Anexate^® (Solution) Instructions for Use

Marketing Authorization Holder

Cheplapharm Arzneimittel, GmbH (Germany)

Manufactured By

Cenexi, SAS (France)

ATC Code

V03AB25 (Flumazenil)

Active Substance

Flumazenil (Rec.INN registered by WHO)

Dosage Form

Anexate®

Solution for intravenous administration 0.5 mg/5 ml: amp. 5 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous administration transparent, colorless or almost colorless.

Excipients: disodium edetate – 0.5 mg, glacial acetic acid – 0.5 mg, sodium chloride – 46.5 mg, sodium hydroxide (0.1M solution) – q.s. to pH 4.0, water for injections – up to 5 ml.

5 ml – glass ampoules (5) – cardboard trays with dividers (1) – cardboard packs with first-opening control*.

* in the form of a semicircular perforated valve on the long side of the lid, glued to a similar perforated side part of the pack; the valve is pressed for first opening.

Clinical-Pharmacological Group

Competitive benzodiazepine antagonist

Pharmacotherapeutic Group

Benzodiazepine antagonist

Pharmacological Action

The instructions were approved by the Pharmacological Committee of the Ministry of Health of the Russian Federation on 07/18/02.

Flumazenil, an imidazobenzodiazepine derivative, is a benzodiazepine antagonist. It specifically suppresses the effects of drugs acting on benzodiazepine receptors in the CNS. It eliminates sedation, amnesia, and psychomotor impairments caused by benzodiazepine receptor agonists. The hypnotic and sedative effects of benzodiazepines disappear within 1-2 minutes after intravenous injection of flumazenil, but may gradually reappear over the next few hours, depending on the half-life and dose of the agonist.

Flumazenil may have weak intrinsic agonistic (e.g., anticonvulsant) activity.

In adult patients who have received large doses of benzodiazepines for several weeks, the administration of flumazenil was accompanied by benzodiazepine withdrawal symptoms, including seizures.

Pharmacokinetics

The pharmacokinetics of flumazenil, both in the therapeutic and in higher dose ranges (up to 100 mg), are dose-dependent.

Distribution

As a weak lipophilic base, Flumazenil is 50% bound to plasma proteins. Two-thirds of the protein binding is accounted for by albumin. Flumazenil undergoes extensive distribution in the extravascular space. T_1/2 is biphasic. The initial T_1/2 is 4-11 minutes. V_d at steady-state concentration is 0.9-1.1 L/kg.

Metabolism

Flumazenil undergoes intensive metabolism in the liver. The main inactive metabolite in plasma (free form) and urine (free form and glucuronide) is the carboxylic acid.

Excretion

The total clearance of flumazenil is 0.7-1.3 L/h/kg, is carried out mainly by the liver and depends on the magnitude and rate of hepatic blood flow. Less than 1% of the administered dose is excreted unchanged in the urine, suggesting complete metabolic degradation of the drug. Urinary excretion is 90-95%, biliary excretion is 5-10% within 72 hours. Elimination is rapid, as evidenced by the short terminal T_1/2 of 40-80 minutes.

Food intake during intravenous infusion of flumazenil leads to a 50% increase in clearance, most likely due to increased hepatic blood flow accompanying food intake.

Pharmacokinetics in special clinical groups

In patients with impaired liver function, the T_1/2 of flumazenil increases and the total clearance decreases. The pharmacokinetics of flumazenil do not change significantly in elderly and senile patients, and do not depend on gender, hemodialysis, or renal failure. In children over 1 year of age, the T_1/2 is more variable than in adults and averages 40 minutes (range 20-75 minutes). Clearance and V_d, adjusted for body weight, are within the same limits as in adults.

Indications

Complete or partial elimination of the central sedative effects of benzodiazepines. The drug is used in anesthesiology and intensive care for the following indications.

Anesthesiology

• Reversal of general anesthesia induced and maintained with benzodiazepines in hospitalized patients;
• Elimination of the sedative effect of benzodiazepines during short-term diagnostic and therapeutic procedures in hospitalized and outpatient patients.

Intensive care and management of patients with loss of consciousness of unknown etiology

• For differential diagnosis in loss of consciousness of unknown etiology: establishing or ruling out a diagnosis of benzodiazepine poisoning;
• Benzodiazepine poisoning: specific elimination of the central effects of benzodiazepines in case of their overdose (restoration of spontaneous breathing and consciousness, which eliminates the need for intubation or allows extubation of the patient).

ICD codes

Dosage Regimen

Standard dosing regimen: Flumazenil is administered only intravenously under the supervision of a qualified anesthesiologist or therapist. Compatible with 5% aqueous glucose solution, Ringer’s lactate solution or 0.9% sodium chloride solution. The dose should be titrated to achieve the desired effect. Since the duration of action of some benzodiazepines may exceed that of flumazenil, repeated administration of the drug may be required if sedation recurs after consciousness is restored.

Anesthesiology: initial dose – 0.2 mg IV over 15 seconds. If the desired recovery of consciousness does not occur within 60 seconds, a second dose (0.1 mg) can be administered and then repeated at 60-second intervals until a total dose of 1 mg is reached. The usual dose is 0.3-0.6 mg, but individual requirements may vary significantly, depending on the dose and duration of action of the previously administered benzodiazepine and the characteristics of the patient.

Intensive care and management of patients with loss of consciousness of unknown etiology: recommended initial dose – 0.3 mg IV. If the desired level of consciousness recovery does not occur, Flumazenil can be administered repeatedly, as described above, until a total dose of no more than 2 mg is reached. If confusion recurs, it is recommended to administer the drug intravenously again, either as a bolus or as an infusion at a rate of 0.1-0.4 mg per hour. The infusion rate is selected individually to achieve the required level of consciousness recovery.

If consciousness or respiratory function does not recover sufficiently after repeated administration of flumazenil, a non-benzodiazepine etiology of the consciousness disorder should be considered.

In intensive care patients, as well as in patients who have received large doses of benzodiazepines for a long time, individually selected doses of flumazenil, when administered slowly, should not cause withdrawal symptoms. If undesirable symptoms of hyperstimulation occur, diazepam or midazolam should be administered intravenously, carefully titrating their doses depending on the patient’s response.

Children over 1 year : to eliminate conscious sedation caused by benzodiazepines, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) IV over 15 seconds. If the desired level of consciousness recovery does not occur after another 45 seconds, additional doses of 0.01 mg/kg (up to 0.2 mg) can be administered at 60-second intervals (but no more than 4 times), up to a maximum total dose of 0.05 mg/kg or 1 mg. The dose is selected individually depending on the patient’s response.

Adverse Reactions

Adults and children tolerate Flumazenil well. Adults tolerate even doses higher than recommended well.

After rapid administration of flumazenil, anxiety, palpitations, and fear sometimes occurred. These undesirable effects usually do not require special treatment.

Very rare cases of seizures have been described in patients suffering from epilepsy or severe liver damage, especially after long-term treatment with benzodiazepines or in the case of mixed drug overdose.

There are reports that in patients with a history of panic disorders, the administration of flumazenil may provoke a panic attack.

Adverse reactions associated with the use of flumazenil, occurring in 3-9% of cases: dizziness, headache, blurred vision, agitation, anxiety, nervousness, dry mouth, tremor, insomnia, ataxia (10%), shortness of breath, hyperventilation, palpitations, pain at the injection site, sweating.

From the gastrointestinal tract nausea, vomiting (11%).

Adverse reactions associated with the use of flumazenil, occurring in 1-3% of cases body as a whole: asthenia, local reactions: thrombophlebitis, rash;

From the cardiovascular system: cutaneous vasodilation, sensations of “hot flashes”.

From the CNS dizziness, paresthesia (sensory disturbance, hypoesthesia), emotional lability (tearfulness), depersonalization, euphoria, dysphoria, depression, paranoia.

From the sensory organs visual impairment (diplopia, visual field defect).

Side effects occurring in less than 1% of cases, possibly associated with the use of flumazenil or benzodiazepine withdrawal.

From the nervous system impaired concentration, delirium, convulsions, drowsiness;

From the sensory organs transient hearing loss, hyperacusis, tinnitus.

Contraindications

• Hypersensitivity to the drug;
• Poisoning with cyclic antidepressants.

Anexate^® is contraindicated in patients who are receiving benzodiazepines to treat a potentially life-threatening condition (e.g., intracranial hypertension or status epilepticus).

Use in Pregnancy and Lactation

Although in animal experiments Flumazenil in large doses did not have mutagenicity, embryotoxicity and teratogenicity and did not affect fertility, its safety in human pregnancy has not been established. Therefore, when prescribing it in such cases, the benefits of use should be carefully weighed against the possible risk to the fetus.

During lactation, parenteral administration of flumazenil in emergency cases is not contraindicated.

Pediatric Use

Flumazenil should be used with caution to reverse conscious sedation in children under 1 year of age, to treat benzodiazepine overdose in children, during resuscitation of newborns, and to reverse the sedative effects of benzodiazepines used for induction of anesthesia in children, because experience with the drug in such situations is limited.

Children over 1 year : to eliminate conscious sedation caused by benzodiazepines, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) IV over 15 seconds. If the desired level of consciousness recovery does not occur after another 45 seconds, additional doses of 0.01 mg/kg (up to 0.2 mg) can be administered at 60-second intervals (but no more than 4 times), up to a maximum total dose of 0.05 mg/kg or 1 mg. The dose is selected individually depending on the patient’s response.

Special Precautions

Special caution is required when prescribing flumazenil in cases of mixed drug overdose, since after the elimination of benzodiazepine effects, the toxic effects (e.g., seizures and cardiac arrhythmias) of other drugs taken in excessive doses (especially cyclic antidepressants) may appear.

Flumazenil is not recommended for use in patients with epilepsy who have been receiving long-term benzodiazepine therapy. Although Flumazenil has its own weak anticonvulsant effect, a sharp decrease in the effect of benzodiazepine in patients with epilepsy can provoke seizures.

Patients who have been administered Flumazenil to reverse the effects of benzodiazepines should be observed for recurrent sedation, respiratory depression and other residual benzodiazepine effects for a certain period of time, taking into account the doses and duration of action of the previously administered benzodiazepines.

Flumazenil is not used until the effect of peripheral muscle relaxants is completely over and neuromuscular blockade is eliminated simultaneously with neuromuscular blockers; it should not be administered until neuromuscular blockade is completely eliminated.

Flumazenil is used with caution in patients with traumatic brain injuries, as it may provoke seizures or change cerebral blood flow in patients who have received benzodiazepines.

Rapid administration of flumazenil should be avoided in patients who have previously received benzodiazepines for a long time and completed treatment within several weeks before prescribing flumazenil, as this may cause withdrawal symptoms, including agitation, anxiety, emotional lability, as well as mild confusion and sensory disturbances.

Flumazenil is not recommended for the treatment of benzodiazepine dependence or for the relief of persistent benzodiazepine withdrawal symptoms.

Flumazenil should be used with caution to reverse conscious sedation in children under 1 year of age, to treat benzodiazepine overdose in children, during resuscitation of newborns, and to reverse the sedative effects of benzodiazepines used for induction of anesthesia in children, because experience with the drug in such situations is limited.

Effect on the ability to drive vehicles and machinery

For the first 24 hours after administration of flumazenil, it is necessary to refrain from activities requiring increased attention (working with machines and mechanisms, driving vehicles), since the effect of previously taken or administered benzodiazepines may resume.

Overdose

No symptoms of overdose are observed even after intravenous administration of doses higher than recommended.

Drug Interactions

Flumazenil suppresses the central effects of benzodiazepines by competitive inhibition at the receptor level. It also blocks the action of non-benzodiazepine agonists on benzodiazepine receptors (zopiclone, triazolopyridazines, etc.).

No pharmacokinetic interaction has been identified between Anexate and benzodiazepine receptor agonists, ethyl alcohol. The pharmacokinetics of benzodiazepine agonists in the presence of flumazenil do not change, just as the pharmacokinetics of flumazenil in the presence of benzodiazepine agonists do not change. There is no pharmacokinetic interaction between flumazenil and ethyl alcohol.

Storage Conditions

List B. Store at a temperature not exceeding 30°C (86°F). Keep out of reach of children.

Shelf Life

The shelf life is 5 years. The drug should not be used after the expiration date (EXP) indicated on the packaging.

To maintain sterility, Flumazenil must be drawn from the ampoule immediately before use; after being drawn into a syringe or diluted with physiological sodium chloride solution or 5% glucose solution, it must be used within 24 hours.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.