Aneksat

General characteristics. Structure:

Active agent: flumazenit 0.5 mg

Excipients: dinatrium эдетат, acetic acid ice, sodium chloride, sodium hydroxide of 0.1 M solution, water for injections.

Pharmacological properties:

Flumazenil, derivative imidazobenzodiazepines - the antagonist of benzodiazepines. Specifically suppresses effects of the drugs operating on benzodiazepine receptors of TsNS. Eliminates the sedation, amnesia and psychomotor disturbances caused by agonists of benzodiazepine receptors. Somnolent and sedative effect of benzodiazepines disappears in 1-2 minutes later in/in an injection of a flumazenil, but can arise gradually again within several next hours, depending on an elimination half-life and a dose of an agonist and the antagonist.

Flumazenil can have own weak agonistic (for example, anticonvulsant) activity.
At adult patients who within several weeks received high doses of benzodiazepines introduction of a flumazenil was followed by symptoms of cancellation of benzodiazepines, including spasms.

Pharmacokinetics. The pharmacokinetics flumazenit, both in therapeutic, and in higher range of doses (up to 100 mg), is dozozavisimy.

Distribution. Flumazenil, the weak lipophilic basis, approximately for 50% contacts proteins of plasma. Two thirds of linkng with proteins fall to the share of albumine. Flumazenil is intensively distributed in extravasated space. Concentration of a flumazenil in plasma decrease with an elimination half-life of 4-11 minutes during a distribution phase. Distribution volume at achievement of equilibrium concentration makes 0.9-1.1 l/kg.

Metabolism. Flumazenil is exposed to intensive metabolism in a liver. The main inactive metabolite in plasma (a free form) and urine (a free form and a glucuronide) is carboxylic acid. The main metabolite has no agonistic or antagonistic benzodiazepine activity by results of pharmacological tests.

Removal. The total clearance of a flumazenil makes 0.8-1.0 l/h/kg, is carried out preferential by a liver (99%) and depends on size and the speed of a hepatic blood-groove. Removal of a flumazenil practically comes to the end in 72 hours, 90-95% are found in urine and 5-10% in Calais. Elimination happens quickly what the short elimination half-life testifies to equal 40-80 minutes to.
Meal during intravenous infusion of a flumazenil leads to 50% to increase in clearance, most likely, due to strengthening of the hepatic blood-groove accompanying meal.

Pharmacokinetics in special clinical groups. At patients with an abnormal liver function an elimination half-life of a flumazenil more long and general clearance is lower, than at healthy volunteers. The pharmacokinetics flumazenit significantly does not change at persons of advanced and senile age, does not depend on a floor, carrying out a hemodialysis or a renal failure.
At children 1 years are more senior the elimination half-life is more subject to fluctuations, than at adults and makes, on average, 40 minutes (range of 20-75 minutes). The clearance and volume of distribution correlated to body weight are in the same limits, as at adults.

Indications to use:

Full or partial elimination of the central sedations of benzodiazepines. Drug is used in anesthesiology and an intensive care according to the following indications.

Anesthesiology:

- removal of inpatients from the general anesthesia begun and supported by means of benzodiazepines;
- elimination of sedative effect of benzodiazepines at short-term diagnostic and therapeutic procedures at stationary and ambulatories.

Intensive care and maintaining patients with a loss of consciousness of not clear etiology:

- differential diagnosis at a loss of consciousness of an unknown etiology: statement or exception of the diagnosis of poisoning with benzodiazepines;
- poisoning with benzodiazepines: specific elimination of the central effects of benzodiazepines at their overdose (recovery of independent breath and consciousness that eliminates need for an intubation or allows to extubate the patient).

Route of administration and doses:

Standard mode of dosing

Aneksat enter only intravenously (bolyusno or infusionally) under control of the qualified specialist of the anesthesiologist or therapist. Drug is compatible from 5% solution of a dextrose or 0.9% sodium chloride solution. For sterility preservation Aneksat has to be taken from an ampoule just before use. After set in the syringe or cultivations of 5% solution of a dextrose or 0.9% sodium chloride solution drug needs to be used within 24 h.
The dose should be titrated before obtaining desirable effect. As duration of effect of some benzodiazepines can exceed that flumazenit, repeated administration of drug can be required if after consciousness recovery sedation arises again.

Anesthesiology

The recommended initial dose makes 0.2 mg in/in in 15 seconds. If in 60 seconds after the first intravenous dose of desirable recovery of consciousness does not occur, then it is possible to enter the second dose (0.1 mg). If necessary this procedure can be carried out with 60-second intervals before achievement of a total dose - 1 mg. Usually the dose equals 0.3-0.6 mg, however individual requirement can vary considerably, depending on a dose and duration of effect of the benzodiazepine entered earlier and features of the patient.

Intensive care and maintaining patients with a loss of consciousness of not clear etiology
The recommended initial dose makes 0.3 mg in / century. If the desirable replacement level of consciousness does not occur, flumazenit it is possible to enter repeatedly as it is described above, before achievement of a total dose no more than 2 mg. When recuring confusion of consciousness it is recommended to administer intravenously the drug repeatedly: or bolyusno, or in the form of intravenous infusion with a speed of 0.1-0.4 mg an hour. Speed of infusion is selected individually before achievement of a necessary replacement level of consciousness.
If after repeated introduction of a flumazenil consciousness or function of breath are recovered insufficiently, it is necessary to assume not benzodiazepine etiology of disturbance of consciousness.

At patients in intensive care units, and also at patients, it is long the benzodiazepines receiving high doses, individually picked up doses of a flumazenil at slow introduction should not cause cancellation symptoms. At emergence of undesirable symptoms of hyper stimulation intravenously enter diazepam or midazolam, carefully titrating their doses depending on reaction of the patient.

Dosing in special cases
Children are more senior than 1 year
For elimination of the sedation with preservation of consciousness caused by benzodiazepines, the recommended initial dose makes 0.01 mg/kg (to 0.2 mg) in/in in 15 seconds. If in 45 seconds of a desirable replacement level of consciousness does not occur, it is possible to enter on 0:01 mg/kg (to 0.2 mg) with 60-second intervals (but no more than 4 times) to the maximum total dose 0.05 mg/kg, but no more than 1 mg. The dose is chosen individually depending on reaction of the patient.

Features of use:

Extra care is necessary at purpose of a flumazenil in cases of the mixed overdose of medicines as after elimination of benzodiazepine effects toxic action (for example, spasms and arrhythmias of heart) other drugs accepted in excess doses (especially cyclic antidepressants) can be shown.
It is not recommended to apply flumazenit at patients with epilepsy who it is long received therapy by benzodiazepines. Though flumazenit possesses own weak anticonvulsant action, sharp decrease in effect of benzodiazepine at patients with epilepsy can provoke spasms.

Patients to whom Aneksat was entered for elimination of effect of benzodiazepines should be observed regarding repeated sedation, respiratory depression and other residual effects of benzodiazepines during certain time, considering a dose and duration of effect of the benzodiazepines entered earlier.
Aneksat do not use before the full end of action of peripheral muscle relaxants and total disappearance of neuromuscular blockade.

Flumazenil with care apply at patients with craniocereberal injuries as he can provoke spasms or change a cerebral blood stream at the patients who received benzodiazepines.
It is necessary to avoid bystry introduction of a flumazenil at patients, it is earlier long receiving benzodiazepines and finished treatment with them within several weeks before purpose of a flumazenil as at the same time there can be cancellation symptoms, including agitation, alarm, emotional lability, and also easy degree of confusion of consciousness and touch disturbances.

Flumazenil is not recommended to apply to treatment of dependence on benzodiazepines or for stopping is long the remaining symptoms of benzodiazepine abstinence.
Flumazenil it is necessary to use with care for elimination of sedation with preservation of consciousness at children till 1 year, for treatment of overdose of benzodiazepines at children, when holding resuscitation actions at newborns and for elimination of sedations of benzodiazepines which were used at introduction to an anesthesia at children as experience of use of drug in such situations is limited.

Influence on driving of vehicles and work with cars and mechanisms
Within the first 24 hours after introduction of a flumazenil it is necessary to abstain from the types of activity requiring special attention (works with cars and mechanisms, driving of vehicles) as effect of earlier accepted or entered benzodiazepines can be resumed.

Side effects:

Adults and children well transfer flumazenit. Adults well transfer even doses above recommended.
After bystry introduction of a flumazenil seldom there were an alarm, heartbeat, sensation of fear. These undesirable effects usually do not demand special treatment.
Cases of convulsive attacks at the patients having epilepsy or severe damages of a liver, especially after prolonged treatment by benzodiazepines or in case of the mixed medicinal overdose are described.
In case of the mixed medicinal overdose, especially cyclic antidepressants, developing of spasms and arrhythmia after elimination of effects of benzodiazepines is possible.
At patients, it is long receiving benzodiazepines and stopped their reception several weeks prior to Aneksat's introduction, development of symptoms of cancellation at bystry introduction of Aneksata is possible.
At patients with panic frustration in the anamnesis introduction of a flumazenil can provoke the panic attack.
The side reactions connected with reception of a flumazenil, which are found in 3-9% of cases: dizziness, a headache, indistinct sight, excitement, alarm, nervousness, dryness in a mouth, a tremor, sleeplessness, an ataxy (10%), short wind, a hyperventilation, heartbeat, pain in the place of an injection, perspiration.

From digestive tract: nausea, vomiting (11%).

The side reactions connected with reception of a flumazenil, which are found in 1-3% of cases:

from an organism in general: adynamy, local reactions (thrombophlebitis, rash);
from cardiovascular system: dilatation of skin vessels, feelings of "inflows";
from the central nervous system: paresthesia (sensitivity disturbance, hypesthesia), emotional lability (tearfulness, depersonalization, euphoria, dysphoria, depression, paranoia); from sense bodys: vision disorder (diplopia, defect of fields of vision).

The side effects which are found less than in 1% of cases which are perhaps connected with reception of a flumazenil or cancellation of benzodiazepines:

from a nervous system: disturbance of concentration of attention, delirium, spasms, drowsiness;
from sense bodys: passing decrease in hearing, hyperacusia, sonitus.

Interaction with other medicines:

Flumazenil suppresses the central effects of benzodiazepines by competitive inhibition at the level of receptors. It also blocks action of not benzodiazepine agonists (for example, зопиклон, triazolpyridazinums, etc.) on benzodiazepine receptors.
Pharmacokinetic interaction between flumazenily and agonists of benzodiazepine receptors, alcohol is not revealed.
The pharmacokinetics of agonists of benzodiazepines in the presence of a flumazenil does not change as does not change and the pharmacokinetics flumazenit in the presence of agonists of benzodiazepines. Pharmacokinetic interaction between flumazenily and alcohol is absent.

Contraindications:

Hypersensitivity to drug or any of its components.
Aneksat is contraindicated to the patients receiving benzodiazepines for treatment of the state which is potentially posing a threat of life (for example, control of intracranial pressure or the epileptic status).
Poisoning with cyclic antidepressants.

Pregnancy and feeding by a breast
Though in experiments on animals flumazenit in high doses did not possess a mutagenicity, embriotoxity, teratogenecity and did not influence fertility, safety of its use for pregnant women is not established. Therefore at its appointment it is necessary to compare carefully advantages of use to mother with possible risk for a fruit.
During the feeding period a breast parenteral administration of a flumazenil in urgent cases is not contraindicated.

Overdose:

Data on acute overdose flumazenily are limited. The specific antidote is absent. At overdose treatment has to consist of the general supporting actions, monitoring of the vital indicators and observation of the clinical status of the patient.
Even at intravenous administration of doses above the recommended symptoms of overdose it was not observed.

Storage conditions:

List B.
To store at a temperature not above 30 °C.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous administration of 0.5 mg / 5 ml
On 5 ml of drug in the ampoules made of glass of a hydrolytic class 1 (EF), hermetically soldered. On an ampoule there is a point of blue color; on an ampoule tip two rings – violet and green color.
5 ampoules place in the cardboard pallet with partitions which together with the application instruction is placed in a cardboard pack.