Sibazon® ic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIBAZON® IC (SIBAZON IC)

Composition:

Active substance: diazepam;

One tablet contains diazepam 5 mg (0.005 g) or 10 mg (0.01 g);

Excipients: lactose monohydrate, potato starch, gelatin, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored tablets, flat cylindrical shape, with bevel and score line; the company's trademark is imprinted on the surface of one side of the tablet.

Pharmacotherapeutic group.

Anxiolytics. Benzodiazepine derivatives. ATC code N05B A01.

Pharmacological properties.

Pharmacodynamics.

Diazepam is one of the main benzodiazepine tranquilizers. It exerts anxiolytic, central muscle relaxant, anticonvulsant, sedative, and mild hypnotic effects. It exhibits minimal autonomic activity.

The mechanism of action of Sibazon**®** IS is associated with GABA, which is an inhibitory mediator in the CNS. It is known that GABAergic neurons inhibit the activity of neurons of other types. The drug reduces the activity of the enzyme GABA-transaminase, thereby increasing the content of GABA in the brain. On the other hand, it increases membrane sensitivity to GABA. All this enhances the inhibitory effect of GABAergic neurons on neurons of other types. The sedative and hypnotic effects of Sibazon**®** IS and other benzodiazepines are due to the inhibition of noradrenergic and dopaminergic neurons. Anticonvulsant and muscle relaxant actions are caused by inhibition of corresponding neurons in cortical centers and the spinal cord. Inhibition of excitation processes in the ascending reticular activating system leads to the development of an anxiolytic effect.

Pharmacokinetics.

Absorption

Diazepam is rapidly and completely absorbed from the gastrointestinal tract; peak plasma concentration is reached within 30–90 minutes after oral administration.

Distribution

Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%), penetrate through the blood-brain and placental barriers, and are excreted into breast milk at concentrations approximately 1/10 of the maternal plasma diazepam concentration. The volume of distribution is 1–2 L/kg.

Metabolism

Diazepam is mainly metabolized into pharmacologically active metabolites (N-desmethyldiazepam, temazepam, and oxazepam). Oxidative metabolism of diazepam is mediated by CYP3A and CYP2C19 isoenzymes. Subsequently, oxazepam and temazepam are conjugated with glucuronic acid.

Elimination

After oral administration, the decline in diazepam plasma concentration profile occurs in two phases: an initial rapid distribution phase is followed by a prolonged elimination phase (elimination half-life – up to 48 hours). The elimination half-life of the active metabolite N-desmethyldiazepam may reach 100 hours. Diazepam and its metabolites are primarily excreted in urine in conjugated forms. The clearance of diazepam is 20–30 mL/min.

Diazepam metabolites may remain unchanged in the body for up to 2 weeks.

The elimination half-life may be prolonged in infants, elderly individuals, and patients with impaired liver function. Reduced renal function does not affect the elimination half-life of diazepam.

Clinical characteristics.

Indications.

Adults.

Anxiety disorders.

Insomnia (benzodiazepines are indicated only for severe disorders, especially in patients with critical pathological conditions).

Relief of muscle spasms associated with cerebral etiology. As part of complex treatment of epilepsy.

Premedication for minor surgical procedures.

Contraindications.

Hypersensitivity to benzodiazepines or to any component of the drug. Myasthenia gravis, severe respiratory insufficiency, sleep apnea syndrome, severe hepatic insufficiency, phobic or obsessive conditions, chronic psychoses, alcohol or drug dependence (except for acute withdrawal syndrome).

Interaction with other medicinal products or other types of interactions.

Pharmacokinetic interactions

Oxidative metabolism of diazepam is mediated by CYP3A and CYP2C19 isoenzymes. Oxazepam and temazepam are subsequently conjugated with glucuronic acid.

Substances that are modulators of CYP3A and/or CYP2C19 may potentially alter the pharmacokinetics of diazepam. Medicinal products such as cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole inhibit CYP3A and CYP2C19, which may lead to enhanced and prolonged sedative effects. There is evidence that phenytoin metabolism affects diazepam.

Cisapride may cause a temporary increase in the sedative effect of orally administered benzodiazepines due to accelerated absorption.

Pharmacodynamic interactions

Enhancement of sedative, respiratory, and hemodynamic effects may occur when diazepam is used concomitantly with central nervous system depressants such as neuroleptics, tranquilizers/sedatives, antidepressants, hypnotics, anticonvulsants, opioid analgesics, anesthetics, and sedative antihistamines, or alcohol.

Alcohol must not be consumed during treatment with benzodiazepines.

Special precautions for use.

Concomitant use of alcohol/CNS depressants

Alcohol and/or CNS depressants must not be consumed during treatment with Sibazon® IS. Such combination enhances the clinical effects of benzodiazepines, including profound sedation, clinically significant respiratory and/or cardiovascular depression.

Sibazon® IS should be administered with caution in patients with a history of alcohol or drug abuse.

Sibazon® IS is not recommended for patients dependent on CNS depressants or alcohol, except during exacerbation of withdrawal syndrome.

Tolerance

Administration of diazepam over several weeks may lead to diminished hypnotic effect due to development of tolerance.

Dependence

Prolonged use of benzodiazepines (even at therapeutic doses) may lead to development of habituation and formation of psychological and physical dependence. The risk of dependence increases with higher doses, prolonged duration of treatment, and in patients with a history of alcohol or drug dependence, or personality disorders. Such patients require regular monitoring; repeated prescriptions should be avoided, and treatment should be discontinued gradually.

Withdrawal syndrome

Sudden discontinuation of benzodiazepines is accompanied by withdrawal syndrome. Symptoms of withdrawal include headache, muscle pain, increased anxiety, tension, agitation, confusion, irritability. In severe cases: derealization (disturbed perception of surroundings), depersonalization, numbness and tingling in extremities, increased sensitivity to light, noise and physical contact, hallucinations, or epileptic seizures.

Rebound insomnia and anxiety

Abrupt discontinuation of diazepam treatment may provoke a rebound phenomenon, characterized by symptom exacerbation followed by rapid symptom reduction (mood changes, anxiety, or sleep disturbances, restlessness). To prevent rebound phenomenon/withdrawal syndrome, gradual dose reduction is recommended.

Treatment duration

Treatment duration should be as short as possible depending on the indication, but should not exceed 4 weeks for insomnia, and 8–12 weeks for anxiety states, including the period of gradual dose reduction. Treatment duration may be extended only after careful assessment of the patient's condition.

Patients should be informed about the start and duration of treatment and advised about gradual dose reduction. Additionally, patients should be warned about the possible occurrence of withdrawal syndrome to reduce anxiety, especially when stopping therapy.

When using benzodiazepines with short duration of action, withdrawal symptoms may occur between doses, particularly when the dose is high. Due to the risk of withdrawal syndrome, switching from long-acting benzodiazepines to short-acting ones during treatment is not recommended.

Amnesia

It should be noted that benzodiazepines may cause anterograde amnesia. Anterograde amnesia may occur even at therapeutic doses, and the risk increases with higher doses. Amnestic effects may be associated with inappropriate behavior. This condition most commonly occurs within a few hours after oral administration of benzodiazepines; therefore, to reduce the risk, patients should be allowed uninterrupted sleep for 7–8 hours.

Psychiatric and paradoxical reactions

During benzodiazepine therapy, reactions such as restlessness, excitement, irritability, aggression, rage, hallucinations, nightmares, delusions, psychoses, inappropriate behavior, and other behavioral disorders may occur. If such reactions occur, treatment should be discontinued. These reactions are more commonly observed in children and elderly patients.

Special patient groups

Elderly and debilitated patients require dose reduction (see section "Dosage and administration"). Due to the muscle-relaxant effect, there is a risk of falls and fractures in this patient group.

Low doses are also recommended in patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Benzodiazepines are not indicated for treatment of patients with severe hepatic impairment, as they may precipitate encephalopathy. Doses should be reduced in patients with chronic liver disease.

Standard precautions should be observed when treating patients with renal dysfunction. The half-life of diazepam is not altered in renal impairment; therefore, dose adjustment is not required in these patients.

Benzodiazepines are not recommended for primary treatment of psychoses.

Benzodiazepines should not be used solely for treatment of depression or anxiety states associated with depression due to the risk of suicidal behavior in such patients.

Benzodiazepines may delay psychological recovery in patients experiencing symptoms related to severe loss of a close person.

Alcohol consumption is contraindicated during treatment with Sibazon® IS.

The product contains lactose and therefore should not be administered to patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Do not use during pregnancy.

Diazepam passes into breast milk; therefore, if treatment with this drug is necessary, breastfeeding should be discontinued.

If the drug is prescribed to women of reproductive age, they should inform their physician if they become pregnant or suspect pregnancy, so that treatment can be discontinued.

Ability to affect reaction speed when driving or operating machinery.

Patients should refrain from driving or operating machinery during treatment with this medicinal product.

Dosage and Administration

For optimal therapeutic effect, doses should be individually adjusted by a physician for each patient. Treatment should be initiated with the lowest effective dose appropriate to the specific indication.

Tablets are for oral use.

Duration of treatment

The duration of treatment should be as short as possible depending on the indication. In the treatment of insomnia, the course should not exceed 4 weeks; in anxiety states – 8–12 weeks, including the period of gradual dose reduction.

At the beginning of treatment, patients should be informed that therapy will be of limited duration and should be explained the schedule for gradual dose reduction. To reduce anxiety related to the possible occurrence of rebound phenomena, patients should be aware of such possibility during treatment (see section "Special precautions").

It should be noted that when using benzodiazepines with short duration of action, withdrawal symptoms may occur between doses, especially when high doses are used. Benzodiazepines with long duration of action should not be replaced by short-acting benzodiazepines due to the risk of withdrawal syndrome.

Adults

The dose is individually adjusted by a physician depending on the patient's condition.

Anxiety disorders

Usual adult dose: 5 mg per day.

Maximum dose: up to 30 mg per day in divided doses. The dosing regimen should be individually determined by the physician.

Insomnia associated with anxiety in adults: 5–15 mg before bedtime.

The lowest effective doses that control symptoms should be used.

Treatment at full dose should not be continued for longer than 4 weeks.

Prolonged use of the drug is not recommended.

Discontinuation of the drug should be carried out by gradual dose reduction. Patients who have been taking benzodiazepines for a prolonged period may require a longer tapering period. Dose reduction should only be performed by a physician.

Muscle spasm conditions

Muscle spasms: 5–15 mg per day in divided doses.

Centrally-mediated spasms in individual cases: 2–60 mg per day in divided doses.

Premedication

Adults: 5–20 mg.

Children: 2–10 mg.

Benzodiazepines should not be prescribed to children without careful assessment of indications. The duration of treatment should be minimized.

Children

Benzodiazepines may be used in children only in cases of acute necessity and only when administration of other alternative medicinal products is not possible.

The duration of treatment should be as short as possible.

Overdose

Symptoms: drowsiness, ataxia, dysarthria, and nystagmus. Overdose rarely causes life-threatening effects but may lead to areflexia, apnea, arterial hypotension, depression of the cardiovascular and respiratory systems, and coma. Coma usually lasts several hours but may be prolonged and cyclic, especially in elderly patients. Respiratory depression caused by benzodiazepines is more severe in patients with respiratory disorders.

Benzodiazepines enhance the effects of other central nervous system depressants, including alcohol.

Treatment: monitoring of vital functions. Symptomatic therapy aimed at supporting cardiovascular, respiratory, and central nervous system functions.

Further absorption can be prevented by appropriate treatment measures, such as administration of activated charcoal within 1–2 hours. If the patient is unconscious, artificial ventilation should be performed. Gastric lavage is not a routine procedure for drug elimination. In cases of central nervous system depression, flumazenil – a benzodiazepine antagonist – may be used. This should be done under hospital conditions. Flumazenil has a short elimination half-life (approximately 1 hour); therefore, patients receiving flumazenil require careful monitoring after administration. Flumazenil should be used with caution when administered concurrently with drugs that lower the seizure threshold (e.g., tricyclic antidepressants).

For further information on the proper use of flumazenil, the instructions for medical use of this drug should be carefully read.

In case of excitement or agitation, barbiturates should not be used.

Adverse reactions.

The most commonly observed adverse reactions are increased fatigue, drowsiness, and muscle weakness. In most cases, these symptoms spontaneously resolve after several days of treatment. They can also be avoided by reducing the dose of the medication.

Nervous system disorders: ataxia, dysarthria, speech disturbances, headache, tremor, dizziness, mood deterioration, irritability. With increasing therapeutic doses of the drug, the risk of developing anterograde amnesia increases. Amnestic effects may be accompanied by abnormal behavior.

Psychiatric disorders: restlessness, excitement, irritability, aggression, delirium, hostility, nightmares, hallucinations, psychosis, behavioral changes, and other adverse behavioral effects (predominantly in children and elderly patients; if these occur, the drug must be discontinued immediately), confusion, emotional blunting, decreased attention, depression.

Prolonged use of the drug (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of therapy may result in withdrawal syndrome or rebound phenomenon.

There have been reports of benzodiazepine abuse (see section "Special precautions").

Injury, poisoning, and procedural complications: an increased risk of falls and fractures associated with benzodiazepine use has been reported in elderly patients.

Gastrointestinal disorders: nausea, dry mouth or hypersalivation, constipation, and other gastrointestinal disturbances.

Eye disorders: diplopia, blurred vision.

Cardiovascular system disorders: arterial hypotension, circulatory insufficiency, heart failure, including cardiac arrest.

Renal and urinary disorders: urinary incontinence or urinary retention.

Skin and subcutaneous tissue disorders: skin reactions.

Ear and labyrinth disorders: vertigo.

Respiratory system disorders: respiratory depression, including respiratory failure.

Hepatobiliary disorders: very rare cases of jaundice.

Other: joint pain, changes in libido.

Laboratory findings: cardiac arrhythmia; very rare cases of increased blood levels of transaminases and alkaline phosphatase.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 2 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

Interchem LLC with additional liability.

Manufacturer's address and place of business.

40-A, 21st km, Starokyivska Road, Odesa, Ukraine, 65025.