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

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 administration

Composition:

1 ml of the solution contains:

Active substance:

midazolam - 5,00000 mg.

Excipients:

sodium chloride - 5,00000 mg,

hydrochloric acid 0.00234 ml,

1 M sodium hydroxide solution to pH 3.3,

water for injection - up to 1 ml.

Description:Transparent colorless liquid.

Pharmacotherapeutic group:Sleeping Pills

ATX: & nbsp

N.05.C.D.08 Midazolam

Pharmacodynamics:

Mechanism of action

Midazolam is a benzodiazepine of short action, belongs to the group of imidobenzodiazepines. These compounds stimulate the benzodiazepine receptors in the membranes of central nervous system (CNS) neurons, which are allosteric linked to gamma-aminobutyric acid receptors (GABAd receptors). When stimulating benzodiazepine receptors, the sensitivity of GABA receptors to GABA (the inhibitory mediator) increases. When GABA receptors are excited, C1 channels are opened; Cl ions^- enter the nerve cells, this leads to hyperpolarization of the cell membrane. With the action of benzodiazepines, the frequency of opening of the Cl-channels increases.Thus, benzodiazepines enhance the inhibition processes in the central nervous system.

Pharmacological effects of benzodiazepines:

1) anxiolytic (elimination of feelings of anxiety, fear, tension);

2) sedative;

3) hypnotics;

4) myorelaxing;

5) anticonvulsant;

6) amnestic (at high doses, benzodiazepines cause anterograde amnesia about 6 hours, which can be used for premedication before surgical operations).

Pharmacological action is characterized by short duration because of rapid degradation of midazolam. Quickly causes the onset of sleep (after 20 minutes), has little effect on the structure of sleep, almost does not have the effect of aftereffect.

The onset of action: sedative - 15 minutes (intramuscular (IM) administration), 1.5-5 minutes (intravenous (iv) injection); introductory general anesthesia with / in the introduction - 0,75-1,5 minutes (with premedication of narcotic drugs), 1,5-3 minutes (without premedication with narcotic drugs). The duration of the amnestic effect is in direct proportion to the dose. The time of recovery from general anesthesia is 2 hours on average. After intramuscular or intravenous administration, anterograde amnesia of short duration is observed.

Pharmacokinetics:

Absorption

With intramuscular administration, the absorption of midazolam from muscle tissue passes quickly and completely. The maximum concentration in plasma is reached within 30 minutes. Absolute bioavailability after intravenous injection is more than 90%.

Distribution

The pharmacokinetic profile of midazolam is linear. When administered intravenously, the distribution is biphasic. The equilibrium volume of distribution is 0.7-1.2 l / kg. The connection with plasma proteins is 96-98%. Linking primarily with albumin, midazolam penetrates through gistogematicheskie barriers, incl. hematoencephalic and placental barriers, as well as in breast milk. Small concentrations are found in the cerebrospinal fluid.

Metabolism

Midazolam is almost completely exposed to biotransformation, it is excreted mainly in the form of metabolites. Hydroxylated with the isoenzyme CYP3A4 to a-hydroxymidazolam (the main metabolite in plasma and urine). Plasma concentration of a-hydroxymidazolam reaches 12% of the starting material. Pharmacological activity is 10% of the activity of midazolam.

Excretion

In healthy volunteers, the elimination half-life (T_1/2) of midazolam is 1.5-2.5 hours.Plasma clearance is 300-500 ml / min. It is mainly excreted by the kidneys (60-80% of the administered dose) mainly in the form of glucuronide a-hydroxyimidazolam. Less than 1% is excreted unchanged in the urine. T_1/2α-hydroxymidazolam is <1 hour.

Pharmacokinetics with intravenous drip administration: in some intensive care patients, and in some elderly patients who received midazolam drip for prolonged sedation, the half-life was increased to six times. Among the special risk factors are elderly age, pathology of the abdominal cavity, sepsis and reduced renal function. In these patients, the infusion of midazolam at a constant rate led to an increase in the concentration of the drug in the plasma in the equilibrium state. Therefore, the infusion rate should be reduced as soon as a satisfactory clinical effect is obtained.

Pharmacokinetics in specific patient groups

Elderly patients.

In persons over 60 years of age, T_1/2 can be increased fourfold.

Children.

After intravenous administration to children 3-10 years of age, T_1/2 compared with adults shorter (1-1.5 hours), which is explained by the more intensive metabolism of midazolam.

Newborns.

In newborns, the half-life (T_1/2) is increased and averages 6-12 hours, and the clearance of the drug is slowed.

Patients with excessive body weight.

In persons with overweight, the clearance is slow, T_1/2 is 8.4 hours. Patients with hepatic insufficiency.

The half-life period of midazolam in patients with cirrhosis of the liver may be prolonged, and the clearance decreases, in comparison with similar indices in healthy volunteers.

Patients with renal insufficiency.

In patients with chronic renal failure T_1/2 the same as in healthy volunteers.

Severely ill patients.

In patients in extremely serious condition, the half-life (T_1/2) midazolam increases.

Patients with heart failure.

In patients with chronic heart failure compared with healthy volunteers, T_1/2 increases.

Indications:

Adults

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

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 carrying out.

Premedication before introductory anesthesia.

Prolonged sedation in intensive care.

Contraindications:

Hypersensitivity to benzodiazepines or other components of the drug.

Acute respiratory failure, acute respiratory distress syndrome.

Shock, coma, acute alcohol intoxication with oppression of vital functions.

Closed-angle glaucoma.

Period of childbirth (see the section "Application during pregnancy and during breast-feeding").

If you have any of these diseases, consult a doctor before taking the drug.

Carefully:

Chronic heart failure, chronic respiratory failure, liver failure, chronic renal failure, obesity, advanced age, children under 6 months (especially newborns and premature babies), organic brain damage,alcohol and drug intoxication with oppression of vital functions, Myasthenia gravis.

If you have any of these diseases, consult a doctor before taking the drug.

Pregnancy and lactation:

Data for assessing the safety of midazolam in pregnancy is not enough. The use of benzodiazepines is possible only in the absence of other alternative treatments.

Appointment of the drug Midazolam in the last trimester of pregnancy or at high doses during the first stage of labor leads to impaired heart rate of the fetus, hypotension, disruption sucking, hypothermia and moderate respiratory depression in the newborn. 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, nursing mothers should interrupt breast-feeding within 24 hours after the application of midazolam.

Dosing and Administration:

Intravenous, intramuscular.

The drug begins approximately 2 minutes after intravenous administration. The maximum effect is achieved within 5-10 minutes. With intramuscular injection, sedation in adults develops after 15 minutes. Time to achieve maximum sedation with intramuscular injection 30-60 minutes. With intravenous injection for narcosis, the effect manifests itself after 1.5-3 minutes, and against a background of drug premedication after 0.75-1.5 minutes. The time to leave the narcosis is 2 hours (up to 6 hours).

The dose is selected individually, to achieve the desired severity of sedative action, appropriate clinical needs, the physical condition and age of the patient, as well as concomitant drug therapy.

The rate of onset of the therapeutic effect depends on the dose administered and the mode of administration of the drug.

With intravenous administration, to achieve a sedative effect before diagnostic or treatment procedures performed under local anesthesia or without it, and during diagnostic or therapeutic procedures, the development of a sedative effect is achieved between 2.8 and 4.8 minutes.

With an initial anesthesia, the effect develops after about 1.5 minutes (range is 0.3 to 8 minutes). When used for premedication combination with opioid drugs, the effect develops after about 0.75-1.5 minutes.

Approximately two hours are required to completely restore the patient after using midazolam; however, the duration of the effect depends on the dose administered and the use of additional drugs.

For intravenous administration, a solution is prepared in a ratio of 15 mg of midazolam to 100-1000 ml of one of the following solutions for injection: 0.9% sodium chloride solution, 5% or 10% glucose solution (5% and 10% dextrose solution and 5% levulose solution ), Ringer's solution and Hartman's solution.

The standard dosage regimen is shown in the table:

Indication

Adults under the age of 60

Adults over 60 years of age / patients in extremely serious condition, as well as with a high degree of risk

Children

Sedation with preservation of consciousness before diagnostic or treatment procedures, performed under local anesthesia or without it, and also during their

I / O slowly

Initial dose: 2-2.5 mg

Subsequent dose: 1 mg

Average total dose: 3,5-7,5 mg

I / O slowly

Initial dose: 0.5-1 mg

Subsequent doses: 0.5-1 mg

Total dose: <3.5 mg

In / in children from 6 months to 5 years

Initial dose: 0.05-0.1 mg / kg

Total dose: not more than 6 mg

In / in children from 6 to 12 years

Initial dose: 0.025-0.05 mg / kg

Total dose: not more than 10 mg

In / in children from 13 to 18 years

Doses as in adults

In / m for children from 1 to 18 years

0.05-0.15 mg / kg

Total dose: not more than 10 mg

Premedication before introductory anesthesia

I / O slowly

Dose: 1-2 mg, if necessary, repeat the introduction;

w / m

Dose: 0.07-0.1 mg / kg

In / m

Dose: 0.025-0.05 mg / kg

In / m children from 6 months to 18 years

Dose: 0.08-0.2 mg / kg

In children younger than 6 months, including newborns, the drug for this indication is not applied

Introductory anesthesia

I / O slowly

Dose: 0,15-0,2 mg / kg (0,3-0,35 mg / kg without premedication)

I / O slowly

Dose: 0.1-0.2 mg / kg (0.15-0.3 mg / kg without premedication.

0,15-0,25 mg / kg without premedication in patients with severe systemic diseases)

Children do not use this indication

Sedative component with combined anesthesia

I / in slowly fractional

Dose:

0,03-0,1 mg / kg

or continuous intravenous infusion

Dose:

0,03-0,1 mg / kg / h

IV fractional introduction

continuous intravenous infusion

in dosages lower than those recommended for adults <60 years

Children do not use this indication

Long-term sedation in intensive care

I / in slowly fractional

The initial dose: 0.03-0.3 mg / kg,

then 1-2.5 mg for 20-30 seconds with an interval of 2 minutes.

Maintenance dose: 0.03-0.2 mg / kg / h

IV infusion in infants <32 weeks of gestational age

Initial dose:

0.03 mg / kg / h (0.5 μg / kg / min)

IV infusion in newborns> 32 weeks of gestational age and children up to 6 months

Initial dose: 0.06 mg / kg / h (1 μg / kg / min)

In / in slowly to children from 6 months

Initial dose: 0.05-0.2 mg / kg or

Intravenous infusion

Dose: 0.06-0.12 mg / kg / h (1 -2 μg / kg / min)

Sedation with preservation of consciousness before diagnostic or treatment procedures, performed under local anesthesia or without it, and also during their

Adults

The drug solution is administered intravenously slowly, at a rate of about 1 mg per 30 seconds. In adults up to 60 years of age, the initial dose is 2-2.5 mg, the administration takes place 5-10 minutes before the procedure. Further midazolam administered at a dose of 1 mg as needed. The average total doses are in the range 3.5-7.5 mg. A total dose of more than 5 mg is usually not required. In adults over 60 years old / patients who are in extremely serious condition, and also with a high degree of risk, the administration starts with a dose of 0.5-1 mg. Further midazolam administered at a dose of 0.5-1 mg as needed. A total dose greater than 3.5 mg is usually not required.

Children

Intravenous administration

The initial dose of midazolam is slowly administered for 2-3 minutes. Then wait 2-5 minutes to fully assess the sedation before starting the procedure or repeat the introduction of midazolam. Infants and children younger than 5 years of age may require significantly higher doses than older children and adolescents.

Children from 6 months to 5 years: the initial dose of 0.05-0.1 mg / kg, to achieve the expected result, a total dose of up to 0.6 mg / kg is sometimes required, but the total dose should not exceed 6 mg.

Children from 6 to 12 years: the initial dose is 0.025-0.05 mg / kg. The total dose to 0.4 mg / kg, the maximum - 10 mg.

Children from 13 to 18 years: dosing regimen as in adults.

Intramuscular injection

Children from 1 to 18 years: the dose range is 0.05-0.15 mg / kg. The total dose is no more than 10 mg.

Premedication before introductory anesthesia

Adults

Premedication before the procedure has a sedative effect (occurrence of drowsiness, elimination of emotional stress), and also causes preoperative amnesia. For premedication, the drug is administered intravenously or intramuscularly.

Intravenous administration

For preoperative sedation and elimination of memories of preoperative events midazolam administered intravenously in a dose of 1-2 mg, if necessary, the administration is repeated.

Intramuscular injection

The drug is administered 20-60 minutes before the introduction of anesthesia: adults under 60 years of age - 0,07-0,1 mg / kg, patients older than 60 years / patients in extremely serious condition, and also with a high degree of risk, the dose is selected individually (usually it is 0.025-0.05 mg / kg). The total dose is 2-3 mg.

Children from 6 months to 18 years

Children need relatively higher doses of midazolam (per kilogram of body weight) than adults. Doses in the range of 0.08-0.2 mg / kg with intramuscular injection are effective and safe. The drug is injected deeply intramuscularly into a large muscle 30-60 minutes before the initial anesthesia.

In children younger than 6 months, including newborns, the drug is not used for this indication.

Introductory anesthesia

The drug is administered intravenously, slowly, fractionally, every repeated dose (increase no more than 5 mg) is administered for 20-30 seconds, with an interval of 2 minutes. To complete the input into anesthesia, the initial dose is increased by approximately 25%, or inhalation anesthetics are used.When used in combination with other preparations for introductory anesthesia, the initial dose of each drug should be significantly reduced. The desired level of anesthesia is achieved through a step-by-step introduction.

Adult to 60 years of age - 0,15-0,2 mg / kg (for non-premedicated adults up to 60 years, the dose may be increased - 0,3-0,35 mg / kg). With insufficient sedation, the dose of midazolam is increased to 0.6 mg / kg, but such large doses may slow the recovery of consciousness.

Adults over 60 years of age / patients in extremely serious condition, as well as with a high degree of risk - 0.1-0.2 mg / kg (unadjusted to patients older than 60 years, an increased dose of 0.15-0.3 mg / kg is usually required, unadulterated patients with severe systemic diseases usually require a smaller dose - 0 , 15-0.25 mg / kg).

Children

Midazolam is not recommended for induction of anesthesia in children, since the experience of its use in this age group is limited.

Sedative component with combined anesthesia

When used as a sedative in combined anesthesia, intravenously injected fractional low doses of midazolam (0.03-0.1 mg / kg), or a continuous intravenous infusion (0.03-0.1 mg / kg / h),usually in combination with analgesics. The dose and intervals between doses vary according to the patient's individual response.

In persons over 60 years of age / patients in extremely serious condition, as well as with a high degree of risk use lower maintenance doses.

Children

Midazolam is not recommended for use as a sedative in combined anesthesia in children, since the experience of its use in this age group is limited.

Long-term sedation in intensive care

The desired level of sedation is achieved through the gradual administration of midazolam in accordance with clinical need, physical condition, age and concomitant therapy.

Adults

Intravenously fractional: initial dose: 0.03-0.3 mg / kg (each repeated dose of 1-2.5 mg administered for 20-30 seconds, with an interval of 2 minutes). In patients with hypovolemia, vasoconstriction, or hypothermia, the dose is reduced or the administration is skipped.

When the drug is administered together with strong analgesics, the analgesic is administered first, so that the dose of midazolam can be safely titrated against the background of the sedative effect of the analgesic.

Supportive dose: intravenously, 0.03-0.2 mg / kg / h. Patients with hypovolemia, vasoconstriction or hypothermia dose are reduced.

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.

Newborns and children under 6 months - by continuous intravenous infusion from 0.03 mg / kg / h (0.5 μg / kg / min) for infants with gestational ages less than 32 weeks or 0.06 mg / kg / h (1 μg / kg / min) for infants with a gestational age of more than 32 weeks and children up to 6 months. The introduction of an elevated initial dose is not recommended, it is possible to increase the infusion rate within the first few hours to achieve a therapeutic plasma concentration. The rate of infusion should be periodically reviewed, especially in the first 24 hours, to introduce the lowest effective dose and reduce the risk of cumulation of the drug. It is necessary to carefully monitor the frequency of breathing and the saturation of blood with oxygen.

Children over 6 months old, undergoing intubation and ventilation of the lungs, an initial dose of 0.05-0.2 mg / kg is administered intravenously slowly for at least 2-3 minutes,until the desired clinical effect is established or by prolonged 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 midazolam may be administered. If infusion of midazolam is initiated in patients with hemodynamic disorders, the usual loading dose should be titrated in small "steps", controlling hemodynamic parameters (lowering blood pressure). Careful monitoring of respiratory rate and oxygen saturation is necessary.

Special patient groups

Children

The introduction 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. Children younger than 6 months are not recommended intravenous administration of midazolam, due to the propensity to obstruct the airways and hypoventilation, except for cases of sedation in intensive care units. Midazolam Do not use in children for introductory anesthesia, and also as a sedative for combined anesthesia.

Renal insufficiency

In patients with renal insufficiency (creatinine clearance <10 ml / min), the pharmacokinetics of midazolam after a single intravenous administration is comparable to that of healthy volunteers. After a long infusion in the intensive care unit, the average duration of sedation in patients with renal insufficiency was significantly higher, probably due to the accumulation of glucuronide a-hydroxyimidazolam.

Data on the use of midazolam in patients with severe renal insufficiency (creatinine clearance <30 ml / min) are absent.

Liver failure

In patients with hepatic insufficiency, the hepatic clearance of midazolam decreases (with a subsequent increase in its T_1/2), in connection with which its clinical effect can be more pronounced and prolonged. Therefore, a reduction in the dose of midazolam and monitoring of vital body functions is required. Patients over 60 years of age / patients in extremely serious condition, as well as with a high degree of risk, usually require lower doses of midazolam. A thorough and constant monitoring of vital indicators is necessary.

Special instructions for dosing

Solution of the drug Midazolam 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 infusion solution.

Do not dilute the drug Midazolam 6% dextran solution with an average molecular weight of 50,000-70000 Da in dextrose. Do not mix midazolam with alkaline solutions, since midazolam forms 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. Storage time should not exceed 24 hours at a temperature of 2 to 8 ° C and only if the solution was prepared in controlled and validated aseptic conditions.

Ampoules of the preparation Midazolam are only for single use. Unused solution should be disposed of. Before administration, it is necessary to inspect the solution. Only a transparent solution without visible foreign particles is suitable for use.

Side effects:

WHO classification of unwanted adverse reactions according to the frequency of development

Very frequent - 1/10 appointments (≥ 10%)

Frequent - 1/100 appointments (≥ 1%, but <10%)

Infrequent - 1/1000 appointments (≥ 0.1%, but <1%)

Rare - 1/10000 appointments (≥ 0.01%, but <0.1%)

Very rare - less than 1/10000 prescriptions (<0.01%)

The frequency is unknown (can not be estimated from the available data).

From the immune system: frequency unknown: generalized hypersensitivity reactions (skin, cardiovascular, bronchospasm), angioedema, anaphylactic shock.

From the psychic sphere: frequency is unknown: confusion, euphoria, hallucinations, delirium; paradoxical reactions - agitation, involuntary movements (including tonic-clonic convulsions, tremor), hyperactivity, hostility, anger and aggressiveness, excitatory paroxysms (especially in children and senile patients);

The use of midazolam, 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 prolonged intravenous use, may be accompanied by withdrawal symptoms, including seizures.

From the central and peripheral nervous system: frequency is unknown: postoperative drowsiness and prolonged sedation, decreased concentration, headache, dizziness, ataxia, anterograde amnesia, 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 when coming out of anesthesia, athetoid movements, sleep disturbances, dysphonia, fuzzy speech, paresthesia. Preterm infants and newborns may have seizures.

From the digestive system: frequency unknown: nausea, vomiting, constipation, dry mouth, sour taste in mouth, salivation, belching.

From the respiratory system: In rare cases, severe respiratory adverse events developed. They consisted in oppression, stopping breathing, development of apnea, dyspnoea, laryngospasm.The likelihood of such life-threatening reactions is higher in patients 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. Hiccups, bronchospasm, hyperventilation, wheezing, shallow breathing, airway obstruction, tachypnea.

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 patients with concomitant respiratory failure or heart failure, especially if the drug is administered too quickly or in large doses. Tachycardia, bigemia, premature ventricular contraction, vasovagal crisis, rhythm of atrioventricular junction.

From the skin and subcutaneous fat: frequency unknown - skin rash, hives, itching.

From the sense organs: frequency unknown - impairment and deterioration of visual acuity, double vision, nystagmus, miosis, periodic twitching of eyelids, refraction failure, 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, who consume alcohol, as well as patients of elderly and senile age.

General and local reactions: frequency unknown - erythema and pain at the injection site, thrombophlebitis, thrombosis, hypersensitivity.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:

Symptoms

Dizziness, ataxia, dysarthria, nystagmus. Overdose rarely leads to life-threatening conditions, but there may be areflexia, dyspnea, muscle hypotension, oppression of cardiovascular and respiratory activity, coma. Symptoms of overdose usually last for several hours, but may be longer, especially in the elderly, in whom they can be cyclical. In patients with concomitant diseases of the respiratory system, respiratory disorders occur in a more severe form.

Benzodiazepine derivatives can enhance the effect of other drugs that depress the central nervous system, including alcohol.

Treatment

Artificial ventilation of the lungs, measures aimed at maintaining the activity of the cardiovascular system.

In case of severe intoxication accompanied by coma or respiratory depression, a benzodiazepine receptor antagonist is prescribed - flumazenil. It should be used with caution in case of mixed overdose, in patients with epilepsy who have already taken benzodiazepine derivatives; with extreme caution in patients who previously received therapy with drugs that reduce the threshold of convulsive readiness (eg, tricyclic antidepressants) or in patients with abnormalities in the electrocardiogram (ECG) (QRS complex extension and QT interval prolongation). For more details, refer to the instructions for using flumazenil.

Interaction:

Pharmacokinetic interactions

The metabolism of midazolam is mediated mainly by the isoenzyme of the cytochrome P450 system (CYP3A4). The substances, inhibitors and inducers of the isoenzyme CYP3A4 have the potential to increase and decrease the plasma concentration, and, consequently, 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 in the medication of midazolam with other substances. However, there is a theoretical possibility of displacing the drug from the connection with plasma proteins (albumin) while using it with medicinal substances with sufficiently high therapeutic concentrations in the blood plasma.

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 pharmacological effects of midazolam when it is used in conjunction with inhibitors of 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 pharmacokinetics of midazolam may persist for several days 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 the human immunodeficiency virus (HIV) (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, ethinylestradiol / norgestrel, when used as an oral contraceptive, and grapefruit juice (200 ml) do not significantly affect the plasma concentration of midazolam when administered intravenously.The intensity of the inhibitory / inducing action of the drugs varies widely.

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 compared with the oral route of administration can be expected, since modulation of the activity of the CYP3A4 isoenzyme affects not only the overall clearance, but also the bioavailability of midazolam when administered orally.

The following are examples of possible cases of drug interactions between midazolam when administered intravenously with other drugs.

Inhibitors and inducers of this isoenzyme may enter into drug interactions with midazolam.

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 should be performed in the intensive care unit or ward,where there is scope for careful clinical monitoring and the necessary treatment in the event of respiratory depression and / or the development of prolonged sedation. It is necessary to select an individual dose of the drug, as well as a phased introduction, especially in cases of more than a single administration of midazolam. Itraconazole and fluconazole. In 2-3 times increase the plasma concentration of intravenously administered midazolam. Increase the final half-life of midazolam by 2.4 times (itraconazole) and in 1,5 times (fluconazole). With bolus administration of midazolam for short-term sedation itraconazole and fluconazole do not enhance its effects in a clinically significant degree, so dose adjustment is not required. However, when administering midazolam in high doses, dose adjustment may become necessary. Long-term infusion of midazolam to patients receiving systemic antimycotics (for example, in intensive care) may prolong the hypnotic effect of the drug if its dose is not titrated according to the effect.

Posaconazole. The use of posaconazole at a dose of 200 mg once a day increases the area under the concentration-time curve (AUC) of midazolam-substrate CYP3A4 by 83% after its iv injection.Caution should be exercised in the combined use of posaconazole and midazolam administered intravenously, and a reduction in the dose of midazolam may be required. If posaconazole are used in conjunction with midazolam taken orally, which can cause serious adverse effects when the plasma concentration increases, then the concentration of midazolam in the blood should be closely monitored and the possible development of undesirable events should be monitored and, if necessary, its dose reduced.

The use of posaconazole 200 mg twice daily for 7 days increases the maximum concentration (C_max) and AUC of midazolam (0.4 mg iv once a day) on average 1.3 and 4.6 times, respectively. The use of posaconazole 400 mg twice a day for 7 days increases C_max and AUC of midazolam (with its iv introduction) in 1.6 and 6.2 times, respectively. Both dosage regimens posaconazole increase C_max and AUC of midazolam taken internally at a dose of 2 mg once daily, 2.2 and 4.5 times, respectively. In addition, the use of posaconazole in doses of 200 and 400 mg increases T_1/2 midazolam approximately from 3-4 to 8-10 hours when combined. Caution should be exercised in appointing midazolam, which is metabolized by the CYP3A4 isoenzyme, to patients receiving posaconazole.

Voriconazole increases the concentration in the plasma and the half-life of midazolam by 3 times.

Macrolides

Erythromycin. Increases in 1,6-2 times the plasma concentration of intravenously administered midazolam, approximately in 1,5-1,8 times increases the final half-life. Although the observed changes in pharmacodynamics were relatively small, it is recommended that the dose of intravenously administered midazolam be adjusted, especially when large doses are prescribed.

Clarithromycin. Increases in 2.5 times the plasma concentration of intravenously administered midazolam, approximately by a factor of 1.5-2 increases the final half-life.

HIV protease inhibitors

Saquinavir and other HIV protease inhibitors. When joint use of midazolam with lopinavir and ritonavir (boost combination), the plasma concentration of intravenously administered midazolam increases 5.4 times, which is combined with the same increase in the final half-life.

Saquinavir only increased the subjective sensation of midazolam, so patients receiving saquinavir, it is possible to administer intravenous bolus doses of midazolam.When long-term infusion of midazolam is recommended to reduce the initial dose by 50%. Parenteral administration of midazolam in conjunction with HIV protease inhibitors requires adherence to hospitalization conditions. ketoconazole).

Blockers of H2-histamine receptors

Cimetidine and Raichitidine. Cimetidine increases equilibrium concentrations of midazolam in plasma by 26%, and ranitidine they are not affected. Simultaneous administration of midazolam and cimetidine or ranitidine does not have a clinically significant effect on the pharmacokinetics and pharmacodynamics of midazolam. Midazolam can be administered intravenously in usual doses concomitantly with cimetidine and ranitidine.

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%.

Other medicines.

Atorvastatin. In 1,4 times the plasma concentration of intravenously administered midazolam increases.

CYP3A4 isoenzyme induction preparations

Rifampicin. After taking rifampicin for 7 days at a dose of 600 mg per day, the concentration of midazolam in blood plasma with intravenous administration decreases by approximately 60%.The final half-life decreases by about 5-60%.

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

Cyclosporine. There is no pharmacokinetic and pharmacodynamic interaction between cyclosporin and midazolam; correction of the dose of midazolam with simultaneous application with cyclosporine is not required.

Nitrendipine does not affect the pharmacokinetics and pharmacodynamics of the drug midazolam. Both drugs can be administered simultaneously; correction of the dose of midazolam is not required.

Oral contraceptives do not affect the pharmacokinetics of intramuscularly administered midazolam; these drugs can be used at the same time without correcting the dose of midazolam.

Valproic acid. Due to the high therapeutic concentration in serum, valproic acid can displace midazolam from the connection with blood plasma proteins (albumin), which may lead to an increase in the clinical effect of midazolam administered in conditions of emergency sedation. Against the background of valproic acid, CNS depression is increasing.

Pharmacodynamic interactions

The joint administration of midazolam with other sedatives and hypnotics, as well as in combination with alcohol, can lead to increased sedative and hypnotic effects.

Such interaction is possible with the use of opiates and opioids (when taken as analgesics and antitussives, substitution therapy), antipsychotics (neuroleptics), various benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate, also while concurrent administration of midazolam with antidepressants with sedative effect, antihistamines and antihypertensive agents of central action. Midazolam reduces the minimum alveolar concentration of inhaled anesthetics. With such a joint use of medicines, adequatemonitoring of indicators of vital functions. It should avoid simultaneous reception of midazolam and alcohol.

Spinal anesthesia may 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 sedation effect of midazolam.

Ginkgo biloba leaf extract

In clinical studies with ginkgo bilobate leaf extract, both inhibition and induction of cytochrome P450 isoenzymes were detected. With the simultaneous administration of ginkgo bilobate leaves of the extract with midazolam, the concentration of the latter changed presumably because of the effect on the isoenzyme CYP3A4.

Special instructions:

Midazolam should be used only by specialists trained in the methods of its introduction, and also capable of providing resuscitative care, the necessity of which can arise as a result of the development of undesirable reactions. With the use of midazolam, serious adverse drug reactions have been reported, including respiratory depression, apnea, respiratory arrest, cardiac arrest. The likelihood of such life-threatening conditions is higher with a high rate of administration or a high dose of the drug. Particular caution should be exercised when used in patients with impaired breathing function.

When using midazolam for premedication, the patient should be under constant monitoring, as there is a risk of overdose with other drugs.

Use of midazolam in children

The use of midazolam requires extreme caution in children.

In children with concomitant cardiovascular diseases, the dose should be reduced, continuous monitoring of vital functions is necessary. Midazolam Do not use in children for introductory anesthesia, and also as a sedative for combined anesthesia.

Children need relatively higher doses of midazolam (per kilogram of body weight) than adults. The drug is injected deeply intramuscularly into a large muscle 30-60 minutes before the initial anesthesia.

The half-life of midazolam may extend in newborns.

Particular caution is needed for sedation in preterm infants (born less than 36 weeks of gestation) because of the risk of apnea. It should avoid rapid administration of the drug in this group of patients.

Preterm and term infants

Because of the increased risk of developing apnea, it is recommended to exercise special care when used in non-intubated preterm or full-term newborns. In these cases, careful monitoring of respiratory rate and oxygen saturation of blood is necessary. Rapid administration of the drug is not recommended. Due to immaturity of metabolic functions, newborns are prone to respiratory depression. In children with cardiovascular diseases to prevent breathing disorders, the drug should be administered slowly.

Children under 6 months of age

It is not recommended to use the drug to achieve sedation and premedication in children younger than 6 months.

Children under the age of 6 months are particularly susceptible to airway obstruction and hypoventilation, so increase the dose in small steps. In addition, careful monitoring of the respiratory rate and oxygen saturation of blood is necessary (see also subsection "Premature and full-term newborns").

In children younger than 6 months, as well as with a body weight of less than 15 kg, the use of a solution with a concentration above 1 mg / ml is not recommended. The preparation in a higher concentration is preliminarily diluted to 1 mg / ml. When used in children's practice, it must be remembered that intramuscular injection is painful. Also, caution should be exercised when assigning midazolam to the following groups of patients:

- Patients over 60 years of age;

- Patients with severe general condition or chronic diseases (eg, chronic respiratory failure, chronic renal failure, hepatic or heart failure);

- patients with myasthenia gravis, due to the miorelaxing properties of midazolam, as well as other means of depressing the central nervous system;

- Patients with alcoholism or drug addiction (including in history);

- patients with organic brain damage, hospitalized in shock, coma.

Addiction

There are reports of a decrease in efficacy with long-term administration of midazolam for sedation in intensive care units.

Addiction

With long-term use of midazolam (long-term sedation in intensive care units), physical dependence can develop. Its risk increases with increasing dose and duration of treatment, it is also higher in patients with alcoholism and (or) drug addiction in the history.

The "cancellation" syndrome

During long-term treatment with midazolam in the intensive care unit, it is possible to develop mental and physical dependence. With the sudden withdrawal of midazolam, a withdrawal syndrome may develop, which can be manifested by the following symptoms: headache, muscle pain, anxiety, tension, agitation, confusion, irritability, "ricochet" insomnia, mood swings, hallucinations and convulsions. To avoid the syndrome of "cancellation," it is recommended that the dose be gradually reduced until it is discontinued.

Amnesia

Midazolam may cause anterograde amnesia (often a desirable effect, for example, before and during surgical and diagnostic procedures), the duration of which is directly proportional to the dose administered. For ambulatory patients discharged immediately after the operation, prolonged amnesia can cause inconvenience, so after parenteral administration of midazolam, the patient should be discharged only accompanied by medical personnel or persons close to him.

Paradoxical reactions

When using midazolam, paradoxical reactions were recorded: agitation, involuntary movements (including tonic-clonic convulsions and muscle tremors), hyperactivity, hostility, outbursts of anger, aggressiveness, paroxysmal anxiety and attacks. These reactions occur with the administration of high doses and (or) with the rapid administration of the drug. The highest frequency of these reactions is observed in children and the elderly.

The change in the therapeutic efficacy of midazolam

In patients using inducers or inhibitors of the CYP3A4 isoenzyme, the therapeutic efficacy of midazolam may vary, so there may be a need for correcting the dose of midazolam (see Fig.section "Interaction with other medicinal products").

Metabolism of midazolam can be slowed down in patients with hepatic insufficiency, low cardiac output, and in newborns (see section "Pharmacokinetics").

Simultaneous use of alcohol and (or) drugs that oppress the central nervous system. It is necessary to avoid the simultaneous use of midazolam with alcohol or drugs that depress the central nervous system. This use may increase the clinical effects of midazolam and lead to severe sedation or clinically significant respiratory depression (see "Interactions with Other Drugs").

Alcoholism or drug addiction

In patients with alcoholism or drug addiction, a history of midazolam and other benzodiazepine derivatives should be avoided.

Extract from the treatment and prophylactic institution

After the completion of the necessary procedures the patient should be observed until the full restoration of consciousness and motor abilities, the patient must be discharged in the company of persons close to him.

The drug contains sodium, which can be important for patients on a diet with a low salt content.

During the treatment period, you can not take ethanol, especially in the first 6 hours after taking the drug.

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 and 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 / ml.

Packaging:

1 ml or 3 ml into ampoules. 5 ampoules in the outline of the cell.

For 1,2 or 5 contour squares with instruction on the use of the drug, a knife or scarifier ampullum in a pack of cardboard.

For 20, 50 or 100 contour cell packs, together with an equal number of instructions for the use of the drug, knives or scarifiers ampoule in a box of cardboard or in a box of corrugated cardboard (for inpatient).

When you pack ampoules with rings and break points, knives or scarifier ampoules do not.

Storage conditions:

In accordance with the rules for storage of psychotropic substances listed in List III of the "List of narcotic drugs, psychotropic substances and their precursors subject to control in the Russian Federation".

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003720

Date of registration:12.07.2016 / 21.08.2017

Expiration Date:12.07.2021

The owner of the registration certificate:MOSCOW ENDOCRINE FACTORY, FSUE MOSCOW ENDOCRINE FACTORY, FSUE Russia

Manufacturer: & nbsp

MOSCOW ENDOCRINE FACTORY, FSUE Russia

Information update date: & nbsp24.04.2018

Illustrated instructions

Instructions

Midazolam (Midazolam)