Kvimilon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KVIMILON (KVIMILON)

Composition:

Active substance: midazolam;

1 ml of solution contains 5 mg of midazolam;

Excipients: sodium chloride, hydrochloric acid concentrated, sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group. Hypnotics and sedatives. Benzodiazepine derivatives.

ATC code N05CD08.

Pharmacological Properties

Pharmacodynamics

The active ingredient of the medicinal product Quimilon – midazolam – belongs to the group of imidazobenzodiazepine derivatives. The free base is a lipophilic substance with low water solubility.

The presence of a basic nitrogen atom at position 2 of the imidobenzodiazepine ring allows the active substance, midazolam, to form water-soluble salts with acids. These salts are used to prepare injectable and infusion solutions that are well tolerated. Due to its low toxicity, midazolam has a broad therapeutic range.

Mechanism of action

The pharmacological effect of midazolam is characterized by short duration due to rapid metabolic transformation. Midazolam stimulates ionotropic GABA receptors located in the central nervous system (CNS). In the presence of GABA, midazolam binds to benzodiazepine receptors on chloride ion channels, leading to activation of GABA receptors and reduced excitability of subcortical brain structures. As a result, midazolam exerts pronounced sedative and hypnotic effects, as well as anxiolytic, anticonvulsant, and central muscle relaxant effects.

After intramuscular or intravenous administration, short-term anterograde amnesia occurs (the patient does not remember events that occurred during the period of maximum activity of the active substance). Midazolam suppresses psychomotor function after single and/or repeated administration, but causes only minimal hemodynamic changes.

Pharmacokinetics

Absorption

Absorption of midazolam after intramuscular injection is rapid and complete. Maximum plasma concentration (Cmax) is reached within 30 minutes. Absolute bioavailability after intramuscular injection exceeds 90%.

Distribution

After intravenous administration of midazolam, the area under the plasma concentration-time curve (AUC) is characterized by one or two clearly defined distribution phases. The volume of distribution at steady state ranges from 0.7 to 1.2 L/kg. Midazolam is 96–98% bound to plasma proteins, primarily albumin. Midazolam slowly and minimally penetrates into cerebrospinal fluid. It has been demonstrated that in humans, midazolam slowly crosses the placental barrier and enters fetal circulation. Small amounts of midazolam are found in breast milk.

After rectal administration, midazolam is rapidly absorbed. Cmax in plasma is reached within 30 minutes. Absolute bioavailability is approximately 50%.

Biotransformation

Midazolam is almost completely eliminated via biotransformation. The fraction of the dose excreted by the liver is estimated at 30–60%. Midazolam is hydroxylated by the cytochrome P450 3A4 isoenzyme, and the main metabolite in urine and plasma is α-hydroxymidazolam. The concentration of α-hydroxymidazolam in plasma is 12% of the concentration of the parent compound. α-Hydroxymidazolam is pharmacologically active but contributes only minimally (approximately 10%) to the effects of intravenously administered midazolam. Data on the role of genetic polymorphism in the oxidative metabolism of midazolam are lacking.

Elimination

In healthy volunteers, the elimination half-life of midazolam is 1.5–2.5 hours. Plasma clearance ranges from 300 to 500 mL/min. Midazolam is primarily excreted by the kidneys (60–80% of the administered dose), mainly as the glucuronide conjugate of α-hydroxymidazolam. Less than 1% of the dose is excreted unchanged in urine. The elimination half-life of α-hydroxymidazolam is less than 1 hour. When midazolam is administered via intravenous infusion, its elimination kinetics do not differ from those after bolus injection.

Repeated administration of midazolam does not induce enzymes involved in drug metabolism.

Special patient groups

Elderly patients

In adults aged 60 years and older, the elimination half-life may be prolonged up to fourfold.

Children

In children aged 3 to 10 years, the elimination half-life after intravenous administration is shorter (1–1.5 hours) than in adults. This difference corresponds to increased metabolic clearance of the drug.

The rate of rectal absorption in children is similar to that in adults, but bioavailability is lower (5–18%).

Neonates

In neonates, possibly due to hepatic immaturity, the elimination half-life averages 6–12 hours, and drug clearance is reduced (see section "Special instructions").

In neonates with hepatic and renal insufficiency caused by asphyxia, there is a risk of unexpectedly high serum midazolam concentrations due to significantly reduced and variable clearance.

Patients with excessive body weight

The mean elimination half-life is longer in obese patients than in those with normal body weight (5.9 and 2.3 hours, respectively). This is associated with an approximately 50% increase in volume of distribution adjusted for total body weight. Clearance does not significantly differ between obese patients and those with normal body weight.

Patients with impaired liver function

In patients with liver cirrhosis, compared to healthy volunteers, the drug's elimination half-life may be prolonged and clearance reduced (see section "Special instructions").

Patients with impaired kidney function

The elimination half-life of the drug in patients with chronic renal insufficiency is similar to that in healthy volunteers. The main pharmacokinetically active metabolite of midazolam, α-hydroxymidazolam glucuronide, is eliminated by the kidneys and accumulates in patients with severe renal insufficiency. This accumulation leads to prolonged sedation. Therefore, midazolam should be administered cautiously and titrated to the desired level of sedation.

Critically ill patients

In critically ill patients, the elimination half-life of midazolam may be prolonged up to sixfold.

Patients with heart failure

The elimination half-life in patients with congestive heart failure is longer compared to healthy volunteers (see section "Special instructions").

Clinical characteristics.

Indications.

Indicated as a short-acting sedative agent:

Adults:

• for sedation with preservation of consciousness prior to or during diagnostic or therapeutic procedures, with or without local anesthesia;
• for anesthesia:
  • for premedication prior to induction of anesthesia;
  • induction of anesthesia;
  • as a sedative component during combined anesthesia;
• for sedation in intensive care units.

Children:

• for sedation with preservation of consciousness prior to or during diagnostic or therapeutic procedures, with or without local anesthesia;
• for anesthesia:
  • for premedication prior to induction of anesthesia;
• for sedation in intensive care units.

Contraindications.

Hypersensitivity to midazolam, benzodiazepines, or to any of the excipients of the medicinal product. Conscious sedation in patients with severe respiratory insufficiency or acute respiratory depression.

Interaction with other medicinal products and other forms of interaction.

Midazolam is metabolized by cytochrome P450 (CYP3A4 and CYP3A5). Inhibitors and inducers of CYP3A4 may potentially increase or decrease plasma concentrations of the drug, respectively, and consequently affect the action of midazolam, requiring appropriate dose adjustment.

Pharmacokinetic interactions with CYP3A4 inhibitors or inducers are more pronounced after oral administration compared to intravenous administration of midazolam, particularly because CYP3A4 is also present in the upper gastrointestinal tract. This is due to changes in both systemic clearance and bioavailability after oral administration, whereas only systemic clearance is altered after parenteral administration.

After intravenous administration of a single dose of midazolam, the maximum clinical effect of CYP3A4 inhibition is minimal, but the duration of effect may be prolonged. However, after prolonged administration of midazolam, both the intensity and duration of effect increase in the presence of CYP3A4 inhibition.

There are no available study data on the effect of reduced CYP3A4 activity on the pharmacokinetics of midazolam following rectal or intramuscular administration. This interaction is expected to be less pronounced after rectal than after oral administration, since the gastrointestinal tract is not involved, whereas after intramuscular administration, the effect of CYP3A4 modulation should not differ significantly from that observed after intravenous administration of midazolam.

Careful monitoring of clinical effects and vital signs is recommended during administration of midazolam, as its effects may be stronger and longer-lasting when co-administered with a CYP3A4 inhibitor, even if the inhibitor was administered only once. Administration of high doses of the drug or prolonged infusions of midazolam to patients taking strong CYP3A4 inhibitors, for example during intensive care, may result in prolonged sedative effects, delayed recovery of consciousness, and respiratory depression, necessitating dose adjustment.

Regarding induction, it should be noted that the induction process requires several days to reach maximum effect and several days for its decline. Unlike treatment with an inducer over several days, short-term treatment is expected to result in less pronounced drug-drug interaction with midazolam. However, for strong inducers, significant induction cannot be excluded even after short-term treatment.

Midazolam does not alter the pharmacokinetics of other medicinal products.

Medicinal products that inhibit CYP3A4

Azole antifungal agents

Ketoconazole increased plasma concentrations of midazolam following intravenous administration by 5-fold, while the terminal half-life was prolonged approximately 3-fold. When midazolam is administered parenterally in combination with ketoconazole, a strong CYP3A4 inhibitor, it should be administered in an intensive care unit or similar facility providing close clinical monitoring and treatment in case of respiratory depression and/or prolonged sedation. Gradual dose titration or dose adjustment should be considered, especially when more than a single dose of midazolam is administered. This recommendation may also apply to other azole antifungal agents, as increased sedative effects of intravenous midazolam have been reported, although to a lesser extent.

Voriconazole increased plasma concentrations of midazolam following intravenous administration by 3–4-fold, while its half-life was prolonged approximately 3-fold.

Fluconazole and itraconazole increased plasma concentrations of midazolam following intravenous administration by 2–3-fold, also resulting in an increase in terminal half-life by 2.4-fold for itraconazole and 1.5-fold for fluconazole, respectively. Posaconazole increased plasma concentrations of midazolam following intravenous administration by approximately 2-fold.

It should be noted that the effect of orally administered midazolam will be significantly higher than that of the aforementioned agents, especially when co-administered with ketoconazole, itraconazole, or voriconazole.

Midazolam in ampoules is not indicated for oral administration.

Macrolide antibiotics

Erythromycin increased plasma concentrations of midazolam following intravenous administration by approximately 1.6–2-fold, also resulting in a 1.5–1.8-fold increase in terminal half-life.

Clarithromycin increased plasma concentrations of midazolam by 2.5-fold, along with a 1.5–2-fold increase in terminal half-life.

Additional information regarding oral midazolam

Telithromycin may increase plasma concentrations of midazolam by 6-fold following oral administration.

Roxithromycin. Although there are no data on the effect of roxithromycin on intravenously administered midazolam, a weak effect on the terminal half-life of oral midazolam (approximately 30% increase) suggests that roxithromycin may have a minor effect on intravenously administered midazolam.

Intravenous anesthetics

The distribution of intravenous midazolam was also altered by intravenous administration of propofol (AUC and half-life increased by 1.6-fold).

Protease inhibitors

Saqunavir and other HIV protease inhibitors. Concomitant use with protease inhibitors may cause a substantial increase in midazolam concentrations. When administered concurrently with lopinavir boosted by ritonavir, plasma concentrations of intravenously administered midazolam increased by 5.4-fold, also resulting in a similar increase in terminal half-life. When administered parenterally together with HIV protease inhibitors, the treatment regimen should follow the description provided in the section above for azole antifungal agents (ketoconazole).

Hepatitis C virus (HCV) protease inhibitors. Boceprevir and telaprevir reduce midazolam clearance. This effect led to a 3.4-fold increase in midazolam AUC after intravenous administration and a 4-fold increase in half-life.

Additional information regarding oral midazolam

Based on data from other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher following oral administration. Therefore, protease inhibitors should not be administered concomitantly with oral midazolam.

Calcium channel blockers

Diltiazem. When a single dose of diltiazem was administered, plasma concentrations of intravenously administered midazolam increased by approximately 25%, and terminal half-life was prolonged by 43%. This is less than the 4-fold increase observed after oral administration of midazolam.

Additional information regarding oral midazolam

Verapamil increased midazolam concentrations following oral administration by 3-fold. Terminal half-life of midazolam was prolonged by 41%.

Other medicinal products/herbal preparations

Atorvastatin increased plasma concentrations of intravenously administered midazolam by 1.4-fold compared to the control group.

Fentanyl, when administered intravenously, is a weak inhibitor of midazolam elimination. AUC and half-life of intravenous midazolam increased by 1.5-fold in the presence of fentanyl.

Additional information regarding oral midazolam.

Fluvoxamine increased plasma concentrations of midazolam following oral administration (approximately 40%), and terminal half-life doubled.

Nefazodone increased plasma concentrations of midazolam following oral administration by 4.6-fold, with a 1.6-fold increase in terminal half-life.

Tyrosine kinase inhibitors are potent CYP3A4 inhibitors in vitro (imatinib, lapatinib) or after oral administration in vivo (idelalisib). Concomitant use of idelalisib increased exposure to orally administered midazolam by 4.4-fold.

NK1 receptor antagonists (aprepitant, netupitant, casopitant) increased exposure to orally administered midazolam by 1.5–3.5-fold and prolonged its terminal half-life by 1.6–2-fold, depending on dose.

Chlorzoxazone reduced the ratio of the metabolite 1'-hydroxymidazolam (also known as α-hydroxymidazolam), formed by CYP3A, to midazolam, indicating inhibitory action on CYP3A.

A number of medicinal products and herbal preparations have shown weak effects on midazolam elimination with concurrent changes in midazolam exposure (AUC change < 2-fold) (bicalutamide, everolimus, cyclosporine, simeprevir, propiverine, berberine, also present in goldenseal (Hydrastis canadensis)).

This weak interaction is expected to be further attenuated after intravenous administration.

Medicinal products that induce CYP3A4

Rifampicin reduced plasma concentrations of midazolam following intravenous administration by approximately 60% after 7 days of 600 mg rifampicin once daily. Terminal half-life was shortened by approximately 50–60%.

Ticagrelor is a weak inducer of CYP3A and has a negligible effect on intravenous midazolam (-12%) and 4-hydroxymidazolam (-23%).

Additional information regarding oral midazolam.

Rifampicin reduced plasma concentrations of orally administered midazolam by 96% in healthy volunteers, and its psychomotor effect was almost completely lost.

Carbamazepine/phenytoin. Repeated dosing of carbamazepine or phenytoin resulted in up to 90% reduction in plasma concentrations of midazolam after oral administration and a 60% reduction in terminal half-life.

Mitotane/enzalutamide. Very strong induction of CYP3A4 observed after administration of mitotane or enzalutamide led to pronounced and prolonged reduction in midazolam levels in oncology patients. AUC values of orally administered midazolam were reduced to 5% and 14% of normal values, respectively.

Efavirenz and clobazam are weak inducers of midazolam metabolism, reducing initial AUC by approximately 30%. This leads to a 4–5-fold increase in the ratio of active metabolite to parent compound, but the clinical significance of this is unknown.

Vemurafenib affects CYP isoenzymes and is a mild inhibitor of CYP3A4. Repeated dosing resulted in a mean 32% reduction in exposure to orally administered midazolam (up to 80% in some individuals).

Herbal preparations and food

Hypericum perforatum (St. John's wort) reduced plasma concentrations of midazolam by approximately 20–40% and shortened terminal half-life by 15–17%. Depending on the specific extract of Hypericum perforatum, the CYP3A4-inducing effect may vary.

Quercetin (also present in Ginkgo biloba) and Panax ginseng exert weak enzyme-inducing effects and reduce the effect of midazolam after oral administration by approximately 20–30%.

Valproic acid increases free midazolam concentrations due to displacement from plasma protein binding sites, but the clinical significance of this interaction is unknown.

Sedatives and hypnotics

Concomitant administration of midazolam with other sedatives/hypnotics and CNS depressants, including alcohol, is likely to enhance sedative effects and cause cardiovascular depression.

These include opioid derivatives (used as analgesics, antitussives, or for substitution therapy), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate, antidepressants with sedative effects, H1-antihistamines, and centrally acting antihypertensives.

Alcohol

Alcohol may significantly enhance the sedative effect of midazolam; therefore, alcohol consumption is contraindicated during treatment with the medicinal product (see section "Special precautions for use").

Inhalational anesthetics

Midazolam reduces the minimum alveolar concentration (MAC) of inhalational anesthetics.

Opioids

Concomitant use of sedative agents such as benzodiazepines and related compounds with opioids increases the risk of sedation, respiratory depression, coma, and death due to additive CNS depressant effects. Dose and duration of concomitant use should be limited (see section "Special precautions for use").

Special precautions for use.

Midazolam should be administered only by experienced physicians in a fully equipped setting for monitoring and supporting respiratory and cardiovascular functions, and by personnel who have undergone special training in recognizing and managing expected adverse reactions, including respiratory and cardiac resuscitation.

Severe cardiorespiratory adverse reactions have been reported: respiratory depression, apnea, respiratory arrest, and/or cardiac arrest. Such life-threatening events most commonly occur when the injection is performed too rapidly or when a high dose of the drug is administered. Particular caution is required when administering sedation with preserved consciousness to patients with impaired respiratory function.

Benzodiazepines are not recommended for use as primary therapy for psychotic disorders.

Pediatric patients

Infants under 6 months of age are particularly susceptible to airway obstruction and hypoventilation; therefore, careful dose titration with small increments until the desired clinical effect is achieved, along with close monitoring of respiratory rate and oxygen saturation, is essential. When midazolam is used for premedication, adequate post-administration observation of the patient is required due to individual variability in sensitivity and the potential occurrence of overdose symptoms.

Particular caution should be exercised when prescribing midazolam to high-risk patients:

• adults aged 60 years and older;
• chronically ill or debilitated patients:
  • patients with chronic respiratory insufficiency;
  • patients with chronic renal insufficiency, hepatic impairment (benzodiazepines may induce or exacerbate encephalopathy in patients with severe liver dysfunction), or cardiac dysfunction;
• pediatric patients, especially those with cardiovascular instability.

Such high-risk patients require lower doses (see section "Dosage and administration") and continuous monitoring for early signs of vital function disturbances.

As with any substance that exerts a depressant effect on the CNS and/or has muscle relaxant properties, special caution should be exercised when administering midazolam to patients with severe pseudoparalytic myasthenia gravis.

Tolerance

Some reduction in effectiveness has been reported with prolonged use of midazolam for sedation in intensive care units (ICU).

Dependence

When midazolam is used for prolonged sedation in ICU, physical dependence on midazolam may develop. The risk of dependence increases with higher doses and longer treatment duration, and is also higher in patients with a history of alcohol and/or drug abuse (see section "Adverse reactions").

Withdrawal syndrome

Prolonged midazolam treatment in ICU may lead to physical dependence. Therefore, abrupt discontinuation of treatment may result in withdrawal syndrome. Symptoms may include headache, diarrhea, muscle pain, anxiety, tension, restlessness, confusion, irritability, sleep disturbances, and mood changes. In severe cases, symptoms may include depersonalization, hallucinations, seizures, numbness and tingling in extremities, increased sensitivity to light, noise, and physical contact. Since the risk of withdrawal syndrome is higher after abrupt discontinuation, doses should be gradually tapered.

Amnesia

Midazolam causes anterograde amnesia (an effect often desirable during and after surgical and diagnostic procedures), the duration of which is directly related to the administered dose. Prolonged amnesia may pose problems for outpatients discharged immediately after the procedure. After parenteral administration of midazolam, patients should be discharged from outpatient or inpatient care only in the presence of a caregiver.

Paradoxical reactions

Paradoxical reactions have been reported with midazolam use, such as excitement, irritability, involuntary movements (including tonic/clonic seizures and muscle tremor), hyperactivity, hostile behavior, delirium, anger, aggression, restlessness, nervousness, nightmares, unusual dreams, hallucinations, psychoses, maladaptive behavior, and other negative behavioral effects, paroxysmal excitement, and episodes (physical or verbal). Such reactions may occur with high doses and/or rapid administration of the drug. These reactions are more common in children and elderly patients. If such reactions occur, consideration should be given to discontinuing midazolam.

Altered midazolam elimination

Midazolam elimination may be altered in patients receiving substances that are inhibitors or inducers of CYP3A4, and dose adjustment may be required.

Midazolam elimination may be slowed in patients with hepatic impairment, low cardiac output, and in neonates (see section "Pharmacokinetics").

Sleep apnea

Midazolam should be used with particular caution in patients with sleep apnea syndrome. Close monitoring is required.

Preterm infants, neonates, and children under 6 months of age

Due to the increased risk of apnea, extreme caution is recommended when performing non-intubated sedation in preterm infants and neonates. Close monitoring of respiratory rate and oxygen saturation is necessary. Rapid administration of the drug should be avoided in neonates. Neonates have reduced and/or immature organ function and are vulnerable to profound and/or prolonged effects of midazolam. Hemodynamic disturbances have been reported as adverse reactions in pediatric patients with cardiovascular instability; rapid intravenous administration should be avoided in this patient group.

For children under 6 months of age, midazolam is indicated for sedation only in an intensive care unit. Children under 6 months of age are particularly prone to airway obstruction and hypoventilation. Therefore, dose titration with small increments until the desired clinical effect is achieved, along with careful monitoring of respiratory rate and oxygen saturation, is required.

Concomitant use of alcohol / CNS depressant drugs

Concomitant use of midazolam with alcohol and/or CNS depressant drugs should be avoided. Such concomitant use carries a potential risk of enhanced clinical effects of midazolam, including profound sedation, which may lead to coma or fatal outcome, or clinically significant respiratory depression (see section "Interaction with other medicinal products and other forms of interaction").

Risk of concomitant opioid use

Concomitant use of midazolam and opioids may result in sedation, respiratory depression, coma, and fatal outcome. Due to these risks, concomitant prescription of sedative medicinal products such as benzodiazepines or related drugs like midazolam with opioids should only be considered for patients for whom alternative treatment options are not possible. When deciding to use midazolam concomitantly with opioids, the lowest effective dose should be used, and treatment duration should be as short as possible.

Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, patients and their caregivers (where applicable) should be informed about these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Alcohol or drug abuse

The use of midazolam, as with other benzodiazepines, should be avoided in patients with a history of alcohol or drug abuse.

Discharge criteria

After receiving midazolam, patients should be discharged from hospital or outpatient care only upon recommendation of the treating physician or in the presence of a caregiver. It is recommended that a patient be accompanied home after discharge.

Excipients

The medicinal product Quimilon contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

There are insufficient data to assess the safety of midazolam during pregnancy.

Animal studies do not indicate a teratogenic effect, but fetotoxicity has been observed, as with other benzodiazepines. It is presumed that the use of benzodiazepines, including midazolam, during the first trimester of pregnancy is associated with an increased risk of congenital developmental defects.

It has been reported that administration of high doses of midazolam during the third trimester of pregnancy, during labor, or as an anesthetic induction agent for cesarean section leads to adverse reactions in both mother and child (risk of aspiration in the mother, fetal arrhythmia, hypotonia, weak sucking reflex, hypothermia, and respiratory depression in the newborn). Furthermore, infants born to mothers who received benzodiazepines for a prolonged period during the third trimester may develop physical dependence with a certain risk of withdrawal syndrome after birth. Therefore, midazolam should be used during pregnancy only if absolutely necessary. It is recommended to avoid the use of midazolam for cesarean section.

The risk to the newborn should be considered when midazolam is used for any surgical procedure prior to delivery.

Breastfeeding

Midazolam passes into breast milk in small amounts; therefore, women should not breastfeed for 24 hours after midazolam administration.

Ability to affect reaction speed when driving or operating machinery.

Sedation, amnesia, impaired concentration, and muscle function may negatively affect the ability to drive vehicles or operate machinery. Before administering midazolam, patients should be warned not to drive or operate machinery until consciousness is fully restored. The physician must determine when such activities can be resumed. It is recommended that patients be accompanied home after discharge. If the duration of sleep after midazolam administration was insufficient or if the patient consumes alcohol, the likelihood of impaired alertness may be increased.

Dosage and Administration.

Quimilon is a potent sedative agent that requires slow administration and individual dose titration. Dose titration is recommended to achieve a safe and desired level of sedation according to clinical needs, physical condition, age, and concomitant therapy. Quimilon should be administered with caution in patients aged 60 years and older, debilitated patients, chronically ill patients, and children; risk factors for each patient should be individually assessed. Standard dosages are listed in the table below. Additional information is provided in the text following the table.

Dosage for Sedation with Consciousness Preservation

The medicinal product Quimilon is administered intravenously for analgesic sedation prior to diagnostic or surgical procedures. The appropriate dose should be individually titrated. The drug must not be administered rapidly or as a bolus injection, but only by dose titration. The onset of sedative effect may vary individually depending on the patient's physical condition and the dosing regimen used (e.g., rate of administration, dose size). Additional doses may be administered as needed according to individual requirements. The effect begins approximately 2 minutes after injection. Maximum effect is achieved approximately within 5–10 minutes.

Adults

Quimilon should be administered intravenously slowly at a rate of approximately 1 mg/30 seconds. For adults under 60 years of age, an initial dose of 2 to 2.5 mg is administered 5–10 minutes before the procedure. The initial dose may be followed by additional doses of 1 mg as needed. The average total dose ranges from 3.5 to 7.5 mg. Total doses exceeding 5 mg are usually not required.

The initial dose for patients aged 60 years and older, patients with weakened general condition, or patients with chronic diseases is 0.5–1 mg, administered 5–10 minutes before the procedure. Subsequent additional doses of 0.5–1 mg midazolam may be administered as needed. For these patients, a longer time may be required to achieve maximum effect; therefore, additional doses of midazolam should be titrated very slowly and cautiously. Total doses exceeding 3.5 mg are usually not required.

Pediatric Population

Intravenous administration. Midazolam doses are slowly titrated to achieve the desired clinical effect. The initial dose is administered over 2–3 minutes. An additional 2–5 minutes should be allowed to fully assess the sedative effect before proceeding with the procedure or repeating the dose. If enhancement of sedation is required, titration should continue in small increments until the desired level of sedation is achieved. Infants and children under 5 years of age may require significantly higher doses compared to older children and adolescents.

• Children under 6 months of age: this age group is particularly susceptible to airway obstruction and hypoventilation; therefore, conscious sedation is not recommended.
• Children aged 6 months to 5 years: the initial dose is 0.05 to 0.1 mg/kg. Doses up to 0.6 mg/kg may be required to achieve the desired effect, but the total dose should not exceed 6 mg. Higher doses may cause prolonged sedation and risk of hypoventilation.
• Children aged 6 to 12 years: the initial dose is 0.025 to 0.05 mg/kg. A total dose of 0.4 mg/kg may be required (maximum dose – 10 mg). Higher doses may cause prolonged sedation and risk of hypoventilation.
• Children aged 12 to 16 years: use the recommended adult doses.

Rectal administration: the total dose of midazolam is usually 0.3 to 0.5 mg/kg. The solution contained in the ampoule is administered rectally using a plastic applicator attached to a syringe. If the volume to be administered is too small, water may be added to achieve a total volume of 10 ml. The entire dose should be administered immediately. Avoid repeated rectal administration. Rectal administration is not recommended for children under 6 months of age due to limited data in this age group.

Intramuscular administration: doses range from 0.05 to 0.15 mg/kg. Total doses exceeding 10.0 mg are usually not required. Intramuscular administration is possible only in exceptional cases. Rectal administration should be preferred, as intramuscular injection is painful.

Midazolam solutions with a concentration higher than 1 mg/ml are not recommended for children with body weight less than 15 kg. Higher concentrations should be diluted to 1 mg/ml.

Anesthesia Dosage

Premedication

Premedication with midazolam administered shortly before the procedure induces a sedative effect (drowsiness and anxiety relief) and preoperative memory impairment.

Midazolam may also be administered in combination with anticholinergic agents. In such cases, midazolam is administered intravenously or intramuscularly (deeply into muscle mass, 20–60 minutes before anesthesia induction), while rectal administration is preferred for children. After premedication, the patient must be under continuous close monitoring, as individual sensitivity to the drug varies and symptoms of overdose may occur.

Adults

The recommended dose for preoperative sedation and memory impairment regarding preoperative events in patients belonging to ASA physical status classes I and II, as well as for patients under 60 years of age, is 1 to 2 mg intravenously (the dose may be repeated if necessary) or 0.07 to 0.1 mg/kg intramuscularly. For patients aged 60 years and older, weakened patients, or chronically ill patients, the dose should be reduced and adjusted according to the individual case. The recommended initial intravenous dose is 0.5 mg, which may be increased by slow titration if necessary. The recommended initial intramuscular dose is 0.025 to 0.05 mg/kg. When opioids are administered concomitantly, the midazolam dose should be reduced. The usual dose is 2 to 3 mg.

Pediatric Population

Neonates and children under 6 months of age

This medicinal product is not recommended for children under 6 months of age due to limited data in this age group.

Children aged 6 months and older

Rectal administration: the total dose of midazolam (usually in the range of 0.3 to 0.5 mg/kg) should be administered 15–30 minutes before anesthesia induction. The solution contained in the ampoule is administered rectally using a plastic applicator attached to a syringe. If the volume to be administered is too small, water may be added to achieve a total volume of 10 ml.

Intramuscular administration: intramuscular administration is painful; therefore, this route should be used only in exceptional cases. Rectal administration should be preferred. The range of effective and safe doses for intramuscular administration is 0.08 to 0.2 mg/kg. Children aged 1 to 15 years require proportionally higher doses per body weight compared to adults.

Midazolam solution with a concentration higher than 1 mg/ml is not recommended for children with body weight less than 15 kg. Higher concentration solutions should be diluted to 1 mg/ml.

Anesthesia Induction

Adults

When midazolam is used prior to or in combination with other anesthetic agents for anesthesia induction, individual patient response varies widely. The dose should be increased by titration to achieve the desired effect. The dose should be titrated according to the patient's age and clinical status. If midazolam is used before or in combination with other intravenous or inhalational agents used for anesthesia induction, the initial dose of all these agents should be significantly reduced, sometimes to 25% of the usual initial dose.

The desired level of analgesia is achieved by gradual dose escalation. For intravenous anesthesia induction, midazolam is administered slowly in divided doses. Each dose (not exceeding 5 mg) should be administered over 20–30 seconds with 2-minute intervals between doses.

• For adults under 60 years of age who have received premedication, a usual dose of 0.15 to 0.2 mg/kg intravenously is administered.
• For adults under 60 years of age without premedication, higher doses (0.3–0.35 mg/kg intravenously) may be used. Additional doses of approximately 25% of the patient's initial dose may be administered if necessary to complete induction. Induction may also be performed using inhalational anesthetics. In refractory cases, a total dose of up to 0.6 mg/kg may be used for induction, but such higher doses may cause prolonged recovery after anesthesia.
• For adults aged 60 years and older who have received premedication, weakened patients, or patients with chronic diseases, dosing should be significantly reduced, e.g., to 0.05–0.15 mg/kg intravenously, administered over 20–30 seconds, with a drug onset time of 2 minutes.
• For adults aged 60 years and older without premedication, higher midazolam doses are usually required for induction. The recommended initial dose is 0.15 to 0.3 mg/kg. For debilitated patients or patients with severe systemic disease without premedication, a smaller amount of midazolam is usually administered for induction. An initial dose of 0.15 to 0.25 mg/kg is usually sufficient.

As a Sedative Component in Combined Anesthesia

Adults

The medicinal product Quimilon may be administered as a sedative component in combined anesthesia either by further small intravenous doses (in the range of 0.03 to 0.1 mg/kg) or by continuous intravenous infusion of midazolam (in the range of 0.03 to 0.1 mg/kg/hour), usually in combination with analgesics. The dose and intervals between doses vary depending on the individual patient response.

Lower doses are required for maintenance in adults aged 60 years and older, weakened patients, or chronically ill patients.

Sedation in Intensive Care Units

The desired level of sedation is achieved by stepwise titration of midazolam dose followed by either intermittent bolus administration or continuous infusion. Midazolam is administered according to clinical needs, patient status, age, and concomitant medications (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adults

Intravenous loading dose: 0.03 to 0.3 mg/kg, administered slowly with increments. Each dose of 1 to 2.5 mg should be administered over 20–30 seconds with 2-minute intervals between doses. The loading dose should be reduced or omitted for patients with hypovolemia, vasoconstriction, or hypothermia. If midazolam is administered simultaneously with strong analgesics, the analgesics should be administered first. This ensures safe titration of midazolam's sedative effect, thus avoiding the influence of analgesic sedation.

Intravenous maintenance dose: 0.03 to 0.2 mg/kg/hour. The maintenance dose should be reduced for patients with hypovolemia, vasoconstriction, or hypothermia. The level of sedation should be assessed regularly. Prolonged sedation may lead to the development of tolerance, which may require dose escalation.

Pediatric Population

Neonates and children under 6 months of age

The medicinal product Quimilon is administered as a continuous intravenous infusion. The initial dose for neonates with a gestational age less than 32 weeks is 0.03 mg/kg/hour (0.5 µg/kg/min), and for neonates with a gestational age of more than 32 weeks, as well as for children under 6 months of age, it is 0.06 mg/kg/hour (1 µg/kg/min).

Intravenous loading doses are not recommended for preterm neonates, neonates, and children under 6 months of age; a higher infusion rate during the first hours of administration is preferable to achieve therapeutic concentrations. The infusion rate should be frequently and carefully reviewed to select the lowest effective dose and prevent drug accumulation (especially during the first 24 hours). Careful monitoring of respiratory rate and oxygen saturation is required.

Children aged 6 months and older

Children who are mechanically ventilated and intubated should receive a loading dose of 0.05 to 0.2 mg/kg intravenously slowly over at least 2–3 minutes to achieve the desired clinical effect.

Quimilon should not be administered as a rapid intravenous injection. After administration of the loading dose, midazolam should be administered as a continuous infusion at a rate of 0.06 to 0.12 mg/kg/hour (1 to 2 µg/kg/min). The infusion rate may be increased or decreased (usually by 25% from the initial or subsequent infusion rate) as needed, or additional doses of midazolam may be administered intravenously to maintain or enhance the desired effect.

If midazolam infusion is initiated in hemodynamically unstable patients, the usual loading dose should be titrated with low doses, and the patient should be monitored for hemodynamic changes (e.g., hypotension). These patients are more sensitive to the respiratory depressant effects of midazolam; therefore, careful monitoring of respiratory rate and oxygen saturation is required.

Midazolam solutions with a concentration higher than 1 mg/ml are not recommended for preterm neonates, neonates, and children with body weight below 15 kg. Higher concentration solutions should be diluted to 1 mg/ml.

Use in Special Patient Populations

Renal Impairment

In patients with severe renal insufficiency, midazolam may be associated with more pronounced and prolonged sedation, possibly including clinically significant respiratory and cardiovascular depression. Therefore, midazolam should be used with caution in this patient group and titrated to achieve the desired effect (see section "Special Warnings and Precautions for Use").

Hepatic Impairment

In hepatic impairment, clearance of intravenously administered midazolam is reduced, leading to an increased terminal elimination half-life. This may result in a stronger and more prolonged clinical effect. Lower doses of midazolam may be required; therefore, careful monitoring of vital signs is essential (see section "Special Warnings and Precautions for Use").

Instructions for Use

The medicinal product Quimilon is compatible with the following solutions: 0.9% sodium chloride solution, 5% levulose solution, 10% glucose solution, 5% glucose solution.

For intravenous infusion, the contents of Quimilon ampoules may be diluted with one of the above-mentioned solutions at a ratio of 15 mg Quimilon per 100–1000 ml of infusion solution.

For single use only; any unused portion of the solution should be discarded.

The solution should be inspected visually before use. Only clear, particle-free solutions should be used.

Chemical and physical stability has been demonstrated for 24 hours at room temperature and for 3 days at 2–8 °C.

From a microbiological standpoint, the solution should be used immediately. Quimilon is intended for single use. If not used immediately, the responsibility for storage duration and conditions prior to use lies with the user.

The diluted solution may be stored for 24 hours at a temperature of 2 to 8 °C.

Do not freeze.

Children.

Sedation with this medicinal product is not recommended for children under 6 months of age, as this patient group is extremely sensitive to hypoventilation and airway patency disturbances.

Overdose.

Symptoms

Like other benzodiazepines, midazolam usually causes drowsiness, ataxia, dysarthria, and nystagmus. Overdose with midazolam alone is rarely life-threatening but may lead to areflexia, apnea, hypotension, circulatory and respiratory depression, and in rare cases, coma. Coma usually lasts several hours but may be more prolonged and cyclic, especially in elderly patients. The respiratory depressant effect of benzodiazepines is more pronounced in patients with respiratory diseases. Benzodiazepines potentiate the effects of other CNS depressants, including alcohol.

Treatment

Vital signs of the patient should be monitored, and supportive therapy should be initiated according to the patient's clinical status. In particular, patients may require symptomatic treatment aimed at supporting cardiorespiratory function and CNS activity.

In cases of oral ingestion, further absorption should be prevented using an appropriate method, e.g., administration of activated charcoal within 1–2 hours after overdose. If activated charcoal is used, airway protection is mandatory for patients suffering from drowsiness. Gastric lavage may be considered in cases of mixed overdose, but not as a routine measure.

In cases of severe CNS depression, the use of flumazenil, a benzodiazepine antagonist, should be considered. This should be performed only under strict monitoring conditions. Flumazenil has a short elimination half-life (approximately one hour), so patients who have received flumazenil should be observed after its effects cease. Flumazenil should be used with particular caution in cases of concomitant use of medicinal products that lower the seizure threshold (e.g., tricyclic antidepressants). For more detailed information on the proper use of flumazenil, refer to the medicinal product's instructions for medical use.

Adverse Reactions

The following adverse reactions have been reported during intravenous administration of midazolam.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated based on available data).

*Such paradoxical adverse reactions have been observed particularly in children and elderly patients (see section "Special precautions").

**Anterograde amnesia may still be present until the end of the procedure, and prolonged amnesia has been reported in some cases (see section "Special precautions").

***In patients receiving concomitant sedative medicinal products (including alcohol consumption) and in elderly patients, the risk of falls and fractures is increased.

**** Especially after parenteral administration.

Severe cardiorespiratory adverse reactions have been reported. Life-threatening complications are more likely in adults aged 60 years and older and in patients with pre-existing respiratory insufficiency or cardiac dysfunction, particularly with rapid administration or administration of high doses of the drug (see section "Special precautions").

Dependence. Midazolam may cause physical dependence, even when used at therapeutic doses. Discontinuation of treatment (especially abrupt) after prolonged intravenous administration may lead to withdrawal symptoms, including withdrawal syndrome seizures (see section "Special precautions"). Cases of drug abuse have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of the reach of children.

Packaging.

3 ml of solution in an ampoule; 5 ampoules in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LABORATORIOS CERRO PAMEL, S.A.

Manufacturer's address and location of its business operations.

Carretera de Castellvell, No 24, Reus, Tarragona, 43206, Spain