Flumazenil pharmaselect

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUMAZENIL PHARMASELECT (FLUMAZENIL PHARMASELECT)

Composition:

active substance: flumazenil;

1 ml of solution contains flumazenil 0.1 mg;

excipients: sodium chloride, acetic acid / sodium hydroxide (for pH adjustment to 4.2), disodium edetate, water for injections.

Pharmaceutical form. Injection solution

Main physicochemical properties: clear, colorless solution, practically free of visible particles.

Pharmacotherapeutic group. Other therapeutic agents. Antidotes. ATC code V03AB25.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Flumazenil is a benzodiazepine antagonist, an imidazobenzodiazepine derivative, which specifically blocks the effects of substances acting at the benzodiazepine receptor in the central nervous system (CNS) through competitive interaction. Neutralization of paradoxical reactions to benzodiazepines has been reported.

Pharmacodynamic effects. Animal studies have shown that flumazenil does not block the effects of benzodiazepine receptor agonists such as barbiturates, gamma-aminobutyric acid (GABA) mimetics, or adenosine receptor antagonists. Flumazenil blocks the action of non-benzodiazepine agonists such as cyclopyrrolones (zopiclone) and triazolopyridazines. The hypnotic-sedative effects of benzodiazepines rapidly disappear (within 1–2 minutes) after intravenous administration of flumazenil. Depending on the difference in elimination time between the agonist and antagonist, the effect may recur within several hours. Flumazenil may have slight agonist activity (e.g., anticonvulsant).

Clinical efficacy and safety. Animal studies have shown that prolonged treatment with flumazenil may lead to a withdrawal syndrome, including seizures.

Pharmacokinetics

Distribution. Flumazenil is a weak lipophilic base. It binds to approximately 50% of plasma proteins, two-thirds of which is albumin. Flumazenil is extensively distributed into the extravascular space. During the distribution phase, the plasma concentration of flumazenil decreases with a half-life of 4–5 minutes. The volume of distribution at steady state is 0.9–1.1 L/kg.

Metabolism. Flumazenil undergoes extensive hepatic metabolism. The main inactive metabolite in plasma (in free form) and urine (in free and conjugated forms) is carboxylic acid. Pharmacological testing has shown that this metabolite has no agonist or antagonist benzodiazepine activity.

Elimination. Flumazenil is almost completely excreted in the urine. This indicates complete breakdown of the active substance in the body. Radiolabeled drug studies have shown that complete elimination occurs within 72 hours: 90–95% in urine and 5–10% in feces. Elimination is rapid, as evidenced by the short elimination half-life (40–80 minutes). Total clearance of flumazenil is 0.8–1.0 L/h/kg, with metabolism occurring predominantly in the liver.

In patients with moderate or severe hepatic impairment, the elimination half-life of flumazenil is prolonged (by 70–210%), and total clearance is reduced (by 57% to 74%) compared to data from studies in healthy volunteers.

The pharmacokinetics of flumazenil are proportional to the therapeutic dose and do not exceed 100 mg. Food intake during intravenous infusion leads to a 50% increase in its clearance, likely due to increased hepatic blood flow.

Clinical characteristics.

Indications.

The medicinal product is used for partial or complete reversal of central sedative effects of benzodiazepines in adults and children aged 1 year and older. It may be used in anesthesia and intensive care.

Anesthesia:

• to reverse hypnotic-sedative effects of benzodiazepines during general induced and/or maintained anesthesia in hospitalized patients;
• to reverse sedative effects of benzodiazepines during short-term diagnostic and therapeutic procedures in both outpatient and inpatient settings;
• to reverse sedative effects of benzodiazepines in children aged 1 year and older.

Intensive care:

• for specific reversal of central effects of benzodiazepines to restore spontaneous respiration;
• for diagnosis and treatment of intoxication or overdose with benzodiazepines alone or predominantly.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Treatment of life-threatening conditions with benzodiazepines (e.g., control of intracranial pressure or status epilepticus).
• Severe intoxication caused by cyclic antidepressants (seizures, focal seizures, QRS prolongation, arrhythmia, mydriasis, anticholinergic symptoms). In mixed intoxications caused by benzodiazepines and cyclic antidepressants, the toxicity of antidepressants may be masked by the protective effect of benzodiazepines. Therefore, in the presence of autonomic (anticholinergic), motor, or cardiac symptoms of severe intoxication with tricyclic/tetracyclic antidepressants, flumazenil should not be used to reverse the effects of benzodiazepines.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adult patients. Flumazenil antagonizes central effects of benzodiazepines by competitive inhibition at the receptor level. It also blocks the action of non-benzodiazepine agonists (e.g., zopiclone, triazolopyridazines, etc.) at benzodiazepine receptors. However, flumazenil does not block the effects of medicinal products that do not act via this mechanism. No interaction has been observed with other CNS depressants. Flumazenil should be used with particular caution in cases of overdose, as along with reduction of benzodiazepine effects, toxic effects of other psychotropic substances (especially tricyclic antidepressants) administered concomitantly may become enhanced.

When flumazenil is used concomitantly with midazolam, flunitrazepam, and lormetazepam, no changes in pharmacokinetics occur.

There is also no pharmacokinetic interaction between ethanol and flumazenil.

Special precautions for use.

Monitoring. When using flumazenil to reverse benzodiazepine-induced sedation, prolonged monitoring of dose, vital signs (electrocardiogram (ECG), pulse, oximetry, patient's level of consciousness), and other vital parameters such as heart rate, respiratory rate, and blood pressure, as well as the duration of effect of the benzodiazepine used, is required to detect possible recurrence of sedation, respiratory depression, or other signs of residual benzodiazepine effects. Since drug effects may be delayed in patients with impaired liver function, an extended observation period is necessary. In general, flumazenil has a shorter duration of action than benzodiazepines; therefore, sedation may recur, and the patient's clinical status must remain under continuous supervision, preferably in an intensive care unit, until the effect of flumazenil has subsided.

If the patient does not emerge from sedation. The antagonistic effect of flumazenil is specific to benzodiazepines. Therefore, if the patient does not awaken from sedation, other causes should be considered.

Anesthesia. At the end of surgery, when anesthesia is being reversed, flumazenil should only be administered after it has been confirmed that the activity of peripheral muscle relaxants has decreased and there is no longer any opioid-induced respiratory depression (reversal with naloxone).

Special patient groups

The benefits of benzodiazepine sedation versus the risks of rapid awakening should be carefully weighed in critically ill patients. For some patients (e.g., those with cardiac conditions), maintaining a certain level of sedation in the early postoperative period may be preferable to full consciousness.

Patients with epilepsy. Flumazenil is not recommended for patients with epilepsy who have been receiving long-term benzodiazepine therapy. Although flumazenil has minimal intrinsic central nervous system activity, abrupt reversal of the protective effect of benzodiazepines may precipitate seizures in epileptic patients.

Patients with severe head trauma. Flumazenil should be used with caution in patients with severe head injury (and/or unstable intracranial pressure), as it antagonizes the effects of benzodiazepines and may cause increased intracranial pressure, changes in cerebral perfusion, or seizures.

Withdrawal symptoms. Rapid administration of high doses (more than 1 mg) of flumazenil should be avoided in patients who have previously received high doses and/or long-term benzodiazepine therapy (up to several weeks prior to flumazenil administration). In such cases, rapid injection may precipitate withdrawal symptoms, including tachycardia, agitation, anxiety, emotional lability, confusion, and sensory disturbances.

If a patient has been receiving high doses of benzodiazepines for a prolonged period, the benefits of using flumazenil should be weighed against the risk of withdrawal symptoms. If withdrawal symptoms occur despite careful dose titration, an individually adjusted dose of 5 mg diazepam or 5 mg midazolam should be administered slowly via intravenous injection.

Particular caution is required in patients with dependence, chronic benzodiazepine overdose, or mixed intoxications of unknown origin. For such patients, the recommended administration interval (1 minute) should be extended, as the full effect of a single dose may take up to 10 minutes to manifest. In most cases, the lowest effective dose should be used to avoid potential dependence-related symptoms or seizures. In particular, in cases of mixed intoxication with benzodiazepines and cyclic antidepressants, the use of flumazenil may enhance certain toxic effects (such as seizures and cardiac arrhythmias) caused by cyclic antidepressants, which are otherwise less pronounced when benzodiazepines are co-administered.

Anxiety. Flumazenil dosing should be carefully titrated in patients suffering from preoperative anxiety or with a history of chronic or episodic anxiety disorders.

Postoperative pain. Postoperative pain should be taken into account. It may be preferable to maintain the patient in a sedated state.

Use in pediatrics. Due to the risk of recurrent sedation and respiratory depression, children who have experienced sedation following midazolam administration should be closely monitored for at least 2 hours after flumazenil administration. When other sedative benzodiazepines are used, the monitoring period should be adjusted according to their expected duration of action. Due to limited experience, flumazenil should be used with caution and only in the following cases:

• reversal of sedation in children under 1 year of age;
• treatment of overdose in children;
• resuscitation of newborns;
• reversal of sedative effects of benzodiazepines used for anesthesia in children.

Until sufficient data are available, flumazenil should not be used in children under 1 year of age unless the risks to the patient (especially in cases of accidental overdose) outweigh the benefits of treatment.

Due to the lack of data from controlled studies, the use of flumazenil in children and adolescents for indications other than reversal of benzodiazepine-induced sedation is not recommended. The same applies to children under 1 year of age.

Benzodiazepine dependence. Flumazenil is not recommended for the treatment of benzodiazepine dependence or prolonged benzodiazepine withdrawal syndromes.

Panic disorders. Cases of panic attacks have been reported following flumazenil administration in patients with a history of panic disorders.

History of dependence. Flumazenil should be used with caution in patients with frequent benzodiazepine use, alcoholism, drug dependence, or other forms of addiction.

Hepatic impairment. Elimination of flumazenil may be delayed.

Flumazenil Pharmaselect contains approximately 3.6 mg of sodium per 1 ml of injection solution (18 mg in 5 ml of injection solution). This should be taken into account if the patient is on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

Although animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development, the safety of flumazenil during pregnancy has not been established. The benefit-risk ratio should be carefully evaluated, as there are no data on flumazenil use during pregnancy. The effect of flumazenil on the fetus has not been studied in animals.

Breastfeeding

It is unknown whether flumazenil is excreted in breast milk. Breastfeeding should be discontinued for 24 hours after administration of flumazenil.

Ability to affect reaction speed when driving or operating machinery.

Although patients regain consciousness after flumazenil administration, they should be advised not to engage in hazardous activities requiring full mental alertness (such as operating machinery or driving a vehicle) for 24 hours after drug administration, as the effects of the previously administered benzodiazepine may recur.

Administration and Dosage

The drug must be administered by an anesthesiologist or a physician experienced in anesthesiology. Flumazenil is administered intravenously.

Flumazenil may be given undiluted or diluted. When administered by infusion, flumazenil must be diluted prior to administration with 0.9% sodium chloride solution, 5% glucose solution, or Ringer's solution (8.6 g sodium chloride, 0.3 g potassium chloride, and 0.33 g calcium chloride per 1 L). Compatibility of flumazenil with other injectable solutions has not been established. Flumazenil may be used concomitantly with other resuscitation measures.

The medicinal product is intended for single use only. Before administration, visually inspect the solution and use only if it is clear and free of foreign particles.

Use in Adults

Anesthesia

Recommended initial dose: 0.2 mg intravenously over 15 seconds. If the desired effect is not achieved within 60 seconds, administer the next dose of 0.1 mg, repeating administration every 60 seconds as needed up to a maximum dose of 1.0 mg. The usual dose ranges between 0.3 and 0.6 mg and may be adjusted depending on the patient's condition and the benzodiazepine used.

Intensive Care

Recommended initial dose: 0.2 mg intravenously over 15 seconds. If the desired effect is not achieved within 60 seconds, administer the next dose of 0.1 mg, repeating administration every 60 seconds as needed up to a maximum dose of 2.0 mg or until the patient emerges from sedation. If sedation recurs, repeated bolus injections may be given. Additionally, intravenous infusion may be used at a rate of 0.1–0.4 mg/min. The dosage and infusion rate should be adjusted to achieve the desired level of consciousness. Bolus injections may be used to supplement infusion up to a maximum total dose of 2 mg.

If no clear effect on consciousness and respiration is observed after multiple administrations, consider that intoxication is not related to benzodiazepines.

The infusion should be paused every 6 hours to assess whether resedation occurs. To avoid withdrawal symptoms in patients who have received high doses of benzodiazepines for prolonged periods in intensive care units, flumazenil should be administered cautiously, with individualized dosing and slow injection.

Use in Elderly Patients

In the absence of specific data on the use of flumazenil in elderly patients, it should be noted that this group is generally more sensitive to the effects of medicinal products; therefore, flumazenil should be used with caution.

Use in Children and Adolescents (Aged 1 to 17 Years)

Dosing for Reversal of Conscious Sedation

Recommended initial dose: 0.01 mg/kg body weight (up to 0.2 mg), administered intravenously over 15 seconds. If the required level of consciousness is not achieved within 45 seconds, the next injection of 0.01 mg/kg (up to 0.2 mg) may be given at intervals of up to 60 seconds (maximum of 4 injections), up to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower. Dosing should be adjusted according to the patient's response. There are no data on the safety and efficacy of repeated administration of flumazenil in children in case of resedation.

Use in Patients with Hepatic Impairment

Flumazenil is metabolized predominantly in the liver. In patients with impaired liver function, elimination of flumazenil may be delayed; therefore, careful dose selection is recommended.

Children

There is insufficient data on the use of flumazenil in children under 1 year of age. Therefore, flumazenil should be administered to this patient group only if the potential benefit to the patient outweighs the possible risk.

Overdose

In cases of mixed intoxications, particularly in combination with cyclic antidepressants, toxic effects (such as seizures and cardiac arrhythmias) may occur upon recurrence of benzodiazepine effects.

Experience with acute flumazenil overdose is very limited. There is no specific antidote for flumazenil.

Management of flumazenil overdose should consist of general supportive measures, including monitoring of vital signs and clinical observation.

No symptoms of overdose have been observed even when doses higher than recommended (up to 100 mg) were administered.

Adverse reactions.

Adverse reactions associated with the use of flumazenil are classified by system organ classes and frequency of occurrence. Frequency is defined as follows:

very common (≥ 1/10);

common (≥ 1/100 and < 1/10);

uncommon (≥ 1/1000 and < 1/100);

rare (≥ 1/10000 and < 1/1000);

very rare (< 1/10000);

not known (cannot be estimated from the available data).

* After rapid injection; treatment is usually not required.

In patients who have been receiving benzodiazepines for a prolonged period, flumazenil may precipitate a withdrawal syndrome. Symptoms may include: tension, agitation, anxiety, emotional lability, confusion, sensory disturbances, hallucinations, tremor, and seizures.

Rapid administration of high doses (more than 1 mg) of flumazenil should be avoided in patients who previously received high doses and/or long-term benzodiazepine therapy (up to several weeks prior to flumazenil administration). In such cases, rapid injection may cause withdrawal symptoms, including tachycardia, agitation, anxiety, emotional lability, confusion, and sensory disturbances.

** In patients with a history of panic disorders, flumazenil may trigger panic attacks.

Adverse effects in children

Overall, the adverse effect profile in children does not differ significantly from that in adults. When flumazenil is used to reverse conscious sedation in children, abnormal crying, agitation, and aggressive reactions may additionally occur.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life 4 years. After opening the ampoule, use immediately. The shelf life after dilution is 24 hours, provided the solution is stored at 2 °C to 8 °C.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging. 5 ml in an ampoule; packs of 5 or 10 ampoules in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Manufacturer responsible for batch release:

Pharmasect International Beteiligungs GmbH /
Pharmaselect International Beteiligungs GmbH

Address of manufacturer and place of business.

Ernst-Melchior-Gasse 20, 1020 Vienna, Austria /
Ernst-Melchior-Gasse 20, 1020 Vienna, Austria