is recommended for 20-30 seconds, waiting for 2 minutes to assess the effect. Usually this dose is enough.
    Children
    Dormicum® is not recommended for introductory anesthesia in children, since the experience of its use in this age group is limited.
    As a sedative for combined anesthesia
    Adults <60 years
    The use of Dormikum® as a sedative in combined anesthesia is performed either by fractional intravenous administration of small doses (0.03-0.1 mg / kg) or by continuous intravenous infusion at a dose of 0.03-0.1 mg / kg per hour, usually in combination with analgesics. Doses and intervals between administrations depend on the individual reaction of the patient.
    Adults> 60 years, patients in extremely serious condition, and also with a high degree of risk
    To maintain anesthesia, smaller doses are required.
    Children
    The use of Dormikum® as a sedative for combined anesthesia in children is not recommended, as the experience of its use is limited. Long-term sedation in intensive care
    The desired sedative effect is achieved by stepwise titration of the dose, followed by either continuous infusion or fractional fluid administration of the drug, depending on the clinical need, the patient's condition, age and concomitantly administered drugs.
    Adults
    Intravenous loading dose of 0.03-0.3 mg / kg is administered fractional, slow. Each repeated dose of 1-2.5 mg is administered for 20-30 sec, observing the 2-min intervals between the administrations.
    Patients with hypovolemia, vasoconstriction or hypothermia exercise dose are reduced or not administered at all.
    If Dormikum® is used concomitantly with strong analgesics (in particular, morphine, methadone, pethidine, fentanyl, alfentanil, buprenorphine, pentazocine and derivatives of each subgroup), the latter should be administered before it, so that the dose of Dormikum® can be safely titrated at the height of sedation caused by the analgesic.The intravenous maintenance dose may vary between 0.03-0.2 mg / kg per hour. Patients with hypovolemia, vasoconstriction or hypothermia maintain a dose that is reduced. If the condition of the patient allows, the degree of sedation should be regularly assessed. In the case of prolonged sedation, the development of tolerance is possible, as a result of which the dose will need to be increased.
    Children
    Preterm and premature neonates, as well as children with body weight less than 15 kg, do not recommend the administration of solutions of midazolam with a concentration of more than 1 mg / ml. Solutions with a higher concentration should be diluted to a concentration of 1 mg / ml.
    Children under 6 months
    The drug should be administered by continuous intravenous infusion.
    Newborns with gestational age <32 weeks Dormikum® should be administered at an initial dose of 0.03 mg / kg / h (0.5 μg / kg / min).
    Newborns with gestational age> 32 weeks and children younger than 6 months - at a dose of 0.06 mg / kg / h (1 μg / kg / min).
    Intravenous loading dose is not administered, instead, in the first few hours, infusion is somewhat faster to achieve therapeutic concentrations of the drug in the plasma.The rate of infusion should be frequently and carefully reviewed, especially in the first 24 hours, in order to administer the lowest effective dose and reduce the possibility of cumulation of the drug. It is necessary to carefully monitor the frequency of breathing and oxygen saturation.
    Children over 6 months
    For children who are on artificial lung ventilation and intubated, in order to establish the desired clinical effect, the loading dose of 0.05-0.2 mg / kg is administered intravenously slowly for not less than 2-3 minutes (intravenously can not be injected rapidly). After this, they switch to continuous intravenous infusion at a dose of 0.06-0.12 mg / kg / h (1-2 μg / kg / min). If necessary, to increase or maintain the desired effect, the infusion rate can be increased or decreased (usually by 25% of the initial or subsequent rate) or additional doses of Dormikum®. If the infusion of Dormikum® is started in patients with hemodynamic disorders, the usual loading dose should be titrated with small "steps", controlling hemodynamic indicators (lowering blood pressure). These patients have a propensity for respiratory depression when using Dormikum®, therefore careful monitoring of respiratory rate and oxygen saturation is necessary.
    Dosing in special cases
    Children
    Preterm and premature neonates, as well as children with body weight less than 15 kg, do not recommend the administration of solutions of midazolam with a concentration of more than 1 mg / ml. Solutions with a higher concentration should be diluted to a concentration of 1 mg / ml.
    Children younger than 6 months are not recommended intravenous administration of midazolam, as they are particularly prone to airway obstruction and hypoventilation, except in cases of sedation in intensive care units.
    Dormikum® is not indicated for use in children for induction of anesthesia, and as a sedative in combined anesthesia, as there are only limited data on these indications in children.
    Patients over 60 years of age
    Usually, lower doses of midazolam are needed. It is necessary to constantly monitor the indicators of vital functions.
    Patients with impaired renal function
    The pharmacokinetics of free midazolam is similar to that of healthy volunteers. However, it has been shown that in patients with chronic kidney disease, a-hydroxymidazolam accumulates, which may lead to an increase in the duration of the clinical effects of the drug and prolongation of sedation.
    Patients with impaired hepatic function
    In patients with impaired hepatic function, a decrease in the clearance of midazolam after its intravenous administration and, consequently, an increase in the end-of-life period, which may lead to an increase and an increase in the duration of its clinical effects. Such patients may need lower doses of midazolam, as well as in appropriate monitoring of vital signs.
    Special instructions for dosing
    A solution of Dormikum® in ampoules can be diluted with 0.9% sodium chloride solution, 5% and 10% glucose solution (5% and 10% dextrose solution and 5% levulose solution), Ringer's solution and Hartmann solution in a ratio of 15 mg midazolam per 100-1000 ml of the infusion solution. These solutions remain physically and chemically stable for 24 hours at room temperature or 3 days at 5 ° C.
    Do not dilute Dormikum® with 6% dextran solution with cf. Mol. mass of 50000-70000 Da in dextrose. Do not mix Dormikum® with alkaline solutions, since midazolam gives a precipitate with sodium bicarbonate.
    The use of other solvents other than those mentioned above should be avoided.
    From the microbiological point of view, the prepared solution should be used immediately. If the preparation is not used immediately, the time and storage conditions of the prepared solution are the responsibility of the user and should not exceed 24 hours at a temperature of 2 ° C to 8 ° C and only if the solution is prepared in controlled and validated aseptic conditions. Dermicum® ampoules are for single use only. Dispose of unused solution.
    Before administration, it is necessary to inspect the solution. Only a transparent solution without visible foreign particles is suitable for use.
    After freezing, precipitation may occur, which dissolves when shaken at room temperature.
    Side effects:From the immune system: reactions of generalized hypersensitivity (skin, cardiovascular reactions, bronchospasm), angioedema, anaphylactic shock.
    From the psychic sphere: confusion, euphoria, hallucinations.
    Cases of paradoxical reactions, such as agitation,involuntary motor activity (including tonic-clonic convulsions and muscular tremor), hyperactivity, hostile mood, anger and aggressiveness, excitatory paroxysms. especially in children and senile patients.
    The use of Dormikum®, even in therapeutic doses, especially with prolonged sedation, can lead to the formation of physical dependence. The risk of dependence increases with the increase in the dose of the drug and the duration of its use, as well as in patients with alcoholism and / or having a history of drug dependence. The abolition of the drug, especially acute, after its long intravenous use, may be accompanied by withdrawal symptoms, including seizures.
    From the central and peripheral nervous system: long sedation, decreased concentration, headache, dizziness, ataxia, postoperative somnolence, anterograde amnesia, the duration of which depends directly on the dose. Anterograde amnesia may occur at the end of the procedure, in some cases it lasts longer.Retrograde amnesia, anxiety, drowsiness and delirium upon withdrawal from anesthesia, athetoid movements, sleep disturbance, dysphoria, fuzzy speech, paresthesia.
    Preterm infants and neonates described seizures.
    From the cardiovascular system: In rare cases, severe cardiorespiratory adverse events developed. They consisted in cardiac arrest, lowering of arterial pressure, bradycardia, vasodilation. The likelihood of such life-threatening reactions is higher in adults over 60 years of age and in those with concomitant respiratory failure or heart failure, especially if the drug is administered too quickly or in large doses (see section "Special instructions"). Tachycardia, bigemia, premature ventricular contraction, vasovagal crisis, rhythm of atrioventricular junction.
    On the part of the respiratory system: In rare cases, severe cardiorespiratory adverse events developed. They consisted in oppression, stopping breathing, development of apnea, dyspnoea, laryngospasm. The likelihood of such life-threatening reactions is higher in adults over 60 years and in those with concomitant respiratory failure or cardiacinsufficiency, especially if the drug is administered too quickly or in a large dose (see section "Special instructions"). Hiccups, bronchospasm, hyperventilation, wheezing, shallow breathing, airway obstruction, tachypnea.
    From the gastrointestinal tract: nausea, vomiting, constipation, dry mouth, sour taste in the mouth, drooling, belching.
    From the skin and subcutaneous fat: skin rash, hives, itching. General and local reactions: erythema and pain at the injection site, thrombophlebitis, thrombosis, hypersensitivity.
    From the sense organs: impairment and deterioration of visual acuity, double vision, nystagmus, miosis, periodic eyelid twitches, pre-stubborn condition, violation of refraction, stuffiness in the ears, loss of balance.
    The use of benzodiazepines increases the risk of falls and fractures. In the area of ​​special risk are patients who take concomitant sedatives (including alcoholic beverages), as well as patients of elderly and senile age.
    Overdose:Symptoms
    The use of benzodiazepines is often the cause of drowsiness, ataxia, dysarthria and nystagmus.Overdosing of Dormikum® with its isolated intake rarely threatens life, however, it can lead to areflexia, apnea, lowering blood pressure, suppressing cardiorespiratory activity and, in rare cases, coma. If a coma develops, then this condition usually lasts for several hours. However, coma can have a prolonged and recurrent course, especially in elderly patients. The inhibitory effect of benzodiazepines on respiratory function is more pronounced in patients with diseases of the respiratory system. Benzodiazepines increase the effect of drugs that depress the central nervous system, including alcohol. Treatment
    In case of an overdose, it is necessary to monitor vital signs. Depending on the patient's condition, maintenance therapy may be required. In particular, patients may require symptomatic therapy aimed at maintaining cardiovascular and respiratory activities, as well as the functions of the central nervous system.
    If the drug has been ingested, it is necessary to prevent its absorption by suitable methods, in particular,with the use of activated carbon no later than in 1-2 hours. When using activated carbon in unconscious patients, protection of the respiratory tract is necessary. If the mixture is swallowed with anything, gastric lavage is recommended, which, however, is not a standard measure for this case.
    If the CNS depression reaches a significant degree, the use of a benzodiazepine antagonist - flumazenil (Anexat ®) is possible. The administration of flumazenil should be carried out under conditions of careful monitoring of the patient's condition. This drug has a short half-life (about an hour), so it is necessary to monitor the condition of patients who received flumazenil, and after its termination. With extreme caution flumazenil should be used concomitantly with drugs that reduce the convulsive threshold (eg, tricyclic antidepressants). Further information on the proper use of flumazenil (Anexat® preparation) can be obtained from the instructions for its use.
    Interaction:Pharmacokinetic interactions
    The metabolism of midazolam is mediated almost exclusively by the cytochrome P4503A4 system (CYP3A4 isoform).Substances, inhibitors and inducers of the isoenzyme CYP3A4 have the potential to increase and decrease the plasma concentration, and hence the pharmacodynamic effects of midazolam. In addition to the effect on the activity of the isoenzyme CYP3A4, no other mechanism has been found that causes clinically significant changes as a result of the inter-drug interaction of midazolam with other substances. However, there is a theoretical possibility of displacing the drug from the connection with plasma proteins (albumin) with its simultaneous application to medicinal substances with sufficiently high therapeutic concentrations in the blood plasma. For example, this mechanism of inter-drug interaction is assumed for midazolam and valproic acid. There were no cases of midazolam influence on the pharmacokinetics of other drugs.
    Taking into account the fact that it is possible to increase and prolong the duration of the clinical effects of midazolam when it is used in conjunction with substances inhibiting the isoenzyme CYP3A4, careful monitoring of clinical effects as well as indicators of vital functions is recommended.Depending on the degree of inhibitory effect on the isoenzyme CYP3A4, the dose of midazolam can be significantly reduced. On the other hand, the joint use of midazolam with induction preparations of the CYP3A4 isoenzyme may necessitate an increase in the dose of midazolam to achieve the desired effect.
    In the case of induction of the CYP3A4 isoenzyme or its irreversible inhibition (in this case irreversible interaction with cytochrome P450 resulting in complex inactivated complexes), the effect on the medacokinetics of midazolam may persist for several days, up to several weeks after the administration of inhibitors of the CYP3A4 isoenzyme. An example of irreversible inhibition of the CYP3A4 isoenzyme is the use of antibacterial (clarithromycin, erythromycin, isoniazid), antihypertensive drugs (verapamil, diltiazem), drugs for the treatment of HIV infection (HIV protease inhibitors, delavirdine), sex steroid hormones (gestoden), and modulators of their receptors (raloxifene), as well as certain substances of plant origin (bergamotin, which is found in particular in grapefruit).Unlike other irreversible inhibitors (see. Below) ethinyl estradiol / norgestrel when used as an oral contraceptive, and grapefruit juice (200 ml) have no significant effect on the magnitude of plasma concentrations of midazolam when administered intravenously.
    The intensity of inhibitory / inducing effects of drugs varies widely. For example, an antifungal drug ketoconazole is a potent inhibitor of the isoenzyme CYP3A4 and increases the plasma concentration of intravenously administered midazolam by a factor of 5. The drug of tuberculostatic action rifampicin It is one of the most potent inducers of CYP3A4 isoenzyme and its combined use with intravenous midazolam reduces the plasma midazolam concentrations by approximately 60%.
    The use of midazolam also affects the extent of changes in pharmacokinetic parameters due to modulation of the activity of the CYP3A4 isoenzyme. With intravenous administration, a lower degree of change in plasma concentration can be expected compared with the oral route of administration,since the modulation of the activity of the CYP3A4 isoenzyme affects not only the overall clearance, but also the bioavailability of midazolam when administered orally. It should be noted that studies aimed at studying the effect of the altered activity of the CYP3A4 isoenzyme on the pharmacokinetics of midazolam after its intramuscular injection have not been conducted. After intramuscular injection, the drug immediately enters the systemic bloodstream, therefore it is considered that the effect of the altered activity of the CYP3A4 isoenzyme on the pharmacokinetics will be the same as for intravenous administration. In accordance with the pharmacokinetic principles in clinical studies, it was shown that, after a single intravenous dose of midazolam, changes in the magnitude of the maximum clinical effect due to the changed activity of the CYP3A4 isoenzyme are negligible, while the duration of this effect may increase. However, with further administration of the drug (continuation of treatment) against the background of inhibition of the activity of the CYP3A4 isoenzyme, both the magnitude and duration of the clinical effect increase.
    The following are examples of possible cases of inter-drug interaction of midazolam with intravenous administration with other drugs. It is important to note that any drug that has been shown to be able to change the activity of the CYP3A4 isoenzyme in vitro and in vivo can alter the plasma concentration of midazolam and therefore its clinical effectiveness. In the absence of data on the joint administration of a drug with the intravenous form of midazolam, the data obtained in clinical studies of its joint administration with the oral form of midazolam are presented. In this case, it is important to note that the change in the plasma concentration of midazolam due to a change in the activity of the isoenzyme CYP3 A4 is more pronounced when administered orally than with intravenous administration.
    Inhibitor preparations of CYP3A4 isoenzyme
    Antifungal agents from the azole group
    Ketoconazole. 5 times increases the plasma concentration of intravenously administered midazolam, approximately 3-fold increases the final half-life. Parenteral administration of midazolam together with ketoconazole, a potent inhibitor of the isoenzyme CYP3A4,should be performed in the intensive care unit or in some other department where there is scope for careful clinical monitoring and the necessary treatment in the event of respiratory depression and / or prolonged sedation. Individual selection of the dose of the drug is necessary, as well as a phased introduction, especially in cases of more than a single administration of midazalam.
    Fluconazole and itraconazole. In 2-3 times increase the plasma concentration of intravenously administered midazolam. Increase the final half-life period of midazolam by 2.4 times (itraconazole) and 1.5 times (fluconazole).
    Posaconazole. In 2 times the plasma concentration of intravenously administered midazolam increases.
    Macrolides
    Erythromycin. Increases in 1.6-2 times the plasma concentration of intravenously administered midazolam, approximately 1.5-1.8 times the final half-life. Clarithromycin. Increases to 2.5 times the plasma concentration of midazolam, increases the final half-life by 1.5-2 times.
    Additional information for the oral form of midazolam
    Roxithromycin.     Has less influence on the pharmacokinetics of midazolam in comparison with erythromycin and clarithromycin.Increases the plasma concentration of midazolam after oral administration by 50%. For comparison, erythromycin increases this indicator by 4.4 times, clarithromycin - in 2.6 times. Moderate effect on the final half-life of midazolam, namely an increase of 30%, suggests that the effect of roxithromycin on the pharmacokinetics of intravenously administered mid-zolam is negligible.
    HIV protease inhibitors
    Saquinavir and other HIV protease inhibitors. With the joint administration of midazolam with lopinavir and ritonavir (booster combination), the plasma concentration of intravenously administered midazolam increases by a factor of 5.4, which is combined with the same increase in the final half-life. Parenteral administration of midazolam together with HIV protease inhibitors requires certain hospitalization conditions (see para. ketoconazole).
    Blockers of H2-histamine peptoates
    Cimetidine.     Increases the equilibrium plasma concentration of midazolam by 26%.
    Blockers of slow calcium channels
    Diltiazem.     A single dose of diltiazem increases the plasma concentration of midazolam with its intravenous administration by about 25% and extends the final half-life by 43%.
    Additional information for the oral form of midazolam Verapamil / diltiazem. Increase the plasma concentration of the oral form of midazolam by 3 and 4 times, respectively. Increase the final half-life period of midazolam by 41% and by 49%, respectively.
    Other medicinal products / Phytopreparates
    Atorvastatin. In 1.4 times increases the plasma concentration of intravenously administered midazolam.
    Additional information for the oral form of midazolam
    Fluvoxamine.     Causes a moderate increase in the plasma concentration of midazolam after oral administration (by 28%), and also doubles the duration of the final half-life.
    Nefazodone. Increases the plasma concentration of midazolam by 4.6 times, the final half-life extends by 1.6 times.
    Aprepitant. Dose-dependent increases the plasma concentration of midazolam, administered orally. The increase is approximately 3.3 times when taking aprepitant at a dose of 80 mg / day, and the final half-life is doubled.
    Chloroxazone. It causes a decrease in the ratio of a-hydroxymidazolam / midazolam, which indicates the inhibitory effect of chlorocarbose on the isoenzyme CYP3A4. Bicalutamide. Has a negligible effect on the plasma concentration of midazolam after oral administration. Increases plasma concentration by 27%.
    Yellow Canadian (Hydrastis Canadensis). Causes a decrease in the ratio of α-hydroxymidazolam / midazolam by about 40%, indicating an inhibitory effect on the isoenzyme CYP3A4.
    CYP3A4 isoenzyme induction preparations
    Rifampicin.     After taking rifampicin for 7 days at a dose of 600 mg per day, the plasma concentration of midazolam decreases after its intravenous administration by approximately 60%. The final half-life decreases by approximately 5-60%.
    Additional information for the oral form of midazolam is carbamazepine / phenytoin. Taking multiple doses of carbamazepine or phenytoin causes a decrease in the plasma concentration of midazolam administered orally by 90% and shortens the final half-life by 60%.
    Efavirenz. A 5-fold increase in the ratio of the concentrations of α-hydroxymidazolam formed with the isoenzyme CYP3A4 and midazolam indicates an inducing effect on the isoenzyme CYP3 A4.
    Phytomedication and food products
    Extract of the root of Echinacea purpurea.     Reduces the plasma concentration of intravenously administered midazolam by 20%. The final half-life decreases by approximately 42%.
    St. John's Wort (perforated). Reduces the plasma concentration of intravenously administered midazolam by approximately 20-40%. The final half-life decreases by approximately 15-17%.
    Other interactions
    Valproic acid.     There is a potential for the displacement of midazolam from the connection with plasma proteins (albumin) valproic acid. It can not be ruled out that, due to the high therapeutic concentration of valproic acid in the blood serum obtained after its administration, midazolam may be displaced from the bond with serum proteins, which may lead to a change in the clinical effect of midazolam administered in emergency sedation, in the direction of its amplification.
    Pharmacodynamic interactions
    The joint administration of midazolam with other sedatives and hypnotics, including alcohol, may lead to increased sedation and hypnotic effects. This interaction is possible with the use of opiates and opioids (when taken as analgesics,antipsychotics, substitution therapy agents), antipsychotics (antipsychotics), various benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomid, while also taking midazolam with antidepressants with sedative action, antihistamines and antihypertensive drugs means of central action. Midazolam reduces the minimum alveolar concentration of inhaled anesthetics.
    Strengthening the effects of midazolam (sedation effect on the respiratory system and hemodynamics) can occur when it is used simultaneously with any drugs that depress the central nervous system (CNS), including alcohol. With such a joint use of drugs, adequate monitoring of vital signs is necessary. Avoid simultaneous administration of midazolam and alcohol (see section "Special instructions"). Spinal anesthesia can increase the sedation effect of midazolam, with its intravenous administration. In this case, a reduction in the dose of midazolam is necessary.Also, a reduction in the dose of intravenously administered midazolam is necessary in cases of its simultaneous use with lidocaine or bupivacaine when administered intramuscularly.
    Drugs that activate brain activity, improve memory, attention such as an inhibitor of acetylcholinesterase physostigmine, can reduce the hypnotic effect of midazolam. Similarly, 250 mg of caffeine partially reduces the sedative effect of midazolam.
    Incompatibility
    Do not dilute Dormikum® with a 6% solution of dextran with an average molecular weight of 50,000-70000 Da in dextrose. Do not mix Dormikum® with alkaline solutions, since midazolam gives a precipitate with sodium bicarbonate.
    Special instructions:Midazolam for parenteral administration should be used only in the presence of resuscitative equipment, since its intravenous administration can inhibit myocardial contractility and cause respiratory arrest. In rare cases, severe cardiorespiratory adverse events developed. They consisted of oppression, stopping breathing and / or stopping the heart. The likelihood of such life-threatening reactions increases with too rapid administration of the drug or when administered in a large dose (see section "Side effect").
    When conducting sedation with the preservation of consciousness, a non-anesthesiologist should adhere to current practical recommendations.
    When using Dormikum® in a hospital of one day, the patient can be discharged only after an examination by an anesthesiologist. The patient can leave the clinic only with an accompanying person.
    When conducting premedication after the introduction of midazolam, careful monitoring of the patient's condition is mandatory, since individual sensitivity to the drug may differ and it is possible that the symptoms of an overdose may develop.
    Particular care is needed when parenterally administering midazolam to patients at high risk: over 60 years of age, who are extremely ill, suffering from impaired respiratory function, kidney function, liver, and cardiac dysfunction. These patients require smaller doses (see the section on "Method of administration and dose") and continuous monitoring for the early detection of violations of vital functions. With prolonged use of Dormikum® for sedation in the intensive care unit, a certain reduction in the effect of the drug is described.
    Since the abrupt withdrawal of Dormikum®, especially after prolonged intravenous use (more than 2-3 days), may be accompanied by symptoms of withdrawal, it is recommended to reduce its dose gradually. The following symptoms of withdrawal may develop: headache, muscle pain, increased anxiety, tension, arousal, confusion, irritability, "ricochet" insomnia, mood swings, hallucinations, convulsions.
    Dormicum® causes anterograde amnesia. Long-term amnesia may present a problem for patients who are about to be discharged after a surgical or diagnostic procedure.
    Cases of paradoxical reactions, such as agitation, involuntary motor activity (including tonic-clonic convulsions and muscle tremor), hyperactivity, hostile mood, anger and aggressiveness, excitatory paroxysms are described. Such reactions can develop in cases of administration of sufficiently large doses of midazolam, as well as with the rapid administration of the drug. Some increased predisposition to such reactions is described in children and in elderly patients with intravenous administration of high doses of midazolam.
    Simultaneous administration of midazolam with drugs inhibitors / inducers of the isoenzyme CYP3A4 can lead to a change in its metabolism, so that there may be a need for a corresponding change in the dose of midazolam (see section "Interaction with other drugs").
    The half-life of the drug may be prolonged in patients with impaired liver function, low cardiac output, as well as in newborns (see section "Dosage and administration", subsection "Dosage in special cases").
    Particular caution is needed in sedation in preterm infants (born less than 36 weeks of gestation) if they are not intubated, due to the risk of apnea. It is necessary to avoid rapid administration of the drug in this group of patients. Careful monitoring of breathing and oxygen saturation is necessary.
    Children younger than 6 months are particularly prone to airway obstruction and hypoventilation, so in these cases it is extremely important to titrate the dose, increasing it in small "steps" to achieve a clinical effect, and carefully monitor the respiratory rate and oxygen saturation.
    It should avoid sharing the drug Dormikum® with alcohol and / or drugs that depress the central nervous system. In such cases, it is possible to increase the clinical effects of Dormikum®, the development of severe sedation, as well as the clinically significant inhibition of respiratory and cardiovascular activity (see section "Interaction with other drugs").
    It is necessary to avoid the use of Dormikum ® in patients suffering from alcoholism, as well as having a history of drug addiction.
    As with any drug that depresses the central nervous system and has a muscle relaxant effect, special care should be taken when administering midazolam to patients with myastenia gravis.
    Effect on the ability to drive transp. cf. and fur:Sedation, amnesia, reduced concentration of attention, impaired muscle function have a negative effect on the ability to drive a car or work with mechanisms. Do not drive vehicles or work with machines or mechanisms until the effect of the drug is completely eliminated. The resumption of such activities should take place with the permission of the attending physician.
    Form release / dosage:Solution for intravenous and intramuscular injection 5 mg / 1 ml and 15 mg / 3 ml.
    Packaging:1 ml or 3 ml of the drug into ampoules of colorless glass (hydrolytic type 1 according to EF) with a blue break point and marking rings. On the ampoule 5 mg / 1 ml the top ring is light blue, the lower ring is purple-purple; on an ampoule of 15 mg / 3 ml one ring of red color.
    10 ampoules in volume of 1 ml or 5 ampoules in volume of 3 ml together with the instruction on application place in a cardboard pack with cardboard partitions.
    Storage conditions:In accordance with the rules for storage of psychotropic substances listed in Schedule III of the list of narcotic, psychotropic substances and their precursors subject to control in the Russian Federation.
    Store at a temperature of no higher than 30 ° C in a dark place.
    Keep out of the reach of children.
    Shelf life:5 years.
    Do not use after the expiration date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:П N016119 / 01
    Date of registration:24.12.2009 / 11.08.2014
    Expiration Date:Unlimited
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp2016-10-03
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